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Amorphous Drug–Polymer Salt with High Stability under Tropical Conditions and Fast Dissolution: The Case of Clofazimine and Poly(acrylic acid)

Cite this: Mol. Pharmaceutics 2021, 18, 3, 1364–1372
Publication Date (Web):February 1, 2021
https://doi.org/10.1021/acs.molpharmaceut.0c01180

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Abstract

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We report that the stability of amorphous clofazimine (CFZ) against crystallization is vastly improved by salt formation with a polymer without sacrificing dissolution rate. A simple slurry method was used to produce the amorphous salt of CFZ with poly(acrylic acid) (PAA) at 75 wt % drug loading. The synthesis was performed under a mild condition suitable for thermally unstable drugs and polymers. Salt formation was confirmed by visible spectroscopy and glass temperature elevation. The amorphous salt at 75 wt % drug loading is remarkably stable against crystallization at 40 °C and 75% RH for at least 180 days. In contrast, the amorphous solid dispersion containing the un-ionized CFZ dispersed in poly(vinylpyrrolidone) crystallized in 1 week under the same condition. The high stability of the amorphous drug–polymer salt is a result of the absence of a drug–polymer crystalline structure, reduced driving force for crystallizing the free base, and reduced molecular mobility. Despite the elevated stability, the amorphous drug–polymer salt showed fast dissolution and high solution concentration in two biorelevant media (SGF and FaSSIF). Additionally, the amorphous CFZ–PAA salt has improved tabletability and powder flow relative to crystalline CFZ. The CFZ–PAA example suggests a general method to prepare amorphous drugs with high physical stability under tropical conditions and fast dissolution.

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Introduction

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Amorphous formulations can improve the solubility and bioavailability of poorly soluble drugs but must be stable against crystallization. (1) Stability under the highly stressful tropical conditions is a requirement for medicines for global health. Polymers are commonly used to stabilize amorphous drugs against crystallization and to provide other benefits such as improved wetting and dissolution. (2) While many studies employed polymers as bulk additives and dispersion media, (3,4) there has been recent attention to using polymers as coating materials to inhibit surface crystallization and improve wetting. (5−11) Many amorphous drugs have high surface mobility (12−14) and show fast surface crystal growth. (15−17) Thin polymer coatings can immobilize surface molecules, inhibit surface crystallization, and improve wetting and dissolution.
Salt formation is widely used in pharmaceutical science to improve the physical properties of drugs. (18) Pharmaceutical salts usually contain an ionized drug with a small counterion (an inorganic ion or a small charged organic molecule). In contrast, salts formed between drugs and polymers are less well studied. (19) For the purpose of stabilizing amorphous drugs, the formation of drug–polymer salts is expected to be advantageous for many reasons. First, ionic interactions are stronger than van der Waals forces between neutral molecules, and this can reduce the system’s free energy and the driving force for crystallization. Second, an amorphous drug–polymer salt is expected to have a much higher glass transition temperature than a neutral dispersion, again a result of strong ionic interactions. This would lead to lower molecular mobility and greater stability. Third, while many small-molecule salts can crystallize, a drug–polymer salt may be very difficult (if not impossible) to crystallize. This is because a stable crystal packing containing both the drug and the polymer may not exist. For these reasons, we expect an amorphous drug–polymer salt to be significantly more stable than the neutral drug–polymer dispersion, especially under the highly stressful tropical conditions.
There are scattered literature reports that support the notion of high amorphous stability by formation of drug–polymer salts. The basic polymer Eudragit E PO has been used to stabilize acidic drugs naproxen (20) and indomethacin; (21) the acidic polymer poly(acrylic acid) (PAA, Carbomer) has been used to stabilize 2-aminopyridine-containing basic drugs. (22) The recent work on polymer nanocoating takes advantage of the local formation of drug–polymer salts. For example, the basic polymer chitosan is deposited on the surface of the acidic drug indomethacin, (8) and the acidic polymer alginic acid is deposited on the surface of the basic drug clofazimine. (5) In the coating solution, the drug and the polymer are oppositely charged, allowing salt formation. Despite these reports, the hypothesis that drug–polymer salt formation leads to high amorphous stability has not been systematically explored.
This work is concerned with the amorphous salt of clofazimine (CFZ) and the polymer PAA (Scheme 1). CFZ is an antimicrobial drug for treating leprosy and extensively drug-resistant tuberculosis and one of the World Health Organization’s essential medicines. (23) CFZ is in class II of the Biopharmaceuticals Classification System (low solubility and high permeability), suggesting the potential for improved absorption by enhancing solubility. CFZ is a weak base with a pKa of 8.5. (24) The polymer PAA is a weak acid with a pKa of 4.5. (25) The large difference between their pKa values suggests potential for salt formation. (26)

Scheme 1

Scheme 1. Chemical Structures of CFZ, PAA, PVP and PVP/VAa
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aThe functional groups of CFZ and PAA responsible for basicity and acidity are highlighted along with pKa values.

We report that the CFZ–PAA salt can be synthesized using a simple slurry method and exhibits high physical stability during storage at high temperature and humidity. The synthesis was performed under mild conditions, preventing the thermal decomposition of CFZ (27) and PAA. (28) Salt formation was verified by thermal analysis and spectroscopy. The amorphous salt was stable against crystallization at 40 °C and 75% RH for at least 180 days, vastly outperforming a neutral drug–polymer dispersion tested under the same condition. Despite its high stability, the amorphous drug–polymer salt showed fast dissolution and high solution concentration in two biorelevant media (simulated gastric fluid, SGF, and fasted state simulated intestinal fluid, FaSSIF) relative to crystalline CFZ.

Materials and Methods

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Clofazimine [N,5-bis(4-chlorophenyl)-3-(1-methylethylimino)-5H-phenazin-2-amine, CFZ, ≥98% pure], poly(acrylic acid) (PAA, average Mv of 450 kg/mol), polyvinylpyrrolidone (PVP K15, average Mw of 8000 g/mol), sodium dodecyl sulfate (SDS, ≥98% pure), sodium chloride, and sodium phosphate monobasic monohydrate were purchased from Sigma-Aldrich (St. Louis, MO) and used as received. Kollidon VA 64 (PVP/VA 64, average Mv of 45–70 kg/mol) was purchased from BASF.
Amorphous CFZ–PAA salt particles were prepared as follows. 2 mL of ethanol was added to the mixture of 375 mg of CFZ and 125 mg of PAA. The suspension was magnetically stirred at 75 °C maintained by a sand bath for 1 h (Fisher Thermix stirring hot plate model 301T). During reaction, the color of the solid phase in the slurry changed from red (color of CFZ crystals) to black. The solid product was filtered, washed twice with ethanol, and dried in vacuum at room temperature overnight. The product was ground in a mortar with a pestle, and particles in the size range 45–75 μm (between two sieves) were collected for characterization.
Amorphous solid dispersions of CFZ–PVP and CFZ–PVP/VA were prepared at a drug loading of 75 wt % by mixing 375 mg of CFZ and 125 mg of the dispersion polymer in an Al weighing dish and melting the mixture on a hot plate at 217–220 °C. The melt was cooled to room temperature, and the solid material was ground and sieved to obtain particles in the size range 45–75 μm.
Thin films of amorphous CFZ–PAA salt were prepared by spin coating for visible absorption spectroscopy. CFZ and PAA of known ratios were dissolved in ethanol and dichloromethane (1:1 v/v). The concentration of CFZ was 5 mg/mL. Drops of each solution were deposited on a silicate glass coverslip affixed to a spin-coater (TC100 desktop spin coater, MTI Corporation). The rotation speed was 200 rpm, and the coating time was 1 min. After coating, a transparent film was formed on the coverslip. Visible absorption spectra were collected through the films using an Agilent 8453 UV–visible spectrophotometer.
PAA-coated CFZ particles were prepared for ζ potential measurement. 100 mg of crystalline CFZ particles was placed in a 20 mL glass vial containing a magnetic stirrer and 1 mL of the PAA solution (2 mg/mL). The vial was placed on its side, and the slurry was stirred at 100 rpm for 2 min. The slurry was filtered and rinsed with the coating solution. The particles were dried in vacuum at room temperature for 3 h.
ζ potential measurements were performed with a Zetasizer Nano ZS (Malvern Instruments, USA). CFZ–PAA particles of different drug loading and PAA-coated CFZ were suspended in Milli-Q water for this measurement.
Crystallization of amorphous particles was monitored by powder X-ray diffraction (PXRD; Bruker D8 Advance diffractometer with a Cu Kα source, λ = 1.54178 Å; Figure 1). Single-crystal X-ray diffraction was performed with a Bruker D8 VENTURE Photon III four-circle diffractormeter with a Cu Kα source, λ = 1.54178 Å. See the deposited CIF file under the deposition number 2046715 for details of structural solution for the salt of CFZ and dodecyl sulfate (CFZ–DS), which can be obtained free of charge from the Cambridge Crystallographic Data Centre www.ccdc.cam.ac.uk/structures.

Figure 1

Figure 1. PXRD patterns of solid products from reactions performed under different conditions (see Table 2).

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Dissolution testing was performed in two biorelevant media (Table 1), using a USP-II apparatus (paddle) at 37 °C and 100 rpm. 50 mg of CFZ–PAA particles was added in 1000 mL of SGF (29) or 100 mL of FaSSIF (prepared according to the protocol from its powder manufacturer, Biorelevant) to represent the clinical dose. (30) The media volume selections were based on the FDA guideline (31) and the mean fluid volume in the small intestine at the fasted state. (32) At each time point, 3 mL of the solution was withdrawn, filtered through a 0.2 μm syringe filter (polytetrafluoroethylene), and analyzed with a UV–visible spectrometer (Agilent 8453 UV–visible spectrophotometer) at 495 nm (SGF) or 492 nm (FaSSIF). CFZ concentration was calculated using Beer’s law against a calibration curve. After each withdrawal, 3 mL of fresh dissolution medium was added back to the dissolution vessel.
Table 1. Compositions in SGF and FaSSIF
SGFFaSSIF
NaCl (43 mM)NaCl (106 mM)
SDS (3.5 mM)NaH2PO4 (29 mM)
HCl (0.01 N)sodium taurocholate (3 mM)
pH 2soybean lecithin (0.75 mM)
 NaOH (10 mM)
 pH 6.5
Differential scanning calorimetry (DSC) was conducted with a TA Instruments Q2000 at 10 °C/min under N2 purge (50 mL/min). Thermogravimetric analysis (TGA) was conducted at 10 °C/min in open Al pans using a TA Q600 SDT unit. 1H NMR was measured in d-DMSO using a Bruker Avance III HD 400 MHz instrument at room temperature.
To assess tabletability, approximately 50 mg of powder was filled into a 6 mm diameter die and compressed using flat-faced punches on a Carver Press Auto M3890. Tablets were allowed to relax for 24 h under ambient conditions before testing. The diametric breaking force was measured using a Benchsaver series VK 200 tablet hardness tester. Tablet tensile strength σ (MPa) was calculated from the maximum breaking force F (N), tablet diameter D (m), and tablet thickness T (m) as follows: (33)
Angle of repose was measured by pouring 500 mg of powder through a funnel whose outlet was 4 mm inside diameter and placed 1 in. above a horizontal receiving surface. A picture was taken of the rested powder from the side, and the angle of repose was measured from the image.

Results and Discussion

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Synthesis

In our synthesis of the amorphous CFZ–PAA salt, CFZ crystals reacted with PAA in a slurry to produce an amorphous solid. During the reaction, the initially red crystals of CFZ turned black. We used the product’s degree of crystallinity, measured by PXRD, as a measure to optimize reaction conditions, with a goal of obtaining fully amorphous product in a short time at a high drug loading. The parameters to be optimized included reaction temperature and solvent.
In Table 2, runs 1–4 were all conducted at 50% drug loading at 50 °C for 60 min but with different solvents. With water as solvent (or without solvent), no reaction was observed (no loss of CFZ crystallinity; see runs 1 and 2). With ethanol or acetone as solvent, crystalline CFZ completely turned amorphous (runs 3 and 4). This is attributed to the fact that ethanol and acetone are better solvents of CFZ than water. We chose ethanol as the solvent for further development given its lower toxicity and environmental impact. (34)
Table 2. Experiments to Optimize Synthetic Conditions
rundrug loading (wt %)solventtemperature (°C)time (min)% crystallinity
150none5060100
250water5060100
350ethanol50600
450acetone50600
550ethanol23144080
650ethanol7510
775ethanol75600
880ethanol756025
Runs 3, 5, and 6 were used to optimize reaction temperature. These runs were all performed at 50 wt % drug loading and with ethanol as solvent. Reaction was complete in 1 min at 75 °C (run 6) and in 60 min at 50 °C (run 3) but was 20% complete after 24 h at 23 °C (run 5). 75 °C was chosen as the temperature for synthesis.
Under the chosen reaction conditions, 75 wt % CFZ (run 7) was the maximal drug loading obtainable. A further increase to 80 wt % resulted in unreacted crystals (run 8). 75 wt % drug loading corresponds to a molar ratio 1:2 for CFZ:PAA monomer (the molecular weight of clofazimine is 473 g/mol, and that of the monomer of PAA is 72 g/mol). This high drug loading exceeds those reported previously for amorphous drug-polymer salts. (20−22)
No chemical degradation of the drug occurred during synthesis. This was demonstrated by analysis by 1H NMR (Figure S1 in Supporting Information). This is not surprising given the reaction temperature 75 °C is well below the melting point of CFZ, 221 °C, near which the drug does decompose rapidly. The mild conditions employed in our method are suitable for thermally unstable drugs and polymers and can be easily deployed in developing countries.

Salt Formation

Salt formation between CFZ and PAA is indicated by Tg elevation and visible spectroscopy. Figure 2 shows the DSC result of amorphous CFZ–PAA particles along with the results of CFZ and PAA. Glass transitions are detected in CFZ and PAA as steps in heat flow at 91 and 126 °C, respectively. In contrast, no transition is detected in CFZ–PAA in the same temperature range. These data indicate the glass transition temperature (Tg) of CFZ–PAA must be above the Tg values of the components; it must be higher than 160 °C, above which CFZ and PAA decompose, obscuring detection. For a drug–polymer dispersion without salt formation, Tg usually falls between the component Tg values, conforming to mixing rules like the Fox equation. The elevated Tg relative to the pure components indicates strong interactions between CFZ and PAA, consistent with ionic interactions and salt formation. (35)

Figure 2

Figure 2. Glass transitions in PAA, amorphous CFZ–PAA salt, and CFZ detected by DSC.

