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Solid-State Study of the Structure, Dynamics, and Thermal Processes of Safinamide Mesylate─A New Generation Drug for the Treatment of Neurodegenerative Diseases
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Solid-State Study of the Structure, Dynamics, and Thermal Processes of Safinamide Mesylate─A New Generation Drug for the Treatment of Neurodegenerative Diseases
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Molecular Pharmaceutics

Cite this: Mol. Pharmaceutics 2022, 19, 1, 287–302
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https://doi.org/10.1021/acs.molpharmaceut.1c00779
Published December 2, 2021

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Abstract

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Safinamide mesylate (SM), the pure active pharmaceutical ingredient (API) recently used in Parkinson disease treatment, recrystallized employing water–ethanol mixture of solvents (vol/vol 1:9) gives a different crystallographic form compared to SM in Xadago tablets. Pure SM crystallizes as a hemihydrate in the monoclinic system with the P21 space group. Its crystal and molecular structure were determined by means of cryo X-ray crystallography at 100 K. SM in the Xadago tablet exists in anhydrous form in the orthorhombic crystallographic system with the P212121 space group. The water migration and thermal processes in the crystal lattice were monitored by solid-state NMR spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. SM in Xadago in the high-humidity environment undergoes phase transformation to the P21 form which can be easily reversed just by heating up to 80 °C. For the commercial form of the API, there is also a reversible thermal transformation observed between Z′ = 1 ↔ Z′ = 3 crystallographic forms in the 0–20 °C temperature range. Analysis of molecular motion in the crystal lattice proves that the observed conformational polymorphism is forced by intramolecular dynamics. All above-mentioned processes were analyzed and described employing the NMR crystallography approach with the support of advanced theoretical calculations.

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Introduction

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Neurodegenerative diseases affect millions of people worldwide. (1,2) With increasing global population and average lifespan, the prevalence of neurological disorders is on the rise. The risk of being affected by a neurodegenerative disease increases dramatically with age. In developed countries, life expectancy is now rising well above 80 years. (3,4) Although in older people, the prevailing death causes are still cardiovascular diseases and cancer, Alzheimer’s disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis, and other neurodegenerative disorders are known to be strongly age-related. (5,6) Among the 10 top illnesses ending with death, neurodegenerative diseases cannot yet be fully cured or slowed down. Therefore, it is not surprising that a great deal of effort goes into finding new medicines to treat neurodegenerative diseases. Very recently, a new drug under the Xadago brand name has been introduced in the pharmaceutical market for the treatment of PD’s disease. (7,8) The active pharmaceutical ingredient (API) of Xadago is safinamide mesylate (SM) salt (molecular structure shown schematically in Figure 1). (9,10)

Figure 1

Figure 1. Chemical structure of SM and numbering system.

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The mechanism of the drug action operates through the inhibition of monoamino oxidase-B, an enzyme responsible for the breakdown of dopamine. As a result, an increase of the dopamine level in the brain for subsequent dopaminergic activity in PD patients is observed. Moreover, safinamide shows nondopaminergic actions such as sodium channel blocking and inhibition of glutamate release. (11) Xadago was approved in Europe in February 2015, in the United States in March 2017, and in Canada in January 2019. This drug is administered orally in the form of solid tablets.
Despite very advanced clinical studies, little is known about the solid-state properties of SM, both as a pure API and as a tablet component. Although an international patent describing the three crystallographic forms of SM has been known for many years, to the best of our knowledge, there are no detailed studies showing the complexity of this system. (12) Very recently, Nanubolu has reported in-depth X-ray studies of safinamide acid hydrochloride. (13) Two concomitant polymorphs were obtained in an attempt to prepare the O-protonated amide salt of safinamide from ethanolic HCl solution. Polymorph I crystallized in the triclinic space group P1 with three molecules in the asymmetric unit (Z′ = 3), while polymorph II crystallized in the orthorhombic space group P212121 with a single molecule in the asymmetric unit (Z′ = 1). The high Z′ = 3 structure showed a phase transition to a Z′ = 2 structure in a single-crystal to single-crystal fashion. In contrast, the Z′ = 1 polymorph I did not show any such phase transition.
Polymorphism and thermal stability of an API are the most important properties that determine the usefulness of drugs in therapeutic treatment. (14−16) Polymorphism is the ability of the substance to crystallize in more than one crystalline phase with different arrangements or conformations of the molecules in the crystal lattice. (17) Over 50% APIs are estimated to have more than one polymorphic form. It is well known that polymorphs differ in physical properties such as molecular packing, melting point, fusion enthalpy, dissolution behavior, and bioavailability. (18,19) API polymorphs can also exhibit different physical and mechanical properties, including hygroscopicity, particle shape, density, flowability, and compactibility, (20−22) which can affect the processing of manufacturing of the drug product and require control over all stages of synthesis, application, and storage. (23,24) The most important issue in the research of API polymorphs is to identify their properties as part of the quality assurance process. To find the best form of the drug, many different advanced characterization techniques should be used. The ultimate goal is to select the most thermodynamically stable form to be able to manufacture it consistently. An incident involving the anti-HIV/AIDS drug ritonavir highlighted the need for greater control of the drug‘s polymorphism and prompted companies and scientists to undertake the comprehensive screening of polymorphous modifications. (25) Since the goal of finding polymorphs with the most desirable properties is not easily accessible, works in this area are very important.
The facts mentioned above and the general knowledge about drug polymorphism prompted us to deal with Xadago tablets in detail employing advanced instrumental techniques [solid-state NMR spectroscopy, single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA)] and theoretical approaches.

Experimental Procedures

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Obtaining of Starting Materials

Xadago is a commercially available product. For the purpose of this study, it was purchased from a pharmacy. The production serial number was 9517442106126 with the expiration date of 03/2024.

Single-Crystal X-ray Measurements

The X-ray data were collected on a diffractometer (XtaLAB Synergy, Dualflex, Pilatus 300K, Rigaku Corporation, Tokyo, Japan) at 100 K with a microsource of Cu-Kα radiation (λ = 1.5418 Å) and a Titan detector (Oxford Diffraction, Agilent Technologies, Yarnton, U. K.) equipped with an 800 Cryostream low-temperature unit (Oxford Cryosystems, Oxford, U.K.).
Diffraction data collection, cell refinement, data reduction, and absorption correction were performed using CrysAlis PRO software (Agilent Technologies UK Ltd., Yarnton, England). Structures were solved by the direct method SHELXS (26) and then refined using the full-matrix least-squares method SHELXL 2015 (27) implemented in the OLEX2 package. (28) In all of the crystal structures, the non-hydrogen atoms were present in the direct method solution.

PXRD Measurements

PANalytical X’Pert PRO MPD powder diffractometer was used in the collection of diffraction data on the powder samples. The instrument was equipped with a sealed LFF X-ray tube with a copper anode, an elliptic X-ray focusing mirror, and a PIXCEL detector. Divergence slit of 1/2° and 0.02 rad. Soller slits (in both incident and diffracted beam paths) were applied. The powder sample was packed inside a 0.7 mm diameter Hilgenberg borosilicate glass capillary and measured in a repeated scan mode during a four scan measurement. The registered data range was 3–85° 2θ with a step of 0.02°, and the collection time setting made each scan last 3.5 h. The obtained scans were tested for any discrepancies suggesting adverse reaction of the sample to X-ray irradiation and summed up.
The experimental diffraction data were indexed in an orthorhombic cell applying the successive dichotomy method DICVOL04 as implemented in Expo2014 software. (29−31) The global optimization technique using FOX (32,33) with the application of a safinamide and methanesulfonate molecule model was applied. Multiple runs of calculations were performed with 8 × 106 trials per run, and the best obtained solution was selected based on the smallest data fitting discrepancies, as well as the general sense of the calculated model was chosen for the structure refinement stage. Rietveld method implemented in GSAS-II was used in the refinement step. (34) At the final fitting, 15 Chebyshev points were used to describe the background. The refinement of the non-hydrogen atomic positions was carried out with bonds and angles restraints based on Mogul CCDC parameters. (35,36)

NMR Spectroscopy

Cross-polarization magic-angle spinning (CP MAS) NMR, one-pulse 1H MAS, and polarization inversion spin exchange at the magic angle (PISEMA) MAS (37−39) experiments were performed on a 400 MHz Bruker AVANCE III spectrometer operating at 400.15, 100.62, and 40.55 MHz for 1H, 13C, and 15N, respectively, equipped with a HX MAS probe head using 4 mm rotors.
A sample of U–13C, 15N-labeled histidine hydrochloride was used to set the Hartmann–Hahn condition for 13C and 15N. 1H → 13C and 1H → 15N CP MAS experiments on the 400 MHz Avance III spectrometer were performed at a MAS frequency of 8 kHz with a proton 90° pulse length of 4 μs and a contact time of 2 ms for 13C and 8 ms for 15N. For CP, the nutation frequency was 54.5 kHz for 13C as well as for 15N with a 1H ramp shape from 90 to 100% with a 1H nutation frequency of 62.5 kHz. For 13C and 15N, 3.5k and 2k data points were acquired for a spectral width of 40 and 28 kHz, respectively. In all cases, SPINAL-64 decoupling sequence (40) with a 1H nutation frequency of 71.4 kHz and a pulse length of 7 μs were applied (also for the PISEMA experiment described below).
The PISEMA MAS experiment (37−39) was carried out with an 1H nutation frequency of 82.5 kHz in all of the experiments, and the 13C spin-lock field strengths were adjusted to the first-order sideband condition, ω13C = ω1H ± ωr. The spinning frequency was 13 kHz and was regulated to ±3 Hz by a pneumatic control unit. 256 coadded transients for each of 64 t1 FIDs correspond to a total experimental time at 23 h. The 2D PISEMA MAS experiments incremented the SEMA contact time using a step of 16.28 μs, with a maximum t1 evolution time of approximately 1 ms. Since the t1 time signal increases with increasing SEMA contact time, the ω1 dimension was processed using the baseline correction mode “qfil” in Bruker TopSpin 3.5 program software, (41) which subtracted a constant intensity from the time signals prior to the Fourier transformation and yielded spectra free from the dominant zero-frequency peak that gives the 1H–13C doublet.
Fast MAS spectra were recorded on a 600 MHz Bruker Avance III spectrometer operating at 600.13 and 150.90 MHz for 1H and 13C, respectively, equipped with a HCN MAS probe head operating in the double-resonance mode using 1.3 mm ZrO2 rotors with a spin rate of 60 kHz. The 13C–1H-invHETCOR experiments were performed using the pulse sequence described elsewhere. (42−44) The following parameters were used: a proton 90° pulse length of 2.5 μs and a first and second contact time of 2 ms and 100 100 μs, respectively, both with a 1H 90–100% ramp shape. The 1H and 13C nutation frequency was 160 and 109 kHz, respectively, for both CP steps. The acquisition data were collected with a SWf-TPPM (45,46) decoupling sequence with a 1H nutation frequency of 10 kHz and a pulse length of 50 μs. (40) The States-time-proportional phase incrementation method was employed for sign discrimination. (47)
The 13C chemical shift was referenced indirectly by using adamantane (resonances at 38.48 and 29.46 ppm) as an external secondary reference. (48,49) The 15N glycine (resonances at 34.40 ppm) was used as a secondary chemical shift reference for 15N. (49,50) The real temperature inside the MAS rotor is different from the ambient temperature, mostly due to frictional effects caused by rotor spinning. (51) Because of that, Pb(NO3)2 was used for temperature calibration. (52) Except where otherwise stated, a recycle delay of 5 s was used.

Quantum Mechanics Calculations

Density functional theory (DFT) calculations were performed with periodic boundary conditions using the CASTEP 19.11 code. (53) The geometry optimization was performed using the X-ray diffraction crystal structures as an input file by varying all atoms and the unit cell parameters. The geometry optimizations were performed until the energy converged to within 10–7 eV. The generalized density approximation DFT functional Perdew–Burke–Ernzerhof with the TS dispersion correction scheme (DFT-D method) was applied. (54,55) A comparison of the average forces remaining on the atoms after geometry optimization with a convergence limit of 0.02 eV/Å was carried out by using a maximum plane wave cutoff energy of 620 eV and an ultrasoft pseudopotential. (56) The optimization algorithm was BFSG, (57) and the Monkhorst–Pack grid (58) of minimum sample spacing 0.07 × 2π Å–1 was used to sample the Brillouin zone. The NMR chemical shifts were computed using the gauge-including projected augmented wave (GIPAW) method. (53,59,60) The calculated NMR chemical shieldings were converted into chemical shifts by linear regression between calculated and experimental results.

Other Methods (DSC, TGA, Elemental Analysis)

DSC and TGA were recorded using a DSC 2920 (TA Instruments) calorimeter with the heating rate of 5 °C min–1. Elemental analysis of hydrogen, carbon, and nitrogen was performed using CE Instruments.

Results and Discussion

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PXRD and Solid-State NMR Analysis of Xadago Tablet

We began our study with PXRD and 13C CP MAS NMR measurements carried out at ambient temperature for a commercially available Xadago tablet (Figure 2). Both techniques clearly proved that the tablet contains SM in the crystalline form. However, apart from the high-crystalline components, there are also much broader reflexes (Figure 2a) or signals (Figure 2b) visible, reflecting the amorphous background (Figure 2a). It is not surprising since the drug formulation usually contains various substances that support the manufacturing process. According to the product characteristic declaration, the Xadago drug apart from the SM substance contains a series of following excipients: cellulose, polyvidone, magnesium stearate, and colloidal anhydrous silica. (10) These additional components complicate the precise analysis of the crystalline form of SM, and hence in the next step, we decided to extract the pure API from the tablet.

Figure 2

Figure 2. Results for the Xadago drug (a,b) and API extracted from tablets (c,d) at room temperature: (a,c) X-ray powder pattern recorded in Bragg Brentano geometry with a Cu Kα (λ = 1.5425 Å) source. (b,d) 13C CP MAS NMR spectrum of the Xadago drug recorded at a spinning rate of 8 kHz and a 1H Larmor frequency of 400.1 MHz. The recycle delay was 30 s. Asterisks indicate spinning sidebands.

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It was possible to isolate pure SM by fast filtering-off the insoluble components using water as a solvent. Next, the API was crystallized from water solution by isothermic evaporation. Figure 2c,d shows the X-ray powder pattern and the 13C CP MAS spectrum of the extracted API. As one can see, both measurements prove that the obtained sample is pure, homogeneous, very well organized, and crystalline without the large amorphous background visible in the X-ray powder pattern of the Xadago tablet (Figure 2a). At this point, the most thought-provoking observation was the mismatch for the reflection positions (PXRD) as well as the signal positions (solid-state NMR) between the Xadago tablet and the extracted API material. The first, simple explanation of these discrepancies is based on the assumption that we observe different polymorphs of SM. The detailed explanation of that will be presented in the following sections.

X-ray Determination of the SM_E Single-Crystal X-ray Structure

In order to test the susceptibility of SM to form different polymorphs, the API sample was recrystallized from various solvents belonging to the Generally Recognized as Safe FDA list. (61) After several attempts, the best quality material allowing to determine the crystal structure from single-crystal X-ray diffraction data was obtained by the recrystallization of API from water/ethanol (1:9) solution (further referred to as SM_E form). The structure deposited in CCDC under no. 1899715 is shown in Figure 3. The corresponding crystallographic data are presented in Table 1.

Figure 3

Figure 3. Asymmetric part of the unit cell of SM_E showing the crystallographic atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level except for the H atoms.

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Table 1. Crystal Structure and Refinement Data for SM_E
empirical formula2(C17H20FN2O2)·2(CH3O3S)·H2O
formula weight814.90
temperature100 K
crystal systemmonoclinic
space groupP21
a (Å)5.6001 (3)
b (Å)20.4399 (9)
c (Å)16.7486 (9)
α (deg)95.839 (4)
volume (Å)31907.19 (17)
Z4
Z′2
R-factor (%)7.67
no. of measured, independent and observed [I > 2s(I)] reflections13021, 6368, 5527
Rint0.072
R[F2 > 2s(F2)], wR(F2), S0.077, 0.210, 1.10
Up to date, only two safinamide polymorphs are known (refcodes TUWFIB and TUWFIB01), (62) and no other crystal structures containing safinamide have been deposited in Cambridge Structural Database (CSD). (63) The SM_E form obtained in our work was also reported in the patent claim as form H1, though there are no structural details provided except for the unit cell dimensions and positions of powder pattern reflections. (12) Even a brief look at the structure of the SM_E crystal shows that the introduction of the mesylate anion significantly changes the organization of the crystal lattice compared to the safinamide polymorphs TOWFIQ and TUWF IB01. (62) The SM_E crystallizes under the P21 symmetry with 1905.0 Å3 volume. There are two independent safinamide molecules (further referred to as “A” and “B”) in the crystal lattice exhibiting different hydrogen-bonding motifs. The unit cell also contains an equivalent number of mesylate anions and a water molecule per two safinamide molecules (Figure 4a) which classifies the structure as a hemihydrate. The first visible geometrical difference between A and B molecules is the position of the aromatic ring containing the fluorine atom. For molecule B, the fluorinated phenyl ring (or more specifically the fluorine atom) occupies two positions, whereas it is not the case for molecule A. In this way, two alternative conformations of the B molecule arise, which we will denote in the text as B′ and B″ and refer their names to the safinamide molecules as presented in Figure 4a,b. There are two theoretically justified variants of the rigid structure most probably connected with either positional disorder or molecular dynamics of the phenyl ring with a jump angle of 180°. The second important feature is connected with different contacts (hydrogen bonds) between molecules A and B (Figure 4b). As it is clearly seen, one of the safinamide molecules (colored blue) does not conjugate with water, whereas the other (colored green) has such an interaction. The last important difference can be easily recognized by making a superposition of both nonequivalent safinamide molecules (Figure 4d). The main difference comes from the C8–O–C9–C10 torsional angle (differing by ∼10°) in both forms. These observations will be confronted later in the text with solid-state MAS NMR results.

Figure 4

Figure 4. Crystal structure of SM_E indicating (a,b) asymmetric parts of the unit cell with two possible locations of F atoms (fractionally occupied) outlined by dotted green lines, (c) hydrogen bond motifs (colored orange), and (d) superposition of nonequivalent molecules A and B extracted from the single-crystal diffraction-based structure of SM_E. Molecules (c,d) are colored according to symmetry equivalence and shown without hydrogens (except for the water molecule).

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Keeping in mind that the structure of SM_E presents an uncertain location of the fluorine atom, we investigated the nature of this feature and pointed out the most plausible orientation of the fluorophenyl ring. At this stage, we constructed two B′ and B″ theoretical models with a different location of the fluorine atom in molecule B and performed the DFT-D optimization of all atomic positions as well as unit cell parameters for them. The obtained structures have less than 1% difference in the unit cell parameters and extreme similarity of atomic positions except for the fluorine atom (see the attached crystallographic structure after DFT-D calculations in the Supporting Information). Figure 5 shows the energy difference between the two models in pictorial form. The total crystal lattice energy differs between structures containing orientations B′ and B″ only by about 1.12 kJ. It means that B′, where the fluorine atom is “trans” with respect to oxygen, is slightly more preferred. It is an extremely small value, and it suggests that the orientation of the phenyl ring may be easily inverse to the opposite conformation at the room temperature. Note that such DFT calculations only probe the thermodynamics (i.e., equivalent to 0 K), and temperature-dependent kinetic effects are not considered. Apart from the above, the inspection of close contacts and free volume analysis in the unit cell using Mercury software (64,65) do not support the possibility of reorientation process because the packing in the crystal lattice forbids it. It means that the observed feature has to be determined during the crystallization process and later remains unchanged. The absence of a determining energetic preference and steric effect is consistent with nearly 50% occupancy of the fluorine atom in both refined positions. In that way, such an observation is a clear example of a static disorder.

Figure 5

Figure 5. Schematic representation of two possible orientations of fluorine in molecule B and the relative total crystal lattice energy difference at the DFT-D level between structures containing B′ and B′ conformers.

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Validation of SM_E X-ray Structure by Means of Advanced Solid-State NMR and DFT-D Calculations. Analysis of 13C and 15N Chemical Shifts

As the first point of the validation of the SM_E structure, we applied advanced NMR methodologies for precise assignment of the 13C and 15N chemical shifts. Based on the liquid-state NMR measurements, we attempted to assign NMR signals in the solid state. Although it might be a valid strategy to obtain a first approximation, the large number of observed resonances and their insufficient dispersion in 13C CP MAS spectra for more complicated cases cause the need to apply a more advanced methodology. It should be noted that the position and assignment of signals for solid-state and liquid-state NMR can change, especially for peaks which are very close to one other. (66,67) Therefore, the uncritical cloning of the liquid-state assignments to the solid-state spectra should not be attempted at all. In our case, we decided to apply theoretical calculations and compare them with the experimental data. The details regarding the computations and experimental methods will be discussed later in this chapter.
The 13C and 15N CP MAS spectra of SM_E are shown in Figure 6. As it was described in the previous section, the SM_E structure contains two crystallographically nonequivalent molecules in the asymmetric part of the unit cell. However, even a brief look at the 13C spectrum shows that most of the positions are isochronous and overlap giving single resonances. Moreover, the differences between those which are separated are not very large and constitute up to 3.5 ppm. The image of 13C as well as 15N CP MAS spectra confirms without a shadow of a doubt the presence of two nonequivalent molecules in the asymmetric part of the unit cell. The full assignment of 13C and 15N signals to the conformers “A” and “B” is not straightforward. To solve this problem, we applied the GIPAW method, (33−35) which constitutes a breakthrough in the theoretical prediction of NMR parameters for solid materials. This approach has been used in many spectacular applications, and its usefulness in the spectral analysis is unquestionable. (68−81) Using the GIPAW strategy, the signal assignment was made by comparing the experimental values of chemical shifts and those calculated theoretically. The final result is shown in Figure 7. Excellent agreement is observed between experimental and calculated 13C chemical shifts (GIPAW), as reflected by the small root-mean-squared error (RMSE) values of 2.0 ppm (Table S1). (72,82−86) Using the machine learning method, Emsley et al. established the RMSE threshold for organic molecules at the level of 4.3 ppm for 13C, which defines the correctness of the structure solution. (87) Our results (RMSE equal 2) clearly prove that the selected monocrystal for X-ray measurement is representative of the bulk material.

Figure 6

Figure 6. 13C (a) and 15N (b) CP MAS NMR spectra of SM_E recorded at a spinning rate of 8 kHz and a 1H Larmor frequency of 400.1 MHz at ambient temperature. Assignments are colored blue for molecule “A”, green for molecule “B,” and purple for overlapped signals. Asterisks indicate spinning sidebands.

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Figure 7

Figure 7. Correlation of experimental 13C chemical shift (δ) and calculated nuclear shielding parameters (σ) of SM_E.

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The colors used to label the NMR signal (Figure 6) match the colors of the structure shown in Figure 4c (purple indicates overlapping signals). If we compare the NMR results with the structure shown in Figure 4c, it is obvious that the positions for which we observed the main geometrical discrepancies between the molecules “A” and “B” are also recognized as magnetically nonequivalent in the NMR spectrum. 13C CP MAS measurements, often used in pharmaceutical sciences (39,50,56−76) for comparative drug analysis, show that SM_E and API material extracted from a tablet using the procedure described in section (i) represent a similar crystallographic form, but the crystallinity of SM_E is much higher. It is worth recalling that according to PXRD and 13C CP MAS measurements in Xadago tablets, we observed a different form of API. This inconsistency prompted us to undertake further studies.

Thermal Transformations of Sample SM_E

In the course of our studies, we observed a broadening of the NMR signals and a change of the 13C CP MAS SM_E spectral pattern with the change of the rotor spinning rate (see Figure S1). We assumed that this effect could be due to two factors, the change in temperature and/or the power of the centrifuge. The spinning of the NMR rotor causes heating through air friction. The temperature of the sample increases rapidly as the spinning speed increases. We observed up to a 15 °C factor at 13 kHz spinning speed compared to only ca. 5 °C at 8 kHz from ambient temperature using a 4 mm probe head. These values are consistent with the previously published data. (51,52)
According to the X-ray data-based structure, the SM_E form contains water molecules in the crystal lattice (see X-ray Determination of the SM_E Single Crystal X-ray Structure). It is known that in some cases, weakly bound crystallographic water can be removed from the lattice with increasing temperature. Such a thermal effect could be a possible explanation for the difference between the structure of SM_E and that of the Xadago tablet.
To examine, we performed a detailed DSC and TGA study of the SM_E sample (Figure 8). In the first stage, thermal stability was tested by DSC in the temperature range between 0 and 250 °C (Figure 8a). The DSC profile shows two endothermic peaks. The strongest one at 215.9 °C can be easily assigned to the melting process of the material (according to the literature data, mp 208–212 °C). (88) Much more interesting in the context of this study is the broad endothermic peak with a maximum at 55.7 °C. The energetic effect is quite significant and suggests an important reorganization of the phase. The TGA analysis (Figure 8b) shows a loss of 2.346% total weight around 30–60 °C. The observed value is very close to the theoretical content of water in the SM_E (2.211%). Such an agreement clearly suggests that the discussed phase transition could be assigned to the loss of one molecule of water from the crystal lattice. Usually, a good practice to apply in such cases is to check the observed effect in a new portion of the sample by performing multiple heating-cooling runs in the range of temperatures below the melting point (Figure 8c,d). Since the thermal effect was attributed to the dehydration process, it should be only observed during the first heating run (Figure 8c). However, after the first run, another, very subtle thermal process is registered. The observed transitions are fully repetitive through multiple heating-cooling procedures (see Figure S2 for the additional heating-cooling curve). Both peaks at around 21 °C (while heating) and around 0 °C (while cooling) have the same very weak thermal effect of ca. 6.8 J/g and represent a fully reversible phase transition. The 20 °C difference in the position of the thermal transformation while cooling and heating is a well-known effect of shifting of the peak position by the thermal gradients in the sample. (89) A very similar observation, though without a detailed explanation, was reported in the patent claim mentioned earlier in the text. (12)

Figure 8

Figure 8. DSC (a) and TGA (b) plots for the SM_E sample with the heating rate of 5 °C min–1. Additional DSC plots using a new portion of the sample during (c) first heating and (d) first cooling and second heating runs in the range of temperatures below the melting point with the rate of 5 °C min–1.

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Keeping in mind the significant evidence of a dehydration process of SM_E, we prepared a new sample called SM_D by heating the starting material SM_E at 80 °C for 1 h in an oven. For both samples, we performed an elemental analysis of the total carbon, hydrogen, and nitrogen contents. This analysis also supported the loss of one molecule of water while the SM_E sample is heated. Just for testing purposes, we verified if SM_E undergoes the same transformation when it is kept over P2O5 in a desiccator for a week. It was also possible to transform the SM_D form to SM_E by placing the SM_D in an open Petri dish and keeping it without a direct solvent-sample contact for 14 days in a diffusion vessel filled with water. These simple procedures confirmed the reversibility of the dehydration/hydration process. It is worth noting that very similar rehydration processes were observed in the case of Xadago when a mechanically damaged tablet was stored in a humid environment (see Figure S3). This means that such unexpected events can occur even with commercial drugs during storage.
The first examination of the obtained material (SM_D) was performed by 13C as well as 15N CP MAS spectroscopies at ambient temperature (Figure 9a,b). The difference in relation to 13C and 15N CP MAS for SM_E is clear (see the Figure 6). At a first glance, it is obvious that the characteristic doubling of NMR peaks for SM_E (Z′ = 2 structure) is gone or at least significantly reduced in the case of the SM_D structure. It suggests that the number of safinamide (as well as mesylate) molecules in the asymmetric part of the unit cell may have changed. Additionally, most of the solid-state NMR resonances overlap with the resonances observed for molecule “A” in SM_E (blue arrows). It is not surprising because molecule “A” in contrast to molecule “B” does not have any hydrogen bonds with the water molecule which was discussed supra. A thought-provoking observation is also the very low intensity and broadening of CH signals in the aromatic region. Trying to explain the nature of these ambiguities, we varied the setup in the CP MAS experiment. Unfortunately, despite several attempts, no spectral improvement was observed. Another important feature of the 13C CP MAS results is the straightforward evidence about the equivalence between SM_D and the SM polymorph originally found in the Xadago tablet (see Figures 2b and 9a).

Figure 9

Figure 9. 13C and 15N CP MAS NMR spectra of SM_D at ambient temperature (a,b), at 50 °C (c,d), and at −30 °C (e,f) recorded at a spinning rate of 8 kHz and a 1H Larmor frequency of 400.1 MHz. The blue (molecule “A”), green (molecule “B”). and purple (overlapped) arrows indicate positions of resonances for SM_E (a,b). The assignment of signals (c–e) is shown according to the results from Thermal Transformations of Sample SM_E and Determination of SM_D Crystal Structure Based on the Data Obtained in a PXRD Measurement and Its Validation Using Advanced Solid-State NMR and GIPAW Calculations. Asterisks indicated spinning sidebands.

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Taking into account the fact that the DSC measurements of SM_D indicate a reversible phase transition very close to room temperature, it seems to be important to record the NMR spectra above and below this point to see whether change of temperature influences the shape of NMR signals. Figure 9c–f depicts the spectra of SM_D recorded at 50 °C as well as at −30 °C. Both of them are significantly different from the room-temperature results (Figure 9a,b) which have to be carefully examined.
Typically, thermal processes affect the intensity and/or broadening of NMR signals. However, in our case, the 13C CP MAS SM_D spectrum recorded at −30 °C also shows changes in the position of the signals compared to the spectrum recorded at higher temperatures (Figure 9a–d). This is most evident for the C-9 position, where two distinct singularities suggest a crystallographic system with the Z′ value higher than 1. In addition, the relative intensities of the 13C CP MAS peaks for position C-9 appear to be different from 1:1, which additionally excludes the possibility that Z′ is equal to an even number. All of that is also supported by the 15N CP MAS spectrum (Figure 9f), where we observed “ragged” rather than clean and smooth shapes of the signals, especially for N-1. It would be very hard to explain all of these effects assuming that Z′ is equal to 1 or 2. This problem will be discussed in chapter v employing the PXRD technique.
Since the intensity and shape of 13C CP MAS CH aromatic signals are changed significantly in the temperature range of −30 to 50 °C (Figure 9), it prompted us to analyze the molecular dynamics of both SM_DLT as well as SM_D forms. Molecular motion on various time scales can be easily probed by solid-state NMR spectroscopy. Here, we applied the 2D PISEMA MAS experiment. (37−39) This is a well-established solid-state NMR method to measure 13C–1H dipolar couplings and to study dynamic processes on the kHz time scale. (90,91) The 2D PISEMA MAS spectra record the dipolar coupling between the specific carbon and the closely located protons. According to the equation D = −(μ0ℏ/8π2)(γiγj)/rij3, the dipolar coupling constant for a typical 13C–1H distance equal to 1.09 Å is 23.3 kHz. The experimentally measured splitting values are lower than the calculated ones due to the scaling factor which reduced observed splitting. (92) For the PISEMA MAS NMR experiment, the exact Hartmann–Hahn matching condition gives a scaling factor of 0.577 (cos 54.7°), which gives the expected splitting value of ca. 13.4 kHz (23.3 kHz × 0.577). (37) Furthermore, since motional processes reduce the observed dipolar coupling value, it can be quantitatively probed by comparing the observed value to the rigid limit. (93−95)
Figure 10 shows the 2D PISEMA MAS NMR spectra for samples SM_E (at ambient temperature), SM_D (recorded at 50 °C), and SM_DLT displayed in the 2D contour plots. In the case of SM_D, a short explanation is necessary here. Since, the SM_D form exhibits very low intensity aromatic signals at room temperature, it was not possible to perform a dynamic analysis with confidence at this point. Therefore, for the purpose of the 2D PISEMA MAS NMR experiment, the sample was heated up to 50 °C to be above the coalescence temperature. As it is easily seen in Figure 10, the dehydration process made significant changes in the matter of dynamic behaviors. The starting material (SM_E) can be assigned as the rigid system (except the −CH3 groups). It is consistent with our previous observation reported in PXRD and Solid-State NMR Analysis of Xadago Tablet where we concluded the presence of a static (rather than dynamic) disorder for the fluorophenyl group in molecule “B.” The dehydrated polymorphs of SM present much higher flexibility than the hydrated form of SM. The spectrum for SM_D at 50 °C (Figure 10b) proves without any doubt the presence of molecular dynamics of both aromatic parts of the molecule. It means the movement of the aromatic rings is not blocked as it was happening for SM_E. (93,95) Additionally, the fact that we observe a slightly higher dipolar coupling value for C-6/6′/7/7′ (7.0 kHz) than for C-11/14/15 (6.1 kHz) of CH aromatic resonances is very interesting. It suggests a different topology of the dynamic process for both rings. According to our previous study, we can assign the latter value to the 180° ring flip, while the higher value observed for the fluorophenyl ring corresponds to the slightly smaller topological movement as the wobbling with lower than 180° amplitude. (75,96) Interestingly, the 13C–1H dipolar coupling for the C-13 position, which also belongs to the part of the molecule affected by the dynamic process, has the value very close to the rigid limit. It can be easily explained by the fact that C-13 is located directly on the rotation axis of the fluorophenyl ring and thus does not undergo molecular motion. All of these observations nicely support the assignments of aromatic carbon signals primarily presented in Figure 9c. Unfortunately, due to the very broad peaks in the aromatic region of SM_DLT, it is difficult to discuss its dynamic processes in detail. However, the average dipolar coupling value of ca. 10.4 kHz allows to assign it as a low-amplitude wobbling of aromatic rings. (75,93,95−97)

Figure 10

Figure 10. 2D PISEMA MAS spectra for samples SM_E (a), SM_D at 50 °C (b), and SM_DLT (c). The highest splitting values are labeled in each spectrum. Spectra were acquired at a 13 kHz spinning rate and a 1H Larmor frequency of 400.1 MHz.

