The determination of crystal structures of active pharmaceutical ingredients from X-ray powder diffraction data: a brief, practical introduction, with fexofenadine hydrochloride as example.

OBJECTIVES: This study describes the general method for the determination of the crystal structures of active pharmaceutical ingredients (API) from powder diffraction data and demonstrates its use to determine the hitherto unknown crystal structure of fexofenadine hydrochloride, a third-generation antihistamine drug. METHODS: Fexofenadine hydrochloride was subjected to a series of crystallisation experiments using re-crystallisation from solvents, gas diffusion, layering with an antisolvent and gel crystallisation. Powder diffraction patterns of all samples were recorded and inspected for polymorphism and for crystallinity. KEY FINDINGS: All samples corresponded to the same polymorph. The crystal structure was determined from an X-ray powder diffraction pattern using a real-space method with subsequent Rietveld refinement. The structure exhibits a two-dimensional hydrogen bond network. CONCLUSION: Crystal structures of API can be determined from X-ray powder diffraction data with good reliability. Fexofenadine exhibits only one polymorphic form, which is stabilised in the crystal by strong hydrogen bonds of the type (+)N-H···Cl(-), O-H···Cl(-), and between COOH groups.

Erythromycin A dimethyl sulfoxide disolvate 1.43-hydrate.

The title compound, C(37)H(67)NO(13)·2C(2)H(6)OS·1.43H(2)O, is a macrolide anti-biotic with better solubility and better dermal penetration abilities than erythromycin A itself. The asymmetric unit of this form contains one erythromycin A mol-ecule, two dimethyl sulfoxide (DMSO) solvent mol-ecules, a fully occupied water mol-ecule and a partially occupied water mol-ecule with an occupancy factor of 0.432 (11). The 14-membered ring of the erythronolide fragment has a conformation which differs considerably from that in erythromycin A dihydrate [Stephenson, Stowell, Toma, Pfeiffer & Byrn (1997 ▶). J. Pharm. Sci.86, 1239-1244]. One of the two DMSO mol-ecules is disordered over two orientations; the orientation depends on the presence or absence of the second, partially occupied, water mol-ecule. In the crystal, erythromycin mol-ecules are connected by O-H⋯O hydrogen bonds involving the hy-droxy groups and the fully occupied water mol-ecule to form layers parallel to (010). These layers are connected along the b-axis direction only by a possible hydrogen-bonding contact involving the partially occupied water mol-ecule.

Antidiarrhetic loperamide hydrochloride.

Single crystals of the anhydrous form of the title compound {systematic name: 1-[3-(dimethylcarbamoyl)-3,3-diphenylpropyl]-4-hydroxy-4-(4-chlorophenyl)piperidin-1-ium chloride}, C(29)H(34)ClN(2)O(2)(+)·Cl(-), were obtained by diffusion of acetone into a solution in 2-propanol. In the structure, N-H...Cl(-) and O-H...Cl(-) hydrogen bonds connect neighbouring molecules and chloride anions to form chains along the c-axis direction. Neighbouring chains along the b-axis direction are connected by intermolecular C-H...Cl(-) contacts, defining layers parallel to the (100) planes. The layers are connected by weak intermolecular C-H...Cl interactions only, which may account for the plate-like shape of the crystals.

1,5-Dianilinopentane-1,3,5-trione: a crystal structure containing two polymorphic domains.

Single crystals of the title compound, C(17)H(16)N(2)O(3), were obtained by gas diffusion. The observed diffraction pattern is compatible with a superposition of reflections from two monoclinic unit cells with the space group C2/c. The two cells share the a and b axes but not the c axis. Both structures contain layers parallel to (001), with molecules connected by intermolecular N-H···O=C hydrogen bonds. The bonding between adjacent layers is weak. Layer displacements result in a crystal structure containing two closely related polymorphic domains. The structure of one polymorph can be derived from the structure of the other if subsequent layers are displaced by (a/4, b/4, 0) for odd-numbered layers and by (a/4, -b/4, 0) for even-numbered layers. Three different crystals were analysed and their observed diffraction patterns were similar, showing all three crystals to contain the polymorphic domain structure.

Characterization of a new solvate of risedronate.

Three new forms of the osteoporosis drug sodium risedronate, sodium [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonate, were identified and designated as the J, K, and M phases. Form J is an acetic acid disolvate with the chemical composition Na(+) [C(7) H(10) NO(7) P(2)](-) · 2CH(3) COOH, as determined by single-crystal structure analysis. This novel solvate is easily formed by the recrystallization of sodium risedronate from acetic acid. Dissolution of the new disolvate was characterized in distilled water, a compendial buffer, simulated gastric fluid sine pepsin (pH 1.2), and a biorelevant buffer system FaSSIF-V2 (pH 6.8). It was demonstrated that solubility of the disolvate in physiological buffers differed significantly from that of the original molecule, with delayed dissolution under simulated esophageal and gastric conditions, but rapid and complete dissolution under simulated intestinal conditions. These studies suggest that through the generation of novel solvates, the biopharmaceutical properties of poorly soluble drug candidates can be improved.

