(R)-(+)-2-{[(3-Methyl-4-nitro-pyridin-2-yl)meth-yl]sulfin-yl}-1H-benzimidazole.

The title compound, C(14)H(12)N(4)O(3)S, is an inter-mediate of Dexlansoprazole, a proton pump inhibitor (PPI) mainly developed for anti-ulcer activity. The absolute configuration of the title compound was determined as R. The crystal structure reveals that the mol-ecules form chains along the b axis through N-H⋯N and C-H⋯O hydrogen-bonded dimers. These chains are connected via weak C-H⋯O hydrogen bonds.

5-Meth-oxy-2,2-dimethyl-6-[(2E)-2-methyl-but-2-eno-yl]-10-phenyl-2H,8H-pyrano[2,3-f]chromen-8-one (calophyllolide).

The title compound, C(26)H(24)O(5), was isolated from calophyllum inophyllum seeds. In the mol-ecule, the phenyl and 2-methyl-but-2-enoyl groups are almost orthogonal to the chromene fragment [C-C-C-C torsion angles = 81.4 (3) and -90.1 (2)°, respectively]. In the crystal packing, centrosymmetrically related mol-ecules are linked by C-H⋯O contacts into dimers, which are connected via further C-H⋯O inter-actions into a double chain along [010].

1-[(4S)-4-Benzyl-2-thioxo-1,3-thia-zol-idin-3-yl]propan-1-one.

The analysis of the title chiral auxiliary compound, C(13)H(15)NOS(2), has enabled the determination of the absolute configuration at the benzyl-bearing ring C atom as S. In the crystal structure, mol-ecules aggregate into helical chains along the b axis via C-H⋯O contacts.

(3S,4R)-4-(4-Fluoro-phen-yl)-3-(hydroxy-meth-yl)piperidinium chloride.

The title compound, C(12)H(17)FNO(+)·Cl(-), is a degradation impurity of paroxetine hydro-chloride hemihydrate (PAXIL), an anti-depressant belonging to the group of drugs called selective serotonin reuptake inhibitors (SSRIs). Similar to the paroxetine hydro-chloride salt with protonation having taken place on the basic piperidine ring, the degradation impurity also exists as the hydro-chloride salt. The cyclic six-membered piperidinium ring adopts a chair conformation with the hydroxy-methyl and 4-fluoro-phenyl groups in the equatorial positions. The ions form a tape along the b axis through charge-assisted N(+)-H⋯Cl(-) hydrogen bonds; these tapes are connected by O-H⋯Cl(-) hydrogen bonds along the a axis.

Supramolecular synthon polymorphism in 2 : 1 co-crystal of 4-hydroxybenzoic acid and 2,3,5,6-tetramethylpyrazine.

Co-crystals of 4-hydroxybenzoic acid and 2,3,5,6-tetramethylpyrazine (2 : 1) exhibit the first supramolecular synthon polymorphism in a co-crystal; metastable anti-hierarchic polymorph I converts to stable hierarchic form II.

(S)-3-(Ammoniomethyl)-5-methylhexanoate (pregabalin).

The title compound, C(8)H(17)NO(2), exists as a zwitterion, adopting a propeller conformation. Molecules self-assemble to form a hydrogen-bonded layer parallel to the ab crystallographic plane connected by N+-H...O- and C-H...O- hydrogen bonds. These layers are stacked along the c axis and are stabilized by van der Waals interactions.

Hierarchy of supramolecular synthons: persistent hydroxyl...pyridine hydrogen bonds in cocrystals that contain a cyano acceptor.

An analysis of the Cambridge Structural Database reveals >99% occurrence of the hydroxyl...pyridine supramolecular heterosynthon in crystal structures that contain hydroxyl and pyridine moieties in the absence of other hydrogen-bonding moieties. The occurrence of the hydroxyl...cyano supramolecular heterosynthon in crystal structures that contain hydroxyl and cyano moieties is ca. 77%. Such high frequencies indicate that these heterosynthons are strongly favored over the competing hydroxyl...hydroxyl supramolecular homosynthon. However, the CSD does not contain enough information to evaluate which supramolecular heterosynthon prevails when only OH, pyridine, and CN moieties are present in a crystal structure. We have addressed the competition between the hydroxyl...pyridine and the hydroxyl...cyano supramolecular heterosynthons by characterizing a series of 17 cocrystals that are composed of cocrystal formers which contain a permutation of OH, pyridine, and CN functional groups. Structural analysis reveals that all cocrystals are sustained by the hydroxyl...pyridine heterosynthon.

Pharmaceutical co-crystals.

Crystal engineering has evolved in such a manner that it is now synonymous with the paradigm of supramolecular synthesis, that is, it invokes self-assembly of existing molecules to generate a wide range of new solid forms without the need to break or form covalent bonds. This review addresses how crystal engineering has been applied to active pharmaceutical ingredients, API's, with emphasis upon how pharmaceutical co-crystals, a long known but little explored alternative to the four traditionally known forms of API, can be generated in a rational fashion. Case studies on Carbamazepine (CBZ) and Piracetam are presented which illustrate the relative ease with which pharmaceutical co-crystals can be prepared and their diversity in terms of composition and physical properties.

The predictably elusive form II of aspirin.

The elusive form II of aspirin has been obtained during co-crystallization experiments with levetiracetam or acetamide, and it has been characterized by IR, DSC, HPLC, and single-crystal X-ray diffraction.

Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients.

The carboxylic acid-primary amide supramolecular heterosynthon is exploited for the generation of pharmaceutical co-crystals that contain two active pharmaceutical ingredients that are polymorphic in their pure forms.

Supramolecular synthons based on N-H...N and C-H...O hydrogen bonds. Crystal engineering of a helical structure with 5,5-diethylbarbituric acid.

5,5-Diethylbarbituric acid is a convenient molecular precursor for a newly identified N-H...N/C-H...O synthon, which is robust enough for the design of a helix architecture.

Recurrence of carboxylic acid-pyridine supramolecular synthon in the crystal structures of some pyrazinecarboxylic acids.

X-ray crystal structures of pyrazinic acid 1 and isomeric methylpyrazine carboxylic acids 2-4 are analyzed to examine the occurrence of carboxylic acid-pyridine supramolecular synthon V in these heterocyclic acids. Synthon V, assembled by (carboxyl)O-H...N(pyridine) and (pyridine)C-H...O(carbonyl) hydrogen bonds, controls self-assembly in the crystal structures of pyridine and pyrazine monocarboxylic acids. The recurrence of acid-pyridine heterodimer V compared to the more common acid-acid homodimer I in the crystal structures of pyridine and pyrazine monocarboxylic acids is explained by energy computations in the RHF 6-31G* basis set. Both the O-H.N and the C-H...O hydrogen bonds in synthon V result from activated acidic donor and basic acceptor atoms in 1-4. Pyrazine 2,3- and 2,5-dicarboxylic acids 10 and 11 crystallize as dihydrates with a (carboxyl)O-H...O(water) hydrogen bond in synthon VII, a recurring pattern in the diacid structures. In summary, the carboxylic acid group forms an O-H...N hydrogen bond in pyrazine monocarboxylic acids and an O-H...O hydrogen bond in pyrazine dicarboxylic acids. This structural analysis correlates molecular features with supramolecular synthons in pyridine and pyrazine carboxylic acids for future crystal engineering strategies.