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Determination of SM_D Crystal Structure Based on the Data Obtained in a PXRD Measurement and Its Validation Using Advanced Solid-State NMR and GIPAW Calculations

The material obtained after thermal treatment did not allow single-crystal X-ray measurements to be performed because it was not possible to select a crystal of adequate quality for that purpose. Since it is a very frequent situation when the desolvation process causes changes in the morphology of crystallites eliminating the possibility of single-crystal X-ray measurement, we also made an attempt to obtain monocrystalline SM_D material by crystallization procedures from various solvents. The motivation for the search of optimal crystallization conditions was the general information in the patent claim that good quality crystals of the anhydrous form of SM can be obtained. (12) Unfortunately, despite long and intense efforts, our attempt concluded without a success. Therefore, the application of NMR crystallography was the best choice to determine the crystal structure. First, we applied PXRD methodology. The experimental powder diffraction data for SM_D were successfully indexed in an orthorhombic cell by applying the successive dichotomy method DICVOL04 as implemented in Expo2014 software. (29−31) The obtained cell parameters accounted for all but three small impurity lines among the observed diffraction peaks. Despite numerous attempts to find alternative indexing that would include these lines, no better solution was detected. Based on the systematic absence analysis and Le Bail fitting, (98) the space group P212121 was selected with the Rwp value equal to 5.75%. The model of the crystal structure was generated using the global optimization technique implemented in FOX. (32,33)Figure 11 presents the Rietveld refinement result for SM_D diffractogram by utilizing GSAS-II software. (34) In the Rietveld refinement, standard restraints were applied to bond lengths and angles, as well as planar restraints to the aromatic parts of the molecule. Since the molecular dynamic investigation (Thermal Transformations of Sample SM_E) suggests molecular motion of aromatic rings, the fractional occupation of the fluorine atom in two positions was applied. Finally, the structure model gave a satisfactory fit to the measured diffraction data, which is reflected in the difference curve (Δ/σ) and the Rwp = 6.70% value. The broad reflex at 9.7° which makes the highest Δ/σ value is an artifact of the measurement setup, and it was not taken into account during the analysis. The obtained crystal structure solution is attached to the Supporting Information as a crystallographic information file (cif). The crystallographic details as well as the unit cell view are shown in Table 2 and Figure 12 respectively. The technical details are presented in the Experimental Section.

Figure 11

Figure 11. Rietveld curves for SM_D.

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Figure 12

Figure 12. PXRD unit cell of SM_D polymorph displayed along the “c” direction.

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Table 2. Crystallographic Details Obtained from the PXRD Analysis of SM_D
empirical formulaC18FN2O5S
dormula weight375.27
a (Å)22.7568(3)
b [Å)15.5428(4)
c [Å)5.55510(10)
α (deg)90
β [deg]90
γ [deg]90
V [Å3]1964.86(5)
Z4
Z′1
radiation wavelength [Å]1.5418
space groupP212121 (19)
Rwp6.70
density (calc) [g/cm3]1.2686
It has to be stressed that the PXRD patterns for SM_D explain most of the observed PXRD reflexes for the Xadago tablet (Figure 2a). It is consistent with our solid-state NMR results and confirms that SM_D polymorph is the commercial form of SM. Based on the PXRD reflex positions, we identified our SM_D form as the A1 reported in the patent claim mentioned earlier. (12)
In principle, the NMR Crystallography workflow requires at least rough atomic coordinates as the starting point to proceed to the computational stage. The PXRD crystal structure solution result usually is characterized by sufficient precision for DFT-D calculations. Preceding the calculations of the NMR parameters (important for final validation of the structure), geometry optimization allowing the variation of all atomic positions was performed. The final DFT-D optimized structure is only slightly different compared to the starting PXRD model. If we superimpose both crystal structures, we can see that the RMSD among equivalent atomic positions is as low as 0.5 Å for clusters containing 30 molecules (see Figure S4).
The final validation of the DFT-D structure was made with the help of solid-state NMR methodology. Although simple 1D solid-state NMR spectra allow a quick distinction between all of the discussed SM forms through the fingerprint of a specific material, they do not allow to obtain enough structural constraints to judge the atomic scale arrangement. Therefore, the validation of the SM_D form needed a more robust technique such as the fast MAS NMR, allowing for spinning 1.3 mm rotors up to 67 kHz. There are several advantages of such a method. For example, it allows a significant reduction in the amount of required sample for the measurement, and there is a possibility to record 1H spectra with lower broadening of signals or the option to apply inverse detected pulse sequences and acquire 2D solid-state NMR correlations. Unfortunately, fast MAS application, besides a lot of tremendous advantages, carries some drawbacks. The extremely high spinning rate of the sample significantly increases the heating of the rotor through air friction up to a factor of 60 °C. Moreover, the centrifuge power is extremely high which can further accelerate the phase transitions. It is worth mentioning that, despite several attempts, we were not able to run measurements for SM_E as well as SM_DLT employing the very fast MAS technique. The application of a cooling system combined with the relatively small spinning frequency (40 kHz) failed and did not prevent the change of the SM_E and SM_DLT to SM_D sample during the measurement. In the end, we were able to perform the fast MAS measurements for SM_D form only.
From NMR spectroscopy point of view, the 1H nucleus is the most sensitive probe for studying the local structure and remote contacts. Unfortunately, the measurement and assignment of signals in 1H solid-state NMR spectra are incomparably more difficult than for a 13C nucleus. Whereas proton NMR experiments are the most routine measurements in the liquid state, their solid-state equivalent still is challenging. The main problem with 1H solid-state NMR spectra for organic solids at natural abundance is the low signal resolution due to the extremely strong homogeneous 1H–1H dipolar couplings. Fortunately, outstanding developments in fast MAS probes significantly reduce the broadening of NMR signals. In particular, it allows measuring of 2D heteronuclear experiments with indirect inverse (inv) observation via 1H such as a 13C–1H invHETCOR MAS NMR experiment. Figure 13a shows the 13C–1H invHETCOR MAS spectra acquired with a short (100 μs) 13C → 1H CP contact time such that only cross peaks corresponding to short C···H distances, mostly direct C–H bonds, are observed. The 1H–13C invHETCOR provided 1H chemical shifts which can be used for final validation of the DFT-D SM_D structure solution. As we have shown in previous section, the correlation between the calculated and experimental 13C chemical shifts can be used as a method of verifying the quality of the structure refinement. 1H nucleus, as shown for the SM_E sample, is even more sensitive to the local arrangement of atoms in the crystal lattice. (72,82−86) In that case, for the PXRD-based structure solutions, where the accuracy is much lower than for single-crystal-based X-ray diffraction methods, it is preferred to validate the obtained crystallographic data not only by 13C but also with the assistance of 1H chemical shifts. Figure 13b,c shows the correlation between calculated (GIPAW) and experimental NMR parameters. The RMSE values of 0.22 and 2.3 ppm for 1H and 13C, respectively, (Table S2) represent a very good agreement between experimental and GIPAW-calculated chemical shifts. (72,82−86) The obtained correlations support the correctness of the proposed structural solution.

Figure 13

Figure 13. (a) 13C–1H invHETCOR MAS NMR spectra of SM_D recorded at 90 °C with a spinning rate of 60 kHz at a 1H Larmor frequency of 600.1 MHz with a second 13C → 1H CP contact time of 100 μs. A one-pulse 1H MAS spectrum is shown at the top. The orange crosses represent GIPAW-calculated NMR correlations for C···H distances up to 1.5 Å. Isotropic 13C (a) and 1H (b) NMR values correlation (experimental chemical shifts vs GIPAW nuclear shieldings) for SM_D.

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Determination of SM_DLT Crystal Structure Based on the PXRD Measurements and Its Relation to the SM_D Structure

Analogous treatment with PXRD-related methods to the one used for SM_D was applied for SM_DLT. The obtained Le Bail fitting with the Rwp value equal to 7.05% gave the same crystal symmetry as for SM_D with very similar unit cell parameters, except for vector b which was approximately 3 times longer than for SM_D. It clearly suggests that the structure is Z′ = 3. It is also justified to assume that the molecular packing is not very different between SM_D and SM_DLT. It is also consistent with the 13C CP MAS spectra (Figure 9e) of SM_DLT suggesting Z′ > 2 type of structure with very similar peak positions to the SM_D (Figure 9c). Taking all of the above into account, our structural model was refined in a similar workflow as presented in Determination of SM_D Crystal Structure Based on the Data Obtained in a PXRD Measurement and Its Validation Using Advanced Solid-State NMR and GIPAW Calculations. The final Rietveld fit is shown in Figure 14 with its difference curve (Δ/σ). The obtained Rwp = 9.37% is a bit worse than for SM_D. However, when we consider that SM_DLT is a much larger system than SM_D, the obtained value is still reasonable. The crystallographic details are shown in Table 3.

Figure 14

Figure 14. Rietveld curves for SM_DLT.

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Table 3. Crystallographic Details Obtained from the PXRD Analysis of SM_DLT
empirical formulaC18FN2O5S
formula weight375.27
a [Å]5.52277(25)
b [Å]46.5689(27)
c [Å]22.3161(11)
α [deg]90
β [deg]90
γ [deg]90
V [Å3]5739.5(7)
Z12
Z′3
radiation wavelength [Å]1.5418
space groupP212121 (19)
Rwp9.37
density (calc) [g/cm3]1.3029
This nondestructive transformation fits well to the already available literature showing the great tendency of safinamide derivatives for creating various temperature-dependent polymorphic forms. (13) Taking into account all facts above, it is obvious that the reversible transformation SM_DLT ↔ SM_D is connected with the Z′ = 3 ↔ Z′ = 1 change that is pictographically shown in Figure 15. The most probable explanation of this phase change is that while SM_D form is cooled, molecular dynamic is slowing down what causes the formation of three slightly different conformers of safinamide (Figure 16). In this way, the system reduces its symmetry in the crystal lattice and has to be described by a unit cell 3 times as large as the one observed for SM_D.

Figure 15

Figure 15. Relation Z′ = 1 ↔ Z′ = 3 between PXRD unit cells of SM_DLT and SM_D. Molecules are colored according to the symmetry equivalence and shown without hydrogens.

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Figure 16

Figure 16. Superposition of nonequivalent molecules in SM_DLT (green, blue, and red) and SM_D (orange).

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Our observations for SM_D are consistent with the conclusions described by Nangia who showed that polymorphs with a larger number of symmetry-independent molecules (high Z′) generally led to the occurrence of polymorphism when compared with the polymorphs with lower Z′ values. (99) The SM_D case confirms that organic molecules with flexible torsions and low-energy conformers have a greater likelihood of exhibiting conformational polymorphism. (100)

Conclusions

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In this work, we showed how complex and nonobvious processes can be observed in the crystal lattices of compounds that are used as commercial drugs. When examining Xadago tablets, which contain SM as the API, we noticed several processes, each of which is reversible. The first is hydration and dehydration which is controlled by the temperature and humidity of the environment. The freshly crystallized SM employing a mixture of solvents water/ethanol (vol/vol 1:9) forms a hemihydrate (orthorhombic system with the P212121 space group). At moderate temperature (60–80 °C), the crystals lose water creating an anhydrous form with P21 space groups. This process can be reversed when the sample is stored in a humid environment. The anhydrous form undergoes thermal phase transition forming different polymorphs SM_DLT (Z′ = 3) ↔ SM_D (Z′ = 1). This polymorphic alternation takes place in the temperature range 0–20 °C which is the typical temperature for drug storage. Studying the correlation of structural changes in MS with the therapeutic properties of a drug is beyond the scope of our work. However, it seems apparent that such effects must be considered when formulating and storing a drug.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.1c00779.

  • 13C CP MAS NMR spectra recorded at a spinning rate of 8 and 13 kHz, additional DSC plots, results for the Xadago drug when a mechanically damaged tablet was stored in a humid environment at room temperature, superposition of the PXRD crystal structure solution prior and after DFT-D geometry optimization, and tables containing the experimental chemical shifts and GIPAW-calculated NMR shieldings (PDF)

  • Crystallographic information for the crystal structures solved by the PXRD methodology (ZIP)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
  • Authors
    • Marcin Oszajca - Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
    • Małgorzata Szczesio - Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Lodz, Poland
    • Marek J. Potrzebowski - Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland;  Orcidhttps://orcid.org/0000-0001-5672-0638
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors thank Agnieszka Jóźwiak for technical support. The computational resources were partially provided by the Polish Infrastructure for Supporting Computational Science in the European Research Space (PL-GRID). The project no. 04.04.00-00-4374/17-01 (Homing/2017 4/37) is carried out within the HOMING programme of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund.