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Figure 3A shows the visible absorption spectra of amorphous CFZ–PAA films at different concentrations. Pure CFZ has the strongest absorption at λmax = 452 nm. With addition of PAA, the absorption peak shifts to a longer wavelength; the shift increases and saturates at 493 nm as drug concentration is reduced below 60 wt %. This saturation behavior is shown in Figure 3B where λmax is plotted against drug concentration. By extrapolation, the drug concentration at which saturation occurs is 70 wt %. This spectral shift results in a change of film color: pure CFZ is red, and the addition of PAA deepens the color, eventually making it dark purple. Similar spectral changes have been reported for CFZ in the presence of the polymer HPMCP, which also has carboxylic acid groups able to form a salt with CFZ. (26) A noteworthy feature in Figure 3A is the isosbestic point: despite their differences, all the spectra intersect at 480 nm.

Figure 3

Figure 3. (A) Visible absorption spectra of amorphous CFZ–PAA films at different drug concentration. (B) λmax (wavelength of maximal absorption) vs drug concentration. The color of each data point corresponds to the spectrum in (A) of the same color. By extrapolation, the saturation drug concentration is determined at 70 wt %. (C) Percentage of protonated CFZ vs drug loading by fitting the spectra in (A) to a two-state model.

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All these results are indicative of salt formation. An acid–base reaction between PAA and CFZ means that at each concentration, the drug can exist as the unreacted free base and as the protonated conjugate acid. These two species have different spectra, and the spectrum at each concentration can be represented as the weighted average of the spectra of the free base and the conjugated acid. This two-state model can fit all the observed spectra; see the residuals of fitting at the bottom of Figure 3A, which are small relative to the spectral intensity. The two-state model also accounts for the isosbestic point in Figure 3A: this is the crossing point of the spectra of the protonated and unprotonated CFZ. From the two-state model fitting, we obtain the percentage of CFZ that is protonated at each drug loading (Figure 3C). Pure CFZ is unprotonated; with the addition of PAA (decreasing drug loading), the fraction of protonation increases; protonation is complete below 70 wt % drug loading. This saturation behavior arises from the stoichiometry of the salt. At high drug concentration, there is excess free base; at low drug concentration, all the free base has reacted with PAA and the only spectrum observed is that of the salt. As a result, the spectrum shifts with increasing concentration of PAA but the effect saturates at high enough PAA concentration. It is worth noting that the saturation limit for λmax, 70 wt % drug, is close to the synthetic limit, 75 wt %, for drug loading in amorphous CFZ–PAA salts.
The red-shift of the absorption spectrum of CFZ is also consistent with salt formation. The absorption of CFZ at λmax = 452 nm is an excitation of the π electron system. Protonation at the imine site (Scheme 1) introduces a positive charge, pulling π electrons toward the charge. This leads to a change in electronic energy levels and a red-shift of the spectrum. (36)
Taken together, the elevation of Tg and the spectral change both indicate salt formation between CFZ and PAA. This conclusion is consistent with the large difference between the pKa values of the two components: the base CFZ has a pKa of 8.5; the acid PAA has a pKa of 4.5; they are expected to form a salt according to the rule (37,38) that proton transfer can happen when the pKa difference exceeds 2.

Stability at High Temperature and Humidity against Crystallization

The amorphous CFZ–PAA salt has remarkable stability against crystallization during storage at high temperature and humidity. Figure 4 shows that at 75 wt % drug loading, the salt remains amorphous after 180 days at 40 °C and 75% RH. This passes the accelerated stability testing for all climate zones. (39) In contrast, at the same drug loading, the neutral CFZ–PVP and CFZ–PVP/VA dispersions show significant crystallization under the same condition. PVP and PVP/VA are commonly used dispersion polymers and serve as a reference for PAA. Figure 4B shows the change of crystallinity as a function of time. While the CFZ–PAA salt shows no crystallization, the neutral CFZ–PVP and CFZ–PVP/VA dispersions are 60% and 40% crystallized, respectively.

Figure 4

Figure 4. Physical stability of amorphous CFZ–PAA salt at 40 °C and 75% RH. (A) PXRD patterns before and after storage of the CFZ–PAA salt and of the neutral CFZ–PVP and CFZ–PVP/VA dispersions. The CFZ–PAA salt remained amorphous after 180 days, but the neutral CFZ–PVP and CFZ–PVP/VA dispersions crystallized as the free base (bottom trace). (B) Crystallinity change as a function of time.

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It is noteworthy that the amorphous CFZ–PAA salt is stable against crystallization even after absorbing a significant amount of water. The high humidity in tropical climate causes drug products to absorb moisture. During storage at 40 °C and 75% RH, the water content in the CFZ–PAA salt increases to 5 wt % from the initial 1 wt % (Figure S2). Despite this, the amorphous salt remains stable against crystallization.

Dissolution Rate

The amorphous CFZ–PAA salt shows fast dissolution in two biorelevant media, SGF and FaSSIF. In SGF, amorphous CFZ–PAA salt dissolves much faster than the crystalline CFZ of the same particle size tested under the same condition (Figure 5). After 2 h, the salt reaches a solution concentration 20 times higher than that reached by crystalline CFZ. We interpret the plateau concentration, 45 μg/mL, as the solubility of the amorphous salt in SGF. This solubility is 10 times higher than the solubility of crystalline CFZ, 4 μg/mL. (5) The high solution concentration is sustained for at least 3 h, resulting in an enhancement by a factor of 20 of the area under the curve within the gastric emptying time (4 h). (40) It should be emphasized that the enhanced dissolution rate is unaffected by storage at 40 °C and 75% RH (see the pink curve in Figure 5A). This is another evidence for the high stability of the drug–polymer amorphous salt under the highly stressful conditions of 40 °C and 75% RH.

Figure 5

Figure 5. (A) Dissolution kinetics of crystalline CFZ and amorphous CFZ–PAA salt as prepared and after 180 days at 40 °C and 75% RH in SGF. 75 wt % drug loading in the amorphous salt. The error bar indicates standard deviation of two independent preparations tested. (B) PXRD patterns of solid residues after dissolution in SGF. The crystalline CFZ and the amorphous CFZ–PAA salt both transformed to a crystalline CFZ–DS salt.

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Upon prolonged contact with SGF and stirring, the amorphous CFZ–PAA salt gradually crystallized, leading to reduced solution concentration. After 27 h, the concentration was reduced to 4.2 μg/mL, the same concentration reached by crystalline CFZ. In both cases, analysis of the solid residues indicated a crystalline material different from the CFZ free base (Figure 5B). This solid material proved to be a salt of CFZ with dodecyl sulfate (DS, a component of SGF). In the crystal structure, the drug is protonated (see the circled site in the molecular structure), consistent with the ability of CFZ to form salts (see the CIF in the Supporting Information for details). An intriguing observation is that the CFZ–DS salt crystals are thin and easily bent and twisted (Figure S3), a phenomenon of some recent interest. (41)
The amorphous CFZ–PAA also shows fast dissolution in FaSSIF relative to crystalline CFZ (Figure 6A). At 75 wt % drug loading, the amorphous salt dissolves 10 times faster than crystalline CFZ in the first 15 min. The amorphous salt reaches a maximal solution concentration at 20 min, after which the concentration decreases and approaches the solubility of crystalline CFZ. The area under the curve for amorphous CFZ–PAA is 1.5 times that for crystalline CFZ within the small intestinal transit time (4 h). (42) Analysis of the solid residues after dissolution indicated mostly crystalline CFZ (Figure 6B). This common solid form determined the final drug concentration in FaSSIF. An interesting difference between the dissolution kinetics in the two media used is that the onset of crystallization is sooner in FaSSIF than in SGF. This may reflect the different nucleation rates of the CFZ free base and the CFZ–DS salt.

Figure 6

Figure 6. (A) Dissolution kinetics of amorphous CFZ–PAA salt and crystalline CFZ in FaSSIF. 75 wt % drug loading in the amorphous salt. (B) PXRD of solid residues after dissolution in FaSSIF. They are mostly crystalline CFZ.

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Does PAA Form a Surface Coating?

A polyelectrolyte similar to PAA, alginic acid, has been used in a surface coating on CFZ (5) and other amorphous drugs by electrostatic deposition. (8) The coating process involves dipping CFZ in a polymer solution at a pH such that the two components are oppositely charged. Given the coating conditions are similar to the conditions of synthesizing the amorphous salt, it is of interest to determine whether the amorphous salt contains a surface coating of PAA. We answer this question by measuring the ζ potential of the amorphous salt. Previous work has shown that amorphous CFZ can be coated by alginic acid and the coating changes the ζ potential in water from +44 mV for CFZ to −50 mV for alginic-acid-coated CFZ. If the amorphous salt has a surface coating of PAA, a negative ζ potential should be observed at high drug loading.
Figure 7 shows the ζ potential of the amorphous CFZ–PAA salt particles dispersed in pure water. Pure CFZ particles have a positive surface charge (+44 mV). This is expected for a basic drug with a pKa of 8.5 at neutral pH; the drug is protonated, gaining a positive charge. With the addition of PAA, the surface potential decreases, eventually becoming negative near 70 wt %. Below 60 wt % drug concentration, the surface potential equilibrates near −37 mV. This is a result of the neutralization of the positive charge of CFZ by the negative charge of PAA and by the dilution of CFZ by PAA. PAA is an acid with a pKa of 4.5 and is negatively charged at neutral pH. By salt formation, PAA neutralizes the charges of CFZ molecules. With enough PAA added, all CFZ charges are neutralized and the surface charge is dictated by the charge of PAA, which is negative. (43)

Figure 7

Figure 7. ζ potentials of the amorphous CFZ–PAA salt as a function of drug loading and of CFZ particles coated with PAA and alginic acid, as labeled. Error bar is the standard deviation for three measurements.

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Figure 7 also shows the ζ potentials of CFZ particles coated by PAA and alginic acid. With a polymer surface coating, the ζ potential of CFZ becomes negative, as expected. Since the polymer coating is only several nanometers thin, these data points are placed in the figure near 100% drug loading, as the coated particles are almost pure CFZ. The very thin surface coating is consistent with the observation that there is no significant change of the red color of CFZ particles after coating, whereas upon salt formation in the bulk, the particle color changes from red to black.
An important conclusion we draw from Figure 7 is that the amorphous CFZ–PAA salt particles have no surface coating of PAA. The state of surface charge closely tracks the state of ionization in the bulk (Figure 3). From Figure 3, we saw that in the bulk, complete neutralization of the drug occurs at 70% drug concentration. This is the same concentration at which the surface charge changes sign (Figure 7). This argues that there is no strong surface enrichment or depletion effect for the polymer in the amorphous salt. Together, the results on surface coating and bulk doping indicate many possibilities to incorporate a polymer into an amorphous drug, so it is mostly on the surface or in the bulk. The ability to manipulate the polymer’s location in this way provides flexibility to engineer amorphous formulations. This ability is related to the low mobility of polymer chains. An interesting question for future work is, what is the equilibrium location for trace polymer in an amorphous drug?

Tabletability and Powder Flow

The amorphous CFZ–PAA salt shows improved tabletability and powder flow relative to crystalline CFZ. Figure 8A shows the tablet tensile strength as a function of compaction pressure. Amorphous CFZ–PAA salt produces stronger tablets than crystalline CFZ when compared at the same compaction pressure. The strongest CFZ tablet, prepared at 150 MPa, barely meets the acceptable tensile strength of 2 MPa, while the tablet prepared with the amorphous salt is twice strong. This improvement of tabletability is likely a result of the better tabletability of the polymer. (44) We observed no compaction-induced crystallization of the amorphous salt, even at a compaction pressure outside the normal range (350 MPa; see Figure 8B).

Figure 8

Figure 8. (A) Tensile strength of tablets prepared with amorphous CFZ–PAA (75 wt % drug loading) and crystalline CFZ. The amorphous salt produces stronger tablets at a given compaction pressure. (B) PXRD patterns of amorphous CFZ–PAA salt before and after compaction, indicating no crystallization during compaction. (C) Angles of repose of amorphous CFZ–PAA salt (75 wt % drug loading) and the physical mixture of CFZ and PAA.

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Figure 8C compares the angles of repose of the amorphous CFZ–PAA salt and the physical mixture of crystalline CFZ and PAA at the same drug loading (75 wt %). The amorphous salt has a smaller angle of repose than the physical mixture, indicating improved flowability upon salt formation. Good flowability is important for producing tablets and capsules at high speed with content uniformity. (45)

Discussion

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A key finding of this work is the high stability of the amorphous CFZ–PAA salt at high temperature and humidity. The salt remained amorphous after 180 days at 40 °C and 75% RH, whereas the neutral CFZ–PVP and CFZ–PVP/VA dispersions crystallized significantly under the same condition. This high stability was observed despite the significant uptake of moisture during storage. Our finding is consistent with scattered literature reports for stability enhancement by complexation between acidic drugs and basic polymers (20,21) or between a zwitterionic drug and an acidic polymer, (46) but in this study, drug loading was significantly higher and stability testing was performed for the longest time at 40 °C and 75% RH. These results suggest that the use of drug–polymer salts can vastly improve the stability of amorphous drugs against crystallization. We now discuss why amorphous drug–polymer salts provide high stability in this regard.
We attribute the high stability of amorphous drug–polymer salts against crystallization to (1) reduced thermodynamic driving force and (2) increased kinetic barrier. Figure 9 shows the free energy of mixing in a drug–polymer system. Curve 1 represents the mixing of a neutral drug and a neutral polymer (e.g., CFZ in PVP). Curve 2 represents the mixing of a drug and a polymer where mutual ionization (salt formation) occurs; in the case illustrated, a basic drug is protonated by an acidic polymer. Curve 3 represents a mixture of the crystalline free base in a polymer matrix. The drawings to the right illustrate the three structures. In principle, a fourth structure is possible in which the drug–polymer salt crystallizes, but this is unlikely given the difficulty for the ionized drug and the ionized polymer to pack in regular arrays to form a crystal. That is, the only viable pathway of crystallization is the formation of a neutral-drug crystalline phase embedded in a polymer matrix (structure 3). Because of the strong ionic interactions in a drug–polymer salt, curve 2 is expected to be below curve 1. This means that the driving force for crystallization (arrow toward curve 3) is reduced or even nonexistent. This is the thermodynamic reason for the strong resistance of an amorphous drug–polymer salt to crystallization.

Figure 9

Figure 9. Enhanced stability of amorphous drug–polymer salts against crystallization. The curves represent the free energies of mixing to form (1) a neutral drug dispersed in a neutral polymer, (2) an amorphous drug–polymer salt, and (3) neutral-drug crystals in a polymer matrix.

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From a kinetic standpoint, salt formation elevates the glass transition temperature Tg of the drug–polymer mixture to a greater extent than simply mixing the components. In the case of CFZ, Tg is 86 °C for a neutral dispersion in PVP at 75% drug loading but is above 160 °C upon salt formation at the same drug loading. This elevation of Tg means reduced mobility and enhanced kinetic barrier for crystallization. This provides the kinetic reason for the strong resistance of an amorphous drug–polymer salt to crystallization. Together, thermodynamics and kinetics combine to make the CFZ–PAA salt exceptionally stable against crystallization at high temperature and humidity. It is likely that this principle applies in general to other drug–polymer salts.

