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Anormal Thermal History Effect on the Structural Dynamics of Probucol Infiltrated into Porous Alumina

  • Agnieszka Talik*
    Agnieszka Talik
    Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland
    Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    *Email: [email protected]
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    Orcidhttp://orcid.org/0000-0001-7940-6967
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  • Magdalena Tarnacka*
    Magdalena Tarnacka
    Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland
    Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    *Email: [email protected]
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    Orcidhttp://orcid.org/0000-0002-9444-3114
  • , 
  • Aldona Minecka
    Aldona Minecka
    Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, ul. Jagiellonska 4, 41-200 Sosnowiec, Poland
    More by Aldona Minecka
    Orcidhttp://orcid.org/0000-0001-5603-032X
  • , 
  • Barbara Hachuła
    Barbara Hachuła
    Institute of Chemistry, University of Silesia in Katowice, Szkolna 9, 40-006 Katowice, Poland
    Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    More by Barbara Hachuła
  • , 
  • Joanna Grelska
    Joanna Grelska
    Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland
    Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    More by Joanna Grelska
  • , 
  • Karolina Jurkiewicz
    Karolina Jurkiewicz
    Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland
    Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
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    Orcidhttp://orcid.org/0000-0002-4289-7827
  • , 
  • Kamil Kaminski
    Kamil Kaminski
    Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland
    Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    More by Kamil Kaminski
    Orcidhttp://orcid.org/0000-0002-5871-0203
  • , 
  • Marian Paluch
    Marian Paluch
    Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland
    Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    More by Marian Paluch
  • , and 
  • Ewa Kaminska
    Ewa Kaminska
    Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, ul. Jagiellonska 4, 41-200 Sosnowiec, Poland
    More by Ewa Kaminska
    Orcidhttp://orcid.org/0000-0001-9725-8654
Cite this: J. Phys. Chem. C 2021, 125, 7, 3901–3912
Publication Date (Web):February 16, 2021
https://doi.org/10.1021/acs.jpcc.0c10560

Copyright © 2022 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Herein, broadband dielectric (BDS) and Fourier transform infrared spectroscopy (FTIR), together with differential scanning calorimetry (DSC) and X-ray diffraction (XRD), were applied to study the molecular dynamics, molecular interactions as well as physical stability of an amorphous Active Pharmaceutical Ingredient (API)—probucol (PRO)—infiltrated into anodic aluminum oxide (AAO) membranes of pore size, d ∼ 10–160 nm. Interestingly, the behavior of examined substance strongly depends on the applied thermal protocol. Remarkably, for the first time, we observed that the structural dynamics of the slowly cooled PRO under confinement is significantly enhanced when compared to that of the quenched material. This unusual behavior was interpreted as a result of surface-induced effects (including the formation of well-resolved interfacial H-bonded layer and adsorption–desorption processes near the interface) that are magnified by the extremely high sensitivity to density fluctuation of studied PRO, reflected in the enormous pressure coefficient of the glass transition temperature dTg/dp = 427 K/GPa. In fact, FTIR investigations revealed that PRO tends to self-associate under confinement and forms a strongly bonded interfacial layer, which controls the variation in the structural dynamics of core molecules. Finally, we observed that the tendency to crystallize of confined API is reduced with respect to the bulk, even though the critical size of PRO nuclei (rc ∼ 3 nm) is significantly lower than the smallest examined pore size. Nevertheless, after few weeks of storage, the investigated substance crystallized in larger pores, while it remained stable in the nanochannels of d = 10 nm. A combination of XRD and DSC measurements indicated that the infiltrated PRO forms two polymorphs, the stable form I (dominating in bulk) and unstable form II (prevailing under confinement). That means that porous matrices might be used to obtain and maintain prolonged stability of unstable polymorphic forms of API.

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1. Introduction

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Almost 40% of available and commercially used Active Pharmaceutical Ingredients (APIs), and the majority of the new API candidates are poorly water-soluble drugs (classified as the second and fourth class of the Biopharmaceutics Classification System, BCS). Therefore, a great effort has been put into increasing their solubility and bioavailability, allowing application of lower therapeutic doses and reducing toxic side effects. (1) In fact, to date, different strategies have been considered and developed to enhance these pharmaceutically important parameters, including (i) the use of pro-drugs, (2) (ii) salt formation (tartrate, succinate, mesylate, nitrate, hydrochloric), (3,4) (iii) micronization, (5−7) (iv) cocrystallization, (8,9) (v) formation of solid dispersions with soluble polymers (or saccharides), (10,11) and (vi) amorphization. (12) In recent years, the last approach attracted increasing attention of the scientists and industry since the amorphous APIs are generally characterized by higher solubility (due to the lower energy barrier required to dissolve the molecule (13,14)) and, consequently, bioavailability with respect to their crystalline counterparts. However, it should be pointed out that the commercial use of pharmaceuticals prepared in the amorphous form is limited, mainly due to their physical instability, which is reflected in a strong tendency to recrystallization. As a consequence, the advantages given by the amorphous state are lost during storage. (12) The most convenient way to stabilize amorphous APIs is mixing them with various excipients, (15) i.e., modified mono-, di, and oligosaccharides, (10,16−20) polymers, (21−25) and amino acids. (26−28) In such case, so-called coamorphous systems of enhanced physical stability are created. The other unique alternative to affect and stabilize disordered pharmaceuticals is infiltration them into porous templates made of inert, biocompatible, nontoxic materials composed of pores of varying geometry, morphology, and size (d), considered as 2D confinement. (15)
Systematic studies on various highly crystallizing active substances, such as, i.e., menthol, (29) ezetimibe, (33) naproxen, (30) and ibuprofen (31,32) at the nanoscale successfully demonstrated that when the size of the nanochannel is smaller than the diameter of the critical radius of nucleation, rc, the infiltrated materials reveal no tendency to crystallization and remain amorphous upon long-term storage. (33,34) In this context, one can briefly mention that the bulk naproxen and menthol cannot be supercooled below their glass transition temperature (Tg), avoiding crystallization, irrespective of the applied cooling rate. (35) A similar situation was observed in the case of water. However, after the infiltration of water into pores of nanometrical diameter, d = 2.6 nm, which is smaller than its rc, the crystallization was strongly suppressed. The other benefit of investigations on confined water is a unique opportunity to calculate approximately its Tg and verify the fragile to strong transition in this system, both hotly debated problems in the literature. It is also worth mentioning the studies by Floudas group, which revealed the change in character of the nucleation that can be tuned by the pore diameter. (36) The authors demonstrated a transition from the heterogeneous nucleation of hexagonal ice (Ih) to the homogeneous nucleation of predominantly cubic ice (Ic) in AAO membranes characterized by different pore sizes. (37,38)
In the literature, one can also find a lot of reports concerning the studies on the crystallization kinetics in liquids/APIs infiltrated in pores. (34,43) It was shown that the rate of crystallization as well as the maximum in the temperature dependence of the constant rates of this process change in pores of varying diameter and surface functionality. Moreover, it was noted that the melting temperature of the formed crystals decreases with pore size. (34) In fact, the modeling of this relationship using the Gibbs–Thomson equation (39,40) allows calculating the interfacial free energy between crystal and liquid states, σcl, which cannot be obtained from any other currently available experimental methods. One can add that this parameter is a key quantity to evaluate the critical radius of nuclei and predict the energy barrier for the nucleation process. It is also worth stressing that the application of nanoporous templates of varying morphologies can be very useful to obtain new polymorphic forms of APIs, which are often characterized by different physicochemical properties. Such a scenario was noted for salol incorporated into AAO templates, where dependent on the pore size, stable (orthorhombic crystal) or unstable (monoclinic form) polymorphic forms of this API were obtained in larger and smaller pores, respectively. (43) As mentioned above, a similar finding was also reported for water, where a clear change in the crystal lattice from the hexagonal ice into the cubic one, due to increased interactions with the pore walls, was observed. (35,36) Moreover, it is worth adding that the incorporation of glycine into pores allowed one to enhance the stability of the nonstable β-polymorph inside nanoporous host matrices with respect to the bulk state of this amino acid, for which a more thermodynamically stable α-form is preferred. (41) Additionally, the crystallization kinetics changes have also been reported for acetaminophen drug confined into controlled porous glasses (CPGs), where three different crystalline forms were investigated, dependent on the applied pore diameter. (42) Therefore, it seems that by using porous templates of appropriate pore size, one can increase the control over both the overall crystallization process and the growth of new polymorphs. (43)
Simultaneously to studying the crystallization of materials infiltrated into porous templates, a great effort has been made to understand the variation in molecular dynamics of such systems, which, aside from the thermodynamic driving force, is one of the most important factors that control the rate of nucleus formation and growth of crystals. It was found that, for most confined liquids, a clear deviation of structural/segmental and local relaxation times from the bulk behavior is observed. (34,33) In the literature, this finding is usually discussed in the context of competition between the finite-size effects and free volume or surface interactions. (31,32,44−47) However, the contribution of these factors remains a challenge and requires further investigations.
In this paper, we examined the molecular dynamics of probucol (PRO) incorporated into AAO membranes of varying pore diameters, d ∼ 10–160 nm, by means of different experimental techniques, broadband dielectric (BDS) and Fourier transform infrared (FTIR) spectroscopy, as well as differential scanning calorimetry (DSC). Additionally, the structure of bulk and confined PRO was examined using X-ray diffraction (XRD). This type of investigations seems to be important considering previous report demonstrating the enhancement in dissolution rate and antioxidant properties of PRO confined in mesoporous silica with respect to the bulk crystalline material. (48) It is also worth stressing that recent studies have indicated that this API is characterized by an extremely high (one of the highest reported to date) pressure coefficient of the glass transition temperature, dTg/dp = 427 K/GPa, (49) which quantifies the sensitivity of the structural relaxation dynamics to the density fluctuation. Therefore, it seems to be a perfect candidate to probe the impact of surface interactions with pore walls on the molecular mobility for the samples confined into porous templates.

2. Experimental Section

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2.1. Materials

Probucol, 4,4′-[propane-2,2-diylbis(thio)]bis(2,6-di-tert-butylphenol), C31H48O2S2, with Mw = 516.84 g/mol, and purity >98%, was supplied by TCI Europe. The nanoporous alumina oxide membranes used in this study (supplied from InRedox) are composed of uniaxial channels (open from both sides) with well-defined pore diameter, d ∼ 160, 120, 80, 20, 10 ± 2 nm, thickness ∼50 ± 2 μm, and porosity ∼12 ± 2%. Details concerning the pore density, distribution, etc., can be found on the webpage of the producer. (50)

2.2. Sample Preparation

The applied AAO membranes were dried in an oven at T = 423 K under a vacuum (10–2 bar) for at least t = 24 h to remove any volatile impurities from the nanochannels. After cooling, probucol was placed on the top of the AAO templates. Then, the whole system was kept at T = 398 K under vacuum for at least 6 h, which allows the liquid to flow inside the nanopores by capillary forces (chemical stability of PRO has been confirmed by nuclear magnetic resonance (NMR) studies). The membranes were weighted before and after infiltration. The complete filling was obtained if the mass of the membrane ceased to increase. After completing the infiltration process, the surface of the AAO membrane was heated to T = 398 K and dried at atmospheric pressure to remove the excess sample on the surface by a metal blade and a paper towel.

2.3. Methods

2.3.1. Broadband Dielectric Spectroscopy (BDS)

Isobaric measurements of the complex dielectric permittivity ε*(ω) = ε′(ω) – iε″ (ω) were carried out using the Novocontrol Alpha dielectric spectrometer over the frequency range from 10–1 to 106 Hz at ambient pressure. The temperature uncertainty controlled by a Quatro Cryosystem using a nitrogen gas cryostat was better than 0.1 K. The data for bulk substance have been taken from ref (49). The sample was placed in the capacitor with 20 mm of diameter and 0.1 mm distance between the plates. Examined samples were prepared by the vitrification method at ambient pressure. The bulk PRO was cooled from above the melting temperature deeply below Tg and then measured on heating, in the temperature range from 223 to 331 K. For details, please see ref (49).
For confined systems, dielectric measurements were carried out on AAO membranes filled with PRO and placed in a capacitor with 10 mm of diameter (membrane thickness: 0.05 mm). (51,52) Nevertheless, the confined sample is a heterogeneous dielectric consisting of a matrix and an investigated compound. Because the applied electric field is parallel to the long pore axes, the equivalent circuit consists of two capacitors in parallel composed of ε*compound and ε*AAO. Thus, the measured total impedance is related to the individual values through 1/Z*c = 1/Z*compound + 1/Z*AAO, where the contribution of the matrix is marginal. The measured dielectric spectra were corrected according to the method presented in ref (53).
Note that during dielectric measurements of the examined confined systems, we applied two different temperature protocols: (i) “slow cooling from the room temperature (RT),” where the samples have been slowly cooled (cooling rate dT/dt tends to 0 K/min) from T = 298 K below Tg; and (ii) “slow heating of the quenched samples,” where the samples have been cooled deeply below Tg (with the cooling rate 50 K/min) and then slowly heated (heating rate dT/dt tends to 0 K/min) from the glassy state into the higher temperatures.

2.3.2. Differential Scanning Calorimetry (DSC)

Calorimetric measurements were carried out using a Mettler–Toledo DSC apparatus (Mettler-Toledo International, Inc., Greifensee, Switzerland) equipped with a liquid nitrogen cooling accessory and an HSS8 ceramic sensor. Temperature and enthalpy calibrations were investigated using indium and zinc standards, and the heat capacity, Cp, calibration was performed using a sapphire disc. Measurements of confined systems were carried out by crushed filled membranes to fix the measurement alumina crucibles. After placing crushed templates in the crucibles, they were sealed and measured over a wide temperature range with different cooling rates, 2, 10, and 20 K/min, and a heating rate equal to 10 K/min.

2.3.3. Fourier Transform Infrared Spectroscopy (FTIR)

FTIR measurements were performed on a Thermo Scientific Nicolet iS50 spectrometer equipped with a Linkam THMS 600 (Linkam Scientific Instruments Ltd., Surrey, U.K.) heating/cooling stage. FTIR spectra were collected at a spectral resolution of 4 cm–1 with 32 coadding scans in the frequency range of 4000–1300 cm–1. The limited measurement range resulted from the absorption of AAO membranes. The temperature stabilization accuracy was equal to ±0.1 K. In the first rate-dependent experiment, the confined PRO within AAO membranes was heated to 343 K at a heating rate of 10 K min–1, held for 5 min and then cooled to 308 K at the different cooling rates (5, 10, 15, 20, and 30 K min–1). For the second time-dependent experiment, the melted samples were cooled to 308 K with a constant 20 K min–1 cooling rate. The time-dependent IR spectra were collected at 1 min intervals at T = 308 K for 30 min.

2.3.4. X-ray Diffraction (XRD)

XRD measurements were performed on a Rigaku-Denki S/MAX RAPID II-R diffractometer equipped with an image plate detector, a rotating Ag anode and an incident beam (002) graphite monochromator (wavelength of incident beam λ = 0.56 Å). Samples of bulk PRO (measured as received from TCI Europe) and PRO infiltrated into AAO membrane of d = 80 nm were ground in a mortar, packed into glass-capillaries of 1.5 mm diameter and measured at T = 293 K. Additionally, pure AAO membrane was probed. The sample of PRO within the AAO template was measured just after 1 and 50 days of storage under normal conditions. The diffraction data were collected as two-dimensional patterns and converted into a one-dimensional function of scattering intensity versus the scattering angle 2θ. The final results show the diffractograms with subtracted background from an empty capillary.

3. Results and Discussion

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Dielectric loss spectra (ε″(ω)) obtained for the bulk PRO and the API confined into AAO membranes of different pore sizes (d = 10 nm and d = 20 nm) are shown in Figure 1. The spectra of PRO infiltrated into alumina templates of higher pore diameters (d = 80 nm and d = 120 nm) are presented in Figure S1 in the Supporting Information. As shown, the measured spectra revealed the presence of dc-conductivity, responsible for the charge transport, a well-resolved structural (α) relaxation process, related to the cooperative motions of molecules and responsible for the glass transition, as well as the secondary Johari–Goldstein (JG) β-process, having intermolecular character and originating from local motions of the whole molecules. (49,54) It is important to note that this universal secondary mobility is well-observed for both bulk and confined PRO (the inset of Figure 1a), which is not always the case, especially in spatially restricted systems. Moreover, the data presented in Figure 1a reveal a systematic drop of the amplitude of α-relaxation process of bulk API measured above T > 320 K due to the ongoing crystallization. (49) On the other hand, for the infiltrated PRO, no crystallization can be seen upon the increasing temperature; see parts b and c of Figure 1. This implies the increased physical stability (lower crystallization ability) of supercooled and glassy PRO under confinement when compared to its bulk counterpart. Note that this issue will be discussed in detail in the last section of this paper.

Figure 1

Figure 1. Dielectric loss spectra of bulk probucol (PRO) (a) and confined into AAO templates of d = 20 nm (b) and d = 10 nm (c). As the inset in panel a, the superposed dielectric spectra measured in the vicinity of Tg were presented to highlight the presence of the β-process. Additionally, in the insets to panels b and c, the normalized loss spectra collected for bulk PRO and API infiltrated into AAO pores of d = 10 nm at T = 308 K (b), which further were shifted horizontally to superpose at the maximum (c), are shown. Note that the data for the bulk sample were taken from ref (49).

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Moreover, as illustrated in the inset to Figure 1c, a significant broadening of the α-relaxation for the confined samples with respect to the bulk is observed. It is worth recalling that such behavior commonly discussed in the context of increasing heterogeneity of the relaxation dynamics or the strength of interactions between molecules and pore walls is a common feature for substances infiltrated into porous templates. (55) This finding agrees with earlier reports for polypropylene glycol (PPG) or polyisoprene (PI) incorporated into silica and alumina templates. (56,57) Additionally, it should be mentioned that for the confined substances, we did not detect any interfacial process, reflecting the reorientational motions of adsorbed molecules. In this context, one can be remind that for many glass formers, especially those interacting with the matrix, the existence of such mobility is reported. (58−61,46)
Since recent studies on various low- and high- molecular weight glass formers infiltrated into AAO templates have indicated that the structural/segmental dynamics strongly depends on the thermal history of the confined sample, (62−64) we decided to explore this effect on spatially restricted PRO—a compound that is characterized by one of the highest pressure coefficient of the glass transition temperature, dTg/dp = 427 K/GPa. For that purpose, dielectric measurements on the confined API were performed using two different temperature protocols described in detail in the Experimental Section. At first glance, any significant differences between samples measured at either slow cooling or heating were detected. However, when we compared dielectric spectra of bulk sample and API confined in pores of d = 10 nm, measured at the same temperature (T = 308 K), we noted a major variation in dynamical properties (shape and relaxation time) of the structural process for both systems, see inset to Figure 1b. Remarkably, the spectra of confined substance measured upon various experimental protocols differed significantly between each other. As shown, the α-relaxation peak recorded upon slow cooling is clearly shifted toward higher frequencies with respect to that obtained for the quenched API. It should be mentioned that all experiments reported to date have revealed opposite effects, i.e., very fast (quenched) systems were characterized by enhanced dynamics when approaching the Tg. (29−32,34)
To quantify the observed extraordinary differences between slowly cooled and quenched samples, we further analyzed the temperature dependences of structural relaxation times, τα. For that purpose, the measured dielectric loss spectra of the examined PRO systems, recorded upon both thermal protocols at T > Tg, have been analyzed using the Havriliak–Negami (HN) function with the conductivity term: (65)
(1)
Here αHN and βHN are shape parameters representing the symmetric and asymmetric broadening of given relaxation peaks, τHN is the HN relaxation time, ε0 is the vacuum permittivity, Δε is the dielectric relaxation strength, and ω̅ is an angular frequency (ω̅ = 2πf). Then, using the procedure described in ref (66), τα values have been obtained from τHN. The temperature dependences of τα estimated for all investigated samples, both bulk and confined, measured on slow cooling and heating, are presented in Figure 2. As can be seen, the relaxation times remain bulk-like at high temperatures and deviate at some specific conditions labeled as Tg,interfacial. One can recall that this deviation occurring at Tg,interfacial has been rationalized in terms of, i.e., the limited length scale of dynamic cooperativity of molecular motions, (67,68) or the vitrification of molecules strongly interacting with the interface (the interfacial layer). (62) Although the results obtained previously for glycerol infiltrated in metal–organic frameworks (MOF) supported the first hypothesis, (69,70) there are many reports, also coming from our group, confirming the latter explanation that was validated based on the combined dielectric and calorimetric investigations. Note that the data collected for various glass formers infiltrated into AAO templates of different d revealed that the deviation of τα(T)-dependences occurring at Tg,interfacial corresponds well with the calorimetric high glass transition temperature recorded in thermograms. Simultaneously, the lower glass transition temperature is consistent (within a few kelvin) with the one calculated from τα(T)-dependences at temperature, at which τα = 100 s. These findings are in fair agreement with the very simple two-layer (60) (or shell–core) model describing the heterogeneity of the liquids confined in pores. In view of this approach, due to the various distance from the interface, there are at least two fractions of molecules within infiltrated materials: (i) those located in the center of porous nanochannels (“core”) and (ii) those attached to the interface (“interfacial”), both characterized by different mobility and consequently Tg. (60) It should be pointed out that the comprehensive calorimetric measurements performed for the confined PRO have clearly shown two endothermic heat capacity jumps related to the glass transitions of interfacial, Tg,interfacial, and core, Tg,core, molecules (Figure S4). As observed, the values of Tg,interfacial determined from DSC studies are in agreement with the temperatures, at which the deviation of τα(T)-dependences for infiltrated samples occur; see Table 1 and Figure 2. Therefore, herein, we assigned the vitrification of the interfacial layer as the origin of the variation of τα(T) upon decreasing temperature.

Figure 2

Figure 2. Temperature dependences of α-relaxation times for bulk PRO and API confined into AAO templates of various pore sizes. Black solid and red dashed lines are the best fits using VFT and Arrhenius equations, respectively. Inset: τα(T)-dependences obtained for PRO infiltrated into AAO membranes of d = 10 nm measured using two different protocols. Note that τα(T)-dependences determined for PRO within AAO templates of d = 80 nm are presented in Figure S2.

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Table 1. Values of Tg Estimated from Dielectric and Calorimetric Measurements for Bulk and Confined Samples Subjected to Different Thermal Treatments with Measurement Error ±2 Ka
 BDS measurementsDSC measurements
 slow coolingslow heatingheating rate 10 K/min
sampleTg,interfacial [K]Tg,core [K] for τα = 100 sTg,interfacial [K]Tg,core [K] for τα = 100 sTg,interfacial [K]Tg,core [K]
bulk294294299
PRO confined within AAO templates
d = 80 nm313270323289322309
d = 20 nm318261323289314290
d = 10 nm328248323280316290
a

Note that Tgs from calorimetric measurements were determined from the midpoint of the observed heat capacity jumps.

Interestingly, as presented in Figure 2, the characteristic departure of τα from the bulk-like behavior can be noted for all examined infiltrated PRO independently to the applied thermal protocol. However, with decreasing temperature below Tg,interfacial, a significant difference in the slope of τα(T)-dependences between quenched and slowly cooled samples is observed. Remarkably, τα(T)-dependences of quenched materials are significantly steeper than the ones measured on slow cooling from RT, see the inset in Figure 2 and Figure S3. Consequently, the Tg,core (related to the vitrification of core molecules) values of quenched samples are much higher with respect to those estimated for the slowly cooled API, whereas Tg,interfacial (marked in Figure 2), reaches comparable values independent of the applied experimental protocol. For details concerning the determination of Tg,interfacial and Tg,core, please see the Supporting Infomation. Note that the values of Tgs estimated from BDS measurements performed on the quenched samples were in good agreement with those determined from calorimetric measurements performed at a heating rate of 10 K/min; see Table 1.
We would like to highlight that, as mentioned above, the variation of the structural dynamics of confined PRO, where the slowly cooled sample is characterized by the enhanced dynamics when approaching Tg,core, is unexpected. One can add that the literature data for other glass formers confined at the nanoscale, i.e., for triphenyl phosphite (TPP), (62) PPG (57) and poly(methylphenylsiloxane) (PMPS), (71) show a different behavior. As reported, the slow cooling of infiltrated material results in more homogeneous dynamics and denser material with a higher Tg,core, whereas the quenching leads to a larger anisotropy and lower Tg,core. The differences between applied experimental protocols were assigned to the variation in density packing at the interface. It was assumed that in the former case, the infiltrated molecules have enough time for the local rearrangements and density equilibration (as well as the kinetic mass exchange between interface-core fractions). On the other hand, the rapid cooling freezes the local conformation of molecules under confinement, which cannot evolve upon the measurements.
To confirm the quite unusual behavior of the confined PRO observed upon dielectric studies, we carried out additional calorimetric measurements on infiltrated API, applying two different cooling rates (2 and 20 K/min) followed by a 10 K/min heating rate. The purpose of these experiments was to see how the thermal history affects the glass transition temperature (and thus, indirectly, the molecular dynamics) of confined systems. DSC thermograms of PRO infiltrated into AAO templates of d = 10 nm are shown in Figure 3a. Note that in this experiment, the investigated system was molten and then cooled with cooling rates, either 2 or 20 K/min, followed in both cases by a 10 K/min heating rate. The existence of the two Tgs can be confirmed by additional data treatment relying on the temperature derivative representation of specific heat capacity jumps, where two maxima peaks can be easily observed; please see Figure S5a. Interestingly, one can observe that the lowest Tg related to the vitrification of core molecules changes significantly with the experimental protocol, where Tg,core= 273 K and Tg,core= 288 K for cooling rates of 2 and 20 K/min, respectively. At this point, we would like to emphasize two issues. First, the variation of Tg,core with the heating rate is significantly higher than the one usually observed in calorimetric measurements (note that it normally reaches ΔTg ∼ 5–6 K, not ΔTg ∼ 15 K as reported herein). Second, this behavior confirms the strong variation in Tg,core determined from the analysis of dielectric data obtained for the confined PRO subjected to different thermal treatments, where the values of this temperature for the quenched samples were much higher than those estimated for the slowly cooled materials.

Figure 3

Figure 3. (a) DSC thermograms collected for PRO infiltrated into AAO templates of d = 10 nm measured at two different cooling rates, 2 and 20 K/min, with the following 10 K/min heating rate. (b) DSC thermograms of the crystalline bulk sample and PRO infiltrated into AAO membranes of various pore size (d = 40–120 nm), measured on heating with rate 10 K/min from RT well above the melting temperature of bulk API.

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Additionally, it is worth pointing out that DSC thermograms of PRO infiltrated into AAO templates of d = 10 nm revealed, remarkably, the presence of the third endothermic heat capacity jump in the temperature range T > 320 K. Note that also in the case of the temperature derivative representation of DSC curved obtained for PRO confined within AAO templates of d = 10 nm, we can observe three maxima confirming the occurrence of an additional third glass transition temperature, see Figure S5b. One can add that this endothermic event changes accordingly to the applied heating rate; therefore, we considered it as a “normal” glass transition and not as an experimental artifact. This finding indicates the occurring of an additional third glass transition temperature of unknown origin (labeled as Tg,add). In this context, one can recall some earlier works on poly(methyl methacrylate) (PMMA), (72) PPG, (63) and PMPS (71) confined within AAO porous templates, reporting the existence of the third Tg, located between Tg,core and Tg,interfacial upon different heating/cooling rates due to the formation of the intermediate layer between the adsorbed and core molecules. (72) However, in our case, the additional Tg, add is located far above Tg,interfacial, suggesting a different origin of this anomalous glass transition temperature. In fact, taking into account that the mobility of molecules under confinement reduces with a decreasing distance from the substrate/matrix interface, one can assume that the detected third heat capacity jump of unknown origin can be correlated to the response of, i.e., the molecules irreversible adsorbed on the pore walls. Alternatively, it might be due to some phase transition related to the change in the materials’ wettability upon temperature decrease. However, at the moment, it is very difficult to verify which hypothesis is correct.
All the data reported and discussed above indicated rather peculiar behavior of PRO infiltrated into the porous matrix. Thus, the question arises, what is the origin of the observed anomalous structural dynamics of the confined API? Is it related to the variation in the density packing as previously reported in the literature? (53,73) Or rather with the formation of an irreversibly adsorbed layer (IAL) at the interface? One can recall that many factors are considered to affect soft matter’s behavior spatially restricted to the nanoscale, including, i.e., finite size, (47) free volume, (74) and negative pressure. (59) However, the majority of recent papers devoted to this issue highlighted, in fact, the key role of surface effects on the dynamics of those materials. (53,59,75) Herein, we would also like to discuss the observed quite unusual behavior of incorporated PRO in terms of surface effects. We suppose that upon slow cooling, the infiltrated API molecules have more time to the density equilibration. Alternatively (or even additionally), the variation within the interface might include both adsorption–desorption processes at the interface and the exchange between core and interfacial molecules. Consequently, a well-resolved interfacial layer (or even IAL) might be formed. The dynamical and static properties of adsorbed molecules or eventual their vitrification further affect the behavior of confined PRO. In contrast, in the case of quenched API within AAO templates of d = 10 nm (and d = 120 nm), there is no well-resolved interfacial layer formed upon fast cooling. The applied “quenching” thermal protocol might result in a reduced surface interaction of molecules near the interface, and likely decreases the surface coverage as they weaker interact with pore walls with respect to the ones adsorbed upon slow cooling. Therefore, the systems are characterized by a rather bulk-like behavior. Note that no difference between the quenched and slowly cooled PRO infiltrated into AAO membranes of d = 120 nm might result from a rather high value of pore diameter and low surface-to-volume ratio. At those conditions, the surface effects cannot be a dominant factor as in case of pores of much lower radius. Thus, even the presence of the strongly adsorbed interfacial layer does not have so great impact on the behavior of confined PRO. Additionally, it should be mentioned that the examined API is characterized by one of the highest values of the dTg/dp coefficient (=427 K/GPa, which quantifies the sensitivity of this compound to the density changes) reported to date when compared to the other systems described earlier in the literature. (76−79,49) As previously shown by some of us, (75) the higher the value of the dTg/dp, the greater the deviation of the Tg,core from the Tg, bulk is noted. However, to observe this effect, there must be formed an interfacial layer strongly bonded to the pore walls. Our data clearly indicated that once the sample is cooled very quickly or very slowly below Tg, the confinement-induced effects on the structural dynamics and the Tg depression are either minimal or significant. One can suppose that this experimental finding can be assigned to the adsorption of the API to the pore walls or a formation of H bonds between host and guest materials, which is a time-dependent phenomenon. Contrary to the quenched sample, in the case of slowly cooled systems, there is enough time for API to form a strongly bonded interfacial layer, whose freezing out induces density or free volume fluctuations. As a consequence, a clear deviation in molecular dynamics of the core fraction from the bulk-like behavior and significant depression of the glass transition temperature are detected.
To get a deeper understanding of this phenomenon and verify a hypothesis discussed above, we performed further FTIR measurements. Figure S7 shows FTIR spectra of the crystalline and glassy PRO and the API confined within the AAO membrane in the 3800–2700 cm–1 frequency range. In this spectral region, narrow peaks between 3030 and 2830 cm–1 are associated with the CH groups’ stretching vibrations, while the intense band above 3630 cm–1 corresponds to the stretching vibrations of the non-H-bonded “free” hydroxyl groups. The assignment of the low-frequency bands in the IR spectrum of PRO was presented in our earlier work and is not the purpose of this paper. (49) Herein, we focus only on the OH group vibration region, which can provide information about intermolecular, including guest–host, interactions. The existence of exclusively one band about 3630 cm–1 indicates that in neat PRO (crystalline and glassy samples), there are no molecular interactions of the O–H···O type as the hydroxyl groups are strongly protected by the steric effect of tert-butyl groups. In fact, the literature data for this API show that molecules are held exclusively by weak dispersion forces. (82,83,80) Therefore, it is extremely interesting to study the behavior of such a nonassociating system under spatially limited conditions.
On the other hand, FTIR spectra of confined PRO within AAO membrane revealed as interesting as unexpected results, which are related to the appearance of additional bands that were not detected in the spectra of the bulk system. Interestingly, next to the band of “free” OH groups, a new peak at 3547 cm–1 is visible (Figure S6). To explore the nature of this new vibration, we refer to our previous work devoted to PRO glass recovered from the high-pressure experiments. (49) In the case of the compressed PRO, the appearance of the band at 3541 cm–1 was assigned to the formation of very weak intermolecular O–H···S hydrogen bonds. It is worthwhile to stress that additional density functional theory (DFT) computations supported such an interpretation. Hence, a close agreement between band positions (3547 and 3541 cm–1) suggests the formation of similar kind weak O–H···S H-bonding interactions in pores. Therefore, quite unexpectedly, in contrast to the literature data showing the suppression of specific interactions for the spatially restricted samples, the infiltration of API into porous alumina templates triggers the self-association process. However, at the same time, it is worth pointing out that we are unable to exclude, whether the interactions of PRO molecules with the membrane surface contribute to this new peak as well. At this point, it should be noted that FTIR spectra of the confined PRO are also distorted by the additional contribution of the stretching vibrations of the OH groups derived from the AAO pore surface; i.e., the maximum of the OH band appears at 3460 cm–1 (Figure S8). Hence, the presence of this parasitic band makes the whole analysis and interpretation more difficult.
To verify whether the additional guest–host interactions exist in the studied system, cooling rate and time-dependent IR investigations were performed. Note that the confined PRO was cooled with different cooling rates (5–30 K/min) from T = 343 K prior to measurements at T = 308 K started. Interestingly, the spectra of the confined API showed that the intensity of the IR absorption bands located at 3635 and 3547 cm–1, respectively, decrease and increase as the cooling rate is lowered (see Figure 4a). Assuming that the number of self-assembled H-bonded molecules of API is barely temperature and time-dependent, one can suppose that this effect is related to the change in population of the API adsorbed via H-bonds to the pore walls. Consequently, the slower reduction of temperature, the greater the number of PRO molecules interacting with the alumina surface. Moreover, the band intensity at 3547 cm–1 also increases over time, indicating an increasing degree of guest–host interactions due to annealing of the sample previously cooled from T = 343 K with 20 K/min cooling rate (see Figure 4b). Therefore, the observed spectral effects imply the existence of additional processes taking place at the interface, leading to the formation of specific H-bond type interactions of PRO molecules with the surface of the pore walls. This finding confirms that most likely, aside from the O–H···S H association of API molecules, interfacial H-bond type interactions of PRO and alumina matrix also contribute to the additional vibration detected at 3547 cm–1. Furthermore, results obtained from FTIR investigations strongly support the hypothesis that the peculiar behavior of structural dynamics of confined API prepared via two different ways is strongly connected to the time-dependent adsorption and formation of the interfacial H-bonded layer. Once the layer is formed and more strongly adsorbed to the pore walls, the surface effects become magnified. Therefore, the selection of a system with so high dTg/dp allowed us to prove that not ony the pressure coefficient of the glass transition temperature itself but also properties of interfacial layer underlie the response of the core fraction of molecules confined in porous templates.