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    Crystal Growth & Design (2021), 21 (1), 133-148CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Two concomitant polymorphs of safinamide acid hydrochloride were obtained in an attempt to prep. the O-protonated amide salt of safinamide from ethanolic HCl soln. Polymorph I crystd. in the triclinic space group P1 with three mols. in the asym. unit (Z' = 3) while polymorph II crystd. in the orthorhombic space group P212121 with a single mol. in the asym. unit (Z' = 1). Structural differences at the conformational level and their influence on intermol. interactions in the crystals led to the occurrence of polymorphism in the title compd. Both Z' = 1 and Z' = 3 polymorphic forms of safinamide acid hydrochloride were sustained by similar strong O-H···Cl- and N+-H···Cl- hydrogen-bonded interactions but differed significantly in the mol. conformations and hence their mol. arrangements in the crystal lattice. The C-H···O and C-H···F hydrogen bonds along with the strong hydrogen bonds facilitated one-dimensional supramol. aggregates and caused the occurrence of the Z' > 1 situation. The high-Z' polymorph showed an interesting phase transition behavior during variable-temp. single-crystal X-ray diffraction studies (VT-SCXRD). When the sample was rapidly cooled from 293 K (room temp.) to 100 K (low temp.), the Z' = 3 polymorph was stable; however, when the same crystal was subjected to gradual cooling from room temp. to 100 K, the Z' = 3 polymorph transformed to a novel Z' = 2 structure (in the transition temp. range 260-265 K). When the sample was warmed from 100 K to RT, the phase transition was found to be reversible from Z' = 2 to Z' = 3 (in the transition temp. range 270-275 K). Differential scanning calorimetry studies were conducted to confirm the reversible phase transition nature (Z' = 3 ↔ Z' = 2). An intermediate short-lived crystal form with four mols. in the asym. unit (Z' = 4) was captured at 272 K during the VT-SCXRD warming cycle, which facilitated a better understanding of the structural reorganization process during the phase transition. The Z' = 4 structure can be referred as a "crystal on the way" in the Z' = 2 to Z' = 3 phase transition. The close structural similarities among Z' = 3, 2, and 4 accounted for the phase transformation in a single-crystal to single-crystal manner. A temp.-dependent reversible phase transition behavior of a high-Z' polymorph of safinamide acid HCl in a single-crystal to single-fashion and the influence of cooling rates on the phase transformation are presented. The high-Z' polymorph (Z' = 3) transforms to a low-Z' structure (Z' = 2) when it is gradually cooled from 293 to 100 K, while it retains its high Z' when it is rapidly cooled to 100 K. The phase transition Z' = 2 ↔ Z' = 3 is facilitated via an intermediate Z' = 4 phase. The Z' = 1 polymorph, on the other hand, shows no phase transformations during variable-temp. studies.
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    Brittain, H. G. Polymorphism in Pharmaceutical Solids; M. Dekker: New York, 1999.
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    Polymorphism in Pharmaceutical Solids, 2nd ed.; Brittain, H. G., Ed.; Drugs and the Pharmaceutical Sciences; Informa Healthcare: New York, 2009.
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    Domingos, S.; André, V.; Quaresma, S.; Martins, I. C. B.; Minas da Piedade, M. F.; Duarte, M. T. New Forms of Old Drugs: Improving without Changing: New Forms of Old Drugs. J. Pharm. Pharmacol. 2015, 67, 830– 846,  DOI: 10.1111/jphp.12384
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    New forms of old drugs: improving without changing
    Domingos, Sofia; Andre, Vania; Quaresma, Silvia; Martins, Ines C. B.; Minas da Piedade, M. Fatima; Duarte, Maria Teresa
    Journal of Pharmacy and Pharmacology (2015), 67 (6), 830-846CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)
    Objectives : In a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful examples will be given. Key findings : This overview presents a possible step to overcome the 10-15 years of hard work involved in launching a new drug in the market: the use of new forms of well-known APIs, and improve their efficiency by enhancing their bioavailability and pharmacokinetics. It discusses some of the latest progresses. Summary : We want to present, in a brief overview, what recently has been done to improve the discovery of innovative methods of using well-known APIs, and improve their efficiency. Multicomponent crystal forms have shown to be the most promising achievements to accomplish these aims, by altering API physico-chem. properties, such as soly., thermal stability, shelf life, dissoln. rate and compressibility. API-ionic liqs. (ILs) and their advantages will be briefly referred. An outline of what has recently been achieved in metal drug coordination and in drug storage and delivery using bio-inspired metal-org. frameworks (BioMOFs) will also be addressed.
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    Singhal, D. Drug Polymorphism and Dosage Form Design: A Practical Perspective. Adv. Drug Deliv. Rev. 2004, 56, 335– 347,  DOI: 10.1016/j.addr.2003.10.008
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    Drug polymorphism and dosage form design: a practical perspective
    Singhal, Dharmendra; Curatolo, William
    Advanced Drug Delivery Reviews (2004), 56 (3), 335-347CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science B.V.)
    A review and discussion. Formulators are charged with the responsibility to formulate a product which is phys. and chem. stable, manufacturable, and bioavailable. Most drugs exhibit structural polymorphism, and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf life under a variety of real-world storage conditions. There are occasional situations in which the development of a metastable cryst. or amorphous form is justified because a medical benefit is achieved. Such situations include those in which a faster dissoln. rate or higher concn. are desired, in order to achieve rapid absorption and efficacy, or to achieve acceptable systemic exposure for a low-soly. drug. Another such situation is one in which the drug remains amorphous despite extensive efforts to crystallize it. If there is no particular medical benefit, there is less justification for accepting the risks of intentional development of a metastable cryst. or amorphous form. Whether or not there is medical benefit, the risks assocd. with development of a metastable form must be mitigated by lab. work which provides assurance that (a) the largest possible form change will have no substantive effect on product quality or bioavailability, and/or (b) a change will not occur under all reasonable real-world storage conditions, and/or (c) anal. methodol. and sampling procedures are in place which assure that a problem will be detected before dosage forms which have compromised quality or bioavailability can reach patients.
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    Yu, L.; Stephenson, G. A.; Mitchell, C. A.; Bunnell, C. A.; Snorek, S. V.; Bowyer, J. J.; Borchardt, T. B.; Stowell, J. G.; Byrn, S. R. Thermochemistry and Conformational Polymorphism of a Hexamorphic Crystal System. J. Am. Chem. Soc. 2000, 122, 585– 591,  DOI: 10.1021/ja9930622
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    Thermochemistry and Conformational Polymorphism of a Hexamorphic Crystal System
    Yu, Lian; Stephenson, Gregory A.; Mitchell, Christine A.; Bunnell, Charles A.; Snorek, Sharon V.; Bowyer, J. Joe; Borchardt, Thomas B.; Stowell, Joseph G.; Byrn, Stephen R.
    Journal of the American Chemical Society (2000), 122 (4), 585-591CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was crystd. as 6 solvent-free polymorphs, which differ in the mode of packing and in mol. conformation. The conformational difference results principally from the thiophene torsion relative to the o-nitroaniline fragment, which leads to different crystal colors (red, orange, and yellow). Thermodn. stability relations between polymorphs were detd. from solid-state conversions and calorimetric data of melting and eutectic melting. Vibrational spectroscopy and ab initio calcns. showed that most conformers in soln. feature perpendicularly arranged thiophene and o-nitroaniline fragments, although a minor population of more planar conformers also exist. Crystn. has a stabilizing effect for more planar and higher dipole conformers over perpendicular ones by 3-6 kJ/mol. The only exception to this pattern is the one polymorph contg. weak intermol. H bonds.
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    Pudipeddi, M.; Serajuddin, A. T. M. Trends in Solubility of Polymorphs. J. Pharm. Sci. 2005, 94, 929– 939,  DOI: 10.1002/jps.20302
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    Trends in solubility of polymorphs
    Pudipeddi, Madhu; Serajuddin, Abu T. M.
    Journal of Pharmaceutical Sciences (2005), 94 (5), 929-939CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
    Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. Considering the multitude of reports on soly. or dissoln. of polymorphs in the literature, an attempt is made in this study to answer the question: How big is the impact of polymorphism on soly.. A large no. of literature reports on soly. or dissoln. of polymorphs were reviewed and the data were analyzed for trends in soly. ratio of polymorphs. The general trend reveals that the ratio of polymorph soly. is typically less than 2, although occasionally higher ratios can be obsd. A similar trend is also obsd. for anhydrate/hydrate soly. ratios, although anhydrate/hydrate soly. ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. An attempt is also made in this commentary to est. the ratio of solubilities of polymorphs from thermal data. The trend in estd. soly. ratio shows good agreement with the one obsd. with exptl. detd. soly. values.
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    Sun, C.; Grant, D. J. W. Compaction Properties of L-Lysine Salts. Pharm. Res. 2001, 18, 281– 286,  DOI: 10.1023/a:1011090510875
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    Compaction properties of L-lysine salts
    Sun, Changquan; Grant, David J. W.
    Pharmaceutical Research (2001), 18 (3), 281-286CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
    The purpose of this research was to examine the effects of salt form, i.e., different anions with a common cation (L-lysinium), on compaction properties and to identify the factors that det. the tensile strength of tablets. L-Lysine salts with the following anions were compressed at various pressures acetate, monochloride, dichloride, L-aspartate, L-glutamate (dihydrate), and L-lysine (zwitterionic monohydrate). The yield strength of each salt was evaluated from the "out-of-die" Heckel plot. At low compaction pressures, the tensile strength of the compacts increases linearly with increasing compaction pressure. Simultaneously, the compact tensile strength decreases exponentially with increasing yield strength of the salt. However, at high compaction pressures, the compact tensile strength is detd. by the interparticulate bonding strength and not by the yield strength. The compact tensile strength, extrapolated to zero porosity, increases linearly with increasing melting temp. of the salts. The counterion affects the tableting properties of L-lysine salts. The tensile strength is controlled by both the yield strength and the interparticulate interaction strength with the former predominant at low compaction pressures and the latter predominant at high compaction pressures. The melting temp. of each L-lysine salt is a good indicator of the tensile strength of its compacts at zero porosity.
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    Picker-Freyer, K. M.; Liao, X.; Zhang, G.; Wiedmann, T. S. Evaluation of the Compaction of Sulfathiazole Polymorphs. J. Pharm. Sci. 2007, 96, 2111– 24,  DOI: 10.1002/jps.21042
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    Evaluation of the compaction of sulfathiazole polymorphs
    Picker-Freyer, Katharina Maria; Liao, Xiangmin; Zhang, Guifang; Wiedmann, Timothy Scott
    Journal of Pharmaceutical Sciences (2007), 96 (8), 2111-2124CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
    The aim of this study was to relate the tableting performance assessed by an instrumented tableting machine to the mech. properties measured by nanoindentation. Three different polymorphic forms of sulfathiazole were prepd. by recrystn., and the d. and x-ray powder diffraction patterns were measured and compared with theor. d. and simulated powder patterns, resp. Tablets were prepd. using a series of applied pressures, and the results were subjected to energy anal., 3D-modeling, and traditional Heckel anal. With these approaches, form I was consistently the most brittle material, but the subtle differences between forms II and III were only revealed by 3D modeling. The rank order of the crushing force was form I ≃ form II < form III. From nanoindentation, form III was much harder than forms I and II, and III also had a much higher Young's modulus. The energy calcns. of the nanoindentation curves showed that form III was distinct from forms I and II, which is consistent with the presence of slip planes that are only present in form III. However, in this system, there was little correspondence between the macroscopic and microscopic measurements, and thus particle-particle interactions may to be of paramount importance.
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    Khomane, K. S.; More, P. K.; Bansal, A. K. Counterintuitive Compaction Behavior of Clopidogrel Bisulfate Polymorphs. J. Pharm. Sci. 2012, 101, 2408– 2416,  DOI: 10.1002/jps.23148
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    Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs
    Khomane, Kailas S.; More, Parth K.; Bansal, Arvind K.
    Journal of Pharmaceutical Sciences (2012), 101 (7), 2408-2416CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    Being a d. violator, clopidogrel bisulfate (CLP) polymorphic system (forms I and II) allows us to study individually the impact of mol. packing (true d.) and thermodn. properties such as heat of fusion on the compaction behavior. These two polymorphs of CLP were investigated for in-die and out-of-die compaction behavior using CTC profile, Heckel, and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. Detailed examns. of the mol. packing of each form revealed that arrangement of the sulfate anion differs significantly in both crystal forms, thus conferring different compaction behavior to two forms. Close cluster packing of mols. in form I offers a rigid structure, which has poor compressibility and hence resists deformation under compaction pressure. This results into lower densification, higher yield strength, and mean yield pressure, as compared with form II at a given pressure. However, by virtue of higher bonding strength, form I showed superior tabletability, despite its poor compressibility and deformation behavior. Form I, having higher true d. and lower heat of fusion showed higher bonding strength. Hence, true d. and not heat of fusion can be considered predictor of bonding strength of the pharmaceutical powders. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
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    Ainurofiq, A.; Dinda, K. E.; Pangestika, M. W.; Himawati, U.; Wardhani, W. D.; Sipahutar, Y. T. The Effect of Polymorphism on Active Pharmaceutical Ingredients: A Review. Int. J. Res. Pharm. Sci. 2020, 11, 1621– 1630,  DOI: 10.26452/ijrps.v11i2.2044
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    Dudek, M. K.; Kazmierski, S.; Kostrzewa, M.; Potrzebowski, M. J. Solid-State NMR Studies of Molecular Crystals. Annual Reports on NMR Spectroscopy; Elsevier, 2018; Vol. 95, pp 1– 81.
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    Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Ritonavir: An Extraordinary Example of Conformational Polymorphism. Pharmaceut. Res. 2001, 18, 859,  DOI: 10.1023/A:1011052932607
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    Ritonavir: an extraordinary example of conformational polymorphism
    Bauer, John; Spanton, Stephen; Henry, Rodger; Quick, John; Dziki, Walter; Porter, William; Morris, John
    Pharmaceutical Research (2001), 18 (6), 859-866CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
    Purpose. In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less sol. crystal form of ritonavir. This report provides characterization of the 2 polymorphs and the structures and hydrogen bonding network for each form. Methods. Ritonavir polymorphism was investigated by solid state spectroscopy and microscopy techniques including solid state NMR, near-IR Spectroscopy, powder x-ray Diffraction and single crystal x-ray. A sensitive seed detection test was developed. Results. Ritonavir polymorphs were thoroughly characterized and the structures detd. An unusual conformation was found for form II that results in a strong hydrogen bonding network. A possible mechanism for heterogeneous nucleation of form II was investigated. Conclusions. Ritonavir exhibited conformational polymorphism with two unique crystal lattices having significantly different soly. properties. Although the polymorph (form II) corresponding to the "cis" conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersatd. solns. The coincidence of a highly supersatd. soln. and a probable heterogeneous nucleation by a degrdn. product resulted in the sudden appearance of the more stable form II polymorph.
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    Sheldrick, G. M. Short History of SHELX. Acta Crystallogr. A 2008, 64, 112– 122,  DOI: 10.1107/s0108767307043930
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    A short history of SHELX
    Sheldrick, George M.
    Acta Crystallographica, Section A: Foundations of Crystallography (2008), 64 (1), 112-122CODEN: ACACEQ; ISSN:0108-7673. (International Union of Crystallography)
    An account is given of the development of the SHELX system of computer programs from SHELX-76 to the present day. In addn. to identifying useful innovations that have come into general use through their implementation in SHELX, a crit. anal. is presented of the less-successful features, missed opportunities and desirable improvements for future releases of the software. An attempt is made to understand how a program originally designed for photog. intensity data, punched cards and computers over 10000 times slower than an av. modern personal computer has managed to survive for so long. SHELXL is the most widely used program for small-mol. refinement and SHELXS and SHELXD are often employed for structure soln. despite the availability of objectively superior programs. SHELXL also finds a niche for the refinement of macromols. against high-resoln. or twinned data; SHELXPRO acts as an interface for macromol. applications. SHELXC, SHELXD and SHELXE are proving useful for the exptl. phasing of macromols., esp. because they are fast and robust and so are often employed in pipelines for high-throughput phasing. This paper could serve as a general literature citation when one or more of the open-source SHELX programs (and the Bruker AXS version SHELXTL) are employed in the course of a crystal-structure detn.
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    Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta Crystallogr. Sect. C Cryst. Struct. Commun. 2015, 71, 3– 8,  DOI: 10.1107/s2053229614024218
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    Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. a. K.; Puschmann, H. OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Crystallogr. 2009, 42, 339– 341,  DOI: 10.1107/s0021889808042726
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    OLEX2: a complete structure solution, refinement and analysis program
    Dolomanov, Oleg V.; Bourhis, Luc J.; Gildea, Richard J.; Howard, Judith A. K.; Puschmann, Horst
    Journal of Applied Crystallography (2009), 42 (2), 339-341CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
    New software, OLEX2, was developed for the detn., visualization and anal. of mol. crystal structures. The software has a portable mouse-driven workflow-oriented and fully comprehensive graphical user interface for structure soln., refinement and report generation, as well as novel tools for structure anal. OLEX2 seamlessly links all aspects of the structure soln., refinement and publication process and presents them in a single workflow-driven package, with the ultimate goal of producing an application which will be useful to both chemists and crystallographers.
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    Boultif, A.; Louër, D. Powder Pattern Indexing with the Dichotomy Method. J. Appl. Crystallogr. 2004, 37, 724– 731,  DOI: 10.1107/s0021889804014876
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    Powder pattern indexing with the dichotomy method
    Boultif, Ali; Louer, Daniel
    Journal of Applied Crystallography (2004), 37 (5), 724-731CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)
    The efficiency of the successive dichotomy method for powder diffraction pattern indexing [Louer and Louer (1972). J. Appl. Cryst. 5, 271-275] was proved over >30 yr of usage. Features implemented in the new version of the computer program DICVOL04 include (i) a tolerance to the presence of impurity (or inaccurately measured) diffraction lines, (ii) a refinement of the 'zero-point' position, (iii) a reviewing of all input lines from the soln. found from, generally, the 1st 20 lines, (iv) a cell anal., based on the concept of the reduced cell, to identify equiv. monoclinic and triclinic solns., and (v) an optional anal. of input powder data to detect the presence of a significant 'zero-point' offset. New search strategies also were introduced, e.g. each crystal system is scanned sep., within the input vol. limits, to limit the risk of missing a soln. characterized by a metric lattice singularity. The default values in the input file were extended to 25 Å for the linear parameters and 2500 Å3 for the cell vol. The search is carried out exhaustively within the input parameter limits and the abs. error on peak position measurements. Many tests with data from the literature and from powder data of pharmaceutical materials, collected with the capillary technique and lab. monochromatic x-rays, were performed with a high success rate, covering all crystal symmetries from cubic to triclinic. Some examples reported as 'difficult' cases are also discussed. Addnl., a few recommendations for the correct practice of powder pattern indexing are reported.
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    Altomare, A.; Caliandro, R.; Camalli, M.; Cuocci, C.; Giacovazzo, C.; Moliterni, A. G. G.; Rizzi, R. Automatic Structure Determination from Powder Data with EXPO2004. J. Appl. Crystallogr. 2004, 37, 1025– 1028,  DOI: 10.1107/s0021889804021417
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    Automatic structure determination from powder data with EXPO2004
    Altomare, Angela; Caliandro, Rocco; Camalli, Mercedes; Cuocci, Corrado; Giacovazzo, Carmelo; Moliterni, Anna Grazia Giuseppina; Rizzi, Rosanna
    Journal of Applied Crystallography (2004), 37 (6), 1025-1028CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)
    EXPO2004 is the updated version of the EXPO program [Altomare et al. (1999). J. Appl. Cryst. 32, 339-340]. The traditional steps of the ab initio powder soln. process were performed automatically: indexing, space-group detn., decompn. of the pattern for extg. the obsd. structure-factor moduli, structure soln. by direct methods, model refinement by Rietveld technique. Special strategies may be applied to improve both the ests. of the extd. structure-factor moduli and the quality of the structure model. The use of special procedures exploiting available supplementary information on mol. geometry can be successfully adopted. The graphical interface also was improved.
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    Altomare, A.; Cuocci, C.; Giacovazzo, C.; Moliterni, A.; Rizzi, R.; Corriero, N.; Falcicchio, A. EXPO2013 : A Kit of Tools for Phasing Crystal Structures from Powder Data. J. Appl. Crystallogr. 2013, 46, 1231– 1235,  DOI: 10.1107/s0021889813013113
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    EXPO2013: a kit of tools for phasing crystal structures from powder data
    Altomare, Angela; Cuocci, Corrado; Giacovazzo, Carmelo; Moliterni, Anna; Rizzi, Rosanna; Corriero, Nicola; Falcicchio, Aurelia
    Journal of Applied Crystallography (2013), 46 (4), 1231-1235CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
    EXPO2013, the heir of EXPO2009, was enriched by a variety of new algorithms and graphical tools aiming at strengthening the individual steps of the powder structure soln. pathway. Particular attention was addressed to the procedures devoted to improving structural models provided by direct methods in ab initio approaches. A new procedure was implemented, working in direct space, which may be chosen by the user as an alternative to the traditional simulated annealing algorithm.
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    Černý, R.; Favre-Nicolin, V.; Rohlíček, J.; Hušák, M. FOX, Current State and Possibilities. Crystals 2017, 7, 322
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    FOX, current state and possibilities
    Cerny, Radovan; Favre-Nicolin, Vincent; Rohlicek, Jan; Husak, Michal
    Crystals (2017), 7 (10), 322/1-322/10CODEN: CRYSBC; ISSN:2073-4352. (MDPI AG)
    FOX (Free Objects for Xtallog.) is a computer program for solving crystal structures of all types of compds. using the powder data (but also the single crystal data) measured using X-ray, neutron and electron diffraction. It works in direct space using the reversed Monte Carlo algorithm of global optimization. Since its release fifteen years ago, it has developed into a powerful tool, simplifying the powder pattern anal. starting from the background detn., indexing and space group selection over the structure modeling using various pre-programmed structural fragments up to the validation of the proposed structural model.
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    Favre-Nicolin, V.; Černý, R. FOX, free Objects for Crystallography’: A Modular Approach to Ab Initio Structure Determination from Powder Diffraction. J. Appl. Crystallogr. 2002, 35, 734– 743,  DOI: 10.1107/s0021889802015236
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    FOX, 'free objects for crystallography': a modular approach to ab initio structure determination from powder diffraction
    Favre-Nicolin, Vincent; Cerny, Radovan
    Journal of Applied Crystallography (2002), 35 (6), 734-743CODEN: JACGAR; ISSN:0021-8898. (Blackwell Munksgaard)
    A new program was developed for ab initio crystal structure detn. from powder diffraction data (x-ray and neutron). It uses global-optimization algorithms to solve the structure by performing trials in direct space. It is a modular program, capable of using several criteria for evaluating each trial configuration (e.g. multi-pattern). It is also modular in the description of the crystal content, with the possibility of describing building blocks in the sample, such as polyhedra or mols., and with automatic adaptive handling of special positions and sharing of identical atoms between neighboring building blocks. It can therefore find the correct structure without any assumption about the connectivity of the building blocks and is suitable for any kind of material. Several optimization algorithms (simulated annealing, parallel tempering) are available, with the possibility of choosing the convergence criterion as a combination of available cost functions. This program is freely available for Linux and Windows platforms; it is also fully 'open source', which, combined with an object-oriented design and a complete developer documentation, ensures its future evolution.
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    Toby, B. H.; Von Dreele, R. B. GSAS-II : The Genesis of a Modern Open-Source All Purpose Crystallography Software Package. J. Appl. Crystallogr. 2013, 46, 544– 549,  DOI: 10.1107/s0021889813003531
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    GSAS-II: the genesis of a modern open-source all purpose crystallography software package
    Toby, Brian H.; Von Dreele, Robert B.
    Journal of Applied Crystallography (2013), 46 (2), 544-549CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
    The newly developed GSAS-II software is a general purpose package for data redn., structure soln. and structure refinement that can be used with both single-crystal and powder diffraction data from both neutron and x-ray sources, including lab. and synchrotron sources, collected on both two- and 1-dimensional detectors. It is intended that GSAS-II will eventually replace both the GSAS and the EXPGUI packages, as well as many other utilities. GSAS-II is open source and is written largely in object-oriented Python but offers speeds comparable to compiled code because of its reliance on the Python NumPy and SciPy packages for computation. It runs on all common computer platforms and offers highly integrated graphics, both for a user interface and for interpretation of parameters. The package can be applied to all stages of crystallog. anal. for const.-wavelength x-ray and neutron data. Plans for considerable addnl. development are discussed.
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    Bruno, I. J.; Cole, J. C.; Kessler, M.; Luo, J.; Motherwell, W. D. S.; Purkis, L. H.; Smith, B. R.; Taylor, R.; Cooper, R. I.; Harris, S. E.; Orpen, A. G. Retrieval of Crystallographically-Derived Molecular Geometry Information. J. Chem. Inf. Comput. Sci. 2004, 44, 2133– 2144,  DOI: 10.1021/ci049780b
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    Retrieval of Crystallographically-Derived Molecular Geometry Information
    Bruno, Ian J.; Cole, Jason C.; Kessler, Magnus; Luo, Jie; Motherwell, W. D. Sam; Purkis, Lucy H.; Smith, Barry R.; Taylor, Robin; Cooper, Richard I.; Harris, Stephanie E.; Orpen, A. Guy
    Journal of Chemical Information and Computer Sciences (2004), 44 (6), 2133-2144CODEN: JCISD8; ISSN:0095-2338. (American Chemical Society)
    The crystallog. detd. bond length, valence angle, and torsion angle information in the Cambridge Structural Database (CSD) has many uses. However, accessing it by conventional substructure searching requires nontrivial user intervention. In consequence, these valuable data were underused and were not directly accessible to client applications. The situation was remedied by development of a new program (Mogul) for automated retrieval of mol. geometry data from the CSD. The program uses a system of keys to encode the chem. environments of fragments (bonds, valence angles, and acyclic torsions) from CSD structures. Fragments with identical keys are deemed to be chem. identical and are grouped together, and the distribution of the appropriate geometrical parameter (bond length, valence angle, or torsion angle) is computed and stored. Use of a search tree indexed on key values, together with a novel similarity calcn., then enables the distribution matching any given query fragment (or the distributions most closely matching, if an adequate exact match is unavailable) to be found easily and with no user intervention. Validation expts. indicate that, with rare exceptions, search results afford precise and unbiased ests. of mol. geometrical preferences. Such ests. may be used, for example, to validate the geometries of libraries of modeled mols. or of newly detd. crystal structures or to assist structure soln. from low-resoln. (e.g. powder diffraction) x-ray data.
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    Cottrell, S. J.; Olsson, T. S. G.; Taylor, R.; Cole, J. C.; Liebeschuetz, J. W. Validating and Understanding Ring Conformations Using Small Molecule Crystallographic Data. J. Chem. Inf. Model. 2012, 52, 956– 962,  DOI: 10.1021/ci200439d
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    Validating and Understanding Ring Conformations Using Small Molecule Crystallographic Data
    Cottrell, Simon J.; Olsson, Tjelvar S. G.; Taylor, Robin; Cole, Jason C.; Liebeschuetz, John W.
    Journal of Chemical Information and Modeling (2012), 52 (4), 956-962CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
    Understanding the conformational preferences of ring structures is fundamental to structure-based drug design. Although the Cambridge Structural Database (CSD) provides information on the preferred conformations of small mols., analyzing this data can be very time-consuming. In order to overcome this hurdle, tools have been developed for quickly extg. geometrical preferences from the CSD. Here we describe how the program Mogul has been extended to analyze and compare ring conformations, using a library derived from over 900 000 ring fragments in the CSD. We illustrate how these can be used to understand the conformational preferences of mols. in a crystal lattice and bound to proteins.
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    Dvinskikh, S. V.; Zimmermann, H.; Maliniak, A.; Sandström, D. Heteronuclear Dipolar Recoupling in Liquid Crystals and Solids by PISEMA-Type Pulse Sequences. J. Magn. Reson. 2003, 164, 165– 170,  DOI: 10.1016/s1090-7807(03)00180-0
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    Heteronuclear dipolar recoupling in liquid crystals and solids by PISEMA-type pulse sequences
    Dvinskikh, Sergey V.; Zimmermann, Herbert; Maliniak, Arnold; Sandstrom, Dick
    Journal of Magnetic Resonance (2003), 164 (1), 165-170CODEN: JMARF3; ISSN:1090-7807. (Elsevier Science)
    A pulse sequence is described for the recoupling of heteronuclear dipolar interactions under MAS. The method is similar to the PISEMA expt., but employs a well-defined amplitude modulation of one of the two radiofrequency fields. The technique is used for measurements of 1H-13C dipolar couplings in unoriented solid and liq.-cryst. samples.
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    Dvinskikh, S. V.; Sandström, D. Frequency Offset Refocused PISEMA-Type Sequences. J. Magn. Reson. 2005, 175, 163– 169,  DOI: 10.1016/j.jmr.2005.03.016
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    Frequency offset refocused PISEMA-type sequences
    Dvinskikh, Sergey V.; Sandstroem, Dick
    Journal of Magnetic Resonance (2005), 175 (1), 163-169CODEN: JMARF3; ISSN:1090-7807. (Elsevier)
    The popular PISEMA expt. is highly sensitive to the 1H chem. shift dispersion and the choice of the 1H carrier frequency. This is due to the off-resonance 1H irradn. in the FSLG-CP sequence employed during the dipolar evolution period. In the modified approach described in this work, the interfering frequency offset terms are suppressed. In the new pulse schemes, conventional FSLG-CP is intercalated with 180° pulses applied simultaneously to both frequency channels, and with phases set orthogonal to those of the spin-lock fields. The technique is demonstrated on a nematic liq.-cryst. sample. Extensions to amplitude-modulated FSLG-CP recoupling under MAS are also presented.
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    Ramamoorthy, A.; Opella, S. J. Two-Dimensional Chemical Shift/Heteronuclear Dipolar Coupling Spectra Obtained with Polarization Inversion Spin Exchange at the Magic Angle and Magic-Angle Sample Spinning (PISEMAMAS). Solid State Nucl. Magn. Reson. 1995, 4, 387– 392,  DOI: 10.1016/0926-2040(95)00054-t
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    Two-dimensional chemical shift/heteronuclear dipolar coupling spectra obtained with polarization inversion spin exchange at the magic angle and magic-angle sample spinning (PISEMAMAS)
    Ramamoorthy, A.; Opella, S. J.
    Solid State Nuclear Magnetic Resonance (1995), 4 (6), 387-92CODEN: SSNRE4; ISSN:0926-2040. (Elsevier)
    High-resoln. two-dimensional 15N chem. shift/1H-15N dipolar coupling polarization inversion spin exchange at the magic angle (PISEMA) spectra of a polycryst. sample of 15N-acetylvaline were obtained with and without magic-angle sample spinning. These spectra demonstrate the advantages of the PISEMA expt. over conventional approaches to sepd. local-field spectroscopy, esp. the high resoln. in the dipolar dimension where the spinning sidebands have uniformly narrow linewidths.
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    Fung, B. M.; Khitrin, A. K.; Ermolaev, K. An Improved Broadband Decoupling Sequence for Liquid Crystals and Solids. J. Magn. Reson. 2000, 142, 97– 101,  DOI: 10.1006/jmre.1999.1896
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    An Improved Broadband Decoupling Sequence for Liquid Crystals and Solids
    Fung, B. M.; Khitrin, A. K.; Ermolaev, Konstantin
    Journal of Magnetic Resonance (2000), 142 (1), 97-101CODEN: JMARF3; ISSN:1090-7807. (Academic Press)
    Recently the authors developed an efficient broadband decoupling sequence called SPARC-16 for liq. crystals [J. Magn. Reson. 130, 317(1998)]. The sequence is based upon a 16-step phase cycling of the 2-step TPPM decoupling method for solids [J. Chem. Phys. 103, 6951(1995)]. Since then, a stepwise variation of the phase angle in the TPPM sequence offers even better results. The application of this new method to a liq. cryst. compd., 4-n-pentyl-4'-cyanobiphenyl, and a solid, l-tyrosine hydrochloride, is reported. The reason for the improvement is explained by an anal. of the problem in the rotating frame. (c) 2000 Academic Press.
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    Topspin, version 3.5; Bruker Biospin Gmbh: Karlsruhe, Germany.
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    Mao, K.; Wiench, J. W.; Lin, V. S.-Y.; Pruski, M. Indirectly Detected Through-Bond Chemical Shift Correlation NMR Spectroscopy in Solids under Fast MAS: Studies of Organic–Inorganic Hybrid Materials. J. Magn. Reson. 2009, 196, 92– 95,  DOI: 10.1016/j.jmr.2008.10.010
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    Indirectly detected through-bond chemical shift correlation NMR spectroscopy in solids under fast MAS: Studies of organic-inorganic hybrid materials
    Mao, Kanmi; Wiench, Jerzy W.; Lin, Victor S.-Y.; Pruski, Marek
    Journal of Magnetic Resonance (2009), 196 (1), 92-95CODEN: JMARF3; ISSN:1090-7807. (Elsevier B.V.)
    Indirectly detected, through-bond NMR correlation spectra between 13C and 1H nuclei are reported for the first time in solid state. The capabilities of the new method are demonstrated using naturally abundant org.-inorg. mesoporous hybrid materials. The time performance is significantly better, almost by a factor of 10, than in the corresponding 13C detected expt. The proposed scheme represents a new anal. tool for studying other solid-state systems and the basis for the development of more advanced 2D and 3D correlation methods.
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    Ishii, Y.; Tycko, R. Sensitivity Enhancement in Solid State 15N NMR by Indirect Detection with High-Speed Magic Angle Spinning. J. Magn. Reson. 2000, 142, 199– 204,  DOI: 10.1006/jmre.1999.1976
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    Sensitivity Enhancement in Solid State 15N NMR by Indirect Detection with High-Speed Magic Angle Spinning
    Ishii, Yoshitaka; Tycko, Robert
    Journal of Magnetic Resonance (2000), 142 (1), 199-204CODEN: JMARF3; ISSN:1090-7807. (Academic Press)
    Enhancement of sensitivity in solid state 15N NMR by indirect detection through 1H NMR signals under high-speed magic angle spinning and high-field conditions is demonstrated exptl. on two 15N-labeled peptides, polycryst. AlaGlyGly and the helix-forming, 17-residue peptide MB(i + 4)EK in lyophilized form. Sensitivity enhancement factors ranging from 2.0 to 3.2 are obsd. exptl., depending on the 15N and 1H linewidths and polarization transfer efficiencies. The 1H-detected two-dimensional 1H/15N correlation spectrum of AlaGlyGly illustrates the possibility of increased spectral resoln. and resonance assignments in indirectly detected expts., in addn. to the sensitivity enhancement. (c) 2000 Academic Press.
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    Wiench, J. W.; Bronnimann, C. E.; Lin, V. S.-Y.; Pruski, M. Chemical Shift Correlation NMR Spectroscopy with Indirect Detection in Fast Rotating Solids: Studies of Organically Functionalized Mesoporous Silicas. J. Am. Chem. Soc. 2007, 129, 12076– 12077,  DOI: 10.1021/ja074746+
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    Chemical Shift Correlation NMR Spectroscopy with Indirect Detection in Fast Rotating Solids: Studies of Organically Functionalized Mesoporous Silicas
    Wiench, Jerzy W.; Bronnimann, Charles E.; Lin, Victor S.-Y.; Pruski, Marek
    Journal of the American Chemical Society (2007), 129 (40), 12076-12077CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The first indirectly detected 13C-1H solid-state NMR correlation spectra of species bound to a surface are reported. The expts. were performed at 14.1 T under fast (40 kHz) MAS. The sensitivity gain was demonstrated on a mesoporous silica sample contg. approx. 300 μg of covalently bound allyl groups, in the absence of templating mols. and without isotope enrichment. A well-resolved two-dimensional spectrum was acquired in 15 min, which is more than 10 times faster than using direct detection of 13C nuclei.
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    Thakur, R. S.; Kurur, N. D.; Madhu, P. K. Swept-Frequency Two-Pulse Phase Modulation for Heteronuclear Dipolar Decoupling in Solid-State NMR. Chem. Phys. Lett. 2006, 426, 459– 463,  DOI: 10.1016/j.cplett.2006.06.007
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    Swept-frequency two-pulse phase modulation for heteronuclear dipolar decoupling in solid-state NMR
    Thakur, Rajendra Singh; Kurur, Narayanan D.; Madhu, P. K.
    Chemical Physics Letters (2006), 426 (4-6), 459-463CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)
    We introduce a heteronuclear dipolar decoupling sequence for application in solid-state NMR. The sequence, called swept-frequency two-pulse phase modulation (SWf-TPPM), is based on one of the decoupling sequences, TPPM. The sequence is robust in performance with respect to various exptl. parameters, such as, the pulse flip angle, pulse phase, and offset and a comparison is made with other decoupling schemes, namely TPPM, SPINAL, and XiX, on a sample of U-13C-labeled tyrosine for magic-angle spinning speeds up to 14 kHz.
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    Vinod Chandran, C.; Madhu, P. K.; Kurur, N. D.; Bräuniger, T. Swept-Frequency Two-Pulse Phase Modulation (SW f -TPPM) Sequences with Linear Sweep Profile for Heteronuclear Decoupling in Solid-State NMR. Magn. Reson. Chem. 2008, 46, 943– 947,  DOI: 10.1002/mrc.2285
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    Swept-frequency two-pulse phase modulation (SWf-TPPM) sequences with linear sweep profile for heteronuclear decoupling in solid-state NMR
    Vinod Chandran C; Madhu P K; Kurur Narayanan D; Brauniger Thomas
    Magnetic resonance in chemistry : MRC (2008), 46 (10), 943-7 ISSN:.
    Recently, a pulse scheme for heteronuclear spin decoupling in solid-state NMR, called swept-frequency two-pulse phase modulation (SW(f)-TPPM), was introduced which outperforms the standard TPPM and small phase incremental alteration (SPINAL) schemes. It has also been shown that the frequency-sweep profile can be varied to achieve optimal efficiency for crystalline and liquid-crystalline samples, respectively. Here we present a detailed comparison of the proton decoupling performance for SW(f)-TPPM sequences with tangential sweep profiles (SW(f) (tan)-TPPM) and linear sweep profiles (SW(f) (lin)-TPPM). Using the (13)CH(2) resonance of crystalline tyrosine as a model system, it is shown that linear profiles have a decoupling performance which is at least as good and in some instances slightly better than that obtained from tangential sweep profiles. While tangential sweep profiles require a tangent cut-off angle as an additional parameter, the lack of that parameter makes linear sweep profiles easier to implement and optimise.
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    Marion, D.; Ikura, M.; Tschudin, R.; Bax, A. Rapid Recording of 2D NMR Spectra without Phase Cycling. Application to the Study of Hydrogen Exchange in Proteins. J. Magn. Reson. 1989, 85, 393– 399,  DOI: 10.1016/0022-2364(89)90152-2
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    Rapid recording of 2D NMR spectra without phase cycling: application to the study of hydrogen exchange in proteins
    Marion, Dominique; Ikura, Mitsuhiko; Tschudin, Rolf; Bax, Ad
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    High quality 2-dimensional NMR spectra can be recorded very rapidly without using phase cycling. This makes it possible to study H exchange phenomena in proteins with spectra too complex for anal. by 1-dimensional NMR. This approach is demonstrated on calmodulin and a trypsin inhibitor.
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    Morcombe, C. R.; Zilm, K. W. Chemical Shift Referencing in MAS Solid State NMR. J. Magn. Reson. 2003, 162, 479– 486,  DOI: 10.1016/s1090-7807(03)00082-x
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    Chemical shift referencing in MAS solid state NMR
    Morcombe, Corey R.; Zilm, Kurt W.
    Journal of Magnetic Resonance (2003), 162 (2), 479-486CODEN: JMARF3; ISSN:1090-7807. (Elsevier Science)
    Solid state 13C magic angle spinning (MAS) NMR spectra are typically referenced externally using a probe which does not incorporate a field frequency lock. Soln. NMR shifts however, are more often detd. with respect to an internal ref. and using a deuterium based field frequency lock. Further differences arise in soln. NMR of proteins and nucleic acids where both 13C and 1H shifts are referenced by recording the frequency of the 1H resonance of DSS (sodium salt of 2,2-dimethyl-2-silapentane-5-sulfonic acid) instead of TMS (tetramethylsilane). The authors study the difficulties in relating shifts measured relative to TMS and DSS by these various approaches in soln. and solids NMR, and calibrate adamantane as an external 13C std. for solids NMR. External chem. shift referencing of magic angle spinning spectra is typically quite reproducible and accurate, with better than ±0.03 ppm accuracy being straight forward to achieve. Solid state and liq. phase NMR shifts obtained by magic angle spinning with external referencing agree with those measured using typical soln. NMR hardware with the sample tube aligned with the applied field as long as magnetic susceptibility corrections and solvent shifts are taken into account. The DSS and TMS ref. scales for 13C and 1H are related accurately using MAS NMR. Large solvent shifts for the 13C resonance in TMS in either deuterochloroform or methanol are obsd., being +0.71 ppm and -0.74 ppm from external TMS, resp. The ratio of the 13C resonance frequencies for the two carbons in solid adamantane to the 1H resonance of TMS is reported.
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    Harris, R. K.; Becker, E. D.; Cabral de Menezes, S. M.; Goodfellow, R.; Granger, P. NMR Nomenclature. Nuclear Spin Properties and Conventions for Chemical Shifts(IUPAC Recommendations 2001). Pure Appl. Chem. 2001, 73, 1795– 1818,  DOI: 10.1351/pac200173111795
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    NMR nomenclature. Nuclear spin properties and conventions for chemical shifts (IUPAC recommendations 2001)
    Harris, Robin K.; Becker, Edwin D.; Cabral De Menezes, Sonia M.; Goodfellow, Robin; Granger, Pierre
    Pure and Applied Chemistry (2001), 73 (11), 1795-1818CODEN: PACHAS; ISSN:0033-4545. (International Union of Pure and Applied Chemistry)
    A review. A unified scale is recommended for reporting the NMR chem. shifts of all nuclei relative to the 1H resonance of tetramethylsilane (TMS). The unified scale is designed to provide a precise ratio, Ξ, of the resonance frequency of a given nuclide to that of the primary ref., the 1H resonance of TMS in dil. soln. (vol. fraction, φ < 1%) in CHCl3. Referencing procedures are discussed, including matters of practical application of the unified scale. Special attention is paid to recommended ref. samples, and values of Ξ for secondary refs. on the unified scale are listed, many of which are the results of new measurements. Some earlier recommendations relating to the reporting of chem. shifts are endorsed. The chem. shift, δ, is redefined to avoid previous ambiguities but to leave practical usage unchanged. Relations between the unified scale and recently published recommendations for referencing in aq. solns. (for specific use in biochem. work) are discussed, as well as the special effects of working in the solid state with magic-angle spinning. In all, nine new recommendations relating to chem. shifts are made. Standardized nuclear spin data are also presented in tabular form for the stable (and some unstable) isotopes of all elements with nonzero quantum nos. The information given includes quantum nos., isotopic abundances, magnetic moments, magnetogyric ratios and receptivities, together with quadrupole moments and line-width factors where appropriate.
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    Bertani, P.; Raya, J.; Bechinger, B. 15N Chemical Shift Referencing in Solid State NMR. Solid State Nucl. Magn. Reson. 2014, 61–62, 15– 18,  DOI: 10.1016/j.ssnmr.2014.03.003
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    15N chemical shift referencing in solid state NMR
    Bertani, Philippe; Raya, Jesus; Bechinger, Burkhard
    Solid State Nuclear Magnetic Resonance (2014), 61-62 (), 15-18CODEN: SSNRE4; ISSN:0926-2040. (Elsevier)
    Solid-state NMR spectroscopy has much advanced during the last decade and provides a multitude of data that can be used for high-resoln. structure detn. of biomols., polymers, inorg. compds. or macromols. In some cases the chem. shift referencing has become a limiting factor to the precision of the structure calcns. and we have therefore evaluated a no. of methods used in proton-decoupled 15N solid-state NMR spectroscopy. For 13C solid-state NMR spectroscopy adamantane is generally accepted as an external std., but to calibrate the 15N chem. shift scale several stds. are in use. As a consequence the published chem. shift values exhibit considerable differences (up to 22 ppm). In this paper we report the 15N chem. shift of several commonly used refs. compds. in order to allow for comparison and recalibration of published data and future work. We show that 15NH4Cl in its powd. form (at 39.3 ppm with respect to liq. NH3) is a suitable external ref. as it produces narrow lines when compared to other ref. compds. and at the same time allows for the set-up of cross-polarization NMR expts. The compd. is suitable to calibrate magic angle spinning and static NMR expts. Finally the temp. variation of 15NH4Cl chem. shift is reported.
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    Bielecki, A.; Burum, D. P. Temperature Dependence of 207 Pb MAS Spectra of Solid Lead Nitrate. An Accurate, Sensitive Thermometer for Variable-Temperature MAS. J. Magn. Reson., Ser. A 1995, 116, 215– 220,  DOI: 10.1006/jmra.1995.0010
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    Temperature dependence of 207Pb MAS spectra of solid lead nitrate. An accurate, sensitive thermometer for variable-temperature MAS
    Bielecki, Anthony; Burum, Douglas P.
    Journal of Magnetic Resonance, Series A (1995), 116 (2), 215-20CODEN: JMRAE2; ISSN:1064-1858. (Academic)
    The remarkably sensitive temp. dependence of the 207Pb chem. shift in magic-angle-spinning (MAS) spectra of lead nitrate provides an excellent method for thermometry in solid-state NMR. The temp. dependence is uniform over a range of at least -130 to +150°, and also the NMR sensitivity and linewidth are very favorable. Lead nitrate can be used in MAS probes to measure sample temp. changes, temp. gradients, MAS heating effects, and the dynamics of temp. jumps.
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    Hronský, V. Measurement of Sample Temperatures and Temperature Gradients in Magic-Angle Spinning NMR. Acta Electrotech. Inform. 2013, 13, 95,  DOI: 10.2478/aeei-2013-0021
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    First principles methods using CASTEP
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    Zeitschrift fuer Kristallographie (2005), 220 (5-6), 567-570CODEN: ZEKRDZ; ISSN:0044-2968. (Oldenbourg Wissenschaftsverlag GmbH)
    The CASTEP code for first principles electronic structure calcns. is described. A brief, non-tech. overview is given and some of the features and capabilities highlighted. Some features which are unique to CASTEP are described and near-future development plans outlined.
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    McNellis, E. R.; Meyer, J.; Reuter, K. Azobenzene at Coinage Metal Surfaces: Role of Dispersive van Der Waals Interactions. Phys. Rev. B 2009, 80, 205414,  DOI: 10.1103/physrevb.80.205414
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    Azobenzene at coinage metal surfaces: Role of dispersive van der Waals interactions
    McNellis, Erik R.; Meyer, Joerg; Reuter, Karsten
    Physical Review B: Condensed Matter and Materials Physics (2009), 80 (20), 205414/1-205414/10CODEN: PRBMDO; ISSN:1098-0121. (American Physical Society)
    We use different semiempirical dispersion correction schemes to assess the role of long-range van der Waals interactions in the adsorption of the prototypical mol. switch azobenzene (C6H5-N2-C6H5) at the coinage metal surfaces Cu(111), Ag(111), and Au(111). Compared to preceding d.-functional theory results employing a semilocal exchange and correlation functional we obtain partly sizable changes in the computed adsorption geometry and energetics. The discomforting scatter in the results provided by the different schemes is largely attributed to the unknown form of the damping function in the semiempirical correction expression. Using the congeneric problem of the adsorption of benzene as a vehicle to connection with expt., we cautiously conclude that the account of dispersive interactions at the metal surfaces provided by the various schemes is in the right ballpark, with the more recent, general schemes likely to overbind.
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    Tkatchenko, A.; Scheffler, M. Accurate Molecular Van Der Waals Interactions from Ground-State Electron Density and Free-Atom Reference Data. Phys. Rev. Lett. 2009, 102, 073005,  DOI: 10.1103/physrevlett.102.073005
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    Tkatchenko, Alexandre; Scheffler, Matthias
    Physical Review Letters (2009), 102 (7), 073005/1-073005/4CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
    We present a parameter-free method for an accurate detn. of long-range van der Waals interactions from mean-field electronic structure calcns. Our method relies on the summation of interat. C6 coeffs., derived from the electron d. of a mol. or solid and accurate ref. data for the free atoms. The mean abs. error in the C6 coeffs. is 5.5% when compared to accurate exptl. values for 1225 intermol. pairs, irresp. of the employed exchange-correlation functional. We show that the effective at. C6 coeffs. depend strongly on the bonding environment of an atom in a mol. Finally, we analyze the van der Waals radii and the damping function in the C6R-6 correction method for d.-functional theory calcns.
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    A theory for the ab initio calcn. of all-electron NMR chem. shifts in insulators using pseudopotentials is presented. It is formulated for both finite and infinitely periodic systems and is based on an extension to the projector augmented-wave approach of Blochl [P. E. Blochl, Phys. Rev. B 50, 17953 (1994)] and the method of Mauri et al. [F. Mauri, B. G. Pfrommer, and S. G. Louie, Phys. Rev. Lett. 77, 5300 (1996)]. The theory is successfully validated for mols. by comparison with a selection of quantum chem. results, and in periodic systems by comparison with plane-wave all-electron results for diamond.
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    Yates, J. R.; Pickard, C. J.; Mauri, F. Calculation of NMR Chemical Shifts for Extended Systems Using Ultrasoft Pseudopotentials. Phys. Rev. B: Condens. Matter Mater. Phys. 2007, 76, 024401,  DOI: 10.1103/physrevb.76.024401
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    Calculation of NMR chemical shifts for extended systems using ultrasoft pseudopotentials
    Yates, Jonathan R.; Pickard, Chris J.; Mauri, Francesco
    Physical Review B: Condensed Matter and Materials Physics (2007), 76 (2), 024401/1-024401/11CODEN: PRBMDO; ISSN:1098-0121. (American Physical Society)
    The authors present a scheme for the calcn. of magnetic response parameters in insulators using ultrasoft pseudopotentials. It uses the gauge-including projector augmented wave method [C. J. Pickard and F. Mauri, Phys. Rev. B 63, 245101(2001)] to obtain all-electron accuracy for both finite and infinitely periodic systems. In detail the calcn. of NMR chem. shieldings are considered. The approach is successfully validated 1st for mol. systems by comparing calcd. chem. shieldings for a range of mols. with quantum chem. results and then in the solid state by comparing 17O NMR parameters calcd. for silicates with expt.
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    Ravikumar, Krishnan; Sridhar, Balasubramanian
    Acta Crystallographica, Section C: Crystal Structure Communications (2010), 66 (6), o317-o320CODEN: ACSCEE; ISSN:0108-2701. (International Union of Crystallography)
    Two polymorphs of safinamide {systematic name: (2S)-2-[4-(3-fluorobenzyloxy)benzylamino]propionamide}, C17H19FN2O2, a potent selective and reversible monoamine oxidase B (MAO-B) inhibitor, are described. Both forms are orthorhombic and regarded as conformational polymorphs due to the differences in the orientation of the 3-fluorobenzyloxy and propanamide groups. Both structures pack with layers in the ac plane. In polymorph (I), the layers have discrete wide and narrow regions which are complementary when located next to adjacent layers. In polymorph (II), the layer has long flanges protruding from each side, which interdigitate when packed with the adjacent layers. N-H···O hydrogen bonds are present in both structures, whereas N-H···F hydrogen bonding is seen in polymorph (I), while N-H···N hydrogen bonding is seen in polymorph (II).
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    Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The Cambridge Structural Database. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 171– 179,  DOI: 10.1107/s2052520616003954
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    The Cambridge Structural Database
    Groom, Colin R.; Bruno, Ian J.; Lightfoot, Matthew P.; Ward, Suzanna C.
    Acta Crystallographica, Section B: Structural Science, Crystal Engineering and Materials (2016), 72 (2), 171-179CODEN: ACSBDA; ISSN:2052-5206. (International Union of Crystallography)
    The Cambridge Structural Database (CSD) contains a complete record of all published org. and metal-org. small-mol. crystal structures. The database has been in operation for over 50 years and continues to be the primary means of sharing structural chem. data and knowledge across disciplines. As well as structures that are made public to support scientific articles, it includes many structures published directly as CSD Communications. All structures are processed both computationally and by expert structural chem. editors prior to entering the database. A key component of this processing is the reliable assocn. of the chem. identity of the structure studied with the exptl. data. This important step helps ensure that data is widely discoverable and readily reusable. Content is further enriched through selective inclusion of addnl. exptl. data. Entries are available to anyone through free CSD community web services. Linking services developed and maintained by the CCDC, combined with the use of std. identifiers, facilitate discovery from other resources. Data can also be accessed through CCDC and third party software applications and through an application programming interface.
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    Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; van de Streek, J. Mercury : Visualization and Analysis of Crystal Structures. J. Appl. Crystallogr. 2006, 39, 453– 457,  DOI: 10.1107/s002188980600731x
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    Mercury: visualization and analysis of crystal structures
    Macrae, Clare F.; Edgington, Paul R.; McCabe, Patrick; Pidcock, Elna; Shields, Greg P.; Taylor, Robin; Towler, Matthew; van de Streek, Jacco