Conclusions

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The amorphous salt of the basic drug CFZ and the acidic polymer PAA can be synthesized using a simple slurry method under mild conditions. This method is easy to implement and suitable for thermally unstable drugs and polymers. Salt formation is indicated by visible spectroscopy and Tg elevation. The amorphous drug–polymer salt is remarkably stable against crystallization under the highly stressful conditions of 40 °C and 75% RH. The high drug loading achieved exceeds the levels reported previously. (20−22) Despite elevated stability, the amorphous salt shows fast dissolution in biorelevant media. Furthermore, the amorphous CFZ–PAA salt shows improved tabletability and powder flow relative to crystalline CFZ.
We attribute the high stability of the amorphous CFZ–PAA salt under harshly stressful conditions to reduced thermodynamic driving force and increased kinetic stability. The strong ionic interaction in a drug–polymer salt makes the free energy of mixing more negative relative to a neutral drug–polymer dispersion. This in turn reduces the driving force for crystallization. From a kinetic standpoint, salt formation elevates the glass transition temperature to a greater extent than dispersing a neutral drug in a polymer matrix. This reduces molecular mobility and enhances kinetic stability. Given the generality of these effects, we expect salt formation to provide a general approach to stabilizing amorphous drugs against crystallization, especially under the highly stressful tropical conditions for global health applications.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.0c01180.

  • 1H NMR of amorphous CFZ–PAA salt; TGA of amorphous CFZ–PAA salt; structure of CFZ–DS crystal (PDF)

  • Crystallographic data for CFZ–DS at 100 K (CIF)

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Author Information

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  • Corresponding Author
  • Authors
    • Yue Gui - School of Pharmacy and , University of Wisconsin−Madison, Madison, Wisconsin 53705, United States;  Orcidhttp://orcid.org/0000-0002-4416-3907
    • Erin C. McCann - School of Pharmacy and , University of Wisconsin−Madison, Madison, Wisconsin 53705, United States
    • Xin Yao - School of Pharmacy and , University of Wisconsin−Madison, Madison, Wisconsin 53705, United States;  Orcidhttp://orcid.org/0000-0002-7657-4997
    • Yuhui Li - School of Pharmacy and , University of Wisconsin−Madison, Madison, Wisconsin 53705, United States;  Orcidhttp://orcid.org/0000-0002-2043-4338
    • Karen J. Jones - Zeeh Pharmaceutical Experiment Station, School of Pharmacy and , University of Wisconsin−Madison, Madison, Wisconsin 53705, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We thank the Bill and Melinda Gates Foundation (OPP1160408) for financial support, Ilia A. Guzei, Amelia M. Wheaton, Junguang Yu, Changlin Yao, Hao Wu, and Lauren Repp for experimental assistance, and Mark Sacchetti, Niya Bowers, Phil Goliber, and Ellen Harrington for helpful discussions. The Bruker D8 VENTURE Photon III X-ray diffractometer was partially funded by an NSF Award CHE-1919350 to the UW—Madison Department of Chemistry. Bruker Quazar APEX2 was purchased by UW—Madison Department of Chemistry with a portion of a generous gift from Paul J. and Margaret M. Bender.

Abbreviations

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CFZ

clofazimine

PAA

poly(acrylic acid)

PVP

polyvinylpyrrolidone

PVP/VA

poly(vinylpyrrolidone-co-vinyl-acetate)

SDS

sodium dodecyl sulfate

SGF

simulated gastric fluid

FaSSIF

fasted state simulated intestinal fluid; Tg, glass transition temperature

References

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    Surface-Enhanced Crystallization of Amorphous Nifedipine
    Zhu, Lei; Wong, Letitia; Yu, Lian
    Molecular Pharmaceutics (2008), 5 (6), 921-926CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Amorphous solids are generally more sol. and faster dissolving than their cryst. counterparts, a property useful for delivering poorly sol. drugs. Amorphous drugs must be stable against crystn., for crystn. negates their advantages. Recent studies found that crystal growth in amorphous indomethacin is orders of magnitude faster at the free surface than through the bulk and this surface-enhanced crystn. can be inhibited by an ultrathin coating. Herein, we report a second system that exhibits the same phenomena. Crystal growth at the free surface of amorphous nifedipine (NIF) was at least 1 order of magnitude faster than that through the bulk below the glass transition temp. Tg (42 °C). A thin coating of gold (10 nm) reduced the surface crystal growth rate to the bulk crystal growth rate. Surface-enhanced crystal growth was more pronounced near and below Tg than substantially above Tg, which suggests that this growth mode is more important for the glassy state. Our results support the view that a thin layer of mols. near the surface have higher mobility than the bulk mols. and can enable faster crystal growth. The higher mobility of surface mols. and the resulting fast crystal growth can be suppressed by an ultrathin coating.
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    Shi, Q.; Cai, T. Fast crystal growth of amorphous griseofulvin: relations between bulk and surface growth modes. Cryst. Growth Des. 2016, 16, 3279– 3286,  DOI: 10.1021/acs.cgd.6b00252
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    Fast Crystal Growth of Amorphous Griseofulvin: Relations between Bulk and Surface Growth Modes
    Shi, Qin; Cai, Ting
    Crystal Growth & Design (2016), 16 (6), 3279-3286CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Griseofulvin (GSF), a poorly H2O-sol. antifungal drug, is a model system for studying the phys. stability of amorphous pharmaceuticals. The crystn. kinetics of GSF in the bulk and at the surface was examd. as a function of temp. A sudden 10-fold rise of bulk crystal growth rate was obsd. near Tg, a phenomenon similar to that obsd. in other mol. glasses and termed glass-to-crystal (GC) growth. Analogous to other mol. glasses, GSF grows crystals much faster at the free surface than in the bulk. What distinguishes GSF from other systems is that surface crystn. can occur well above Tg (up to Tg + 62°). Another peculiar feature of GSF is that during bulk crystal growth at 130-150°, some crystals protruded well ahead of the normal growth front at the same growth rate as surface crystals. The authors suspect this protruding crystal growth is a surface-facilitated process through the formation of voids and free surfaces during bulk crystal growth. These new findings are important for understanding the mechanisms and connections for the bulk and surface crystn. in amorphous pharmaceutical solids.
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    Huang, C.; Ruan, S.; Cai, T.; Yu, L. Fast surface diffusion and crystallization of amorphous griseofulvin. J. Phys. Chem. B 2017, 121, 9463– 9468,  DOI: 10.1021/acs.jpcb.7b07319
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    Fast surface diffusion and crystallization of amorphous Griseofulvin
    Huang, Chengbin; Ruan, Shigang; Cai, Ting; Yu, Lian
    Journal of Physical Chemistry B (2017), 121 (40), 9463-9468CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Among mol. glasses, griseofulvin (GSF) is one of the fastest crystg. To understand this property, we have measured the surface diffusion in GSF using the method of surface grating decay. Surface diffusion in amorphous GSF is extremely fast, outpacing bulk diffusion by a factor of 108 at the glass transition temp. Tg (361 K). Among all mol. glasses studied (13 in all), GSF has the second fastest surface diffusion (to o-terphenyl) when compared at Tg. The GSF result fits the overall trend for mol. glasses without intermol. hydrogen bonds, where surface diffusion systematically slows down with increasing mol. size. This result is particularly noteworthy because GSF has many hydrogen-bond acceptors but no donors, indicating that, so long as they do not participate in hydrogen bonding, the polar functional groups have a similar effect on surface diffusion as the nonpolar hydrocarbon groups. In contrast, the formation of intermol. hydrogen bonds strongly inhibits surface diffusion. The surface crystal growth rate of amorphous GSF is nearly proportional to its surface diffusion coeff., as noted for other systems, supporting the view that surface crystal growth is controlled by surface diffusion. In addn., the fast surface diffusion of GSF glasses explains the fast crystal growth along fracture surfaces and suggests a basis to understand fast crystal growth in the bulk through continuous creation of microcracks.
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    Kindermann, C.; Matthée, K.; Strohmeyer, J.; Sievert, F.; Breitkreutz, J. Tailor-made release triggering from hot-melt extruded complexes of basic polyelectrolyte and poorly water-soluble drugs. Eur. J. Pharm. Biopharm. 2011, 79, 372– 381,  DOI: 10.1016/j.ejpb.2011.05.001
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    Tailor-made release triggering from hot-melt extruded complexes of basic polyelectrolyte and poorly water-soluble drugs
    Kindermann, Christoph; Matthee, Karin; Strohmeyer, Jutta; Sievert, Frank; Breitkreutz, Joerg
    European Journal of Pharmaceutics and Biopharmaceutics (2011), 79 (2), 372-381CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
    The aim of the study was the formulation of polyelectrolyte complexes composed of poorly water-sol. acid drugs and basic polymethacrylates by hot-melt extrusion enabling a tailor-made release pattern by the addn. of inorg. salts. The influence of different electrolytes was analyzed at varying conditions in order to control drug delivery from the complexes. Poorly water-sol. model drugs naproxen and furosemide were applied in their non-ionic form. After hot-melt extrusion of the naproxen-polymethacrylate powder blend, XRPD and DSC measurements indicated the formation of a single-phase amorphous system. Milled extrudates were stable under storage at long-term and intermediate conditions. Polyelectrolyte complex formation by an acid-base reaction during hot-melt extrusion could be proven by the lack of vibrations of dimethylamino and carboxylic groups by FT-IR and Raman spectroscopy. The complexes did not dissolve in demineralized water. Drug release could be immediately induced by addn. of neutral electrolytes. Tailor-made dissoln. profiles were realized by controlled electrolyte triggering. Maximal effects were achieved by concns. of 0.05-0.15 M NaCl. Different anions of alkali halogenides revealed variant magnitudes of the effect depending on the anion radius. Polyelectrolyte complex formation and dissoln. principles were also confirmed for furosemide.
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    Xie, T.; Gao, W.; Taylor, L. S. Impact of Eudragit EPO and hydroxypropyl methylcellulose on drug release rate, supersaturation, precipitation outcome and redissolution rate of indomethacin amorphous solid dispersions. Int. J. Pharm. 2017, 531, 313– 323,  DOI: 10.1016/j.ijpharm.2017.08.099
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    Impact of Eudragit EPO and hydroxypropyl methylcellulose on drug release rate, supersaturation, precipitation outcome and redissolution rate of indomethacin amorphous solid dispersions
    Xie, Tian; Gao, Wei; Taylor, Lynne S.
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 531 (1), 313-323CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    The purpose of this work was to evaluate the impact of polymer(s) on the dissoln. rate, supersatn. and pptn. of indomethacin amorphous solid dispersions (ASD), and to understand the link between ppt. characteristics and redissoln. kinetics. The cryst. and amorphous solubilities of indomethacin were detd. in the absence and presence of hydroxypropylmethyl cellulose (HPMC) and/or Eudragit EPO to establish relevant phase boundaries. At acidic pH, HPMC could maintain supersatn. of the drug by effectively inhibiting soln. crystn. while EPO increased both the cryst. and amorphous soly. of the drug, but did not inhibit crystn. The HPMC dispersion dissolved relatively slowly without undergoing crystn. while the supersatn. generated by rapid dissoln. of the EPO ASD was short-lived due to crystn. The crystals thus generated underwent rapid redissoln. upon pH increase, dissolving faster than the ref. cryst. material, and at a comparable rate to the amorphous HPMC dispersion. A ternary dispersion contg. both EPO and HPMC dissolved rapidly, generating an apparent drug concn. that exceeded the amorphous soly. of indomethacin, leading to the formation of a new nanosized droplet phase. These nanodroplets dissolved virtually immediately when the pH was increased. In conclusion, the concn.-time profiles achieved from indomethacin ASD dissoln. are a complex interplay of drug release rate, pptn. kinetics and outcome, and ppt. redissoln. rate, whereby each of these processes is highly dependent on the polymer(s) employed in the formulation.
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    Duggirala, N. K.; Li, J.; Kumar, N. S. K.; Gopinath, T.; Suryanarayanan, R. A supramolecular synthon approach to design amorphous solid dispersions with exceptional physical stability. Chem. Commun. 2019, 55, 5551– 5554,  DOI: 10.1039/C9CC02021G
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    A supramolecular synthon approach to design amorphous solid dispersions with exceptional physical stability
    Duggirala, Naga Kiran; Li, Jinghan; Kumar, N. S. Krishna; Gopinath, Tata; Suryanarayanan, Raj
    Chemical Communications (Cambridge, United Kingdom) (2019), 55 (39), 5551-5554CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A supramol. synthon approach was exploited to design amorphous solid dispersions (ASDs) of drugs contg. an amino arom. nitrogen moiety and a polyacrylic acid polymer. The interaction between a drug and polymer was confirmed by differential scanning calorimetry, spectroscopy (IR and 15N NMR), and X-ray crystallog. The interaction decreased the mol. mobility, conferred exceptional phys. stability and enhanced the drug dissoln.
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    Cholo, M. C.; Steel, H. C.; Fourie, P. B.; Germishuizen, W. A.; Anderson, R. Clofazimine: Current status and future prospects. J. Antimicrob. Chemother. 2012, 67, 290– 298,  DOI: 10.1093/jac/dkr444
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    Clofazimine: current status and future prospects
    Cholo, Moloko C.; Steel, Helen C.; Fourie, P. B.; Germishuizen, Willem A.; Anderson, Ronald
    Journal of Antimicrobial Chemotherapy (2012), 67 (2), 290-298CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
    A review. Clofazimine, a lipophilic riminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities. However, its efficacy has been demonstrated only in the treatment of leprosy, not in human tuberculosis, despite the fact that this agent is impressively active in vitro against multidrug-resistant strains of Mycobacterium tuberculosis. Recent insights into novel targets and mechanisms of antimicrobial and anti-inflammatory activity coupled with the acquisition of innovative drug delivery technologies have, however, rekindled interest in clofazimine as a potential therapy for multidrug- and extensively multidrug-resistant tuberculosis in particular, as well as several autoimmune diseases. The primary objective of this review is to critically evaluate these recent developments and to assess their potential impact on improving the therapeutic efficacy and versatility of clofazimine.
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    Quigley, J. M.; Blake, J. M.; Bonner, F. J. The effect of ionization on the partitioning of clofazimine in the 2,2,4-trimetylpentane-water system. Int. J. Pharm. 1989, 54, 155– 159,  DOI: 10.1016/0378-5173(89)90335-9
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    The effect of ionization on the partitioning of clofazimine in the 2,2,4-trimethylpentane-water system
    Quigley, John M.; Blake, Joan M.; Bonner, Francis J.
    International Journal of Pharmaceutics (1989), 54 (2), 155-9CODEN: IJPHDE; ISSN:0378-5173.
    The pH dependence of the 2,2,4-trimethylpentane-water partition coeff. of clofazimine (I) is studied at 37°. A model is presented which includes contributions from the ionized (Pi) and unionized (Pu) species to the obsd. apparent partition coeff. (P'). The value of Pi is much smaller than that of Pu with the ratio Pi/Pu, designated Q, equal to 1.012 × 10-4. However, at low pH, the former term becomes increasingly predominant and it is desirable to assess its contribution quant. to the apparent partition coeff.
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    Swift, T.; Swanson, L.; Geoghegan, M.; Rimmer, S. The pH-responsive behavior of poly(acrylic acid) in aqueous solution is dependent on molar mass. Soft Matter 2016, 12, 2542– 2549,  DOI: 10.1039/C5SM02693H
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    The pH-responsive behaviour of poly(acrylic acid) in aqueous solution is dependent on molar mass
    Swift, Thomas; Swanson, Linda; Geoghegan, Mark; Rimmer, Stephen
    Soft Matter (2016), 12 (9), 2542-2549CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
    Fluorescence spectroscopy on a series of aq. solns. of poly(acrylic acid) contg. a luminescent label showed that polymers with molar mass, Mn < 16.5 kDa did not exhibit a pH responsive conformational change, which is typical of higher molar mass poly(acrylic acid). Below this molar mass, polymers remained in an extended conformation, regardless of pH. Above this molar mass, a pH-dependent conformational change was obsd. Diffusion-ordered NMR spectroscopy confirmed that low molar mass polymers did not undergo a conformational transition, although large molar mass polymers did exhibit pH-dependent diffusion.
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    Nie, H.; Su, Y.; Zhang, M.; Song, Y.; Leone, A.; Taylor, L. S.; Marsac, P. J.; Li, T.; Byrn, S. R. Solid-state spectroscopic inverstigation of molecular interactions between clofazimine and Hypromellose phthalate in amorphous solid dispersions. Mol. Pharmaceutics 2016, 13, 3964– 3975,  DOI: 10.1021/acs.molpharmaceut.6b00740
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    Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions
    Nie, Haichen; Su, Yongchao; Zhang, Mingtao; Song, Yang; Leone, Anthony; Taylor, Lynne S.; Marsac, Patrick J.; Li, Tonglei; Byrn, Stephen R.
    Molecular Pharmaceutics (2016), 13 (11), 3964-3975CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    It has been tech. challenging to specify the detailed mol. interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug-polymer interactions from a mol. perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and phys. stability, was selected as a model system. The CLF-HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including UV-visible (UV/Vis), IR, and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addn., multivariate anal. of spectra was applied to optimize the concn. of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was exptl. investigated from 2D 1H-1H homonuclear double quantum NMR spectra by utilizing the ultrafast Magic-Angle Spinning (MAS) technique. The mol. interaction pattern and the crit. bonding structure in CLF-HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chem. calcns. These high resoln. investigations provide crit. structural information of API-polymer interaction, which can be useful for rational selection of appropriate polymeric carriers which are effective crystn. inhibitors for amorphous drugs.
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    Bannigan, P.; Zeglinski, J.; Lusi, M.; O’Brien, J.; Hudson, S. P. Investigation into the solid and solution properties of known and novel polymorphs of the antimicrobial molecule clofazimine. Cryst. Growth Des. 2016, 16, 7240– 7250,  DOI: 10.1021/acs.cgd.6b01411
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    Investigation into the Solid and Solution Properties of Known and Novel Polymorphs of the Antimicrobial Molecule Clofazimine
    Bannigan, Pauric; Zeglinski, Jacek; Lusi, Matteo; O'Brien, John; Hudson, Sarah P.
    Crystal Growth & Design (2016), 16 (12), 7240-7250CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Clofazimine is an anti-mycobacterial agent used as part of a multidrug treatment for leprosy. Recently clofazimine has shown promising activity against multidrug resistant tuberculosis. Clofazimine has been previously known to exist in two different crystal forms, or polymorphs, which are triclinic (F I) and monoclinic (F II) in crystal structure. The thermodn. relationship between, and the soly. of, these different crystal structures of clofazimine has not previously been characterized. In this work, their solid and soln. properties are studied, and as a result, two novel polymorphs of clofazimine (an orthorhombic crystal polymorph and a high temp. polymorph with a monoclinic structure) are reported. The properties of these new solid forms are compared and contrasted with those of the two previously reported polymorphs using thermal, spectroscopic, and microscopic techniques. Mol. modeling studies were also carried out to predict the relative thermodn. relationship and the crystal morphol. of the polymorphs. There was an excellent correlation obsd. between the aforementioned exptl. and mol. modeling results, allowing for the unequivocal detn. of the thermodn. relationship between all four polymorphs of clofazimine.
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    McNeill, I. C.; Sadeghi, S. M. T. Thermal stability and degradation mechanisms of poly(acrylic acid) and its salts: Part I – poly(acrylic acid). Polym. Degrad. Stab. 1990, 29, 233– 246,  DOI: 10.1016/0141-3910(90)90034-5
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    Thermal stability and degradation mechanisms of poly(acrylic acid) and its salts. Part 1. Poly(acrylic acid)
    McNeill, I. C.; Sadeghi, S. M. T.
    Polymer Degradation and Stability (1990), 29 (2), 233-46CODEN: PDSTDW; ISSN:0141-3910.
    The thermal degrdn. of poly(acrylic acid) (I) was studied using thermal volatilization anal. (TVA) and thermogravimetry (TG). The degrdn. studies were carried out using two approaches. Programmed heating was carried out at 10°/min to 170-500° and I was also heated isothermally at 210° for different times, under TVA conditions. Quant. measurements of the main product fractions were made. The gaseous, volatile liq. and cold ring fraction (CRF) products from TVA degrdn. were analyzed by IR, MS and GC-MS techniques. I gave H2O and CO2 as major products. The degraded I develops anhydride ring structures in the chain as a result of a dehydration process. At higher degrdn. temps., chain fragments with anhydride rings and/or acid groups are formed, together with various minor volatile products. The mechanism of degrdn. is discussed.
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    Valetti, S.; Xia, X.; Costa-Gouveia, J.; Brodin, P.; Bernet-Camard, M.-F.; Andersson, M.; Feiler, A. Clofazimine encapsulation in nanoporous silica particles for the oral treatment of antibiotic-resistant Mycobacterium tuberculosis infections. Nanomedicine 2017, 12, 831– 844,  DOI: 10.2217/nnm-2016-0364
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    Clofazimine encapsulation in nanoporous silica particles for the oral treatment of antibiotic-resistant Mycobacterium tuberculosis infections
    Valetti, Sabrina; Xia, Xin; Costa-Gouveia, Joana; Brodin, Priscille; Bernet-Camard, Marie-Francoise; Andersson, Margareta; Feiler, Adam
    Nanomedicine (London, United Kingdom) (2017), 12 (8), 831-844CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)
    Aim: First extensive reformulation of clofazimine (CLZ) in nanoporous silica particles (NSPs) for tackling antibiotic-resistant tuberculosis (TB) infections. Materials & methods: Solid-state characterization of several CLZ-encapsulated NSP formulations was followed by in vitro drug soly., Caco-2 intestinal cells drug permeability and TB antibacterial activity. Results: NSPs stabilize the amorphous state of CLZ (shelf stability >6 mo) and dramatically increase the drug soly. in simulated gastric fluid (up to 20-fold) with different dissoln. kinetics depending on the NSPs used. CLZ encapsulation in NSP substantially enhances the permeation through model intestinal cell layer, achieving effective antimicrobial concns. in TB-infected macrophages. Conclusion: Promising results toward refurbishment of an approved marketed drug for a different indication suitable for oral anti-TB formulation.
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    Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging
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    AIM: The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging. METHODS: Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging. RESULTS: While food intake reduced the mean fluid volumes in the small intestine (105 +/- 72 mL vs. 54 +/- 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 +/- 12 mL vs. 18 +/- 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01). CONCLUSIONS: The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex.
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    Determination of tablet strength by the diametral-compression test
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    The strength of lactose tablets was measured by application of the diametral-compression test. The relative value of tensile, compressive, and shear stresses within the tablet varies, depending on the characteristics of the tablets and the surface providing the applied compression. To obtain reproducible results for the strength of tablets prepd. at a given compression force, the tablet must break in such a manner that the tensile stress is the major stress. For a given tablet, this may require the placing of suitable padding material between the tablet and the compressing surfaces. Assessment of the type of failure can be made visually and under the correct conditions, the results expressed as a tensile strength. There are, however, a range of conditions which ensure tensile failure resulting in different values for the tensile strength. These values are characteristic of the tablet and test conditions and are not abs. values of tensile strength.
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    Solvents define a major part of the environmental performance of processes in the chem. industry and also impact on cost, safety and health issues. The idea of "green" solvents expresses the goal of minimizing the environmental impact resulting from the use of solvents in chem. prodn. Here the question is raised of how to measure how "green" a solvent is. We propose a comprehensive framework for the environmental assessment of solvents that covers major aspects of the environmental performance of solvents in chem. prodn., as well as important health and safety issues. The framework combines the assessment of substance-specific hazards with the quantification of emissions and resource use over the full life-cycle of a solvent. The proposed framework is demonstrated on 26 org. solvents. The results show that simple alcs. (methanol, ethanol) or alkanes (heptane, hexane) are environmentally preferable solvents, whereas the use of dioxane, acetonitrile, acids, formaldehyde, and THF is not recommendable from an environmental perspective. Addnl., a case study is presented in which the framework is applied for the assessment of various alc.-water or pure alc. mixts. used for solvolysis of p-methoxybenzoyl chloride. The results of this case study indicate that methanol-water or ethanol-water mixts. are environmentally favorable as compared to pure alc. or propanol-water mixts. The two applications demonstrate that the presented framework is a useful instrument for selection of green solvents or environmentally sound solvent mixts. for processes in chem. industry. The same framework can also be used for a comprehensive assessment of new solvent technols. as soon as the present lack of data can be overcome.
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  • Abstract