Figure 4

Figure 4. (a) FTIR spectra obtained in the wavenumber region of 3675–3475 cm–1 of a confined PRO within AAO membrane (d = 10 nm). The sample was heated to 343 K at a heating rate 10 K min–1, held for 5 min at this temperature and then cooled to Tanneal = 308 K at different cooling rates (5, 10, 15, 20, and 30 K min–1). Arrows indicate the direction of band intensity changes with decreasing cooling rate. b) Time-dependent FTIR spectra of a confined PRO within AAO membrane (d = 10 nm) obtained in the wavenumber region of 3800–3020 cm–1. The melted samples were cooled to Tanneal = 308 K with a constant cooling rate of 20 K min–1. The arrow indicates the direction of band intensity changes with increasing time.

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Finally, as the last point of our investigation, we probed the physical stability of PRO under confinement. One can recall that controlling the crystallization process by the appropriate parameters of nanoporous host matrices allows developing novel drug carrier systems, which successfully stabilize APIs. (19,41,43,81) Moreover, interestingly, the application of constraining medium also enables to obtain new crystalline (polymorphic) forms of various compounds (including APIs), which are often characterized by different physicochemical properties. (19,41,43) As was clearly shown above, PRO infiltrated into AAO templates of the following pore size, d ∼ 10–160 nm, is amorphous and does not tend to crystallize on the experimental time scale. Thus, to probe the eventual crystallization of the confined API, it was stored for 50 days. After that time, we performed successive DSC and XRD measurements.
The recorded DSC thermograms of the recrystallized both bulk and confined PRO are presented in Figure 3b (the data for bulk API were taken from ref (49)). Note that in the case of API infiltrated in AAO templates of d = 10 nm, it remains amorphous even after 50 days; hence, only the data for d > 40 nm are presented. Interestingly, for bulk PRO, one endothermic process, related to melting at Tm = 400 K, can be observed, see Figure 3b. On the other hand, for the confined samples, two melting peaks of significantly different enthalpies, ΔHm, can be distinguished independently from the applied pore diameter. As illustrated, both peaks shift toward lower temperature with decreasing d when compared to the bulk, see Figure 3b. One can suppose that the presence of two melting points for the infiltrated PRO might be a result of two scenarios, either the crystallization of two various fractions of molecules (interfacial and core) or the existence of two different polymorphs of PRO. Note that previous studies of bulk PRO revealed the presence of two polymorphic forms characterized by different Tm. The stable form I is characterized by a higher melting temperature. Tm,I ∼ 398 K, whereas the second unstable form II has a melting point at Tm,II ∼ 389 K. (82,83)
To determine the origin of the observed melting peaks in the recorded DSC thermograms, we carried out additional XRD measurements. The diffraction pattern of bulk crystalline PRO exhibits the presence of two polymorphic forms in the sample; see Figure 5a. The greater part of the bulk PRO is composed of the polymorph I, identified as a monoclinic system with P21/c space group symmetry and a ≈ 16.9 Å, b ≈ 10.5 Å, c ≈ 19.0 Å, α ≈ 90°, β ≈ 113.7°, and γ ≈ 90°, according to the Crystallography Open Database (CCDC code: 1172913). (82) The small admixture of polymorph II, which crystallizes in monoclinic system with P21/n space group and a ≈ 11.2 Å, b ≈ 16.0 Å, c ≈ 18.8 Å, α ≈ 90°, β ≈ 104.0°, and γ ≈ 90° (CCDC code: 1172912), might also be recognized in the bulk sample based on the positions of the Bragg peaks (marked with blue lines). This observation is in line with earlier reports for bulk PRO, (82) which revealed different conformations in the two polymorphs, where in form II, the C–S–C–S–C chain is extended, and the molecular symmetry approximates C2v. On the other hand, in the case of form I, two S–C–S–C torsion angles are roughly 80° and 165°. As shown, the less symmetrical conformer of polymorph I is more stable than the polymorph II (difference around ∼26 kJ mol–1). The XRD pattern for the sample of PRO confined in AAO pores with d = 80 nm just after 2 and 50 days of storage is presented in Figure 5b. In the case of the sample stored for 1 day, only broad low-intense peaks might be distinguished from the diffraction pattern of the amorphous AAO membrane. However, their positions correspond directly to sharper peaks seen for the sample after 50 days of storage. It means that, during this time, the crystallization of PRO progresses. The confined material is also composed of two polymorphic forms: I and II, as evidenced by the positions of the observed Bragg peaks. However, it should be mentioned that in contrast to the bulk form, PRO infiltrated into AAO is composed of mainly polymorph II and a smaller amount of polymorph I. This means that the observed multiple melting points of PRO under confinement detected by DSC measurements actually originate from the crystallization of various polymorphic forms. Moreover, it should be mentioned that the differences in the melting intensities also indicate that, surprisingly, the less stable form II (with higher intensity) is more favored under confinement in contrast to the bulk sample.

Figure 5

Figure 5. Comparison of X-ray diffraction patterns of bulk PRO sample together with pure references of I and II polymorphic forms (a) and PRO confined into AAO template (d = 80 nm) just after 1 and 50 days of sample storage together with the data for neat AAO membrane (b).

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As we confirmed that the observed two melting temperatures are related to the various polymorphic forms of PRO, we decided to calculate the surface energy between crystal and liquid, σcl, of PRO, that is a key quantity to evaluate the critical radius of nucleation, rc, as well as to predict the energetic barrier for the nucleation process. It should be highlighted that σcl cannot be determined experimentally for bulk materials; (34,84) however, accordingly to the Gibbs–Thomson (GT) equation, (39) it might be easily calculated for confined samples:
(2)
where Tm(d) is a melting temperature of crystals formed in pores of different pore diameters, ρc is a crystal density, and ΔHm is a melting enthalpy. The following parameters, ρc, σcl, and ΔHm, refer to bulk values. Note that according to the literature, form I is characterized by ρc = 1.1 ± 0.1 g/cm3 and ΔHm = 64 J/g, whereas form II is characterized by ρc= 1.049 g/cm3 and ΔHm = 68 J/g. (80,82) It should be mentioned that both melting points of the examined confined systems decrease with a reduction of pore size, as postulated by the GT relation. Consequently, the surface energy of PRO, calculated using the values of Tm,I and Tm.,II, respectively, is equal to σcl ∼ 23 mJ/m2 and σcl ∼ 26.5 mJ/m2. It should be highlighted that, for these systems, the surface energy, σcl, is quite similar to those calculated for other low molecular weight systems. (85−87)
Subsequently, we also calculated the critical radius of nucleation, rc, of both forms: (34,84)
(3)
where Tm,i is a melting point of bulk material (Tm,I = 400 K and Tm,II = 389 K, respectively). Afterward, we determined the critical size of nuclei for different pore sizes as a function of reduced temperature, ΔTi = Tm,i – T, see Figure S9. Note that rc was calculated with the use of both observed Tms. The obtained size of nuclei decreases with increasing undercooling, reaching approximately rc ∼ 3 nm at RT for both polymorphic forms. This relatively low value of rc means that PRO should be able to crystallize even inside the smallest pore size applied in this study, d = 10 nm. However, it is not the case. Interestingly, similar behavior (rc < d) has been reported for fenofibrate confined within controlled pore glass (CPG of d < 20 nm), where the crystallization of this pharmaceutical was completely suppressed. (88) One can suppose that the inhibition of crystallization of PRO infiltrated into AAO templates of d = 10 nm might be related to the enhanced surface H-bonded type interactions between the API and pore walls as well as the self-association process, completely absent for the bulk substance but induced in the confined PRO.

4. Conclusions

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In conclusion, the molecular dynamics of PRO confined into AAO matrices of various pore diameters was strongly dependent on the applied thermal pathway. Although for all confined samples, we observed a “typical” deviation of τα(T)-dependences from the bulk-like behavior, these dependencies in the case of the quenched systems differed significantly from those measured on slow cooling. As illustrated, the slowly cooled materials are characterized by enhanced molecular dynamics when approaching Tg. To the best of our knowledge, the effect observed herein (as well as enormous variations between both thermal histories) is reported for the first time for the liquid infiltrated into pores. We assume that the differences between the dynamics of confined PRO measured on slow cooling and heating might be strictly correlated with surface effects, especially the density perturbation within the interfacial layer as well as the adsorption–desorption effects occurring near the interface. The impact of these processes affecting the density packing fluctuations is magnified in PRO since it is characterized by the extremely high value of the pressure coefficient of the glass transition temperature (dTg/dp). Additionally, as concluded from FTIR studies, the pores induce the association process between PRO molecules. The H-bonded interfacial layer, whose properties depend on the time of annealing and cooling rate, is formed. We assumed that the (re)formed H-bonding structure of PRO influences its structural dynamics and contributes to the peculiar behavior of confined API. Thus, a selection of a system with so high a dTg/dp allowed us to prove that not only this parameter itself but also properties of interfacial layer underlie the response of the core fraction of molecules confined in porous templates. Moreover, it was found that the applied nanometrical geometrical restriction reduces the tendency to crystallization of amorphous PRO infiltrated into AAO templates when compared to the bulk. Simultaneously, it should be mentioned that the recrystallized API revealed the presence of two melting temperatures under confinement. XRD measurements confirmed that they correspond to the two polymorphic forms, stable form I (dominating in bulk) and unstable form II (prevailing under confinement). We believe that the presented results shed new light on the mutual correlation between the surface effects and the sensitivity to the density fluctuation, and they impact on the behavior of soft matter confined in porous templates.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpcc.0c10560.

  • Additional figures, including dielectric spectra collected for PRO within pore diameters d = 120 nm and d = 80 nm; relaxation maps for PRO infiltrated into AAO membranes with different pore diameters; DSC thermograms; derivative representation of the heat flow for confined PRO; FTIR spectra; and estimation of the radius of critical nuclei, rc (PDF)

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Author Information

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  • Corresponding Authors
    • Agnieszka Talik - Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland;  Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland;  Orcidhttp://orcid.org/0000-0001-7940-6967;  Email: [email protected]
    • Magdalena Tarnacka - Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland;  Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland;  Orcidhttp://orcid.org/0000-0002-9444-3114;  Email: [email protected]
  • Authors
    • Aldona Minecka - Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, ul. Jagiellonska 4, 41-200 Sosnowiec, Poland;  Orcidhttp://orcid.org/0000-0001-5603-032X
    • Barbara Hachuła - Institute of Chemistry, University of Silesia in Katowice, Szkolna 9, 40-006 Katowice, Poland;  Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    • Joanna Grelska - Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland;  Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    • Karolina Jurkiewicz - Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland;  Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland;  Orcidhttp://orcid.org/0000-0002-4289-7827
    • Kamil Kaminski - Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland;  Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland;  Orcidhttp://orcid.org/0000-0002-5871-0203
    • Marian Paluch - Institute of Physics, University of Silesia in Katowice, 75 Pulku Piechoty 1, 41-500 Chorzow, Poland;  Silesian Center of Education and Interdisciplinary Research, University of Silesia in Katowice, 75 Pulku Piechoty 1A, 41-500 Chorzow, Poland
    • Ewa Kaminska - Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, ul. Jagiellonska 4, 41-200 Sosnowiec, Poland;  Orcidhttp://orcid.org/0000-0001-9725-8654
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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M.T., K.K. and M.P. are thankful for financial support from the Polish National Science Centre within the OPUS project (Dec. No. 2019/33/B/ST3/00500). E.K. is grateful for the financial support from the National Science Centre within the framework of the Sonata BIS project (Dec. No. 2016/22/E/NZ7/00266). K.J. is thankful for the financial support from the Foundation for Polish Science within the START program. A.M. is grateful for financial support from the Medical University of Silesia within Research for Young Scientists (Contract No. KNW-2-O-34/D/9/N).