    Journal of Applied Crystallography (2006), 39 (3), 453-457CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)
    Since its original release, the popular crystal structure visualization program Mercury has undergone continuous further development. Comparisons between crystal structures are facilitated by the ability to display multiple structures simultaneously and to overlay them. Improvements were made to many aspects of the visual display, including the addn. of depth cueing, and highly customizable lighting and background effects. Textual and numeric data assocd. with structures can be shown in tables or spreadsheets, the latter opening up new ways of interacting with the visual display. At. displacement ellipsoids, calcd. powder diffraction patterns and predicted morphologies can now be shown. Some limited mol.-editing capabilities were added. The object-oriented nature of the C++ libraries underlying Mercury makes it easy to re-use the code in other applications, and this has facilitated three-dimensional visualization in several other programs produced by the Cambridge Crystallog. Data Center.
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    Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. Mercury CSD 2.0 – New Features for the Visualization and Investigation of Crystal Structures. J. Appl. Crystallogr. 2008, 41, 466– 470,  DOI: 10.1107/s0021889807067908
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    Mercury CSD 2.0 - new features for the visualization and investigation of crystal structures
    Macrae, Clare F.; Bruno, Ian J.; Chisholm, James A.; Edgington, Paul R.; McCabe, Patrick; Pidcock, Elna; Rodriguez-Monge, Lucia; Taylor, Robin; van de Streek, Jacco; Wood, Peter A.
    Journal of Applied Crystallography (2008), 41 (2), 466-470CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
    The program Mercury, developed by the Cambridge Crystallog. Data Center, is designed primarily as a crystal structure visualization tool. A new module of functionality has been produced, called the Materials Module, which allows highly customizable searching of structural databases for intermol. interaction motifs and packing patterns. This new module also includes the ability to perform packing similarity calcns. between structures contg. the same compd. In addn. to the Materials Module, a range of further enhancements to Mercury has been added in this latest release, including void visualization and links to ConQuest, Mogul and IsoStar.
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    Komatsu, T.; Kikuchi, J. Comprehensive Signal Assignment of 13C-Labeled Lignocellulose Using Multidimensional Solution NMR and 13C Chemical Shift Comparison with Solid-State NMR. Anal. Chem. 2013, 85, 8857– 8865,  DOI: 10.1021/ac402197h
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    Comprehensive Signal Assignment of 13C-Labeled Lignocellulose Using Multidimensional Solution NMR and 13C Chemical Shift Comparison with Solid-State NMR
    Komatsu, Takanori; Kikuchi, Jun
    Analytical Chemistry (Washington, DC, United States) (2013), 85 (18), 8857-8865CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    A multidimensional soln. NMR method has been developed using various pulse programs including HCCH-COSY and 13C-HSQC-NOESY for the structural characterization of com. available 13C labeled lignocellulose from potatoes (Solanum tuberosum L.), chicory (Cichorium intybus), and corn (Zea mays). This new method allowed for 119 of the signals in the 13C-HSQC spectrum of lignocelluloses to be assigned and was successfully used to characterize the structures of lignocellulose samples from three plants in terms of their xylan and xyloglucan structures, which are the major hemicelluloses in angiosperm. Furthermore, this new method provided greater insight into fine structures of lignin by providing a high resoln. to the arom. signals of the β-aryl ether and resinol moieties, as well as the diastereomeric signals of the β-aryl ether. Finally, the 13C chem. shifts assigned in this study were compared with those from solid-state NMR and indicated the presence of heterogeneous dynamics in the polysaccharides where rigid cellulose and mobile hemicelluloses moieties existed together.
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    Sousa, E. G. R. d.; Carvalho, E. M. d.; San Gil, R. A. d. S.; Santos, T. C. d.; Borré, L. B.; Santos-Filho, O. A.; Ellena, J. Solution and Solid State Nuclear Magnetic Resonance Spectroscopic Characterization of Efavirenz. J. Pharm. Sci. 2016, 105, 2656– 2664,  DOI: 10.1016/j.xphs.2015.10.006
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    Solution and Solid State Nuclear Magnetic Resonance Spectroscopic Characterization of Efavirenz
    Sousa Eduardo Gomes Rodrigues de; Carvalho Erika Martins de; Santos Tereza Cristina Dos; Santos-Filho Osvaldo Andrade; San Gil Rosane Aguiar da Silva; Borre Leandro Bandeira; Ellena Javier
    Journal of pharmaceutical sciences (2016), 105 (9), 2656-2664 ISSN:.
    Samples of efavirenz (EFZ) were evaluated to investigate the influence of the micronization process on EFZ stability. A combination of X-ray diffraction, thermal analysis, FTIR, observations of isotropic chemical shifts of (1)H in distinct solvents, their temperature dependence and spin-lattice relaxation time constants (T1), solution (1D and 2D) (13)C nuclear magnetic resonance (NMR), and solid-state (13)C NMR (CPMAS NMR) provides valuable structural information and structural elucidation of micronized EFZ and heptane-recrystallized polymorphs (EFZ/HEPT). This study revealed that the micronization process did not affect the EFZ crystalline structure. It was observed that the structure of EFZ/HEPT is in the same form as that obtained from ethyl acetate/hexane, as shown in the literature. A comparison of the solid-state NMR spectra revealed discrepancies regarding the assignments of some carbons published in the literature that have been resolved.
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    Price, S. L.; Reutzel-Edens, S. M. The Potential of Computed Crystal Energy Landscapes to Aid Solid-Form Development. Drug Discov. Today 2016, 21, 912– 923,  DOI: 10.1016/j.drudis.2016.01.014
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    The potential of computed crystal energy landscapes to aid solid-form development
    Price Sarah L; Reutzel-Edens Susan M
    Drug discovery today (2016), 21 (6), 912-23 ISSN:.
    Solid-form screening to identify all solid forms of an active pharmaceutical ingredient (API) has become increasingly important in ensuring the quality by design of pharmaceutical products and their manufacturing processes. However, despite considerable enlargement of the range of techniques that have been shown capable of producing novel solid forms, it is possible that practically important forms might not be found in the short timescales currently allowed for solid-form screening. Here, we report on the state-of-the-art use of computed crystal energy landscapes to complement pharmaceutical solid-form screening. We illustrate how crystal energy landscapes can help establish molecular-level understanding of the crystallization behavior of APIs and enhance the ability of solid-form screening to facilitate pharmaceutical development.
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    Li, X.; Neumann, M. A.; van de Streek, J. The Application of Tailor-Made Force Fields and Molecular Dynamics for NMR Crystallography: A Case Study of Free Base Cocaine. IUCrJ 2017, 4, 175– 184,  DOI: 10.1107/s2052252517001415
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    The application of tailor-made force fields and molecular dynamics for NMR crystallography: a case study of free base cocaine
    Li, Xiaozhou; Neumann, Marcus A.; van de Streek, Jacco
    IUCrJ (2017), 4 (2), 175-184CODEN: IUCRAJ; ISSN:2052-2525. (International Union of Crystallography)
    Motional averaging has been proven to be significant in predicting the chem. shifts in ab initio solid-state NMR calcns., and the applicability of motional averaging with mol. dynamics has been shown to depend on the accuracy of the mol. mech. force field. The performance of a fully automatically generated tailor-made force field (TMFF) for the dynamic aspects of NMR crystallog. is evaluated and compared with existing benchmarks, including static dispersion-cor. d. functional theory calcns. and the COMPASS force field. The crystal structure of free base cocaine is used as an example. The results reveal that, even though the TMFF outperforms the COMPASS force field for representing the energies and conformations of predicted structures, it does not give significant improvement in the accuracy of NMR calcns. Further studies should direct more attention to anisotropic chem. shifts and development of the method of solid-state NMR calcns.
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    Hartman, J. D.; Monaco, S.; Schatschneider, B.; Beran, G. J. O. Fragment-Based 13 C Nuclear Magnetic Resonance Chemical Shift Predictions in Molecular Crystals: An Alternative to Planewave Methods. J. Chem. Phys. 2015, 143, 102809,  DOI: 10.1063/1.4922649
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    Fragment-based 13C nuclear magnetic resonance chemical shift predictions in molecular crystals: An alternative to planewave methods
    Hartman, Joshua D.; Monaco, Stephen; Schatschneider, Bohdan; Beran, Gregory J. O.
    Journal of Chemical Physics (2015), 143 (10), 102809/1-102809/14CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    The authors assess the quality of fragment-based ab initio isotropic 13C chem. shift predictions for a collection of 25 mol. crystals with eight different d. functionals. They explore the relative performance of cluster, two-body fragment, combined cluster/fragment, and the planewave gauge-including projector augmented wave (GIPAW) models relative to expt. When electrostatic embedding is employed to capture many-body polarization effects, the simple and computationally inexpensive two-body fragment model predicts both isotropic 13C chem. shifts and the chem. shielding tensors as well as both cluster models and the GIPAW approach. Unlike the GIPAW approach, hybrid d. functionals can be used readily in a fragment model, and all four hybrid functionals tested here (PBE0, B3LYP, B3PW91, and B97-2) predict chem. shifts in noticeably better agreement with expt. than the four generalized gradient approxn. (GGA) functionals considered (PBE, OPBE, BLYP, and BP86). A set of recommended linear regression parameters for mapping between calcd. chem. shieldings and obsd. chem. shifts are provided based on these benchmark calcns. Statistical cross-validation procedures are used to demonstrate the robustness of these fits. (c) 2015 American Institute of Physics.
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    Baias, M.; Dumez, J.-N.; Svensson, P. H.; Schantz, S.; Day, G. M.; Emsley, L. De Novo Determination of the Crystal Structure of a Large Drug Molecule by Crystal Structure Prediction-Based Powder NMR Crystallography. J. Am. Chem. Soc. 2013, 135, 17501– 17507,  DOI: 10.1021/ja4088874
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    De Novo Determination of the Crystal Structure of a Large Drug Molecule by Crystal Structure Prediction-Based Powder NMR Crystallography
    Baias, Maria; Dumez, Jean-Nicolas; Svensson, Per H.; Schantz, Staffan; Day, Graeme M.; Emsley, Lyndon
    Journal of the American Chemical Society (2013), 135 (46), 17501-17507CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-benzoic acid is detd. using a protocol for NMR powder crystallog. at natural isotopic abundance combining solid-state 1H NMR spectroscopy, crystal structure prediction, and d. functional theory chem. shift calcns. This is the first example of NMR crystal structure detn. for a mol. compd. of previously unknown structure, and at 422 g/mol this is the largest compd. to which this method has been applied so far.
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    Webber, A. L.; Emsley, L.; Claramunt, R. M.; Brown, S. P. NMR Crystallography of Campho[2,3-c]Pyrazole ( Z ′ = 6): Combining High-Resolution 1 H- 13 C Solid-State MAS NMR Spectroscopy and GIPAW Chemical-Shift Calculations. J. Phys. Chem. A 2010, 114, 10435– 10442,  DOI: 10.1021/jp104901j
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    NMR Crystallography of Campho[2,3-c]pyrazole (Z' = 6): Combining High-Resolution 1H-13C Solid-State MAS NMR Spectroscopy and GIPAW Chemical-Shift Calculations
    Webber, Amy L.; Emsley, Lyndon; Claramunt, Rosa M.; Brown, Steven P.
    Journal of Physical Chemistry A (2010), 114 (38), 10435-10442CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    1H-13C two-dimensional magic-angle spinning (MAS) solid-state NMR correlation spectra, recorded with the MAS-J-HMQC expt., are presented for campho[2,3-c]pyrazole (I). For each 13C moiety, there are six resonances assocd. with the six distinct mols. in the asym. unit cell (Z' = 6). The one-bond C-H correlations obsd. in the 2D 1H-13C MAS-J-HMQC spectra allow the exptl. detn. of the 1H and 13C chem. shifts assocd. with the sep. CH, CH2, and CH3 groups. 1H and 13C chem. shifts calcd. by using the GIPAW (Gauge Including Projector Augmented Waves) plane-wave pseudopotential approach are presented. Calcns. for the whole unit cell (12 × 29 = 348 atoms, with geometry optimization of all atoms) allow the assignment of the exptl. 1H and 13C chem. shifts to the six distinct mols. The calcd. chem. shifts for the full crystal structure are compared with those for isolated mols. as extd. from the geometry-optimized crystal structure. In this way, the effect of intermol. interactions on the obsd. chem. shifts is quantified. In particular, the calcns. are sufficiently precise to differentiate the small (<1 ppm) differences between the 1H chem. shifts of the six resonances assocd. with each distinct CH or CH2 moiety.
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    Sardo, M.; Santos, S. M.; Babaryk, A. A.; López, C.; Alkorta, I.; Elguero, J.; Claramunt, R. M.; Mafra, L. Diazole-Based Powdered Cocrystal Featuring a Helical Hydrogen-Bonded Network: Structure Determination from PXRD, Solid-State NMR and Computer Modeling. Solid State Nucl. Magn. Reson. 2015, 65, 49– 63,  DOI: 10.1016/j.ssnmr.2014.12.005
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    Diazole-based powdered cocrystal featuring a helical hydrogen-bonded network: Structure determination from PXRD, solid-state NMR and computer modeling
    Sardo, Mariana; Santos, Sergio M.; Babaryk, Artem A.; Lopez, Concepcion; Alkorta, Ibon; Elguero, Jose; Claramunt, Rosa M.; Mafra, Luis
    Solid State Nuclear Magnetic Resonance (2015), 65 (), 49-63CODEN: SSNRE4; ISSN:0926-2040. (Elsevier)
    The authors present the structure of a new equimolar 1:1 cocrystal formed by 3,5-dimethyl-1H-pyrazole (dmpz) and 4,5-dimethyl-1H-imidazole (dmim), detd. by means of powder X-ray diffraction data combined with solid-state NMR that provided insight into topol. details of hydrogen bonding connectivities and weak interactions such as C-H···π contacts. The use of various 1D/2D 13C, 15N and 1H high-resoln. solid-state NMR techniques provided structural insight on local length scales revealing internuclear proximities and relative orientations between the dmim and dmpz mol. building blocks of the studied cocrystal. Mol. modeling and DFT calcns. were also employed to generate meaningful structures. DFT refinement was able to decrease the figure of merit R(F2) from ∼11% (PXRD only) to 5.4%. An attempt was made to rationalize the role of N-H···N and C-H···π contacts in stabilizing the reported cocrystal. For this purpose four imidazole derivs. with distinct placement of Me substituents were reacted with dmpz to understand the effect of methylation in blocking or enabling certain intermol. contacts. Only one imidazole deriv. (dmim) was able to incorporate into the dmpz trimeric motif thus resulting in a cocrystal, which contains both hydrophobic (Me groups) and hydrophilic components that self-assemble to form an atypical 1D network of helicoidal hydrogen bonded pattern, featuring structural similarities with alpha-helix arrangements in proteins. The 1:1 dmpz···dmim compd. I is the first example of a cocrystal formed by two different azoles.
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    Santos, S. M.; Rocha, J.; Mafra, L. NMR Crystallography: Toward Chemical Shift-Driven Crystal Structure Determination of the β-Lactam Antibiotic Amoxicillin Trihydrate. Cryst. Growth Des. 2013, 13, 2390– 2395,  DOI: 10.1021/cg4002785
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    NMR Crystallography: Toward Chemical Shift-Driven Crystal Structure Determination of the β-Lactam Antibiotic Amoxicillin Trihydrate
    Santos, Sergio M.; Rocha, Joao; Mafra, Luis
    Crystal Growth & Design (2013), 13 (6), 2390-2395CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    A new strategy for NMR crystallog. of multiple-component mol. crystals was reported in which 1H NMR chem. shifts entered directly in the structure generation step, governed by a genetic algorithm. Chem. shifts were also used in the structure-refinement step as pseudoforces acting on the models, leading to the lowest-energy structure. This methodol., which avoided the use of time-consuming ab initio chem. shift calcns., was successfully applied to powd. amoxicillin trihydrate, a widely used β-lactamic antibiotic.
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    Pawlak, T.; Trzeciak-Karlikowska, K.; Czernek, J.; Ciesielski, W.; Potrzebowski, M. J. Computed and Experimental Chemical Shift Parameters for Rigid and Flexible YAF Peptides in the Solid State. J. Phys. Chem. B 2012, 116, 1974– 1983,  DOI: 10.1021/jp2111567
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    Computed and Experimental Chemical Shift Parameters for Rigid and Flexible YAF Peptides in the Solid State
    Pawlak, Tomasz; Trzeciak-Karlikowska, Katarzyna; Czernek, Jiri; Ciesielski, Wlodzimierz; Potrzebowski, Marek J.
    Journal of Physical Chemistry B (2012), 116 (6), 1974-1983CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    DFT methods were employed to compute the 13C NMR chem. shift tensor (CST) parameters for crystals of YAF (Tyr-Ala-Phe) peptides with different stereochem. for the Ala residue. Tyr-D-Ala-Phe (1) crystallizes in the C2 space group while Tyr-L-Ala-Phe crystallizes in either the P21212 space group (2a) or the P65 space group (2b). PISEMA MAS measurements for samples with a natural abundance of 1H and 13C nuclei and 2H QUADECHO expts. for samples with deuterium labeled arom. rings were used to analyze the geometry and time scale of the mol. motion. At ambient temp., the tyrosine ring of sample 1 is rigid and the phenylalanine ring undergoes a π-jump, both rings in sample 2a are static, and both rings in sample 2b undergo a fast regime exchange. The theor. values of the CST were obtained for isolated mols. (IM) and clusters employing the ONIOM approach. The exptl. 13C δii parameters for all of the samples were measured via a 2D PASS sequence. Significant scatter of the computed vs. the exptl. 13C CST parameters was obsd. for 1 and 2b, while the obsd. correlation was very good for 2a. In this report, we show that the quality of the 13C σii/13C δii correlations, when properly interpreted, can be a source of important information about local mol. motions.
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    Jaworska, M.; Pawlak, T.; Kruszyński, R.; Ćwiklińska, M.; Krzemiński, M. NMR Crystallography Comparative Studies of Chiral (1 R ,2 S ,3 R ,5 R )-3-Amino-6,6-Dimethylbicyclo[3.1.1]Heptan-2-Ol and Its p -Toluenesulfonamide Derivative. Cryst. Growth Des. 2012, 12, 5956– 5965,  DOI: 10.1021/cg300940k
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    NMR Crystallography Comparative Studies of Chiral (1R,2S,3R,5R)-3-Amino-6,6-dimethylbicyclo[3.1.1]heptan-2-ol and Its p-Toluenesulfonamide Derivative
    Jaworska, Magdalena; Pawlak, Tomasz; Kruszynski, Rafal; Cwiklinska, Marta; Krzeminski, Marek
    Crystal Growth & Design (2012), 12 (12), 5956-5965CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    The crystal structure of (1R,2S,3R,5R)-3-amino-6,6-dimethyl-2-hydroxybicyclo[3.1.1]heptane 1 was detd. and it is presented in ref. to the structure of (1R,2S,3R,5R)-3-(p-tosylamino)-6,6-dimethyl-2-hydroxybicyclo[3.1.1]heptane 2. 1H and 13C chem. shifts parameters for both structures and for whole unit cells were calcd. by using the GIPAW (gauge including projector augmented waves) method. Theor. calcd. chem. shift tensor parameters were verified by 13C CP MAS, 2-dimensional PASS, and 13C-1H FSLG HETCOR results to obtain a full structural assignment for 13C and 1H resonances in the solid-state. PISEMA MAS expt. was performed to det. the mol. dynamics of aminoalc. 1. The comparison of two structures, obtained after all-atom positions optimization after the GIPAW calcns., revealed small conformational differences consistent with the single-crystal x-ray diffraction results.
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    Watts, A. E.; Maruyoshi, K.; Hughes, C. E.; Brown, S. P.; Harris, K. D. M. Combining the Advantages of Powder X-Ray Diffraction and NMR Crystallography in Structure Determination of the Pharmaceutical Material Cimetidine Hydrochloride. Cryst. Growth Des. 2016, 16, 1798– 1804,  DOI: 10.1021/acs.cgd.6b00016
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    Combining the Advantages of Powder X-ray Diffraction and NMR Crystallography in Structure Determination of the Pharmaceutical Material Cimetidine Hydrochloride
    Watts, Abigail E.; Maruyoshi, Keisuke; Hughes, Colan E.; Brown, Steven P.; Harris, Kenneth D. M.
    Crystal Growth & Design (2016), 16 (4), 1798-1804CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    The crystal structure is reported of the anhyd. phase of cimetidine hydrochloride, detd. directly from powder x-ray diffraction data. The material was prepd. by dehydration of the readily obtained monohydrate form of cimetidine hydrochloride, the only form for which a crystal structure was previously reported. As such, solid-state dehydration processes typically yield the product phase as a microcryst. powder, and structure detn. was carried out directly from powder x-ray diffraction data, using the direct-space genetic algorithm technique for structure soln. followed by Rietveld refinement. The structure detd. from powder x-ray diffraction was further validated by calcg. solid-state 13C NMR data for the crystal structure (using 1st-principles periodic DFT techniques within the GIPAW approach) and assessing the quality of agreement with the corresponding exptl. solid-state 13C CPMAS NMR data. This strategy provides a robust vindication of the correctness of the crystal structure by assessing the quality of agreement of the structure both with exptl. powder x-ray diffraction data and with exptl. solid-state 13C NMR data.
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    Nilsson Lill, S. O.; Widdifield, C. M.; Pettersen, A.; Svensk Ankarberg, A.; Lindkvist, M.; Aldred, P.; Gracin, S.; Shankland, N.; Shankland, K.; Schantz, S.; Emsley, L. Elucidating an Amorphous Form Stabilization Mechanism for Tenapanor Hydrochloride: Crystal Structure Analysis Using X-Ray Diffraction, NMR Crystallography, and Molecular Modeling. Mol. Pharm. 2018, 15, 1476– 1487,  DOI: 10.1021/acs.molpharmaceut.7b01047
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    Elucidating an amorphous form stabilization mechanism for tenapanor hydrochloride: Crystal structure analysis using X-ray diffraction, NMR Crystallography, and Molecular Modeling
    Nilsson Lill, Sten O.; Widdifield, Cory M.; Pettersen, Anna; Svensk Ankarberg, Anna; Lindkvist, Maria; Aldred, Peter; Gracin, Sandra; Shankland, Norman; Shankland, Kenneth; Schantz, Staffan; Emsley, Lyndon
    Molecular Pharmaceutics (2018), 15 (4), 1476-1487CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    By the combined use of powder and single-crystal X-ray diffraction, solid-state NMR, and mol. modeling, the crystal structures of two systems contg. the unusually large tenapanor drug mol. have been detd.: the free form, ANHY, and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallog. investigations were found essential for the final assignment and were used to validate the crystal structure of ANHY. From a structural informatics anal. of ANHY and 2HCl, conformational ring differences in one part of the mol. were obsd. which influence the relative orientation of a Me group on a ring nitrogen and thereby impact the crystallizability of the dihydrochloride salt. From quantum chem. calcns., the dynamics between different ring conformations in tenapanor is predicted to be fast. Addn. of HCl to tenapanor results in general in a mixt. of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qual. verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amt. of the cryst. material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between the minor and major conformations of ANHY in soln. Thus, by controlling the soln. pH value to well below the pKa of ANHY, the equil. between ANHY and 2HCl can be controlled and by this mechanism the crystn. of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized.
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    Leclaire, J.; Poisson, G.; Ziarelli, F.; Pepe, G.; Fotiadu, F.; Paruzzo, F. M.; Rossini, A. J.; Dumez, J.-N.; Elena-Herrmann, B.; Emsley, L. Structure Elucidation of a Complex CO2-Based Organic Framework Material by NMR Crystallography. Chem. Sci. 2016, 7, 4379– 4390,  DOI: 10.1039/c5sc03810c
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    Structure elucidation of a complex CO2-based organic framework material by NMR crystallography
    Leclaire, Julien; Poisson, Guillaume; Ziarelli, Fabio; Pepe, Gerard; Fotiadu, Frederic; Paruzzo, Federico M.; Rossini, Aaron J.; Dumez, Jean-Nicolas; Elena-Herrmann, Benedicte; Emsley, Lyndon
    Chemical Science (2016), 7 (7), 4379-4390CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A three-dimensional structural model of a complex CO2-based org. framework made from high mol. wt., self-assembled, flexible and multi-functional oligomeric constituents has been detd. de novo by solid-state NMR including DNP-enhanced expts. The complete assignment of the 15N, 13C and 1H resonances was obtained from a series of two-dimensional through space and through bond correlation expts. MM-QM calcns. were used to generate different model structures for the material which were then evaluated by comparing multiple exptl. and calcd. NMR parameters. Both NMR and powder X-ray diffraction were evaluated as tools to det. the packing by crystal modeling, and at the level of structural modeling used here PXRD was found not to be a useful complement. The structure detd. reveals a highly optimized H-bonding network that explains the unusual selectivity of the self-assembly process which generates the material. The NMR crystallog. approach used here should be applicable for the structure detn. of other complex solid materials.
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    Dudenko, D. V.; Williams, P. A.; Hughes, C. E.; Antzutkin, O. N.; Velaga, S. P.; Brown, S. P.; Harris, K. D. M. Exploiting the Synergy of Powder X-Ray Diffraction and Solid-State NMR Spectroscopy in Structure Determination of Organic Molecular Solids. J. Phys. Chem. C 2013, 117, 12258– 12265,  DOI: 10.1021/jp4041106
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    Exploiting the Synergy of Powder X-ray Diffraction and Solid-State NMR Spectroscopy in Structure Determination of Organic Molecular Solids
    Dudenko, Dmytro V.; Williams, P. Andrew; Hughes, Colan E.; Antzutkin, Oleg N.; Velaga, Sitaram P.; Brown, Steven P.; Harris, Kenneth D. M.
    Journal of Physical Chemistry C (2013), 117 (23), 12258-12265CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    The authors report a strategy for structure detn. of org. materials in which complete solid-state NMR spectral data was used within the context of structure detn. from powder XRD data. Following detn. of the crystal structure from powder XRD data, first-principles d. functional theory-based techniques within the GIPAW approach are exploited to calc. the solid-state NMR data for the structure, followed by careful scrutiny of the agreement with exptl. solid-state NMR data. The successful application of this approach is demonstrated by structure detn. of the 1:1 cocrystal of indomethacin and nicotinamide. The 1H and 13C chem. shifts calcd. for the crystal structure detd. from the powder XRD data are in excellent agreement with those measured exptl., notably including the two-dimensional correlation of 1H and 13C chem. shifts for directly bonded 13C-1H moieties. The key feature of this combined approach is that the quality of the structure detd. is assessed both against exptl. powder XRD data and against exptl. solid-state NMR data, thus providing a very robust validation of the veracity of the structure.
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    Be̅rziņš, A.; Hodgkinson, P. Solid-State NMR and Computational Investigation of Solvent Molecule Arrangement and Dynamics in Isostructural Solvates of Droperidol. Solid State Nucl. Magn. Reson. 2015, 65, 12– 20,  DOI: 10.1016/j.ssnmr.2014.09.001
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    Solid-state NMR and computational investigation of solvent molecule arrangement and dynamics in isostructural solvates of droperidol
    Berzins, Agris; Hodgkinson, Paul
    Solid State Nuclear Magnetic Resonance (2015), 65 (), 12-20CODEN: SSNRE4; ISSN:0926-2040. (Elsevier)
    13C, 15N and 2H solid-state NMR spectroscopy were used to rationalize arrangement and dynamics of solvent mols. in a set of isostructural solvates of droperidol. The solvent mols. are dynamically disordered in the methanol and ethanol solvates, while they are ordered in the acetonitrile and nitromethane solvates. 2H NMR spectra of deuterium-labeled samples allowed the characterization of the solvent mol. dynamics in the alc. solvates and the nonstoichiometric hydrate. The likely motion of the alc. mols. is rapid libration within a site, plus occasional exchange into an equiv. site related by the inversion symmetry, while the water mols. are more strongly disordered. DFT calcns. strongly suggest that the differences in dynamics between the solvates are related to differences in the energetic penalty for reversing the orientation of a solvent mol.
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    Pinon, A. C.; Rossini, A. J.; Widdifield, C. M.; Gajan, D.; Emsley, L. Polymorphs of Theophylline Characterized by DNP Enhanced Solid-State NMR. Mol. Pharm. 2015, 12, 4146– 4153,  DOI: 10.1021/acs.molpharmaceut.5b00610
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    Polymorphs of Theophylline Characterized by DNP Enhanced Solid-State NMR
    Pinon, Arthur C.; Rossini, Aaron J.; Widdifield, Cory M.; Gajan, David; Emsley, Lyndon
    Molecular Pharmaceutics (2015), 12 (11), 4146-4153CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    We show how dynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy can be used to characterize polymorphs and solvates of org. solids. We applied DNP to three polymorphs and one hydrated form of the asthma drug mol. theophylline. For some forms of theophylline, sample grinding and impregnation with the radical-contg. soln., which are necessary to prep. the samples for DNP, were found to induce polymorphic transitions or desolvation between some forms. We present protocols for sample prepn. for solid-state magic-angle spinning (MAS) DNP expts. that avoid the polymorphic phase transitions in theophylline. These protocols include cryogrinding, grinding under inert atm., and the appropriate choice of the impregnating liq. By applying these procedures, we subsequently demonstrate that two-dimensional correlation expts., such as 1H-13C and 1H-15N HETCOR or 13C-13C INADEQUATE, can be obtained at natural isotopic abundance in reasonable times, thus enabling more advanced structural characterization of polymorphs.
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    Pawlak, T.; Potrzebowski, M. J. Fine Refinement of Solid-State Molecular Structures of Leu- and Met-Enkephalins by NMR Crystallography. J. Phys. Chem. B 2014, 118, 3298– 3309,  DOI: 10.1021/jp500379e
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    83
    Fine refinement of solid-state mol. structures of Leu- and Met-Enkephalins by NMR crystallog.
    Pawlak, Tomasz; Potrzebowski, Marek J.
    Journal of Physical Chemistry B (2014), 118 (12), 3298-3309CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    This paper presents a methodol. that allows the fine refinement of the crystal and mol. structure for compds. for which the data deposited in the crystallog. bases are of poor quality. Such species belong to the group of samples with mol. disorder. In the Cambridge Crystallog. Data Center (CCDC), there are approx. 22 000 deposited structures with an R-factor over 10. The powerful methodol. we present employs crystal data for Leu-enkephalin (two crystallog. forms) with R-factor values of 14.0 and 8.9 and for Met-enkephalin (one form) with an R-factor of 10.5. NMR crystallog. was employed in testing the X-ray data and the quality of the structure refinement. The GIPAW (gauge invariant projector augmented wave) method was used to optimize the coordinates of the enkephalins and to compute NMR parameters. As we reveal, this complementary approach makes it possible to generate a reasonable set of new coordinates that better correlate to real samples. This methodol. is general and can be employed in the study of each compd. possessing magnetically active nuclei.
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    Kerr, H. E.; Mason, H. E.; Sparkes, H. A.; Hodgkinson, P. Testing the Limits of NMR Crystallography: The Case of Caffeine–Citric Acid Hydrate. CrystEngComm 2016, 18, 6700– 6707,  DOI: 10.1039/c6ce01453d
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    Testing the limits of NMR crystallography: the case of caffeine-citric acid hydrate
    Kerr, Hannah E.; Mason, Helen E.; Sparkes, Hazel A.; Hodgkinson, Paul
    CrystEngComm (2016), 18 (35), 6700-6707CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
    The crystal structure of a new 1 : 2 caffeine-citric acid hydrate cocrystal is presented. The caffeine mols. are disordered over two positions, with the nature of the disorder confirmed to be static by 13C solid-state NMR. NMR linewidths in statically disordered systems reflect the distribution of local chem. environments, and this study investigates whether the disorder contribution to 13C linewidths can be predicted computationally. The limits of NMR crystallog. calcns. using d. functional theory are tested by investigating how geometry optimization conditions affect calcd. NMR parameters. Careful optimization is shown to reduce differences between 13C consts. of symmetry-related sites to about 0.1 ppm. This is just sufficient to observe a correlation between calcd. and exptl. linewidths, and also show that systematic errors assocd. with geometry optimization do not compromise other applications of "NMR crystallog.". In addn., the unit cell enthalpies calcd. after careful optimizations provide insight into why the disordered structure is adopted.
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    Dudenko, D. V.; Yates, J. R.; Harris, K. D. M.; Brown, S. P. An NMR Crystallography DFT-D Approach to Analyse the Role of Intermolecular Hydrogen Bonding and π–π Interactions in Driving Cocrystallisation of Indomethacin and Nicotinamide. CrystEngComm 2013, 15, 8797,  DOI: 10.1039/c3ce41240g
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    85
    An NMR crystallography DFT-D approach to analyze the role of intermolecular hydrogen bonding and π-π interactions in driving cocrystallization of indomethacin and nicotinamide
    Dudenko, Dmytro V.; Yates, Jonathan R.; Harris, Kenneth D. M.; Brown, Steven P.
    CrystEngComm (2013), 15 (43), 8797-8807CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
    D. functional theory (DFT) calcns. using the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional are presented for a 1 : 1 cocrystal formed by indomethacin and nicotinamide (IND-NIC) as well as for crystal structures of the individual components. DFT-D approaches which correct the DFT energy for dispersion effects, specifically the Grimme (G06) and Tkatchenko-Scheffler (TS) schemes, are investigated: for geometry optimization starting with crystal structures detd. exptl. by diffraction and allowing the at. positions and the unit cell to vary, closest agreement with the exptl. unit cell parameters is achieved with the PBE-TS approach (calcd. vols. are less than 4% smaller than in expt.). Calcns. of solid-state NMR chem. shifts using the GIPAW (gauge including projector augmented wave) approach are presented. Closest agreement between NMR chem. shifts calcd. with variable and fixed (exptl.) unit cell parameters is also obsd. for the PBE-TS approach: the root mean squared std. deviation difference is 0.15 ppm (1H) and 0.29 ppm (13C) for PBE-TS, as compared to 0.45 ppm (1H) and 0.68 ppm (13C) with std. PBE. Differences in 1H chem. shifts calcd. for the full periodic crystal structure and for isolated mols. extd. from the geometry-optimized crystal structure are presented in conjunction with NICS (nucleus independent chem. shift) maps, so as to sep. quantify intermol. hydrogen bonding and π-π interactions. This anal. is complemented by total energy calcns., including also at the B97D/6-311+G* level of theory with basis set superposition error correction, in order to understand the interactions that drive cocrystn.
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    Tatton, A. S.; Blade, H.; Brown, S. P.; Hodgkinson, P.; Hughes, L. P.; Lill, S. O. N.; Yates, J. R. Improving Confidence in Crystal Structure Solutions Using NMR Crystallography: The Case of β-Piroxicam. Cryst. Growth Des. 2018, 18, 3339– 3351,  DOI: 10.1021/acs.cgd.8b00022
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    86
    Improving Confidence in Crystal Structure Solutions Using NMR Crystallography: The Case of β-Piroxicam
    Tatton, Andrew S.; Blade, Helen; Brown, Steven P.; Hodgkinson, Paul; Hughes, Leslie P.; Lill, Sten O. Nilsson; Yates, Jonathan R.
    Crystal Growth & Design (2018), 18 (6), 3339-3351CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    NMR crystallog. techniques are used to validate a structure of β-piroxicam detd. from powder X-ray diffraction (PXRD) with a relatively poor R-factor. Geometry optimization of PXRD- and single-crystal XRD- derived structures results in convergence to the same energy of the structures, with minimal at. displacements, and good agreement of gauge-included projector augmented wave (GIPAW) calcd. and exptl. detd. NMR 1H, 13C, and 15N chem. shifts, and 14N quadrupolar parameters. Calcns. on isolated mols. combined with 2D magic-angle spinning (MAS) 1H double-quantum (DQ) and 14N-1H NMR expts. confirm the 3D packing arrangement of β-piroxicam. NMR crystallog. is shown to be an effective means of validating crystal structures that might otherwise be considered sceptically on the basis of diffraction data alone.
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    Paruzzo, F. M.; Hofstetter, A.; Musil, F.; De, S.; Ceriotti, M.; Emsley, L. Chemical Shifts in Molecular Solids by Machine Learning. Nat. Commun. 2018, 9, 4501,  DOI: 10.1038/s41467-018-06972-x
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    Chemical shifts in molecular solids by machine learning
    Paruzzo Federico M; Hofstetter Albert; Emsley Lyndon; Musil Felix; De Sandip; Ceriotti Michele
    Nature communications (2018), 9 (1), 4501 ISSN:.
    Due to their strong dependence on local atonic environments, NMR chemical shifts are among the most powerful tools for strucutre elucidation of powdered solids or amorphous materials. Unfortunately, using them for structure determination depends on the ability to calculate them, which comes at the cost of high accuracy first-principles calculations. Machine learning has recently emerged as a way to overcome the need for quantum chemical calculations, but for chemical shifts in solids it is hindered by the chemical and combinatorial space spanned by molecular solids, the strong dependency of chemical shifts on their environment, and the lack of an experimental database of shifts. We propose a machine learning method based on local environments to accurately predict chemical shifts of molecular solids and their polymorphs to within DFT accuracy. We also demonstrate that the trained model is able to determine, based on the match between experimentally measured and ML-predicted shifts, the structures of cocaine and the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butylpyrazol-1-yl]benzoic acid.
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    https://www.drugfuture.com/chemdata/safinamide.html (accessed Aug 04, 2021).
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    Saeed, R. M. R.; Schlegel, J. P.; Castano, C. H.; Sawafta, R. I. Uncertainty of Thermal Characterization of Phase Change Material by Differential Scanning Calorimetry Analysis. Int. J. Eng. Res. Technol. 2016, 5, 405
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    Krushelnitsky, A.; Reichert, D. Solid-State NMR and Protein Dynamics. Prog. Nucl. Magn. Reson. Spectrosc. 2005, 47, 1– 25,  DOI: 10.1016/j.pnmrs.2005.04.001
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    Solid-state NMR and protein dynamics
    Krushelnitsky, Alexey; Reichert, Detlef
    Progress in Nuclear Magnetic Resonance Spectroscopy (2005), 47 (1-2), 1-25CODEN: PNMRAT; ISSN:0079-6565. (Elsevier B.V.)
    A review.
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    Schanda, P.; Ernst, M. Studying Dynamics by Magic-Angle Spinning Solid-State NMR Spectroscopy: Principles and Applications to Biomolecules. Prog. Nucl. Magn. Reson. Spectrosc. 2016, 96, 1– 46,  DOI: 10.1016/j.pnmrs.2016.02.001
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    Studying dynamics by magic-angle spinning solid-state NMR spectroscopy: Principles and applications to biomolecules
    Schanda, Paul; Ernst, Matthias
    Progress in Nuclear Magnetic Resonance Spectroscopy (2016), 96 (), 1-46CODEN: PNMRAT; ISSN:0079-6565. (Elsevier B.V.)
    Magic-angle spinning solid-state NMR spectroscopy is an important technique to study mol. structure, dynamics and interactions, and is rapidly gaining importance in biomol. sciences. Here we provide an overview of exptl. approaches to study mol. dynamics by MAS solid-state NMR, with an emphasis on the underlying theor. concepts and differences of MAS solid-state NMR compared to soln.-state NMR. The theor. foundations of nuclear spin relaxation are revisited, focusing on the particularities of spin relaxation in solid samples under magic-angle spinning. We discuss the range of validity of Redfield theory, as well as the inherent multi-exponential behavior of relaxation in solids. Exptl. challenges for measuring relaxation parameters in MAS solid-state NMR and a few recently proposed relaxation approaches are discussed, which provide information about time scales and amplitudes of motions ranging from picoseconds to milliseconds. We also discuss the theor. basis and exptl. measurements of anisotropic interactions (chem.-shift anisotropies, dipolar and quadrupolar couplings), which give direct information about the amplitude of motions. The potential of combining relaxation data with such measurements of dynamically-averaged anisotropic interactions is discussed. Although the focus of this review is on the theor. foundations of dynamics studies rather than their application, we close by discussing a small no. of recent dynamics studies, where the dynamic properties of proteins in crystals are compared to those in soln.
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    Fu, R.; Tian, C.; Kim, H.; Smith, S. A.; Cross, T. A. The Effect of Hartmann–Hahn Mismatching on Polarization Inversion Spin Exchange at the Magic Angle. J. Magn. Reson. 2002, 159, 167– 174,  DOI: 10.1016/s1090-7807(02)00036-8
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    The effect of Hartmann-Hahn mismatching on polarization inversion spin exchange at the magic angle
    Fu, Riqiang; Tian, Changlin; Kim, Hyeongnam; Smith, Scott A.; Cross, Timothy A.
    Journal of Magnetic Resonance (2002), 159 (2), 167-174CODEN: JMARF3; ISSN:1090-7807. (Elsevier Science)
    The effect of the Hartmann-Hahn mismatch Δ=ωeff-ω1S during polarization inversion spin exchange at the magic angle (PISEMA) was studied, where ωeff and ω1S represent the amplitudes of the 1H effective spin-locking field at the magic angle and the 15N RF spin-locking field, resp. During the PISEMA evolution period, the exact Hartmann-Hahn match condition (i.e., Δ=0) yields a max. dipolar scaling factor of 0.816 for PISEMA expts., while any mismatch results in two different effective fields for the 1st and 2nd half of each frequency switched Lee-Goldburg (FSLG) cycle. The mismatch effect on the scaling factor depends strongly on the transition angle from one effective field to the other within each FSLG cycle as well as on the cycle time. At low RF spin-lock amplitudes in which the FSLG cycle time is relatively long, the scaling factor rapidly becomes smaller as ω1S becomes greater than ωeff. However, when ω1S<ωeff, there is relatively little effect on the scaling factor with variation in Δ. As a result, the presence of RF inhomogeneities may significantly broaden the line-width in the dipolar dimension because of the mismatch effect. Higher RF spin-lock amplitudes result in a relatively small variation for the scaling factor. Also, ramped amplitude of the 15N RF spin-lock field in synchronization with the flip-flop of the FSLG sequence minimizes the transition angle between the two effective fields within the FSLG cycle. It is shown exptl. that such a ramped amplitude not only gives rise to the same scaling factor but also results in a narrower dipolar line-width in comparison with the rectangular amplitude.
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    Hong, M.; Yao, X.; Jakes, K.; Huster, D. Investigation of Molecular Motions by Lee-Goldburg Cross-Polarization NMR Spectroscopy. J. Phys. Chem. B 2002, 106, 7355– 7364,  DOI: 10.1021/jp0156064
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    Investigation of molecular motions by Lee-Goldburg cross-polarization NMR spectroscopy
    Hong, Mei; Yao, Xiaolan; Jakes, Karen; Huster, Daniel
    Journal of Physical Chemistry B (2002), 106 (29), 7355-7364CODEN: JPCBFK; ISSN:1089-5647. (American Chemical Society)
    We demonstrate the use of Lee-Goldburg cross-polarization (LG-CP) NMR under fast magic-angle spinning (MAS) to investigate the amplitude and geometry of segmental motions in biomol. and polymeric solids. Motional geometry information was previously available only from 2H NMR, which, however, has limited site resoln. and requires site-specific isotopic labeling. Using a 2D LG-CP technique, we resolve the 13C-1H or 15N-1H dipolar couplings according to the 13C or 15N isotropic chem. shift. Applications to systems undergoing 180° phenylene ring flips show spectral line shapes reflecting the geometry of the motion. Using this LG-CP technique, we measured the 13C-1H and 15N-1H dipolar couplings in the water-sol. and membrane-bound states of the colicin Ia channel domain. The backbone motions of the membrane-bound colicin scale both the Cα-Hα and N-H couplings similarly, thus ruling out rotation of the α-helixes around their axes as a specific mechanism of motion. We also show that the sensitivity of the LG-CP spectra can be enhanced by the addn. of a phase-inverted 1H-13C cross-polarization step, and the site resoln. of the 15N-1H LG-CP spectra can be enhanced by 13C indirect detection.
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    Lorieau, J.; McDermott, A. E. Order Parameters Based On 13C1H, 13C1H2 and 13C1H3 Heteronuclear Dipolar Powder Patterns: A Comparison of MAS-Based Solid-State NMR Sequences. Magn. Reson. Chem. 2006, 44, 334– 347,  DOI: 10.1002/mrc.1773
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    94
    Order parameters based on 13C1H, 13C1H2 and 13C1H3 heteronuclear dipolar powder patterns: a comparison of MAS-based solid-state NMR sequences
    Lorieau, Justin; McDermott, Ann E.
    Magnetic Resonance in Chemistry (2006), 44 (3), 334-347CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
    Order parameters describing conformational exchange processes on the nanosecond to microsecond timescale can be obtained from powder patterns in solid-state NMR (SSNMR) expts. Extensions of these expts. to magic-angle spinning (MAS) based high-resoln. expts. were demonstrated, which show a great promise for site-specific probes of biopolymers. The authors present a detailed comparison of two pulse sequences, transverse Manfield-Rhim-Elleman-Vaughn (T-MREV) and Lee-Goldburg cross-polarization (LGCP), using exptl. and simulation tools to explore their utility in the study of order parameters. The authors discuss systematic errors due to passively coupled 13C or 1H nuclei, as well as due to B1 inhomogeneity. Both pulse sequences can provide quant. measurements of the order parameter, but the LGCP expt. is capable of greater accuracy provided that the B1 field is highly homogeneous. The T-MREV expt. is far better compensated for B1 inhomogeneity, and it also performs better in situations with limited signal.
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    Achilles, A.; Bärenwald, R.; Lechner, B.-D.; Werner, S.; Ebert, H.; Tschierske, C.; Blume, A.; Bacia, K.; Saalwächter, K. Self-Assembly of X-Shaped Bolapolyphiles in Lipid Membranes: Solid-State NMR Investigations. Langmuir 2016, 32, 673– 682,  DOI: 10.1021/acs.langmuir.5b03712
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    Self-Assembly of X-Shaped Bolapolyphiles in Lipid Membranes: Solid-State NMR Investigations
    Achilles, Anja; Baerenwald, Ruth; Lechner, Bob-Dan; Werner, Stefan; Ebert, Helgard; Tschierske, Carsten; Blume, Alfred; Bacia, Kirsten; Saalwaechter, Kay
    Langmuir (2016), 32 (3), 673-682CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    A novel class of rigid-rod bolapolyphilic mols. with three philicities (rigid arom. core, mobile aliph. side chains, polar end groups) has recently been demonstrated to incorporate into and span lipid membranes, and to exhibit a rich variety of self-organization modes, including macroscopically ordered snowflake structures with 6-fold symmetry. In order to support a structural model and to better understand the self-organization on a mol. scale, we here report on proton and carbon-13 high-resoln. magic-angle spinning solid-state NMR investigations of two different bolapolyphiles (BPs) in model membranes of two different phospholipids (DPPC, DOPC). We elucidate the changes in mol. dynamics assocd. with three new phase transitions detected by calorimetry in composite membranes of different compn., namely, a change in π-π-packing, the melting of lipid tails assocd. with the superstructure, and the dissoln. and onset of free rotation of the BPs. We derive dynamic order parameters assocd. with different H-H and C-H bond directions of the BPs, demonstrating that the arom. cores are well packed below the final phase transition, showing only 180° flips of the Ph ring, and that they perform free rotations with addnl. oscillations of the long axis when dissolved in the fluid membrane. Our data suggests that BPs not only form ordered superstructures, but also rather homogeneously dispersed π-packed filaments within the lipid gel phase, thus reducing the corrugation of large vesicles.
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    Pawlak, T.; Czajkowska-Szczykowska, D.; Jastrzebska, I.; Santillan, R.; Seroka, B.; Maj, J.; Morzycki, J. W.; Labra-Vázquez, P.; Farfán, N.; Bujacz, G. D.; Potrzebowski, M. J. Influence of Hydrogen/Fluorine Substitution on Structure, Thermal Phase Transitions, and Internal Molecular Motion of Aromatic Residues in the Crystal Lattice of Steroidal Rotors. Cryst. Growth Des. 2020, 20, 2202– 2216,  DOI: 10.1021/acs.cgd.9b01179
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    96
    Influence of Hydrogen/Fluorine Substitution on Structure, Thermal Phase Transitions, and Internal Molecular Motion of Aromatic Residues in the Crystal Lattice of Steroidal Rotors
    Pawlak, Tomasz; Czajkowska-Szczykowska, Dorota; Jastrzebska, Izabella; Santillan, Rosa; Seroka, Barbara; Maj, Jadwiga; Morzycki, Jacek W.; Labra-Vazquez, Pablo; Farfan, Norberto; Bujacz, Grzegorz D.; Potrzebowski, Marek J.
    Crystal Growth & Design (2020), 20 (4), 2202-2216CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Two, acyclic (1) and cyclic (2), steroidal mol. rotors contg. 1,4-diethynyl-2,3-difluoro-phenylene units as rotators were investigated by means of single crystal X-ray diffraction, high resoln. solid state NMR spectroscopy, and computer methods. The aim of this study was to understand and search for a correlation between the size of difluoro-phenylene units and free space in the crystal lattice required for mol. reorientation as well as the topol. and time scale of dynamic processes. As a primary tool for anal. of mol. motions in the solid state, 1H-13C PISEMA, a technique which allows following the dynamics in the range of 10-3-10-6 s, was employed. The PISEMA data defining the 1H-13C dipolar couplings, whose values are sensitive to local motion, were confronted with 13C CSA parameters. Our studies revealed that replacing hydrogen by fluorine in acyclic rotors has significant consequences for dynamic processes. In the case of hydrogen-substituted species, free rotation around the 1-4 axis of the benzene ring was proven. For fluorine derivs. 1, only small amplitude wobbling of arom. residues was obsd. The only large amplitude reorientation, a so-called π-jump around the 1-4 axis, was obsd. during the phase transition related with solvent migration from the crystal lattice. For cyclic rotors (2) two crystallog. forms 2A (triclinic, P1 space group) and 2B (monoclinic, P21 space group) are established. The form 2B contg. a heptane mol. in the crystal lattice undergoes a thermal transition with large amplitude motion of building units of the steroidal frame. The high dynamics of the fluorinated rotator for 2A is proven. Two, acyclic and cyclic, mol. rotors contg. 1,4-diethynyl-2,3-difluoro-phenylene units as rotators were investigated by means of single crystal X-ray diffraction, high resoln. solid state NMR spectroscopy, and computer methods. Our studies revealed that replacing hydrogen by fluorine in acyclic rotors has significant consequences for dynamic processes. The fast rotation of a fluorinated rotator for one of the crystallog. forms of a cyclic steroidal compd. is proven.
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    Pawlak, T.; Sudgen, I.; Bujacz, G.; Iuga, D.; Brown, S. P.; Potrzebowski, M. J. Synergy of Solid-State NMR, Single-Crystal X-Ray Diffraction, and Crystal Structure Prediction Methods: A Case Study of Teriflunomide (TFM). Cryst. Growth Des. 2021, 21, 3328,  DOI: 10.1021/acs.cgd.1c00123
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    Synergy of Solid-State NMR, Single-Crystal X-ray Diffraction, and Crystal Structure Prediction Methods: A Case Study of Teriflunomide (TFM)
    Pawlak, Tomasz; Sudgen, Isaac; Bujacz, Grzegorz; Iuga, Dinu; Brown, Steven P.; Potrzebowski, Marek J.
    Crystal Growth & Design (2021), 21 (6), 3328-3343CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    In this work, for the first time, we present the X-ray diffraction crystal structure and spectral properties of a new, room-temp. polymorph of teriflunomide (TFM), CSD code 1969989. As revealed by DSC, the low-temp. TFM polymorph recently reported by Gunnam et al. undergoes a reversible thermal transition at -40°C. This reversible process is related to a change in Z' value, from 2 to 1, as obsd. by variable-temp. 1H-13C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR, while the crystallog. system is preserved (triclinic). Two-dimensional 13C-1H and 1H-1H double-quantum MAS NMR spectra are consistent with the new room-temp. structure, including comparison with GIPAW (gauge-including projector augmented waves) calcd. NMR chem. shifts. A crystal structure prediction procedure found both exptl. teriflunomide polymorphs in the energetic global min. region. Differences between the polymorphs are seen for the torsional angle describing the orientation of the Ph ring relative to the planarity of the TFM mol. In the low-temp. structure, there are two torsion angles of 4.5 and 31.9° for the two Z' = 2 mols., while in the room-temp. structure, there is disorder that is modeled with ~ 50% occupancy between torsion angles of -7.8 and 28.6°. These observations are consistent with a broad energy min. as revealed by DFT calcns. PISEMA solid-state NMR expts. show a redn. in the C-H dipolar coupling in comparison to the static limit for the arom. CH moieties of 75% and 51% at 20 and 40°C, resp., that is indicative of ring flips at the higher temp. Our study shows the power of combining expts., namely DSC, X-ray diffraction, and MAS NMR, with DFT calcns. and CSP to probe and understand the solid-state landscape, and in particular the role of dynamics, for pharmaceutical mols.
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    A review. Polymorphs are different cryst. modifications of the same chem. substance. When different conformers of the same mol. occur in different crystal forms, the phenomenon is termed conformational polymorphism. Occasionally, more than one conformer is present in the same crystal structure. The influence of mol. conformation changes on the formation and stability of polymorphs is the focus of this Account. X-ray crystal structures of conformational polymorphs were analyzed to understand the interplay of intramol. (conformer) and intermol. (lattice) energy in the crystn. and stability of polymorphs. Polymorphic structures stabilized by strong O-H···O/N-H···O hydrogen bonds, weak C-H···O interactions, and close packing were considered. 4,4-Diphenyl-2,5-cyclohexadienone (1) and bis(p-tolyl) ketone p-tosylhydrazone (3) are prototypes of C-H···O and N-H···O hydrogen-bonded structures. Distance-angle scatter plots of O-H···O and C-H···O hydrogen bonds extd. from the Cambridge Structural Database indicate that polymorphs with a larger no. of symmetry-independent mols. (high Z') generally have better interactions when compared with the polymorphs with lower Z' values, with the implication that these symmetry-independent mols. have different conformations. Since mol. conformer (Econf) and crystal lattice (Ulatt) energy differences are of the same magnitude in org. crystals (typically <5 kcal mol-1), situations wherein these two factors compensate or cancel one another are illustrative. Calcn. of conformer and lattice energies using Gaussian 03 and Cerius in 23 recently published polymorph sets shows that a strained conformer (higher Econf) is stabilized by stronger interactions or better crystal packing (lower Ulatt) in 2/3 of the cases, whereas there is no energy balance in the remaining structures. Org. mols. with flexible torsions and low-energy conformers have a greater likelihood of exhibiting polymorphism because (1) different conformations lead to new hydrogen -bonding and close-packing modes and (2) the tradeoff reduces the total energy difference between alternative crystal structures. As a test case, polymorph promiscuity in fuchsones (6) is related to the conformational diversity at the exo-methylene Ph rings and the small energy difference computed for di-Me fuchsone polymorphs. These ideas find application in the design of putative pharmaceutical polymorphs and crystal structure prediction.
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  1. Aurélien Lemercier, Yohann Cartigny, Pierrick Morice, Elise Vanbiervliet, Massimiliano Forcato, Gérard Coquerel. Spherical Agglomeration of Safinamide Mesylate: A Case Study of a Simultaneous Control of Crystalline Landscape and Micromeritic Properties. Organic Process Research & Development 2023, 27 (4) , 669-679. https://doi.org/10.1021/acs.oprd.2c00396
  2. Neethu Thomas, Claire Welton, Tomasz Pawlak, Parth Raval, Julien Trébosc, Sheetal K. Jain, G.N. Manjunatha Reddy. Deuteron-proton isotope correlation spectroscopy at high magnetic fields. Solid State Nuclear Magnetic Resonance 2025, 136 , 101993. https://doi.org/10.1016/j.ssnmr.2025.101993
  3. Teobald Kupka. Theory and computation of nuclear shielding. 2024, 1-23. https://doi.org/10.1039/9781837675630-00001
  4. Songül Şahin, Nisa Nur Can. A Schiff Base with Polymorphic Structure ( Z ′ = 2): Investigations with Computational Techniques and in Silico Predictions. Polycyclic Aromatic Compounds 2023, 43 (10) , 9269-9294. https://doi.org/10.1080/10406638.2022.2161585
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  • Abstract

