Intermolecular interactions and disorder in six isostructural celecoxib solvates.

Six isostructural crystalline solvates of the active pharmaceutical ingredient celecoxib {4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide; C17H14F3N3O2S} are described, containing dimethylformamide (DMF, C3H7NO, 1), dimethylacetamide (DMA, C4H9NO, 2), N-methylpyrrolidin-2-one (NMP, C5H9NO, 3), tetramethylurea (TMU, C5H12N2O, 4), 1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one (DMPU, C6H12N2O, 5) or dimethyl sulfoxide (DMSO, C2H6OS, 6). The host celecoxib structure contains one-dimensional channel voids accommodating the solvent molecules, which accept hydrogen bonds from the NH2 groups of two celecoxib molecules. The solvent binding sites have local twofold rotation symmetry, which is consistent with the point symmetry of the solvent molecule in 4 and 5, but introduces orientational disorder for the solvent molecules in 1, 2, 3 and 6. Despite the isostructurality of 1-6, the unit-cell volume and solvent-accessible void space show significant variation. In particular, 4 and 5 show an enlarged and skewed unit cell, which can be attributed to a specific interaction between an N-CH3 group in the solvent molecule and the toluene group of celecoxib. Intermolecular interaction energies calculated using the PIXEL method show that the total interaction energy between the celecoxib and solvent molecules is broadly correlated with the molecular volume of the solvent, except in 6, where the increased polarity of the S=O bond leads to greater overall stabilization compared to the similarly-sized DMF molecule in 1. In the structures showing disorder, the most stable orientations of the solvent molecules make C-H...O contacts to the S=O groups of celecoxib

Design and Preparation of a 4:1 Lamivudine–Oxalic Acid CAB Cocrystal for Improving the Lamivudine Purification Process

Lamivudine (LMV), a cytosine derivative and a reverse transcriptase inhibitor, faces the challenge of inefficient purification after its chemical synthesis. Currently available methods of purification involve salt formation (salicylate or oxalate) followed by treatment with a toxic base, triethyl amine (TEA), to neutralize the protonated LMV. Any reduction in the use of TEA will make the purification process greener and more economical. In this context, we designed and successfully isolated a new and elusive 4:1 CAB cocrystal between LMV and oxalic acid (OXA) that has the potential to significantly improve the efficiency of the LMV purification process. The new CAB cocrystal of LMV was efficiently produced by carefully controlling the ratio of LMV to OXA in the crystallization medium. Compared to salts currently used for purification, much less TEA is required for the 4:1 CAB cocrystal (LMV/LMVH⁺/OXA^2– at 2:2:1 mole ratio) because only half of the LMV is protonated that requires TEA treatment

Design, Synthesis, and Characterization of New 5‑Fluorocytosine Salts

5-Fluorocytosine (FC), an antifungal drug and a cytosine derivative, has a complex solid-state landscape that challenges its development into a drug product. A total of eight new FC salts, both cytosinium and hemicytosinium, with four strong acids were prepared by controlling acid concentration in the crystallization medium. The pharmaceutically acceptable saccharin salt of FC exhibits superior phase stability and, hence, has the potential to address the instability problem of FC associated with hydration

Protonation of Cytosine: Cytosinium vs Hemicytosinium Duplexes

Cytosine, a nucleobase, can exhibit two protonated states, cytosinium and hemicytosinium. The controlled synthesis of structures containing these ions is highly desired but not yet achieved. Herein, we report strategies for robust synthesis of both structures by controlling the strength of an acid used for protonation and its concentration. The duplex structure is always obtained by using an acid with a p<i>K</i>_a > 4.2, which is incapable of disrupting the relatively stable duplex structure. When stronger acids (p<i>K</i>_a < 4.19) are used, the duplex structure is obtained by controlling acid concentration to protonate a half of cytosine in solution, and the cytosinium structure is obtained with excess acid. These strategies are successfully applied to synthesize both forms of 5-fluorocytosine, an antifungal drug. The hemicytosinium structure exhibits superior physicochemical properties than the parent drug and the cytosinium salt. These strategies may be useful to prepare materials important to various branches of science, ranging from biology to nanodevice fabrication and to pharmaceuticals

Correlation Among Crystal Structure, Mechanical Behavior, and Tabletability in the Co-Crystals of Vanillin Isomers

Tuning mechanical performance of molecular materials is currently attractive owing to their practical applications in pharmaceutical, food, and fine chemical industries and optoelectronics. Here we employed a crystal engineering approach to transform four food flavouring agents, vanillin isomers, from brittle to soft solids by forming co-crystals with 6-chloro-2,4-dinitroaniline (<b>cda</b>). The series includes vanillin (<b>van</b>), ethylvanillin (<b>evan</b>), <i>iso</i>-vanillin (<b>ivan</b>), as well as a Schiff base of <i>ortho</i>-vanillin (<b>ovan)</b> with ethylene diamine (<b>sb-ovan</b>). All the co-crystals adopt flat two-dimensional (2D) layer packing, except the <b>sb-ovan:cda</b>, which adopts a corrugated layer packing with the presence of slip planes. The mechanical properties of the co-crystals were studied by (1) a qualitative method, (2) nanoindentation, and (3) powder compaction techniques, which allowed for successfully establishing the relationship among crystal structure, mechanical properties, and tablet tensile strength. The simple qualitative mechanical (deformation) tests confirmed plastic shearing deformation behavior in the <b>cda</b> co-crystals with <b>van</b>, <b>evan</b>, and <b>ivan</b>, while the co-crystal of <b>sb-ovan:cda</b> showed plastic bending due to the presence of slip planes formed by van der Waals interactions in the structure. The measured tensile strengths of the vanillin isomers and their respective co-crystals, which followed the order: <b>sb-ovan:cda</b> > <b>evan</b> > <b>van</b> > <b>ivan:cda</b> > <b>evan:cda</b> > <b>van:cda</b> > <b>sb-ovan</b> > <b>ivan</b>, confirmed that the plastically bendable co-crystal, <b>sb-ovan:cda</b>, shows a significant improvement in the compaction properties compared to any other form studied. In contrast to the initial brittle forms with isotropic structures, the new co-crystal solids show improved plasticity due to their anisotropic 2D-layer structures with active slip planes that facilitate the plastic deformation, which enhances tabletability, particularly in the plastic bendable solid. The study also suggests that the bending type crystals are potentially far better suitable for tabletability than the shearing and brittle type crystals

Probing Interfaces between Pharmaceutical Crystals and Polymers by Neutron Reflectometry

Pharmaceutical powder engineering often involves forming interfaces between the drug and a suitable polymer. The structure at the interface plays a critical role in the properties and performance of the composite. However, interface structures have not been well understood due to a lack of suitable characterization tool. In this work, we have used ellipsometry and neutron reflectometry to characterize the structure of such interfaces in detail. Ellipsometry provided a quick estimate of the number of layers and their thicknesses, whereas neutron reflectometry provided richer structural information such as density, thickness, roughness, and intermixing of different layers. The combined information allowed us to develop an accurate model about the layered structure and provided information about intermixing of different layer components. Systematic use of these characterization techniques on several model systems suggests that the nature of the polymer had a small effect on the interfacial structure, while the solvent used in polymer coating had a large effect. These results provide useful information on the efforts of engineering particle properties through the control of the interfacial chemistry