Monothioindigo, determined by microcrystal structure analysis.

Indigo and thioindigo pigments are used for a wide range of applications. The crystal structure of the mixed compound monothioindigo [systematic name: (E)-2-(3-oxo-2,3-dihydro-1-benzothiophen-2-ylidene)-2,3-dihydro-1H-indol-3-one], C(16)H(9)NO(2)S, has been determined by microcrystal structure analysis from a crystal with a size of just 1 x 2 x 10 microm. The crystal structure of monothioindigo resembles those of indigo and thioindigo. The molecules show orientational disorder, with site-occupation factors of 0.962 (2) and 0.038 (2) for the major and minor disorder components, respectively. The indigo fragment donates an intermolecular hydrogen bond, leading to a criss-cross arrangement of molecules similar to that in indigo, whereas the thioindigo fragment exhibits only van der Waals interactions and molecular stacking, similar to that in thioindigo.

Ezetimibe anhydrate, determined from laboratory powder diffraction data.

Ezetimibe {systematic name: (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one}, C(24)H(21)F(2)NO(3), is used to lower cholesterol levels by inhibiting cholesterol resorption in the human intestine. The crystal structure of ezetimibe anhydrate was solved from laboratory powder diffraction data by means of real-space methods using the program DASH [David et al. (2006). J. Appl. Cryst. 39, 910-915]. Subsequent Rietveld refinement with TOPAS Academic [Coelho (2007). TOPAS Academic User Manual. Version 4.1. Coelho Software, Brisbane, Australia] led to a final R(wp) value of 8.19% at 1.75 A resolution. The compound crystallizes in the space group P2(1)2(1)2(1) with one molecule in the asymmetric unit. The molecules are closely packed and two intermolecular hydrogen bonds form an extended hydrogen-bond architecture.

7-Methoxy-2,3-dioxo-1,4-dihydroquinoxalin-6-aminium chloride monohydrate.

Single crystals of the title compound, C(9)H(10)N(3)O(3)(+).Cl(-).H(2)O, were obtained by recrystallization from hydrochloric acid. The cations stack along the crystallographic a direction. The 2,3-dioxo-1,4-dihydroquinoxaline group shows a significant deviation from planarity [r.m.s. deviation from the best plane = 0.063 (2) A]. Hydrogen bonding links the cations, chloride anions and water molecules to form an extended three-dimensional architecture.

Three solvates of a bis-mesoionic fluorescent yellow pigment.

p-Phenylenebis(2-oxo-3-phenyl-1,2-dihydropyrido[1,2-a]pyrimidin-5-ium-4-olate), C(34)H(22)N(4)O(4), is a bis-mesoionic yellow pigment that shows fluorescence in the solid state. During a polymorph screening, single crystals of three solvates were grown and their crystal structures determined. Solvent-free crystals were not obtained. A solvate with N-methylpyrrolidone (NMP) and propan-2-ol, C(34)H(22)N(4)O(4).2C(5)H(9)NO.C(3)H(8)O, (Ia), and an NMP trisolvate, C(34)H(22)N(4)O(4).3C(5)H(9)NO, (Ib), crystallize with pigment molecules on inversion centres. The NMP/propan-2-ol mixed solvate (Ia) forms O-H...O hydrogen bonds between the different solvent molecules. In both structures, at least one of the solvent molecules is disordered. A third solvate structure, C(34)H(22)N(4)O(4).0.5C(5)H(9)NO.C(4)H(10)O, (Ic), was obtained by crystallization from NMP and butan-1-ol. In this case, there are two symmetry-independent pigment molecules, both situated on inversion centres. The solvent molecules are heavily disordered and their contribution to the scattering was suppressed. This solvate displays a channel structure, whereas the other two solvates form layer structures.

Electron diffraction, X-ray powder diffraction and pair-distribution-function analyses to determine the crystal structures of Pigment Yellow 213, C23H21N5O9.

The crystal structure of the nanocrystalline alpha phase of Pigment Yellow 213 (P.Y. 213) was solved by a combination of single-crystal electron diffraction and X-ray powder diffraction, despite the poor crystallinity of the material. The molecules form an efficient dense packing, which explains the observed insolubility and weather fastness of the pigment. The pair-distribution function (PDF) of the alpha phase is consistent with the determined crystal structure. The beta phase of P.Y. 213 shows even lower crystal quality, so extracting any structural information directly from the diffraction data is not possible. PDF analysis indicates the beta phase to have a columnar structure with a similar local structure as the alpha phase and a domain size in column direction of approximately 4 nm.

Structures of six industrial benzimidazolone pigments from laboratory powder diffraction data.