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    Figure 1

    Figure 1. Chemical structure of SM and numbering system.

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    Figure 2

    Figure 2. Results for the Xadago drug (a,b) and API extracted from tablets (c,d) at room temperature: (a,c) X-ray powder pattern recorded in Bragg Brentano geometry with a Cu Kα (λ = 1.5425 Å) source. (b,d) 13C CP MAS NMR spectrum of the Xadago drug recorded at a spinning rate of 8 kHz and a 1H Larmor frequency of 400.1 MHz. The recycle delay was 30 s. Asterisks indicate spinning sidebands.

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    Figure 3

    Figure 3. Asymmetric part of the unit cell of SM_E showing the crystallographic atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level except for the H atoms.

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    Figure 4

    Figure 4. Crystal structure of SM_E indicating (a,b) asymmetric parts of the unit cell with two possible locations of F atoms (fractionally occupied) outlined by dotted green lines, (c) hydrogen bond motifs (colored orange), and (d) superposition of nonequivalent molecules A and B extracted from the single-crystal diffraction-based structure of SM_E. Molecules (c,d) are colored according to symmetry equivalence and shown without hydrogens (except for the water molecule).

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    Figure 5

    Figure 5. Schematic representation of two possible orientations of fluorine in molecule B and the relative total crystal lattice energy difference at the DFT-D level between structures containing B′ and B′ conformers.

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    Figure 6

    Figure 6. 13C (a) and 15N (b) CP MAS NMR spectra of SM_E recorded at a spinning rate of 8 kHz and a 1H Larmor frequency of 400.1 MHz at ambient temperature. Assignments are colored blue for molecule “A”, green for molecule “B,” and purple for overlapped signals. Asterisks indicate spinning sidebands.

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    Figure 7

    Figure 7. Correlation of experimental 13C chemical shift (δ) and calculated nuclear shielding parameters (σ) of SM_E.

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    Figure 8

    Figure 8. DSC (a) and TGA (b) plots for the SM_E sample with the heating rate of 5 °C min–1. Additional DSC plots using a new portion of the sample during (c) first heating and (d) first cooling and second heating runs in the range of temperatures below the melting point with the rate of 5 °C min–1.

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    Figure 9

    Figure 9. 13C and 15N CP MAS NMR spectra of SM_D at ambient temperature (a,b), at 50 °C (c,d), and at −30 °C (e,f) recorded at a spinning rate of 8 kHz and a 1H Larmor frequency of 400.1 MHz. The blue (molecule “A”), green (molecule “B”). and purple (overlapped) arrows indicate positions of resonances for SM_E (a,b). The assignment of signals (c–e) is shown according to the results from Thermal Transformations of Sample SM_E and Determination of SM_D Crystal Structure Based on the Data Obtained in a PXRD Measurement and Its Validation Using Advanced Solid-State NMR and GIPAW Calculations. Asterisks indicated spinning sidebands.

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    Figure 10

    Figure 10. 2D PISEMA MAS spectra for samples SM_E (a), SM_D at 50 °C (b), and SM_DLT (c). The highest splitting values are labeled in each spectrum. Spectra were acquired at a 13 kHz spinning rate and a 1H Larmor frequency of 400.1 MHz.

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    Figure 11

    Figure 11. Rietveld curves for SM_D.

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    Figure 12

    Figure 12. PXRD unit cell of SM_D polymorph displayed along the “c” direction.

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    Figure 13

    Figure 13. (a) 13C–1H invHETCOR MAS NMR spectra of SM_D recorded at 90 °C with a spinning rate of 60 kHz at a 1H Larmor frequency of 600.1 MHz with a second 13C → 1H CP contact time of 100 μs. A one-pulse 1H MAS spectrum is shown at the top. The orange crosses represent GIPAW-calculated NMR correlations for C···H distances up to 1.5 Å. Isotropic 13C (a) and 1H (b) NMR values correlation (experimental chemical shifts vs GIPAW nuclear shieldings) for SM_D.

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    Figure 14

    Figure 14. Rietveld curves for SM_DLT.

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    Figure 15

    Figure 15. Relation Z′ = 1 ↔ Z′ = 3 between PXRD unit cells of SM_DLT and SM_D. Molecules are colored according to the symmetry equivalence and shown without hydrogens.

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    Figure 16

    Figure 16. Superposition of nonequivalent molecules in SM_DLT (green, blue, and red) and SM_D (orange).