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    Scheme 1

    Scheme 1. Chemical Structures of CFZ, PAA, PVP and PVP/VAa
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    aThe functional groups of CFZ and PAA responsible for basicity and acidity are highlighted along with pKa values.

    Figure 1

    Figure 1. PXRD patterns of solid products from reactions performed under different conditions (see Table 2).

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    Figure 2

    Figure 2. Glass transitions in PAA, amorphous CFZ–PAA salt, and CFZ detected by DSC.

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    Figure 3

    Figure 3. (A) Visible absorption spectra of amorphous CFZ–PAA films at different drug concentration. (B) λmax (wavelength of maximal absorption) vs drug concentration. The color of each data point corresponds to the spectrum in (A) of the same color. By extrapolation, the saturation drug concentration is determined at 70 wt %. (C) Percentage of protonated CFZ vs drug loading by fitting the spectra in (A) to a two-state model.

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    Figure 4

    Figure 4. Physical stability of amorphous CFZ–PAA salt at 40 °C and 75% RH. (A) PXRD patterns before and after storage of the CFZ–PAA salt and of the neutral CFZ–PVP and CFZ–PVP/VA dispersions. The CFZ–PAA salt remained amorphous after 180 days, but the neutral CFZ–PVP and CFZ–PVP/VA dispersions crystallized as the free base (bottom trace). (B) Crystallinity change as a function of time.

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    Figure 5

    Figure 5. (A) Dissolution kinetics of crystalline CFZ and amorphous CFZ–PAA salt as prepared and after 180 days at 40 °C and 75% RH in SGF. 75 wt % drug loading in the amorphous salt. The error bar indicates standard deviation of two independent preparations tested. (B) PXRD patterns of solid residues after dissolution in SGF. The crystalline CFZ and the amorphous CFZ–PAA salt both transformed to a crystalline CFZ–DS salt.

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    Figure 6

    Figure 6. (A) Dissolution kinetics of amorphous CFZ–PAA salt and crystalline CFZ in FaSSIF. 75 wt % drug loading in the amorphous salt. (B) PXRD of solid residues after dissolution in FaSSIF. They are mostly crystalline CFZ.

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    Figure 7

    Figure 7. ζ potentials of the amorphous CFZ–PAA salt as a function of drug loading and of CFZ particles coated with PAA and alginic acid, as labeled. Error bar is the standard deviation for three measurements.

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    Figure 8

    Figure 8. (A) Tensile strength of tablets prepared with amorphous CFZ–PAA (75 wt % drug loading) and crystalline CFZ. The amorphous salt produces stronger tablets at a given compaction pressure. (B) PXRD patterns of amorphous CFZ–PAA salt before and after compaction, indicating no crystallization during compaction. (C) Angles of repose of amorphous CFZ–PAA salt (75 wt % drug loading) and the physical mixture of CFZ and PAA.

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    Figure 9

    Figure 9. Enhanced stability of amorphous drug–polymer salts against crystallization. The curves represent the free energies of mixing to form (1) a neutral drug dispersed in a neutral polymer, (2) an amorphous drug–polymer salt, and (3) neutral-drug crystals in a polymer matrix.

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  • References

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    This article references 46 other publications.