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    A control strategy for bioavailability enhancement by size reduction: Effect of micronization conditions on the bulk, surface and blending characteristics of an active pharmaceutical ingredient
    Olusanmi, Dolapo; Jayawickrama, Dimuthu; Bu, Dongsheng; McGeorge, Gary; Sailes, Helen; Kelleher, Joanne; Gamble, John F.; Shah, Umang V.; Tobyn, Mike
    Powder Technology (2014), 258 (), 222-233CODEN: POTEBX; ISSN:0032-5910. (Elsevier B.V.)
    In a Quality by Design (QbD) development environment the effect of early process parameters on downstream manufg. parameters, and the ultimate effect on drug product quality, need to be understood. For poorly sol. drugs, size redn. is frequently employed to obtain consistent in-vivo exposures. As a result, micronization is a key early stage processing step for many active pharmaceutical ingredients (APIs). This paper demonstrates the effect of varying micronization conditions on an API for which micronization is deemed necessary to ensure consistent drug delivery after human administration. Material micronized to different extents are confirmed as different by surface area, surface energy, particle size anal., bulk d. and surface adhesion measurements. These material characteristics can be correlated with the outcomes from a key processing step, blending. The evolution of the blending process is followed using PAT techniques, so that an overall understanding of the relationship between particle properties and blend uniformity can be demonstrated. Execution of such a study during drug development can enable selection of the appropriate control strategy to ensure prodn. of API in the desired range where consistent optimal bioavailability and downstream processability are achieved.
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  7. 7
    D, S.; Muthudoss, P.; Khullar, P.; A, R. V. Micronization and agglomeration: Understanding the impact of API particle properties on dissolution and permeability using solid state and biopharmaceutical “Toolbox. J. Pharm. Innov. 2020,  DOI: 10.1007/s12247-019-09424-1
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    Karagianni, A.; Malamatari, M.; Kachrimanis, K. Pharmaceutical cocrystals: New solid phase modification approaches for the formulation of APIs. Pharmaceutics 2018, 10, 18,  DOI: 10.3390/pharmaceutics10010018
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    Pharmaceutical cocrystals: new solid phase modification approaches for the formulation of APIs
    Karagianni, Anna; Malamatari, Maria; Kachrimanis, Kyriakos
    Pharmaceutics (2018), 10 (1), 18/1-18/30CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)
    Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochem. and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermol. interactions in cocrystals and the methods for their prepn. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development.
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    Dai, X.-L.; Chen, J.-M.; Lu, T.-B. Pharmaceutical cocrystallization: an effective approach to modulate the physicochemical properties of solid-state drugs. CrystEngComm 2018, 20, 5292– 5316,  DOI: 10.1039/C8CE00707A
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    Pharmaceutical cocrystallization: an effective approach to modulate the physicochemical properties of solid-state drugs
    Dai, Xia-Lin; Chen, Jia-Mei; Lu, Tong-Bu
    CrystEngComm (2018), 20 (36), 5292-5316CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
    Pharmaceutical cocrystn. affords an opportunity to modify the physicochem. properties of a solid-state drug without covalent modification of its mol. structure. This review presents an update on various applications of pharmaceutical cocrystn. with considerations on both cocrystals and salts, focusing on the property modification relevant to clin. efficacy and safety, and manufacturability of drugs. Some prominent examples of drug cocrystals/salts, which exhibit improved soly. and/or permeability and pharmacokinetics, stability and mechanic properties, are highlighted.
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  10. 10
    Saito, M.; Ugajin, T.; Nozawa, Y.; Sadzuka, Y.; Miyagishima, A.; Sonobe, T. Preparation and dissolution characteristics of griseofulvin solid dispersions with saccharides. Int. J. Pharm. 2002, 249, 71– 79,  DOI: 10.1016/S0378-5173(02)00455-6
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    10
    Preparation and dissolution characteristics of griseofulvin solid dispersions with saccharides
    Saito, Masataka; Ugajin, Takashi; Nozawa, Yasuo; Sadzuka, Yasuyuki; Miyagishima, Atsuo; Sonobe, Takashi
    International Journal of Pharmaceutics (2002), 249 (1-2), 71-79CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)
    To improve the soly. of poorly water-sol. drugs, we studied phys. characteristics of griseofulvin (GF) solid dispersions with saccharides as the dispersion carrier using a roll mixing method. In all carriers tested, roll mixts. of GF and saccharides gradually became amorphous, and the soly. of GF increased. The soly. of GF was higher in the mixts. with higher mol. wt. carriers such as corn starch and processed starch. The dissoln. of GF was markedly improved by the GF-British gum roll mixt. The initial dissoln. rate of these mixts. was 170-fold higher than GF alone. The surface tension of carrier aq. solns. was low in the processed starch with branched sugar chains. The initial dissoln. rate of GF in phys. mixts. was correlated with the surface tension of carrier aq. solns. The stability of the amorphous state of GF at a high humidity was maintained in the mixts. with carriers with a high mol. wt. The soly. of GF was markedly improved in the roll mixts. The saccharides with a high mol. wt. are useful carriers for solid dispersions.
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    Kawakami, K. Recent progress in solid dispersion technology. Pharmaceutics; MDPI: 2019.
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    Zhou, D.; Zhang, G. G. Z.; Law, D.; Grant, D.W. J.; Schmitt, E. A. Physical stability of amorphous pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility. J. Pharm. Sci. 2002, 91, 1863– 1872,  DOI: 10.1002/jps.10169
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    12
    Physical stability of amorphous pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility
    Zhou, Deliang; Zhang, Geoff G. Z.; Law, Devalina; Grant, David J. W.; Schmitt, Eric A.
    Journal of Pharmaceutical Sciences (2002), 91 (8), 1863-1872CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
    This work relates the thermodn. quantities (Gc, Hc, and Sc) and the mol. mobility values (1/τ) of five structurally diverse amorphous compds. to their crystn. behavior. The model compds. included: ritonavir, ABT-229, fenofibrate, sucrose, and acetaminophen. Modulated temp. DSC was used to measure the heat capacities as a function of temp. for the amorphous and cryst. phases of each compd. Knowledge of the heat capacities and fusion data allowed calcn. of the configurational thermodn. quantities and the Kauzmann temps. (TK) using established relationships. The mol. relaxation time consts. (τ) were then calcd. from the Vogel-Tammann-Fulcher representation of the Adam-Gibbs model. Amorphous samples were heated at 1 K/min and a reduced crystn. temp., defined as (Tc-Tg)/(Tm-Tg), was used to compare crystn. tendencies. Crystn. was obsd. for all compds. except ritonavir. The configurational free energy values (Gc) show that thermodn. driving forces for crystn. follow the order: ritonavir > acetaminophen ≈ fenofibrate > sucrose > ABT-229. The entropic barrier to crystn., which is inversely related to the probability that the mols. are in the proper orientation, followed the order: ritonavir > fenofibrate > ABT-229 > acetaminophen ≈ sucrose. Mol. mobility values, which are proportional to mol. collision rates, followed the order: acetaminophen > fenofibrate > sucrose > ABT-229 ≈ ritonavir. Crystn. studies under non-isothermal conditions revealed that compds. with the highest entropic barriers and lowest mobilities were most difficult to crystallize, regardless of the thermodn. driving forces. This investigation demonstrates the importance of both configurational entropy and mol. mobility to understanding the phys. stability of amorphous pharmaceuticals.
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    Hancock, B. C.; Zografi, G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 1997, 86, 1– 12,  DOI: 10.1021/js9601896
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    Characteristics and Significance of the Amorphous State in Pharmaceutical Systems
    Hancock, Bruno C.; Zografi, George
    Journal of Pharmaceutical Sciences (1997), 86 (1), 1-12CODEN: JPMSAE; ISSN:0022-3549. (American Chemical Society)
    A review with 134 refs. The amorphous state is crit. in detg. the solid-state phys. and chem. properties of many pharmaceutical dosage forms. This review describes the characteristics of the amorphous state and some of the most common methods that can be used to measure them. Examples of pharmaceutical situations where the presence of the amorphous state plays an important role are presented. The application of the current knowledge to pharmaceutical formulation problems is illustrated, and some strategies for working with amorphous character in pharmaceutical systems are provided.
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    Wyttenbach, N.; Kuentz, M. Glass-forming ability of compounds in marketed amorphous drug products. Eur. J. Pharm. Biopharm. 2017, 112, 204– 208,  DOI: 10.1016/j.ejpb.2016.11.031
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    14
    Glass-forming ability of compounds in marketed amorphous drug products
    Wyttenbach, Nicole; Kuentz, Martin
    European Journal of Pharmaceutics and Biopharmaceutics (2017), 112 (), 204-208CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
    This note is about the glass-forming ability (GFA) of drugs marketed as amorphous solid dispersions or as pure amorphous compds. A thermoanal. method was complemented with an in silico study, which made use of mol. properties that were identified earlier as being relevant for GFA. Thus, molar volume together with effective nos. of torsional bonds and hydrogen bonding were used to map drugs that are as amorphous products on the market either as solid dispersion of without co-processed carrier as amorphous drug in a solid dosage form. Differential scanning calorimetry expts. showed that most compds. were stable glass formers (GFs) (class III) followed by so-called unstable GFs (class II) and finally, only vemurafenib was found in class I with increased crystn. propensity. The in silico results, however showed that all drugs were either clearly in the chem. space expected for GFs or they were borderline to the region that holds for high crystn. tendency. Interestingly, the pure amorphous compds. scattered in a very confined region of the mol. predictors. These findings can guide amorphous product development of future drug candidates. Based on the compd. location in the given chem. space, amorphous formulation opportunities can be balanced against the risks of phys. instability upon storage.
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    Yu, L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv. Drug Delivery Rev. 2001, 48, 27– 42,  DOI: 10.1016/S0169-409X(01)00098-9
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    15
    Amorphous pharmaceutical solids: preparation, characterization and stabilization
    Yu, L.
    Advanced Drug Delivery Reviews (2001), 48 (1), 27-42CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)
    A review with 114 refs. The importance of amorphous pharmaceutical solids lies in their useful properties, common occurrence, and physicochem. instability relative to corresponding crystals. Some pharmaceuticals and excipients have a tendency to exist as amorphous solids, while others require deliberate prevention of crystn. to enter and remain in the amorphous state. Amorphous solids can be produced by common pharmaceutical processes, including melt quenching, freeze- and spray-drying, milling, wet granulation, and drying of solvated crystals. The characterization of amorphous solids reveals their structures, thermodn. properties, and changes (crystn. and structural relaxation) in single- and multi-component systems. Current research in the stabilization of amorphous solids focuses on: (i) the stabilization of labile substances (e.g., proteins and peptides) during processing and storage using additives, (ii) the prevention of crystn. of the excipients that must remain amorphous for their intended functions, and (iii) the selection of appropriate storage conditions under which amorphous solids are stable.
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  16. 16
    Grzybowska, K.; Paluch, M.; Włodarczyk, P.; Grzybowski, A.; Kaminski, K.; Hawelek, L.; Zakowiecki, D.; Kasprzycka, A.; Jankowska-Sumara, I. Enhancement of amorphous celecoxib stability by mixing it with octaacetylmaltose: The molecular dynamics study. Mol. Pharmaceutics 2012, 9, 894– 904,  DOI: 10.1021/mp200436q
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    16
    Enhancement of Amorphous Celecoxib Stability by Mixing It with Octaacetylmaltose: The Molecular Dynamics Study
    Grzybowska, K.; Paluch, M.; Wlodarczyk, P.; Grzybowski, A.; Kaminski, K.; Hawelek, L.; Zakowiecki, D.; Kasprzycka, A.; Jankowska-Sumara, I.
    Molecular Pharmaceutics (2012), 9 (4), 894-904CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    In this paper, the authors present a novel way of stabilization of amorphous celecoxib (CEL) against recrystn. by prepg. binary amorphous celecoxib-octaacetylmaltose (CEL-acMAL) systems by quench-cooling of the molten phase. As far as the authors know this is the first application of carbohydrate derivs. with acetate groups to enhance the stability of an amorphous drug. CEL in the amorphous mixt. with acMAL is characterized by a much better soly. than pure CEL. Very promising results of the long-term measurements of stability of the CEL-acMAL binary amorphous system with small amt. of stabilizer during its storage at room temp. were reported. Moreover, the effect of adding acMAL on mol. dynamics of CEL in the wide temp. range in both the supercooled liq. and glassy states were examd. The mol. mobility of the mixt. of CEL with 10 wt.% acMAL in the glassy state is much more limited than that in the case of pure CEL, which correlates with the better stability of the amorphous binary system. By dielec. measurements and theor. calcns. within the framework of d. functional theory (DFT), the role of acMAL in enhancing the stability of amorphous CEL in mixts. was studied and postulated which interactions between CEL and acMAL mols. can be responsible for preventing devitrification.
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  17. 17
    Schammé, B.; Couvrat, N.; Tognetti, V.; Delbreilh, L.; Dupray, V.; Dargent, E.; Coquerel, G. Investigation of drug-excipient interactions in biclotymol amorphous solid dispersions. Mol. Pharmaceutics 2018, 15, 1112– 1125,  DOI: 10.1021/acs.molpharmaceut.7b00993
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    17
    Investigation of Drug-Excipient Interactions in Biclotymol Amorphous Solid Dispersions
    Schamme, Benjamin; Couvrat, Nicolas; Tognetti, Vincent; Delbreilh, Laurent; Dupray, Valerie; Dargent, Eric; Coquerel, Gerard
    Molecular Pharmaceutics (2018), 15 (3), 1112-1125CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    The effect of low mol. wt. excipients on drug-excipient interactions, mol. mobility, and propensity to recrystn. of an amorphous active pharmaceutical ingredient is investigated. Two structurally related excipients (α-pentaacetylglucose and β-pentaacetylglucose), five different drug:excipient ratios (1:5, 1:2, 1:1, 2:1, and 5:1, wt./wt.), and three different solid state characterization tools (differential scanning calorimetry, X-ray powder diffraction, and dielec. relaxation spectroscopy) were selected for the present research. Our investigation has shown that the excipient concn. and its mol. structure reveal quasi-identical mol. dynamic behavior of solid dispersions above and below the glass transition temp. Across to complementary quantum mech. simulations, we point out a clear indication of a strong interaction between biclotymol and the acetylated saccharides. Moreover, the thermodn. study on these amorphous solid dispersions highlighted a stabilizing effect of α-pentaacetylglucose regardless of its quantity while an excessive concn. of β-pentaacetylglucose revealed a poor crystn. inhibition. Finally, through long-term stability studies, we also showed the limiting excipient concn. needed to stabilize our amorphous API. Herewith, the developed procedure in this paper appears to be a promising tool for solid-state characterization of complex pharmaceutical formulations.
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  18. 18
    Kaminska, E.; Adrjanowicz, K.; Tarnacka, M.; Kolodziejczyk, K.; Dulski, M.; Mapesa, E. U.; Zakowiecki, D.; Hawełek, Ł.; Kaczmarczyk-Sedlak, I.; Kaminski, K. Impact of inter- and intramolecular interactions on the physical stability of indomethacin dispersed in acetylated saccharides. Mol. Pharmaceutics 2014, 11, 2935– 2947,  DOI: 10.1021/mp500286b
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    18
    Impact of Inter- and Intramolecular Interactions on the Physical Stability of Indomethacin Dispersed in Acetylated Saccharides
    Kaminska, E.; Adrjanowicz, K.; Tarnacka, M.; Kolodziejczyk, K.; Dulski, M.; Mapesa, E. U.; Zakowiecki, D.; Hawelek, L.; Kaczmarczyk-Sedlak, I.; Kaminski, K.
    Molecular Pharmaceutics (2014), 11 (8), 2935-2947CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Differential scanning calorimetry (DSC), broadband dielec. (BDS), and Fourier transform IR (FTIR) spectroscopies as well as theor. computations were applied to investigate inter- and intramol. interactions between the active pharmaceutical ingredient (API) indomethacin (IMC) and a series of acetylated saccharides. It was found that solid dispersions formed by modified glucose and IMC are the least phys. stable of all studied samples. Dielec. measurements showed that this finding is related to neither the global nor local mobility, as the two were fairly similar. On the other hand, combined studies with the use of d. functional theory (DFT) and FTIR methods indicated that, in contrast to acetylated glucose, modified disaccharides (maltose and sucrose) interact strongly with indomethacin. As a result, internal H-bonds between IMC mols. become very weak or are eventually broken. Simultaneously, strong H-bonds between the matrix and API are formed. This observation was used to explain the phys. stability of the investigated solid dispersions. Finally, soly. measurements revealed that the soly. of IMC can be enhanced by the use of acetylated carbohydrates, although the obsd. improvement is marginal due to strong interactions.
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  19. 19
    Madejczyk, O.; Kaminska, E.; Tarnacka, M.; Dulski, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M. Studying the crystallization of various polymorphic forms of nifedipine from binary mixtures with the use of different experimental techniques. Mol. Pharmaceutics 2017, 14, 2116– 2125,  DOI: 10.1021/acs.molpharmaceut.7b00228
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    19
    Studying the Crystallization of Various Polymorphic Forms of Nifedipine from Binary Mixtures with the Use of Different Experimental Techniques
    Madejczyk, O.; Kaminska, E.; Tarnacka, M.; Dulski, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M.
    Molecular Pharmaceutics (2017), 14 (6), 2116-2125CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    In this paper the crystal growth of nifedipine from pure system and from binary mixts. composed of active substance (API) and two acetylated disaccharides, maltose and sucrose (NIF-acMAL, NIF-acSUC, 5:1 wt. ratio), was investigated. Optical snapshots supported by X-ray diffraction (XRD) and Fourier transform IR spectroscopy (FTIR) measurements showed that mainly β and α forms of nifedipine grow up in all investigated samples. They also revealed that the morphol. of growing crystals strongly depends on the presence of modified carbohydrates and temp. conditions. Interestingly, it was found that the activation barrier for the crystal growth of the β polymorph is not affected by acetylated saccharides while the one estd. for the α form changes significantly from 48.5 kJ/mol (pure API) up to 122 kJ/mol (NIF-acMAL system). Moreover, the relationship between the crystal growth rate and structural relaxation times for pure NIF and solid dispersions were analyzed. It turned out that there is a clear decoupling between the crystal growth rate and structural dynamics in both NIF-acMAL and NIF-acSUC binary mixts. This is in line with recent reports indicating the decoupling phenomenon to be a universal feature of soft matter in the close vicinity of the glass transition temp.
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  20. 20
    Minecka, A.; Kamińska, E.; Tarnacka, M.; Jurkiewicz, M.; Talik, A.; Wolnica, K.; Dulski, M.; Kasprzycka, A.; Spychalska, P.; Garbacz, G. Does the molecular mobility and flexibility of the saccharide ring affect the glass-forming ability of naproxen in binary mixtures?. Eur. J. Pharm. Sci. 2020, 141, 105091,  DOI: 10.1016/j.ejps.2019.105091
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    20
    Does the molecular mobility and flexibility of the saccharide ring affect the glass-forming ability of naproxen in binary mixtures
    Minecka, A.; Kaminska, E.; Tarnacka, M.; Jurkiewicz, K.; Talik, A.; Wolnica, K.; Dulski, M.; Kasprzycka, A.; Spychalska, P.; Garbacz, G.; Kaminski, K.; Paluch, M.
    European Journal of Pharmaceutical Sciences (2020), 141 (), 105091CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
    In this paper, we studied the impact of saccharides having a similar backbone but differing in the degree of freedom, local mol. mobility, flexibility of the ring and intermol. interactions on the glass-forming ability (GFA) of naproxen (NAP) in binary mixts. For this purpose, a series of Me and acetyl derivs. of glucose (GLS) and anhydroglucose (anhGLS), as well as neat anhGLS have been used to produce homogeneous solid dispersions (SDs) of varying molar concn. of examd. active pharmaceutical ingredient (API). Systematic measurements with the use of Differential Scanning Calorimetry (DSC) and Broadband Dielec. Spectroscopy (BDS) enabled us to det. the phase transitions, homogeneity and mol. mobility of the investigated binary mixts. as well as the impact of excipient on the crystn. tendency of NAP. Finally, since addnl. measurements with the use of Fourier Transform IR (FTIR) Spectroscopy clearly indicated that there are no significant differences in the intermol. interactions in the systems composed of NAP and all examd. saccharides, one can postulate that the mobility and ring flexibility of the matrix have, the most important impact on the crystn. tendency of NAP upon cooling. Consequently, it seems that in some cases, more mobile/flexible matrixes can be a much better choice to enhance the glass-forming ability of studied pharmaceutical.
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    Taylor, L. S.; Zografi, G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 1997, 14, 1691– 1698,  DOI: 10.1023/A:1012167410376
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    21
    Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions
    Taylor, Lynne S.; Zografi, George
    Pharmaceutical Research (1997), 14 (12), 1691-1698CODEN: PHREEB; ISSN:0724-8741. (Plenum Publishing Corp.)
    The mol. structure of indomethacin-PVP amorphous solid dispersions was studied and specific interactions between the components was identified using vibrational spectroscopy. Solid dispersions of PVP and indomethacin were prepd. using a solvent evapn. technique and IR and FT-Raman spectra were obtained. A comparison of the carbonyl stretching region of γ indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of α indomethacin is not as dimers. Addn. of PVP to amorphous indomethacin increased the intensity of the IR band assigned to non-hydrogen bonded carbonyl. Concomitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a soln. of indomethacin in methylpyrrolidone at the same wt. percent. Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystn. kinetics by preventing the self assocn. of indomethacin mols. The similarity of results for solid dispersions and solns. emphasizes the "soln." nature of this binary amorphous state.
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  22. 22
    Wegiel, L. A.; Mauer, L. I.; Edgar, K. J.; Taylor, L. S. Crystallization of amorphous solid dispersions of resveratrol during preparation and storage—impact of different polymers. J. Pharm. Sci. 2013, 102, 171– 184,  DOI: 10.1002/jps.23358
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    22
    Crystallization of amorphous solid dispersions of resveratrol during preparation and storage-Impact of different polymers
    Wegiel, Lindsay A.; Mauer, Lisa J.; Edgar, Kevin J.; Taylor, Lynne S.
    Journal of Pharmaceutical Sciences (2013), 102 (1), 171-184CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    The objective of this study was to investigate intermol. interactions between resveratrol and polymers in amorphous blends and to study the potential correlations between compd.-polymer interactions, manufacturability, and stability of the amorphous system to crystn. during storage. Polymers included two grades of poly (vinylpyrrolidone) (PVP), Eudragit E100 (E100), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), CM-cellulose acetate butyrate, and poly (acrylic acid) (PAA). Amorphous blends ("solid dispersions") were prepd. by dissolving both resveratrol and polymer in a solvent followed by rotary evapn. Crystallinity was evaluated using X-ray powder diffraction and was studied as a function of time. Mid-IR (IR) spectroscopy was used to investigate resveratrol-polymer interactions. Polymer influence on the crystn. behavior of resveratrol varied and could be correlated to the polymer structure, whereby polymers with good hydrogen bond acceptor groups performed better as crystn. inhibitors. Resveratrol-polymer hydrogen bonding interactions could be inferred from the IR spectra. Somewhat surprisingly, E100 and resveratrol showed evidence of an acid-base reaction, in addn. to intermol. hydrogen bonding interactions. PVP K29/32 appeared to form stronger hydrogen bond interactions with resveratrol relative to HPMC, HPMCAS, and PAA, consistent with acceptor group chem. Long-term stability of the systems against crystn. suggested that stability is linked to the type and strength of intermol. interactions present, whereby resveratrol blended with E100 and PVP K29/32 showed the greatest stability to crystn. In conclusion, amorphous resveratrol is unstable and difficult to form, requiring the assistance of a polymeric crystn. inhibitor to facilitate the formation of an amorphous solid dispersion. Polymers effective at inhibiting crystn. were identified, and it is rationalized that their effectiveness is based on the type and strength of their intermol. interactions with resveratrol. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Khodaverdi, K.; Khalili, N.; Zangiabadi, F.; Homayouni, A. Preparation, characterization and stability studies of glassy solid dispersions of indomethacin using pvp and isomalt as carriers. Iran J. Basic Med. Sci. 2012, 15, 820– 832
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    23
    Preparation, characterization and stability studies of glassy solid dispersions of indomethacin using PVP and isomalt as carriers
    Khodaverdi, Elham; Khalili, Noman; Zangiabadi, Farzad; Homayouni, Alireza
    Iranian Journal of Basic Medical Sciences (2012), 15 (3), 820-832CODEN: IJBMCQ; ISSN:2008-3866. (Mashhad University of Medical Sciences)
    Objective(s) The purpose of the present study was to use the solid dispersion (SD) technique to improve the dissoln. rates of indomethacin (IMC). Materials and Methods IMC solid dispersions in PVP K30 and isomalt (GALEN IQ 990) were prepd. using the solvent evapn. technique and a hot melt method in wt. ratios of 2, 10 and 30% (IMC:PVP). Solid dispersions and phys. mixts. were characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and dissoln. test. Phys. stability tests were also performed at different temps. and humidity conditions. Results The dissoln. rates of all solid dispersions were faster than those of their phys. mixts. In samples contg. 2% or 10% of IMC, there were no significant differences between the dissoln. rates of IMC in PVP and isomalt solid dispersions, but in samples contg. 30% of IMC, the dissoln. rates were higher in isomalt dispersions. The XRPD anal. showed no cryst. peaks in solid dispersions, indicating that IMC was amorphous within the carrier. The DSC results showed that an interaction occurred between the drug and the carrier in PVP and isomalt dispersions. Phys. stability tests at severe storage conditions showed that the dissoln. rate of IMC in PVP solid dispersions decreased, while the dissoln. profile of IMC in isomalt solid dispersions did not change significantly. Conclusion It was shown that the dissoln. rates of IMC in PVP and isomalt solid dispersions were substantially increased compared with their phys. mixts. and pure IMC.
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  24. 24
    Sun, Y.; Tao, J.; Zhang, G. G. Z.; Yu, L. Solubilities of crystalline drugs in polymers: An improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc. J. Pharm. Sci. 2010, 99, 4023– 4031,  DOI: 10.1002/jps.22251
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    24
    Solubilities of crystalline drugs in polymers: an improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc
    Sun, Ye; Tao, Jing; Zhang, Geoff G. Z.; Yu, Lian
    Journal of Pharmaceutical Sciences (2010), 99 (9), 4023-4031CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
    A previous method for measuring solubilities of cryst. drugs in polymers has been improved to enable longer equilibration and used to survey the solubilities of indomethacin (IMC) and nifedipine (NIF) in two homo-polymers [polyvinyl pyrrolidone (PVP) and polyvinyl acetate (PVAc)] and their co-polymer (PVP/VA). These data are important for understanding the stability of amorphous drug-polymer dispersions, a strategy actively explored for delivering poorly sol. drugs. Measuring solubilities in polymers is difficult because their high viscosities impede the attainment of soly. equil. In this method, a drug-polymer mixt. prepd. by cryo-milling is annealed at different temps. and analyzed by differential scanning calorimetry to det. whether undissolved crystals remain and thus the upper and lower bounds of the equil. soln. temp. The new annealing method yielded results consistent with those obtained with the previous scanning method at relatively high temps., but revised slightly the previous results at lower temps. It also lowered the temp. of measurement closer to the glass transition temp. For D-mannitol and IMC dissolving in PVP, the polymer's mol. wt. has little effect on the wt.-based soly. For IMC and NIF, the dissolving powers of the polymers follow the order PVP > PVP/VA > PVAc. In each polymer studied, NIF is less sol. than IMC. The activities of IMC and NIF dissolved in various polymers are reasonably well fitted to the Flory-Huggins model, yielding the relevant drug-polymer interaction parameters. The new annealing method yields more accurate data than the previous scanning method when soly. equil. is slow to achieve. In practice, these two methods can be combined for efficiency. The measured solubilities are not readily anticipated, which underscores the importance of accurate exptl. data for developing predictive models. © 2010 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci 99:4023-4031, 2010.
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    Zhao, M.; Barker, S. A.; Belton, P. S.; McGregor, C.; Craig, D. Q. M. Development of fully amorphous dispersions of a low Tg drug via co-spray drying with hydrophilic polymers. Eur. J. Pharm. Biopharm. 2012, 82, 572– 579,  DOI: 10.1016/j.ejpb.2012.07.012
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    25
    Development of fully amorphous dispersions of a low Tg drug via co-spray drying with hydrophilic polymers
    Zhao, Min; Barker, Susan A.; Belton, Peter S.; McGregor, Caroline; Craig, Duncan Q. M.
    European Journal of Pharmaceutics and Biopharmaceutics (2012), 82 (3), 572-579CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
    The aim of the study was to prep. mol. dispersions of a phys. highly unstable amorphous drug, paracetamol (acetaminophen with a Tg of ca. 25 °C) via co-spray drying with a variety of polymers. Solid dispersions at a range of drug loadings (10-90%wt./wt.) using hydroxypropyl methylcellulose/acetate succinate (HPMC/HPMC AS), polyvinylpyrrolidone (PVP) and copovidone were produced and characterized by modulated temp. differential scanning calorimetry (MTDSC), thermogravimetric anal. (TGA), X-ray powder diffraction (XRPD), Fourier transform IR spectroscopy (FTIR) and SEM (SEM). PVP-based polymers showed a greater tendency than the HPMC-based group to generate temp.-stable dispersions. In particular, copovidone (Plasdone S-630) was found to be the most effective of the polymers studied and could formulate mol. dispersions at drug loadings up to and including 40%wt./wt. However, no evidence for direct drug-polymer interactions was found for such systems as a possible stabilizing mechanism. The expected relationship of a higher Tg of the polymer leading to greater stabilization was not obsd., while there was an inverse relationship between viscosity grade and amorphous phase generation. The study has therefore shown that temp.-stable amorphous dispersions of a low Tg drug may be prepd. by co-spray drying, particularly using PVP-based polymers.
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    Löbmann, K.; Grohganz, H.; Laitinen, R.; Strachan, C.; Rades, T. Amino acids as co-amorphous stabilizers for poorly water soluble drugs – Part 1: Preparation, stability and dissolution enhancement. Eur. J. Pharm. Biopharm. 2013, 85, 873– 881,  DOI: 10.1016/j.ejpb.2013.03.014
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    26
    Amino acids as co-amorphous stabilizers for poorly water soluble drugs - Part 1: Preparation, stability and dissolution enhancement
    Lobmann, Korbinian; Grohganz, Holger; Laitinen, Riikka; Strachan, Clare; Rades, Thomas
    European Journal of Pharmaceutics and Biopharmaceutics (2013), 85 (3PB), 873-881CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
    Poor aq. soly. of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical research and development because up to 90% of new API candidates under development are poorly water sol. These drugs usually have a low and variable oral bioavailability, and therefore an unsatisfactory therapeutic effect. One of the most promising approaches to increase dissoln. rate and soly. of these drugs is the conversion of a cryst. form of the drug into its resp. amorphous form, usually by incorporation into hydrophilic polymers, forming glass solns. However, this strategy only led to a small no. of marketed products usually because of inadequate phys. stability of the drug (crystn.). In this study, we investigated a fundamentally different approach to stabilize the amorphous form of drugs, namely the use of amino acids as small mol. wt. excipients that form specific mol. interactions with the drug resulting in co-amorphous forms. The two poorly water sol. drugs carbamazepine and indomethacin were combined with amino acids from the binding sites of the biol. receptors of these drugs. Mixts. of drug and the amino acids arginine, phenylalanine, tryptophan and tyrosine were prepd. by vibrational ball milling. Solid-state characterization with X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) revealed that the various blends could be prepd. as homogeneous, single phase co-amorphous formulations indicated by the appearance of an amorphous halo in the XRPD diffractograms and a single glass transition temp. (Tg) in the DSC measurements. In addn., the Tgs of the co-amorphous mixts. were significantly increased over those of the individual drugs. The drugs remained chem. stable during the milling process and the co-amorphous formulations were generally phys. stable over at least 6 mo at 40 °C under dry conditions. The dissoln. rate of all co-amorphous drug-amino acid mixts. was significantly increased over that of the resp. cryst. and amorphous pure drugs. Amino acids thus appear as promising excipients to solve challenges connected with the stability and dissoln. of amorphous drugs.
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    Löbmann, K.; Laitinen, R.; Strachan, C.; Rades, T.; Grohganz, H. Amino acids as co-amorphous stabilizers for poorly water-soluble drugs – Part 2: Molecular interactions. Eur. J. Pharm. Biopharm. 2013, 85, 882– 888,  DOI: 10.1016/j.ejpb.2013.03.026
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    27
    Amino acids as co-amorphous stabilizers for poorly water-soluble drugs - Part 2: Molecular interactions
    Lobmann, Korbinian; Laitinen, Riikka; Strachan, Clare; Rades, Thomas; Grohganz, Holger
    European Journal of Pharmaceutics and Biopharmaceutics (2013), 85 (3PB), 882-888CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
    The formation of co-amorphous drug-drug mixts. has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissoln. of poorly water-sol. drugs. Mol. interactions in these co-amorphous formulations can play a crucial role in stabilization and dissoln. enhancement. In this regard, Fourier-transform IR spectroscopy (FTIR) is a valuable tool to analyze the mol. near range order of the compds. in the co-amorphous mixts. In this study, several co-amorphous drugs - low mol. wt. excipient blends - have been analyzed with FTIR spectroscopy. Mol. interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biol. target site of both drugs and prepd. as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed anal. of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biol. target site was present in the blends. These peak shifts indicate that the drugs formed specific mol. interactions (hydrogen bonding and π-π interactions) with the amino acids. In the drug-amino acid mixts. that contained amino acids which were not present at the biol. target site, no such interactions were identified. This study shows the potential of amino acids as small mol. wt. excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-sol. drug through strong and specific mol. interactions with the drug.
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    Jensen, K. T.; Löbmann, K.; Rades, T.; Grohganz, H. Improving co-amorphous drug formulations by the addition of the highly water soluble amino acid, proline. Pharmaceutics 2014, 6, 416– 435,  DOI: 10.3390/pharmaceutics6030416
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    28
    Improving Co-amorphous drug formulations by the addition of the highly water soluble amino acid, proline
    Jensen, Katrine Tarp; Loebmann, Korbinian; Rades, Thomas; Grohganz, Holger
    Pharmaceutics (2014), 6 (3), 416-435CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)
    Co-amorphous drug amino acid mixts. were previously shown to be a promising approach to create phys. stable amorphous systems with the improved dissoln. properties of poorly water-sol. drugs. The aim of this work was to expand the co-amorphous drug amino acid mixt. approach by combining the model drug, naproxen (NAP), with an amino acid to phys. stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly sol. amino acid (proline, PRO) for an addnl. improvement of the dissoln. rate. Co-amorphous drug-amino acid blends were prepd. by ball milling and investigated for solid state characteristics, stability and the dissoln. rate enhancement of NAP. All co-amorphous mixts. were stable at room temp. and 40 °C for a min. of 84 days. PRO acted as a stabilizer for the co-amorphous system, including NAP-TRP, through enhancing the mol. interactions in the form of hydrogen bonds between all three components in the mixt. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP-ARG. In comparison to cryst. NAP, binary NAP-TRP and NAP-ARG, it could be shown that the highly sol. amino acid, PRO, improved the dissoln. rate of NAP from the ternary co-amorphous systems in combination with either TRP or ARG. In conclusion, both the soly. of the amino acid and potential interactions between the mols. are crit. parameters to consider in the development of co-amorphous formulations.
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    Cordeiro, T.; Castiñeira, C.; Mendes, D.; Danède, F.; Sotomayor, J.; Fonseca, I. M.; Gomes da Silva, M.; Paiva, A.; Barreiros, S.; Cardoso, M. M. Stabilizing unstable amorphous menthol through inclusion in mesoporous silica hosts. Mol. Pharmaceutics 2017, 14, 3164– 3177,  DOI: 10.1021/acs.molpharmaceut.7b00386
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    29
    Stabilizing Unstable Amorphous Menthol through Inclusion in Mesoporous Silica Hosts
    Cordeiro, Teresa; Castineira, Carmem; Mendes, Davide; Danede, Florence; Sotomayor, Joao; Fonseca, Isabel M.; Gomes da Silva, Marco; Paiva, Alexandre; Barreiros, Susana; Cardoso, M. Margarida; Viciosa, Maria T.; Correia, Natalia T.; Dionisio, Madalena
    Molecular Pharmaceutics (2017), 14 (9), 3164-3177CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    The amorphization of the readily crystallizable therapeutic ingredient and food additive, menthol, was successfully achieved by inclusion of neat menthol in mesoporous silica matrixes of 3.2 and 5.9 nm size pores. Menthol amorphization was confirmed by the calorimetric detection of a glass transition. The resp. glass transition temp., Tg = -54.3 °C, is in good agreement with the one predicted by the compn. dependence of the Tg values detd. for menthol:flurbiprofen therapeutic deep eutectic solvents (THEDESs). Nonisothermal crystn. was never obsd. for neat menthol loaded into silica hosts, which can indicate that menthol rests as a full amorphous/supercooled material inside the pores of the silica matrixes. Menthol mobility was probed by dielec. relaxation spectroscopy, which allowed to identify two relaxation processes in both pore sizes: a faster one assocd. with mobility of neat-like menthol mols. (α-process), and a slower, dominant one due to the hindered mobility of menthol mols. adsorbed at the inner pore walls (S-process). The fraction of mol. population governing the α-process is greater in the higher (5.9 nm) pore size matrix, although in both cases the S-process is more intense than the α-process. A dielec. glass transition temp. was estd. for each α (Tg,dielc(α)) and S (Tg,dielc(S)) mol. population from the temp. dependence of the relaxation times to 100 s. While Tg,dielc(α) agrees better with the value obtained from the linearization of the Fox equation assuming ideal behavior of the menthol:flurbiprofen THEDES, Tg,dielc(S) is close to the value detd. by calorimetry for the silica composites due to a dominance of the adsorbed population inside the pores. Nevertheless, the greater fraction of more mobile bulk-like mols. in the 5.9 nm pore size matrix seems to det. the faster drug release at initial times relative to the 3.2 nm composite. However, the latter inhibits crystn. inside pores since its dimensions are inferior to menthol crit. size for nucleation. This points to a suitability of these composites as drug delivery systems in which the drug release profile can be controlled by tuning the host pore size.
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  30. 30
    Cordeiro, T.; Santos, A. F. M.; Nunes, G.; Cunha, G.; Sotomayor, J. C.; Fonseca, I. M.; Danède, F.; Dias, C. J.; Cardoso, M. M.; Correia, N. T. Accessing the physical state and molecular mobility of naproxen confined to nanoporous silica matrixes. J. Phys. Chem. C 2016, 120, 14390– 14401,  DOI: 10.1021/acs.jpcc.6b04078
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    30
    Accessing the Physical State and Molecular Mobility of Naproxen Confined to Nanoporous Silica Matrixes
    Cordeiro, Teresa; Santos, Andreia F. M.; Nunes, Guilherme; Cunha, Guilherme; Sotomayor, Joao C.; Fonseca, Isabel M.; Danede, Florence; Dias, C. J.; Cardoso, M. Margarida; Correia, Natalia T.; Viciosa, M. Teresa; Dionisio, Madalena
    Journal of Physical Chemistry C (2016), 120 (26), 14390-14401CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The pharmaceutical drug naproxen was loaded in three different silica hosts with pore diams. of 2.4 (MCM), 3.2 (MCM), and 5.9 nm (SBA), resp.: napMCM_2.4 nm, napMCM_3.2 nm, and napSBA_5.9 nm. To access the guest phys. state in the prepd. composites, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and attenuated total reflectance Fourier transform IR spectroscopy were used. The different techniques provided complementary information on a mol. population that was revealed to be distributed among different environments, namely the pore core, the inner pore wall, and the outer surface. It was found that naproxen is semicryst. in the higher pore size matrix being able to crystallize inside pores; after melting it undergoes full amorphization. In the case of the lower pore size matrix, naproxen crystallizes outside pores due to an excess of filling while most of the remaining fraction is incorporated inside the pores as amorphous. Crystallinity in these two composites was obsd. by the emergence of the Bragg peaks in the XRD anal., whereas for napMCM_3.2 nm only the amorphous halo was detected. The latter only exhibits the step due to the glass transition by DSC remaining stable as amorphous at least for 12 mo. The glass transition in the three composites is abnormally broad, shifting to higher temps. as the pore size decreases, coherent with the slowing down of mol. mobility as probed by dielec. relaxation spectroscopy. For napSBA_5.9 nm the dielec. response was deconvoluted in two processes: a hindered surface (S-) process due to mols. interacting with the inner pore wall and a faster α-relaxation assocd. with the dynamic glass transition due to mols. relaxing in the pore core, which seems a manifestation of true confinement effects. The drug incorporation inside a nanoporous matrix, mainly in 3.2 nm pores, was revealed to be a suitable strategy to stabilize the highly crystallizable drug naproxen in the amorphous/supercooled state and to control its release from the silica matrix, allowing full delivery after 90 min in basic media.
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    Bras, A. R.; Merino, E. G.; Neves, P. D.; Fonseca, I. M.; Dionísio, M. A.; Schonhals, A.; Correia, N. T. Amorphous ibuprofen confined in nanostructured silica materials: A dynamical approach. J. Phys. Chem. C 2011, 115, 4616– 4623,  DOI: 10.1021/jp107631m
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    31
    Amorphous ibuprofen confined in nanostructured silica materials: A dynamical approach
    Bras, Ana R.; Merino, Esther G.; Neves, Paulo D.; Fonseca, Isabel M.; Dionisio, Madalena; Schonhals, Andreas; Correia, Natalia T.
    Journal of Physical Chemistry C (2011), 115 (11), 4616-4623CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The mol. mobility of condensed matter confined to nanometer dimensions can be dramatically changed from those of the bulk state in such a way that, when the guest is a drug, it can be advantageously used in pharmaceutical applications. We show by dielec. relaxation spectroscopy that the mol. mobility of the important ibuprofen drug embedded in nanoporous SBA-15 is significantly influenced by the confinement. An evidence of the existence of two families of mols. with different mol. mobilities is provided and investigated in their temp. dependence. One family is due to mols. close to the pores' center with a higher mobility compared with the bulk at low temps., and another family with slower dynamics originated from mols. interacting with the pore walls. The work reports the simultaneous manifestation of true confinement and surface effects in this nanostructured silica host for a drug. For future applications in drug delivery systems, the dynamics detd. by the guest-host interplay and the one of the bulklike mols. can be tuned to achieve a desired release profile.
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    Braś, A. R.; Fonseca, I. M.; Dionísio, M.; Schönhals, A.; Affouard, F.; Correia, N. T. Influence of nanoscale confinement on the molecular mobility of ibuprofen. J. Phys. Chem. C 2014, 118, 13857– 13868,  DOI: 10.1021/jp500630m
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    32
    Influence of Nanoscale Confinement on the Molecular Mobility of Ibuprofen
    Bras, Ana R.; Fonseca, Isabel M.; Dionisio, Madalena; Schonhals, Andreas; Affouard, Frederic; Correia, Natalia T.
    Journal of Physical Chemistry C (2014), 118 (25), 13857-13868CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The mol. mobility of ibuprofen confined to a mesoporous silica host (MCM-41) of 3.6 nm pore diam. is investigated by dielec. relaxation spectroscopy. It is confirmed that crystn. is suppressed; therefore, depending on the temp., the guest exists in the glassy and supercooled state inside of the pores. A detailed relaxation map is provided where multiple processes are dynamically characterized, comprised of three processes that are also found for the bulk and two addnl. ones. The bulk-like processes include two secondary processes, a simple thermally activated one, a γ process and a Johari-Goldstein βJG process, and the one assocd. with the dynamic glass transition of mols. located in the pore center (α process). In confinement, all of these processes display deviations in its dynamical behavior relative to the bulk, the most dramatic one undergone by the α process, which exhibits Arrhenius-like temp. dependence upon approaching the glass transition instead of Vogel/Fulcher/Tammann/Hesse (VFTH) scaling as obeyed by the bulk. The two addnl. relaxations are assocd. with the dynamical behavior of hydrogen-bonded ibuprofen mols. lying in an interfacial layer near the pore wall, an S process for which the mobility is strongly reduced relative to the α process and a Debye-like D process for which the dynamics is closely correlated to the dynamics of the interfacial process, both exhibiting VFTH temp. dependencies. The comparison with the behavior of the same guest in the analogous host, SBA-15, with a higher pore diam. (8.6 nm) leads to the conclusion that the bulk-like mobility assocd. with the dynamic glass transition undergoes finite size effects being accelerated upon a decrease of the pore size with a concomitant redn. of the glass transition temp. relative to the bulk, 22 and 32 K, resp., for the 8.6 and 3.6 nm pore diams. The continuous decrease in the sepn. between the α- and βJG-trace with pore size decrease allows one to conclude that confined ibuprofen is a suitable guest mol. to test the Coupling Model that predicts a transformation of the α process into a βJG-mode under conditions of an extreme nanoconfinement. The overall behavior inside of pores is consistent with the existence of two distinct dynamical domains, originated by ibuprofen mols. in the core of the pore cavity and adjacent to the pore wall, from which a clear picture is given by mol. dynamics simulation.
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    Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Jurkiewicz, K.; Stankiewicz, A.; Paluch, M. Stabilization of the amorphous ezetimibe drug by confining its dimension. Mol. Pharmaceutics 2016, 13, 1308– 1316,  DOI: 10.1021/acs.molpharmaceut.5b00903
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    Stabilization of the Amorphous Ezetimibe Drug by Confining Its Dimension
    Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Jurkiewicz, K.; Stankiewicz, A.; Paluch, M.
    Molecular Pharmaceutics (2016), 13 (4), 1308-1316CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    The purpose of this paper is to investigate the influence of nanoconfinement on the mol. mobility, as well as on the phys. stability, of amorphous ezetimibe drug. Two guest/host systems, ezetimibe-Aeroperl 300 and ezetimibe-Neusilin US2, were prepd. and studied using various exptl. techniques, such as X-ray diffraction (XRD), differential scanning calorimetry (DSC), and broadband dielec. spectroscopy (BDS). Our investigation has shown that the mol. mobility of the examd. anticholesterol agent incorporated into nanopore matrixes strongly depends on the pore size of the host system. Moreover, it was found that the amorphous ezetimibe confined in 30 nm pores of Aeroperl 300 has a tendency to recrystallize, while the drug incorporated into the smaller-5 nm-pores of Neusilin US2 is not able to crystallize. It has been shown that this significant stabilization of ezetimibe drug can be achieved by an interplay of three factors: changes in mol. dynamics of the confined amorphous drug, the immobilization effect of pore walls on a part of ezetimibe mols., and the use of host materials with pores that are smaller than the crit. size of the drug crystal nuclei.
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    Szklarz, G.; Adrjanowicz, K.; Tarnacka, M.; Pionteck, J.; Paluch, M. Confinement-induced changes in the glassy dynamics and crystallization behavior of supercooled fenofibrate. J. Phys. Chem. C 2018, 122, 1384– 1395,  DOI: 10.1021/acs.jpcc.7b10946
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    Confinement-Induced Changes in the Glassy Dynamics and Crystallization Behavior of Supercooled Fenofibrate
    Szklarz, Grzegorz; Adrjanowicz, Karolina; Tarnacka, Magdalena; Pionteck, Jurgen; Paluch, Marian
    Journal of Physical Chemistry C (2018), 122 (2), 1384-1395CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Here, we have studied the effect of spatial restrictions on the mol. dynamics and crystn. behavior of modeled lipophilic drug fenofibrate incorporated into nanoporous aluminum oxide membranes of different pore size. Our measurements demonstrate that, on subsequent cooling, dynamics of confined liq. split up into two distinct fractions, due to the presence of core and interfacial layers. At the temp., at which vitrification of the interfacial layer takes place (Tg_interface), departure from the bulk-like behavior occurs, and mols. in the center of the pores enter quasi-isochoric conditions. Depending on the thermal protocol and pore size, the vol. fixed at Tg_interface might be a bit different so as the core liq.'s dynamics. Interestingly, below that temp., the nanoconfined liq. can still obey the fundamental d. scaling relation (1/TVγ), just like in the bulk phase, while not necessarily isochronal superposition. This is in contrast to a common observation that the validity of the d. scaling in bulk glass-forming systems always goes together with isochronal superposition of the α-relaxation, and vice versa. Finally, our careful anal. of the crystn. kinetics as a function of lowering pore diam. indicates for systematic slowing down crystn. progress, the shift of the max. crystn. rate toward higher undercooling and decrease in the dimensionality of growing crystals.
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    Minecka, A.; Kaminska, E.; Tarnacka, M.; Grudzka-Flak, I.; Bartoszek, M.; Wolnica, K.; Dulski, M.; Kaminski, K.; Paluch, M. The impact of intermolecular interactions, dimeric structures on the glass forming ability of naproxen and a series of its derivatives. Mol. Pharmaceutics 2018, 15, 4764– 4776,  DOI: 10.1021/acs.molpharmaceut.8b00725
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    Impact of Intermolecular Interactions, Dimeric Structures on the Glass Forming Ability of Naproxen, and a Series of Its Derivatives
    Minecka, Aldona; Kaminska, Ewa; Tarnacka, Magdalena; Grudzka-Flak, Iwona; Bartoszek, Mariola; Wolnica, Kamila; Dulski, Mateusz; Kaminski, Kamil; Paluch, Marian
    Molecular Pharmaceutics (2018), 15 (10), 4764-4776CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    In this article, thermal properties, mol. dynamics, crystn. kinetics, and intermol. interactions in pure naproxen (NAP), its amide (NH2-NAP), and four esters (Me, Met-NAP; iso-Pr, Iso-NAP; hexyl, Hex-NAP; and benzyl, Ben-NAP) have been investigated using differential scanning calorimetry as well as broadband dielec. and Fourier transform IR spectroscopies. We found that the modification of the NAP mol. by substituting a hydrogen atom from the hydroxyl group strongly inhibits the crystn. tendency of this active pharmaceutical ingredient (API) and simultaneously increases its glass forming ability (GFA). In this context, it is worthwhile to stress that pure naproxen and its amide crystd. very quickly, regardless of the cooling rate. Therefore, these compds. cannot be classified as good glass-formers. On the other hand, ester derivs. of API can be easily vitrified. Moreover, dielec. measurements revealed that with an increasing mol. wt. of the substituent, the rate of crystn. process slows down significantly. Consequently, Ben-NAP was characterized by the highest GFA among all investigated API esters. Comprehensive FTIR studies clearly indicated that the strong tendency to create dimeric structures in the nonmodified NAP and NH2-NAP is responsible for their enhanced crystn. At the first sight, our results stay in contrast to most literature data, showing that H-bonds favor the glass formation ability. However, this effect is usually obsd. for the materials, which form extensive multidirectional hydrogen bonds and assocs. In NAP and NH2-NAP, the situation is much different, since both compds. exist mainly as dimers. Therefore, one can postulate that specific intermol. interactions are an important parameter detg. the GFA of different materials, including APIs.
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    Suzuki, Y.; Duran, H.; Steinhart, M.; Kappl, M.; Butt, H.-J.; Floudas, G. Homogeneous nucleation of predominantly cubic ice confined in nanoporous alumina. Nano Lett. 2015, 15, 1987– 1992,  DOI: 10.1021/nl504855z
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    Homogeneous Nucleation of Predominantly Cubic Ice Confined in Nanoporous Alumina
    Suzuki, Yasuhito; Duran, Hatice; Steinhart, Martin; Kappl, Michael; Butt, Hans-Juergen; Floudas, George
    Nano Letters (2015), 15 (3), 1987-1992CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    The nucleation mechanism of water can be precisely regulated by confinement within nanoporous alumina. We found a transition from heterogeneous nucleation of hexagonal ice (Ih) to homogeneous nucleation of predominantly cubic ice (Ic) with decreasing pore diam. These results lead to a phase diagram of water under confinement. It contains a (stable) predominant Ic form, a form known to exist only in the upper atm. Possible applications range from cryopreservation to construction materials like cement.
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    Suzuki, Y.; Steinhart, M.; Graf, R.; Butt, H.-J.; Floudas, G. Dynamics of ice/water confined in nanoporous alumina. J. Phys. Chem. B 2015, 119, 14814– 14820,  DOI: 10.1021/acs.jpcb.5b08751
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    Dynamics of Ice/Water Confined in Nanoporous Alumina
    Suzuki, Yasuhito; Steinhart, Martin; Graf, Robert; Butt, Hans-Juergen; Floudas, George
    Journal of Physical Chemistry B (2015), 119 (46), 14814-14820CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Dielec. spectroscopy (DS), IR spectra, and 1H MAS NMR spectra are employed in the study of ice/water confined in nanoporous alumina with pore diams. ranging from 400 nm down to 25 nm. Within nanoporous alumina there is a transformation from heterogeneous nucleation of hexagonal ice in the larger pores to homogeneous nucleation of cubic ice in the smaller pores. DS and IR show excellent agreement in the temp. interval and pore size dependence of the transformation. DS further revealed two dynamic processes under confinement. The "fast" and "slow" processes with an Arrhenius temp. dependence are attributed to ice and supercooled water relaxation, resp. The main relaxation process of ice under confinement ("slow" process) has an activation energy of 44 ± 2 kJ/mol. The latter is in agreement with the reported relaxation times and activation energy of cubic ice prepd. following a completely different route (by pressure). 1H MAS NMR provided new insight in the state of ice structures as well as of supercooled water. Under confinement, a layer of liq.-like water coexists with ice structures. In addn., both ice structures under confinement appear to be more ordered than bulk hexagonal ice. Supercooled water in the smaller pores is different from bulk water. It shows a shift of the signal toward higher chem. shift values which may suggest stronger hydrogen bonding between the water mols. or increasing interactions with the AAO walls.
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    Yao, Y.; Fella, V.; Huang, W.; Zhang, K. A. I.; Landfester, K.; Butt, H.-J.; Vogel, M.; Floudas, G. Crystallization and dynamics of water confined in model mesoporous silica particles: Two ice nuclei and two fractions of water. Langmuir 2019, 35, 5890– 5901,  DOI: 10.1021/acs.langmuir.9b00496
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    Crystallization and Dynamics of Water Confined in Model Mesoporous Silica Particles: Two Ice Nuclei and Two Fractions of Water
    Yao, Yang; Fella, Verena; Huang, Wei; Zhang, Kai A. I.; Landfester, Katharina; Butt, Hans-Juergen; Vogel, Michael; Floudas, George
    Langmuir (2019), 35 (17), 5890-5901CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    The crystn. and dynamics of water confined in model mesoporous silica particles (pore diams. ranging from 2.1 to 5 nm; pore length ≈ 1 μm) are studied in homogeneous aq. suspensions by dielec. spectroscopy, differential scanning calorimetry, and NMR techniques. We establish the phase diagram (T vs. 1/d) of confined water covering a broad range of pore diams. A linear dependence of the heterogeneous and the homogeneous nucleation temps. on the inverse pore diam. is shown. The two lines converge at a pore diam. of ∼2.6 nm, below which formation of stable crystals is suppressed. By combining dielec. spectroscopy and different NMR techniques, we det. the dynamics of water within mesoporous silica over broad temp. and frequency ranges. Both techniques identify two dynamically distinguishable fractions of confined water coexisting within the pores. We attribute the two fractions to an interfacial water layer at the pore walls and confined water in the pore interior. Two alternative scenarios are proposed to rationalize the coexistence of two dynamically distinguishable water fractions. In the first scenario, two liq. fractions of water coexist under extreme confinement conditions for a range of temps.; we discuss similarities with the two ultraviscous liqs. (high-d. liq. and low-d. liq.) put forward for supercooled bulk water. In the second scenario, a liq. and a solid phase coexist; we conjecture that highly distorted and unstable crystal nuclei exist under extreme confinement that exhibit reorientation dynamics with time scales intermediate to the surrounding confined liq. and to bulk ice.