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      Domingos, Sofia; Andre, Vania; Quaresma, Silvia; Martins, Ines C. B.; Minas da Piedade, M. Fatima; Duarte, Maria Teresa
      Journal of Pharmacy and Pharmacology (2015), 67 (6), 830-846CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)
      Objectives : In a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful examples will be given. Key findings : This overview presents a possible step to overcome the 10-15 years of hard work involved in launching a new drug in the market: the use of new forms of well-known APIs, and improve their efficiency by enhancing their bioavailability and pharmacokinetics. It discusses some of the latest progresses. Summary : We want to present, in a brief overview, what recently has been done to improve the discovery of innovative methods of using well-known APIs, and improve their efficiency. Multicomponent crystal forms have shown to be the most promising achievements to accomplish these aims, by altering API physico-chem. properties, such as soly., thermal stability, shelf life, dissoln. rate and compressibility. API-ionic liqs. (ILs) and their advantages will be briefly referred. An outline of what has recently been achieved in metal drug coordination and in drug storage and delivery using bio-inspired metal-org. frameworks (BioMOFs) will also be addressed.
    17. 17
      Singhal, D. Drug Polymorphism and Dosage Form Design: A Practical Perspective. Adv. Drug Deliv. Rev. 2004, 56, 335– 347,  DOI: 10.1016/j.addr.2003.10.008
      17
      Drug polymorphism and dosage form design: a practical perspective
      Singhal, Dharmendra; Curatolo, William
      Advanced Drug Delivery Reviews (2004), 56 (3), 335-347CODEN: ADDREP; ISSN:0169-409X. (Elsevier Science B.V.)
      A review and discussion. Formulators are charged with the responsibility to formulate a product which is phys. and chem. stable, manufacturable, and bioavailable. Most drugs exhibit structural polymorphism, and it is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf life under a variety of real-world storage conditions. There are occasional situations in which the development of a metastable cryst. or amorphous form is justified because a medical benefit is achieved. Such situations include those in which a faster dissoln. rate or higher concn. are desired, in order to achieve rapid absorption and efficacy, or to achieve acceptable systemic exposure for a low-soly. drug. Another such situation is one in which the drug remains amorphous despite extensive efforts to crystallize it. If there is no particular medical benefit, there is less justification for accepting the risks of intentional development of a metastable cryst. or amorphous form. Whether or not there is medical benefit, the risks assocd. with development of a metastable form must be mitigated by lab. work which provides assurance that (a) the largest possible form change will have no substantive effect on product quality or bioavailability, and/or (b) a change will not occur under all reasonable real-world storage conditions, and/or (c) anal. methodol. and sampling procedures are in place which assure that a problem will be detected before dosage forms which have compromised quality or bioavailability can reach patients.
    18. 18
      Yu, L.; Stephenson, G. A.; Mitchell, C. A.; Bunnell, C. A.; Snorek, S. V.; Bowyer, J. J.; Borchardt, T. B.; Stowell, J. G.; Byrn, S. R. Thermochemistry and Conformational Polymorphism of a Hexamorphic Crystal System. J. Am. Chem. Soc. 2000, 122, 585– 591,  DOI: 10.1021/ja9930622
      18
      Thermochemistry and Conformational Polymorphism of a Hexamorphic Crystal System
      Yu, Lian; Stephenson, Gregory A.; Mitchell, Christine A.; Bunnell, Charles A.; Snorek, Sharon V.; Bowyer, J. Joe; Borchardt, Thomas B.; Stowell, Joseph G.; Byrn, Stephen R.
      Journal of the American Chemical Society (2000), 122 (4), 585-591CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was crystd. as 6 solvent-free polymorphs, which differ in the mode of packing and in mol. conformation. The conformational difference results principally from the thiophene torsion relative to the o-nitroaniline fragment, which leads to different crystal colors (red, orange, and yellow). Thermodn. stability relations between polymorphs were detd. from solid-state conversions and calorimetric data of melting and eutectic melting. Vibrational spectroscopy and ab initio calcns. showed that most conformers in soln. feature perpendicularly arranged thiophene and o-nitroaniline fragments, although a minor population of more planar conformers also exist. Crystn. has a stabilizing effect for more planar and higher dipole conformers over perpendicular ones by 3-6 kJ/mol. The only exception to this pattern is the one polymorph contg. weak intermol. H bonds.
    19. 19
      Pudipeddi, M.; Serajuddin, A. T. M. Trends in Solubility of Polymorphs. J. Pharm. Sci. 2005, 94, 929– 939,  DOI: 10.1002/jps.20302
      19
      Trends in solubility of polymorphs
      Pudipeddi, Madhu; Serajuddin, Abu T. M.
      Journal of Pharmaceutical Sciences (2005), 94 (5), 929-939CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
      Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. Considering the multitude of reports on soly. or dissoln. of polymorphs in the literature, an attempt is made in this study to answer the question: How big is the impact of polymorphism on soly.. A large no. of literature reports on soly. or dissoln. of polymorphs were reviewed and the data were analyzed for trends in soly. ratio of polymorphs. The general trend reveals that the ratio of polymorph soly. is typically less than 2, although occasionally higher ratios can be obsd. A similar trend is also obsd. for anhydrate/hydrate soly. ratios, although anhydrate/hydrate soly. ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. An attempt is also made in this commentary to est. the ratio of solubilities of polymorphs from thermal data. The trend in estd. soly. ratio shows good agreement with the one obsd. with exptl. detd. soly. values.
    20. 20
      Sun, C.; Grant, D. J. W. Compaction Properties of L-Lysine Salts. Pharm. Res. 2001, 18, 281– 286,  DOI: 10.1023/a:1011090510875
      20
      Compaction properties of L-lysine salts
      Sun, Changquan; Grant, David J. W.
      Pharmaceutical Research (2001), 18 (3), 281-286CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
      The purpose of this research was to examine the effects of salt form, i.e., different anions with a common cation (L-lysinium), on compaction properties and to identify the factors that det. the tensile strength of tablets. L-Lysine salts with the following anions were compressed at various pressures acetate, monochloride, dichloride, L-aspartate, L-glutamate (dihydrate), and L-lysine (zwitterionic monohydrate). The yield strength of each salt was evaluated from the "out-of-die" Heckel plot. At low compaction pressures, the tensile strength of the compacts increases linearly with increasing compaction pressure. Simultaneously, the compact tensile strength decreases exponentially with increasing yield strength of the salt. However, at high compaction pressures, the compact tensile strength is detd. by the interparticulate bonding strength and not by the yield strength. The compact tensile strength, extrapolated to zero porosity, increases linearly with increasing melting temp. of the salts. The counterion affects the tableting properties of L-lysine salts. The tensile strength is controlled by both the yield strength and the interparticulate interaction strength with the former predominant at low compaction pressures and the latter predominant at high compaction pressures. The melting temp. of each L-lysine salt is a good indicator of the tensile strength of its compacts at zero porosity.
    21. 21
      Picker-Freyer, K. M.; Liao, X.; Zhang, G.; Wiedmann, T. S. Evaluation of the Compaction of Sulfathiazole Polymorphs. J. Pharm. Sci. 2007, 96, 2111– 24,  DOI: 10.1002/jps.21042
      21
      Evaluation of the compaction of sulfathiazole polymorphs
      Picker-Freyer, Katharina Maria; Liao, Xiangmin; Zhang, Guifang; Wiedmann, Timothy Scott
      Journal of Pharmaceutical Sciences (2007), 96 (8), 2111-2124CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
      The aim of this study was to relate the tableting performance assessed by an instrumented tableting machine to the mech. properties measured by nanoindentation. Three different polymorphic forms of sulfathiazole were prepd. by recrystn., and the d. and x-ray powder diffraction patterns were measured and compared with theor. d. and simulated powder patterns, resp. Tablets were prepd. using a series of applied pressures, and the results were subjected to energy anal., 3D-modeling, and traditional Heckel anal. With these approaches, form I was consistently the most brittle material, but the subtle differences between forms II and III were only revealed by 3D modeling. The rank order of the crushing force was form I ≃ form II < form III. From nanoindentation, form III was much harder than forms I and II, and III also had a much higher Young's modulus. The energy calcns. of the nanoindentation curves showed that form III was distinct from forms I and II, which is consistent with the presence of slip planes that are only present in form III. However, in this system, there was little correspondence between the macroscopic and microscopic measurements, and thus particle-particle interactions may to be of paramount importance.
    22. 22
      Khomane, K. S.; More, P. K.; Bansal, A. K. Counterintuitive Compaction Behavior of Clopidogrel Bisulfate Polymorphs. J. Pharm. Sci. 2012, 101, 2408– 2416,  DOI: 10.1002/jps.23148
      22
      Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs
      Khomane, Kailas S.; More, Parth K.; Bansal, Arvind K.
      Journal of Pharmaceutical Sciences (2012), 101 (7), 2408-2416CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
      Being a d. violator, clopidogrel bisulfate (CLP) polymorphic system (forms I and II) allows us to study individually the impact of mol. packing (true d.) and thermodn. properties such as heat of fusion on the compaction behavior. These two polymorphs of CLP were investigated for in-die and out-of-die compaction behavior using CTC profile, Heckel, and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. Detailed examns. of the mol. packing of each form revealed that arrangement of the sulfate anion differs significantly in both crystal forms, thus conferring different compaction behavior to two forms. Close cluster packing of mols. in form I offers a rigid structure, which has poor compressibility and hence resists deformation under compaction pressure. This results into lower densification, higher yield strength, and mean yield pressure, as compared with form II at a given pressure. However, by virtue of higher bonding strength, form I showed superior tabletability, despite its poor compressibility and deformation behavior. Form I, having higher true d. and lower heat of fusion showed higher bonding strength. Hence, true d. and not heat of fusion can be considered predictor of bonding strength of the pharmaceutical powders. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
    23. 23
      Ainurofiq, A.; Dinda, K. E.; Pangestika, M. W.; Himawati, U.; Wardhani, W. D.; Sipahutar, Y. T. The Effect of Polymorphism on Active Pharmaceutical Ingredients: A Review. Int. J. Res. Pharm. Sci. 2020, 11, 1621– 1630,  DOI: 10.26452/ijrps.v11i2.2044
      There is no corresponding record for this reference.
    24. 24
      Dudek, M. K.; Kazmierski, S.; Kostrzewa, M.; Potrzebowski, M. J. Solid-State NMR Studies of Molecular Crystals. Annual Reports on NMR Spectroscopy; Elsevier, 2018; Vol. 95, pp 1– 81.
      There is no corresponding record for this reference.
    25. 25
      Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Ritonavir: An Extraordinary Example of Conformational Polymorphism. Pharmaceut. Res. 2001, 18, 859,  DOI: 10.1023/A:1011052932607
      25
      Ritonavir: an extraordinary example of conformational polymorphism
      Bauer, John; Spanton, Stephen; Henry, Rodger; Quick, John; Dziki, Walter; Porter, William; Morris, John
      Pharmaceutical Research (2001), 18 (6), 859-866CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
      Purpose. In the summer of 1998, Norvir semi-solid capsules supplies were threatened as a result of a new much less sol. crystal form of ritonavir. This report provides characterization of the 2 polymorphs and the structures and hydrogen bonding network for each form. Methods. Ritonavir polymorphism was investigated by solid state spectroscopy and microscopy techniques including solid state NMR, near-IR Spectroscopy, powder x-ray Diffraction and single crystal x-ray. A sensitive seed detection test was developed. Results. Ritonavir polymorphs were thoroughly characterized and the structures detd. An unusual conformation was found for form II that results in a strong hydrogen bonding network. A possible mechanism for heterogeneous nucleation of form II was investigated. Conclusions. Ritonavir exhibited conformational polymorphism with two unique crystal lattices having significantly different soly. properties. Although the polymorph (form II) corresponding to the "cis" conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersatd. solns. The coincidence of a highly supersatd. soln. and a probable heterogeneous nucleation by a degrdn. product resulted in the sudden appearance of the more stable form II polymorph.
    26. 26
      Sheldrick, G. M. Short History of SHELX. Acta Crystallogr. A 2008, 64, 112– 122,  DOI: 10.1107/s0108767307043930
      26
      A short history of SHELX
      Sheldrick, George M.
      Acta Crystallographica, Section A: Foundations of Crystallography (2008), 64 (1), 112-122CODEN: ACACEQ; ISSN:0108-7673. (International Union of Crystallography)
      An account is given of the development of the SHELX system of computer programs from SHELX-76 to the present day. In addn. to identifying useful innovations that have come into general use through their implementation in SHELX, a crit. anal. is presented of the less-successful features, missed opportunities and desirable improvements for future releases of the software. An attempt is made to understand how a program originally designed for photog. intensity data, punched cards and computers over 10000 times slower than an av. modern personal computer has managed to survive for so long. SHELXL is the most widely used program for small-mol. refinement and SHELXS and SHELXD are often employed for structure soln. despite the availability of objectively superior programs. SHELXL also finds a niche for the refinement of macromols. against high-resoln. or twinned data; SHELXPRO acts as an interface for macromol. applications. SHELXC, SHELXD and SHELXE are proving useful for the exptl. phasing of macromols., esp. because they are fast and robust and so are often employed in pipelines for high-throughput phasing. This paper could serve as a general literature citation when one or more of the open-source SHELX programs (and the Bruker AXS version SHELXTL) are employed in the course of a crystal-structure detn.
    27. 27
      Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta Crystallogr. Sect. C Cryst. Struct. Commun. 2015, 71, 3– 8,  DOI: 10.1107/s2053229614024218
      There is no corresponding record for this reference.
    28. 28
      Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. a. K.; Puschmann, H. OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Crystallogr. 2009, 42, 339– 341,  DOI: 10.1107/s0021889808042726
      28
      OLEX2: a complete structure solution, refinement and analysis program
      Dolomanov, Oleg V.; Bourhis, Luc J.; Gildea, Richard J.; Howard, Judith A. K.; Puschmann, Horst
      Journal of Applied Crystallography (2009), 42 (2), 339-341CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
      New software, OLEX2, was developed for the detn., visualization and anal. of mol. crystal structures. The software has a portable mouse-driven workflow-oriented and fully comprehensive graphical user interface for structure soln., refinement and report generation, as well as novel tools for structure anal. OLEX2 seamlessly links all aspects of the structure soln., refinement and publication process and presents them in a single workflow-driven package, with the ultimate goal of producing an application which will be useful to both chemists and crystallographers.
    29. 29
      Boultif, A.; Louër, D. Powder Pattern Indexing with the Dichotomy Method. J. Appl. Crystallogr. 2004, 37, 724– 731,  DOI: 10.1107/s0021889804014876
      29
      Powder pattern indexing with the dichotomy method
      Boultif, Ali; Louer, Daniel
      Journal of Applied Crystallography (2004), 37 (5), 724-731CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)
      The efficiency of the successive dichotomy method for powder diffraction pattern indexing [Louer and Louer (1972). J. Appl. Cryst. 5, 271-275] was proved over >30 yr of usage. Features implemented in the new version of the computer program DICVOL04 include (i) a tolerance to the presence of impurity (or inaccurately measured) diffraction lines, (ii) a refinement of the 'zero-point' position, (iii) a reviewing of all input lines from the soln. found from, generally, the 1st 20 lines, (iv) a cell anal., based on the concept of the reduced cell, to identify equiv. monoclinic and triclinic solns., and (v) an optional anal. of input powder data to detect the presence of a significant 'zero-point' offset. New search strategies also were introduced, e.g. each crystal system is scanned sep., within the input vol. limits, to limit the risk of missing a soln. characterized by a metric lattice singularity. The default values in the input file were extended to 25 Å for the linear parameters and 2500 Å3 for the cell vol. The search is carried out exhaustively within the input parameter limits and the abs. error on peak position measurements. Many tests with data from the literature and from powder data of pharmaceutical materials, collected with the capillary technique and lab. monochromatic x-rays, were performed with a high success rate, covering all crystal symmetries from cubic to triclinic. Some examples reported as 'difficult' cases are also discussed. Addnl., a few recommendations for the correct practice of powder pattern indexing are reported.
    30. 30
      Altomare, A.; Caliandro, R.; Camalli, M.; Cuocci, C.; Giacovazzo, C.; Moliterni, A. G. G.; Rizzi, R. Automatic Structure Determination from Powder Data with EXPO2004. J. Appl. Crystallogr. 2004, 37, 1025– 1028,  DOI: 10.1107/s0021889804021417
      30
      Automatic structure determination from powder data with EXPO2004
      Altomare, Angela; Caliandro, Rocco; Camalli, Mercedes; Cuocci, Corrado; Giacovazzo, Carmelo; Moliterni, Anna Grazia Giuseppina; Rizzi, Rosanna
      Journal of Applied Crystallography (2004), 37 (6), 1025-1028CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)
      EXPO2004 is the updated version of the EXPO program [Altomare et al. (1999). J. Appl. Cryst. 32, 339-340]. The traditional steps of the ab initio powder soln. process were performed automatically: indexing, space-group detn., decompn. of the pattern for extg. the obsd. structure-factor moduli, structure soln. by direct methods, model refinement by Rietveld technique. Special strategies may be applied to improve both the ests. of the extd. structure-factor moduli and the quality of the structure model. The use of special procedures exploiting available supplementary information on mol. geometry can be successfully adopted. The graphical interface also was improved.
    31. 31
      Altomare, A.; Cuocci, C.; Giacovazzo, C.; Moliterni, A.; Rizzi, R.; Corriero, N.; Falcicchio, A. EXPO2013 : A Kit of Tools for Phasing Crystal Structures from Powder Data. J. Appl. Crystallogr. 2013, 46, 1231– 1235,  DOI: 10.1107/s0021889813013113
      31
      EXPO2013: a kit of tools for phasing crystal structures from powder data
      Altomare, Angela; Cuocci, Corrado; Giacovazzo, Carmelo; Moliterni, Anna; Rizzi, Rosanna; Corriero, Nicola; Falcicchio, Aurelia
      Journal of Applied Crystallography (2013), 46 (4), 1231-1235CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
      EXPO2013, the heir of EXPO2009, was enriched by a variety of new algorithms and graphical tools aiming at strengthening the individual steps of the powder structure soln. pathway. Particular attention was addressed to the procedures devoted to improving structural models provided by direct methods in ab initio approaches. A new procedure was implemented, working in direct space, which may be chosen by the user as an alternative to the traditional simulated annealing algorithm.
    32. 32
      Černý, R.; Favre-Nicolin, V.; Rohlíček, J.; Hušák, M. FOX, Current State and Possibilities. Crystals 2017, 7, 322
      32
      FOX, current state and possibilities
      Cerny, Radovan; Favre-Nicolin, Vincent; Rohlicek, Jan; Husak, Michal
      Crystals (2017), 7 (10), 322/1-322/10CODEN: CRYSBC; ISSN:2073-4352. (MDPI AG)
      FOX (Free Objects for Xtallog.) is a computer program for solving crystal structures of all types of compds. using the powder data (but also the single crystal data) measured using X-ray, neutron and electron diffraction. It works in direct space using the reversed Monte Carlo algorithm of global optimization. Since its release fifteen years ago, it has developed into a powerful tool, simplifying the powder pattern anal. starting from the background detn., indexing and space group selection over the structure modeling using various pre-programmed structural fragments up to the validation of the proposed structural model.
    33. 33
      Favre-Nicolin, V.; Černý, R. FOX, free Objects for Crystallography’: A Modular Approach to Ab Initio Structure Determination from Powder Diffraction. J. Appl. Crystallogr. 2002, 35, 734– 743,  DOI: 10.1107/s0021889802015236
      33
      FOX, 'free objects for crystallography': a modular approach to ab initio structure determination from powder diffraction
      Favre-Nicolin, Vincent; Cerny, Radovan
      Journal of Applied Crystallography (2002), 35 (6), 734-743CODEN: JACGAR; ISSN:0021-8898. (Blackwell Munksgaard)
      A new program was developed for ab initio crystal structure detn. from powder diffraction data (x-ray and neutron). It uses global-optimization algorithms to solve the structure by performing trials in direct space. It is a modular program, capable of using several criteria for evaluating each trial configuration (e.g. multi-pattern). It is also modular in the description of the crystal content, with the possibility of describing building blocks in the sample, such as polyhedra or mols., and with automatic adaptive handling of special positions and sharing of identical atoms between neighboring building blocks. It can therefore find the correct structure without any assumption about the connectivity of the building blocks and is suitable for any kind of material. Several optimization algorithms (simulated annealing, parallel tempering) are available, with the possibility of choosing the convergence criterion as a combination of available cost functions. This program is freely available for Linux and Windows platforms; it is also fully 'open source', which, combined with an object-oriented design and a complete developer documentation, ensures its future evolution.
    34. 34
      Toby, B. H.; Von Dreele, R. B. GSAS-II : The Genesis of a Modern Open-Source All Purpose Crystallography Software Package. J. Appl. Crystallogr. 2013, 46, 544– 549,  DOI: 10.1107/s0021889813003531
      34
      GSAS-II: the genesis of a modern open-source all purpose crystallography software package
      Toby, Brian H.; Von Dreele, Robert B.
      Journal of Applied Crystallography (2013), 46 (2), 544-549CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
      The newly developed GSAS-II software is a general purpose package for data redn., structure soln. and structure refinement that can be used with both single-crystal and powder diffraction data from both neutron and x-ray sources, including lab. and synchrotron sources, collected on both two- and 1-dimensional detectors. It is intended that GSAS-II will eventually replace both the GSAS and the EXPGUI packages, as well as many other utilities. GSAS-II is open source and is written largely in object-oriented Python but offers speeds comparable to compiled code because of its reliance on the Python NumPy and SciPy packages for computation. It runs on all common computer platforms and offers highly integrated graphics, both for a user interface and for interpretation of parameters. The package can be applied to all stages of crystallog. anal. for const.-wavelength x-ray and neutron data. Plans for considerable addnl. development are discussed.
    35. 35
      Bruno, I. J.; Cole, J. C.; Kessler, M.; Luo, J.; Motherwell, W. D. S.; Purkis, L. H.; Smith, B. R.; Taylor, R.; Cooper, R. I.; Harris, S. E.; Orpen, A. G. Retrieval of Crystallographically-Derived Molecular Geometry Information. J. Chem. Inf. Comput. Sci. 2004, 44, 2133– 2144,  DOI: 10.1021/ci049780b
      35
      Retrieval of Crystallographically-Derived Molecular Geometry Information
      Bruno, Ian J.; Cole, Jason C.; Kessler, Magnus; Luo, Jie; Motherwell, W. D. Sam; Purkis, Lucy H.; Smith, Barry R.; Taylor, Robin; Cooper, Richard I.; Harris, Stephanie E.; Orpen, A. Guy
      Journal of Chemical Information and Computer Sciences (2004), 44 (6), 2133-2144CODEN: JCISD8; ISSN:0095-2338. (American Chemical Society)
      The crystallog. detd. bond length, valence angle, and torsion angle information in the Cambridge Structural Database (CSD) has many uses. However, accessing it by conventional substructure searching requires nontrivial user intervention. In consequence, these valuable data were underused and were not directly accessible to client applications. The situation was remedied by development of a new program (Mogul) for automated retrieval of mol. geometry data from the CSD. The program uses a system of keys to encode the chem. environments of fragments (bonds, valence angles, and acyclic torsions) from CSD structures. Fragments with identical keys are deemed to be chem. identical and are grouped together, and the distribution of the appropriate geometrical parameter (bond length, valence angle, or torsion angle) is computed and stored. Use of a search tree indexed on key values, together with a novel similarity calcn., then enables the distribution matching any given query fragment (or the distributions most closely matching, if an adequate exact match is unavailable) to be found easily and with no user intervention. Validation expts. indicate that, with rare exceptions, search results afford precise and unbiased ests. of mol. geometrical preferences. Such ests. may be used, for example, to validate the geometries of libraries of modeled mols. or of newly detd. crystal structures or to assist structure soln. from low-resoln. (e.g. powder diffraction) x-ray data.
    36. 36
      Cottrell, S. J.; Olsson, T. S. G.; Taylor, R.; Cole, J. C.; Liebeschuetz, J. W. Validating and Understanding Ring Conformations Using Small Molecule Crystallographic Data. J. Chem. Inf. Model. 2012, 52, 956– 962,  DOI: 10.1021/ci200439d
      36
      Validating and Understanding Ring Conformations Using Small Molecule Crystallographic Data
      Cottrell, Simon J.; Olsson, Tjelvar S. G.; Taylor, Robin; Cole, Jason C.; Liebeschuetz, John W.
      Journal of Chemical Information and Modeling (2012), 52 (4), 956-962CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
      Understanding the conformational preferences of ring structures is fundamental to structure-based drug design. Although the Cambridge Structural Database (CSD) provides information on the preferred conformations of small mols., analyzing this data can be very time-consuming. In order to overcome this hurdle, tools have been developed for quickly extg. geometrical preferences from the CSD. Here we describe how the program Mogul has been extended to analyze and compare ring conformations, using a library derived from over 900 000 ring fragments in the CSD. We illustrate how these can be used to understand the conformational preferences of mols. in a crystal lattice and bound to proteins.
    37. 37
      Dvinskikh, S. V.; Zimmermann, H.; Maliniak, A.; Sandström, D. Heteronuclear Dipolar Recoupling in Liquid Crystals and Solids by PISEMA-Type Pulse Sequences. J. Magn. Reson. 2003, 164, 165– 170,  DOI: 10.1016/s1090-7807(03)00180-0
      37
      Heteronuclear dipolar recoupling in liquid crystals and solids by PISEMA-type pulse sequences
      Dvinskikh, Sergey V.; Zimmermann, Herbert; Maliniak, Arnold; Sandstrom, Dick
      Journal of Magnetic Resonance (2003), 164 (1), 165-170CODEN: JMARF3; ISSN:1090-7807. (Elsevier Science)
      A pulse sequence is described for the recoupling of heteronuclear dipolar interactions under MAS. The method is similar to the PISEMA expt., but employs a well-defined amplitude modulation of one of the two radiofrequency fields. The technique is used for measurements of 1H-13C dipolar couplings in unoriented solid and liq.-cryst. samples.
    38. 38
      Dvinskikh, S. V.; Sandström, D. Frequency Offset Refocused PISEMA-Type Sequences. J. Magn. Reson. 2005, 175, 163– 169,  DOI: 10.1016/j.jmr.2005.03.016
      38
      Frequency offset refocused PISEMA-type sequences
      Dvinskikh, Sergey V.; Sandstroem, Dick
      Journal of Magnetic Resonance (2005), 175 (1), 163-169CODEN: JMARF3; ISSN:1090-7807. (Elsevier)
      The popular PISEMA expt. is highly sensitive to the 1H chem. shift dispersion and the choice of the 1H carrier frequency. This is due to the off-resonance 1H irradn. in the FSLG-CP sequence employed during the dipolar evolution period. In the modified approach described in this work, the interfering frequency offset terms are suppressed. In the new pulse schemes, conventional FSLG-CP is intercalated with 180° pulses applied simultaneously to both frequency channels, and with phases set orthogonal to those of the spin-lock fields. The technique is demonstrated on a nematic liq.-cryst. sample. Extensions to amplitude-modulated FSLG-CP recoupling under MAS are also presented.
    39. 39
      Ramamoorthy, A.; Opella, S. J. Two-Dimensional Chemical Shift/Heteronuclear Dipolar Coupling Spectra Obtained with Polarization Inversion Spin Exchange at the Magic Angle and Magic-Angle Sample Spinning (PISEMAMAS). Solid State Nucl. Magn. Reson. 1995, 4, 387– 392,  DOI: 10.1016/0926-2040(95)00054-t
      39
      Two-dimensional chemical shift/heteronuclear dipolar coupling spectra obtained with polarization inversion spin exchange at the magic angle and magic-angle sample spinning (PISEMAMAS)
      Ramamoorthy, A.; Opella, S. J.
      Solid State Nuclear Magnetic Resonance (1995), 4 (6), 387-92CODEN: SSNRE4; ISSN:0926-2040. (Elsevier)
      High-resoln. two-dimensional 15N chem. shift/1H-15N dipolar coupling polarization inversion spin exchange at the magic angle (PISEMA) spectra of a polycryst. sample of 15N-acetylvaline were obtained with and without magic-angle sample spinning. These spectra demonstrate the advantages of the PISEMA expt. over conventional approaches to sepd. local-field spectroscopy, esp. the high resoln. in the dipolar dimension where the spinning sidebands have uniformly narrow linewidths.
    40. 40
      Fung, B. M.; Khitrin, A. K.; Ermolaev, K. An Improved Broadband Decoupling Sequence for Liquid Crystals and Solids. J. Magn. Reson. 2000, 142, 97– 101,  DOI: 10.1006/jmre.1999.1896
      40
      An Improved Broadband Decoupling Sequence for Liquid Crystals and Solids
      Fung, B. M.; Khitrin, A. K.; Ermolaev, Konstantin
      Journal of Magnetic Resonance (2000), 142 (1), 97-101CODEN: JMARF3; ISSN:1090-7807. (Academic Press)
      Recently the authors developed an efficient broadband decoupling sequence called SPARC-16 for liq. crystals [J. Magn. Reson. 130, 317(1998)]. The sequence is based upon a 16-step phase cycling of the 2-step TPPM decoupling method for solids [J. Chem. Phys. 103, 6951(1995)]. Since then, a stepwise variation of the phase angle in the TPPM sequence offers even better results. The application of this new method to a liq. cryst. compd., 4-n-pentyl-4'-cyanobiphenyl, and a solid, l-tyrosine hydrochloride, is reported. The reason for the improvement is explained by an anal. of the problem in the rotating frame. (c) 2000 Academic Press.
    41. 41
      Topspin, version 3.5; Bruker Biospin Gmbh: Karlsruhe, Germany.
      There is no corresponding record for this reference.
    42. 42
      Mao, K.; Wiench, J. W.; Lin, V. S.-Y.; Pruski, M. Indirectly Detected Through-Bond Chemical Shift Correlation NMR Spectroscopy in Solids under Fast MAS: Studies of Organic–Inorganic Hybrid Materials. J. Magn. Reson. 2009, 196, 92– 95,  DOI: 10.1016/j.jmr.2008.10.010
      42
      Indirectly detected through-bond chemical shift correlation NMR spectroscopy in solids under fast MAS: Studies of organic-inorganic hybrid materials
      Mao, Kanmi; Wiench, Jerzy W.; Lin, Victor S.-Y.; Pruski, Marek
      Journal of Magnetic Resonance (2009), 196 (1), 92-95CODEN: JMARF3; ISSN:1090-7807. (Elsevier B.V.)
      Indirectly detected, through-bond NMR correlation spectra between 13C and 1H nuclei are reported for the first time in solid state. The capabilities of the new method are demonstrated using naturally abundant org.-inorg. mesoporous hybrid materials. The time performance is significantly better, almost by a factor of 10, than in the corresponding 13C detected expt. The proposed scheme represents a new anal. tool for studying other solid-state systems and the basis for the development of more advanced 2D and 3D correlation methods.
    43. 43
      Ishii, Y.; Tycko, R. Sensitivity Enhancement in Solid State 15N NMR by Indirect Detection with High-Speed Magic Angle Spinning. J. Magn. Reson. 2000, 142, 199– 204,  DOI: 10.1006/jmre.1999.1976
      43
      Sensitivity Enhancement in Solid State 15N NMR by Indirect Detection with High-Speed Magic Angle Spinning
      Ishii, Yoshitaka; Tycko, Robert
      Journal of Magnetic Resonance (2000), 142 (1), 199-204CODEN: JMARF3; ISSN:1090-7807. (Academic Press)
      Enhancement of sensitivity in solid state 15N NMR by indirect detection through 1H NMR signals under high-speed magic angle spinning and high-field conditions is demonstrated exptl. on two 15N-labeled peptides, polycryst. AlaGlyGly and the helix-forming, 17-residue peptide MB(i + 4)EK in lyophilized form. Sensitivity enhancement factors ranging from 2.0 to 3.2 are obsd. exptl., depending on the 15N and 1H linewidths and polarization transfer efficiencies. The 1H-detected two-dimensional 1H/15N correlation spectrum of AlaGlyGly illustrates the possibility of increased spectral resoln. and resonance assignments in indirectly detected expts., in addn. to the sensitivity enhancement. (c) 2000 Academic Press.
    44. 44
      Wiench, J. W.; Bronnimann, C. E.; Lin, V. S.-Y.; Pruski, M. Chemical Shift Correlation NMR Spectroscopy with Indirect Detection in Fast Rotating Solids: Studies of Organically Functionalized Mesoporous Silicas. J. Am. Chem. Soc. 2007, 129, 12076– 12077,  DOI: 10.1021/ja074746+
      44
      Chemical Shift Correlation NMR Spectroscopy with Indirect Detection in Fast Rotating Solids: Studies of Organically Functionalized Mesoporous Silicas
      Wiench, Jerzy W.; Bronnimann, Charles E.; Lin, Victor S.-Y.; Pruski, Marek
      Journal of the American Chemical Society (2007), 129 (40), 12076-12077CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The first indirectly detected 13C-1H solid-state NMR correlation spectra of species bound to a surface are reported. The expts. were performed at 14.1 T under fast (40 kHz) MAS. The sensitivity gain was demonstrated on a mesoporous silica sample contg. approx. 300 μg of covalently bound allyl groups, in the absence of templating mols. and without isotope enrichment. A well-resolved two-dimensional spectrum was acquired in 15 min, which is more than 10 times faster than using direct detection of 13C nuclei.
    45. 45
      Thakur, R. S.; Kurur, N. D.; Madhu, P. K. Swept-Frequency Two-Pulse Phase Modulation for Heteronuclear Dipolar Decoupling in Solid-State NMR. Chem. Phys. Lett. 2006, 426, 459– 463,  DOI: 10.1016/j.cplett.2006.06.007
      45
      Swept-frequency two-pulse phase modulation for heteronuclear dipolar decoupling in solid-state NMR
      Thakur, Rajendra Singh; Kurur, Narayanan D.; Madhu, P. K.
      Chemical Physics Letters (2006), 426 (4-6), 459-463CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)
      We introduce a heteronuclear dipolar decoupling sequence for application in solid-state NMR. The sequence, called swept-frequency two-pulse phase modulation (SWf-TPPM), is based on one of the decoupling sequences, TPPM. The sequence is robust in performance with respect to various exptl. parameters, such as, the pulse flip angle, pulse phase, and offset and a comparison is made with other decoupling schemes, namely TPPM, SPINAL, and XiX, on a sample of U-13C-labeled tyrosine for magic-angle spinning speeds up to 14 kHz.
    46. 46
      Vinod Chandran, C.; Madhu, P. K.; Kurur, N. D.; Bräuniger, T. Swept-Frequency Two-Pulse Phase Modulation (SW f -TPPM) Sequences with Linear Sweep Profile for Heteronuclear Decoupling in Solid-State NMR. Magn. Reson. Chem. 2008, 46, 943– 947,  DOI: 10.1002/mrc.2285
      46
      Swept-frequency two-pulse phase modulation (SWf-TPPM) sequences with linear sweep profile for heteronuclear decoupling in solid-state NMR
      Vinod Chandran C; Madhu P K; Kurur Narayanan D; Brauniger Thomas
      Magnetic resonance in chemistry : MRC (2008), 46 (10), 943-7 ISSN:.
      Recently, a pulse scheme for heteronuclear spin decoupling in solid-state NMR, called swept-frequency two-pulse phase modulation (SW(f)-TPPM), was introduced which outperforms the standard TPPM and small phase incremental alteration (SPINAL) schemes. It has also been shown that the frequency-sweep profile can be varied to achieve optimal efficiency for crystalline and liquid-crystalline samples, respectively. Here we present a detailed comparison of the proton decoupling performance for SW(f)-TPPM sequences with tangential sweep profiles (SW(f) (tan)-TPPM) and linear sweep profiles (SW(f) (lin)-TPPM). Using the (13)CH(2) resonance of crystalline tyrosine as a model system, it is shown that linear profiles have a decoupling performance which is at least as good and in some instances slightly better than that obtained from tangential sweep profiles. While tangential sweep profiles require a tangent cut-off angle as an additional parameter, the lack of that parameter makes linear sweep profiles easier to implement and optimise.
    47. 47
      Marion, D.; Ikura, M.; Tschudin, R.; Bax, A. Rapid Recording of 2D NMR Spectra without Phase Cycling. Application to the Study of Hydrogen Exchange in Proteins. J. Magn. Reson. 1989, 85, 393– 399,  DOI: 10.1016/0022-2364(89)90152-2
      47
      Rapid recording of 2D NMR spectra without phase cycling: application to the study of hydrogen exchange in proteins
      Marion, Dominique; Ikura, Mitsuhiko; Tschudin, Rolf; Bax, Ad
      Journal of Magnetic Resonance (1969-1992) (1989), 85 (2), 393-9CODEN: JOMRA4; ISSN:0022-2364.