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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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      Newman, A.; Knipp, G.; Zografi, G. Assessing the performance of amorphous solid dispersions. J. Pharm. Sci. 2012, 101, 1355– 1377,  DOI: 10.1002/jps.23031
      2
      Assessing the performance of amorphous solid dispersions
      Newman, Ann; Knipp, Gregory; Zografi, George
      Journal of Pharmaceutical Sciences (2012), 101 (4), 1355-1377CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
      A review. The characterization and performance of stable amorphous solid dispersion systems were evaluated in 40 research papers reporting active pharmaceutical ingredient (API) dissoln. and bioavailability from various systems contg. polymers. The results from these studies were broadly placed into three categories: amorphous dispersions that improved bioavailability (∼82% of the cases), amorphous dispersions possessing lower bioavailability than the ref. material (∼8% of the cases), and amorphous dispersions demonstrating similar bioavailabilities as the ref. material (∼10% of the cases). A comparative anal. of these studies revealed several in vitro and in vivo variables that could have influenced the results. The in vitro factors compared primarily centered on dissoln. testing and equipment, content and amt. of dissoln. media, sink or nonsink conditions, agitation rates, media pH, dissoln. characteristics of the polymer, and dispersion particle size. The in vivo factors included ref. materials used for bioavailability comparisons, animal species utilized, fasting vs. fed conditions, and regional differences in gastrointestinal (GI) content and vol. On the basis of these considerations, a no. of recommendations were made on issues ranging from the assessment of phys. stability of API-polymer dispersions to in vivo GI physiol. factors that require consideration in the performance evaluation of these systems. © 2011 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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      Huang, C.; Powell, C. T.; Sun, Y.; Cai, T.; Yu, L. Effect of low-concentration polymers on crytal growth in molecular glasses: a controlling role for polymer segmental mobility relative to host dynamics. J. Phys. Chem. B 2017, 121, 1963– 1971,  DOI: 10.1021/acs.jpcb.6b11816
      3
      Effect of Low-Concentration Polymers on Crystal Growth in Molecular Glasses: A Controlling Role for Polymer Segmental Mobility Relative to Host Dynamics
      Huang, Chengbin; Powell, C. Travis; Sun, Ye; Cai, Ting; Yu, Lian
      Journal of Physical Chemistry B (2017), 121 (8), 1963-1971CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Low-concn. polymers can strongly affect crystal growth in small-mol. glasses, a phenomenon important for improving phys. stability against crystn. We measured the velocities of crystal growth in two mol. glasses, nifedipine (NIF) and o-terphenyl (OTP), each doped with 4 or 5 different polymers. For each polymer, the concn. was fixed at 1 wt % and a wide range of mol. wts. was tested. We find that a polymer additive can strongly alter the rate of crystal growth, from a 10-fold redn. to a 10-fold increase. For a given polymer, increasing mol. wt. systematically slows down crystal growth and the effect sats. around DP = 100, where DP is the d.p. For all the systems studied, the polymer effect on crystal growth rate forms a master curve in the variable (Tg polymer - Tg host)/T cryst, where Tg is the glass transition temp. and Tcryst is the crystn. temp. These results support the view that a polymer's effect on crystal growth is controlled by its segmental mobility relative to the host-mol. dynamics. In the proposed model, crystal growth rejects impurities and creates local polymer-rich regions, which must be traversed by host mols. to sustain crystal growth at rates detd. by segmental mobility. Our results do not support the view that host-polymer hydrogen bonding plays a controlling role in crystal growth inhibition.
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    4. 4
      Yao, X.; Huang, C.; Benson, E. G.; Shi, C.; Zhang, G. G. Z.; Yu, L. Effect of polymers on crystallization in glass-forming molecular liquids: equal suppression of nucleation and growth and master curve for prediction. Cryst. Growth Des. 2020, 20, 237– 244,  DOI: 10.1021/acs.cgd.9b01095
      4
      Effect of Polymers on Crystallization in Glass-Forming Molecular Liquids: Equal Suppression of Nucleation and Growth and Master Curve for Prediction
      Yao, Xin; Huang, Chengbin; Benson, Emily G.; Shi, Chenyang; Zhang, Geoff G. Z.; Yu, Lian
      Crystal Growth & Design (2020), 20 (1), 237-244CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Crystal nucleation plays a crit. role in the stability of supercooled liqs. and glasses and is often controlled through addn. of polymers. A dissolved polymer alters both the thermodn. and the kinetics of nucleation, but the current understanding of these effects is limited. The rate of crystal nucleation has been measured in two mol. liqs., D-sorbitol and D-arabitol, contg. polyvinylpyrrolidone (PVP) at different concns. (0-15 wt %) and mol. wts. (224 g/mol for the dimer up to 2 Mg/mol). We observe a significant inhibitory effect of PVP on crystal nucleation. Near the peak temp. for the nucleation rate (∼20 K above the glass transition temp.), 10 wt % PVP can slow down nucleation by approx. 1 order of magnitude, and the effect increases with polymer concn. exponentially and with mol. wt. Remarkably, the polymer effect on the nucleation rate is nearly the same as that on the crystal growth rate so that the ratio of the two rates is nearly const. at a given temp. independent of polymer concn. and mol. wt. This "master curve" behavior can be used to predict nucleation rates in multicomponent systems from more easily measured growth rates. It argues that nucleation and growth in these viscous liqs. are both mobility-limited and that a polymer solute functions mainly as a mobility modifier, suppressing nucleation and growth to a similar degree. A polymer dissolved in a host liq. causes equal suppression of crystal growth and nucleation. This allows prediction of nucleation rates from the more easily measured growth rates.
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    5. 5
      Gui, Y.; Chen, Y.; Chen, Z.; Jones, K. J.; Yu, L. Improving stability and dissolution of amorphous clofazimine by polymer nano-coating. Pharm. Res. 2019, 36, 67,  DOI: 10.1007/s11095-019-2584-9
      5
      Improving Stability and Dissolution of Amorphous Clofazimine by Polymer Nano-Coating
      Gui Yue; Chen Yinshan; Chen Zhenxuan; Yu Lian; Jones Karen J; Yu Lian
      Pharmaceutical research (2019), 36 (5), 67 ISSN:.
      PURPOSE: To inhibit the surface crystallization and enhance the dissolution of the basic amorphous drug clofazimine by polymer nano-coating. METHODS: The free surface of amorphous clofazimine was coated by dip coating in an alginate solution at pH 7. The stability of the coated amorphous drug against crystallization was evaluated by X-ray diffraction and light microscopy. The effect of coating on dissolution rate was measured in simulated gastric fluid in an USP-II apparatus at 37°C. RESULTS: At pH 7, the weak base clofazimine (pKa = 8.5) is positively charged, while the weak alginic acid (pKa = 3.5) is negatively charged, allowing coating by electrostatic deposition. Coated amorphous particles remain nearly amorphous after one year under the accelerated testing condition 40°C/75% R.H. and show faster dissolution than uncoated particles. In the first hour of dissolution, coated amorphous particles dissolve 50% faster than uncoated amorphous particles, and a factor of 3 faster than crystalline particles of the same size. CONCLUSIONS: A pharmaceutically acceptable polymer, alginate, is coated on amorphous clofazimine by electrostatic deposition and effectively inhibits its surface crystallization and enhances its dissolution rate. This is the first time the nano-coating technique is applied to a basic drug using the principle of electrostatic deposition, demonstrating the generality of the approach.
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    6. 6
      Novakovic, D.; Peltonen, L.; Isomäki, A.; Fraser-Miller, S. J.; Nielsen, L. H.; Laaksonen, T.; Strachan, C. J. Surface stabilization and dissolution rate improvement of amorphous compacts with thin polymer coatings: Can we have it all?. Mol. Pharmaceutics 2020, 17, 1248– 1260,  DOI: 10.1021/acs.molpharmaceut.9b01263
      6
      Surface Stabilization and Dissolution Rate Improvement of Amorphous Compacts with Thin Polymer Coatings: Can We Have It All?
      Novakovic, Dunja; Peltonen, Leena; Isomaki, Antti; Fraser-Miller, Sara J.; Nielsen, Line Hagner; Laaksonen, Timo; Strachan, Clare J.
      Molecular Pharmaceutics (2020), 17 (4), 1248-1260CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      The distinction between surface and bulk crystn. of amorphous pharmaceuticals, as well as the importance of surface crystn. for pharmaceutical performance, is becoming increasingly evident. An emerging strategy in stabilizing the amorphous drug form is to utilize thin coatings at the surface. While the phys. stability of systems coated with pharmaceutical polymers has recently been studied, the effect on dissoln. performance as a function of storage time, as a further necessary step toward the success of these formulations, has not been previously studied. Furthermore, the effect of coating thickness has not been elucidated. This study investigated the effect of these polymer-coating parameters on the interplay between amorphous surface crystn. and drug dissoln. for the first time. The study utilized simple tablet-like coated dosage forms, comprising a continuous amorphous drug core and thin polymer coating (hundreds of nanometers to a micrometer thick). Monitoring included anal. of both the solid-state of the model drug (with SEM, XRD, and ATR FTIR spectroscopy) and dissoln. performance (and assocd. morphol. and solid-state changes) after different storage times. Stabilization of the amorphous form (dependent on the coating thickness) and maintenance of early-stage intrinsic dissoln. rates characteristic for the unaged amorphous drug were achieved. However, dissoln. in the latter stages was likely inhibited by the presence of a polymer at the surface. Overall, this study introduced a versatile coated system for studying the dissoln. of thin-coated amorphous dosage forms suitable for different drugs and coating agents. It demonstrated the importance of multiple factors that need to be taken into consideration when aiming to achieve both phys. stability and improved release during the shelf life of amorphous formulations.
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    7. 7
      Teerakapibal, R.; Gui, Y.; Yu, L. Gelatin nano-coating for inhibiting surface crystallization of amorphous drugs. Pharm. Res. 2018, 35, 23– 29,  DOI: 10.1007/s11095-017-2315-z
      7
      Gelatin Nano-coating for Inhibiting Surface Crystallization of Amorphous Drugs
      Teerakapibal Rattavut; Gui Yue; Yu Lian; Yu Lian
      Pharmaceutical research (2018), 35 (1), 23 ISSN:.
      PURPOSE: Inhibit the fast surface crystallization of amorphous drugs with gelatin nano-coatings. METHODS: The free surface of amorphous films of indomethacin or nifedipine was coated by a gelatin solution (type A or B) and dried. The coating's effect on surface crystallization was evaluated. Coating thickness was estimated from mass change after coating. RESULTS: For indomethacin (weak acid, pKa = 4.5), a gelatin coating of either type deposited at pH 5 and 10 inhibited its fast surface crystal growth. The coating thickness was 20 ± 10 nm. A gelatin coating deposited at pH 3, however, provided no protective effect. These results suggest that an effective gelatin coating does not require that the drug and the polymer have opposite charges. The ineffective pH 3 coating might reflect the poor wetting of indomethacin's neutral, hydrophobic surface by the coating solution. For nifedipine (weak base, pKa = 2.6), a gelatin coating of either type deposited at pH 5 inhibited its fast surface crystal growth. CONCLUSIONS: Gelatin nano-coatings can be conveniently applied to amorphous drugs from solution to inhibit fast surface crystallization. Unlike strong polyelectrolyte coatings, a protective gelatin coating does not require strict pairing of opposite charges. This could make gelatin coating a versatile, pharmaceutically acceptable coating for stabilizing amorphous drugs.
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    8. 8
      Li, Y.; Yu, J.; Hu, S.; Chen, Z.; Sacchetti, M.; Sun, C. C.; Yu, L. Polymer nanocoating of amorphous drugs for improving stability, dissolution, powder flow, and tabletability: The case of chitosan-coated indomethacin. Mol. Pharmaceutics 2019, 16, 1305– 1311,  DOI: 10.1021/acs.molpharmaceut.8b01237
      8
      Polymer Nanocoating of Amorphous Drugs for Improving Stability, Dissolution, Powder Flow, and Tabletability: The Case of Chitosan-Coated Indomethacin
      Li, Yuhui; Yu, Junguang; Hu, Shenye; Chen, Zhenxuan; Sacchetti, Mark; Sun, Changquan Calvin; Yu, Lian
      Molecular Pharmaceutics (2019), 16 (3), 1305-1311CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      As a result of its higher mol. mobility, the surface of an amorphous drug can grow crystals much more rapidly than the bulk, causing poor stability and slow dissoln. of drug products. We show that a nanocoating of chitosan (a pharmaceutically acceptable polymer) can be deposited on the surface of amorphous indomethacin by electrostatic deposition, leading to significant improvement of phys. stability, wetting by aq. media, dissoln. rate, powder flow, and tabletability. The coating condition was chosen so that the pos. charged polymer deposits on the neg. charged drug. Chitosan coating is superior to gelatin coating with respect to stability against crystn. and agglomeration of coated particles.
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    9. 9
      Capece, M.; Davé, R. Enhanced physical stability of amorphous drug formulations via dry polymer coating. J. Pharm. Sci. 2015, 104, 2076– 2084,  DOI: 10.1002/jps.24451
      9
      Enhanced physical stability of amorphous drug Formulations via dry polymer coating
      Capece, Maxx; Dave, Rajesh
      Journal of Pharmaceutical Sciences (2015), 104 (6), 2076-2084CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
      Although amorphous solid drug formulations may be advantageous for enhancing the bioavailability of poorly sol. active pharmaceutical ingredients, they exhibit poor phys. stability and undergo recrystn. To address this limitation, this study investigates stability issues assocd. with amorphous solids through anal. of the crystn. behavior for acetaminophen (APAP), known as a fast crystallizer, using a modified form of the Avrami equation that kinetically models both surface and bulk crystn. It is found that surface-enhanced crystn., occurring faster at the free surface than in the bulk, is the major impediment to the stability of amorphous APAP. It is hypothesized that a novel use of a dry-polymer-coating process referred to as mech.-dry-polymer-coating may be used to inhibit surface crystn. and enhance stability. The proposed process, which is examd., simultaneously mills and coats amorphous solids with polymer, while avoiding solvents or solns., which may otherwise cause stability or crystn. issues during coating. It is shown that solid dispersions of APAP (64% loading) with a small particle size (28 μm) could be prepd. and coated with the polymer, carnauba wax, in a vibratory ball mill. The resulting amorphous solid was found to have excellent stability as a result of inhibition of surface crystn. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    10. 10
      Zeng, A.; Yao, X.; Gui, Y.; Li, Y.; Jones, K. J.; Yu, L. Inhibiting surface crystallization and improving dissolution of amorphous loratadine by dextran sulfate nanocoating. J. Pharm. Sci. 2019, 108, 2391– 2396,  DOI: 10.1016/j.xphs.2019.02.018
      10
      Inhibiting surface crystallization and improving dissolution of amorphous loratadine by dextran sulfate nanocoating
      Zeng, Aiguo; Yao, Xin; Gui, Yue; Li, Yuhui; Jones, Karen J.; Yu, Lian
      Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) (2019), 108 (7), 2391-2396CODEN: JPMSAE; ISSN:0022-3549. (Elsevier Inc.)
