Ranjit Thakuria

Pharmaceutical cocrystals and poorly soluble drugs.

In recent years cocrystal formation has emerged as a viable strategy towards improving the solubility and bioavailability of poorly soluble drugs. In this review the success of numerous pharmaceutical cocrystals for the improvement of the solubility and dissolution rates of poorly soluble drugs is demonstrated using various examples taken from the literature. The role of crystal engineering principles in the selection of appropriate coformers and the nature of the supramolecular synthons present within the crystals are described. Evidence for improved animal pharmacokinetic data is given for several systems. A summary is provided of our current understanding of the relationship between cocrystal structure and solution phase interactions on solubility as well as those factors that influence overall cocrystal thermodynamic stability.

Highly soluble olanzapinium maleate crystalline salts

Olanzapinium monomaleate and dimaleate salts (OLNH+ MA− 1:1 and OLN2H+ 2MA− 1:2) of crystalline and amorphous states were prepared. The crystalline salts exhibit significantly higher solubility (225–550 times) compared to the almost insoluble free base drug Olanzapine (43 mg L−1). The faster dissolution rate of the 1:2 salt compared to 1:1 is explained by their crystal structure analysis.

An Investigation of the Causes of Cocrystal Dissociation at High Humidity

The dissociation at high humidity of cocrystals formed between caffeine and theophylline with a series of dicarboxylic acids is investigated and found to be driven by the partial dissolution of the acid, rather than by the formation of caffeine/theophylline hydrate. It is shown that partial dissociation occurs under all humidity conditions, and that cocrystals of compounds which do not form hydrates also dissociate by this mechanism. The observations made in this study indicate that cocrystal instability at high humidity will be a widespread issue, especially for cocrystals where the two coformers have widely differing aqueous solubilities, as is likely for systems where cocrystallisation is being used as means of improving the aqueous solubility, or dissolution rate, of a compound.

Use of in situ atomic force microscopy to follow phase changes at crystal surfaces in real time.

AFM of cocrystals: Atomic force microscopy can be used to observe phase changes at crystal surfaces where the transformation is accompanied by a change in the spacing between layers of molecules. The conversion of a metastable polymorph of the caffeine-glutaric acid cocrystal into the thermodynamically stable form was analyzed continuously in situ using intermittent-contact-mode atomic force microscopy.

Silver(I) complexes of N-4-halophenyl-N′-4-pyridyl ureas. Isostructurality, urea⋯nitrate hydrogen bonding, and Ag⋯halogen interaction

Silver–pyridyl complexes of N-4-X-phenyl-N′-4-pyridyl urea (X = Cl, Br, I, F, H; L1–L5) are crystalline solids of the formula [Ag(L)2](S)(NO3) (S = MeCN) for chloro, bromo and iodo ligands (1–3). Solid solution crystals 7–9 of bromo and iodo derivatives were prepared with L2 : L3 : mixed ligands ratio of 46 : 37 : 17, 65 : 19 : 16 and 94 : 0 : 6 (mixed = bromo–Ag–iodo) in the product. The significance of Ag⋯halogen interaction decreases in the expected order I > Br > Cl in isostructural crystal structures. Interestingly, the polar δ+ region of the C–X bond interacts with nitrate O− in a near-linear approach and the equatorial δ− region approaches Ag+ metal atom at a bent angle, consistent with charge polarization at the heavy halogens. The fluoro and protio ligand silver complexes 4–6 are quite different from structures 1–3. Urea–nitrate N–H⋯O hydrogen bonds have R22(8), R21(6), R43(14) and R44(16) cyclic motifs.

Polymorphic form IV of olanzapine.

2-Methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine, C(17)H(20)N(4)S, commonly known as olanzapine, is a psychotropic agent that belongs to the thienobenzodiazepine class of drugs. A new polymorph form IV was obtained upon attempted cocrystallization with nicotinamide in a 1:1 ratio from an ethyl acetate solution. Two butterfly-like molecules form centrosymmetric dimers stabilized by weak C-H···π interactions between the 4-methylpiperazin-1-yl fragment and the benzene/thiophene aromatic system. Form IV consists of a herringbone arrangement of dimers, whereas the previously reported form II has parallel dimers. Both crystal structures are sustained by an N-H···N hydrogen bond.