      High quality 2-dimensional NMR spectra can be recorded very rapidly without using phase cycling. This makes it possible to study H exchange phenomena in proteins with spectra too complex for anal. by 1-dimensional NMR. This approach is demonstrated on calmodulin and a trypsin inhibitor.
    48. 48
      Morcombe, C. R.; Zilm, K. W. Chemical Shift Referencing in MAS Solid State NMR. J. Magn. Reson. 2003, 162, 479– 486,  DOI: 10.1016/s1090-7807(03)00082-x
      48
      Chemical shift referencing in MAS solid state NMR
      Morcombe, Corey R.; Zilm, Kurt W.
      Journal of Magnetic Resonance (2003), 162 (2), 479-486CODEN: JMARF3; ISSN:1090-7807. (Elsevier Science)
      Solid state 13C magic angle spinning (MAS) NMR spectra are typically referenced externally using a probe which does not incorporate a field frequency lock. Soln. NMR shifts however, are more often detd. with respect to an internal ref. and using a deuterium based field frequency lock. Further differences arise in soln. NMR of proteins and nucleic acids where both 13C and 1H shifts are referenced by recording the frequency of the 1H resonance of DSS (sodium salt of 2,2-dimethyl-2-silapentane-5-sulfonic acid) instead of TMS (tetramethylsilane). The authors study the difficulties in relating shifts measured relative to TMS and DSS by these various approaches in soln. and solids NMR, and calibrate adamantane as an external 13C std. for solids NMR. External chem. shift referencing of magic angle spinning spectra is typically quite reproducible and accurate, with better than ±0.03 ppm accuracy being straight forward to achieve. Solid state and liq. phase NMR shifts obtained by magic angle spinning with external referencing agree with those measured using typical soln. NMR hardware with the sample tube aligned with the applied field as long as magnetic susceptibility corrections and solvent shifts are taken into account. The DSS and TMS ref. scales for 13C and 1H are related accurately using MAS NMR. Large solvent shifts for the 13C resonance in TMS in either deuterochloroform or methanol are obsd., being +0.71 ppm and -0.74 ppm from external TMS, resp. The ratio of the 13C resonance frequencies for the two carbons in solid adamantane to the 1H resonance of TMS is reported.
    49. 49
      Harris, R. K.; Becker, E. D.; Cabral de Menezes, S. M.; Goodfellow, R.; Granger, P. NMR Nomenclature. Nuclear Spin Properties and Conventions for Chemical Shifts(IUPAC Recommendations 2001). Pure Appl. Chem. 2001, 73, 1795– 1818,  DOI: 10.1351/pac200173111795
      49
      NMR nomenclature. Nuclear spin properties and conventions for chemical shifts (IUPAC recommendations 2001)
      Harris, Robin K.; Becker, Edwin D.; Cabral De Menezes, Sonia M.; Goodfellow, Robin; Granger, Pierre
      Pure and Applied Chemistry (2001), 73 (11), 1795-1818CODEN: PACHAS; ISSN:0033-4545. (International Union of Pure and Applied Chemistry)
      A review. A unified scale is recommended for reporting the NMR chem. shifts of all nuclei relative to the 1H resonance of tetramethylsilane (TMS). The unified scale is designed to provide a precise ratio, Ξ, of the resonance frequency of a given nuclide to that of the primary ref., the 1H resonance of TMS in dil. soln. (vol. fraction, φ < 1%) in CHCl3. Referencing procedures are discussed, including matters of practical application of the unified scale. Special attention is paid to recommended ref. samples, and values of Ξ for secondary refs. on the unified scale are listed, many of which are the results of new measurements. Some earlier recommendations relating to the reporting of chem. shifts are endorsed. The chem. shift, δ, is redefined to avoid previous ambiguities but to leave practical usage unchanged. Relations between the unified scale and recently published recommendations for referencing in aq. solns. (for specific use in biochem. work) are discussed, as well as the special effects of working in the solid state with magic-angle spinning. In all, nine new recommendations relating to chem. shifts are made. Standardized nuclear spin data are also presented in tabular form for the stable (and some unstable) isotopes of all elements with nonzero quantum nos. The information given includes quantum nos., isotopic abundances, magnetic moments, magnetogyric ratios and receptivities, together with quadrupole moments and line-width factors where appropriate.
    50. 50
      Bertani, P.; Raya, J.; Bechinger, B. 15N Chemical Shift Referencing in Solid State NMR. Solid State Nucl. Magn. Reson. 2014, 61–62, 15– 18,  DOI: 10.1016/j.ssnmr.2014.03.003
      50
      15N chemical shift referencing in solid state NMR
      Bertani, Philippe; Raya, Jesus; Bechinger, Burkhard
      Solid State Nuclear Magnetic Resonance (2014), 61-62 (), 15-18CODEN: SSNRE4; ISSN:0926-2040. (Elsevier)
      Solid-state NMR spectroscopy has much advanced during the last decade and provides a multitude of data that can be used for high-resoln. structure detn. of biomols., polymers, inorg. compds. or macromols. In some cases the chem. shift referencing has become a limiting factor to the precision of the structure calcns. and we have therefore evaluated a no. of methods used in proton-decoupled 15N solid-state NMR spectroscopy. For 13C solid-state NMR spectroscopy adamantane is generally accepted as an external std., but to calibrate the 15N chem. shift scale several stds. are in use. As a consequence the published chem. shift values exhibit considerable differences (up to 22 ppm). In this paper we report the 15N chem. shift of several commonly used refs. compds. in order to allow for comparison and recalibration of published data and future work. We show that 15NH4Cl in its powd. form (at 39.3 ppm with respect to liq. NH3) is a suitable external ref. as it produces narrow lines when compared to other ref. compds. and at the same time allows for the set-up of cross-polarization NMR expts. The compd. is suitable to calibrate magic angle spinning and static NMR expts. Finally the temp. variation of 15NH4Cl chem. shift is reported.
    51. 51
      Bielecki, A.; Burum, D. P. Temperature Dependence of 207 Pb MAS Spectra of Solid Lead Nitrate. An Accurate, Sensitive Thermometer for Variable-Temperature MAS. J. Magn. Reson., Ser. A 1995, 116, 215– 220,  DOI: 10.1006/jmra.1995.0010
      51
      Temperature dependence of 207Pb MAS spectra of solid lead nitrate. An accurate, sensitive thermometer for variable-temperature MAS
      Bielecki, Anthony; Burum, Douglas P.
      Journal of Magnetic Resonance, Series A (1995), 116 (2), 215-20CODEN: JMRAE2; ISSN:1064-1858. (Academic)
      The remarkably sensitive temp. dependence of the 207Pb chem. shift in magic-angle-spinning (MAS) spectra of lead nitrate provides an excellent method for thermometry in solid-state NMR. The temp. dependence is uniform over a range of at least -130 to +150°, and also the NMR sensitivity and linewidth are very favorable. Lead nitrate can be used in MAS probes to measure sample temp. changes, temp. gradients, MAS heating effects, and the dynamics of temp. jumps.
    52. 52
      Hronský, V. Measurement of Sample Temperatures and Temperature Gradients in Magic-Angle Spinning NMR. Acta Electrotech. Inform. 2013, 13, 95,  DOI: 10.2478/aeei-2013-0021
      There is no corresponding record for this reference.
    53. 53
      Clark, S. J.; Segall, M. D.; Pickard, C. J.; Hasnip, P. J.; Probert, M. I. J.; Refson, K.; Payne, M. C. First Principles Methods Using CASTEP. Z. Kristallogr. 2005, 220, 567– 570,  DOI: 10.1524/zkri.220.5.567.65075
      53
      First principles methods using CASTEP
      Clark, Stewart J.; Segall, Matthew D.; Pickard, Chris J.; Hasnip, Phil J.; Probert, Matt I. J.; Refson, Keith; Payne, Mike C.
      Zeitschrift fuer Kristallographie (2005), 220 (5-6), 567-570CODEN: ZEKRDZ; ISSN:0044-2968. (Oldenbourg Wissenschaftsverlag GmbH)
      The CASTEP code for first principles electronic structure calcns. is described. A brief, non-tech. overview is given and some of the features and capabilities highlighted. Some features which are unique to CASTEP are described and near-future development plans outlined.
    54. 54
      McNellis, E. R.; Meyer, J.; Reuter, K. Azobenzene at Coinage Metal Surfaces: Role of Dispersive van Der Waals Interactions. Phys. Rev. B 2009, 80, 205414,  DOI: 10.1103/physrevb.80.205414
      54
      Azobenzene at coinage metal surfaces: Role of dispersive van der Waals interactions
      McNellis, Erik R.; Meyer, Joerg; Reuter, Karsten
      Physical Review B: Condensed Matter and Materials Physics (2009), 80 (20), 205414/1-205414/10CODEN: PRBMDO; ISSN:1098-0121. (American Physical Society)
      We use different semiempirical dispersion correction schemes to assess the role of long-range van der Waals interactions in the adsorption of the prototypical mol. switch azobenzene (C6H5-N2-C6H5) at the coinage metal surfaces Cu(111), Ag(111), and Au(111). Compared to preceding d.-functional theory results employing a semilocal exchange and correlation functional we obtain partly sizable changes in the computed adsorption geometry and energetics. The discomforting scatter in the results provided by the different schemes is largely attributed to the unknown form of the damping function in the semiempirical correction expression. Using the congeneric problem of the adsorption of benzene as a vehicle to connection with expt., we cautiously conclude that the account of dispersive interactions at the metal surfaces provided by the various schemes is in the right ballpark, with the more recent, general schemes likely to overbind.
    55. 55
      Tkatchenko, A.; Scheffler, M. Accurate Molecular Van Der Waals Interactions from Ground-State Electron Density and Free-Atom Reference Data. Phys. Rev. Lett. 2009, 102, 073005,  DOI: 10.1103/physrevlett.102.073005
      55
      Accurate Molecular Van Der Waals Interactions from Ground-State Electron Density and Free-Atom Reference Data
      Tkatchenko, Alexandre; Scheffler, Matthias
      Physical Review Letters (2009), 102 (7), 073005/1-073005/4CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
      We present a parameter-free method for an accurate detn. of long-range van der Waals interactions from mean-field electronic structure calcns. Our method relies on the summation of interat. C6 coeffs., derived from the electron d. of a mol. or solid and accurate ref. data for the free atoms. The mean abs. error in the C6 coeffs. is 5.5% when compared to accurate exptl. values for 1225 intermol. pairs, irresp. of the employed exchange-correlation functional. We show that the effective at. C6 coeffs. depend strongly on the bonding environment of an atom in a mol. Finally, we analyze the van der Waals radii and the damping function in the C6R-6 correction method for d.-functional theory calcns.
    56. 56
      Vanderbilt, D. Soft Self-Consistent Pseudopotentials in a Generalized Eigenvalue Formalism. Phys. Rev. B: Condens. Matter Mater. Phys. 1990, 41, 7892– 7895,  DOI: 10.1103/physrevb.41.7892
      56
      Soft self-consistent pseudopotentials in a generalized eigenvalue formalism
      Vanderbilt
      Physical review. B, Condensed matter (1990), 41 (11), 7892-7895 ISSN:0163-1829.
      There is no expanded citation for this reference.
    57. 57
      Nocedal, J.; Wright, S. J. Numerical Optimization; Springer Science+Business Media, LLC., Springer e-books: New York, NY, 2006.
      There is no corresponding record for this reference.
    58. 58
      Monkhorst, H. J.; Pack, J. D. Special Points for Brillouin-Zone Integrations. Phys. Rev. B 1976, 13, 5188– 5192,  DOI: 10.1103/physrevb.13.5188
      There is no corresponding record for this reference.
    59. 59
      Pickard, C. J.; Mauri, F. All-Electron Magnetic Response with Pseudopotentials: NMR Chemical Shifts. Phys. Rev. B 2001, 63, 245101,  DOI: 10.1103/physrevb.63.245101
      59
      All-electron magnetic response with pseudopotentials: NMR chemical shifts
      Pickard, Chris J.; Mauri, Francesco
      Physical Review B: Condensed Matter and Materials Physics (2001), 63 (24), 245101/1-245101/13CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)
      A theory for the ab initio calcn. of all-electron NMR chem. shifts in insulators using pseudopotentials is presented. It is formulated for both finite and infinitely periodic systems and is based on an extension to the projector augmented-wave approach of Blochl [P. E. Blochl, Phys. Rev. B 50, 17953 (1994)] and the method of Mauri et al. [F. Mauri, B. G. Pfrommer, and S. G. Louie, Phys. Rev. Lett. 77, 5300 (1996)]. The theory is successfully validated for mols. by comparison with a selection of quantum chem. results, and in periodic systems by comparison with plane-wave all-electron results for diamond.
    60. 60
      Yates, J. R.; Pickard, C. J.; Mauri, F. Calculation of NMR Chemical Shifts for Extended Systems Using Ultrasoft Pseudopotentials. Phys. Rev. B: Condens. Matter Mater. Phys. 2007, 76, 024401,  DOI: 10.1103/physrevb.76.024401
      60
      Calculation of NMR chemical shifts for extended systems using ultrasoft pseudopotentials
      Yates, Jonathan R.; Pickard, Chris J.; Mauri, Francesco
      Physical Review B: Condensed Matter and Materials Physics (2007), 76 (2), 024401/1-024401/11CODEN: PRBMDO; ISSN:1098-0121. (American Physical Society)
      The authors present a scheme for the calcn. of magnetic response parameters in insulators using ultrasoft pseudopotentials. It uses the gauge-including projector augmented wave method [C. J. Pickard and F. Mauri, Phys. Rev. B 63, 245101(2001)] to obtain all-electron accuracy for both finite and infinitely periodic systems. In detail the calcn. of NMR chem. shieldings are considered. The approach is successfully validated 1st for mol. systems by comparing calcd. chem. shieldings for a range of mols. with quantum chem. results and then in the solid state by comparing 17O NMR parameters calcd. for silicates with expt.
    61. 61
      Nutrition, C. for F. S. and A. Generally Recognized as Safe (GRAS) https://www.fda.gov/food/food-ingredients-packaging/generally-recognized-safe-gras (accessed Aug 04, 2021).
      There is no corresponding record for this reference.
    62. 62
      Ravikumar, K.; Sridhar, B. Two Polymorphs of Safinamide, a Selective and Reversible Inhibitor of Monoamine Oxidase B. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2010, 66, o317– o320,  DOI: 10.1107/s0108270110019384
      62
      Two polymorphs of safinamide, a selective and reversible inhibitor of monoamine oxidase B
      Ravikumar, Krishnan; Sridhar, Balasubramanian
      Acta Crystallographica, Section C: Crystal Structure Communications (2010), 66 (6), o317-o320CODEN: ACSCEE; ISSN:0108-2701. (International Union of Crystallography)
      Two polymorphs of safinamide {systematic name: (2S)-2-[4-(3-fluorobenzyloxy)benzylamino]propionamide}, C17H19FN2O2, a potent selective and reversible monoamine oxidase B (MAO-B) inhibitor, are described. Both forms are orthorhombic and regarded as conformational polymorphs due to the differences in the orientation of the 3-fluorobenzyloxy and propanamide groups. Both structures pack with layers in the ac plane. In polymorph (I), the layers have discrete wide and narrow regions which are complementary when located next to adjacent layers. In polymorph (II), the layer has long flanges protruding from each side, which interdigitate when packed with the adjacent layers. N-H···O hydrogen bonds are present in both structures, whereas N-H···F hydrogen bonding is seen in polymorph (I), while N-H···N hydrogen bonding is seen in polymorph (II).
    63. 63
      Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The Cambridge Structural Database. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 171– 179,  DOI: 10.1107/s2052520616003954
      63
      The Cambridge Structural Database
      Groom, Colin R.; Bruno, Ian J.; Lightfoot, Matthew P.; Ward, Suzanna C.
      Acta Crystallographica, Section B: Structural Science, Crystal Engineering and Materials (2016), 72 (2), 171-179CODEN: ACSBDA; ISSN:2052-5206. (International Union of Crystallography)
      The Cambridge Structural Database (CSD) contains a complete record of all published org. and metal-org. small-mol. crystal structures. The database has been in operation for over 50 years and continues to be the primary means of sharing structural chem. data and knowledge across disciplines. As well as structures that are made public to support scientific articles, it includes many structures published directly as CSD Communications. All structures are processed both computationally and by expert structural chem. editors prior to entering the database. A key component of this processing is the reliable assocn. of the chem. identity of the structure studied with the exptl. data. This important step helps ensure that data is widely discoverable and readily reusable. Content is further enriched through selective inclusion of addnl. exptl. data. Entries are available to anyone through free CSD community web services. Linking services developed and maintained by the CCDC, combined with the use of std. identifiers, facilitate discovery from other resources. Data can also be accessed through CCDC and third party software applications and through an application programming interface.
    64. 64
      Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; van de Streek, J. Mercury : Visualization and Analysis of Crystal Structures. J. Appl. Crystallogr. 2006, 39, 453– 457,  DOI: 10.1107/s002188980600731x
      64
      Mercury: visualization and analysis of crystal structures
      Macrae, Clare F.; Edgington, Paul R.; McCabe, Patrick; Pidcock, Elna; Shields, Greg P.; Taylor, Robin; Towler, Matthew; van de Streek, Jacco
      Journal of Applied Crystallography (2006), 39 (3), 453-457CODEN: JACGAR; ISSN:0021-8898. (Blackwell Publishing Ltd.)
      Since its original release, the popular crystal structure visualization program Mercury has undergone continuous further development. Comparisons between crystal structures are facilitated by the ability to display multiple structures simultaneously and to overlay them. Improvements were made to many aspects of the visual display, including the addn. of depth cueing, and highly customizable lighting and background effects. Textual and numeric data assocd. with structures can be shown in tables or spreadsheets, the latter opening up new ways of interacting with the visual display. At. displacement ellipsoids, calcd. powder diffraction patterns and predicted morphologies can now be shown. Some limited mol.-editing capabilities were added. The object-oriented nature of the C++ libraries underlying Mercury makes it easy to re-use the code in other applications, and this has facilitated three-dimensional visualization in several other programs produced by the Cambridge Crystallog. Data Center.
    65. 65
      Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. Mercury CSD 2.0 – New Features for the Visualization and Investigation of Crystal Structures. J. Appl. Crystallogr. 2008, 41, 466– 470,  DOI: 10.1107/s0021889807067908
      65
      Mercury CSD 2.0 - new features for the visualization and investigation of crystal structures
      Macrae, Clare F.; Bruno, Ian J.; Chisholm, James A.; Edgington, Paul R.; McCabe, Patrick; Pidcock, Elna; Rodriguez-Monge, Lucia; Taylor, Robin; van de Streek, Jacco; Wood, Peter A.
      Journal of Applied Crystallography (2008), 41 (2), 466-470CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
      The program Mercury, developed by the Cambridge Crystallog. Data Center, is designed primarily as a crystal structure visualization tool. A new module of functionality has been produced, called the Materials Module, which allows highly customizable searching of structural databases for intermol. interaction motifs and packing patterns. This new module also includes the ability to perform packing similarity calcns. between structures contg. the same compd. In addn. to the Materials Module, a range of further enhancements to Mercury has been added in this latest release, including void visualization and links to ConQuest, Mogul and IsoStar.
    66. 66
      Komatsu, T.; Kikuchi, J. Comprehensive Signal Assignment of 13C-Labeled Lignocellulose Using Multidimensional Solution NMR and 13C Chemical Shift Comparison with Solid-State NMR. Anal. Chem. 2013, 85, 8857– 8865,  DOI: 10.1021/ac402197h
      66
      Comprehensive Signal Assignment of 13C-Labeled Lignocellulose Using Multidimensional Solution NMR and 13C Chemical Shift Comparison with Solid-State NMR
      Komatsu, Takanori; Kikuchi, Jun
      Analytical Chemistry (Washington, DC, United States) (2013), 85 (18), 8857-8865CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      A multidimensional soln. NMR method has been developed using various pulse programs including HCCH-COSY and 13C-HSQC-NOESY for the structural characterization of com. available 13C labeled lignocellulose from potatoes (Solanum tuberosum L.), chicory (Cichorium intybus), and corn (Zea mays). This new method allowed for 119 of the signals in the 13C-HSQC spectrum of lignocelluloses to be assigned and was successfully used to characterize the structures of lignocellulose samples from three plants in terms of their xylan and xyloglucan structures, which are the major hemicelluloses in angiosperm. Furthermore, this new method provided greater insight into fine structures of lignin by providing a high resoln. to the arom. signals of the β-aryl ether and resinol moieties, as well as the diastereomeric signals of the β-aryl ether. Finally, the 13C chem. shifts assigned in this study were compared with those from solid-state NMR and indicated the presence of heterogeneous dynamics in the polysaccharides where rigid cellulose and mobile hemicelluloses moieties existed together.
    67. 67
      Sousa, E. G. R. d.; Carvalho, E. M. d.; San Gil, R. A. d. S.; Santos, T. C. d.; Borré, L. B.; Santos-Filho, O. A.; Ellena, J. Solution and Solid State Nuclear Magnetic Resonance Spectroscopic Characterization of Efavirenz. J. Pharm. Sci. 2016, 105, 2656– 2664,  DOI: 10.1016/j.xphs.2015.10.006
      67
      Solution and Solid State Nuclear Magnetic Resonance Spectroscopic Characterization of Efavirenz
      Sousa Eduardo Gomes Rodrigues de; Carvalho Erika Martins de; Santos Tereza Cristina Dos; Santos-Filho Osvaldo Andrade; San Gil Rosane Aguiar da Silva; Borre Leandro Bandeira; Ellena Javier
      Journal of pharmaceutical sciences (2016), 105 (9), 2656-2664 ISSN:.
      Samples of efavirenz (EFZ) were evaluated to investigate the influence of the micronization process on EFZ stability. A combination of X-ray diffraction, thermal analysis, FTIR, observations of isotropic chemical shifts of (1)H in distinct solvents, their temperature dependence and spin-lattice relaxation time constants (T1), solution (1D and 2D) (13)C nuclear magnetic resonance (NMR), and solid-state (13)C NMR (CPMAS NMR) provides valuable structural information and structural elucidation of micronized EFZ and heptane-recrystallized polymorphs (EFZ/HEPT). This study revealed that the micronization process did not affect the EFZ crystalline structure. It was observed that the structure of EFZ/HEPT is in the same form as that obtained from ethyl acetate/hexane, as shown in the literature. A comparison of the solid-state NMR spectra revealed discrepancies regarding the assignments of some carbons published in the literature that have been resolved.
    68. 68
      Price, S. L.; Reutzel-Edens, S. M. The Potential of Computed Crystal Energy Landscapes to Aid Solid-Form Development. Drug Discov. Today 2016, 21, 912– 923,  DOI: 10.1016/j.drudis.2016.01.014
      68
      The potential of computed crystal energy landscapes to aid solid-form development
      Price Sarah L; Reutzel-Edens Susan M
      Drug discovery today (2016), 21 (6), 912-23 ISSN:.
      Solid-form screening to identify all solid forms of an active pharmaceutical ingredient (API) has become increasingly important in ensuring the quality by design of pharmaceutical products and their manufacturing processes. However, despite considerable enlargement of the range of techniques that have been shown capable of producing novel solid forms, it is possible that practically important forms might not be found in the short timescales currently allowed for solid-form screening. Here, we report on the state-of-the-art use of computed crystal energy landscapes to complement pharmaceutical solid-form screening. We illustrate how crystal energy landscapes can help establish molecular-level understanding of the crystallization behavior of APIs and enhance the ability of solid-form screening to facilitate pharmaceutical development.
    69. 69
      Li, X.; Neumann, M. A.; van de Streek, J. The Application of Tailor-Made Force Fields and Molecular Dynamics for NMR Crystallography: A Case Study of Free Base Cocaine. IUCrJ 2017, 4, 175– 184,  DOI: 10.1107/s2052252517001415
      69
      The application of tailor-made force fields and molecular dynamics for NMR crystallography: a case study of free base cocaine
      Li, Xiaozhou; Neumann, Marcus A.; van de Streek, Jacco
      IUCrJ (2017), 4 (2), 175-184CODEN: IUCRAJ; ISSN:2052-2525. (International Union of Crystallography)
      Motional averaging has been proven to be significant in predicting the chem. shifts in ab initio solid-state NMR calcns., and the applicability of motional averaging with mol. dynamics has been shown to depend on the accuracy of the mol. mech. force field. The performance of a fully automatically generated tailor-made force field (TMFF) for the dynamic aspects of NMR crystallog. is evaluated and compared with existing benchmarks, including static dispersion-cor. d. functional theory calcns. and the COMPASS force field. The crystal structure of free base cocaine is used as an example. The results reveal that, even though the TMFF outperforms the COMPASS force field for representing the energies and conformations of predicted structures, it does not give significant improvement in the accuracy of NMR calcns. Further studies should direct more attention to anisotropic chem. shifts and development of the method of solid-state NMR calcns.
    70. 70
      Hartman, J. D.; Monaco, S.; Schatschneider, B.; Beran, G. J. O. Fragment-Based 13 C Nuclear Magnetic Resonance Chemical Shift Predictions in Molecular Crystals: An Alternative to Planewave Methods. J. Chem. Phys. 2015, 143, 102809,  DOI: 10.1063/1.4922649
      70
      Fragment-based 13C nuclear magnetic resonance chemical shift predictions in molecular crystals: An alternative to planewave methods
      Hartman, Joshua D.; Monaco, Stephen; Schatschneider, Bohdan; Beran, Gregory J. O.
      Journal of Chemical Physics (2015), 143 (10), 102809/1-102809/14CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
      The authors assess the quality of fragment-based ab initio isotropic 13C chem. shift predictions for a collection of 25 mol. crystals with eight different d. functionals. They explore the relative performance of cluster, two-body fragment, combined cluster/fragment, and the planewave gauge-including projector augmented wave (GIPAW) models relative to expt. When electrostatic embedding is employed to capture many-body polarization effects, the simple and computationally inexpensive two-body fragment model predicts both isotropic 13C chem. shifts and the chem. shielding tensors as well as both cluster models and the GIPAW approach. Unlike the GIPAW approach, hybrid d. functionals can be used readily in a fragment model, and all four hybrid functionals tested here (PBE0, B3LYP, B3PW91, and B97-2) predict chem. shifts in noticeably better agreement with expt. than the four generalized gradient approxn. (GGA) functionals considered (PBE, OPBE, BLYP, and BP86). A set of recommended linear regression parameters for mapping between calcd. chem. shieldings and obsd. chem. shifts are provided based on these benchmark calcns. Statistical cross-validation procedures are used to demonstrate the robustness of these fits. (c) 2015 American Institute of Physics.
    71. 71
      Baias, M.; Dumez, J.-N.; Svensson, P. H.; Schantz, S.; Day, G. M.; Emsley, L. De Novo Determination of the Crystal Structure of a Large Drug Molecule by Crystal Structure Prediction-Based Powder NMR Crystallography. J. Am. Chem. Soc. 2013, 135, 17501– 17507,  DOI: 10.1021/ja4088874
      71
      De Novo Determination of the Crystal Structure of a Large Drug Molecule by Crystal Structure Prediction-Based Powder NMR Crystallography
      Baias, Maria; Dumez, Jean-Nicolas; Svensson, Per H.; Schantz, Staffan; Day, Graeme M.; Emsley, Lyndon
      Journal of the American Chemical Society (2013), 135 (46), 17501-17507CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-benzoic acid is detd. using a protocol for NMR powder crystallog. at natural isotopic abundance combining solid-state 1H NMR spectroscopy, crystal structure prediction, and d. functional theory chem. shift calcns. This is the first example of NMR crystal structure detn. for a mol. compd. of previously unknown structure, and at 422 g/mol this is the largest compd. to which this method has been applied so far.
    72. 72
      Webber, A. L.; Emsley, L.; Claramunt, R. M.; Brown, S. P. NMR Crystallography of Campho[2,3-c]Pyrazole ( Z ′ = 6): Combining High-Resolution 1 H- 13 C Solid-State MAS NMR Spectroscopy and GIPAW Chemical-Shift Calculations. J. Phys. Chem. A 2010, 114, 10435– 10442,  DOI: 10.1021/jp104901j
      72
      NMR Crystallography of Campho[2,3-c]pyrazole (Z' = 6): Combining High-Resolution 1H-13C Solid-State MAS NMR Spectroscopy and GIPAW Chemical-Shift Calculations
      Webber, Amy L.; Emsley, Lyndon; Claramunt, Rosa M.; Brown, Steven P.
      Journal of Physical Chemistry A (2010), 114 (38), 10435-10442CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
      1H-13C two-dimensional magic-angle spinning (MAS) solid-state NMR correlation spectra, recorded with the MAS-J-HMQC expt., are presented for campho[2,3-c]pyrazole (I). For each 13C moiety, there are six resonances assocd. with the six distinct mols. in the asym. unit cell (Z' = 6). The one-bond C-H correlations obsd. in the 2D 1H-13C MAS-J-HMQC spectra allow the exptl. detn. of the 1H and 13C chem. shifts assocd. with the sep. CH, CH2, and CH3 groups. 1H and 13C chem. shifts calcd. by using the GIPAW (Gauge Including Projector Augmented Waves) plane-wave pseudopotential approach are presented. Calcns. for the whole unit cell (12 × 29 = 348 atoms, with geometry optimization of all atoms) allow the assignment of the exptl. 1H and 13C chem. shifts to the six distinct mols. The calcd. chem. shifts for the full crystal structure are compared with those for isolated mols. as extd. from the geometry-optimized crystal structure. In this way, the effect of intermol. interactions on the obsd. chem. shifts is quantified. In particular, the calcns. are sufficiently precise to differentiate the small (<1 ppm) differences between the 1H chem. shifts of the six resonances assocd. with each distinct CH or CH2 moiety.
    73. 73
      Sardo, M.; Santos, S. M.; Babaryk, A. A.; López, C.; Alkorta, I.; Elguero, J.; Claramunt, R. M.; Mafra, L. Diazole-Based Powdered Cocrystal Featuring a Helical Hydrogen-Bonded Network: Structure Determination from PXRD, Solid-State NMR and Computer Modeling. Solid State Nucl. Magn. Reson. 2015, 65, 49– 63,  DOI: 10.1016/j.ssnmr.2014.12.005
      73
      Diazole-based powdered cocrystal featuring a helical hydrogen-bonded network: Structure determination from PXRD, solid-state NMR and computer modeling
      Sardo, Mariana; Santos, Sergio M.; Babaryk, Artem A.; Lopez, Concepcion; Alkorta, Ibon; Elguero, Jose; Claramunt, Rosa M.; Mafra, Luis
      Solid State Nuclear Magnetic Resonance (2015), 65 (), 49-63CODEN: SSNRE4; ISSN:0926-2040. (Elsevier)
      The authors present the structure of a new equimolar 1:1 cocrystal formed by 3,5-dimethyl-1H-pyrazole (dmpz) and 4,5-dimethyl-1H-imidazole (dmim), detd. by means of powder X-ray diffraction data combined with solid-state NMR that provided insight into topol. details of hydrogen bonding connectivities and weak interactions such as C-H···π contacts. The use of various 1D/2D 13C, 15N and 1H high-resoln. solid-state NMR techniques provided structural insight on local length scales revealing internuclear proximities and relative orientations between the dmim and dmpz mol. building blocks of the studied cocrystal. Mol. modeling and DFT calcns. were also employed to generate meaningful structures. DFT refinement was able to decrease the figure of merit R(F2) from ∼11% (PXRD only) to 5.4%. An attempt was made to rationalize the role of N-H···N and C-H···π contacts in stabilizing the reported cocrystal. For this purpose four imidazole derivs. with distinct placement of Me substituents were reacted with dmpz to understand the effect of methylation in blocking or enabling certain intermol. contacts. Only one imidazole deriv. (dmim) was able to incorporate into the dmpz trimeric motif thus resulting in a cocrystal, which contains both hydrophobic (Me groups) and hydrophilic components that self-assemble to form an atypical 1D network of helicoidal hydrogen bonded pattern, featuring structural similarities with alpha-helix arrangements in proteins. The 1:1 dmpz···dmim compd. I is the first example of a cocrystal formed by two different azoles.
    74. 74
      Santos, S. M.; Rocha, J.; Mafra, L. NMR Crystallography: Toward Chemical Shift-Driven Crystal Structure Determination of the β-Lactam Antibiotic Amoxicillin Trihydrate. Cryst. Growth Des. 2013, 13, 2390– 2395,  DOI: 10.1021/cg4002785
      74
      NMR Crystallography: Toward Chemical Shift-Driven Crystal Structure Determination of the β-Lactam Antibiotic Amoxicillin Trihydrate
      Santos, Sergio M.; Rocha, Joao; Mafra, Luis
      Crystal Growth & Design (2013), 13 (6), 2390-2395CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      A new strategy for NMR crystallog. of multiple-component mol. crystals was reported in which 1H NMR chem. shifts entered directly in the structure generation step, governed by a genetic algorithm. Chem. shifts were also used in the structure-refinement step as pseudoforces acting on the models, leading to the lowest-energy structure. This methodol., which avoided the use of time-consuming ab initio chem. shift calcns., was successfully applied to powd. amoxicillin trihydrate, a widely used β-lactamic antibiotic.
    75. 75
      Pawlak, T.; Trzeciak-Karlikowska, K.; Czernek, J.; Ciesielski, W.; Potrzebowski, M. J. Computed and Experimental Chemical Shift Parameters for Rigid and Flexible YAF Peptides in the Solid State. J. Phys. Chem. B 2012, 116, 1974– 1983,  DOI: 10.1021/jp2111567
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      Computed and Experimental Chemical Shift Parameters for Rigid and Flexible YAF Peptides in the Solid State
      Pawlak, Tomasz; Trzeciak-Karlikowska, Katarzyna; Czernek, Jiri; Ciesielski, Wlodzimierz; Potrzebowski, Marek J.
      Journal of Physical Chemistry B (2012), 116 (6), 1974-1983CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      DFT methods were employed to compute the 13C NMR chem. shift tensor (CST) parameters for crystals of YAF (Tyr-Ala-Phe) peptides with different stereochem. for the Ala residue. Tyr-D-Ala-Phe (1) crystallizes in the C2 space group while Tyr-L-Ala-Phe crystallizes in either the P21212 space group (2a) or the P65 space group (2b). PISEMA MAS measurements for samples with a natural abundance of 1H and 13C nuclei and 2H QUADECHO expts. for samples with deuterium labeled arom. rings were used to analyze the geometry and time scale of the mol. motion. At ambient temp., the tyrosine ring of sample 1 is rigid and the phenylalanine ring undergoes a π-jump, both rings in sample 2a are static, and both rings in sample 2b undergo a fast regime exchange. The theor. values of the CST were obtained for isolated mols. (IM) and clusters employing the ONIOM approach. The exptl. 13C δii parameters for all of the samples were measured via a 2D PASS sequence. Significant scatter of the computed vs. the exptl. 13C CST parameters was obsd. for 1 and 2b, while the obsd. correlation was very good for 2a. In this report, we show that the quality of the 13C σii/13C δii correlations, when properly interpreted, can be a source of important information about local mol. motions.
    76. 76
      Jaworska, M.; Pawlak, T.; Kruszyński, R.; Ćwiklińska, M.; Krzemiński, M. NMR Crystallography Comparative Studies of Chiral (1 R ,2 S ,3 R ,5 R )-3-Amino-6,6-Dimethylbicyclo[3.1.1]Heptan-2-Ol and Its p -Toluenesulfonamide Derivative. Cryst. Growth Des. 2012, 12, 5956– 5965,  DOI: 10.1021/cg300940k
      76
      NMR Crystallography Comparative Studies of Chiral (1R,2S,3R,5R)-3-Amino-6,6-dimethylbicyclo[3.1.1]heptan-2-ol and Its p-Toluenesulfonamide Derivative
      Jaworska, Magdalena; Pawlak, Tomasz; Kruszynski, Rafal; Cwiklinska, Marta; Krzeminski, Marek
      Crystal Growth & Design (2012), 12 (12), 5956-5965CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      The crystal structure of (1R,2S,3R,5R)-3-amino-6,6-dimethyl-2-hydroxybicyclo[3.1.1]heptane 1 was detd. and it is presented in ref. to the structure of (1R,2S,3R,5R)-3-(p-tosylamino)-6,6-dimethyl-2-hydroxybicyclo[3.1.1]heptane 2. 1H and 13C chem. shifts parameters for both structures and for whole unit cells were calcd. by using the GIPAW (gauge including projector augmented waves) method. Theor. calcd. chem. shift tensor parameters were verified by 13C CP MAS, 2-dimensional PASS, and 13C-1H FSLG HETCOR results to obtain a full structural assignment for 13C and 1H resonances in the solid-state. PISEMA MAS expt. was performed to det. the mol. dynamics of aminoalc. 1. The comparison of two structures, obtained after all-atom positions optimization after the GIPAW calcns., revealed small conformational differences consistent with the single-crystal x-ray diffraction results.
    77. 77
      Watts, A. E.; Maruyoshi, K.; Hughes, C. E.; Brown, S. P.; Harris, K. D. M. Combining the Advantages of Powder X-Ray Diffraction and NMR Crystallography in Structure Determination of the Pharmaceutical Material Cimetidine Hydrochloride. Cryst. Growth Des. 2016, 16, 1798– 1804,  DOI: 10.1021/acs.cgd.6b00016
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      Combining the Advantages of Powder X-ray Diffraction and NMR Crystallography in Structure Determination of the Pharmaceutical Material Cimetidine Hydrochloride
      Watts, Abigail E.; Maruyoshi, Keisuke; Hughes, Colan E.; Brown, Steven P.; Harris, Kenneth D. M.
      Crystal Growth & Design (2016), 16 (4), 1798-1804CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      The crystal structure is reported of the anhyd. phase of cimetidine hydrochloride, detd. directly from powder x-ray diffraction data. The material was prepd. by dehydration of the readily obtained monohydrate form of cimetidine hydrochloride, the only form for which a crystal structure was previously reported. As such, solid-state dehydration processes typically yield the product phase as a microcryst. powder, and structure detn. was carried out directly from powder x-ray diffraction data, using the direct-space genetic algorithm technique for structure soln. followed by Rietveld refinement. The structure detd. from powder x-ray diffraction was further validated by calcg. solid-state 13C NMR data for the crystal structure (using 1st-principles periodic DFT techniques within the GIPAW approach) and assessing the quality of agreement with the corresponding exptl. solid-state 13C CPMAS NMR data. This strategy provides a robust vindication of the correctness of the crystal structure by assessing the quality of agreement of the structure both with exptl. powder x-ray diffraction data and with exptl. solid-state 13C NMR data.