      Amorphous formulations provide a soln. to poor soly. and slow dissoln. of many drugs, but fast surface crystn. can negate their advantages. As in the case of many amorphous drugs, loratadine (LTD) shows much faster crystal growth on the free surface than in the bulk, and its surface crystn. can be inhibited by a polymer nanocoating. LTD is a weak base with a pKa of 5.25. Dextran sulfate (DTS), a pharmaceutically acceptable polymer, is deposited on amorphous LTD from coating soln. at pH 3.5 at which LTD is pos. charged. Zeta potential measurements support the mechanism of nanocoating by electrostatic deposition. DTS nanocoating is as good as gold coating for inhibiting surface crystn. of amorphous LTD and significantly increases its rate of dissoln. The enhanced dissoln. is likely a result of improved wetting of amorphous particles by an aq. medium. These results indicate that fast surface crystn. of amorphous LTD is enabled by high mobility of surface mols., and an ultrathin nanocoating can immobilize surface mols. and inhibit surface crystn. This nanocoating technique can be used to stabilize amorphous drugs prone to surface crystn. and improve their dissoln., and DTS is an effective nanocoating material for basic drugs such as LTD.
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      Wu, T.; Sun, Y.; Li, N.; de Villiers, M. M.; Yu, L. Inhibiting surface crystallization of amorphous indomethacin by nanocoating. Langmuir 2007, 23, 5148– 5153,  DOI: 10.1021/la070050i
      11
      Inhibiting Surface Crystallization of Amorphous Indomethacin by Nanocoating
      Wu, Tian; Sun, Ye; Li, Ning; De Villiers, Melgardt M.; Yu, Lian
      Langmuir (2007), 23 (9), 5148-5153CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      An amorphous solid (glass) may crystallize faster at the surface than through the bulk, making surface crystn. a mechanism of failure for amorphous pharmaceuticals and other materials. An ultrathin coating of gold or polyelectrolytes inhibited the surface crystn. of amorphous indomethacin (IMC), an anti-inflammatory drug and model org. glass. The gold coating (10 nm) was deposited by sputtering, and the polyelectrolyte coating (3-20 nm) was deposited by an electrostatic layer-by-layer assembly of cationic poly(dimethyldiallyl ammonium chloride) (PDDA) and anionic sodium poly(styrenesulfonate) in aq. soln. The coating also inhibited the growth of existing crystals. The inhibition was strong even with one layer of PDDA. The polyelectrolyte coating still permitted fast dissoln. of amorphous IMC and improved its wetting and flow. The finding supports the view that the surface crystn. of amorphous IMC is enabled by the mobility of a thin layer of surface mols., and this mobility can be suppressed by a coating of only a few nanometers. This technique may be used to stabilize amorphous drugs prone to surface crystn., with the aq. coating process esp. suitable for drugs of low aq. soly.
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      Zhu, L.; Brian, C. W.; Swallen, S. F.; Straus, P. T.; Ediger, M. D.; Yu, L. Surface self-diffusion of an organic glass. Phys. Rev. Lett. 2011, 106, 256103,  DOI: 10.1103/PhysRevLett.106.256103
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      Surface self-diffusion of an organic glass
      Zhu, L.; Brian, C. W.; Swallen, S. F.; Straus, P. T.; Ediger, M. D.; Yu, L.
      Physical Review Letters (2011), 106 (25), 256103/1-256103/4CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
      Surface self-diffusion was measured for an org. glass. The flattening of 1000 nm surface gratings of liq. indomethacin occurs by viscous flow at 12 K or more above the glass transition temp. and by surface diffusion at lower temps. Surface diffusion is at least 106 times faster than bulk diffusion, indicating a highly mobile surface. Surface diffusion is the leading mechanism of surface evolution for org. glasses at micrometer to nanometer length scales.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosFWltLo%253D&md5=6d1c2121cdb86e1ac9ce35f11072548e
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      Brian, C. W.; Yu, L. Surface self-diffusion of organic glasses. J. Phys. Chem. A 2013, 117, 13303– 13309,  DOI: 10.1021/jp404944s
      13
      Surface Self-Diffusion of Organic Glasses
      Brian, Caleb W.; Yu, Lian
      Journal of Physical Chemistry A (2013), 117 (50), 13303-13309CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
      Surface self-diffusion coeffs. were detd. for the org. glass Nifedipine using the method of surface grating decay. The flattening of 1000 nm surface gratings occurs by viscous flow at 12 K or more above the glass transition temp. and by surface diffusion at lower temps. Surface diffusion is at least 107 times faster than bulk diffusion, indicating a highly mobile surface. Nifedipine glasses have faster surface diffusion than the previously studied Indomethacin glasses, despite their similar bulk relaxation times. Both glasses exhibit fast surface crystal growth, and its rate scales with surface diffusivity. The obsd. rate of surface diffusion implies substantial surface rearrangement during the prepn. of low-energy glasses by vapor deposition. The Random First Order Transition Theory and the Coupling Model successfully predict the large surface-enhancement of mobility and its increase on cooling, but disagree with the exptl. observation of the faster surface diffusion of Nifedipine.
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      Zhang, W.; Brian, C. W.; Yu, L. Fast surface diffusion of amorphous o-terphenyl and its competition with viscous flow in surface evolution. J. Phys. Chem. B 2015, 119, 5071– 5078,  DOI: 10.1021/jp5127464
      14
      Fast Surface Diffusion of Amorphous o-Terphenyl and Its Competition with Viscous Flow in Surface Evolution
      Zhang, Wei; Brian, Caleb W.; Yu, Lian
      Journal of Physical Chemistry B (2015), 119 (15), 5071-5078CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Surface self-diffusion coeffs. have been measured for the model mol. glass o-terphenyl (OTP) through surface-grating decay driven by capillarity. The decay mechanism transitions from viscous flow at high temps. to surface diffusion at low temps.; for 1000 nm wavelength gratings, the transition occurs at Tg + 11 K. The surface diffusion of OTP is 108 times faster than bulk diffusion at Tg and even faster at lower temps. because of its weaker temp. dependence. At Tg, OTP has approx. the same bulk diffusivity as the previously studied mol. liq. indomethacin, but its surface diffusion is 100 times faster. While the mol. glass-formers exhibit transitions from viscous flow to surface diffusion as the mechanism of capillarity-driven surface flattening, polystyrenes and silicates show no such transition under comparable conditions, suggesting slower surface diffusion on these materials and a general dependence of surface diffusion on intermol. forces. The velocity of surface crystal growth on mol. glasses is proportional to surface diffusivity, indicating a common kinetic barrier for both processes for temps. below Tg.
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      Zhu, L.; Wong, L.; Yu, L. Surface-enhanced crystallization of amorphous nifedipine. Mol. Pharmaceutics 2008, 5, 921– 926,  DOI: 10.1021/mp8000638
      15
      Surface-Enhanced Crystallization of Amorphous Nifedipine
      Zhu, Lei; Wong, Letitia; Yu, Lian
      Molecular Pharmaceutics (2008), 5 (6), 921-926CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Amorphous solids are generally more sol. and faster dissolving than their cryst. counterparts, a property useful for delivering poorly sol. drugs. Amorphous drugs must be stable against crystn., for crystn. negates their advantages. Recent studies found that crystal growth in amorphous indomethacin is orders of magnitude faster at the free surface than through the bulk and this surface-enhanced crystn. can be inhibited by an ultrathin coating. Herein, we report a second system that exhibits the same phenomena. Crystal growth at the free surface of amorphous nifedipine (NIF) was at least 1 order of magnitude faster than that through the bulk below the glass transition temp. Tg (42 °C). A thin coating of gold (10 nm) reduced the surface crystal growth rate to the bulk crystal growth rate. Surface-enhanced crystal growth was more pronounced near and below Tg than substantially above Tg, which suggests that this growth mode is more important for the glassy state. Our results support the view that a thin layer of mols. near the surface have higher mobility than the bulk mols. and can enable faster crystal growth. The higher mobility of surface mols. and the resulting fast crystal growth can be suppressed by an ultrathin coating.
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    16. 16
      Shi, Q.; Cai, T. Fast crystal growth of amorphous griseofulvin: relations between bulk and surface growth modes. Cryst. Growth Des. 2016, 16, 3279– 3286,  DOI: 10.1021/acs.cgd.6b00252
      16
      Fast Crystal Growth of Amorphous Griseofulvin: Relations between Bulk and Surface Growth Modes
      Shi, Qin; Cai, Ting
      Crystal Growth & Design (2016), 16 (6), 3279-3286CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Griseofulvin (GSF), a poorly H2O-sol. antifungal drug, is a model system for studying the phys. stability of amorphous pharmaceuticals. The crystn. kinetics of GSF in the bulk and at the surface was examd. as a function of temp. A sudden 10-fold rise of bulk crystal growth rate was obsd. near Tg, a phenomenon similar to that obsd. in other mol. glasses and termed glass-to-crystal (GC) growth. Analogous to other mol. glasses, GSF grows crystals much faster at the free surface than in the bulk. What distinguishes GSF from other systems is that surface crystn. can occur well above Tg (up to Tg + 62°). Another peculiar feature of GSF is that during bulk crystal growth at 130-150°, some crystals protruded well ahead of the normal growth front at the same growth rate as surface crystals. The authors suspect this protruding crystal growth is a surface-facilitated process through the formation of voids and free surfaces during bulk crystal growth. These new findings are important for understanding the mechanisms and connections for the bulk and surface crystn. in amorphous pharmaceutical solids.
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    17. 17
      Huang, C.; Ruan, S.; Cai, T.; Yu, L. Fast surface diffusion and crystallization of amorphous griseofulvin. J. Phys. Chem. B 2017, 121, 9463– 9468,  DOI: 10.1021/acs.jpcb.7b07319
      17
      Fast surface diffusion and crystallization of amorphous Griseofulvin
      Huang, Chengbin; Ruan, Shigang; Cai, Ting; Yu, Lian
      Journal of Physical Chemistry B (2017), 121 (40), 9463-9468CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Among mol. glasses, griseofulvin (GSF) is one of the fastest crystg. To understand this property, we have measured the surface diffusion in GSF using the method of surface grating decay. Surface diffusion in amorphous GSF is extremely fast, outpacing bulk diffusion by a factor of 108 at the glass transition temp. Tg (361 K). Among all mol. glasses studied (13 in all), GSF has the second fastest surface diffusion (to o-terphenyl) when compared at Tg. The GSF result fits the overall trend for mol. glasses without intermol. hydrogen bonds, where surface diffusion systematically slows down with increasing mol. size. This result is particularly noteworthy because GSF has many hydrogen-bond acceptors but no donors, indicating that, so long as they do not participate in hydrogen bonding, the polar functional groups have a similar effect on surface diffusion as the nonpolar hydrocarbon groups. In contrast, the formation of intermol. hydrogen bonds strongly inhibits surface diffusion. The surface crystal growth rate of amorphous GSF is nearly proportional to its surface diffusion coeff., as noted for other systems, supporting the view that surface crystal growth is controlled by surface diffusion. In addn., the fast surface diffusion of GSF glasses explains the fast crystal growth along fracture surfaces and suggests a basis to understand fast crystal growth in the bulk through continuous creation of microcracks.
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    18. 18
      Stahl, P. H. In Handbook of Pharmaceutical Salts: Properties, Selection, and Use; Wermuth, C. G., Stahl, P. H., Eds.; Verlag Helvetica Chimica Acta: Zürich, Switzerland; and Wiley-VCH: Weinheim, Germany, 2008.
      There is no corresponding record for this reference.
    19. 19
      Albano, A. A.; Phuapradit, W.; Sandhu, H. K.; Shah, N. H. Stable complexes of poorly soluble compounds in ionic polymers. United States Patent US6350786B1, 2002.
      There is no corresponding record for this reference.
    20. 20
      Kindermann, C.; Matthée, K.; Strohmeyer, J.; Sievert, F.; Breitkreutz, J. Tailor-made release triggering from hot-melt extruded complexes of basic polyelectrolyte and poorly water-soluble drugs. Eur. J. Pharm. Biopharm. 2011, 79, 372– 381,  DOI: 10.1016/j.ejpb.2011.05.001
      20
      Tailor-made release triggering from hot-melt extruded complexes of basic polyelectrolyte and poorly water-soluble drugs
      Kindermann, Christoph; Matthee, Karin; Strohmeyer, Jutta; Sievert, Frank; Breitkreutz, Joerg
      European Journal of Pharmaceutics and Biopharmaceutics (2011), 79 (2), 372-381CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)
      The aim of the study was the formulation of polyelectrolyte complexes composed of poorly water-sol. acid drugs and basic polymethacrylates by hot-melt extrusion enabling a tailor-made release pattern by the addn. of inorg. salts. The influence of different electrolytes was analyzed at varying conditions in order to control drug delivery from the complexes. Poorly water-sol. model drugs naproxen and furosemide were applied in their non-ionic form. After hot-melt extrusion of the naproxen-polymethacrylate powder blend, XRPD and DSC measurements indicated the formation of a single-phase amorphous system. Milled extrudates were stable under storage at long-term and intermediate conditions. Polyelectrolyte complex formation by an acid-base reaction during hot-melt extrusion could be proven by the lack of vibrations of dimethylamino and carboxylic groups by FT-IR and Raman spectroscopy. The complexes did not dissolve in demineralized water. Drug release could be immediately induced by addn. of neutral electrolytes. Tailor-made dissoln. profiles were realized by controlled electrolyte triggering. Maximal effects were achieved by concns. of 0.05-0.15 M NaCl. Different anions of alkali halogenides revealed variant magnitudes of the effect depending on the anion radius. Polyelectrolyte complex formation and dissoln. principles were also confirmed for furosemide.
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    21. 21
      Xie, T.; Gao, W.; Taylor, L. S. Impact of Eudragit EPO and hydroxypropyl methylcellulose on drug release rate, supersaturation, precipitation outcome and redissolution rate of indomethacin amorphous solid dispersions. Int. J. Pharm. 2017, 531, 313– 323,  DOI: 10.1016/j.ijpharm.2017.08.099
      21
      Impact of Eudragit EPO and hydroxypropyl methylcellulose on drug release rate, supersaturation, precipitation outcome and redissolution rate of indomethacin amorphous solid dispersions
      Xie, Tian; Gao, Wei; Taylor, Lynne S.
      International Journal of Pharmaceutics (Amsterdam, Netherlands) (2017), 531 (1), 313-323CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      The purpose of this work was to evaluate the impact of polymer(s) on the dissoln. rate, supersatn. and pptn. of indomethacin amorphous solid dispersions (ASD), and to understand the link between ppt. characteristics and redissoln. kinetics. The cryst. and amorphous solubilities of indomethacin were detd. in the absence and presence of hydroxypropylmethyl cellulose (HPMC) and/or Eudragit EPO to establish relevant phase boundaries. At acidic pH, HPMC could maintain supersatn. of the drug by effectively inhibiting soln. crystn. while EPO increased both the cryst. and amorphous soly. of the drug, but did not inhibit crystn. The HPMC dispersion dissolved relatively slowly without undergoing crystn. while the supersatn. generated by rapid dissoln. of the EPO ASD was short-lived due to crystn. The crystals thus generated underwent rapid redissoln. upon pH increase, dissolving faster than the ref. cryst. material, and at a comparable rate to the amorphous HPMC dispersion. A ternary dispersion contg. both EPO and HPMC dissolved rapidly, generating an apparent drug concn. that exceeded the amorphous soly. of indomethacin, leading to the formation of a new nanosized droplet phase. These nanodroplets dissolved virtually immediately when the pH was increased. In conclusion, the concn.-time profiles achieved from indomethacin ASD dissoln. are a complex interplay of drug release rate, pptn. kinetics and outcome, and ppt. redissoln. rate, whereby each of these processes is highly dependent on the polymer(s) employed in the formulation.
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    22. 22
      Duggirala, N. K.; Li, J.; Kumar, N. S. K.; Gopinath, T.; Suryanarayanan, R. A supramolecular synthon approach to design amorphous solid dispersions with exceptional physical stability. Chem. Commun. 2019, 55, 5551– 5554,  DOI: 10.1039/C9CC02021G
      22
      A supramolecular synthon approach to design amorphous solid dispersions with exceptional physical stability
      Duggirala, Naga Kiran; Li, Jinghan; Kumar, N. S. Krishna; Gopinath, Tata; Suryanarayanan, Raj