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    Jackson, C. L.; Mckenna, G. B. The melting behavior of organic materials confined in porous solids. J. Chem. Phys. 1990, 93, 9002– 9011,  DOI: 10.1063/1.459240
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    The melting behavior of organic materials confined in porous solids
    Jackson, Catheryn L.; McKenna, Gregory B.
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    The solid-liq. phase transition temps. and heats of fusion ΔHf of nonpolar org. solids confined in the pores of controlled pore glasses were measured by DSC. The pore diams. (d) were in the range 40-730 Å and the orgs. studied were cis-decalin, trans-decalin, cyclohexane, benzene, chlorobenzene, naphthalene, and heptane. In accordance with previous studies of primarily inorg. materials, the m.p. of the pore solid T(d) decreased with decreasing pore diam. In addn., a large redn. in the bulk enthalpy of fusion ΔHf of the pore solid was measured, which apparently has not been studied in detail by other workers. A linear correlation was found between the m.p. depression (ΔTm) and the reciprocal diam., as predicted by theories of solidification in a capillary. The calcd. values of the solid-liq. interfacial energy σsl were in reasonable agreement with values reported in the literature based on other methods of measurement.
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    Bishara, H.; Berger, S. Polymorphism and piezoelectricity of glycine nano-crystals grown inside alumina nano-pores. J. Mater. Sci. 2019, 54, 4619– 4625,  DOI: 10.1007/s10853-018-03211-y
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    Polymorphism and piezoelectricity of glycine nano-crystals grown inside alumina nano-pores
    Bishara, Hanna; Berger, Shlomo
    Journal of Materials Science (2019), 54 (6), 4619-4625CODEN: JMTSAS; ISSN:0022-2461. (Springer)
    Glycine nanocrystals were grown inside alumina nanopores due to a pptn. process from over-satd. aq. liq. solns. The α-glycine polymorph crystals were formed at a higher over-satn. concn. than that of the β-glycine polymorph crystals. The results indicate that the type of the glycine polymorph formed inside the alumina pores is kinetically controlled. A model is suggested to explain the competition between formations of the two polymorphs inside nano-pores. The β-glycine polymorph crystals are distinguished from the α-glycine polymorph crystals not only by XRD measurements but mainly by piezoelec. measurements, where only the non-centro-sym. β-glycine polymorph crystals show a piezoelec. current response to applied mech. pressures as low as 1 Pa in the environmental pressure of 1 atm (10-3% pressure change).
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    Rengarajan, G. T.; Enke, D.; Beiner, M. Crystallization behavior of acetaminophen in nanopores. Open Phys. Chem. J. 2007, 1, 18– 24,  DOI: 10.2174/1874067700701010018
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    Crystallization behavior of acetaminophen in nanopores
    Rengarajan, Gopalakrishnan T.; Enke, Dirk; Beiner, Mario
    Open Physical Chemistry Journal (2007), 1 (), 18-24CODEN: OPCJAQ; ISSN:1874-0677. (Bentham Science Publishers Ltd.)
    The influence of nanoconfinement on the crystn. behavior of acetaminophen, a polymorphic drug occurring in three different cryst. forms, is investigated. Differential scanning calorimetry (DSC) and wide angle X-ray scattering (WAXS) data for a series of controlled porous glasses (CPGs) filled with acetaminophen are presented. The results show clearly that (i) the usually inaccessible cryst. form III of acetaminophen can be produced in pores with diams. between 22 and 103 nm and that (ii) the life time of amorphous acetaminophen is significantly increased in 10 nm pores. Bulk melting temp. and heat of melting of form III are estd. based on the Gibbs-Thomson equation. The exptl. findings are confronted with the predictions of theor. approaches aimed to describe thermodn. and crystn. kinetics in nano-sized systems in order to understand the phys. background of the obsd. changes.
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    Kołodziejczyk, K.; Tarnacka, M.; Kaminska, E.; Dulski, M.; Kaminski, K.; Paluch, M. The crystallization’s kinetic under confinement. Manipulation of the crystalline form of salol by varying pore diameter. Cryst. Growth Des. 2016, 16, 1218– 1227,  DOI: 10.1021/acs.cgd.5b01181
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    Crystallization Kinetics under Confinement. Manipulation of the Crystalline Form of Salol by Varying Pore Diameter
    Kolodziejczyk, Karolina; Tarnacka, Magdalena; Kaminska, Ewa; Dulski, Mateusz; Kaminski, Kamil; Paluch, Marian
    Crystal Growth & Design (2016), 16 (3), 1218-1227CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    The crystn. and melting behavior of Ph salicylate under confinement were studied by dielec. spectroscopy (BDS) and DSC. From the anal. of the kinetics of crystn. crystals formed in bulk and under confinement are characterized by varying the rate of growth, dimensionality, and crystal lattice. Depending on the degree of confinement the crystn. can be accelerated or suppressed completely. The activation barrier for the crystn. either increases or decreases with respect to the bulk conditions. Further study of the melting temp. of the formed crystals indicated unequivocally that it is connected to the formation of different polymorphic forms of salol. FTIR measurements confirmed that thesis. Based on calorimetric data obtained for the confined samples, at pores of higher diam. the unstable (monoclinic) form is preferred, while at lower pores the original stable (orthorhombic) crystal is formed.
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    Adrjanowicz, K.; Kolodziejczyk, K.; Kipnusu, W. K.; Tarnacka, M.; Mapesa, E. U.; Kaminska, E.; Pawlus, S.; Kaminski, K.; Paluch, M. Decoupling between the interfacial and core molecular dynamics of salol in 2D confinement. J. Phys. Chem. C 2015, 119, 14366– 14374,  DOI: 10.1021/acs.jpcc.5b01391
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    Decoupling between the Interfacial and Core Molecular Dynamics of Salol in 2D Confinement
    Adrjanowicz, Karolina; Kolodziejczyk, Karolina; Kipnusu, Wycliffe Kiprop; Tarnacka, Magdalena; Mapesa, Emmanuel Urandu; Kaminska, Ewa; Pawlus, Sebastian; Kaminski, Kamil; Paluch, Marian
    Journal of Physical Chemistry C (2015), 119 (25), 14366-14374CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Dielec. spectroscopy and differential scanning calorimetry (DSC) were applied to study the mol. dynamics and thermal properties of a low-mol.-wt. glass-forming liq., salol (Ph salicylate), confined in anodic aluminum oxide membranes of different pore diams. (100-13 nm). On increasing the geometrical confinement, the glass transition temp. shifts toward lower temps., while at the same time broadening of the shape of the structural relaxation is obsd. This was attributed to the interplay between surface and confinement effects leading to the transition from Vogel-Fulcher-Tammann-like to Arrhenius-like dependence of the structural relaxation times. We have noticed that the temp. of such crossover agrees with the endothermic process detected by DSC. Combined dielec. and calorimetric data have indicated that this phenomenon is related to the decoupling of the dynamics of mols. attached to the pore walls and those at the center. The enhancement of the structural relaxation of the core mols. increases with decreasing pore size possibly due to changes in the packing d. This finding gives a new insight into the behavior of glass-forming liqs. under confinement and helps in the understand of the characteristic shift of the dynamic glass transition temp. with decreasing of the pore diam.
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    Tarnacka, M.; Kipnusu, W. K.; Kaminska, E.; Pawlus, S.; Kaminski, K.; Paluch, M. The peculiar behavior of the molecular dynamics of a glass-forming liquid confined in native porous materials – the role of negative pressure. Phys. Chem. Chem. Phys. 2016, 18, 23709– 23714,  DOI: 10.1039/C6CP03923E
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    The peculiar behavior of the molecular dynamics of a glass-forming liquid confined in native porous materials - the role of negative pressure
    Tarnacka, Magdalena; Kipnusu, Wycliffe K.; Kaminska, Ewa; Pawlus, Sebastian; Kaminski, Kamil; Paluch, Marian
    Physical Chemistry Chemical Physics (2016), 18 (34), 23709-23714CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    In this paper, we combine Broadband Dielec. Spectroscopy (BDS) at ambient and high pressure, and positron annihilation lifetime spectroscopy (PALS) data of 2-ethylhexanol in the bulk state and when infiltrated in native silica nanopores to elucidate the relative role of surface effects on the Debye and structural relaxation processes under 2D spatial constraints. We show that the two processes have different sensitivities to (i) the changes in d. as quantified by the EV/Hp ratio and (ii) the degree of confinement. Significant enhancement of the dynamics of the confined mols. at low temps. is related to the vitrification of the interfacial mols. (Tg,int) affecting the packing d. of the core mols. This is corroborated by the PALS measurements, which demonstrated that the effective vol. for the confined samples is slightly higher and seems to be temp. invariant below Tg,int. Consequently, neg. pressure systematically develops with lowering temp. reaching values of -100 and -110 MPa (depending on the pore size) at the glass transition temp. This result offers a better understanding of the counterbalance between surface and finite size effects as well as the role of neg. pressure in controlling the dynamics and the glass transition of liqs. under 2D spatial restrictions.
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    Kipnusu, W. K.; Elmahdy, M. M.; Elsayed, M.; Krause-Rehberg, R.; Kremer, F. Counterbalance between surface and confinement effects as studied for amino-terminated poly(propylene glycol) constraint in silica nanopores. Macromolecules 2019, 52, 1864– 1873,  DOI: 10.1021/acs.macromol.8b02687
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    Counterbalance between Surface and Confinement Effects As Studied for Amino-Terminated Poly(propylene glycol) Constraint in Silica Nanopores
    Kipnusu, Wycliffe K.; Elmahdy, Mahdy M.; Elsayed, Mohamed; Krause-Rehberg, Reinhard; Kremer, Friedrich
    Macromolecules (Washington, DC, United States) (2019), 52 (4), 1864-1873CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Broadband dielec. spectroscopy (BDS) and orthopositronium annihilation lifetime spectroscopy (PALS) are combined to study the mol. dynamics and the free vol. of poly(propylene glycol) terminated with amino end groups (PPG-NH2) in the bulk state and when confined in native and silanized unidirectional silica nanopores with av. diams. of 4, 6, and 8 nm. In the bulk state, three dielec. relaxation processes are obsd.: (1) the fast β-relaxation assigned to the librational fluctuations of the -O-NH2 moiety, (2) the α-process corresponding to the dynamic glass transition, and (3) the (slower) chain dynamics or normal mode (NM) relaxation. Under confinement in native nanopores, the β-process becomes slower, while the α and the normal mode relaxation processes become faster and broader and demonstrate a lower dielec. strength with decreasing pore diam. In silanized nanopores the normal and β-processes are nearly bulklike, but the α-process still remains faster than bulk closer to the Tg. All these findings can be comprehended as controlled by the counterbalance between surface and confinement effects. The former are caused by attractive interactions with the solid walls of the nanopores (resulting in an addnl. slower process which is removed after silanization), and the latter are caused by an increase of the free vol. of the polymer segments due to a less efficient packing as proven by orthopositronium annihilation lifetime spectroscopy. These results conform to the cooperative free vol. model (CFV).
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    Morineau, D.; Xia, Y.; Alba-Simionesco, C. Finite-size and surface effects on the glass transition of liquid toluene confined in cylindrical mesopores. J. Chem. Phys. 2002, 117, 8966– 8972,  DOI: 10.1063/1.1514664
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    Finite-size and surface effects on the glass transition of liquid toluene confined in cylindrical mesopores
    Morineau, Denis; Xia, Yongde; Alba-Simionesco, Christiane
    Journal of Chemical Physics (2002), 117 (19), 8966-8972CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    Some of the most regular porous silicates (MCM-41 and SBA-15), with several different pore diams. from 2.4 to 8.7 nm, are used to study the van der Waals fragile liq. toluene in confined geometry. We measure two major macroscopic signatures of a glass transition, i.e., a discontinuous change in the heat capacity and in the thermal expansion, by adiabatic calorimetry and neutron scattering expts. A nontrivial size dependence of the glass transition features, most notably a nonmonotonic variation of the mean glass transition temp., is obsd. The range of the glass transition is found extremely broad. This supports the notion of competition between surface boundary conditions and cutoff or finite-size effects.
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    Lau, M.; Giri, K.; Garcia-Bennett, A. E. Antioxidant properties of probucol released from mesoporous silica. Eur. J. Pharm. Sci. 2019, 138, 105038,  DOI: 10.1016/j.ejps.2019.105038
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    Antioxidant properties of probucol released from mesoporous silica
    Lau, Michael; Giri, Kalpeshkumar; Garcia-Bennett, Alfonso E.
    European Journal of Pharmaceutical Sciences (2019), 138 (), 105038CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
    Antioxidants play a vital role in scavenging reactive oxygen species (ROS) produced by the redn. of mol. oxygen from various cellular mechanisms. Drug compds. with potent antioxidant properties are typically poorly water sol. and highly hydrophobic. In this study, PB was loaded in mesoporous silica at various drug loadings to understand the changes to the phys. properties of the loaded drug, and it's in vitro drug release. Further in vitro studies were conducted in endothelial and microglia cell models to compare the free radical scavening efficiency of ascorbic acid, PB, and PB release from mesoporous silica particles. Out of the three different mesostructured particles studied, the max. loading of PB was achieved for large pore mesoporous particles (SBA-15) at 50 wt% drug loading, before complete pore filling was obsd. For all materials, loadings above complete pore filling resulted in the recrystn. of PB on the external surface. In vitro drug release measurements showed a rapid dissoln. rate at low drug loadings compared to a bimodal release profile of amorphous and cryst. drug at higher drug loadings. PB loaded in mesoporous particle was shown to enhance the antioxidant response to extracellular ROS in the endothelial cell line model, and to intracellular ROS in the microglia cell model. Our results indicate that the antioxidant properties of PB can be significantly improved by using mesoporous silica as a delivery vehicle.
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    Kamińska, E.; Minecka, A.; Tarnacka, M.; Kamiński, K.; Paluch, M. Breakdown of the isochronal structural (α) and secondary (JG β) exact superpositioning in probucol - A low molecular weight pharmaceutical. J. Mol. Liq. 2020, 299, 112169,  DOI: 10.1016/j.molliq.2019.112169
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    Breakdown of the isochronal structural (a) and secondary (JG β) exact superpositioning in probucol - A low molecular weight pharmaceutical
    Kaminska, E.; Minecka, A.; Tarnacka, M.; Kaminski, K.; Paluch, M.
    Journal of Molecular Liquids (2020), 299 (), 112169CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
    In this paper, Broadband Dielec. Spectroscopy (BDS) has been applied to study the mol. dynamics of the two active pharmaceutical ingredients (APIs), probucol (PRO) and droperidol (DRO), above and below the glass transition temp., at varying thermodn. conditions. We found that the structural (a)-relaxation process in both compds. is sensitive to compression. In this context, it is worthwhile to emphasize that dTg/dp calcd. for the latter API is the highest reported to date for the low mol. wt. glass formers. Furthermore, the data collected upon squeezing samples revealed that the pressure dependence of the relaxation times of the Johari Goldstein (JG) β-process in PRO is weaker with respect to that of structural relaxation. This phenomenon, which is consistent with the approx. invariance of the ratio of these two relaxation times to change of thermodn. conditions (as predicted by the Coupling Model), was assigned to the increasing torsional rigidity of the macromol. backbone or alternatively to the non-uniform responses to variations of temp. and pressure of the distributed modes composing the JG β-process, resulting in changes of the spectral shape and different fβ(p,T) obtained from the fitting procedure. Finally, the data reported herein emphasize the impact of mol. aspects related to specific interactions on the correlation between a- and JG β-relaxation at varying T and p conditions.
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    Iacob, C.; Sangoro, J. R.; Papadopoulos, P.; Schubert, T.; Naumov, S.; Valiullin, R.; Karger, J.; Kremer, F. Charge transport and diffusion of ionic liquids in nanoporous silica membranes. Phys. Chem. Chem. Phys. 2010, 12, 13798,  DOI: 10.1039/c004546b
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    Charge transport in 1-hexyl-3-methylimidazolium hexafluorophosphate ionic liq. in oxidized nanoporous silicon membranes was studied in a wide frequency and temp. range by a combination of Broadband Dielec. Spectroscopy (BDS) and Pulsed Field Gradient NMR (PFG NMR). By applying the Einstein-Smoluchowski relations to the dielec. spectra, diffusion coeff. was obtained in quant. agreement with independent PFG NMR measurements. More than 10-fold systematic decrease in the effective diffusion coeff. from the bulk value is obsd. in hydrophilic silica nanopores. A model assuming a reduced mobility at the pore-matrix interface provides a quant. explanation for the remarkable decrease of effective transport quantities (such as diffusion coeff., d.c. cond. and consequently, the dielec. loss) of the ionic liq. in nonsilanized membranes. This approach is supported by the observation that silanization of porous silica membranes results in a significant increase of the effective diffusion coeff., which approaches the value for the bulk liq.
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    Kipnusu, W. K.; Kossack, W.; Iacob, C.; Jasiurkowska, M.; Rume Sangoro, J.; Kremer, F. Molecular order and dynamics of tris(2ethylhexyl)phosphate confined in uni-directional nanopores. Z. Phys. Chem. 2012, 226, 797– 805,  DOI: 10.1524/zpch.2012.0287
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    Molecular order and dynamics of tris(2-ethylhexyl)phosphate confined in uni-directional nanopores
    Kipnusu, Wycliffe Kiprop; Kossack, Wilhem; Iacob, Ciprian; Jasiurkowska, Malgorzata; Sangoro, Joshua Rume; Kremer, Friedrich
    Zeitschrift fuer Physikalische Chemie (Muenchen, Germany) (2012), 226 (7-8), 797-805CODEN: ZPCFAX; ISSN:0942-9352. (Oldenbourg Wissenschaftsverlag GmbH)
    IR Transition Moment Orientational Anal. (IR-TMOA) and Broadband Dielec. Spectroscopy (BDS) are combined to study mol. order and dynamics of the glass-forming liq. Tris(2-ethylhexy)phosphate (TEHP) confined in uni-directional nanopores with diams. of 4, 8, and 10.4 nm. The former method enables one to det. the mol. order parameter of specific IR transition moments. It is obsd. that the central P=O moiety of TEHP has a weak orientational effect (mol. order parameter Sz = -0.1 ± 0.04) due the nanoporous confinement, in contrast to the terminal C-H groups. BDS traces the dynamic glass transition of the guest mols. in a broad spectral range and at widely varying temp. An enhancement of the mobility takes place when approaching the glass transition temp. and becomes more pronounced with decreasing pore diam. This is attributed to a slight redn. of the d. of the confined liq. caused by the 2-dimensional geometrical constraint.
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    Alexandris, S.; Papadopoulos, P.; Sakellariou, G.; Steinhart, M.; Butt, H.-J.; Floudas, G. Interfacial energy and glass temperature of polymers confined to nanoporous alumina. Macromolecules 2016, 49, 7400– 7414,  DOI: 10.1021/acs.macromol.6b01484
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    Interfacial Energy and Glass Temperature of Polymers Confined to Nanoporous Alumina
    Alexandris, Stelios; Papadopoulos, Periklis; Sakellariou, Georgios; Steinhart, Martin; Butt, Hans-Jurgen; Floudas, George
    Macromolecules (Washington, DC, United States) (2016), 49 (19), 7400-7414CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    We report on the effect of interfacial energy on the glass temp., Tg, of several amorphous polymers with various glass temps. and polymer/substrate interactions confined within self-ordered nanoporous alumina (AAO). The polymers studied include poly(phenylmethylsiloxane) (PMPS), poly(vinyl acetate) (PVAc), 1,4-polybutadiene (PB), oligostyrene (PS), and poly(dimethylsiloxane) (PDMS). The segmental dynamics and assocd. Tg's are studied by means of dielec. spectroscopy. The interfacial energy for the polymer/substrate interface, γSL, is calcd. with Young's equation whereas the AAO membrane surface energy is obtained by measuring contact angles for several ref. liqs. We find that interfacial energy plays a significant role in the segmental dynamics of polymers under confinement within AAO. There is a trend for a decreasing glass temp. relative to the bulk with increasing interfacial energy. PDMS exhibits the highest interfacial energy and the highest redn. in glass temp. within AAO. Other effects that may also contribute to changes in Tg are discussed.
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    Tarnacka, M.; Dulski, M.; Geppert-Rybczyńska, M.; Talik, A.; Kaminska, E.; Kaminski, K.; Paluch, M. Variation in the molecular dynamics of DGEBA confined within AAO templates above and below the glass transition temperature. J. Phys. Chem. C 2018, 122, 28033– 28044,  DOI: 10.1021/acs.jpcc.8b07522
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    Variation in the Molecular Dynamics of DGEBA Confined within AAO Templates above and below the Glass-Transition Temperature
    Tarnacka, Magdalena; Dulski, Mateusz; Geppert-Rybczynska, Monika; Talik, Agnieszka; Kaminska, Ewa; Kaminski, Kamil; Paluch, Marian
    Journal of Physical Chemistry C (2018), 122 (49), 28033-28044CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The mol. dynamics above and below the glass transition temp. of bisphenol-A diglycidyl ether (known as DGEBA, Mn = 340 g/mol) infiltrated in nanoporous alumina (AAO) templates of various pore size were studied by broadband dielec. and Raman spectroscopies. The temp. dependence of the structural relaxation times is different under confinement with respect to the bulk sample even in the high temp. regime. Below the glass transition temp., the slow secondary process (β) was not detected in dielec. loss spectra of confined DGEBA; while the relaxation times of the faster secondary process (γ) were unaffected by the pore size. To explain this phenomenon, 2 different scenarios, considering either suppression of the motions related to this mobility or enhancement of its dynamics, were taken into account. Addnl. annealing expts., that lead to d. perturbation, enabled one to recover bulk-like temp. dependence of structural relaxation times for all confined systems. This finding was discussed in view of the outcome of Raman and contact angle measurements, that showed rather weak interactions between DGEBA and template. It is also worthwhile to add that except for the clear broadening of the fast secondary relaxation peak, the relaxation times of this process varied within exptl. uncertainties due to annealing.
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    Alexandris, S.; Sakellariou, G.; Steinhart, M.; Floudas, G. Dynamics of unentangled cis-1,4-polyisoprene confined to nanoporous alumina. Macromolecules 2014, 47, 3895– 3900,  DOI: 10.1021/ma5006638
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    Dynamics of Unentangled cis-1,4-Polyisoprene Confined to Nanoporous Alumina
    Alexandris, Stelios; Sakellariou, Georgios; Steinhart, Martin; Floudas, George
    Macromolecules (Washington, DC, United States) (2014), 47 (12), 3895-3900CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    The dynamics of unentangled cis-1,4-polyisoprene confined within self-ordered nanoporous alumina (AAO) is studied as a function of mol. wt. (5000-300 g/mol) and pore size (400-25 nm) with dielec. spectroscopy. The main effects are the pronounced broadening of both segmental and chain modes with decreasing AAO pore diam. This suggests that the global chain relaxation is retarded on confinement. Remarkably, the distribution of relaxation times is broadened even within pores with size 50 times the unperturbed chain dimensions. The glass temp. is unaffected by confinement. These results are discussed in terms of confinement and adsorption effects. Confinement effects are negligible for the studied mol. wts. Chain adsorption, on the other hand, involves time and length scales distinctly different from the bulk that can account for the exptl. findings.
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    Tarnacka, M.; Kaminski, K.; Mapesa, E. U.; Kaminska, E.; Paluch, M. Studies on the temperature and time induced variation in the segmental and chain dynamics in poly(propylene glycol) confined at the nanoscale. Macromolecules 2016, 49, 6678– 6686,  DOI: 10.1021/acs.macromol.6b01237
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    Studies on the Temperature and Time Induced Variation in the Segmental and Chain Dynamics in Poly(propylene glycol) Confined at the Nanoscale
    Tarnacka, Magdalena; Kaminski, Kamil; Mapesa, Emmanuel U.; Kaminska, Ewa; Paluch, Marian
    Macromolecules (Washington, DC, United States) (2016), 49 (17), 6678-6686CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    The effect of 2D confinement on the dynamics of the normal modes (chain mobility) and segmental relaxation in poly(propylene glycol) (PPG) has been studied with the use of Broadband Dielec. Spectroscopy (BDS) and Differential Scanning Calorimetry (DSC). It is shown that both processes become faster with increasing degree of confinement. Interestingly, the crossover from VFT to the Arrhenius-like behavior of chain and segmental dynamics, obsd. in the examd. system, is strictly related to the vitrification of the adsorbed polymers. The mean relaxation times of the normal, τNM, and segmental modes, τα, depend on the history of confined PPG and can be significantly modified using different thermal treatments. It is demonstrated that annealing of the samples below the crossover temp., Tc, leads to a systematic shift of the segmental relaxation and normal mode toward lower frequencies, resulting in an increase in the glass transition temp. of the spatially restricted PPG. This observation to d. equilibration after annealing indicated that a system with higher d. characterized by more homogeneous dynamics can be obtained. It is therefore possible to modify and control the properties of the confined material by using different thermal treatment protocols.
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    Huwe, A.; Arndt, M.; Kremer, F.; Haggenmüller, C.; Behrens, P. Dielectric investigations of the molecular dynamics of propanediol in mesoporous silica materials. J. Chem. Phys. 1997, 107, 9699– 9701,  DOI: 10.1063/1.475265
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    Dielectric investigations of the molecular dynamics of propanediol in mesoporous silica materials
    Huwe, A.; Arndt, M.; Kremer, F.; Haggenmuller, C.; Behrens, P.
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    Broadband dielec. spectroscopy (10-2-1.8×109 Hz) is employed to study the mol. dynamics of the glass-forming hydrogen-bonded liq. propanediol confined to mesoporous M41S silica materials having two different topologies. It is shown that the dynamic glass transition takes place in the mesoporous system (diam. 2.7 nm). With respect to the bulk its relaxation rates are decreased when approaching the calorimetric glass transition. Silanization of the inner surfaces acts as a mol. lubrication and makes the mol. dynamics of the confined liq. comparable to the bulk.
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    Adrjanowicz, K.; Kaminski, K.; Koperwas, K.; Paluch, M. Negative pressure vitrification of the isochorically confined liquid in nanopores. Phys. Rev. Lett. 2015, 115, 265702,  DOI: 10.1103/PhysRevLett.115.265702
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    Negative pressure vitrification of the isochorically confined liquid in nanopores
    Adrjanowicz, K.; Kaminski, K.; Koperwas, K.; Paluch, M.
    Physical Review Letters (2015), 115 (26), 265702/1-264702/5CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
    Dielec. relaxation studies for model glass-forming liqs. confined to nanoporous alumina matrixes were examd. together with high-pressure results. For confined liqs. which show the deviation from bulk dynamics upon approaching the glass transition (the change from the Vogel-Fulcher-Tammann to the Arrhenius law), we have obsd. a striking agreement between the temp. dependence of the a-relaxation time in the Arrhenius-like region and the isochoric relaxation times extrapolated from the pos. range of pressure to the neg. pressure domain. Our finding provides strong evidence that glass-forming liq. confined to native nanopores enters the isochoric conditions once the mobility of the interfacial layer becomes frozen in. This results in the neg. pressure effects on cooling. We also demonstrate that differences in the sensitivity of various glass-forming liqs. to the "confinement effects" can be rationalized by considering the relative importance of thermal energy and d. contributions in controlling the a-relaxation dynamics (the Eυ/Ep ratio).
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    Park, J.-Y.; McKenna, G. B. Size and confinement effects on the glass transition behavior of Polystyrene/O-terphenyl polymer solutions. Phys. Rev. B: Condens. Matter Mater. Phys. 2000, 61, 6667– 6676,  DOI: 10.1103/PhysRevB.61.6667
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    Size and confinement effects on the glass transition behavior of polystyrene/o-terphenyl polymer solutions
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    Physical Review B: Condensed Matter and Materials Physics (2000), 61 (10), 6667-6676CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)
    Polystyrene (PS)/o-terphenyl (oTP) solns. confined to nanometer scale pores were studied by differential scanning calorimetry to investigate size and confinement effects on the glass transition. We obsd. two glass transitions Tg in all thermograms for materials confined in the controlled pore glasses. One was at a lower temp. than the bulk state Tg and the other was at a higher temp. The lower transition temp. decreases with decreasing pore size, which is consistent with previous reports from this lab. on small-mol. glass formers and some other reports in similar systems. Although oTP and oTP/PS are not hydrogen-bonding materials, we interpret the higher temp. transition as due to the existence of an interacting layer at the pore surface. A two-layer model in which there exists a "core" liq. in the center surrounded by the interacting layer at the pore surface is consistent with our observations.
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    Dielectric investigations of the dynamic glass transition in nanopores
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    Physical Review E: Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics (1996), 54 (5), 5377-5390CODEN: PLEEE8; ISSN:1063-651X. (American Physical Society)
    Broadband dielec. spectroscopy (10-2-109 Hz) is employed to study the dynamic glass transition of low-mol.-wt. glass-forming liqs.: salol (one hydroxy group), pentalene glycol (two hydroxy groups), and glycerol (three hydroxy groups) were chosen. The authors interpret the dielec. spectra in terms of a two-state model with dynamic exchange between a bulklike phase in the pore vol. and an interfacial phase close to the pore wall. This enables one to analyze in detail the interplay between the mol. dynamics in the two subsystems (bulklike and interfacial), its dynamic exchange, and hence their growth and decline in dependence on the temp. and strength of the mol. interactions. For glycerol it is shown that a bulklike dynamic glass transition takes place in subvolumes as well as about 1 nm.
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    Tarnacka, M.; Kaminska, E.; Kaminski, K.; Roland, C. M.; Paluch, M. Interplay between core and interfacial mobility and its impact on the measured glass transition: Dielectric and calorimetric studies. J. Phys. Chem. C 2016, 120, 7373– 7380,  DOI: 10.1021/acs.jpcc.5b12745
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    Interplay between Core and Interfacial Mobility and Its Impact on the Measured Glass Transition: Dielectric and Calorimetric Studies
    Tarnacka, Magdalena; Kaminska, Ewa; Kaminski, Kamil; Roland, C. Michael; Paluch, Marian
    Journal of Physical Chemistry C (2016), 120 (13), 7373-7380CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The dynamics and thermodn. of confined tri-Ph phosphite (TPP) were studied using broadband dielec. spectroscopy (BDS) and differential scanning calorimetry (DSC). Geometric confinement in channels having length scales commensurate with the mol. size of TPP causes bifurcation of the dynamics: two populations are obsd., distinguished by their reorientational mobilities and glass transition temps. Upon cooling, significant changes in the relaxation process and temp. dependence occur due to the slow vitrification of the mols. in close proximity to the interface. Such a kinetic aspect of glass formation is unusual. This surface interaction alleviates constraints on the mols., allowing their glass transition to shift to lower temps. Simultaneously, it was obsd. that the structural relaxation process shifts to lower frequencies, and the distribution of the relaxation times becomes narrower upon annealing. This effect is esp. visible at lower frequencies, indicating the decreasing contribution of those mols. characterized by slower dynamics. In addn., it was found that structural relaxation times, as well as the glass transition temps., can be significantly modified by annealing samples over a particular range of temps. This work facilitated the understanding of the interplay between different kinds of mobility and its impact on changes in the glass transition temp. for two-dimensional confined materials.
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    Talik, A.; Tarnacka, M.; Geppert-Rybczyńska, M.; Hachuła, B.; Kaminski, K.; Paluch, M. The Impact of confinement on the dynamics and H-bonding pattern in low-molecular weight poly(propylene glycols). J. Phys. Chem. C 2020, 124, 17607– 17621,  DOI: 10.1021/acs.jpcc.0c04062
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    Impact of Confinement on the Dynamics and H-Bonding Pattern in Low-Molecular Weight Poly(propylene glycols)
    Talik, Agnieszka; Tarnacka, Magdalena; Geppert-Rybczynska, Monika; Hachula, Barbara; Kaminski, Kamil; Paluch, Marian
    Journal of Physical Chemistry C (2020), 124 (32), 17607-17621CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Herein we explored thermal properties, dynamics wettability and H-bonding pattern in various poly(propylene glycols) (PPG) of Mn = 400 g/mol confined into two types of nanoporous templates: silica (d=4 nm) and alumina (d=18 nm). Unexpectedly it was found that mobility of the interfacial layer and depression of the glass transition temp. weakly depend on the pore size, surface functionalization and wettability. Finally, we have reported a strengthening of the hydrogen bonds in samples confined in silica pores. Further, unique annealing expts. with the use of FTIR spectroscopy revealed reorganization of the mols. close to the interface and formation of the three distinct interfacial, intermediate and bulk-like fractions of mols. for PPG infiltrated in pores. These expts. may shed new lights on the variation of the segmental/structural relaxation times due to annealing of the materials of different mol. wt. infiltrated into pores or deposited in the form of a thin layer.
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    Adrjanowicz, K.; Paluch, M. Discharge of the nanopore confinement effect on the glass transition dynamics via viscous flow. Phys. Rev. Lett. 2019, 122, 176101,  DOI: 10.1103/PhysRevLett.122.176101
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    Discharge of the nanopore confinement effect on the glass transition dynamics via viscous flow
    Adrjanowicz, K.; Paluch, M.
    Physical Review Letters (2019), 122 (17), 176101CODEN: PRLTAO; ISSN:1079-7114. (American Physical Society)
    Using dielec. spectroscopy, we demonstrate that confinement-induced changes in the glass transition dynamics, as obsd. for polymethylphenylsiloxane in alumina nanopores, reveal a pronounced nonequil. nature. Our results indicate that glass formers confined to nanopores are able to recover their bulklike mobility. We found that the characteristic time const. of such an equilibration process correlates with an extremely slow viscous flow rate in cylindrical channels of nanometer size. Thus, all the way to equil., confinement effects seen in faster segmental dynamics are released through the viscous flow which eventually helps to eliminate surplus vol. gained by nanoconstrained polymers upon cooling.
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    A complex plane representation of dielectric and mechanical relaxation processes in some polymers
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    cf. CA 66: 55869h; Scaife, CA 58: 12039d. The changes in the relaxation curve, obtained by plotting the imaginary coordinate of the complex polarizability of a dielec. sphere of unit radius against its real counterpart, were studied for 20 polymers whose dielec. dispersions were linear at high frequencies and circular arcs at low frequencies. An analogous transformation procedure was constructed empirically for mech. dispersions. The mech. and dielec. dispersions were analogous mechanisms when appropriately normalized. Polymers studied were poly(nonyl methacrylate), polycarbonate of bisphenol, poly(m-chlorostyrene), poly(vinyl laurate), poly(n-octyl methacrylate), poly(isobutyl methacrylate), poly(n-hexyl methacrylate), poly(cyclohexyl methacrylate), poly(vinyl decanoate), poly(n-butyl methacrylate), poly(vinyl octanoate), polychloroprene, poly(vinyl formal), poly(Me acrylate), poly(trifluorochloroethylene), poly(vinyl acetate), poly(vinyl chloroacetate), poly(vinyl acetal), and polyisobutylene. Similar data were obtained for glycerol and an unidentified copolymer. 41 references.
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    The mol. dynamics in the glass transition of the "quasi"-van der Waals glass salol confined to nanopores (2.5, 5.0, and 7.5 nm) with lubricated inner surfaces is found to be faster (by up to 2 orders of magnitude) than in the bulk liq. This effect of confinement is more pronounced for smaller pores. It reflects the cooperativity of mol. motions in the glass transition and enables its length scale to be detd. quant.
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    Hong, L.; Gujrati, P. D.; Novikov, V. N.; Sokolov, A. P. Molecular cooperativity in the dynamics of glass-forming systems: A new insight. J. Chem. Phys. 2009, 131, 194511,  DOI: 10.1063/1.3266508
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    Journal of Chemical Physics (2009), 131 (19), 194511/1-194511/7CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    The mechanism behind the steep slowing down of mol. motions upon approaching the glass transition remains a great puzzle. Most of the theories relate this mechanism to the cooperativity in mol. motion. In this work, we est. the length scale of mol. cooperativity ξ for many glass-forming systems from the collective vibrations (the so-called boson peak). The obtained values agree well with the dynamic heterogeneity length scale estd. using four-dimensional NMR. We demonstrate that ξ directly correlates to the dependence of the structural relaxation on vol. This dependence presents only one part of the mechanism of slowing down the structural relaxation. Our anal. reveals that another part, the purely thermal variation in the structural relaxation (at const. vol.), does not have a direct correlation with mol. cooperativity. These results call for a conceptually new approach to the anal. of the mechanism of the glass transition and to the role of mol. cooperativity. (c) 2009 American Institute of Physics.
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    Journal of Chemical Physics (2015), 143 (15), 154505/1-154505/7CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    The authors examine the use of metal-org. framework (MOF) systems as host materials for the investigation of glassy dynamics in confined geometry. The confinement of the mol. glass former glycerol in three MFU-type MOFs with different pore sizes (MFU stands for "metal-org. framework Ulm-university") and the dynamics of the confined liq. are studied via dielec. spectroscopy. In accord with previous reports on confined glass formers, different degrees of deviations from bulk behavior are found depending on pore size, demonstrating that MOFs are well-suited host systems for confinement investigations. (c) 2015 American Institute of Physics.
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    Uhl, M.; Fischer, J. K. H.; Sippel, P.; Bunzen, H.; Lunkenheimer, P.; Volkmer, D.; Loidl, A. Glycerol confined in zeolitic imidazolate frameworks: The temperature-dependent cooperativity length scale of glassy freezing. J. Chem. Phys. 2019, 150, 024504,  DOI: 10.1063/1.5080334
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    Glycerol confined in zeolitic imidazolate frameworks: The temperature-dependent cooperativity length scale of glassy freezing
    Uhl, M.; Fischer, J. K. H.; Sippel, P.; Bunzen, H.; Lunkenheimer, P.; Volkmer, D.; Loidl, A.
    Journal of Chemical Physics (2019), 150 (2), 024504/1-024504/9CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    In the present work, we employ broadband dielec. spectroscopy to study the mol. dynamics of the prototypical glass former glycerol confined in two microporous zeolitic imidazolate frameworks (ZIF-8 and ZIF-11) with well-defined pore diams. of 1.16 and 1.46 nm, resp. The spectra reveal information on the modified α relaxation of the confined supercooled liq., whose temp. dependence exhibits clear deviations from the typical super-Arrhenius temp. dependence of the bulk material, depending on the temp. and pore size. This allows assigning well-defined cooperativity length scales of mol. motion to certain temps. above the glass transition. We relate these and previous results on glycerol confined in other host systems to the temp.-dependent length scale deduced from nonlinear dielec. measurements. The combined exptl. data can be consistently described by a crit. divergence of this correlation length as expected within theor. approaches assuming that the glass transition is due to an underlying phase transition. (c) 2019 American Institute of Physics.
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    Winkler, R.; Tu, W.; Laskowski, Ł.; Adrjanowicz, K. Effect of surface chemistry on the glass-transition dynamics of poly(phenyl methyl siloxane) confined in alumina nanopores. Langmuir 2020, 36, 7553– 7565,  DOI: 10.1021/acs.langmuir.0c01194
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    Effect of surface chemistry on the glass-transition dynamics of poly(phenyl methyl siloxane) confined in alumina nanopores
    Winkler, Roksana; Tu, Wenkang; Laskowski, Lukasz; Adrjanowicz, Karolina
    Langmuir (2020), 36 (26), 7553-7565CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Broadband dielec. spectroscopy (BDS) and differential scanning calorimetry (DSC) are combined to study the effect of changes in the surface chem. on the segmental dynamics of glass-forming polymer, poly(methylphenylsiloxane) (PMPS), confined in anodized aluminum oxide (AAO) nanopores. Measurements were carried for native and silanized nanopores of the same pore sizes. Nanopore surfaces are modified with the use of two silanizing agents, chlorotrimethylsilane (ClTMS) and (3-aminopropyl)trimethoxysilane (APTMOS), of much different properties. The results of the dielec. studies have demonstrated that for the studied polymer located in 55 nm pores, changes in the surface chem. and thermal treatment allows the confinement effect seen in temp. evolution of the segmental relaxation time, τα(T) to be removed. The bulk-like evolution of the segmental relaxation time can also be restored upon long-time annealing. Interestingly, the time scale of such equilibration process was found to be independent of the surface conditions. The calorimetric measurements reveal the presence of two glass-transition events in DSC thermograms of all considered systems, implying that the changes in the interfacial interactions introduced by silanization are not strong enough to inhibit the formation of the interfacial layer. Although DSC traces confirmed the two-glass-transition scenario, there is no clear evidence that vitrification of the interfacial layer affects τα(T) for nanopore-confined polymer.
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    Li, L.; Chen, J.; Deng, W.; Zhang, C.; Sha, Y.; Cheng, Z.; Xue, G.; Zhou, D. Glass transitions of poly(methyl methacrylate) confined in nanopores: Conversion of three- and two-layer models. J. Phys. Chem. B 2015, 119, 5047– 5054,  DOI: 10.1021/jp511248q
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    Glass Transitions of Poly(methyl methacrylate) Confined in Nanopores: Conversion of Three- and Two-Layer Models
    Li, Linling; Chen, Jiao; Deng, Weijia; Zhang, Chen; Sha, Ye; Cheng, Zhen; Xue, Gi; Zhou, Dongshan
    Journal of Physical Chemistry B (2015), 119 (15), 5047-5054CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    The glass transitions of poly(Me methacrylate) (PMMA) oligomer confined in alumina nanopores with diams. much larger than the polymer chain dimension were investigated. Compared with the case of 80 nm nanopores, PMMA oligomer confined in 300 nm nanopores shows three glass transition temps. (from from low to high, denoted as Tg,lo, Tg,inter, and Tg,hi). Such phenomenon can be interpreted by a three-layer model: there exists an interphase between the adsorbed layer and core vol. called the interlayer, which has an intermediate Tg. The behavior of multi-Tg parameters is ascribed to the propagation of the interfacial interaction during vitrifaction process. Besides, because of the nonequil. effect in the adsorbed layer, the cooling rate plays an important role in the glass transitions: the fast cooling rate generates a single Tg; the intermediate cooling rate induces three Tg values, while the ultraslow cooling rate results in two Tg values. With decreasing the cooling rate, the thickness of interlayer would continually decrease, while those of the adsorbed layer and core vol. gradually increase; meanwhile, the Tg,lo gradually increases, Tg,inter almost stays const., and the Tg,hi value keeps decreasing. In such a process, the dynamic exchanges between the interlayer and adsorbed layer, core vol. should be dominant.
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    Casalini, R.; Roland, C. M. Temperature and density effects on the local segmental and global chain dynamics of poly-(oxybutylene). Macromolecules 2005, 38, 1779– 1788,  DOI: 10.1021/ma0476902
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    Temperature and Density Effects on the Local Segmental and Global Chain Dynamics of Poly(oxybutylene)
    Casalini, R.; Roland, C. M.
    Macromolecules (2005), 38 (5), 1779-1788CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Dielec. spectroscopy measurements over a broad range of temp. and pressure were carried out on poly(oxybutylene) (POB), a type A polymer (dielec. active normal mode). There are three dynamic processes appearing at lower frequency: the normal and segmental relaxation modes and a cond. arising from ionic impurities. In combination with pressure-vol.-temp. measurements, the dielec. data were used to assess the resp. roles of thermal energy and d. in controlling the relaxation times and their variation with T and P. We find that the local segmental and the global relaxation times are both a single function of the product of the temp. times the sp. vol., with the latter raised to the power of 2.65. The fact that this scaling exponent is the same for both modes indicates they are governed by the same local friction coeff., an idea common to most models of polymer dynamics. Nevertheless, near Tg, their temp. dependences diverge. The magnitude of the scaling exponent reflects the relatively weak effect of d. on the relaxation times. This is usual for polymers, as the intramol. bonding, and thus interactions between directly bonded segments, are only weakly sensitive to pressure. This insensitivity also means that the chain end-to-end distance is invariant to P, conferring a near pressure independence of the (d.-normalized) normal mode dielec. strength. The ionic cond. dominates the low-frequency portion of the spectra. At lower temps. and higher pressures, this cond. becomes decoupled from the relaxation modes (different T dependence) and exhibits a significantly weaker d. effect. At frequencies higher than the structural relaxation, both an excess wing on the flank of the α-peak and a secondary relaxation are obsd. From their relative sensitivities to pressure, we ascribe the former to an unresolved Johari-Goldstein (JG) relaxation, while the higher frequency peak is unrelated to the glass transition. These designations are consistent with the relaxation time calcd. for the JG process. The dynamic properties of the POB are essentially the same as those of poly(propylene glycol), in accord with their similar chem. structures. However, POB is less fragile (weaker Tg-normalized temp. dependence), its relaxation times are less sensitive to d. changes, and, facilitating the measurements herein, its normal mode has a substantially larger dielec. strength.
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    Kipnusu, W. K.; Elsayed, M.; Kossack, W.; Pawlus, S.; Adrjanowicz, K.; Tress, M.; Mapesa, E. U.; Krause-Rehberg, R.; Kaminski, K.; Kremer, F. Confinement for more space: A larger free volume and enhanced glassy dynamics of 2-ethyl-1-hexanol in nanopores. J. Phys. Chem. Lett. 2015, 6, 3708– 3712,  DOI: 10.1021/acs.jpclett.5b01533
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    Confinement for More Space: A Larger Free Volume and Enhanced Glassy Dynamics of 2-Ethyl-1-hexanol in Nanopores
    Kipnusu, Wycliffe K.; Elsayed, Mohamed; Kossack, Wilhelm; Pawlus, Sebastian; Adrjanowicz, Karolina; Tress, Martin; Mapesa, Emmanuel U.; Krause-Rehberg, Reinhard; Kaminski, Kamil; Kremer, Friedrich
    Journal of Physical Chemistry Letters (2015), 6 (18), 3708-3712CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
    Broadband dielec. spectroscopy and positron annihilation lifetime spectroscopy are employed to study the mol. dynamics and effective free vol. of 2-ethyl-1-hexanol (2E1H) in the bulk state and when confined in unidirectional nanopores with av. diams. of 4, 6, and 8 nm. Enhanced α-relaxations with decreasing pore diams. closer to the calorimetric glass-transition temp. (Tg) correlate with the increase in the effective free vol. This indicates that the glassy dynamics of 2D constrained 2E1H is mainly controlled by d. variation.
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    Talik, A.; Tarnacka, M.; Geppert-Rybczynska, M.; Minecka, A.; Kaminska, E.; Kaminski, K.; Paluch, M. Impact of the interfacial energy and density fluctuations on the shift of the glass-transition temperature of liquids confined in pores. J. Phys. Chem. C 2019, 123, 5549– 5556,  DOI: 10.1021/acs.jpcc.8b12551
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    Impact of the Interfacial Energy and Density Fluctuations on the Shift of the Glass-Transition Temperature of Liquids Confined in Pores
    Talik, Agnieszka; Tarnacka, Magdalena; Geppert-Rybczynska, Monika; Minecka, Aldona; Kaminska, Ewa; Kaminski, Kamil; Paluch, Marian
    Journal of Physical Chemistry C (2019), 123 (9), 5549-5556CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The behavior of the low- and high-mol. wt. glass formers confined in nanoporous templates remains an unsolved puzzle despite the intensive long-term studies in this matter. Special effort is taken to understand the enhancement of segmental or structural dynamics and the depression of the glass-transition temps., Tgs in materials infiltrated in pores of the nanometric size. In this paper, we have analyzed dielec., calorimetric, and contact angle data collected for various systems to det. which factors are responsible for these effects. It turned out that with increasing interfacial energy, mols. attached to the pore walls (interfacial layer) vitrify at higher temps. Moreover, the dynamics of core mols. starts to deviate from bulk-like behavior. Therefore, a greater depression of the glass-transition temp., Tg, of this fraction of mols. is noted. Also, it was found that the sensitivity of structural dynamics to the d. fluctuations, quantified by the pressure coeff. of the glass-transition temp., dTg/dp, is another useful parameter to predict the shift of the glass-transition temp. of the confined glass formers. The results presented herein emphasize the great importance of surface effects, which play a primary role in a unified description of the impact of the nanometric spatial restriction on the dynamics of confined materials.
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    Kaminska, E.; Tarnacka, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M. High pressure dielectric studies on the structural and orientational glass. J. Chem. Phys. 2016, 144, 054503,  DOI: 10.1063/1.4940776
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    High pressure dielectric studies on the structural and orientational glass
    Kaminska, E.; Tarnacka, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M.
    Journal of Chemical Physics (2016), 144 (5), 054503/1-054503/11CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    High pressure dielec. studies on the H-bonded liq. D-glucose and Orientationally Disordered Crystal (ODIC) 1,6-anhydro-D-glucose (levoglucosan) were carried out. It was shown that in both compds., the structural relaxation is weakly sensitive to compression. It is well reflected in the low pressure coeff. of the glass transition and orientational glass transition temps. which is equal to 60 K/GPa for both D-glucose and 1,6-anhydro-D-glucose. Although it should be noted that .vdelta.Tg0/.vdelta.p evaluated for the latter compd. seems to be enormously high with respect to other systems forming ODIC phase. We also found that the shape of the α-loss peak stays const. for the given relaxation time independently on the thermodn. condition. Consequently, the Time Temp. Pressure (TTP) rule is satisfied. This exptl. finding seems to be quite intriguing since the TTP rule was shown to work well in the van der Waals liqs., while in the strongly assocg. compds., it is very often violated. We have also demonstrated that the sensitivity of the structural relaxation process to the temp. change measured by the steepness index (mp) drops with pressure. Interestingly, this change is much more significant in the case of D-glucose with respect to levoglucosan, where the fragility changes only slightly with compression. Finally, kinetics of ODIC-crystal phase transition was studied at high compression. It is worth mentioning that in the recent paper, Tombari and Johari [J. Chem. Phys. 142, 104501 (2015)] have shown that ODIC phase in 1,6-anhydro-D-glucose is stable in the wide range of temps. and there is no tendency to form more ordered phase at ambient pressure. On the other hand, our isochronal measurements performed at varying thermodn. conditions indicated unquestionably that the application of pressure favors solid (ODIC)-solid (crystal) transition in 1,6-anhydro-D-glucose. This result mimics the impact of pressure on the crystn. of fully disordered supercooled van der Waals liqs. (c) 2016 American Institute of Physics.
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    Casalini, R.; Roland, C. M. Dielectric α-relaxation and ionic conductivity in propylene glycol and its oligomers measured at elevated pressure. J. Chem. Phys. 2003, 119, 11951,  DOI: 10.1063/1.1624401
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    Dielectric α-relaxation and ionic conductivity in propylene glycol and its oligomers measured at elevated pressure
    Casalini, Riccardo; Roland, C. Michael
    Journal of Chemical Physics (2003), 119 (22), 11951-11956CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    Structural dynamics and vol. were measured as a function of both temp. and pressure for a propylene glycol and its oligomers (PPG), and the results compared with previous data on higher mol. wt. polypropylene glycols. PPG is of special interest because the terminal groups form hydrogen bonds; thus, by studying different mol. wts., the manner in which hydrogen bonding influences the dynamics in the supercooled regime can be systematically investigated. The fragility (Tg-normalized temp. dependence) of the dimer and trimer of PPG increases with pressure, similar to results for other H-bonded liqs., but different from van der Waals glass formers. This behavior is believed to be due to the effect of pressure in decreasing the extent of hydrogen bonding. From the combined temp. and vol. dependences of the relaxation times, the relative degree to which thermal energy and vol. govern the dynamics was quantified. With decreasing mol. wt., the relative contribution of thermal energy to the dynamics was found to strongly increase, reflecting the role of hydrogen bonding. By comparing the ionic cond. and the dielec. relaxation times, a decoupling between rotational and translational motions was obsd. Interestingly, this decoupling was independent of both pressure and mol. wt., indicating that hydrogen bonds have a negligible effect on the phenomenon.
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    Atake, T.; Angell, C. A. Pressure dependence of the glass transition temperature in molecular liquids and plastic crystals. J. Phys. Chem. 1979, 83, 3218– 3223,  DOI: 10.1021/j100488a007
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    Rexrode, R. N.; Orien, J.; King, M. D. Effects of solvent stabilization on pharmaceutical crystallization: Investigating conformational polymorphism of probucol using combined solid-state density functional theory, molecular dynamics, and terahertz spectroscopy. J. Phys. Chem. A 2019, 123, 6937– 6947,  DOI: 10.1021/acs.jpca.9b00792
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    Effects of Solvent Stabilization on Pharmaceutical Crystallization: Investigating Conformational Polymorphism of Probucol Using Combined Solid-State Density Functional Theory, Molecular Dynamics, and Terahertz Spectroscopy
    Rexrode, Neilson R.; Orien, Jordan; King, Matthew D.
    Journal of Physical Chemistry A (2019), 123 (32), 6937-6947CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    Solid-state d. functional theory (DFT), mol. dynamics (MD), and terahertz (THz) spectroscopy were used to study the formation of enantiotropically related conformational Form I and Form II polymorphs of the pharmaceutical compd., probucol. DFT calcns. were performed on the crystal systems to compare relative lattice energies and the solvent stabilization of the metastable Form II structure. The thermodn. of solvent inclusion in the Form II·MeOH crystal system were detd. from MD simulations, as was the favored conformation of mol. probucol in methanol and ethanol solns. The findings from both solid-state DFT and MD calcns. suggest that the preferred mol. orientations of the probucol mol. in soln. and the probable inclusion of methanol in the crystal lattice during the crystn. process lead to the solvent selectivity of the probucol polymorph formation. The addnl. stabilization energy provided by the crystn. solvent facilitates the nucleation and growth of the Form II polymorph under conditions that favor this metastable crystal form over the thermodynamically stable Form I, despite the higher energy mol. and cryst. configurations of probucol Form II. We demonstrate the influence of solvent on the formation of pharmaceutical polymorphs and provide a mol.-level view of complex interactions leading to polymorphism using a combination of computational methods and THz spectral data.
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    Jiang, Q.; Ward, M. D. Crystallization under nanoscale confinement. Chem. Soc. Rev. 2014, 43, 2066– 2079,  DOI: 10.1039/C3CS60234F
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    Crystallization under nanoscale confinement
    Jiang, Qi; Ward, Michael D.
    Chemical Society Reviews (2014), 43 (7), 2066-2079CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Classical crystal growth models posit that crystn. outcomes are detd. by nuclei that resemble mature crystal phases, but at a crit. size where the vol. free energy of nuclei begins to offset the unfavorable surface free energy arising from the interface with the growth medium. Crystn. under nanoscale confinement offers an opportunity to examine nucleation and phase transformations at length scales corresponding to the crit. size, at which kinetics and thermodn. of nucleation and growth intersect and dramatic departures in stability compared to bulk crystals can appear. This tutorial review focuses on recent investigations of the crystn. of org. compds. in nanoporous matrixes that effectively provide millions of nanoscale reactors in a single sample, ranging from controlled porous glass (CPG) beads to nanoporous block-copolymer monoliths to anodic Al2O3 membranes. Confinement of crystal growth in this manner provides a snapshot of the earliest stages of crystal growth, with insights into nucleation, size-dependent polymorphism, and thermotropic behavior of nanoscale crystals. Moreover, these matrixes can be used to screen for crystal polymorphs and assess their stability as nanocrystals. The well-aligned cylindrical nanoscale pores of polymer monoliths or AAO also allow detn. of preferred orientation of embedded nanocrystals, affording insight into the competitive nature of nucleation, crit. sizes, and phase transition mechanisms. Collectively, these investigations have increased our understanding of crystn. at length scales that are deterministic while suggesting strategies for controlling crystn. outcomes.
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  • Abstract