    78. 78
      Nilsson Lill, S. O.; Widdifield, C. M.; Pettersen, A.; Svensk Ankarberg, A.; Lindkvist, M.; Aldred, P.; Gracin, S.; Shankland, N.; Shankland, K.; Schantz, S.; Emsley, L. Elucidating an Amorphous Form Stabilization Mechanism for Tenapanor Hydrochloride: Crystal Structure Analysis Using X-Ray Diffraction, NMR Crystallography, and Molecular Modeling. Mol. Pharm. 2018, 15, 1476– 1487,  DOI: 10.1021/acs.molpharmaceut.7b01047
      78
      Elucidating an amorphous form stabilization mechanism for tenapanor hydrochloride: Crystal structure analysis using X-ray diffraction, NMR Crystallography, and Molecular Modeling
      Nilsson Lill, Sten O.; Widdifield, Cory M.; Pettersen, Anna; Svensk Ankarberg, Anna; Lindkvist, Maria; Aldred, Peter; Gracin, Sandra; Shankland, Norman; Shankland, Kenneth; Schantz, Staffan; Emsley, Lyndon
      Molecular Pharmaceutics (2018), 15 (4), 1476-1487CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      By the combined use of powder and single-crystal X-ray diffraction, solid-state NMR, and mol. modeling, the crystal structures of two systems contg. the unusually large tenapanor drug mol. have been detd.: the free form, ANHY, and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallog. investigations were found essential for the final assignment and were used to validate the crystal structure of ANHY. From a structural informatics anal. of ANHY and 2HCl, conformational ring differences in one part of the mol. were obsd. which influence the relative orientation of a Me group on a ring nitrogen and thereby impact the crystallizability of the dihydrochloride salt. From quantum chem. calcns., the dynamics between different ring conformations in tenapanor is predicted to be fast. Addn. of HCl to tenapanor results in general in a mixt. of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qual. verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amt. of the cryst. material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between the minor and major conformations of ANHY in soln. Thus, by controlling the soln. pH value to well below the pKa of ANHY, the equil. between ANHY and 2HCl can be controlled and by this mechanism the crystn. of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized.
    79. 79
      Leclaire, J.; Poisson, G.; Ziarelli, F.; Pepe, G.; Fotiadu, F.; Paruzzo, F. M.; Rossini, A. J.; Dumez, J.-N.; Elena-Herrmann, B.; Emsley, L. Structure Elucidation of a Complex CO2-Based Organic Framework Material by NMR Crystallography. Chem. Sci. 2016, 7, 4379– 4390,  DOI: 10.1039/c5sc03810c
      79
      Structure elucidation of a complex CO2-based organic framework material by NMR crystallography
      Leclaire, Julien; Poisson, Guillaume; Ziarelli, Fabio; Pepe, Gerard; Fotiadu, Frederic; Paruzzo, Federico M.; Rossini, Aaron J.; Dumez, Jean-Nicolas; Elena-Herrmann, Benedicte; Emsley, Lyndon
      Chemical Science (2016), 7 (7), 4379-4390CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      A three-dimensional structural model of a complex CO2-based org. framework made from high mol. wt., self-assembled, flexible and multi-functional oligomeric constituents has been detd. de novo by solid-state NMR including DNP-enhanced expts. The complete assignment of the 15N, 13C and 1H resonances was obtained from a series of two-dimensional through space and through bond correlation expts. MM-QM calcns. were used to generate different model structures for the material which were then evaluated by comparing multiple exptl. and calcd. NMR parameters. Both NMR and powder X-ray diffraction were evaluated as tools to det. the packing by crystal modeling, and at the level of structural modeling used here PXRD was found not to be a useful complement. The structure detd. reveals a highly optimized H-bonding network that explains the unusual selectivity of the self-assembly process which generates the material. The NMR crystallog. approach used here should be applicable for the structure detn. of other complex solid materials.
    80. 80
      Dudenko, D. V.; Williams, P. A.; Hughes, C. E.; Antzutkin, O. N.; Velaga, S. P.; Brown, S. P.; Harris, K. D. M. Exploiting the Synergy of Powder X-Ray Diffraction and Solid-State NMR Spectroscopy in Structure Determination of Organic Molecular Solids. J. Phys. Chem. C 2013, 117, 12258– 12265,  DOI: 10.1021/jp4041106
      80
      Exploiting the Synergy of Powder X-ray Diffraction and Solid-State NMR Spectroscopy in Structure Determination of Organic Molecular Solids
      Dudenko, Dmytro V.; Williams, P. Andrew; Hughes, Colan E.; Antzutkin, Oleg N.; Velaga, Sitaram P.; Brown, Steven P.; Harris, Kenneth D. M.
      Journal of Physical Chemistry C (2013), 117 (23), 12258-12265CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      The authors report a strategy for structure detn. of org. materials in which complete solid-state NMR spectral data was used within the context of structure detn. from powder XRD data. Following detn. of the crystal structure from powder XRD data, first-principles d. functional theory-based techniques within the GIPAW approach are exploited to calc. the solid-state NMR data for the structure, followed by careful scrutiny of the agreement with exptl. solid-state NMR data. The successful application of this approach is demonstrated by structure detn. of the 1:1 cocrystal of indomethacin and nicotinamide. The 1H and 13C chem. shifts calcd. for the crystal structure detd. from the powder XRD data are in excellent agreement with those measured exptl., notably including the two-dimensional correlation of 1H and 13C chem. shifts for directly bonded 13C-1H moieties. The key feature of this combined approach is that the quality of the structure detd. is assessed both against exptl. powder XRD data and against exptl. solid-state NMR data, thus providing a very robust validation of the veracity of the structure.
    81. 81
      Be̅rziņš, A.; Hodgkinson, P. Solid-State NMR and Computational Investigation of Solvent Molecule Arrangement and Dynamics in Isostructural Solvates of Droperidol. Solid State Nucl. Magn. Reson. 2015, 65, 12– 20,  DOI: 10.1016/j.ssnmr.2014.09.001
      81
      Solid-state NMR and computational investigation of solvent molecule arrangement and dynamics in isostructural solvates of droperidol
      Berzins, Agris; Hodgkinson, Paul
      Solid State Nuclear Magnetic Resonance (2015), 65 (), 12-20CODEN: SSNRE4; ISSN:0926-2040. (Elsevier)
      13C, 15N and 2H solid-state NMR spectroscopy were used to rationalize arrangement and dynamics of solvent mols. in a set of isostructural solvates of droperidol. The solvent mols. are dynamically disordered in the methanol and ethanol solvates, while they are ordered in the acetonitrile and nitromethane solvates. 2H NMR spectra of deuterium-labeled samples allowed the characterization of the solvent mol. dynamics in the alc. solvates and the nonstoichiometric hydrate. The likely motion of the alc. mols. is rapid libration within a site, plus occasional exchange into an equiv. site related by the inversion symmetry, while the water mols. are more strongly disordered. DFT calcns. strongly suggest that the differences in dynamics between the solvates are related to differences in the energetic penalty for reversing the orientation of a solvent mol.
    82. 82
      Pinon, A. C.; Rossini, A. J.; Widdifield, C. M.; Gajan, D.; Emsley, L. Polymorphs of Theophylline Characterized by DNP Enhanced Solid-State NMR. Mol. Pharm. 2015, 12, 4146– 4153,  DOI: 10.1021/acs.molpharmaceut.5b00610
      82
      Polymorphs of Theophylline Characterized by DNP Enhanced Solid-State NMR
      Pinon, Arthur C.; Rossini, Aaron J.; Widdifield, Cory M.; Gajan, David; Emsley, Lyndon
      Molecular Pharmaceutics (2015), 12 (11), 4146-4153CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      We show how dynamic nuclear polarization (DNP) enhanced solid-state NMR spectroscopy can be used to characterize polymorphs and solvates of org. solids. We applied DNP to three polymorphs and one hydrated form of the asthma drug mol. theophylline. For some forms of theophylline, sample grinding and impregnation with the radical-contg. soln., which are necessary to prep. the samples for DNP, were found to induce polymorphic transitions or desolvation between some forms. We present protocols for sample prepn. for solid-state magic-angle spinning (MAS) DNP expts. that avoid the polymorphic phase transitions in theophylline. These protocols include cryogrinding, grinding under inert atm., and the appropriate choice of the impregnating liq. By applying these procedures, we subsequently demonstrate that two-dimensional correlation expts., such as 1H-13C and 1H-15N HETCOR or 13C-13C INADEQUATE, can be obtained at natural isotopic abundance in reasonable times, thus enabling more advanced structural characterization of polymorphs.
    83. 83
      Pawlak, T.; Potrzebowski, M. J. Fine Refinement of Solid-State Molecular Structures of Leu- and Met-Enkephalins by NMR Crystallography. J. Phys. Chem. B 2014, 118, 3298– 3309,  DOI: 10.1021/jp500379e
      83
      Fine refinement of solid-state mol. structures of Leu- and Met-Enkephalins by NMR crystallog.
      Pawlak, Tomasz; Potrzebowski, Marek J.
      Journal of Physical Chemistry B (2014), 118 (12), 3298-3309CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      This paper presents a methodol. that allows the fine refinement of the crystal and mol. structure for compds. for which the data deposited in the crystallog. bases are of poor quality. Such species belong to the group of samples with mol. disorder. In the Cambridge Crystallog. Data Center (CCDC), there are approx. 22 000 deposited structures with an R-factor over 10. The powerful methodol. we present employs crystal data for Leu-enkephalin (two crystallog. forms) with R-factor values of 14.0 and 8.9 and for Met-enkephalin (one form) with an R-factor of 10.5. NMR crystallog. was employed in testing the X-ray data and the quality of the structure refinement. The GIPAW (gauge invariant projector augmented wave) method was used to optimize the coordinates of the enkephalins and to compute NMR parameters. As we reveal, this complementary approach makes it possible to generate a reasonable set of new coordinates that better correlate to real samples. This methodol. is general and can be employed in the study of each compd. possessing magnetically active nuclei.
    84. 84
      Kerr, H. E.; Mason, H. E.; Sparkes, H. A.; Hodgkinson, P. Testing the Limits of NMR Crystallography: The Case of Caffeine–Citric Acid Hydrate. CrystEngComm 2016, 18, 6700– 6707,  DOI: 10.1039/c6ce01453d
      84
      Testing the limits of NMR crystallography: the case of caffeine-citric acid hydrate
      Kerr, Hannah E.; Mason, Helen E.; Sparkes, Hazel A.; Hodgkinson, Paul
      CrystEngComm (2016), 18 (35), 6700-6707CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
      The crystal structure of a new 1 : 2 caffeine-citric acid hydrate cocrystal is presented. The caffeine mols. are disordered over two positions, with the nature of the disorder confirmed to be static by 13C solid-state NMR. NMR linewidths in statically disordered systems reflect the distribution of local chem. environments, and this study investigates whether the disorder contribution to 13C linewidths can be predicted computationally. The limits of NMR crystallog. calcns. using d. functional theory are tested by investigating how geometry optimization conditions affect calcd. NMR parameters. Careful optimization is shown to reduce differences between 13C consts. of symmetry-related sites to about 0.1 ppm. This is just sufficient to observe a correlation between calcd. and exptl. linewidths, and also show that systematic errors assocd. with geometry optimization do not compromise other applications of "NMR crystallog.". In addn., the unit cell enthalpies calcd. after careful optimizations provide insight into why the disordered structure is adopted.
    85. 85
      Dudenko, D. V.; Yates, J. R.; Harris, K. D. M.; Brown, S. P. An NMR Crystallography DFT-D Approach to Analyse the Role of Intermolecular Hydrogen Bonding and π–π Interactions in Driving Cocrystallisation of Indomethacin and Nicotinamide. CrystEngComm 2013, 15, 8797,  DOI: 10.1039/c3ce41240g
      85
      An NMR crystallography DFT-D approach to analyze the role of intermolecular hydrogen bonding and π-π interactions in driving cocrystallization of indomethacin and nicotinamide
      Dudenko, Dmytro V.; Yates, Jonathan R.; Harris, Kenneth D. M.; Brown, Steven P.
      CrystEngComm (2013), 15 (43), 8797-8807CODEN: CRECF4; ISSN:1466-8033. (Royal Society of Chemistry)
      D. functional theory (DFT) calcns. using the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional are presented for a 1 : 1 cocrystal formed by indomethacin and nicotinamide (IND-NIC) as well as for crystal structures of the individual components. DFT-D approaches which correct the DFT energy for dispersion effects, specifically the Grimme (G06) and Tkatchenko-Scheffler (TS) schemes, are investigated: for geometry optimization starting with crystal structures detd. exptl. by diffraction and allowing the at. positions and the unit cell to vary, closest agreement with the exptl. unit cell parameters is achieved with the PBE-TS approach (calcd. vols. are less than 4% smaller than in expt.). Calcns. of solid-state NMR chem. shifts using the GIPAW (gauge including projector augmented wave) approach are presented. Closest agreement between NMR chem. shifts calcd. with variable and fixed (exptl.) unit cell parameters is also obsd. for the PBE-TS approach: the root mean squared std. deviation difference is 0.15 ppm (1H) and 0.29 ppm (13C) for PBE-TS, as compared to 0.45 ppm (1H) and 0.68 ppm (13C) with std. PBE. Differences in 1H chem. shifts calcd. for the full periodic crystal structure and for isolated mols. extd. from the geometry-optimized crystal structure are presented in conjunction with NICS (nucleus independent chem. shift) maps, so as to sep. quantify intermol. hydrogen bonding and π-π interactions. This anal. is complemented by total energy calcns., including also at the B97D/6-311+G* level of theory with basis set superposition error correction, in order to understand the interactions that drive cocrystn.
    86. 86
      Tatton, A. S.; Blade, H.; Brown, S. P.; Hodgkinson, P.; Hughes, L. P.; Lill, S. O. N.; Yates, J. R. Improving Confidence in Crystal Structure Solutions Using NMR Crystallography: The Case of β-Piroxicam. Cryst. Growth Des. 2018, 18, 3339– 3351,  DOI: 10.1021/acs.cgd.8b00022
      86
      Improving Confidence in Crystal Structure Solutions Using NMR Crystallography: The Case of β-Piroxicam
      Tatton, Andrew S.; Blade, Helen; Brown, Steven P.; Hodgkinson, Paul; Hughes, Leslie P.; Lill, Sten O. Nilsson; Yates, Jonathan R.
      Crystal Growth & Design (2018), 18 (6), 3339-3351CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      NMR crystallog. techniques are used to validate a structure of β-piroxicam detd. from powder X-ray diffraction (PXRD) with a relatively poor R-factor. Geometry optimization of PXRD- and single-crystal XRD- derived structures results in convergence to the same energy of the structures, with minimal at. displacements, and good agreement of gauge-included projector augmented wave (GIPAW) calcd. and exptl. detd. NMR 1H, 13C, and 15N chem. shifts, and 14N quadrupolar parameters. Calcns. on isolated mols. combined with 2D magic-angle spinning (MAS) 1H double-quantum (DQ) and 14N-1H NMR expts. confirm the 3D packing arrangement of β-piroxicam. NMR crystallog. is shown to be an effective means of validating crystal structures that might otherwise be considered sceptically on the basis of diffraction data alone.
    87. 87
      Paruzzo, F. M.; Hofstetter, A.; Musil, F.; De, S.; Ceriotti, M.; Emsley, L. Chemical Shifts in Molecular Solids by Machine Learning. Nat. Commun. 2018, 9, 4501,  DOI: 10.1038/s41467-018-06972-x
      87
      Chemical shifts in molecular solids by machine learning
      Paruzzo Federico M; Hofstetter Albert; Emsley Lyndon; Musil Felix; De Sandip; Ceriotti Michele
      Nature communications (2018), 9 (1), 4501 ISSN:.
      Due to their strong dependence on local atonic environments, NMR chemical shifts are among the most powerful tools for strucutre elucidation of powdered solids or amorphous materials. Unfortunately, using them for structure determination depends on the ability to calculate them, which comes at the cost of high accuracy first-principles calculations. Machine learning has recently emerged as a way to overcome the need for quantum chemical calculations, but for chemical shifts in solids it is hindered by the chemical and combinatorial space spanned by molecular solids, the strong dependency of chemical shifts on their environment, and the lack of an experimental database of shifts. We propose a machine learning method based on local environments to accurately predict chemical shifts of molecular solids and their polymorphs to within DFT accuracy. We also demonstrate that the trained model is able to determine, based on the match between experimentally measured and ML-predicted shifts, the structures of cocaine and the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butylpyrazol-1-yl]benzoic acid.
    88. 88
      https://www.drugfuture.com/chemdata/safinamide.html (accessed Aug 04, 2021).
      There is no corresponding record for this reference.
    89. 89
      Saeed, R. M. R.; Schlegel, J. P.; Castano, C. H.; Sawafta, R. I. Uncertainty of Thermal Characterization of Phase Change Material by Differential Scanning Calorimetry Analysis. Int. J. Eng. Res. Technol. 2016, 5, 405
      There is no corresponding record for this reference.
    90. 90
      Krushelnitsky, A.; Reichert, D. Solid-State NMR and Protein Dynamics. Prog. Nucl. Magn. Reson. Spectrosc. 2005, 47, 1– 25,  DOI: 10.1016/j.pnmrs.2005.04.001
      90
      Solid-state NMR and protein dynamics
      Krushelnitsky, Alexey; Reichert, Detlef
      Progress in Nuclear Magnetic Resonance Spectroscopy (2005), 47 (1-2), 1-25CODEN: PNMRAT; ISSN:0079-6565. (Elsevier B.V.)
      A review.
    91. 91
      Schanda, P.; Ernst, M. Studying Dynamics by Magic-Angle Spinning Solid-State NMR Spectroscopy: Principles and Applications to Biomolecules. Prog. Nucl. Magn. Reson. Spectrosc. 2016, 96, 1– 46,  DOI: 10.1016/j.pnmrs.2016.02.001
      91
      Studying dynamics by magic-angle spinning solid-state NMR spectroscopy: Principles and applications to biomolecules
      Schanda, Paul; Ernst, Matthias
      Progress in Nuclear Magnetic Resonance Spectroscopy (2016), 96 (), 1-46CODEN: PNMRAT; ISSN:0079-6565. (Elsevier B.V.)
      Magic-angle spinning solid-state NMR spectroscopy is an important technique to study mol. structure, dynamics and interactions, and is rapidly gaining importance in biomol. sciences. Here we provide an overview of exptl. approaches to study mol. dynamics by MAS solid-state NMR, with an emphasis on the underlying theor. concepts and differences of MAS solid-state NMR compared to soln.-state NMR. The theor. foundations of nuclear spin relaxation are revisited, focusing on the particularities of spin relaxation in solid samples under magic-angle spinning. We discuss the range of validity of Redfield theory, as well as the inherent multi-exponential behavior of relaxation in solids. Exptl. challenges for measuring relaxation parameters in MAS solid-state NMR and a few recently proposed relaxation approaches are discussed, which provide information about time scales and amplitudes of motions ranging from picoseconds to milliseconds. We also discuss the theor. basis and exptl. measurements of anisotropic interactions (chem.-shift anisotropies, dipolar and quadrupolar couplings), which give direct information about the amplitude of motions. The potential of combining relaxation data with such measurements of dynamically-averaged anisotropic interactions is discussed. Although the focus of this review is on the theor. foundations of dynamics studies rather than their application, we close by discussing a small no. of recent dynamics studies, where the dynamic properties of proteins in crystals are compared to those in soln.
    92. 92
      Fu, R.; Tian, C.; Kim, H.; Smith, S. A.; Cross, T. A. The Effect of Hartmann–Hahn Mismatching on Polarization Inversion Spin Exchange at the Magic Angle. J. Magn. Reson. 2002, 159, 167– 174,  DOI: 10.1016/s1090-7807(02)00036-8
      92
      The effect of Hartmann-Hahn mismatching on polarization inversion spin exchange at the magic angle
      Fu, Riqiang; Tian, Changlin; Kim, Hyeongnam; Smith, Scott A.; Cross, Timothy A.
      Journal of Magnetic Resonance (2002), 159 (2), 167-174CODEN: JMARF3; ISSN:1090-7807. (Elsevier Science)
      The effect of the Hartmann-Hahn mismatch Δ=ωeff-ω1S during polarization inversion spin exchange at the magic angle (PISEMA) was studied, where ωeff and ω1S represent the amplitudes of the 1H effective spin-locking field at the magic angle and the 15N RF spin-locking field, resp. During the PISEMA evolution period, the exact Hartmann-Hahn match condition (i.e., Δ=0) yields a max. dipolar scaling factor of 0.816 for PISEMA expts., while any mismatch results in two different effective fields for the 1st and 2nd half of each frequency switched Lee-Goldburg (FSLG) cycle. The mismatch effect on the scaling factor depends strongly on the transition angle from one effective field to the other within each FSLG cycle as well as on the cycle time. At low RF spin-lock amplitudes in which the FSLG cycle time is relatively long, the scaling factor rapidly becomes smaller as ω1S becomes greater than ωeff. However, when ω1S<ωeff, there is relatively little effect on the scaling factor with variation in Δ. As a result, the presence of RF inhomogeneities may significantly broaden the line-width in the dipolar dimension because of the mismatch effect. Higher RF spin-lock amplitudes result in a relatively small variation for the scaling factor. Also, ramped amplitude of the 15N RF spin-lock field in synchronization with the flip-flop of the FSLG sequence minimizes the transition angle between the two effective fields within the FSLG cycle. It is shown exptl. that such a ramped amplitude not only gives rise to the same scaling factor but also results in a narrower dipolar line-width in comparison with the rectangular amplitude.
    93. 93
      Hong, M.; Yao, X.; Jakes, K.; Huster, D. Investigation of Molecular Motions by Lee-Goldburg Cross-Polarization NMR Spectroscopy. J. Phys. Chem. B 2002, 106, 7355– 7364,  DOI: 10.1021/jp0156064
      93
      Investigation of molecular motions by Lee-Goldburg cross-polarization NMR spectroscopy
      Hong, Mei; Yao, Xiaolan; Jakes, Karen; Huster, Daniel
      Journal of Physical Chemistry B (2002), 106 (29), 7355-7364CODEN: JPCBFK; ISSN:1089-5647. (American Chemical Society)
      We demonstrate the use of Lee-Goldburg cross-polarization (LG-CP) NMR under fast magic-angle spinning (MAS) to investigate the amplitude and geometry of segmental motions in biomol. and polymeric solids. Motional geometry information was previously available only from 2H NMR, which, however, has limited site resoln. and requires site-specific isotopic labeling. Using a 2D LG-CP technique, we resolve the 13C-1H or 15N-1H dipolar couplings according to the 13C or 15N isotropic chem. shift. Applications to systems undergoing 180° phenylene ring flips show spectral line shapes reflecting the geometry of the motion. Using this LG-CP technique, we measured the 13C-1H and 15N-1H dipolar couplings in the water-sol. and membrane-bound states of the colicin Ia channel domain. The backbone motions of the membrane-bound colicin scale both the Cα-Hα and N-H couplings similarly, thus ruling out rotation of the α-helixes around their axes as a specific mechanism of motion. We also show that the sensitivity of the LG-CP spectra can be enhanced by the addn. of a phase-inverted 1H-13C cross-polarization step, and the site resoln. of the 15N-1H LG-CP spectra can be enhanced by 13C indirect detection.
    94. 94
      Lorieau, J.; McDermott, A. E. Order Parameters Based On 13C1H, 13C1H2 and 13C1H3 Heteronuclear Dipolar Powder Patterns: A Comparison of MAS-Based Solid-State NMR Sequences. Magn. Reson. Chem. 2006, 44, 334– 347,  DOI: 10.1002/mrc.1773
      94
      Order parameters based on 13C1H, 13C1H2 and 13C1H3 heteronuclear dipolar powder patterns: a comparison of MAS-based solid-state NMR sequences
      Lorieau, Justin; McDermott, Ann E.
      Magnetic Resonance in Chemistry (2006), 44 (3), 334-347CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      Order parameters describing conformational exchange processes on the nanosecond to microsecond timescale can be obtained from powder patterns in solid-state NMR (SSNMR) expts. Extensions of these expts. to magic-angle spinning (MAS) based high-resoln. expts. were demonstrated, which show a great promise for site-specific probes of biopolymers. The authors present a detailed comparison of two pulse sequences, transverse Manfield-Rhim-Elleman-Vaughn (T-MREV) and Lee-Goldburg cross-polarization (LGCP), using exptl. and simulation tools to explore their utility in the study of order parameters. The authors discuss systematic errors due to passively coupled 13C or 1H nuclei, as well as due to B1 inhomogeneity. Both pulse sequences can provide quant. measurements of the order parameter, but the LGCP expt. is capable of greater accuracy provided that the B1 field is highly homogeneous. The T-MREV expt. is far better compensated for B1 inhomogeneity, and it also performs better in situations with limited signal.
    95. 95
      Achilles, A.; Bärenwald, R.; Lechner, B.-D.; Werner, S.; Ebert, H.; Tschierske, C.; Blume, A.; Bacia, K.; Saalwächter, K. Self-Assembly of X-Shaped Bolapolyphiles in Lipid Membranes: Solid-State NMR Investigations. Langmuir 2016, 32, 673– 682,  DOI: 10.1021/acs.langmuir.5b03712
      95
      Self-Assembly of X-Shaped Bolapolyphiles in Lipid Membranes: Solid-State NMR Investigations
      Achilles, Anja; Baerenwald, Ruth; Lechner, Bob-Dan; Werner, Stefan; Ebert, Helgard; Tschierske, Carsten; Blume, Alfred; Bacia, Kirsten; Saalwaechter, Kay
      Langmuir (2016), 32 (3), 673-682CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      A novel class of rigid-rod bolapolyphilic mols. with three philicities (rigid arom. core, mobile aliph. side chains, polar end groups) has recently been demonstrated to incorporate into and span lipid membranes, and to exhibit a rich variety of self-organization modes, including macroscopically ordered snowflake structures with 6-fold symmetry. In order to support a structural model and to better understand the self-organization on a mol. scale, we here report on proton and carbon-13 high-resoln. magic-angle spinning solid-state NMR investigations of two different bolapolyphiles (BPs) in model membranes of two different phospholipids (DPPC, DOPC). We elucidate the changes in mol. dynamics assocd. with three new phase transitions detected by calorimetry in composite membranes of different compn., namely, a change in π-π-packing, the melting of lipid tails assocd. with the superstructure, and the dissoln. and onset of free rotation of the BPs. We derive dynamic order parameters assocd. with different H-H and C-H bond directions of the BPs, demonstrating that the arom. cores are well packed below the final phase transition, showing only 180° flips of the Ph ring, and that they perform free rotations with addnl. oscillations of the long axis when dissolved in the fluid membrane. Our data suggests that BPs not only form ordered superstructures, but also rather homogeneously dispersed π-packed filaments within the lipid gel phase, thus reducing the corrugation of large vesicles.
    96. 96
      Pawlak, T.; Czajkowska-Szczykowska, D.; Jastrzebska, I.; Santillan, R.; Seroka, B.; Maj, J.; Morzycki, J. W.; Labra-Vázquez, P.; Farfán, N.; Bujacz, G. D.; Potrzebowski, M. J. Influence of Hydrogen/Fluorine Substitution on Structure, Thermal Phase Transitions, and Internal Molecular Motion of Aromatic Residues in the Crystal Lattice of Steroidal Rotors. Cryst. Growth Des. 2020, 20, 2202– 2216,  DOI: 10.1021/acs.cgd.9b01179
      96
      Influence of Hydrogen/Fluorine Substitution on Structure, Thermal Phase Transitions, and Internal Molecular Motion of Aromatic Residues in the Crystal Lattice of Steroidal Rotors
      Pawlak, Tomasz; Czajkowska-Szczykowska, Dorota; Jastrzebska, Izabella; Santillan, Rosa; Seroka, Barbara; Maj, Jadwiga; Morzycki, Jacek W.; Labra-Vazquez, Pablo; Farfan, Norberto; Bujacz, Grzegorz D.; Potrzebowski, Marek J.
      Crystal Growth & Design (2020), 20 (4), 2202-2216CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Two, acyclic (1) and cyclic (2), steroidal mol. rotors contg. 1,4-diethynyl-2,3-difluoro-phenylene units as rotators were investigated by means of single crystal X-ray diffraction, high resoln. solid state NMR spectroscopy, and computer methods. The aim of this study was to understand and search for a correlation between the size of difluoro-phenylene units and free space in the crystal lattice required for mol. reorientation as well as the topol. and time scale of dynamic processes. As a primary tool for anal. of mol. motions in the solid state, 1H-13C PISEMA, a technique which allows following the dynamics in the range of 10-3-10-6 s, was employed. The PISEMA data defining the 1H-13C dipolar couplings, whose values are sensitive to local motion, were confronted with 13C CSA parameters. Our studies revealed that replacing hydrogen by fluorine in acyclic rotors has significant consequences for dynamic processes. In the case of hydrogen-substituted species, free rotation around the 1-4 axis of the benzene ring was proven. For fluorine derivs. 1, only small amplitude wobbling of arom. residues was obsd. The only large amplitude reorientation, a so-called π-jump around the 1-4 axis, was obsd. during the phase transition related with solvent migration from the crystal lattice. For cyclic rotors (2) two crystallog. forms 2A (triclinic, P1 space group) and 2B (monoclinic, P21 space group) are established. The form 2B contg. a heptane mol. in the crystal lattice undergoes a thermal transition with large amplitude motion of building units of the steroidal frame. The high dynamics of the fluorinated rotator for 2A is proven. Two, acyclic and cyclic, mol. rotors contg. 1,4-diethynyl-2,3-difluoro-phenylene units as rotators were investigated by means of single crystal X-ray diffraction, high resoln. solid state NMR spectroscopy, and computer methods. Our studies revealed that replacing hydrogen by fluorine in acyclic rotors has significant consequences for dynamic processes. The fast rotation of a fluorinated rotator for one of the crystallog. forms of a cyclic steroidal compd. is proven.
    97. 97
      Pawlak, T.; Sudgen, I.; Bujacz, G.; Iuga, D.; Brown, S. P.; Potrzebowski, M. J. Synergy of Solid-State NMR, Single-Crystal X-Ray Diffraction, and Crystal Structure Prediction Methods: A Case Study of Teriflunomide (TFM). Cryst. Growth Des. 2021, 21, 3328,  DOI: 10.1021/acs.cgd.1c00123
      97
      Synergy of Solid-State NMR, Single-Crystal X-ray Diffraction, and Crystal Structure Prediction Methods: A Case Study of Teriflunomide (TFM)
      Pawlak, Tomasz; Sudgen, Isaac; Bujacz, Grzegorz; Iuga, Dinu; Brown, Steven P.; Potrzebowski, Marek J.
      Crystal Growth & Design (2021), 21 (6), 3328-3343CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      In this work, for the first time, we present the X-ray diffraction crystal structure and spectral properties of a new, room-temp. polymorph of teriflunomide (TFM), CSD code 1969989. As revealed by DSC, the low-temp. TFM polymorph recently reported by Gunnam et al. undergoes a reversible thermal transition at -40°C. This reversible process is related to a change in Z' value, from 2 to 1, as obsd. by variable-temp. 1H-13C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR, while the crystallog. system is preserved (triclinic). Two-dimensional 13C-1H and 1H-1H double-quantum MAS NMR spectra are consistent with the new room-temp. structure, including comparison with GIPAW (gauge-including projector augmented waves) calcd. NMR chem. shifts. A crystal structure prediction procedure found both exptl. teriflunomide polymorphs in the energetic global min. region. Differences between the polymorphs are seen for the torsional angle describing the orientation of the Ph ring relative to the planarity of the TFM mol. In the low-temp. structure, there are two torsion angles of 4.5 and 31.9° for the two Z' = 2 mols., while in the room-temp. structure, there is disorder that is modeled with ~ 50% occupancy between torsion angles of -7.8 and 28.6°. These observations are consistent with a broad energy min. as revealed by DFT calcns. PISEMA solid-state NMR expts. show a redn. in the C-H dipolar coupling in comparison to the static limit for the arom. CH moieties of 75% and 51% at 20 and 40°C, resp., that is indicative of ring flips at the higher temp. Our study shows the power of combining expts., namely DSC, X-ray diffraction, and MAS NMR, with DFT calcns. and CSP to probe and understand the solid-state landscape, and in particular the role of dynamics, for pharmaceutical mols.
    98. 98
      Le Bail, A. Whole Powder Pattern Decomposition Methods and Applications: A Retrospection. Powder Diffr. 2005, 20, 316– 326,  DOI: 10.1154/1.2135315
      98
      Whole powder pattern decomposition methods and applications: A retrospection
      Le Bail, Armel
      Powder Diffraction (2005), 20 (4), 316-326CODEN: PODIE2; ISSN:0885-7156. (American Institute of Physics)
      A review is given on methods extg. fast all the peak intensities from a complete powder diffraction pattern. The genesis of the modern whole powder pattern decompn. methods (the so-called Pawley and Le Bail methods) is detailed and their importance and domains of application are decoded from the most cited papers citing them. These methods represented a decisive step toward the possibility to solve more easily, if not routinely, a structure solely from a powder sample. The contributions from the Louer's group during the rising years 1987-1993 are stressed.
    99. 99
      Nangia, A. Conformational Polymorphism in Organic Crystals. Acc. Chem. Res. 2008, 41, 595– 604,  DOI: 10.1021/ar700203k
      99
      Conformational Polymorphism in Organic Crystals
      Nangia, Ashwini
      Accounts of Chemical Research (2008), 41 (5), 595-604CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Polymorphs are different cryst. modifications of the same chem. substance. When different conformers of the same mol. occur in different crystal forms, the phenomenon is termed conformational polymorphism. Occasionally, more than one conformer is present in the same crystal structure. The influence of mol. conformation changes on the formation and stability of polymorphs is the focus of this Account. X-ray crystal structures of conformational polymorphs were analyzed to understand the interplay of intramol. (conformer) and intermol. (lattice) energy in the crystn. and stability of polymorphs. Polymorphic structures stabilized by strong O-H···O/N-H···O hydrogen bonds, weak C-H···O interactions, and close packing were considered. 4,4-Diphenyl-2,5-cyclohexadienone (1) and bis(p-tolyl) ketone p-tosylhydrazone (3) are prototypes of C-H···O and N-H···O hydrogen-bonded structures. Distance-angle scatter plots of O-H···O and C-H···O hydrogen bonds extd. from the Cambridge Structural Database indicate that polymorphs with a larger no. of symmetry-independent mols. (high Z') generally have better interactions when compared with the polymorphs with lower Z' values, with the implication that these symmetry-independent mols. have different conformations. Since mol. conformer (Econf) and crystal lattice (Ulatt) energy differences are of the same magnitude in org. crystals (typically <5 kcal mol-1), situations wherein these two factors compensate or cancel one another are illustrative. Calcn. of conformer and lattice energies using Gaussian 03 and Cerius in 23 recently published polymorph sets shows that a strained conformer (higher Econf) is stabilized by stronger interactions or better crystal packing (lower Ulatt) in 2/3 of the cases, whereas there is no energy balance in the remaining structures. Org. mols. with flexible torsions and low-energy conformers have a greater likelihood of exhibiting polymorphism because (1) different conformations lead to new hydrogen -bonding and close-packing modes and (2) the tradeoff reduces the total energy difference between alternative crystal structures. As a test case, polymorph promiscuity in fuchsones (6) is related to the conformational diversity at the exo-methylene Ph rings and the small energy difference computed for di-Me fuchsone polymorphs. These ideas find application in the design of putative pharmaceutical polymorphs and crystal structure prediction.
    100. 100
      Fernandes, J. A.; Sardo, M.; Mafra, L.; Choquesillo-Lazarte, D.; Masciocchi, N. X-Ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding. Cryst. Growth Des. 2015, 15, 3674– 3683,  DOI: 10.1021/acs.cgd.5b00279
      100
      X-ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding
      Fernandes, Jose A.; Sardo, Mariana; Mafra, Luis; Choquesillo-Lazarte, Duane; Masciocchi, Norberto
      Crystal Growth & Design (2015), 15 (8), 3674-3683CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Two new cocrystals of theophylline were prepd. by liq. assisted grinding. While compd. 1 (theophylline:4-aminosalicylic acid 2:1) was characterized by single crystal X-ray diffraction, the crystal structure of compd. 2 (theophylline:4-aminobenzoic acid 1:1) was detd. by combining X-ray powder diffraction (XRPD), solid-state NMR and DFT calcns. The use of 1D/2D 1H high-resoln. solid-state NMR techniques provided structural insight on local length scales revealing internuclear proximities and relative orientations between the building blocks of compd. 2, thus providing information on the type of hydrogen bond synthons formed. DFT calcns. were also employed to generate meaningful structures and calc. NMR 1H and 13C chem. shifts to further validate the XRPD model. Compd. 2 shows an unusual structure, in which the amino groups do not participate in hydrogen bonds, while compd. 1 exhibits an extended hydrogen-bonding network, in which planar subunits can be recognized.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.1c00779.

    • 13C CP MAS NMR spectra recorded at a spinning rate of 8 and 13 kHz, additional DSC plots, results for the Xadago drug when a mechanically damaged tablet was stored in a humid environment at room temperature, superposition of the PXRD crystal structure solution prior and after DFT-D geometry optimization, and tables containing the experimental chemical shifts and GIPAW-calculated NMR shieldings (PDF)

    • Crystallographic information for the crystal structures solved by the PXRD methodology (ZIP)


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