Pharmaceutical cocrystals and a nitrate salt of voriconazole

Voriconazole ((2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, VZL) is an antifungal drug with low aqueous solubility of 0.71 mg mL−1 and a BCS class II drug (Biopharmaceutics Classification System) of the azole family. We have prepared a nitrate salt and three cocrystals of VZL with p-hydroxybenzoic acid, p-aminobenzoic acid (both are GRAS compounds) and m-nitrobenzoic acid coformers to improve the physicochemical properties. All four multi-component crystals of voriconazole were obtained by solution crystallization as well as solid-state grinding and their structures were confirmed by X-ray diffraction, FT-IR, Raman and NMR spectroscopy, and thermal techniques. VZL–PHBA and VZL–PABA are isostructural based on XPac calculations and molecular packing arrangement. A notable result from a crystal engineering viewpoint is that the supramolecular synthon between the basic drug and the acidic coformer undergoes a switch based on the pKa of the acid.

Supramolecular networks of a H-shaped aromatic phenol host

X-Ray crystal structures of 1,4-di[bis(hydroxyphenyl)methyl]benzene and its solvates and cocrystals were analyzed for the occurrence of network architectures. From the simplest 1D ladder in EtOAc, DMSO and i-PrOH solvates of 1 (R1 = R2 = R4 = H, R3 = OH), doubly-interpenetrated 1D ladders in its guest-free form and 1D/2D-interpenetrated ladder networks in a cocrystal with phenazine were identified. The dioxane and DMSO solvates of 2 (R1 = R3 = OMe, R2 = OH, R4 = H), and the DMSO and toluene solvates of 4 (R1 = H, R2 = R4 = Me, R3 = OH) also adopt 1D ladder networks. Monomethyl phenol 3 (R1 = R2 = H, R3 = OH, R4 = Me) makes 2D grids of ladders that include nitromethane solvent in the channels. The hexagonal (6,3) net in the cocrystal of 1 with pyrazine-N,N′-dioxide is triply-interpenetrated in a 2D architecture. The DMF solvate of 3 is similar to 1·(PyzNO)2, except that the (6,3) nets are doubly-interpenetrated via Hopf links. An orthorhombic nitromethane solvate of 1 is 2D → 3D polycatenated with a degree of catenation (DOC) = 2/2, whereas the monoclinic polymorph of 1·(CH3NO2)2, as well as the chloroform inclusion structure of 4, adopt the rare (5,34) pentagonal net. Platonic (6,3) and Catalan (5,34) nets in the broader category of a uniform network topology were realized from H-shaped molecules 1–4 in different solvent inclusion and cocrystal structures. Finally, a cocrystal of 1 with quinoxaline forms a polyrotaxane 1D → 1D chain of Euclidean entanglement. Polythreaded rotaxane, pentagonal Catalan and 1D/2D interpenetrated nets are, as such, rare in organic molecular crystals. The role of the solvent/co-former in affording diverse supramolecular networks and entanglement modes are rationalized in the crystal structures.

Synthesis, structure, topology and magnetic properties of new coordination polymers based on 5(–Br/–COOH)-substituted nicotinic acid

Nine new coordination polymers of 5-substituted nicotinic acid (with either –Br, HBNA, or –COOH, 3,5-H2PDC) with d-transition (Co, Ni, Zn and Cd) and f-lanthanoid (La, Ce, Sm and Tb) metal ions have been synthesized. The two metal complexes [Co2(BNA)4(H2O)]n·H2O (1a) and [Cd(BNA)2]n (1b) have polymorphic/isomeric structures to those of metal–organic-frameworks (MOFs) with similar structural building units (SBUs) reported earlier. Modified reaction conditions yielded new isomeric metal complexes in the present case. Reactions of the 3,5-H2PDC linker with different metal ions led to the formation of polymeric complexes [Mn3(3,5-PDC)3(DMA)3]n·DMA (2a), [Zn(3,5-PDC)(DMA)]n·DMA (2b) and [Cd2(3,5-PDC)2(DMA)4]n (2c), as well as lanthanoid MOFs [Sm(3,5-PDC)1.5(DMF)]n·DMF (2d, as well as isomorphous products with La (2f) and Ce (2g) ions) and [Tb2(3,5-PDC)3(DMF)2]n·DMF (2e). Networking diversity observed in these coordination polymers with the conformationally rigid 5-substituted nicotinic acid ligand is discussed. The magnetic properties of 2a, 2d and 2e have been studied as well.

Crystal structures of mirtazapine molecular salts

A few molecular salts of the anti-depressant drug R/S-Mirtazapine with organic carboxylic acids, its HCl salt, and Mirtazapine hemihydrate were crystallized and characterized by X-ray diffraction, IR and Raman spectroscopy, and thermal analysis. Whereas Mirtazapine base sublimed above ambient conditions its molecular salts do not show any sublimation even at elevated temperatures. Crystal structure analysis showed that proton transfer in the hemiadipate salt occurs contrary to the ΔpKa rule. A strong ionic two-point synthon of N+–H⋯O− and C–H⋯O−hydrogen bonds is a recurring motif in Mirtazapinium carboxylate crystal structures.