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    Figure 1

    Figure 1. Dielectric loss spectra of bulk probucol (PRO) (a) and confined into AAO templates of d = 20 nm (b) and d = 10 nm (c). As the inset in panel a, the superposed dielectric spectra measured in the vicinity of Tg were presented to highlight the presence of the β-process. Additionally, in the insets to panels b and c, the normalized loss spectra collected for bulk PRO and API infiltrated into AAO pores of d = 10 nm at T = 308 K (b), which further were shifted horizontally to superpose at the maximum (c), are shown. Note that the data for the bulk sample were taken from ref (49).

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    Figure 2

    Figure 2. Temperature dependences of α-relaxation times for bulk PRO and API confined into AAO templates of various pore sizes. Black solid and red dashed lines are the best fits using VFT and Arrhenius equations, respectively. Inset: τα(T)-dependences obtained for PRO infiltrated into AAO membranes of d = 10 nm measured using two different protocols. Note that τα(T)-dependences determined for PRO within AAO templates of d = 80 nm are presented in Figure S2.

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    Figure 3

    Figure 3. (a) DSC thermograms collected for PRO infiltrated into AAO templates of d = 10 nm measured at two different cooling rates, 2 and 20 K/min, with the following 10 K/min heating rate. (b) DSC thermograms of the crystalline bulk sample and PRO infiltrated into AAO membranes of various pore size (d = 40–120 nm), measured on heating with rate 10 K/min from RT well above the melting temperature of bulk API.

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    Figure 4

    Figure 4. (a) FTIR spectra obtained in the wavenumber region of 3675–3475 cm–1 of a confined PRO within AAO membrane (d = 10 nm). The sample was heated to 343 K at a heating rate 10 K min–1, held for 5 min at this temperature and then cooled to Tanneal = 308 K at different cooling rates (5, 10, 15, 20, and 30 K min–1). Arrows indicate the direction of band intensity changes with decreasing cooling rate. b) Time-dependent FTIR spectra of a confined PRO within AAO membrane (d = 10 nm) obtained in the wavenumber region of 3800–3020 cm–1. The melted samples were cooled to Tanneal = 308 K with a constant cooling rate of 20 K min–1. The arrow indicates the direction of band intensity changes with increasing time.

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    Figure 5

    Figure 5. Comparison of X-ray diffraction patterns of bulk PRO sample together with pure references of I and II polymorphic forms (a) and PRO confined into AAO template (d = 80 nm) just after 1 and 50 days of sample storage together with the data for neat AAO membrane (b).