      Chemical Communications (Cambridge, United Kingdom) (2019), 55 (39), 5551-5554CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      A supramol. synthon approach was exploited to design amorphous solid dispersions (ASDs) of drugs contg. an amino arom. nitrogen moiety and a polyacrylic acid polymer. The interaction between a drug and polymer was confirmed by differential scanning calorimetry, spectroscopy (IR and 15N NMR), and X-ray crystallog. The interaction decreased the mol. mobility, conferred exceptional phys. stability and enhanced the drug dissoln.
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    23. 23
      Cholo, M. C.; Steel, H. C.; Fourie, P. B.; Germishuizen, W. A.; Anderson, R. Clofazimine: Current status and future prospects. J. Antimicrob. Chemother. 2012, 67, 290– 298,  DOI: 10.1093/jac/dkr444
      23
      Clofazimine: current status and future prospects
      Cholo, Moloko C.; Steel, Helen C.; Fourie, P. B.; Germishuizen, Willem A.; Anderson, Ronald
      Journal of Antimicrobial Chemotherapy (2012), 67 (2), 290-298CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
      A review. Clofazimine, a lipophilic riminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities. However, its efficacy has been demonstrated only in the treatment of leprosy, not in human tuberculosis, despite the fact that this agent is impressively active in vitro against multidrug-resistant strains of Mycobacterium tuberculosis. Recent insights into novel targets and mechanisms of antimicrobial and anti-inflammatory activity coupled with the acquisition of innovative drug delivery technologies have, however, rekindled interest in clofazimine as a potential therapy for multidrug- and extensively multidrug-resistant tuberculosis in particular, as well as several autoimmune diseases. The primary objective of this review is to critically evaluate these recent developments and to assess their potential impact on improving the therapeutic efficacy and versatility of clofazimine.
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    24. 24
      Quigley, J. M.; Blake, J. M.; Bonner, F. J. The effect of ionization on the partitioning of clofazimine in the 2,2,4-trimetylpentane-water system. Int. J. Pharm. 1989, 54, 155– 159,  DOI: 10.1016/0378-5173(89)90335-9
      24
      The effect of ionization on the partitioning of clofazimine in the 2,2,4-trimethylpentane-water system
      Quigley, John M.; Blake, Joan M.; Bonner, Francis J.
      International Journal of Pharmaceutics (1989), 54 (2), 155-9CODEN: IJPHDE; ISSN:0378-5173.
      The pH dependence of the 2,2,4-trimethylpentane-water partition coeff. of clofazimine (I) is studied at 37°. A model is presented which includes contributions from the ionized (Pi) and unionized (Pu) species to the obsd. apparent partition coeff. (P'). The value of Pi is much smaller than that of Pu with the ratio Pi/Pu, designated Q, equal to 1.012 × 10-4. However, at low pH, the former term becomes increasingly predominant and it is desirable to assess its contribution quant. to the apparent partition coeff.
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    25. 25
      Swift, T.; Swanson, L.; Geoghegan, M.; Rimmer, S. The pH-responsive behavior of poly(acrylic acid) in aqueous solution is dependent on molar mass. Soft Matter 2016, 12, 2542– 2549,  DOI: 10.1039/C5SM02693H
      25
      The pH-responsive behaviour of poly(acrylic acid) in aqueous solution is dependent on molar mass
      Swift, Thomas; Swanson, Linda; Geoghegan, Mark; Rimmer, Stephen
      Soft Matter (2016), 12 (9), 2542-2549CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
      Fluorescence spectroscopy on a series of aq. solns. of poly(acrylic acid) contg. a luminescent label showed that polymers with molar mass, Mn < 16.5 kDa did not exhibit a pH responsive conformational change, which is typical of higher molar mass poly(acrylic acid). Below this molar mass, polymers remained in an extended conformation, regardless of pH. Above this molar mass, a pH-dependent conformational change was obsd. Diffusion-ordered NMR spectroscopy confirmed that low molar mass polymers did not undergo a conformational transition, although large molar mass polymers did exhibit pH-dependent diffusion.
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    26. 26
      Nie, H.; Su, Y.; Zhang, M.; Song, Y.; Leone, A.; Taylor, L. S.; Marsac, P. J.; Li, T.; Byrn, S. R. Solid-state spectroscopic inverstigation of molecular interactions between clofazimine and Hypromellose phthalate in amorphous solid dispersions. Mol. Pharmaceutics 2016, 13, 3964– 3975,  DOI: 10.1021/acs.molpharmaceut.6b00740
      26
      Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions
      Nie, Haichen; Su, Yongchao; Zhang, Mingtao; Song, Yang; Leone, Anthony; Taylor, Lynne S.; Marsac, Patrick J.; Li, Tonglei; Byrn, Stephen R.
      Molecular Pharmaceutics (2016), 13 (11), 3964-3975CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      It has been tech. challenging to specify the detailed mol. interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug-polymer interactions from a mol. perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and phys. stability, was selected as a model system. The CLF-HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including UV-visible (UV/Vis), IR, and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addn., multivariate anal. of spectra was applied to optimize the concn. of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was exptl. investigated from 2D 1H-1H homonuclear double quantum NMR spectra by utilizing the ultrafast Magic-Angle Spinning (MAS) technique. The mol. interaction pattern and the crit. bonding structure in CLF-HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chem. calcns. These high resoln. investigations provide crit. structural information of API-polymer interaction, which can be useful for rational selection of appropriate polymeric carriers which are effective crystn. inhibitors for amorphous drugs.
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    27. 27
      Bannigan, P.; Zeglinski, J.; Lusi, M.; O’Brien, J.; Hudson, S. P. Investigation into the solid and solution properties of known and novel polymorphs of the antimicrobial molecule clofazimine. Cryst. Growth Des. 2016, 16, 7240– 7250,  DOI: 10.1021/acs.cgd.6b01411
      27
      Investigation into the Solid and Solution Properties of Known and Novel Polymorphs of the Antimicrobial Molecule Clofazimine
      Bannigan, Pauric; Zeglinski, Jacek; Lusi, Matteo; O'Brien, John; Hudson, Sarah P.
      Crystal Growth & Design (2016), 16 (12), 7240-7250CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Clofazimine is an anti-mycobacterial agent used as part of a multidrug treatment for leprosy. Recently clofazimine has shown promising activity against multidrug resistant tuberculosis. Clofazimine has been previously known to exist in two different crystal forms, or polymorphs, which are triclinic (F I) and monoclinic (F II) in crystal structure. The thermodn. relationship between, and the soly. of, these different crystal structures of clofazimine has not previously been characterized. In this work, their solid and soln. properties are studied, and as a result, two novel polymorphs of clofazimine (an orthorhombic crystal polymorph and a high temp. polymorph with a monoclinic structure) are reported. The properties of these new solid forms are compared and contrasted with those of the two previously reported polymorphs using thermal, spectroscopic, and microscopic techniques. Mol. modeling studies were also carried out to predict the relative thermodn. relationship and the crystal morphol. of the polymorphs. There was an excellent correlation obsd. between the aforementioned exptl. and mol. modeling results, allowing for the unequivocal detn. of the thermodn. relationship between all four polymorphs of clofazimine.
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    28. 28
      McNeill, I. C.; Sadeghi, S. M. T. Thermal stability and degradation mechanisms of poly(acrylic acid) and its salts: Part I – poly(acrylic acid). Polym. Degrad. Stab. 1990, 29, 233– 246,  DOI: 10.1016/0141-3910(90)90034-5
      28
      Thermal stability and degradation mechanisms of poly(acrylic acid) and its salts. Part 1. Poly(acrylic acid)
      McNeill, I. C.; Sadeghi, S. M. T.
      Polymer Degradation and Stability (1990), 29 (2), 233-46CODEN: PDSTDW; ISSN:0141-3910.
      The thermal degrdn. of poly(acrylic acid) (I) was studied using thermal volatilization anal. (TVA) and thermogravimetry (TG). The degrdn. studies were carried out using two approaches. Programmed heating was carried out at 10°/min to 170-500° and I was also heated isothermally at 210° for different times, under TVA conditions. Quant. measurements of the main product fractions were made. The gaseous, volatile liq. and cold ring fraction (CRF) products from TVA degrdn. were analyzed by IR, MS and GC-MS techniques. I gave H2O and CO2 as major products. The degraded I develops anhydride ring structures in the chain as a result of a dehydration process. At higher degrdn. temps., chain fragments with anhydride rings and/or acid groups are formed, together with various minor volatile products. The mechanism of degrdn. is discussed.
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    29. 29
      Valetti, S.; Xia, X.; Costa-Gouveia, J.; Brodin, P.; Bernet-Camard, M.-F.; Andersson, M.; Feiler, A. Clofazimine encapsulation in nanoporous silica particles for the oral treatment of antibiotic-resistant Mycobacterium tuberculosis infections. Nanomedicine 2017, 12, 831– 844,  DOI: 10.2217/nnm-2016-0364
      29
      Clofazimine encapsulation in nanoporous silica particles for the oral treatment of antibiotic-resistant Mycobacterium tuberculosis infections
      Valetti, Sabrina; Xia, Xin; Costa-Gouveia, Joana; Brodin, Priscille; Bernet-Camard, Marie-Francoise; Andersson, Margareta; Feiler, Adam
      Nanomedicine (London, United Kingdom) (2017), 12 (8), 831-844CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)
      Aim: First extensive reformulation of clofazimine (CLZ) in nanoporous silica particles (NSPs) for tackling antibiotic-resistant tuberculosis (TB) infections. Materials & methods: Solid-state characterization of several CLZ-encapsulated NSP formulations was followed by in vitro drug soly., Caco-2 intestinal cells drug permeability and TB antibacterial activity. Results: NSPs stabilize the amorphous state of CLZ (shelf stability >6 mo) and dramatically increase the drug soly. in simulated gastric fluid (up to 20-fold) with different dissoln. kinetics depending on the NSPs used. CLZ encapsulation in NSP substantially enhances the permeation through model intestinal cell layer, achieving effective antimicrobial concns. in TB-infected macrophages. Conclusion: Promising results toward refurbishment of an approved marketed drug for a different indication suitable for oral anti-TB formulation.
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    30. 30
      NOVARTIS. U.S. Food and Drug Administration Web site. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=019500.
      There is no corresponding record for this reference.
    31. 31
      Dissolution testing of immediate release solid oral dosage forms. U.S. Food and Drug Administration Web site. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/dissolution-testing-immediate-release-solid-oral-dosage-forms.
      There is no corresponding record for this reference.
    32. 32
      Schiller, C.; Fröhlich, C.-P.; Giessmann, T.; Siegmund, W.; Mönnikes, H.; Hosten, N.; Weitschies, W. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment. Pharmacol. Ther. 2005, 22, 971– 979,  DOI: 10.1111/j.1365-2036.2005.02683.x
      32
      Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging
      Schiller C; Frohlich C-P; Giessmann T; Siegmund W; Monnikes H; Hosten N; Weitschies W
      Alimentary pharmacology & therapeutics (2005), 22 (10), 971-9 ISSN:0269-2813.
      AIM: The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging. METHODS: Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging. RESULTS: While food intake reduced the mean fluid volumes in the small intestine (105 +/- 72 mL vs. 54 +/- 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 +/- 12 mL vs. 18 +/- 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01). CONCLUSIONS: The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex.
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    33. 33
      Fell, J. T.; Newton, J. M. Determination of tablet strength by the diametral-compression test. J. Pharm. Sci. 1970, 59, 688– 691,  DOI: 10.1002/jps.2600590523
      33
      Determination of tablet strength by the diametral-compression test
      Fell, J. T.; Newton, John M.
      Journal of Pharmaceutical Sciences (1970), 59 (5), 688-91CODEN: JPMSAE; ISSN:0022-3549.
      The strength of lactose tablets was measured by application of the diametral-compression test. The relative value of tensile, compressive, and shear stresses within the tablet varies, depending on the characteristics of the tablets and the surface providing the applied compression. To obtain reproducible results for the strength of tablets prepd. at a given compression force, the tablet must break in such a manner that the tensile stress is the major stress. For a given tablet, this may require the placing of suitable padding material between the tablet and the compressing surfaces. Assessment of the type of failure can be made visually and under the correct conditions, the results expressed as a tensile strength. There are, however, a range of conditions which ensure tensile failure resulting in different values for the tensile strength. These values are characteristic of the tablet and test conditions and are not abs. values of tensile strength.
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    34. 34
      Capello, C.; Fischer, U.; Hungerbühler, K. What is a green solvent? A comprehensive framework for the environmental assessment of solvents. Green Chem. 2007, 9, 927– 934,  DOI: 10.1039/b617536h
      34
      What is a green solvent? A comprehensive framework for the environmental assessment of solvents
      Capello, Christian; Fischer, Ulrich; Hungerbuehler, Konrad
      Green Chemistry (2007), 9 (9), 927-934CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
      Solvents define a major part of the environmental performance of processes in the chem. industry and also impact on cost, safety and health issues. The idea of "green" solvents expresses the goal of minimizing the environmental impact resulting from the use of solvents in chem. prodn. Here the question is raised of how to measure how "green" a solvent is. We propose a comprehensive framework for the environmental assessment of solvents that covers major aspects of the environmental performance of solvents in chem. prodn., as well as important health and safety issues. The framework combines the assessment of substance-specific hazards with the quantification of emissions and resource use over the full life-cycle of a solvent. The proposed framework is demonstrated on 26 org. solvents. The results show that simple alcs. (methanol, ethanol) or alkanes (heptane, hexane) are environmentally preferable solvents, whereas the use of dioxane, acetonitrile, acids, formaldehyde, and THF is not recommendable from an environmental perspective. Addnl., a case study is presented in which the framework is applied for the assessment of various alc.-water or pure alc. mixts. used for solvolysis of p-methoxybenzoyl chloride. The results of this case study indicate that methanol-water or ethanol-water mixts. are environmentally favorable as compared to pure alc. or propanol-water mixts. The two applications demonstrate that the presented framework is a useful instrument for selection of green solvents or environmentally sound solvent mixts. for processes in chem. industry. The same framework can also be used for a comprehensive assessment of new solvent technols. as soon as the present lack of data can be overcome.
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    35. 35
      Tong, P.; Zografi, G. Solid-state characteristics of amorphous sodium indomethacin relative to its free acid. Pharm. Res. 1999, 16, 1186– 1192,  DOI: 10.1023/A:1018985110956
      35
      Solid-state characteristics of amorphous sodium indomethacin relative to its free acid
      Tong, Ping; Zografi, George
      Pharmaceutical Research (1999), 16 (8), 1186-1192CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