The crystal structures of six industrially produced benzimidazolone pigments [Pigment Orange 36 (beta phase), Pigment Orange 62, Pigment Yellow 151, Pigment Yellow 154 (alpha phase), Pigment Yellow 181 (beta phase) and Pigment Yellow 194] were determined from laboratory X-ray powder diffraction data by means of real-space methods using the programs DASH and MRIA, respectively. Subsequent Rietveld refinements were carried out with TOPAS. The crystal phases correspond to those produced industrially. Additionally, the crystal structures of the non-commercial compound 'BIRZIL' (a chloro derivative of Pigment Yellow 194) and of a dimethylsulfoxide solvate of Pigment Yellow 154 were determined by single-crystal structure analyses. All eight crystal structures are different; the six industrial pigments even exhibit five different hydrogen-bond topologies. Apparently, the good application properties of the benzimidazolone pigments are not the result of one specific hydrogen-bonding pattern, but are the result of a combination of efficient molecular packing and strong intermolecular hydrogen bonds.

Structure determination of seven phases and solvates of Pigment Yellow 183 and Pigment Yellow 191 from X-ray powder and single-crystal data.

The crystal structures of two industrially produced laked yellow pigments, Pigment Yellow 183 [P.Y. 183, Ca(C16H10Cl2N4O7S2), alpha phase] and Pigment Yellow 191 [P.Y. 191, Ca(C17H13ClN4O7S2), alpha and beta phases], were determined from laboratory X-ray powder diffraction data. The coordinates of the molecular fragments of the crystal structures were found by means of real-space methods (simulated annealing) with the program DASH. The coordinates of the calcium ions and the water molecules were determined by combining real-space methods (DASH and MRIA) and repeated Rietveld refinements (TOPAS) of the partially finished crystal structures. TOPAS was also used for the final Rietveld refinements. The crystal structure of beta-P.Y. 183 was determined from single-crystal data. The alpha phases of the two pigments are isostructural, whereas the beta phases are not. All four phases exhibit a double-layer structure, built from nonpolar layers containing the C/N backbone and polar layers containing the calcium ions, sulfonate groups and water molecules. Furthermore, the crystal structures of an N,N-dimethylformamide solvate of P.Y. 183, and of P.Y. 191 solvates with N,N-dimethylformamide and N,N-dimethylacetamide were determined by single-crystal X-ray analysis.

2-Aminoterephthalic acid dimethyl ester.

Single crystals of the title compound, C(10)H(11)NO(4), an inter-mediate in the industrial synthesis of yellow azo pigments, were obtained from the industrial production. The mol-ecules crystallize as centrosymmetic dimers connected by two symmetry-related N-H⋯O=C hydrogen bonds. Each mol-ecule also contains an intra-molecular N-H⋯O=C hydrogen bond. The dimers form stacks along the a-axis direction. Neighbouring stacks are arranged into a herringbone structure.

Rasagiline ethanedisulfonate: an inhibitor for monoamine oxygenase B (MAO(B)).

Rasagiline is a selective and potent drug used for the treatment of Parkinson's disease. The first crystal structure of a salt of rasagiline, the title compound, bis[(1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-aminium] ethanedisulfonate, 2C(12)H(14)N(+).C(2)H(4)O(6)S(2)(-), was determined from crystals grown by gas diffusion. The compound has monoclinic (C2) symmetry. The ethane group of the ethanedisulfonate anion is disordered over three positions. The C(2)-symmetric ethanedisulfonate anions are connected by four N-H...O hydrogen bonds to four rasagiline cations. This leads to large 18-membered rings which are arranged in ladders in the [010] direction. The extended hydrogen-bonding architecture may explain the stability of the structure. Rasagiline ethanedisulfonate is nonhygroscopic. During a polymorph screen, no hydrates, solvates or polymorphs were found.

Two azo pigments based on beta-naphthol.

There has been much discussion in the literature of the azo-hydrazone tautomerism of pigments. All commercial azo pigments with beta-naphthol as the coupling compound adopt the hydrazone tautomeric form (Ph-NH-N=C) in the solid state. In contrast, the red pigments 1-[4-(dimethylamino)phenyldiazenyl]-2-naphthol, C(18)H(17)N(3)O, (1a), and 1-[4-(diethylamino)phenyldiazenyl]-2-naphthol, C(20)H(21)N(3)O, (1b), have been reported to be azo tautomers or a mixture of azo and hydrazone tautomers in the solid state. To prove these observations, both compounds were synthesized, recrystallized and their crystal structures redetermined by single-crystal structure analysis. Difference electron-density maps show that the H atoms of the hydroxyl groups are indeed bonded to the O atoms. Nevertheless, a small amount of the hydrazone form seems to be present. Hence, the compounds are close to being ;real' azo compounds. Compound (1a) crystallizes with a herring-bone structure and compound (1b) forms a rare double herring-bone structure.