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  • References

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      Pharmaceutical cocrystn. affords an opportunity to modify the physicochem. properties of a solid-state drug without covalent modification of its mol. structure. This review presents an update on various applications of pharmaceutical cocrystn. with considerations on both cocrystals and salts, focusing on the property modification relevant to clin. efficacy and safety, and manufacturability of drugs. Some prominent examples of drug cocrystals/salts, which exhibit improved soly. and/or permeability and pharmacokinetics, stability and mechanic properties, are highlighted.
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    10. 10
      Saito, M.; Ugajin, T.; Nozawa, Y.; Sadzuka, Y.; Miyagishima, A.; Sonobe, T. Preparation and dissolution characteristics of griseofulvin solid dispersions with saccharides. Int. J. Pharm. 2002, 249, 71– 79,  DOI: 10.1016/S0378-5173(02)00455-6
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      Preparation and dissolution characteristics of griseofulvin solid dispersions with saccharides
      Saito, Masataka; Ugajin, Takashi; Nozawa, Yasuo; Sadzuka, Yasuyuki; Miyagishima, Atsuo; Sonobe, Takashi
      International Journal of Pharmaceutics (2002), 249 (1-2), 71-79CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)
      To improve the soly. of poorly water-sol. drugs, we studied phys. characteristics of griseofulvin (GF) solid dispersions with saccharides as the dispersion carrier using a roll mixing method. In all carriers tested, roll mixts. of GF and saccharides gradually became amorphous, and the soly. of GF increased. The soly. of GF was higher in the mixts. with higher mol. wt. carriers such as corn starch and processed starch. The dissoln. of GF was markedly improved by the GF-British gum roll mixt. The initial dissoln. rate of these mixts. was 170-fold higher than GF alone. The surface tension of carrier aq. solns. was low in the processed starch with branched sugar chains. The initial dissoln. rate of GF in phys. mixts. was correlated with the surface tension of carrier aq. solns. The stability of the amorphous state of GF at a high humidity was maintained in the mixts. with carriers with a high mol. wt. The soly. of GF was markedly improved in the roll mixts. The saccharides with a high mol. wt. are useful carriers for solid dispersions.
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      Kawakami, K. Recent progress in solid dispersion technology. Pharmaceutics; MDPI: 2019.
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      Zhou, D.; Zhang, G. G. Z.; Law, D.; Grant, D.W. J.; Schmitt, E. A. Physical stability of amorphous pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility. J. Pharm. Sci. 2002, 91, 1863– 1872,  DOI: 10.1002/jps.10169
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      Physical stability of amorphous pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility
      Zhou, Deliang; Zhang, Geoff G. Z.; Law, Devalina; Grant, David J. W.; Schmitt, Eric A.
      Journal of Pharmaceutical Sciences (2002), 91 (8), 1863-1872CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
      This work relates the thermodn. quantities (Gc, Hc, and Sc) and the mol. mobility values (1/τ) of five structurally diverse amorphous compds. to their crystn. behavior. The model compds. included: ritonavir, ABT-229, fenofibrate, sucrose, and acetaminophen. Modulated temp. DSC was used to measure the heat capacities as a function of temp. for the amorphous and cryst. phases of each compd. Knowledge of the heat capacities and fusion data allowed calcn. of the configurational thermodn. quantities and the Kauzmann temps. (TK) using established relationships. The mol. relaxation time consts. (τ) were then calcd. from the Vogel-Tammann-Fulcher representation of the Adam-Gibbs model. Amorphous samples were heated at 1 K/min and a reduced crystn. temp., defined as (Tc-Tg)/(Tm-Tg), was used to compare crystn. tendencies. Crystn. was obsd. for all compds. except ritonavir. The configurational free energy values (Gc) show that thermodn. driving forces for crystn. follow the order: ritonavir > acetaminophen ≈ fenofibrate > sucrose > ABT-229. The entropic barrier to crystn., which is inversely related to the probability that the mols. are in the proper orientation, followed the order: ritonavir > fenofibrate > ABT-229 > acetaminophen ≈ sucrose. Mol. mobility values, which are proportional to mol. collision rates, followed the order: acetaminophen > fenofibrate > sucrose > ABT-229 ≈ ritonavir. Crystn. studies under non-isothermal conditions revealed that compds. with the highest entropic barriers and lowest mobilities were most difficult to crystallize, regardless of the thermodn. driving forces. This investigation demonstrates the importance of both configurational entropy and mol. mobility to understanding the phys. stability of amorphous pharmaceuticals.
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      Hancock, B. C.; Zografi, G. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 1997, 86, 1– 12,  DOI: 10.1021/js9601896
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      Characteristics and Significance of the Amorphous State in Pharmaceutical Systems
      Hancock, Bruno C.; Zografi, George
      Journal of Pharmaceutical Sciences (1997), 86 (1), 1-12CODEN: JPMSAE; ISSN:0022-3549. (American Chemical Society)
      A review with 134 refs. The amorphous state is crit. in detg. the solid-state phys. and chem. properties of many pharmaceutical dosage forms. This review describes the characteristics of the amorphous state and some of the most common methods that can be used to measure them. Examples of pharmaceutical situations where the presence of the amorphous state plays an important role are presented. The application of the current knowledge to pharmaceutical formulation problems is illustrated, and some strategies for working with amorphous character in pharmaceutical systems are provided.
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      Wyttenbach, N.; Kuentz, M. Glass-forming ability of compounds in marketed amorphous drug products. Eur. J. Pharm. Biopharm. 2017, 112, 204– 208,  DOI: 10.1016/j.ejpb.2016.11.031
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      Glass-forming ability of compounds in marketed amorphous drug products
      Wyttenbach, Nicole; Kuentz, Martin
      European Journal of Pharmaceutics and Biopharmaceutics (2017), 112 (), 204-208CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
      This note is about the glass-forming ability (GFA) of drugs marketed as amorphous solid dispersions or as pure amorphous compds. A thermoanal. method was complemented with an in silico study, which made use of mol. properties that were identified earlier as being relevant for GFA. Thus, molar volume together with effective nos. of torsional bonds and hydrogen bonding were used to map drugs that are as amorphous products on the market either as solid dispersion of without co-processed carrier as amorphous drug in a solid dosage form. Differential scanning calorimetry expts. showed that most compds. were stable glass formers (GFs) (class III) followed by so-called unstable GFs (class II) and finally, only vemurafenib was found in class I with increased crystn. propensity. The in silico results, however showed that all drugs were either clearly in the chem. space expected for GFs or they were borderline to the region that holds for high crystn. tendency. Interestingly, the pure amorphous compds. scattered in a very confined region of the mol. predictors. These findings can guide amorphous product development of future drug candidates. Based on the compd. location in the given chem. space, amorphous formulation opportunities can be balanced against the risks of phys. instability upon storage.
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      Yu, L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv. Drug Delivery Rev. 2001, 48, 27– 42,  DOI: 10.1016/S0169-409X(01)00098-9
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      Amorphous pharmaceutical solids: preparation, characterization and stabilization
      Yu, L.
      Advanced Drug Delivery Reviews (2001), 48 (1), 27-42CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science Ireland Ltd.)
      A review with 114 refs. The importance of amorphous pharmaceutical solids lies in their useful properties, common occurrence, and physicochem. instability relative to corresponding crystals. Some pharmaceuticals and excipients have a tendency to exist as amorphous solids, while others require deliberate prevention of crystn. to enter and remain in the amorphous state. Amorphous solids can be produced by common pharmaceutical processes, including melt quenching, freeze- and spray-drying, milling, wet granulation, and drying of solvated crystals. The characterization of amorphous solids reveals their structures, thermodn. properties, and changes (crystn. and structural relaxation) in single- and multi-component systems. Current research in the stabilization of amorphous solids focuses on: (i) the stabilization of labile substances (e.g., proteins and peptides) during processing and storage using additives, (ii) the prevention of crystn. of the excipients that must remain amorphous for their intended functions, and (iii) the selection of appropriate storage conditions under which amorphous solids are stable.
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    16. 16
      Grzybowska, K.; Paluch, M.; Włodarczyk, P.; Grzybowski, A.; Kaminski, K.; Hawelek, L.; Zakowiecki, D.; Kasprzycka, A.; Jankowska-Sumara, I. Enhancement of amorphous celecoxib stability by mixing it with octaacetylmaltose: The molecular dynamics study. Mol. Pharmaceutics 2012, 9, 894– 904,  DOI: 10.1021/mp200436q
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      16
      Enhancement of Amorphous Celecoxib Stability by Mixing It with Octaacetylmaltose: The Molecular Dynamics Study
      Grzybowska, K.; Paluch, M.; Wlodarczyk, P.; Grzybowski, A.; Kaminski, K.; Hawelek, L.; Zakowiecki, D.; Kasprzycka, A.; Jankowska-Sumara, I.
      Molecular Pharmaceutics (2012), 9 (4), 894-904CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      In this paper, the authors present a novel way of stabilization of amorphous celecoxib (CEL) against recrystn. by prepg. binary amorphous celecoxib-octaacetylmaltose (CEL-acMAL) systems by quench-cooling of the molten phase. As far as the authors know this is the first application of carbohydrate derivs. with acetate groups to enhance the stability of an amorphous drug. CEL in the amorphous mixt. with acMAL is characterized by a much better soly. than pure CEL. Very promising results of the long-term measurements of stability of the CEL-acMAL binary amorphous system with small amt. of stabilizer during its storage at room temp. were reported. Moreover, the effect of adding acMAL on mol. dynamics of CEL in the wide temp. range in both the supercooled liq. and glassy states were examd. The mol. mobility of the mixt. of CEL with 10 wt.% acMAL in the glassy state is much more limited than that in the case of pure CEL, which correlates with the better stability of the amorphous binary system. By dielec. measurements and theor. calcns. within the framework of d. functional theory (DFT), the role of acMAL in enhancing the stability of amorphous CEL in mixts. was studied and postulated which interactions between CEL and acMAL mols. can be responsible for preventing devitrification.
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    17. 17
      Schammé, B.; Couvrat, N.; Tognetti, V.; Delbreilh, L.; Dupray, V.; Dargent, E.; Coquerel, G. Investigation of drug-excipient interactions in biclotymol amorphous solid dispersions. Mol. Pharmaceutics 2018, 15, 1112– 1125,  DOI: 10.1021/acs.molpharmaceut.7b00993
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      17
      Investigation of Drug-Excipient Interactions in Biclotymol Amorphous Solid Dispersions
      Schamme, Benjamin; Couvrat, Nicolas; Tognetti, Vincent; Delbreilh, Laurent; Dupray, Valerie; Dargent, Eric; Coquerel, Gerard
      Molecular Pharmaceutics (2018), 15 (3), 1112-1125CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      The effect of low mol. wt. excipients on drug-excipient interactions, mol. mobility, and propensity to recrystn. of an amorphous active pharmaceutical ingredient is investigated. Two structurally related excipients (α-pentaacetylglucose and β-pentaacetylglucose), five different drug:excipient ratios (1:5, 1:2, 1:1, 2:1, and 5:1, wt./wt.), and three different solid state characterization tools (differential scanning calorimetry, X-ray powder diffraction, and dielec. relaxation spectroscopy) were selected for the present research. Our investigation has shown that the excipient concn. and its mol. structure reveal quasi-identical mol. dynamic behavior of solid dispersions above and below the glass transition temp. Across to complementary quantum mech. simulations, we point out a clear indication of a strong interaction between biclotymol and the acetylated saccharides. Moreover, the thermodn. study on these amorphous solid dispersions highlighted a stabilizing effect of α-pentaacetylglucose regardless of its quantity while an excessive concn. of β-pentaacetylglucose revealed a poor crystn. inhibition. Finally, through long-term stability studies, we also showed the limiting excipient concn. needed to stabilize our amorphous API. Herewith, the developed procedure in this paper appears to be a promising tool for solid-state characterization of complex pharmaceutical formulations.
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    18. 18
      Kaminska, E.; Adrjanowicz, K.; Tarnacka, M.; Kolodziejczyk, K.; Dulski, M.; Mapesa, E. U.; Zakowiecki, D.; Hawełek, Ł.; Kaczmarczyk-Sedlak, I.; Kaminski, K. Impact of inter- and intramolecular interactions on the physical stability of indomethacin dispersed in acetylated saccharides. Mol. Pharmaceutics 2014, 11, 2935– 2947,  DOI: 10.1021/mp500286b
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      18
      Impact of Inter- and Intramolecular Interactions on the Physical Stability of Indomethacin Dispersed in Acetylated Saccharides
      Kaminska, E.; Adrjanowicz, K.; Tarnacka, M.; Kolodziejczyk, K.; Dulski, M.; Mapesa, E. U.; Zakowiecki, D.; Hawelek, L.; Kaczmarczyk-Sedlak, I.; Kaminski, K.
      Molecular Pharmaceutics (2014), 11 (8), 2935-2947CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Differential scanning calorimetry (DSC), broadband dielec. (BDS), and Fourier transform IR (FTIR) spectroscopies as well as theor. computations were applied to investigate inter- and intramol. interactions between the active pharmaceutical ingredient (API) indomethacin (IMC) and a series of acetylated saccharides. It was found that solid dispersions formed by modified glucose and IMC are the least phys. stable of all studied samples. Dielec. measurements showed that this finding is related to neither the global nor local mobility, as the two were fairly similar. On the other hand, combined studies with the use of d. functional theory (DFT) and FTIR methods indicated that, in contrast to acetylated glucose, modified disaccharides (maltose and sucrose) interact strongly with indomethacin. As a result, internal H-bonds between IMC mols. become very weak or are eventually broken. Simultaneously, strong H-bonds between the matrix and API are formed. This observation was used to explain the phys. stability of the investigated solid dispersions. Finally, soly. measurements revealed that the soly. of IMC can be enhanced by the use of acetylated carbohydrates, although the obsd. improvement is marginal due to strong interactions.
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    19. 19
      Madejczyk, O.; Kaminska, E.; Tarnacka, M.; Dulski, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M. Studying the crystallization of various polymorphic forms of nifedipine from binary mixtures with the use of different experimental techniques. Mol. Pharmaceutics 2017, 14, 2116– 2125,  DOI: 10.1021/acs.molpharmaceut.7b00228
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      19
      Studying the Crystallization of Various Polymorphic Forms of Nifedipine from Binary Mixtures with the Use of Different Experimental Techniques
      Madejczyk, O.; Kaminska, E.; Tarnacka, M.; Dulski, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M.
      Molecular Pharmaceutics (2017), 14 (6), 2116-2125CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      In this paper the crystal growth of nifedipine from pure system and from binary mixts. composed of active substance (API) and two acetylated disaccharides, maltose and sucrose (NIF-acMAL, NIF-acSUC, 5:1 wt. ratio), was investigated. Optical snapshots supported by X-ray diffraction (XRD) and Fourier transform IR spectroscopy (FTIR) measurements showed that mainly β and α forms of nifedipine grow up in all investigated samples. They also revealed that the morphol. of growing crystals strongly depends on the presence of modified carbohydrates and temp. conditions. Interestingly, it was found that the activation barrier for the crystal growth of the β polymorph is not affected by acetylated saccharides while the one estd. for the α form changes significantly from 48.5 kJ/mol (pure API) up to 122 kJ/mol (NIF-acMAL system). Moreover, the relationship between the crystal growth rate and structural relaxation times for pure NIF and solid dispersions were analyzed. It turned out that there is a clear decoupling between the crystal growth rate and structural dynamics in both NIF-acMAL and NIF-acSUC binary mixts. This is in line with recent reports indicating the decoupling phenomenon to be a universal feature of soft matter in the close vicinity of the glass transition temp.
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    20. 20
      Minecka, A.; Kamińska, E.; Tarnacka, M.; Jurkiewicz, M.; Talik, A.; Wolnica, K.; Dulski, M.; Kasprzycka, A.; Spychalska, P.; Garbacz, G. Does the molecular mobility and flexibility of the saccharide ring affect the glass-forming ability of naproxen in binary mixtures?. Eur. J. Pharm. Sci. 2020, 141, 105091,  DOI: 10.1016/j.ejps.2019.105091
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      20
      Does the molecular mobility and flexibility of the saccharide ring affect the glass-forming ability of naproxen in binary mixtures
      Minecka, A.; Kaminska, E.; Tarnacka, M.; Jurkiewicz, K.; Talik, A.; Wolnica, K.; Dulski, M.; Kasprzycka, A.; Spychalska, P.; Garbacz, G.; Kaminski, K.; Paluch, M.
      European Journal of Pharmaceutical Sciences (2020), 141 (), 105091CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
      In this paper, we studied the impact of saccharides having a similar backbone but differing in the degree of freedom, local mol. mobility, flexibility of the ring and intermol. interactions on the glass-forming ability (GFA) of naproxen (NAP) in binary mixts. For this purpose, a series of Me and acetyl derivs. of glucose (GLS) and anhydroglucose (anhGLS), as well as neat anhGLS have been used to produce homogeneous solid dispersions (SDs) of varying molar concn. of examd. active pharmaceutical ingredient (API). Systematic measurements with the use of Differential Scanning Calorimetry (DSC) and Broadband Dielec. Spectroscopy (BDS) enabled us to det. the phase transitions, homogeneity and mol. mobility of the investigated binary mixts. as well as the impact of excipient on the crystn. tendency of NAP. Finally, since addnl. measurements with the use of Fourier Transform IR (FTIR) Spectroscopy clearly indicated that there are no significant differences in the intermol. interactions in the systems composed of NAP and all examd. saccharides, one can postulate that the mobility and ring flexibility of the matrix have, the most important impact on the crystn. tendency of NAP upon cooling. Consequently, it seems that in some cases, more mobile/flexible matrixes can be a much better choice to enhance the glass-forming ability of studied pharmaceutical.
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      Taylor, L. S.; Zografi, G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm. Res. 1997, 14, 1691– 1698,  DOI: 10.1023/A:1012167410376
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      Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions
      Taylor, Lynne S.; Zografi, George
      Pharmaceutical Research (1997), 14 (12), 1691-1698CODEN: PHREEB; ISSN:0724-8741. (Plenum Publishing Corp.)
      The mol. structure of indomethacin-PVP amorphous solid dispersions was studied and specific interactions between the components was identified using vibrational spectroscopy. Solid dispersions of PVP and indomethacin were prepd. using a solvent evapn. technique and IR and FT-Raman spectra were obtained. A comparison of the carbonyl stretching region of γ indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of α indomethacin is not as dimers. Addn. of PVP to amorphous indomethacin increased the intensity of the IR band assigned to non-hydrogen bonded carbonyl. Concomitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a soln. of indomethacin in methylpyrrolidone at the same wt. percent. Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystn. kinetics by preventing the self assocn. of indomethacin mols. The similarity of results for solid dispersions and solns. emphasizes the "soln." nature of this binary amorphous state.
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    22. 22
      Wegiel, L. A.; Mauer, L. I.; Edgar, K. J.; Taylor, L. S. Crystallization of amorphous solid dispersions of resveratrol during preparation and storage—impact of different polymers. J. Pharm. Sci. 2013, 102, 171– 184,  DOI: 10.1002/jps.23358
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      22
      Crystallization of amorphous solid dispersions of resveratrol during preparation and storage-Impact of different polymers
      Wegiel, Lindsay A.; Mauer, Lisa J.; Edgar, Kevin J.; Taylor, Lynne S.
      Journal of Pharmaceutical Sciences (2013), 102 (1), 171-184CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
      The objective of this study was to investigate intermol. interactions between resveratrol and polymers in amorphous blends and to study the potential correlations between compd.-polymer interactions, manufacturability, and stability of the amorphous system to crystn. during storage. Polymers included two grades of poly (vinylpyrrolidone) (PVP), Eudragit E100 (E100), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), CM-cellulose acetate butyrate, and poly (acrylic acid) (PAA). Amorphous blends ("solid dispersions") were prepd. by dissolving both resveratrol and polymer in a solvent followed by rotary evapn. Crystallinity was evaluated using X-ray powder diffraction and was studied as a function of time. Mid-IR (IR) spectroscopy was used to investigate resveratrol-polymer interactions. Polymer influence on the crystn. behavior of resveratrol varied and could be correlated to the polymer structure, whereby polymers with good hydrogen bond acceptor groups performed better as crystn. inhibitors. Resveratrol-polymer hydrogen bonding interactions could be inferred from the IR spectra. Somewhat surprisingly, E100 and resveratrol showed evidence of an acid-base reaction, in addn. to intermol. hydrogen bonding interactions. PVP K29/32 appeared to form stronger hydrogen bond interactions with resveratrol relative to HPMC, HPMCAS, and PAA, consistent with acceptor group chem. Long-term stability of the systems against crystn. suggested that stability is linked to the type and strength of intermol. interactions present, whereby resveratrol blended with E100 and PVP K29/32 showed the greatest stability to crystn. In conclusion, amorphous resveratrol is unstable and difficult to form, requiring the assistance of a polymeric crystn. inhibitor to facilitate the formation of an amorphous solid dispersion. Polymers effective at inhibiting crystn. were identified, and it is rationalized that their effectiveness is based on the type and strength of their intermol. interactions with resveratrol. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    23. 23
      Khodaverdi, K.; Khalili, N.; Zangiabadi, F.; Homayouni, A. Preparation, characterization and stability studies of glassy solid dispersions of indomethacin using pvp and isomalt as carriers. Iran J. Basic Med. Sci. 2012, 15, 820– 832
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      23
      Preparation, characterization and stability studies of glassy solid dispersions of indomethacin using PVP and isomalt as carriers
      Khodaverdi, Elham; Khalili, Noman; Zangiabadi, Farzad; Homayouni, Alireza
      Iranian Journal of Basic Medical Sciences (2012), 15 (3), 820-832CODEN: IJBMCQ; ISSN:2008-3866. (Mashhad University of Medical Sciences)
      Objective(s) The purpose of the present study was to use the solid dispersion (SD) technique to improve the dissoln. rates of indomethacin (IMC). Materials and Methods IMC solid dispersions in PVP K30 and isomalt (GALEN IQ 990) were prepd. using the solvent evapn. technique and a hot melt method in wt. ratios of 2, 10 and 30% (IMC:PVP). Solid dispersions and phys. mixts. were characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and dissoln. test. Phys. stability tests were also performed at different temps. and humidity conditions. Results The dissoln. rates of all solid dispersions were faster than those of their phys. mixts. In samples contg. 2% or 10% of IMC, there were no significant differences between the dissoln. rates of IMC in PVP and isomalt solid dispersions, but in samples contg. 30% of IMC, the dissoln. rates were higher in isomalt dispersions. The XRPD anal. showed no cryst. peaks in solid dispersions, indicating that IMC was amorphous within the carrier. The DSC results showed that an interaction occurred between the drug and the carrier in PVP and isomalt dispersions. Phys. stability tests at severe storage conditions showed that the dissoln. rate of IMC in PVP solid dispersions decreased, while the dissoln. profile of IMC in isomalt solid dispersions did not change significantly. Conclusion It was shown that the dissoln. rates of IMC in PVP and isomalt solid dispersions were substantially increased compared with their phys. mixts. and pure IMC.
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    24. 24
      Sun, Y.; Tao, J.; Zhang, G. G. Z.; Yu, L. Solubilities of crystalline drugs in polymers: An improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc. J. Pharm. Sci. 2010, 99, 4023– 4031,  DOI: 10.1002/jps.22251
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      24
      Solubilities of crystalline drugs in polymers: an improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc
      Sun, Ye; Tao, Jing; Zhang, Geoff G. Z.; Yu, Lian
      Journal of Pharmaceutical Sciences (2010), 99 (9), 4023-4031CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
      A previous method for measuring solubilities of cryst. drugs in polymers has been improved to enable longer equilibration and used to survey the solubilities of indomethacin (IMC) and nifedipine (NIF) in two homo-polymers [polyvinyl pyrrolidone (PVP) and polyvinyl acetate (PVAc)] and their co-polymer (PVP/VA). These data are important for understanding the stability of amorphous drug-polymer dispersions, a strategy actively explored for delivering poorly sol. drugs. Measuring solubilities in polymers is difficult because their high viscosities impede the attainment of soly. equil. In this method, a drug-polymer mixt. prepd. by cryo-milling is annealed at different temps. and analyzed by differential scanning calorimetry to det. whether undissolved crystals remain and thus the upper and lower bounds of the equil. soln. temp. The new annealing method yielded results consistent with those obtained with the previous scanning method at relatively high temps., but revised slightly the previous results at lower temps. It also lowered the temp. of measurement closer to the glass transition temp. For D-mannitol and IMC dissolving in PVP, the polymer's mol. wt. has little effect on the wt.-based soly. For IMC and NIF, the dissolving powers of the polymers follow the order PVP > PVP/VA > PVAc. In each polymer studied, NIF is less sol. than IMC. The activities of IMC and NIF dissolved in various polymers are reasonably well fitted to the Flory-Huggins model, yielding the relevant drug-polymer interaction parameters. The new annealing method yields more accurate data than the previous scanning method when soly. equil. is slow to achieve. In practice, these two methods can be combined for efficiency. The measured solubilities are not readily anticipated, which underscores the importance of accurate exptl. data for developing predictive models. © 2010 Wiley-Liss, Inc. and the American Pharmacists Assocn. J Pharm Sci 99:4023-4031, 2010.
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    25. 25
      Zhao, M.; Barker, S. A.; Belton, P. S.; McGregor, C.; Craig, D. Q. M. Development of fully amorphous dispersions of a low Tg drug via co-spray drying with hydrophilic polymers. Eur. J. Pharm. Biopharm. 2012, 82, 572– 579,  DOI: 10.1016/j.ejpb.2012.07.012
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      25
      Development of fully amorphous dispersions of a low Tg drug via co-spray drying with hydrophilic polymers
      Zhao, Min; Barker, Susan A.; Belton, Peter S.; McGregor, Caroline; Craig, Duncan Q. M.
      European Journal of Pharmaceutics and Biopharmaceutics (2012), 82 (3), 572-579CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
      The aim of the study was to prep. mol. dispersions of a phys. highly unstable amorphous drug, paracetamol (acetaminophen with a Tg of ca. 25 °C) via co-spray drying with a variety of polymers. Solid dispersions at a range of drug loadings (10-90%wt./wt.) using hydroxypropyl methylcellulose/acetate succinate (HPMC/HPMC AS), polyvinylpyrrolidone (PVP) and copovidone were produced and characterized by modulated temp. differential scanning calorimetry (MTDSC), thermogravimetric anal. (TGA), X-ray powder diffraction (XRPD), Fourier transform IR spectroscopy (FTIR) and SEM (SEM). PVP-based polymers showed a greater tendency than the HPMC-based group to generate temp.-stable dispersions. In particular, copovidone (Plasdone S-630) was found to be the most effective of the polymers studied and could formulate mol. dispersions at drug loadings up to and including 40%wt./wt. However, no evidence for direct drug-polymer interactions was found for such systems as a possible stabilizing mechanism. The expected relationship of a higher Tg of the polymer leading to greater stabilization was not obsd., while there was an inverse relationship between viscosity grade and amorphous phase generation. The study has therefore shown that temp.-stable amorphous dispersions of a low Tg drug may be prepd. by co-spray drying, particularly using PVP-based polymers.
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    26. 26
      Löbmann, K.; Grohganz, H.; Laitinen, R.; Strachan, C.; Rades, T. Amino acids as co-amorphous stabilizers for poorly water soluble drugs – Part 1: Preparation, stability and dissolution enhancement. Eur. J. Pharm. Biopharm. 2013, 85, 873– 881,  DOI: 10.1016/j.ejpb.2013.03.014
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      26
      Amino acids as co-amorphous stabilizers for poorly water soluble drugs - Part 1: Preparation, stability and dissolution enhancement
      Lobmann, Korbinian; Grohganz, Holger; Laitinen, Riikka; Strachan, Clare; Rades, Thomas
      European Journal of Pharmaceutics and Biopharmaceutics (2013), 85 (3PB), 873-881CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
      Poor aq. soly. of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical research and development because up to 90% of new API candidates under development are poorly water sol. These drugs usually have a low and variable oral bioavailability, and therefore an unsatisfactory therapeutic effect. One of the most promising approaches to increase dissoln. rate and soly. of these drugs is the conversion of a cryst. form of the drug into its resp. amorphous form, usually by incorporation into hydrophilic polymers, forming glass solns. However, this strategy only led to a small no. of marketed products usually because of inadequate phys. stability of the drug (crystn.). In this study, we investigated a fundamentally different approach to stabilize the amorphous form of drugs, namely the use of amino acids as small mol. wt. excipients that form specific mol. interactions with the drug resulting in co-amorphous forms. The two poorly water sol. drugs carbamazepine and indomethacin were combined with amino acids from the binding sites of the biol. receptors of these drugs. Mixts. of drug and the amino acids arginine, phenylalanine, tryptophan and tyrosine were prepd. by vibrational ball milling. Solid-state characterization with X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) revealed that the various blends could be prepd. as homogeneous, single phase co-amorphous formulations indicated by the appearance of an amorphous halo in the XRPD diffractograms and a single glass transition temp. (Tg) in the DSC measurements. In addn., the Tgs of the co-amorphous mixts. were significantly increased over those of the individual drugs. The drugs remained chem. stable during the milling process and the co-amorphous formulations were generally phys. stable over at least 6 mo at 40 °C under dry conditions. The dissoln. rate of all co-amorphous drug-amino acid mixts. was significantly increased over that of the resp. cryst. and amorphous pure drugs. Amino acids thus appear as promising excipients to solve challenges connected with the stability and dissoln. of amorphous drugs.
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      Löbmann, K.; Laitinen, R.; Strachan, C.; Rades, T.; Grohganz, H. Amino acids as co-amorphous stabilizers for poorly water-soluble drugs – Part 2: Molecular interactions. Eur. J. Pharm. Biopharm. 2013, 85, 882– 888,  DOI: 10.1016/j.ejpb.2013.03.026
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      27
      Amino acids as co-amorphous stabilizers for poorly water-soluble drugs - Part 2: Molecular interactions
      Lobmann, Korbinian; Laitinen, Riikka; Strachan, Clare; Rades, Thomas; Grohganz, Holger
      European Journal of Pharmaceutics and Biopharmaceutics (2013), 85 (3PB), 882-888CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
      The formation of co-amorphous drug-drug mixts. has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissoln. of poorly water-sol. drugs. Mol. interactions in these co-amorphous formulations can play a crucial role in stabilization and dissoln. enhancement. In this regard, Fourier-transform IR spectroscopy (FTIR) is a valuable tool to analyze the mol. near range order of the compds. in the co-amorphous mixts. In this study, several co-amorphous drugs - low mol. wt. excipient blends - have been analyzed with FTIR spectroscopy. Mol. interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biol. target site of both drugs and prepd. as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed anal. of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biol. target site was present in the blends. These peak shifts indicate that the drugs formed specific mol. interactions (hydrogen bonding and π-π interactions) with the amino acids. In the drug-amino acid mixts. that contained amino acids which were not present at the biol. target site, no such interactions were identified. This study shows the potential of amino acids as small mol. wt. excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-sol. drug through strong and specific mol. interactions with the drug.
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    28. 28
      Jensen, K. T.; Löbmann, K.; Rades, T.; Grohganz, H. Improving co-amorphous drug formulations by the addition of the highly water soluble amino acid, proline. Pharmaceutics 2014, 6, 416– 435,  DOI: 10.3390/pharmaceutics6030416
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      28
      Improving Co-amorphous drug formulations by the addition of the highly water soluble amino acid, proline
      Jensen, Katrine Tarp; Loebmann, Korbinian; Rades, Thomas; Grohganz, Holger
      Pharmaceutics (2014), 6 (3), 416-435CODEN: PHARK5; ISSN:1999-4923. (MDPI AG)
      Co-amorphous drug amino acid mixts. were previously shown to be a promising approach to create phys. stable amorphous systems with the improved dissoln. properties of poorly water-sol. drugs. The aim of this work was to expand the co-amorphous drug amino acid mixt. approach by combining the model drug, naproxen (NAP), with an amino acid to phys. stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly sol. amino acid (proline, PRO) for an addnl. improvement of the dissoln. rate. Co-amorphous drug-amino acid blends were prepd. by ball milling and investigated for solid state characteristics, stability and the dissoln. rate enhancement of NAP. All co-amorphous mixts. were stable at room temp. and 40 °C for a min. of 84 days. PRO acted as a stabilizer for the co-amorphous system, including NAP-TRP, through enhancing the mol. interactions in the form of hydrogen bonds between all three components in the mixt. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP-ARG. In comparison to cryst. NAP, binary NAP-TRP and NAP-ARG, it could be shown that the highly sol. amino acid, PRO, improved the dissoln. rate of NAP from the ternary co-amorphous systems in combination with either TRP or ARG. In conclusion, both the soly. of the amino acid and potential interactions between the mols. are crit. parameters to consider in the development of co-amorphous formulations.
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    29. 29
      Cordeiro, T.; Castiñeira, C.; Mendes, D.; Danède, F.; Sotomayor, J.; Fonseca, I. M.; Gomes da Silva, M.; Paiva, A.; Barreiros, S.; Cardoso, M. M. Stabilizing unstable amorphous menthol through inclusion in mesoporous silica hosts. Mol. Pharmaceutics 2017, 14, 3164– 3177,  DOI: 10.1021/acs.molpharmaceut.7b00386
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      29
      Stabilizing Unstable Amorphous Menthol through Inclusion in Mesoporous Silica Hosts
      Cordeiro, Teresa; Castineira, Carmem; Mendes, Davide; Danede, Florence; Sotomayor, Joao; Fonseca, Isabel M.; Gomes da Silva, Marco; Paiva, Alexandre; Barreiros, Susana; Cardoso, M. Margarida; Viciosa, Maria T.; Correia, Natalia T.; Dionisio, Madalena
      Molecular Pharmaceutics (2017), 14 (9), 3164-3177CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      The amorphization of the readily crystallizable therapeutic ingredient and food additive, menthol, was successfully achieved by inclusion of neat menthol in mesoporous silica matrixes of 3.2 and 5.9 nm size pores. Menthol amorphization was confirmed by the calorimetric detection of a glass transition. The resp. glass transition temp., Tg = -54.3 °C, is in good agreement with the one predicted by the compn. dependence of the Tg values detd. for menthol:flurbiprofen therapeutic deep eutectic solvents (THEDESs). Nonisothermal crystn. was never obsd. for neat menthol loaded into silica hosts, which can indicate that menthol rests as a full amorphous/supercooled material inside the pores of the silica matrixes. Menthol mobility was probed by dielec. relaxation spectroscopy, which allowed to identify two relaxation processes in both pore sizes: a faster one assocd. with mobility of neat-like menthol mols. (α-process), and a slower, dominant one due to the hindered mobility of menthol mols. adsorbed at the inner pore walls (S-process). The fraction of mol. population governing the α-process is greater in the higher (5.9 nm) pore size matrix, although in both cases the S-process is more intense than the α-process. A dielec. glass transition temp. was estd. for each α (Tg,dielc(α)) and S (Tg,dielc(S)) mol. population from the temp. dependence of the relaxation times to 100 s. While Tg,dielc(α) agrees better with the value obtained from the linearization of the Fox equation assuming ideal behavior of the menthol:flurbiprofen THEDES, Tg,dielc(S) is close to the value detd. by calorimetry for the silica composites due to a dominance of the adsorbed population inside the pores. Nevertheless, the greater fraction of more mobile bulk-like mols. in the 5.9 nm pore size matrix seems to det. the faster drug release at initial times relative to the 3.2 nm composite. However, the latter inhibits crystn. inside pores since its dimensions are inferior to menthol crit. size for nucleation. This points to a suitability of these composites as drug delivery systems in which the drug release profile can be controlled by tuning the host pore size.
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    30. 30
      Cordeiro, T.; Santos, A. F. M.; Nunes, G.; Cunha, G.; Sotomayor, J. C.; Fonseca, I. M.; Danède, F.; Dias, C. J.; Cardoso, M. M.; Correia, N. T. Accessing the physical state and molecular mobility of naproxen confined to nanoporous silica matrixes. J. Phys. Chem. C 2016, 120, 14390– 14401,  DOI: 10.1021/acs.jpcc.6b04078
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      30
      Accessing the Physical State and Molecular Mobility of Naproxen Confined to Nanoporous Silica Matrixes
      Cordeiro, Teresa; Santos, Andreia F. M.; Nunes, Guilherme; Cunha, Guilherme; Sotomayor, Joao C.; Fonseca, Isabel M.; Danede, Florence; Dias, C. J.; Cardoso, M. Margarida; Correia, Natalia T.; Viciosa, M. Teresa; Dionisio, Madalena
      Journal of Physical Chemistry C (2016), 120 (26), 14390-14401CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The pharmaceutical drug naproxen was loaded in three different silica hosts with pore diams. of 2.4 (MCM), 3.2 (MCM), and 5.9 nm (SBA), resp.: napMCM_2.4 nm, napMCM_3.2 nm, and napSBA_5.9 nm. To access the guest phys. state in the prepd. composites, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and attenuated total reflectance Fourier transform IR spectroscopy were used. The different techniques provided complementary information on a mol. population that was revealed to be distributed among different environments, namely the pore core, the inner pore wall, and the outer surface. It was found that naproxen is semicryst. in the higher pore size matrix being able to crystallize inside pores; after melting it undergoes full amorphization. In the case of the lower pore size matrix, naproxen crystallizes outside pores due to an excess of filling while most of the remaining fraction is incorporated inside the pores as amorphous. Crystallinity in these two composites was obsd. by the emergence of the Bragg peaks in the XRD anal., whereas for napMCM_3.2 nm only the amorphous halo was detected. The latter only exhibits the step due to the glass transition by DSC remaining stable as amorphous at least for 12 mo. The glass transition in the three composites is abnormally broad, shifting to higher temps. as the pore size decreases, coherent with the slowing down of mol. mobility as probed by dielec. relaxation spectroscopy. For napSBA_5.9 nm the dielec. response was deconvoluted in two processes: a hindered surface (S-) process due to mols. interacting with the inner pore wall and a faster α-relaxation assocd. with the dynamic glass transition due to mols. relaxing in the pore core, which seems a manifestation of true confinement effects. The drug incorporation inside a nanoporous matrix, mainly in 3.2 nm pores, was revealed to be a suitable strategy to stabilize the highly crystallizable drug naproxen in the amorphous/supercooled state and to control its release from the silica matrix, allowing full delivery after 90 min in basic media.