      Purpose. Having previously studied the amorphous properties of indomethacin (IN) as a model compd. for drugs rendered amorphous during processing, we report on the formation and characterization of its sodium salt in the amorphous state and a comparison between the 2 systems. Methods. Sodium indomethacin (SI) was subjected to lyophilization from aq. soln., rapid pptn. from methanol soln., and dehydration followed by grinding to produce, in each case, a completely amorphous form. The amorphous form of SI was analyzed by DSC, XRD, thermomicroscopy and FTIR. The method of scanning rate dependence of the glass transition temp., Tg, was used to est. the fragility of the SI system. Enthalpy relaxation expts. were carried out to probe the mol. mobility of the SI system below Tg. Results. The amorphous form of SI formed by different methods had a Tg equal to 121° at a scanning rate of 20°C/min. This compares with a Tg for indomethacin of 45°. Estn. of fragility by the scanning rate dependence of Tg indicates no significant differences in fragility between ionized and unionized forms. Enthalpy relaxation measurements reveal very similar relaxation patterns between the 2 systems at the same degree of supercooling relative to their resp. Tg values. Conclusions. The amorphous form of SI made by various methods has a Tg of about 75° greater than that of IN, most likely because of the greater d. and hence lower free vol. of SI. Yet, the change of mol. mobility as a function of temp. relative to Tg is not very different between the ionized and unionized systems.
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    36. 36
      Bureš, F. Fundamental aspects of property tuning in push-pull molecules. RSC Adv. 2014, 4, 58826– 58851,  DOI: 10.1039/C4RA11264D
      36
      Fundamental aspects of property tuning in push-pull molecules
      Bures, Filip
      RSC Advances (2014), 4 (102), 58826-58851CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      A review. Property tuning in selected examples of D-π-A mols. has been discussed and summarized in this review article. The tuning and structure-property relationships have been demonstrated on the particular A, π and D parts of the push-pull mol. Special emphasis has been put on the tuning of the FMO levels and optical properties. Further prospective applications of the given chromophore have also been considered.
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    37. 37
      Cruz-Cabeza, A. J. Acid-base crystalline complexes and the pKa rule. CrystEngComm 2012, 14, 6362– 6365,  DOI: 10.1039/c2ce26055g
      37
      Acid-base crystalline complexes and the pKa rule
      Cruz-Cabeza, Aurora J.
      CrystEngComm (2012), 14 (20), 6362-6365CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
      Differences in the predicted aq. pKa values (ΔpKa) have been calcd. for 6465 cryst. complexes contg. ionized and non-ionized acid-base pairs in the Cambridge Structural Database. A linear relationship between ΔpKa and the probability of proton transfer between acid-base pairs has been derived for cryst. complexes with ΔpKa between -1 and 4. The pKa rule is validated and quantitated.
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    38. 38
      Li, Z. J.; Abramov, Y.; Bordner, J.; Leonard, J.; Medek, A.; Trask, A. V. Solid-State Acid–Base Interactions in Complexes of Heterocyclic Bases with Dicarboxylic Acids: Crystallography, Hydrogen Bond Analysis, and 15N NMR Spectroscopy. J. Am. Chem. Soc. 2006, 128, 8199– 8210,  DOI: 10.1021/ja0541332
      38
      Solid-State Acid-Base Interactions in Complexes of Heterocyclic Bases with Dicarboxylic Acids: Crystallography, Hydrogen Bond Analysis, and 15N NMR Spectroscopy
      Li, Z. Jane; Abramov, Yuriy; Bordner, Jon; Leonard, Jason; Medek, Ales; Trask, Andrew V.
      Journal of the American Chemical Society (2006), 128 (25), 8199-8210CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A cancer candidate, compd. I, is a weak base with two heterocyclic basic nitrogens and five hydrogen-bonding functional groups, and is sparingly sol. in water rendering it unsuitable for pharmaceutical development. The cryst. acid-base pairs of I, collectively termed solid acid-base complexes, provide significant increases in the soly. and bioavailability compared to the free base, I. Three dicarboxylic acid-base complexes, sesquisuccinate 2, dimalonate 3, and dimaleate 4, show the most favorable physicochem. profiles and are studied in greater detail. The structural analyses of the three complexes using crystal structure and solid-state NMR reveal that the proton-transfer behavior in these org. acid-base complexes vary successively correlating with Δ pKa. As a result, 2 is a neutral complex, 3 is a mixed ionic and zwitterionic complex and 4 is an ionic salt. The addn. of the acidic components leads to maximized hydrogen bond interactions forming extended three-dimensional networks. Although structurally similar, the packing arrangements of the three complexes are considerably different due to the presence of multiple functional groups and the flexible backbone of I. The findings in this study provide insight into the structural characteristics of complexes involving heterocyclic bases and carboxylic acids, and demonstrate that x-ray crystallog. and 15N solid-state NMR are truly complementary in elucidating hydrogen bonding interactions and the degree of proton transfer of these complexes.
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    39. 39
      Bajaj, S.; Singla, D.; Sakhuja, N. Stability testing of pharmaceutical products. J. Appl. Pharm. Sci. 2012, 02, 129– 138
      There is no corresponding record for this reference.
    40. 40
      Bolondi, L.; Bortolotti, M.; Santi, V.; Calletti, T.; Gaiani, S.; Labò, G. Measurement of gastric emptying time by real-time ultrasonography. Gastroenterology 1985, 89, 752– 759,  DOI: 10.1016/0016-5085(85)90569-4
      40
      Measurement of gastric emptying time by real-time ultrasonography
      Bolondi L; Bortolotti M; Santi V; Calletti T; Gaiani S; Labo G
      Gastroenterology (1985), 89 (4), 752-9 ISSN:0016-5085.
      This paper describes an ultrasound method of assessing gastric emptying time based on measurements of the gastric antrum, which is visible in almost all subjects before and after meals. A total of 54 subjects were examined including 18 normal subjects and 36 subjects with idiopathic functional dyspepsia. The emptying time was determined in all subjects by measuring the changes in the cross-sectional area of the gastric antrum. In a subgroup of 34 subjects the volume of the whole antropyloric region was also considered. Measurements were taken by the same observer after fasting and at regular 30-min intervals after a standard 800-cal meal. Final emptying time (calculated in relation to the start of the meal) was considered to be the time at which the antral area or volume returned to basal value. Final emptying time (mean +/- SD) was 248 +/- 39 min in normal subjects and 359 +/- 64 min in patients with functional dyspepsia (p less than 0.001). A significantly higher degree of dilatation of the gastric antrum was found in dyspeptic patients than in control subjects. Barium x-ray of the stomach in 19 subjects always confirmed the ultrasound finding on the presence or absence of contents within the stomach. We conclude that this kind of ultrasound study of the antropyloric region allows accurate determination of total gastric emptying time.
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    41. 41
      Reddy, C. M.; Padmanabhan, K. A.; Desiraju, G. R. Structure-property correlations in bending and brittle organic crystals. Cryst. Growth Des. 2006, 6, 2720– 2731,  DOI: 10.1021/cg060398w
      41
      Structure-Property Correlations in Bending and Brittle Organic Crystals
      Reddy, C. Malla; Padmanabhan, K. Anantha; Desiraju, Gautam R.
      Crystal Growth & Design (2006), 6 (12), 2720-2731CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Bending of crystals of mol. solids occurs when the strength of intermol. interactions in orthogonal directions is significantly different. We report here a survey of 60 mol. crystals and establish a causative correlation between bending and crystal packing. This group contains crystals with 4 and 8 Å crystal axes and includes 1D, 2D, 3D, isostructural, polymorphic, stacked, interlocked, single, and multicomponent crystals and solvates. We found that 17 of these 60 crystals may be bent, whereas the rest are brittle and cannot be bent plastically. The bending crystals could be deformed into many shapes; sometimes, they could even be flattened upon themselves without breakage. A model for bending is proposed using the information obtained from X-ray diffraction, face indexing, and mech. property measurements on both bending and non-bending (brittle) crystals. The bending and brittleness of these mol. crystals are discussed in comparison with the deformation behavior of metals. Mol. crystals show practically no change in vol. and the lengths of the inner and the outer arcs and the sample thickness are unchanged following plastic bending. This is in contrast with the bending of metallic materials, in which a decrease in thickness is evident. Isotropic crystals with comparable intermol. interactions in the three orthogonal directions are "cross-linked" and do not bend; they are hard and brittle. Mech. properties of mol. crystals are important because they vary with the crystal form and have major implications for large-scale processing and handling of materials in industry, esp. the pharmaceutical industry.
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    42. 42
      Madsen, J. L. Effects of gender, age, and body mass index on gastrointestinal transit times. Dig. Dis. Sci. 1992, 37, 1548– 1553,  DOI: 10.1007/BF01296501
      42
      Effects of gender, age, and body mass index on gastrointestinal transit times
      Madsen J L
      Digestive diseases and sciences (1992), 37 (10), 1548-53 ISSN:0163-2116.
      This study aimed to assess separately the effects of gender, age, and body mass index on gastric emptying, small intestinal transit, and colonic transit times of a meal containing 99mTc-labeled cellulose fiber and 2- to 3-mm 111In-labeled plastic particles. Seventeen healthy young subjects (nine men; eight women; age 21-27 years; body mass index 18.4-25.1 kg/m2) and 16 healthy older subjects (eight men; eight women; age 55-74 years; body mass index 19.8-36.0 kg/m2) were studied. All transit variables were unaffected by gender. The older subjects had a slower mean colonic transit time of radiolabeled plastic particles than the young subjects (P < 0.05). Age did not affect mean gastric emptying or mean small intestinal transit times of the radiolabeled markers. An inverse association was found between body mass index and mean gastric emptying time of radiolabeled cellulose fiber (P < 0.02). Body mass index had no influence on other transit variables. The study revealed a considerable intersubject and a somewhat smaller intrasubject variability in mean gastric emptying, mean small intestinal, and mean colonic transit times.
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    43. 43
      Nagaraja, A. T.; You, Y.-H.; Choi, J.-W.; Hwang, J.-H.; Meissner, K. E.; McShane, M. J. Layer-by-layer modification of high curvature nanoparticles with weak polyelectrolytes using a multiphase solvent precipitation process. J. Colloid Interface Sci. 2016, 466, 432– 441,  DOI: 10.1016/j.jcis.2015.12.040
      43
      Layer-by-layer modification of high surface curvature nanoparticles with weak polyelectrolytes using a multiphase solvent precipitation process
      Nagaraja, Ashvin T.; You, Yil-Hwan; Choi, Jeong-Wan; Hwang, Jin-Ha; Meissner, Kenith E.; McShane, Michael J.
      Journal of Colloid and Interface Science (2016), 466 (), 432-441CODEN: JCISA5; ISSN:0021-9797. (Elsevier B.V.)
      The layer-by-layer modification of ≈5 nm mercaptocarboxylic acid stabilized gold nanoparticles was studied in an effort to illustrate effective means to overcome practical issues in handling and performing surface modification of such extremely small materials. To accomplish this, each layer deposition cycle was sepd. into a multi-step process wherein soln. pH was controlled in two distinct phases of polyelectrolyte adsorption and centrifugation. Addnl., a solvent pptn. step was introduced to make processing more amenable by concg. the sample and exchanging soln. pH before ultracentrifugation. The pH-dependent assembly on gold nanoparticles was assessed after each layer deposition cycle by monitoring the plasmon peak absorbance location, surface charge, and the percentage of nanoparticles recovered. The selection of soln. pH during the adsorption phase was found to be a crit. parameter to enhance particle recovery and maximize surface charge when coating with weak polyelectrolytes. One bilayer was deposited with a high yield and the modified particles exhibited enhanced colloidal stability across a broad pH range and increased ionic strength. These findings support the adoption of this multi-step processing approach as an effective and generalizable approach to improve stability of high surface curvature particles.
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    44. 44
      Sun, C. C. Decoding powder tabletability: Roles of particle adhesion and plasticity. J. Adhes. Sci. Technol. 2011, 25, 483– 499,  DOI: 10.1163/016942410X525678
      44
      Decoding powder tabletability: roles of particle adhesion and plasticity
      Sun, Changquan Calvin
      Journal of Adhesion Science and Technology (2011), 25 (4-5), 483-499CODEN: JATEE8; ISSN:0169-4243. (VSP)
      Tabletability, the ability to make a tablet of adequate mech. strength by powder compaction, is of paramount importance in the successful manuf. of tablet products. Poor tabletability is a persistent problem in the pharmaceutical industry. Tablet strength can be understood based on a qual. model where contributions of bonding area and bonding strength are simultaneously considered. Formation and elimination of bonding area is related to compaction conditions, mech. properties and particulate properties (such as particle size and shape). Plastic deformation emerges as the most important mechanism for creating a large bonding area among deformation mechanisms. Interfacial adhesion defines bonding strength and is dependent on the chem. nature of the materials involved. An anal. of how the chem., mech. and phys. properties of a powder impact bonding strength and bonding areas leads to an understanding of their effects on powder tabletability. Appropriate use of this model can minimize empiricism in product development and facilitate the design of high quality tablets and robust manufg. processes.
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    45. 45
      Prescott, J. K.; Barnum, R. A. On powder flowability. Pharm. Technol. 2000, 24, 60– 85
      45
      On powder flowability
      Prescott, James K.; Barnum, Roger A.
      Pharmaceutical Technology (2000), 24 (10), 60,62,64,66,68,70,72,74,76,78,80,82,84,236CODEN: PTECDN; ISSN:0147-8087. (Advanstar Communications, Inc.)
      A review with 37 refs. focusing on powder flowability in the context of various pharmaceutical prodn. processes. Topics discussed include the definition of flowability; powder transfer; powder storage; sepn. of a small quantity of powder from the bulk; flow of powder during blending; compaction processes; fluidization; and flow properties as comparative, phys. test methods.
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    46. 46
      Mesallati, H.; Umerska, A.; Paluch, K. J.; Tajber, L. Amorphous polymeric drug salts as ionic solid dispersion forms of ciprofloxacin. Mol. Pharmaceutics 2017, 14, 2209– 2223,  DOI: 10.1021/acs.molpharmaceut.7b00039
      46
      Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin
      Mesallati, Hanah; Umerska, Anita; Paluch, Krzysztof J.; Tajber, Lidia
      Molecular Pharmaceutics (2017), 14 (7), 2209-2223CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Ciprofloxacin (CIP) is a poorly sol. drug that also displays poor permeability. Attempts to improve the soly. of this drug to date have largely focused on the formation of cryst. salts and metal complexes. The aim of this study was to prep. amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examn. of their solid state characteristics and phys. stability, the soly. advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the min. inhibitory concn. (MIC) and min. bactericidal concn. (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100-55, Carbopol, and HPMCAS, were necessary for the amorphization of CIP. In each case, the pos. charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully X-ray amorphous following exposure to 90% RH at 25 °C, and demonstrated higher than predicted glass transition temps. The soly. of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a no. of other soly. enhancing formulations, the ASDs did not decrease the permeability of the drug. Similarly, no decrease in antibiotic efficacy was obsd., and significant improvements in the MIC and MBC of CIP were obtained with ASDs contg. HPMCAS-LG and HPMCAS-MG. Therefore, ASDs may be a viable alternative for formulating CIP with improved soly., bioavailability, and antimicrobial activity.
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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.0c01180.

    • 1H NMR of amorphous CFZ–PAA salt; TGA of amorphous CFZ–PAA salt; structure of CFZ–DS crystal (PDF)

    • Crystallographic data for CFZ–DS at 100 K (CIF)


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