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      Bras, A. R.; Merino, E. G.; Neves, P. D.; Fonseca, I. M.; Dionísio, M. A.; Schonhals, A.; Correia, N. T. Amorphous ibuprofen confined in nanostructured silica materials: A dynamical approach. J. Phys. Chem. C 2011, 115, 4616– 4623,  DOI: 10.1021/jp107631m
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      Amorphous ibuprofen confined in nanostructured silica materials: A dynamical approach
      Bras, Ana R.; Merino, Esther G.; Neves, Paulo D.; Fonseca, Isabel M.; Dionisio, Madalena; Schonhals, Andreas; Correia, Natalia T.
      Journal of Physical Chemistry C (2011), 115 (11), 4616-4623CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The mol. mobility of condensed matter confined to nanometer dimensions can be dramatically changed from those of the bulk state in such a way that, when the guest is a drug, it can be advantageously used in pharmaceutical applications. We show by dielec. relaxation spectroscopy that the mol. mobility of the important ibuprofen drug embedded in nanoporous SBA-15 is significantly influenced by the confinement. An evidence of the existence of two families of mols. with different mol. mobilities is provided and investigated in their temp. dependence. One family is due to mols. close to the pores' center with a higher mobility compared with the bulk at low temps., and another family with slower dynamics originated from mols. interacting with the pore walls. The work reports the simultaneous manifestation of true confinement and surface effects in this nanostructured silica host for a drug. For future applications in drug delivery systems, the dynamics detd. by the guest-host interplay and the one of the bulklike mols. can be tuned to achieve a desired release profile.
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      Braś, A. R.; Fonseca, I. M.; Dionísio, M.; Schönhals, A.; Affouard, F.; Correia, N. T. Influence of nanoscale confinement on the molecular mobility of ibuprofen. J. Phys. Chem. C 2014, 118, 13857– 13868,  DOI: 10.1021/jp500630m
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      Influence of Nanoscale Confinement on the Molecular Mobility of Ibuprofen
      Bras, Ana R.; Fonseca, Isabel M.; Dionisio, Madalena; Schonhals, Andreas; Affouard, Frederic; Correia, Natalia T.
      Journal of Physical Chemistry C (2014), 118 (25), 13857-13868CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The mol. mobility of ibuprofen confined to a mesoporous silica host (MCM-41) of 3.6 nm pore diam. is investigated by dielec. relaxation spectroscopy. It is confirmed that crystn. is suppressed; therefore, depending on the temp., the guest exists in the glassy and supercooled state inside of the pores. A detailed relaxation map is provided where multiple processes are dynamically characterized, comprised of three processes that are also found for the bulk and two addnl. ones. The bulk-like processes include two secondary processes, a simple thermally activated one, a γ process and a Johari-Goldstein βJG process, and the one assocd. with the dynamic glass transition of mols. located in the pore center (α process). In confinement, all of these processes display deviations in its dynamical behavior relative to the bulk, the most dramatic one undergone by the α process, which exhibits Arrhenius-like temp. dependence upon approaching the glass transition instead of Vogel/Fulcher/Tammann/Hesse (VFTH) scaling as obeyed by the bulk. The two addnl. relaxations are assocd. with the dynamical behavior of hydrogen-bonded ibuprofen mols. lying in an interfacial layer near the pore wall, an S process for which the mobility is strongly reduced relative to the α process and a Debye-like D process for which the dynamics is closely correlated to the dynamics of the interfacial process, both exhibiting VFTH temp. dependencies. The comparison with the behavior of the same guest in the analogous host, SBA-15, with a higher pore diam. (8.6 nm) leads to the conclusion that the bulk-like mobility assocd. with the dynamic glass transition undergoes finite size effects being accelerated upon a decrease of the pore size with a concomitant redn. of the glass transition temp. relative to the bulk, 22 and 32 K, resp., for the 8.6 and 3.6 nm pore diams. The continuous decrease in the sepn. between the α- and βJG-trace with pore size decrease allows one to conclude that confined ibuprofen is a suitable guest mol. to test the Coupling Model that predicts a transformation of the α process into a βJG-mode under conditions of an extreme nanoconfinement. The overall behavior inside of pores is consistent with the existence of two distinct dynamical domains, originated by ibuprofen mols. in the core of the pore cavity and adjacent to the pore wall, from which a clear picture is given by mol. dynamics simulation.
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      Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Jurkiewicz, K.; Stankiewicz, A.; Paluch, M. Stabilization of the amorphous ezetimibe drug by confining its dimension. Mol. Pharmaceutics 2016, 13, 1308– 1316,  DOI: 10.1021/acs.molpharmaceut.5b00903
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      Stabilization of the Amorphous Ezetimibe Drug by Confining Its Dimension
      Knapik, J.; Wojnarowska, Z.; Grzybowska, K.; Jurkiewicz, K.; Stankiewicz, A.; Paluch, M.
      Molecular Pharmaceutics (2016), 13 (4), 1308-1316CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      The purpose of this paper is to investigate the influence of nanoconfinement on the mol. mobility, as well as on the phys. stability, of amorphous ezetimibe drug. Two guest/host systems, ezetimibe-Aeroperl 300 and ezetimibe-Neusilin US2, were prepd. and studied using various exptl. techniques, such as X-ray diffraction (XRD), differential scanning calorimetry (DSC), and broadband dielec. spectroscopy (BDS). Our investigation has shown that the mol. mobility of the examd. anticholesterol agent incorporated into nanopore matrixes strongly depends on the pore size of the host system. Moreover, it was found that the amorphous ezetimibe confined in 30 nm pores of Aeroperl 300 has a tendency to recrystallize, while the drug incorporated into the smaller-5 nm-pores of Neusilin US2 is not able to crystallize. It has been shown that this significant stabilization of ezetimibe drug can be achieved by an interplay of three factors: changes in mol. dynamics of the confined amorphous drug, the immobilization effect of pore walls on a part of ezetimibe mols., and the use of host materials with pores that are smaller than the crit. size of the drug crystal nuclei.
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      Szklarz, G.; Adrjanowicz, K.; Tarnacka, M.; Pionteck, J.; Paluch, M. Confinement-induced changes in the glassy dynamics and crystallization behavior of supercooled fenofibrate. J. Phys. Chem. C 2018, 122, 1384– 1395,  DOI: 10.1021/acs.jpcc.7b10946
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      34
      Confinement-Induced Changes in the Glassy Dynamics and Crystallization Behavior of Supercooled Fenofibrate
      Szklarz, Grzegorz; Adrjanowicz, Karolina; Tarnacka, Magdalena; Pionteck, Jurgen; Paluch, Marian
      Journal of Physical Chemistry C (2018), 122 (2), 1384-1395CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Here, we have studied the effect of spatial restrictions on the mol. dynamics and crystn. behavior of modeled lipophilic drug fenofibrate incorporated into nanoporous aluminum oxide membranes of different pore size. Our measurements demonstrate that, on subsequent cooling, dynamics of confined liq. split up into two distinct fractions, due to the presence of core and interfacial layers. At the temp., at which vitrification of the interfacial layer takes place (Tg_interface), departure from the bulk-like behavior occurs, and mols. in the center of the pores enter quasi-isochoric conditions. Depending on the thermal protocol and pore size, the vol. fixed at Tg_interface might be a bit different so as the core liq.'s dynamics. Interestingly, below that temp., the nanoconfined liq. can still obey the fundamental d. scaling relation (1/TVγ), just like in the bulk phase, while not necessarily isochronal superposition. This is in contrast to a common observation that the validity of the d. scaling in bulk glass-forming systems always goes together with isochronal superposition of the α-relaxation, and vice versa. Finally, our careful anal. of the crystn. kinetics as a function of lowering pore diam. indicates for systematic slowing down crystn. progress, the shift of the max. crystn. rate toward higher undercooling and decrease in the dimensionality of growing crystals.
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    35. 35
      Minecka, A.; Kaminska, E.; Tarnacka, M.; Grudzka-Flak, I.; Bartoszek, M.; Wolnica, K.; Dulski, M.; Kaminski, K.; Paluch, M. The impact of intermolecular interactions, dimeric structures on the glass forming ability of naproxen and a series of its derivatives. Mol. Pharmaceutics 2018, 15, 4764– 4776,  DOI: 10.1021/acs.molpharmaceut.8b00725
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      35
      Impact of Intermolecular Interactions, Dimeric Structures on the Glass Forming Ability of Naproxen, and a Series of Its Derivatives
      Minecka, Aldona; Kaminska, Ewa; Tarnacka, Magdalena; Grudzka-Flak, Iwona; Bartoszek, Mariola; Wolnica, Kamila; Dulski, Mateusz; Kaminski, Kamil; Paluch, Marian
      Molecular Pharmaceutics (2018), 15 (10), 4764-4776CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      In this article, thermal properties, mol. dynamics, crystn. kinetics, and intermol. interactions in pure naproxen (NAP), its amide (NH2-NAP), and four esters (Me, Met-NAP; iso-Pr, Iso-NAP; hexyl, Hex-NAP; and benzyl, Ben-NAP) have been investigated using differential scanning calorimetry as well as broadband dielec. and Fourier transform IR spectroscopies. We found that the modification of the NAP mol. by substituting a hydrogen atom from the hydroxyl group strongly inhibits the crystn. tendency of this active pharmaceutical ingredient (API) and simultaneously increases its glass forming ability (GFA). In this context, it is worthwhile to stress that pure naproxen and its amide crystd. very quickly, regardless of the cooling rate. Therefore, these compds. cannot be classified as good glass-formers. On the other hand, ester derivs. of API can be easily vitrified. Moreover, dielec. measurements revealed that with an increasing mol. wt. of the substituent, the rate of crystn. process slows down significantly. Consequently, Ben-NAP was characterized by the highest GFA among all investigated API esters. Comprehensive FTIR studies clearly indicated that the strong tendency to create dimeric structures in the nonmodified NAP and NH2-NAP is responsible for their enhanced crystn. At the first sight, our results stay in contrast to most literature data, showing that H-bonds favor the glass formation ability. However, this effect is usually obsd. for the materials, which form extensive multidirectional hydrogen bonds and assocs. In NAP and NH2-NAP, the situation is much different, since both compds. exist mainly as dimers. Therefore, one can postulate that specific intermol. interactions are an important parameter detg. the GFA of different materials, including APIs.
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      Suzuki, Y.; Duran, H.; Steinhart, M.; Kappl, M.; Butt, H.-J.; Floudas, G. Homogeneous nucleation of predominantly cubic ice confined in nanoporous alumina. Nano Lett. 2015, 15, 1987– 1992,  DOI: 10.1021/nl504855z
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      Homogeneous Nucleation of Predominantly Cubic Ice Confined in Nanoporous Alumina
      Suzuki, Yasuhito; Duran, Hatice; Steinhart, Martin; Kappl, Michael; Butt, Hans-Juergen; Floudas, George
      Nano Letters (2015), 15 (3), 1987-1992CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      The nucleation mechanism of water can be precisely regulated by confinement within nanoporous alumina. We found a transition from heterogeneous nucleation of hexagonal ice (Ih) to homogeneous nucleation of predominantly cubic ice (Ic) with decreasing pore diam. These results lead to a phase diagram of water under confinement. It contains a (stable) predominant Ic form, a form known to exist only in the upper atm. Possible applications range from cryopreservation to construction materials like cement.
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      Suzuki, Y.; Steinhart, M.; Graf, R.; Butt, H.-J.; Floudas, G. Dynamics of ice/water confined in nanoporous alumina. J. Phys. Chem. B 2015, 119, 14814– 14820,  DOI: 10.1021/acs.jpcb.5b08751
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      Dynamics of Ice/Water Confined in Nanoporous Alumina
      Suzuki, Yasuhito; Steinhart, Martin; Graf, Robert; Butt, Hans-Juergen; Floudas, George
      Journal of Physical Chemistry B (2015), 119 (46), 14814-14820CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Dielec. spectroscopy (DS), IR spectra, and 1H MAS NMR spectra are employed in the study of ice/water confined in nanoporous alumina with pore diams. ranging from 400 nm down to 25 nm. Within nanoporous alumina there is a transformation from heterogeneous nucleation of hexagonal ice in the larger pores to homogeneous nucleation of cubic ice in the smaller pores. DS and IR show excellent agreement in the temp. interval and pore size dependence of the transformation. DS further revealed two dynamic processes under confinement. The "fast" and "slow" processes with an Arrhenius temp. dependence are attributed to ice and supercooled water relaxation, resp. The main relaxation process of ice under confinement ("slow" process) has an activation energy of 44 ± 2 kJ/mol. The latter is in agreement with the reported relaxation times and activation energy of cubic ice prepd. following a completely different route (by pressure). 1H MAS NMR provided new insight in the state of ice structures as well as of supercooled water. Under confinement, a layer of liq.-like water coexists with ice structures. In addn., both ice structures under confinement appear to be more ordered than bulk hexagonal ice. Supercooled water in the smaller pores is different from bulk water. It shows a shift of the signal toward higher chem. shift values which may suggest stronger hydrogen bonding between the water mols. or increasing interactions with the AAO walls.
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      Yao, Y.; Fella, V.; Huang, W.; Zhang, K. A. I.; Landfester, K.; Butt, H.-J.; Vogel, M.; Floudas, G. Crystallization and dynamics of water confined in model mesoporous silica particles: Two ice nuclei and two fractions of water. Langmuir 2019, 35, 5890– 5901,  DOI: 10.1021/acs.langmuir.9b00496
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      Crystallization and Dynamics of Water Confined in Model Mesoporous Silica Particles: Two Ice Nuclei and Two Fractions of Water
      Yao, Yang; Fella, Verena; Huang, Wei; Zhang, Kai A. I.; Landfester, Katharina; Butt, Hans-Juergen; Vogel, Michael; Floudas, George
      Langmuir (2019), 35 (17), 5890-5901CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      The crystn. and dynamics of water confined in model mesoporous silica particles (pore diams. ranging from 2.1 to 5 nm; pore length ≈ 1 μm) are studied in homogeneous aq. suspensions by dielec. spectroscopy, differential scanning calorimetry, and NMR techniques. We establish the phase diagram (T vs. 1/d) of confined water covering a broad range of pore diams. A linear dependence of the heterogeneous and the homogeneous nucleation temps. on the inverse pore diam. is shown. The two lines converge at a pore diam. of ∼2.6 nm, below which formation of stable crystals is suppressed. By combining dielec. spectroscopy and different NMR techniques, we det. the dynamics of water within mesoporous silica over broad temp. and frequency ranges. Both techniques identify two dynamically distinguishable fractions of confined water coexisting within the pores. We attribute the two fractions to an interfacial water layer at the pore walls and confined water in the pore interior. Two alternative scenarios are proposed to rationalize the coexistence of two dynamically distinguishable water fractions. In the first scenario, two liq. fractions of water coexist under extreme confinement conditions for a range of temps.; we discuss similarities with the two ultraviscous liqs. (high-d. liq. and low-d. liq.) put forward for supercooled bulk water. In the second scenario, a liq. and a solid phase coexist; we conjecture that highly distorted and unstable crystal nuclei exist under extreme confinement that exhibit reorientation dynamics with time scales intermediate to the surrounding confined liq. and to bulk ice.
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      Jackson, C. L.; Mckenna, G. B. The melting behavior of organic materials confined in porous solids. J. Chem. Phys. 1990, 93, 9002– 9011,  DOI: 10.1063/1.459240
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      The melting behavior of organic materials confined in porous solids
      Jackson, Catheryn L.; McKenna, Gregory B.
      Journal of Chemical Physics (1990), 93 (12), 9002-11CODEN: JCPSA6; ISSN:0021-9606.
      The solid-liq. phase transition temps. and heats of fusion ΔHf of nonpolar org. solids confined in the pores of controlled pore glasses were measured by DSC. The pore diams. (d) were in the range 40-730 Å and the orgs. studied were cis-decalin, trans-decalin, cyclohexane, benzene, chlorobenzene, naphthalene, and heptane. In accordance with previous studies of primarily inorg. materials, the m.p. of the pore solid T(d) decreased with decreasing pore diam. In addn., a large redn. in the bulk enthalpy of fusion ΔHf of the pore solid was measured, which apparently has not been studied in detail by other workers. A linear correlation was found between the m.p. depression (ΔTm) and the reciprocal diam., as predicted by theories of solidification in a capillary. The calcd. values of the solid-liq. interfacial energy σsl were in reasonable agreement with values reported in the literature based on other methods of measurement.
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      Bishara, H.; Berger, S. Polymorphism and piezoelectricity of glycine nano-crystals grown inside alumina nano-pores. J. Mater. Sci. 2019, 54, 4619– 4625,  DOI: 10.1007/s10853-018-03211-y
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      Polymorphism and piezoelectricity of glycine nano-crystals grown inside alumina nano-pores
      Bishara, Hanna; Berger, Shlomo
      Journal of Materials Science (2019), 54 (6), 4619-4625CODEN: JMTSAS; ISSN:0022-2461. (Springer)
      Glycine nanocrystals were grown inside alumina nanopores due to a pptn. process from over-satd. aq. liq. solns. The α-glycine polymorph crystals were formed at a higher over-satn. concn. than that of the β-glycine polymorph crystals. The results indicate that the type of the glycine polymorph formed inside the alumina pores is kinetically controlled. A model is suggested to explain the competition between formations of the two polymorphs inside nano-pores. The β-glycine polymorph crystals are distinguished from the α-glycine polymorph crystals not only by XRD measurements but mainly by piezoelec. measurements, where only the non-centro-sym. β-glycine polymorph crystals show a piezoelec. current response to applied mech. pressures as low as 1 Pa in the environmental pressure of 1 atm (10-3% pressure change).
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      Rengarajan, G. T.; Enke, D.; Beiner, M. Crystallization behavior of acetaminophen in nanopores. Open Phys. Chem. J. 2007, 1, 18– 24,  DOI: 10.2174/1874067700701010018
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      Crystallization behavior of acetaminophen in nanopores
      Rengarajan, Gopalakrishnan T.; Enke, Dirk; Beiner, Mario
      Open Physical Chemistry Journal (2007), 1 (), 18-24CODEN: OPCJAQ; ISSN:1874-0677. (Bentham Science Publishers Ltd.)
      The influence of nanoconfinement on the crystn. behavior of acetaminophen, a polymorphic drug occurring in three different cryst. forms, is investigated. Differential scanning calorimetry (DSC) and wide angle X-ray scattering (WAXS) data for a series of controlled porous glasses (CPGs) filled with acetaminophen are presented. The results show clearly that (i) the usually inaccessible cryst. form III of acetaminophen can be produced in pores with diams. between 22 and 103 nm and that (ii) the life time of amorphous acetaminophen is significantly increased in 10 nm pores. Bulk melting temp. and heat of melting of form III are estd. based on the Gibbs-Thomson equation. The exptl. findings are confronted with the predictions of theor. approaches aimed to describe thermodn. and crystn. kinetics in nano-sized systems in order to understand the phys. background of the obsd. changes.
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      Kołodziejczyk, K.; Tarnacka, M.; Kaminska, E.; Dulski, M.; Kaminski, K.; Paluch, M. The crystallization’s kinetic under confinement. Manipulation of the crystalline form of salol by varying pore diameter. Cryst. Growth Des. 2016, 16, 1218– 1227,  DOI: 10.1021/acs.cgd.5b01181
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      Crystallization Kinetics under Confinement. Manipulation of the Crystalline Form of Salol by Varying Pore Diameter
      Kolodziejczyk, Karolina; Tarnacka, Magdalena; Kaminska, Ewa; Dulski, Mateusz; Kaminski, Kamil; Paluch, Marian
      Crystal Growth & Design (2016), 16 (3), 1218-1227CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      The crystn. and melting behavior of Ph salicylate under confinement were studied by dielec. spectroscopy (BDS) and DSC. From the anal. of the kinetics of crystn. crystals formed in bulk and under confinement are characterized by varying the rate of growth, dimensionality, and crystal lattice. Depending on the degree of confinement the crystn. can be accelerated or suppressed completely. The activation barrier for the crystn. either increases or decreases with respect to the bulk conditions. Further study of the melting temp. of the formed crystals indicated unequivocally that it is connected to the formation of different polymorphic forms of salol. FTIR measurements confirmed that thesis. Based on calorimetric data obtained for the confined samples, at pores of higher diam. the unstable (monoclinic) form is preferred, while at lower pores the original stable (orthorhombic) crystal is formed.
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      Adrjanowicz, K.; Kolodziejczyk, K.; Kipnusu, W. K.; Tarnacka, M.; Mapesa, E. U.; Kaminska, E.; Pawlus, S.; Kaminski, K.; Paluch, M. Decoupling between the interfacial and core molecular dynamics of salol in 2D confinement. J. Phys. Chem. C 2015, 119, 14366– 14374,  DOI: 10.1021/acs.jpcc.5b01391
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      Decoupling between the Interfacial and Core Molecular Dynamics of Salol in 2D Confinement
      Adrjanowicz, Karolina; Kolodziejczyk, Karolina; Kipnusu, Wycliffe Kiprop; Tarnacka, Magdalena; Mapesa, Emmanuel Urandu; Kaminska, Ewa; Pawlus, Sebastian; Kaminski, Kamil; Paluch, Marian
      Journal of Physical Chemistry C (2015), 119 (25), 14366-14374CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Dielec. spectroscopy and differential scanning calorimetry (DSC) were applied to study the mol. dynamics and thermal properties of a low-mol.-wt. glass-forming liq., salol (Ph salicylate), confined in anodic aluminum oxide membranes of different pore diams. (100-13 nm). On increasing the geometrical confinement, the glass transition temp. shifts toward lower temps., while at the same time broadening of the shape of the structural relaxation is obsd. This was attributed to the interplay between surface and confinement effects leading to the transition from Vogel-Fulcher-Tammann-like to Arrhenius-like dependence of the structural relaxation times. We have noticed that the temp. of such crossover agrees with the endothermic process detected by DSC. Combined dielec. and calorimetric data have indicated that this phenomenon is related to the decoupling of the dynamics of mols. attached to the pore walls and those at the center. The enhancement of the structural relaxation of the core mols. increases with decreasing pore size possibly due to changes in the packing d. This finding gives a new insight into the behavior of glass-forming liqs. under confinement and helps in the understand of the characteristic shift of the dynamic glass transition temp. with decreasing of the pore diam.
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      Tarnacka, M.; Kipnusu, W. K.; Kaminska, E.; Pawlus, S.; Kaminski, K.; Paluch, M. The peculiar behavior of the molecular dynamics of a glass-forming liquid confined in native porous materials – the role of negative pressure. Phys. Chem. Chem. Phys. 2016, 18, 23709– 23714,  DOI: 10.1039/C6CP03923E
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      The peculiar behavior of the molecular dynamics of a glass-forming liquid confined in native porous materials - the role of negative pressure
      Tarnacka, Magdalena; Kipnusu, Wycliffe K.; Kaminska, Ewa; Pawlus, Sebastian; Kaminski, Kamil; Paluch, Marian
      Physical Chemistry Chemical Physics (2016), 18 (34), 23709-23714CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      In this paper, we combine Broadband Dielec. Spectroscopy (BDS) at ambient and high pressure, and positron annihilation lifetime spectroscopy (PALS) data of 2-ethylhexanol in the bulk state and when infiltrated in native silica nanopores to elucidate the relative role of surface effects on the Debye and structural relaxation processes under 2D spatial constraints. We show that the two processes have different sensitivities to (i) the changes in d. as quantified by the EV/Hp ratio and (ii) the degree of confinement. Significant enhancement of the dynamics of the confined mols. at low temps. is related to the vitrification of the interfacial mols. (Tg,int) affecting the packing d. of the core mols. This is corroborated by the PALS measurements, which demonstrated that the effective vol. for the confined samples is slightly higher and seems to be temp. invariant below Tg,int. Consequently, neg. pressure systematically develops with lowering temp. reaching values of -100 and -110 MPa (depending on the pore size) at the glass transition temp. This result offers a better understanding of the counterbalance between surface and finite size effects as well as the role of neg. pressure in controlling the dynamics and the glass transition of liqs. under 2D spatial restrictions.
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    46. 46
      Kipnusu, W. K.; Elmahdy, M. M.; Elsayed, M.; Krause-Rehberg, R.; Kremer, F. Counterbalance between surface and confinement effects as studied for amino-terminated poly(propylene glycol) constraint in silica nanopores. Macromolecules 2019, 52, 1864– 1873,  DOI: 10.1021/acs.macromol.8b02687
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      Counterbalance between Surface and Confinement Effects As Studied for Amino-Terminated Poly(propylene glycol) Constraint in Silica Nanopores
      Kipnusu, Wycliffe K.; Elmahdy, Mahdy M.; Elsayed, Mohamed; Krause-Rehberg, Reinhard; Kremer, Friedrich
      Macromolecules (Washington, DC, United States) (2019), 52 (4), 1864-1873CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Broadband dielec. spectroscopy (BDS) and orthopositronium annihilation lifetime spectroscopy (PALS) are combined to study the mol. dynamics and the free vol. of poly(propylene glycol) terminated with amino end groups (PPG-NH2) in the bulk state and when confined in native and silanized unidirectional silica nanopores with av. diams. of 4, 6, and 8 nm. In the bulk state, three dielec. relaxation processes are obsd.: (1) the fast β-relaxation assigned to the librational fluctuations of the -O-NH2 moiety, (2) the α-process corresponding to the dynamic glass transition, and (3) the (slower) chain dynamics or normal mode (NM) relaxation. Under confinement in native nanopores, the β-process becomes slower, while the α and the normal mode relaxation processes become faster and broader and demonstrate a lower dielec. strength with decreasing pore diam. In silanized nanopores the normal and β-processes are nearly bulklike, but the α-process still remains faster than bulk closer to the Tg. All these findings can be comprehended as controlled by the counterbalance between surface and confinement effects. The former are caused by attractive interactions with the solid walls of the nanopores (resulting in an addnl. slower process which is removed after silanization), and the latter are caused by an increase of the free vol. of the polymer segments due to a less efficient packing as proven by orthopositronium annihilation lifetime spectroscopy. These results conform to the cooperative free vol. model (CFV).
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      Morineau, D.; Xia, Y.; Alba-Simionesco, C. Finite-size and surface effects on the glass transition of liquid toluene confined in cylindrical mesopores. J. Chem. Phys. 2002, 117, 8966– 8972,  DOI: 10.1063/1.1514664
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      Finite-size and surface effects on the glass transition of liquid toluene confined in cylindrical mesopores
      Morineau, Denis; Xia, Yongde; Alba-Simionesco, Christiane
      Journal of Chemical Physics (2002), 117 (19), 8966-8972CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      Some of the most regular porous silicates (MCM-41 and SBA-15), with several different pore diams. from 2.4 to 8.7 nm, are used to study the van der Waals fragile liq. toluene in confined geometry. We measure two major macroscopic signatures of a glass transition, i.e., a discontinuous change in the heat capacity and in the thermal expansion, by adiabatic calorimetry and neutron scattering expts. A nontrivial size dependence of the glass transition features, most notably a nonmonotonic variation of the mean glass transition temp., is obsd. The range of the glass transition is found extremely broad. This supports the notion of competition between surface boundary conditions and cutoff or finite-size effects.
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      Lau, M.; Giri, K.; Garcia-Bennett, A. E. Antioxidant properties of probucol released from mesoporous silica. Eur. J. Pharm. Sci. 2019, 138, 105038,  DOI: 10.1016/j.ejps.2019.105038
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      Antioxidant properties of probucol released from mesoporous silica
      Lau, Michael; Giri, Kalpeshkumar; Garcia-Bennett, Alfonso E.
      European Journal of Pharmaceutical Sciences (2019), 138 (), 105038CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
      Antioxidants play a vital role in scavenging reactive oxygen species (ROS) produced by the redn. of mol. oxygen from various cellular mechanisms. Drug compds. with potent antioxidant properties are typically poorly water sol. and highly hydrophobic. In this study, PB was loaded in mesoporous silica at various drug loadings to understand the changes to the phys. properties of the loaded drug, and it's in vitro drug release. Further in vitro studies were conducted in endothelial and microglia cell models to compare the free radical scavening efficiency of ascorbic acid, PB, and PB release from mesoporous silica particles. Out of the three different mesostructured particles studied, the max. loading of PB was achieved for large pore mesoporous particles (SBA-15) at 50 wt% drug loading, before complete pore filling was obsd. For all materials, loadings above complete pore filling resulted in the recrystn. of PB on the external surface. In vitro drug release measurements showed a rapid dissoln. rate at low drug loadings compared to a bimodal release profile of amorphous and cryst. drug at higher drug loadings. PB loaded in mesoporous particle was shown to enhance the antioxidant response to extracellular ROS in the endothelial cell line model, and to intracellular ROS in the microglia cell model. Our results indicate that the antioxidant properties of PB can be significantly improved by using mesoporous silica as a delivery vehicle.
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      Kamińska, E.; Minecka, A.; Tarnacka, M.; Kamiński, K.; Paluch, M. Breakdown of the isochronal structural (α) and secondary (JG β) exact superpositioning in probucol - A low molecular weight pharmaceutical. J. Mol. Liq. 2020, 299, 112169,  DOI: 10.1016/j.molliq.2019.112169
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      Breakdown of the isochronal structural (a) and secondary (JG β) exact superpositioning in probucol - A low molecular weight pharmaceutical
      Kaminska, E.; Minecka, A.; Tarnacka, M.; Kaminski, K.; Paluch, M.
      Journal of Molecular Liquids (2020), 299 (), 112169CODEN: JMLIDT; ISSN:0167-7322. (Elsevier B.V.)
      In this paper, Broadband Dielec. Spectroscopy (BDS) has been applied to study the mol. dynamics of the two active pharmaceutical ingredients (APIs), probucol (PRO) and droperidol (DRO), above and below the glass transition temp., at varying thermodn. conditions. We found that the structural (a)-relaxation process in both compds. is sensitive to compression. In this context, it is worthwhile to emphasize that dTg/dp calcd. for the latter API is the highest reported to date for the low mol. wt. glass formers. Furthermore, the data collected upon squeezing samples revealed that the pressure dependence of the relaxation times of the Johari Goldstein (JG) β-process in PRO is weaker with respect to that of structural relaxation. This phenomenon, which is consistent with the approx. invariance of the ratio of these two relaxation times to change of thermodn. conditions (as predicted by the Coupling Model), was assigned to the increasing torsional rigidity of the macromol. backbone or alternatively to the non-uniform responses to variations of temp. and pressure of the distributed modes composing the JG β-process, resulting in changes of the spectral shape and different fβ(p,T) obtained from the fitting procedure. Finally, the data reported herein emphasize the impact of mol. aspects related to specific interactions on the correlation between a- and JG β-relaxation at varying T and p conditions.
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      Iacob, C.; Sangoro, J. R.; Papadopoulos, P.; Schubert, T.; Naumov, S.; Valiullin, R.; Karger, J.; Kremer, F. Charge transport and diffusion of ionic liquids in nanoporous silica membranes. Phys. Chem. Chem. Phys. 2010, 12, 13798,  DOI: 10.1039/c004546b
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      Charge transport and diffusion of ionic liquids in nanoporous silica membranes
      Iacob, Ciprian; Sangoro, Joshua Rume; Papadopoulos, Periklis; Schubert, Tilman; Naumov, Sergej; Valiullin, Rustem; Kaerger, Joerg; Kremer, Friedrich
      Physical Chemistry Chemical Physics (2010), 12 (41), 13798-13803CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      Charge transport in 1-hexyl-3-methylimidazolium hexafluorophosphate ionic liq. in oxidized nanoporous silicon membranes was studied in a wide frequency and temp. range by a combination of Broadband Dielec. Spectroscopy (BDS) and Pulsed Field Gradient NMR (PFG NMR). By applying the Einstein-Smoluchowski relations to the dielec. spectra, diffusion coeff. was obtained in quant. agreement with independent PFG NMR measurements. More than 10-fold systematic decrease in the effective diffusion coeff. from the bulk value is obsd. in hydrophilic silica nanopores. A model assuming a reduced mobility at the pore-matrix interface provides a quant. explanation for the remarkable decrease of effective transport quantities (such as diffusion coeff., d.c. cond. and consequently, the dielec. loss) of the ionic liq. in nonsilanized membranes. This approach is supported by the observation that silanization of porous silica membranes results in a significant increase of the effective diffusion coeff., which approaches the value for the bulk liq.
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      Kipnusu, W. K.; Kossack, W.; Iacob, C.; Jasiurkowska, M.; Rume Sangoro, J.; Kremer, F. Molecular order and dynamics of tris(2ethylhexyl)phosphate confined in uni-directional nanopores. Z. Phys. Chem. 2012, 226, 797– 805,  DOI: 10.1524/zpch.2012.0287
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      Molecular order and dynamics of tris(2-ethylhexyl)phosphate confined in uni-directional nanopores
      Kipnusu, Wycliffe Kiprop; Kossack, Wilhem; Iacob, Ciprian; Jasiurkowska, Malgorzata; Sangoro, Joshua Rume; Kremer, Friedrich
      Zeitschrift fuer Physikalische Chemie (Muenchen, Germany) (2012), 226 (7-8), 797-805CODEN: ZPCFAX; ISSN:0942-9352. (Oldenbourg Wissenschaftsverlag GmbH)
      IR Transition Moment Orientational Anal. (IR-TMOA) and Broadband Dielec. Spectroscopy (BDS) are combined to study mol. order and dynamics of the glass-forming liq. Tris(2-ethylhexy)phosphate (TEHP) confined in uni-directional nanopores with diams. of 4, 8, and 10.4 nm. The former method enables one to det. the mol. order parameter of specific IR transition moments. It is obsd. that the central P=O moiety of TEHP has a weak orientational effect (mol. order parameter Sz = -0.1 ± 0.04) due the nanoporous confinement, in contrast to the terminal C-H groups. BDS traces the dynamic glass transition of the guest mols. in a broad spectral range and at widely varying temp. An enhancement of the mobility takes place when approaching the glass transition temp. and becomes more pronounced with decreasing pore diam. This is attributed to a slight redn. of the d. of the confined liq. caused by the 2-dimensional geometrical constraint.
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      Alexandris, S.; Papadopoulos, P.; Sakellariou, G.; Steinhart, M.; Butt, H.-J.; Floudas, G. Interfacial energy and glass temperature of polymers confined to nanoporous alumina. Macromolecules 2016, 49, 7400– 7414,  DOI: 10.1021/acs.macromol.6b01484
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      Interfacial Energy and Glass Temperature of Polymers Confined to Nanoporous Alumina
      Alexandris, Stelios; Papadopoulos, Periklis; Sakellariou, Georgios; Steinhart, Martin; Butt, Hans-Jurgen; Floudas, George
      Macromolecules (Washington, DC, United States) (2016), 49 (19), 7400-7414CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      We report on the effect of interfacial energy on the glass temp., Tg, of several amorphous polymers with various glass temps. and polymer/substrate interactions confined within self-ordered nanoporous alumina (AAO). The polymers studied include poly(phenylmethylsiloxane) (PMPS), poly(vinyl acetate) (PVAc), 1,4-polybutadiene (PB), oligostyrene (PS), and poly(dimethylsiloxane) (PDMS). The segmental dynamics and assocd. Tg's are studied by means of dielec. spectroscopy. The interfacial energy for the polymer/substrate interface, γSL, is calcd. with Young's equation whereas the AAO membrane surface energy is obtained by measuring contact angles for several ref. liqs. We find that interfacial energy plays a significant role in the segmental dynamics of polymers under confinement within AAO. There is a trend for a decreasing glass temp. relative to the bulk with increasing interfacial energy. PDMS exhibits the highest interfacial energy and the highest redn. in glass temp. within AAO. Other effects that may also contribute to changes in Tg are discussed.
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      Tarnacka, M.; Dulski, M.; Geppert-Rybczyńska, M.; Talik, A.; Kaminska, E.; Kaminski, K.; Paluch, M. Variation in the molecular dynamics of DGEBA confined within AAO templates above and below the glass transition temperature. J. Phys. Chem. C 2018, 122, 28033– 28044,  DOI: 10.1021/acs.jpcc.8b07522
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      Variation in the Molecular Dynamics of DGEBA Confined within AAO Templates above and below the Glass-Transition Temperature
      Tarnacka, Magdalena; Dulski, Mateusz; Geppert-Rybczynska, Monika; Talik, Agnieszka; Kaminska, Ewa; Kaminski, Kamil; Paluch, Marian
      Journal of Physical Chemistry C (2018), 122 (49), 28033-28044CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The mol. dynamics above and below the glass transition temp. of bisphenol-A diglycidyl ether (known as DGEBA, Mn = 340 g/mol) infiltrated in nanoporous alumina (AAO) templates of various pore size were studied by broadband dielec. and Raman spectroscopies. The temp. dependence of the structural relaxation times is different under confinement with respect to the bulk sample even in the high temp. regime. Below the glass transition temp., the slow secondary process (β) was not detected in dielec. loss spectra of confined DGEBA; while the relaxation times of the faster secondary process (γ) were unaffected by the pore size. To explain this phenomenon, 2 different scenarios, considering either suppression of the motions related to this mobility or enhancement of its dynamics, were taken into account. Addnl. annealing expts., that lead to d. perturbation, enabled one to recover bulk-like temp. dependence of structural relaxation times for all confined systems. This finding was discussed in view of the outcome of Raman and contact angle measurements, that showed rather weak interactions between DGEBA and template. It is also worthwhile to add that except for the clear broadening of the fast secondary relaxation peak, the relaxation times of this process varied within exptl. uncertainties due to annealing.
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      Alexandris, S.; Sakellariou, G.; Steinhart, M.; Floudas, G. Dynamics of unentangled cis-1,4-polyisoprene confined to nanoporous alumina. Macromolecules 2014, 47, 3895– 3900,  DOI: 10.1021/ma5006638
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      Dynamics of Unentangled cis-1,4-Polyisoprene Confined to Nanoporous Alumina
      Alexandris, Stelios; Sakellariou, Georgios; Steinhart, Martin; Floudas, George
      Macromolecules (Washington, DC, United States) (2014), 47 (12), 3895-3900CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      The dynamics of unentangled cis-1,4-polyisoprene confined within self-ordered nanoporous alumina (AAO) is studied as a function of mol. wt. (5000-300 g/mol) and pore size (400-25 nm) with dielec. spectroscopy. The main effects are the pronounced broadening of both segmental and chain modes with decreasing AAO pore diam. This suggests that the global chain relaxation is retarded on confinement. Remarkably, the distribution of relaxation times is broadened even within pores with size 50 times the unperturbed chain dimensions. The glass temp. is unaffected by confinement. These results are discussed in terms of confinement and adsorption effects. Confinement effects are negligible for the studied mol. wts. Chain adsorption, on the other hand, involves time and length scales distinctly different from the bulk that can account for the exptl. findings.
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      Tarnacka, M.; Kaminski, K.; Mapesa, E. U.; Kaminska, E.; Paluch, M. Studies on the temperature and time induced variation in the segmental and chain dynamics in poly(propylene glycol) confined at the nanoscale. Macromolecules 2016, 49, 6678– 6686,  DOI: 10.1021/acs.macromol.6b01237
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      Studies on the Temperature and Time Induced Variation in the Segmental and Chain Dynamics in Poly(propylene glycol) Confined at the Nanoscale
      Tarnacka, Magdalena; Kaminski, Kamil; Mapesa, Emmanuel U.; Kaminska, Ewa; Paluch, Marian
      Macromolecules (Washington, DC, United States) (2016), 49 (17), 6678-6686CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      The effect of 2D confinement on the dynamics of the normal modes (chain mobility) and segmental relaxation in poly(propylene glycol) (PPG) has been studied with the use of Broadband Dielec. Spectroscopy (BDS) and Differential Scanning Calorimetry (DSC). It is shown that both processes become faster with increasing degree of confinement. Interestingly, the crossover from VFT to the Arrhenius-like behavior of chain and segmental dynamics, obsd. in the examd. system, is strictly related to the vitrification of the adsorbed polymers. The mean relaxation times of the normal, τNM, and segmental modes, τα, depend on the history of confined PPG and can be significantly modified using different thermal treatments. It is demonstrated that annealing of the samples below the crossover temp., Tc, leads to a systematic shift of the segmental relaxation and normal mode toward lower frequencies, resulting in an increase in the glass transition temp. of the spatially restricted PPG. This observation to d. equilibration after annealing indicated that a system with higher d. characterized by more homogeneous dynamics can be obtained. It is therefore possible to modify and control the properties of the confined material by using different thermal treatment protocols.
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      Huwe, A.; Arndt, M.; Kremer, F.; Haggenmüller, C.; Behrens, P. Dielectric investigations of the molecular dynamics of propanediol in mesoporous silica materials. J. Chem. Phys. 1997, 107, 9699– 9701,  DOI: 10.1063/1.475265
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      Dielectric investigations of the molecular dynamics of propanediol in mesoporous silica materials
      Huwe, A.; Arndt, M.; Kremer, F.; Haggenmuller, C.; Behrens, P.
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      Broadband dielec. spectroscopy (10-2-1.8×109 Hz) is employed to study the mol. dynamics of the glass-forming hydrogen-bonded liq. propanediol confined to mesoporous M41S silica materials having two different topologies. It is shown that the dynamic glass transition takes place in the mesoporous system (diam. 2.7 nm). With respect to the bulk its relaxation rates are decreased when approaching the calorimetric glass transition. Silanization of the inner surfaces acts as a mol. lubrication and makes the mol. dynamics of the confined liq. comparable to the bulk.
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      Adrjanowicz, K.; Kaminski, K.; Koperwas, K.; Paluch, M. Negative pressure vitrification of the isochorically confined liquid in nanopores. Phys. Rev. Lett. 2015, 115, 265702,  DOI: 10.1103/PhysRevLett.115.265702
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      Negative pressure vitrification of the isochorically confined liquid in nanopores
      Adrjanowicz, K.; Kaminski, K.; Koperwas, K.; Paluch, M.
      Physical Review Letters (2015), 115 (26), 265702/1-264702/5CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
      Dielec. relaxation studies for model glass-forming liqs. confined to nanoporous alumina matrixes were examd. together with high-pressure results. For confined liqs. which show the deviation from bulk dynamics upon approaching the glass transition (the change from the Vogel-Fulcher-Tammann to the Arrhenius law), we have obsd. a striking agreement between the temp. dependence of the a-relaxation time in the Arrhenius-like region and the isochoric relaxation times extrapolated from the pos. range of pressure to the neg. pressure domain. Our finding provides strong evidence that glass-forming liq. confined to native nanopores enters the isochoric conditions once the mobility of the interfacial layer becomes frozen in. This results in the neg. pressure effects on cooling. We also demonstrate that differences in the sensitivity of various glass-forming liqs. to the "confinement effects" can be rationalized by considering the relative importance of thermal energy and d. contributions in controlling the a-relaxation dynamics (the Eυ/Ep ratio).
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      Park, J.-Y.; McKenna, G. B. Size and confinement effects on the glass transition behavior of Polystyrene/O-terphenyl polymer solutions. Phys. Rev. B: Condens. Matter Mater. Phys. 2000, 61, 6667– 6676,  DOI: 10.1103/PhysRevB.61.6667
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      Size and confinement effects on the glass transition behavior of polystyrene/o-terphenyl polymer solutions
      Park, Joon-Yong; McKenna, Gregory B.
      Physical Review B: Condensed Matter and Materials Physics (2000), 61 (10), 6667-6676CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)
      Polystyrene (PS)/o-terphenyl (oTP) solns. confined to nanometer scale pores were studied by differential scanning calorimetry to investigate size and confinement effects on the glass transition. We obsd. two glass transitions Tg in all thermograms for materials confined in the controlled pore glasses. One was at a lower temp. than the bulk state Tg and the other was at a higher temp. The lower transition temp. decreases with decreasing pore size, which is consistent with previous reports from this lab. on small-mol. glass formers and some other reports in similar systems. Although oTP and oTP/PS are not hydrogen-bonding materials, we interpret the higher temp. transition as due to the existence of an interacting layer at the pore surface. A two-layer model in which there exists a "core" liq. in the center surrounded by the interacting layer at the pore surface is consistent with our observations.
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      Arndt, M.; Stannarius, R.; Gorbatschow, W.; Kremer, F. Dielectric investigations of the dynamic glass transition in nanopores. Phys. Rev. E: Stat. Phys., Plasmas, Fluids, Relat. Interdiscip. Top. 1996, 54, 5377– 5390,  DOI: 10.1103/PhysRevE.54.5377
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      Dielectric investigations of the dynamic glass transition in nanopores
      Arndt, M.; Stannarius, R.; Gorbatschow, W.; Kremer, F.
      Physical Review E: Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics (1996), 54 (5), 5377-5390CODEN: PLEEE8; ISSN:1063-651X. (American Physical Society)
      Broadband dielec. spectroscopy (10-2-109 Hz) is employed to study the dynamic glass transition of low-mol.-wt. glass-forming liqs.: salol (one hydroxy group), pentalene glycol (two hydroxy groups), and glycerol (three hydroxy groups) were chosen. The authors interpret the dielec. spectra in terms of a two-state model with dynamic exchange between a bulklike phase in the pore vol. and an interfacial phase close to the pore wall. This enables one to analyze in detail the interplay between the mol. dynamics in the two subsystems (bulklike and interfacial), its dynamic exchange, and hence their growth and decline in dependence on the temp. and strength of the mol. interactions. For glycerol it is shown that a bulklike dynamic glass transition takes place in subvolumes as well as about 1 nm.
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      Tarnacka, M.; Kaminska, E.; Kaminski, K.; Roland, C. M.; Paluch, M. Interplay between core and interfacial mobility and its impact on the measured glass transition: Dielectric and calorimetric studies. J. Phys. Chem. C 2016, 120, 7373– 7380,  DOI: 10.1021/acs.jpcc.5b12745
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      Interplay between Core and Interfacial Mobility and Its Impact on the Measured Glass Transition: Dielectric and Calorimetric Studies
      Tarnacka, Magdalena; Kaminska, Ewa; Kaminski, Kamil; Roland, C. Michael; Paluch, Marian
      Journal of Physical Chemistry C (2016), 120 (13), 7373-7380CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The dynamics and thermodn. of confined tri-Ph phosphite (TPP) were studied using broadband dielec. spectroscopy (BDS) and differential scanning calorimetry (DSC). Geometric confinement in channels having length scales commensurate with the mol. size of TPP causes bifurcation of the dynamics: two populations are obsd., distinguished by their reorientational mobilities and glass transition temps. Upon cooling, significant changes in the relaxation process and temp. dependence occur due to the slow vitrification of the mols. in close proximity to the interface. Such a kinetic aspect of glass formation is unusual. This surface interaction alleviates constraints on the mols., allowing their glass transition to shift to lower temps. Simultaneously, it was obsd. that the structural relaxation process shifts to lower frequencies, and the distribution of the relaxation times becomes narrower upon annealing. This effect is esp. visible at lower frequencies, indicating the decreasing contribution of those mols. characterized by slower dynamics. In addn., it was found that structural relaxation times, as well as the glass transition temps., can be significantly modified by annealing samples over a particular range of temps. This work facilitated the understanding of the interplay between different kinds of mobility and its impact on changes in the glass transition temp. for two-dimensional confined materials.
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      Talik, A.; Tarnacka, M.; Geppert-Rybczyńska, M.; Hachuła, B.; Kaminski, K.; Paluch, M. The Impact of confinement on the dynamics and H-bonding pattern in low-molecular weight poly(propylene glycols). J. Phys. Chem. C 2020, 124, 17607– 17621,  DOI: 10.1021/acs.jpcc.0c04062
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      Impact of Confinement on the Dynamics and H-Bonding Pattern in Low-Molecular Weight Poly(propylene glycols)
      Talik, Agnieszka; Tarnacka, Magdalena; Geppert-Rybczynska, Monika; Hachula, Barbara; Kaminski, Kamil; Paluch, Marian
      Journal of Physical Chemistry C (2020), 124 (32), 17607-17621CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Herein we explored thermal properties, dynamics wettability and H-bonding pattern in various poly(propylene glycols) (PPG) of Mn = 400 g/mol confined into two types of nanoporous templates: silica (d=4 nm) and alumina (d=18 nm). Unexpectedly it was found that mobility of the interfacial layer and depression of the glass transition temp. weakly depend on the pore size, surface functionalization and wettability. Finally, we have reported a strengthening of the hydrogen bonds in samples confined in silica pores. Further, unique annealing expts. with the use of FTIR spectroscopy revealed reorganization of the mols. close to the interface and formation of the three distinct interfacial, intermediate and bulk-like fractions of mols. for PPG infiltrated in pores. These expts. may shed new lights on the variation of the segmental/structural relaxation times due to annealing of the materials of different mol. wt. infiltrated into pores or deposited in the form of a thin layer.
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      Adrjanowicz, K.; Paluch, M. Discharge of the nanopore confinement effect on the glass transition dynamics via viscous flow. Phys. Rev. Lett. 2019, 122, 176101,  DOI: 10.1103/PhysRevLett.122.176101
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      Discharge of the nanopore confinement effect on the glass transition dynamics via viscous flow
      Adrjanowicz, K.; Paluch, M.
      Physical Review Letters (2019), 122 (17), 176101CODEN: PRLTAO; ISSN:1079-7114. (American Physical Society)
      Using dielec. spectroscopy, we demonstrate that confinement-induced changes in the glass transition dynamics, as obsd. for polymethylphenylsiloxane in alumina nanopores, reveal a pronounced nonequil. nature. Our results indicate that glass formers confined to nanopores are able to recover their bulklike mobility. We found that the characteristic time const. of such an equilibration process correlates with an extremely slow viscous flow rate in cylindrical channels of nanometer size. Thus, all the way to equil., confinement effects seen in faster segmental dynamics are released through the viscous flow which eventually helps to eliminate surplus vol. gained by nanoconstrained polymers upon cooling.
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      Havriliak, S.; Negami, S. A complex plane representation of dielectric and mechanical relaxation processes in some polymers. Polymer 1967, 8, 161– 210,  DOI: 10.1016/0032-3861(67)90021-3
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      A complex plane representation of dielectric and mechanical relaxation processes in some polymers
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      cf. CA 66: 55869h; Scaife, CA 58: 12039d. The changes in the relaxation curve, obtained by plotting the imaginary coordinate of the complex polarizability of a dielec. sphere of unit radius against its real counterpart, were studied for 20 polymers whose dielec. dispersions were linear at high frequencies and circular arcs at low frequencies. An analogous transformation procedure was constructed empirically for mech. dispersions. The mech. and dielec. dispersions were analogous mechanisms when appropriately normalized. Polymers studied were poly(nonyl methacrylate), polycarbonate of bisphenol, poly(m-chlorostyrene), poly(vinyl laurate), poly(n-octyl methacrylate), poly(isobutyl methacrylate), poly(n-hexyl methacrylate), poly(cyclohexyl methacrylate), poly(vinyl decanoate), poly(n-butyl methacrylate), poly(vinyl octanoate), polychloroprene, poly(vinyl formal), poly(Me acrylate), poly(trifluorochloroethylene), poly(vinyl acetate), poly(vinyl chloroacetate), poly(vinyl acetal), and polyisobutylene. Similar data were obtained for glycerol and an unidentified copolymer. 41 references.
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      The mol. dynamics in the glass transition of the "quasi"-van der Waals glass salol confined to nanopores (2.5, 5.0, and 7.5 nm) with lubricated inner surfaces is found to be faster (by up to 2 orders of magnitude) than in the bulk liq. This effect of confinement is more pronounced for smaller pores. It reflects the cooperativity of mol. motions in the glass transition and enables its length scale to be detd. quant.
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      Hong, L.; Gujrati, P. D.; Novikov, V. N.; Sokolov, A. P. Molecular cooperativity in the dynamics of glass-forming systems: A new insight. J. Chem. Phys. 2009, 131, 194511,  DOI: 10.1063/1.3266508
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      Molecular cooperativity in the dynamics of glass-forming systems: A new insight
      Hong, L.; Gujrati, P. D.; Novikov, V. N.; Sokolov, A. P.
      Journal of Chemical Physics (2009), 131 (19), 194511/1-194511/7CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      The mechanism behind the steep slowing down of mol. motions upon approaching the glass transition remains a great puzzle. Most of the theories relate this mechanism to the cooperativity in mol. motion. In this work, we est. the length scale of mol. cooperativity ξ for many glass-forming systems from the collective vibrations (the so-called boson peak). The obtained values agree well with the dynamic heterogeneity length scale estd. using four-dimensional NMR. We demonstrate that ξ directly correlates to the dependence of the structural relaxation on vol. This dependence presents only one part of the mechanism of slowing down the structural relaxation. Our anal. reveals that another part, the purely thermal variation in the structural relaxation (at const. vol.), does not have a direct correlation with mol. cooperativity. These results call for a conceptually new approach to the anal. of the mechanism of the glass transition and to the role of mol. cooperativity. (c) 2009 American Institute of Physics.
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      Fischer, J. K. H; Sippel, P.; Denysenko, D.; Lunkenheimer, P.; Volkmer, D.; Loidl, A. Metal-organic frameworks as host materials of confined supercooled liquids. J. Chem. Phys. 2015, 143, 154505,  DOI: 10.1063/1.4933308
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      Metal-organic frameworks as host materials of confined supercooled liquids
      Fischer, J. K. H.; Sippel, P.; Denysenko, D.; Lunkenheimer, P.; Volkmer, D.; Loidl, A.
      Journal of Chemical Physics (2015), 143 (15), 154505/1-154505/7CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      The authors examine the use of metal-org. framework (MOF) systems as host materials for the investigation of glassy dynamics in confined geometry. The confinement of the mol. glass former glycerol in three MFU-type MOFs with different pore sizes (MFU stands for "metal-org. framework Ulm-university") and the dynamics of the confined liq. are studied via dielec. spectroscopy. In accord with previous reports on confined glass formers, different degrees of deviations from bulk behavior are found depending on pore size, demonstrating that MOFs are well-suited host systems for confinement investigations. (c) 2015 American Institute of Physics.
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      Uhl, M.; Fischer, J. K. H.; Sippel, P.; Bunzen, H.; Lunkenheimer, P.; Volkmer, D.; Loidl, A. Glycerol confined in zeolitic imidazolate frameworks: The temperature-dependent cooperativity length scale of glassy freezing. J. Chem. Phys. 2019, 150, 024504,  DOI: 10.1063/1.5080334
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      Glycerol confined in zeolitic imidazolate frameworks: The temperature-dependent cooperativity length scale of glassy freezing
      Uhl, M.; Fischer, J. K. H.; Sippel, P.; Bunzen, H.; Lunkenheimer, P.; Volkmer, D.; Loidl, A.
      Journal of Chemical Physics (2019), 150 (2), 024504/1-024504/9CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      In the present work, we employ broadband dielec. spectroscopy to study the mol. dynamics of the prototypical glass former glycerol confined in two microporous zeolitic imidazolate frameworks (ZIF-8 and ZIF-11) with well-defined pore diams. of 1.16 and 1.46 nm, resp. The spectra reveal information on the modified α relaxation of the confined supercooled liq., whose temp. dependence exhibits clear deviations from the typical super-Arrhenius temp. dependence of the bulk material, depending on the temp. and pore size. This allows assigning well-defined cooperativity length scales of mol. motion to certain temps. above the glass transition. We relate these and previous results on glycerol confined in other host systems to the temp.-dependent length scale deduced from nonlinear dielec. measurements. The combined exptl. data can be consistently described by a crit. divergence of this correlation length as expected within theor. approaches assuming that the glass transition is due to an underlying phase transition. (c) 2019 American Institute of Physics.
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      Winkler, R.; Tu, W.; Laskowski, Ł.; Adrjanowicz, K. Effect of surface chemistry on the glass-transition dynamics of poly(phenyl methyl siloxane) confined in alumina nanopores. Langmuir 2020, 36, 7553– 7565,  DOI: 10.1021/acs.langmuir.0c01194
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      Effect of surface chemistry on the glass-transition dynamics of poly(phenyl methyl siloxane) confined in alumina nanopores
      Winkler, Roksana; Tu, Wenkang; Laskowski, Lukasz; Adrjanowicz, Karolina
      Langmuir (2020), 36 (26), 7553-7565CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Broadband dielec. spectroscopy (BDS) and differential scanning calorimetry (DSC) are combined to study the effect of changes in the surface chem. on the segmental dynamics of glass-forming polymer, poly(methylphenylsiloxane) (PMPS), confined in anodized aluminum oxide (AAO) nanopores. Measurements were carried for native and silanized nanopores of the same pore sizes. Nanopore surfaces are modified with the use of two silanizing agents, chlorotrimethylsilane (ClTMS) and (3-aminopropyl)trimethoxysilane (APTMOS), of much different properties. The results of the dielec. studies have demonstrated that for the studied polymer located in 55 nm pores, changes in the surface chem. and thermal treatment allows the confinement effect seen in temp. evolution of the segmental relaxation time, τα(T) to be removed. The bulk-like evolution of the segmental relaxation time can also be restored upon long-time annealing. Interestingly, the time scale of such equilibration process was found to be independent of the surface conditions. The calorimetric measurements reveal the presence of two glass-transition events in DSC thermograms of all considered systems, implying that the changes in the interfacial interactions introduced by silanization are not strong enough to inhibit the formation of the interfacial layer. Although DSC traces confirmed the two-glass-transition scenario, there is no clear evidence that vitrification of the interfacial layer affects τα(T) for nanopore-confined polymer.
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      Li, L.; Chen, J.; Deng, W.; Zhang, C.; Sha, Y.; Cheng, Z.; Xue, G.; Zhou, D. Glass transitions of poly(methyl methacrylate) confined in nanopores: Conversion of three- and two-layer models. J. Phys. Chem. B 2015, 119, 5047– 5054,  DOI: 10.1021/jp511248q
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      Glass Transitions of Poly(methyl methacrylate) Confined in Nanopores: Conversion of Three- and Two-Layer Models
      Li, Linling; Chen, Jiao; Deng, Weijia; Zhang, Chen; Sha, Ye; Cheng, Zhen; Xue, Gi; Zhou, Dongshan
      Journal of Physical Chemistry B (2015), 119 (15), 5047-5054CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      The glass transitions of poly(Me methacrylate) (PMMA) oligomer confined in alumina nanopores with diams. much larger than the polymer chain dimension were investigated. Compared with the case of 80 nm nanopores, PMMA oligomer confined in 300 nm nanopores shows three glass transition temps. (from from low to high, denoted as Tg,lo, Tg,inter, and Tg,hi). Such phenomenon can be interpreted by a three-layer model: there exists an interphase between the adsorbed layer and core vol. called the interlayer, which has an intermediate Tg. The behavior of multi-Tg parameters is ascribed to the propagation of the interfacial interaction during vitrifaction process. Besides, because of the nonequil. effect in the adsorbed layer, the cooling rate plays an important role in the glass transitions: the fast cooling rate generates a single Tg; the intermediate cooling rate induces three Tg values, while the ultraslow cooling rate results in two Tg values. With decreasing the cooling rate, the thickness of interlayer would continually decrease, while those of the adsorbed layer and core vol. gradually increase; meanwhile, the Tg,lo gradually increases, Tg,inter almost stays const., and the Tg,hi value keeps decreasing. In such a process, the dynamic exchanges between the interlayer and adsorbed layer, core vol. should be dominant.
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      Casalini, R.; Roland, C. M. Temperature and density effects on the local segmental and global chain dynamics of poly-(oxybutylene). Macromolecules 2005, 38, 1779– 1788,  DOI: 10.1021/ma0476902
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      Temperature and Density Effects on the Local Segmental and Global Chain Dynamics of Poly(oxybutylene)
      Casalini, R.; Roland, C. M.
      Macromolecules (2005), 38 (5), 1779-1788CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Dielec. spectroscopy measurements over a broad range of temp. and pressure were carried out on poly(oxybutylene) (POB), a type A polymer (dielec. active normal mode). There are three dynamic processes appearing at lower frequency: the normal and segmental relaxation modes and a cond. arising from ionic impurities. In combination with pressure-vol.-temp. measurements, the dielec. data were used to assess the resp. roles of thermal energy and d. in controlling the relaxation times and their variation with T and P. We find that the local segmental and the global relaxation times are both a single function of the product of the temp. times the sp. vol., with the latter raised to the power of 2.65. The fact that this scaling exponent is the same for both modes indicates they are governed by the same local friction coeff., an idea common to most models of polymer dynamics. Nevertheless, near Tg, their temp. dependences diverge. The magnitude of the scaling exponent reflects the relatively weak effect of d. on the relaxation times. This is usual for polymers, as the intramol. bonding, and thus interactions between directly bonded segments, are only weakly sensitive to pressure. This insensitivity also means that the chain end-to-end distance is invariant to P, conferring a near pressure independence of the (d.-normalized) normal mode dielec. strength. The ionic cond. dominates the low-frequency portion of the spectra. At lower temps. and higher pressures, this cond. becomes decoupled from the relaxation modes (different T dependence) and exhibits a significantly weaker d. effect. At frequencies higher than the structural relaxation, both an excess wing on the flank of the α-peak and a secondary relaxation are obsd. From their relative sensitivities to pressure, we ascribe the former to an unresolved Johari-Goldstein (JG) relaxation, while the higher frequency peak is unrelated to the glass transition. These designations are consistent with the relaxation time calcd. for the JG process. The dynamic properties of the POB are essentially the same as those of poly(propylene glycol), in accord with their similar chem. structures. However, POB is less fragile (weaker Tg-normalized temp. dependence), its relaxation times are less sensitive to d. changes, and, facilitating the measurements herein, its normal mode has a substantially larger dielec. strength.
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      Kipnusu, W. K.; Elsayed, M.; Kossack, W.; Pawlus, S.; Adrjanowicz, K.; Tress, M.; Mapesa, E. U.; Krause-Rehberg, R.; Kaminski, K.; Kremer, F. Confinement for more space: A larger free volume and enhanced glassy dynamics of 2-ethyl-1-hexanol in nanopores. J. Phys. Chem. Lett. 2015, 6, 3708– 3712,  DOI: 10.1021/acs.jpclett.5b01533
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      Confinement for More Space: A Larger Free Volume and Enhanced Glassy Dynamics of 2-Ethyl-1-hexanol in Nanopores
      Kipnusu, Wycliffe K.; Elsayed, Mohamed; Kossack, Wilhelm; Pawlus, Sebastian; Adrjanowicz, Karolina; Tress, Martin; Mapesa, Emmanuel U.; Krause-Rehberg, Reinhard; Kaminski, Kamil; Kremer, Friedrich
      Journal of Physical Chemistry Letters (2015), 6 (18), 3708-3712CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
      Broadband dielec. spectroscopy and positron annihilation lifetime spectroscopy are employed to study the mol. dynamics and effective free vol. of 2-ethyl-1-hexanol (2E1H) in the bulk state and when confined in unidirectional nanopores with av. diams. of 4, 6, and 8 nm. Enhanced α-relaxations with decreasing pore diams. closer to the calorimetric glass-transition temp. (Tg) correlate with the increase in the effective free vol. This indicates that the glassy dynamics of 2D constrained 2E1H is mainly controlled by d. variation.
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      Talik, A.; Tarnacka, M.; Geppert-Rybczynska, M.; Minecka, A.; Kaminska, E.; Kaminski, K.; Paluch, M. Impact of the interfacial energy and density fluctuations on the shift of the glass-transition temperature of liquids confined in pores. J. Phys. Chem. C 2019, 123, 5549– 5556,  DOI: 10.1021/acs.jpcc.8b12551
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      Impact of the Interfacial Energy and Density Fluctuations on the Shift of the Glass-Transition Temperature of Liquids Confined in Pores
      Talik, Agnieszka; Tarnacka, Magdalena; Geppert-Rybczynska, Monika; Minecka, Aldona; Kaminska, Ewa; Kaminski, Kamil; Paluch, Marian
      Journal of Physical Chemistry C (2019), 123 (9), 5549-5556CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The behavior of the low- and high-mol. wt. glass formers confined in nanoporous templates remains an unsolved puzzle despite the intensive long-term studies in this matter. Special effort is taken to understand the enhancement of segmental or structural dynamics and the depression of the glass-transition temps., Tgs in materials infiltrated in pores of the nanometric size. In this paper, we have analyzed dielec., calorimetric, and contact angle data collected for various systems to det. which factors are responsible for these effects. It turned out that with increasing interfacial energy, mols. attached to the pore walls (interfacial layer) vitrify at higher temps. Moreover, the dynamics of core mols. starts to deviate from bulk-like behavior. Therefore, a greater depression of the glass-transition temp., Tg, of this fraction of mols. is noted. Also, it was found that the sensitivity of structural dynamics to the d. fluctuations, quantified by the pressure coeff. of the glass-transition temp., dTg/dp, is another useful parameter to predict the shift of the glass-transition temp. of the confined glass formers. The results presented herein emphasize the great importance of surface effects, which play a primary role in a unified description of the impact of the nanometric spatial restriction on the dynamics of confined materials.
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      Kaminska, E.; Tarnacka, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M. High pressure dielectric studies on the structural and orientational glass. J. Chem. Phys. 2016, 144, 054503,  DOI: 10.1063/1.4940776
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      High pressure dielectric studies on the structural and orientational glass
      Kaminska, E.; Tarnacka, M.; Jurkiewicz, K.; Kaminski, K.; Paluch, M.
      Journal of Chemical Physics (2016), 144 (5), 054503/1-054503/11CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      High pressure dielec. studies on the H-bonded liq. D-glucose and Orientationally Disordered Crystal (ODIC) 1,6-anhydro-D-glucose (levoglucosan) were carried out. It was shown that in both compds., the structural relaxation is weakly sensitive to compression. It is well reflected in the low pressure coeff. of the glass transition and orientational glass transition temps. which is equal to 60 K/GPa for both D-glucose and 1,6-anhydro-D-glucose. Although it should be noted that .vdelta.Tg0/.vdelta.p evaluated for the latter compd. seems to be enormously high with respect to other systems forming ODIC phase. We also found that the shape of the α-loss peak stays const. for the given relaxation time independently on the thermodn. condition. Consequently, the Time Temp. Pressure (TTP) rule is satisfied. This exptl. finding seems to be quite intriguing since the TTP rule was shown to work well in the van der Waals liqs., while in the strongly assocg. compds., it is very often violated. We have also demonstrated that the sensitivity of the structural relaxation process to the temp. change measured by the steepness index (mp) drops with pressure. Interestingly, this change is much more significant in the case of D-glucose with respect to levoglucosan, where the fragility changes only slightly with compression. Finally, kinetics of ODIC-crystal phase transition was studied at high compression. It is worth mentioning that in the recent paper, Tombari and Johari [J. Chem. Phys. 142, 104501 (2015)] have shown that ODIC phase in 1,6-anhydro-D-glucose is stable in the wide range of temps. and there is no tendency to form more ordered phase at ambient pressure. On the other hand, our isochronal measurements performed at varying thermodn. conditions indicated unquestionably that the application of pressure favors solid (ODIC)-solid (crystal) transition in 1,6-anhydro-D-glucose. This result mimics the impact of pressure on the crystn. of fully disordered supercooled van der Waals liqs. (c) 2016 American Institute of Physics.
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      Casalini, R.; Roland, C. M. Dielectric α-relaxation and ionic conductivity in propylene glycol and its oligomers measured at elevated pressure. J. Chem. Phys. 2003, 119, 11951,  DOI: 10.1063/1.1624401
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      Dielectric α-relaxation and ionic conductivity in propylene glycol and its oligomers measured at elevated pressure
      Casalini, Riccardo; Roland, C. Michael
      Journal of Chemical Physics (2003), 119 (22), 11951-11956CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      Structural dynamics and vol. were measured as a function of both temp. and pressure for a propylene glycol and its oligomers (PPG), and the results compared with previous data on higher mol. wt. polypropylene glycols. PPG is of special interest because the terminal groups form hydrogen bonds; thus, by studying different mol. wts., the manner in which hydrogen bonding influences the dynamics in the supercooled regime can be systematically investigated. The fragility (Tg-normalized temp. dependence) of the dimer and trimer of PPG increases with pressure, similar to results for other H-bonded liqs., but different from van der Waals glass formers. This behavior is believed to be due to the effect of pressure in decreasing the extent of hydrogen bonding. From the combined temp. and vol. dependences of the relaxation times, the relative degree to which thermal energy and vol. govern the dynamics was quantified. With decreasing mol. wt., the relative contribution of thermal energy to the dynamics was found to strongly increase, reflecting the role of hydrogen bonding. By comparing the ionic cond. and the dielec. relaxation times, a decoupling between rotational and translational motions was obsd. Interestingly, this decoupling was independent of both pressure and mol. wt., indicating that hydrogen bonds have a negligible effect on the phenomenon.
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      Atake, T.; Angell, C. A. Pressure dependence of the glass transition temperature in molecular liquids and plastic crystals. J. Phys. Chem. 1979, 83, 3218– 3223,  DOI: 10.1021/j100488a007
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      Rexrode, R. N.; Orien, J.; King, M. D. Effects of solvent stabilization on pharmaceutical crystallization: Investigating conformational polymorphism of probucol using combined solid-state density functional theory, molecular dynamics, and terahertz spectroscopy. J. Phys. Chem. A 2019, 123, 6937– 6947,  DOI: 10.1021/acs.jpca.9b00792
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      Effects of Solvent Stabilization on Pharmaceutical Crystallization: Investigating Conformational Polymorphism of Probucol Using Combined Solid-State Density Functional Theory, Molecular Dynamics, and Terahertz Spectroscopy
      Rexrode, Neilson R.; Orien, Jordan; King, Matthew D.
      Journal of Physical Chemistry A (2019), 123 (32), 6937-6947CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
      Solid-state d. functional theory (DFT), mol. dynamics (MD), and terahertz (THz) spectroscopy were used to study the formation of enantiotropically related conformational Form I and Form II polymorphs of the pharmaceutical compd., probucol. DFT calcns. were performed on the crystal systems to compare relative lattice energies and the solvent stabilization of the metastable Form II structure. The thermodn. of solvent inclusion in the Form II·MeOH crystal system were detd. from MD simulations, as was the favored conformation of mol. probucol in methanol and ethanol solns. The findings from both solid-state DFT and MD calcns. suggest that the preferred mol. orientations of the probucol mol. in soln. and the probable inclusion of methanol in the crystal lattice during the crystn. process lead to the solvent selectivity of the probucol polymorph formation. The addnl. stabilization energy provided by the crystn. solvent facilitates the nucleation and growth of the Form II polymorph under conditions that favor this metastable crystal form over the thermodynamically stable Form I, despite the higher energy mol. and cryst. configurations of probucol Form II. We demonstrate the influence of solvent on the formation of pharmaceutical polymorphs and provide a mol.-level view of complex interactions leading to polymorphism using a combination of computational methods and THz spectral data.
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      Jiang, Q.; Ward, M. D. Crystallization under nanoscale confinement. Chem. Soc. Rev. 2014, 43, 2066– 2079,  DOI: 10.1039/C3CS60234F
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      Crystallization under nanoscale confinement
      Jiang, Qi; Ward, Michael D.
      Chemical Society Reviews (2014), 43 (7), 2066-2079CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Classical crystal growth models posit that crystn. outcomes are detd. by nuclei that resemble mature crystal phases, but at a crit. size where the vol. free energy of nuclei begins to offset the unfavorable surface free energy arising from the interface with the growth medium. Crystn. under nanoscale confinement offers an opportunity to examine nucleation and phase transformations at length scales corresponding to the crit. size, at which kinetics and thermodn. of nucleation and growth intersect and dramatic departures in stability compared to bulk crystals can appear. This tutorial review focuses on recent investigations of the crystn. of org. compds. in nanoporous matrixes that effectively provide millions of nanoscale reactors in a single sample, ranging from controlled porous glass (CPG) beads to nanoporous block-copolymer monoliths to anodic Al2O3 membranes. Confinement of crystal growth in this manner provides a snapshot of the earliest stages of crystal growth, with insights into nucleation, size-dependent polymorphism, and thermotropic behavior of nanoscale crystals. Moreover, these matrixes can be used to screen for crystal polymorphs and assess their stability as nanocrystals. The well-aligned cylindrical nanoscale pores of polymer monoliths or AAO also allow detn. of preferred orientation of embedded nanocrystals, affording insight into the competitive nature of nucleation, crit. sizes, and phase transition mechanisms. Collectively, these investigations have increased our understanding of crystn. at length scales that are deterministic while suggesting strategies for controlling crystn. outcomes.
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      Gerber, J. J.; Caira, M. R.; Lötter, A. P. Structures of two conformational polymorphs of the cholesterol-lowering drug probucol. J. Crystallogr. Spectrosc. Res. 1993, 23, 863– 869,  DOI: 10.1007/BF01195733
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      Structures of two conformational polymorphs of the cholesterol-lowering drug probucol
      Gerber, J. J.; Caira, M. R.; Lotter, A. P.
      Journal of Crystallographic and Spectroscopic Research (1993), 23 (11), 863-9CODEN: JCREDB; ISSN:0277-8068.
      Two polymorphic forms of the drug probucol, (4,4'-[(1-methylethylidene)bis(thio)]bis[2,6-bis(1,1-dimethylethyl)phenol]), were isolated and characterized by thermal anal., x-ray powder diffraction and single crystal x-ray analyses. Form I, with onset m.p. 125°, is monoclinic, space group P21/c with a 16.972(5), b 10.534(4), c 19.03(1) Å, β 113.66(3)°; Z = 4; R = 0.052. Form II, with onset melting temp. 116°, is monoclinic, space group P21/n with a 11.226(2), b 15.981(2), c 18.800(3) Å, β 104.04(1)°; Z = 4; R = 0.048. At. coordinates are given. The probucol mol. adopts different conformations in the 2 polymorphs. In form II, the C-S-C-S-C chain is extended and the mol. symmetry approximates C2v whereas in form I, the 2 S-C-S-C torsion angles are approx. 80 and 165°. Mol. mechanics calcns. show that the less sym. conformer of form I is more stable than the conformer in form II by approx. 26 kJ mol-1. Crystal packing in both polymorphs is detd. by van der Waals interactions only. X-ray powder diffraction indicates that form II converts to Form I on grinding.
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      Producing stable nanocrystals confined to porous excipient media is a desirable way to increase the dissoln. rate and improve the bioavailability of poorly water sol. pharmaceuticals. The poorly sol. pharmaceutical fenofibrate was crystd. in controlled pore glass (CPG) of 10 different pore sizes between 12 nm and 300 nm. High drug loadings of greater than 20 wt% were achieved across all pore sizes greater than 20 nm. Nanocryst. fenofibrate was formed in pore sizes greater than 20 nm and showed characteristic m.p. depressions following a Gibbs-Thomson relationship as well as enhanced dissoln. rates. Solid-state NMR (NMR) was employed to characterize the crystallinity of the confined mols. These results help to advance the fundamental understanding of nanocrystn. in confined pores.
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    • Additional figures, including dielectric spectra collected for PRO within pore diameters d = 120 nm and d = 80 nm; relaxation maps for PRO infiltrated into AAO membranes with different pore diameters; DSC thermograms; derivative representation of the heat flow for confined PRO; FTIR spectra; and estimation of the radius of critical nuclei, rc (PDF)


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