The curious case of (caffeine)·(benzoic acid): how heteronuclear seeding allowed the formation of an elusive cocrystal

Dejan-Krešimir Bučar,John R. G. Sander,Ivan Halasz,Leonard R. MacGillivray,Melinda J. Duer,Geoff G. Z. Zhang,William Jones,Graeme M. Day,David G. Reid

doi:10.1039/c3sc51419f

Abstract

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals, yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine)·(benzoic acid) cocrystal (1), which persistently failed to form using a broad range of established techniques. State-of-the-art crystal structure prediction methods were employed to assess the possible existence of a thermodynamically stable form of 1, hence to identify appropriate heteronuclear seeds for cocrystallization. Once introduced, the designed heteronuclear seeds facilitated the formation of 1 and, significantly they (or seeds of the product cocrystal) continued to act as long-lasting laboratory “contaminants”, which encouraged cocrystal formation even when present at such low levels as to evade detection. The seeding technique described thus enables the synthesis of cocrystals regarded as unobtainable under desired conditions, and potentially signifies a new direction in the field of materials research.

Highlights

In many areas of applied solid-state research, including the pharmaceutical eld, it is crucial that a compound in development be prepared and characterized in the largest possible number of solid forms.[1]
We describe a strategy for the synthesis of the pharmaceutically relevant$(benzoic acid) cocrystal (1), which persistently failed to form using a broad range of established techniques
In the solution-mediated phase transformation34 (SMPT) and sonic slurry30 (SS) methods, for example, the potential for cocrystal formation is maximized once the activities of both components are kept at values higher than their respective critical values, which is certainly accomplished in suspensions of physical mixtures of the cocrystal components.[34]

Summary

Introduction

The risks inherent in the development and marketing of organic solids in the pharmaceutical arena are well illustrated by the widely-known cases of the HIV protease inhibitor Ritonavir[7] (Norvir), and the dopamine agonist Rotigotine[8] (Neupro). Rigid-molecule lattice energy minimizations were performed on approximately 13 000 of the lowest energy structures with an improved intermolecular model potential, using the same exp-6 repulsion–dispersion parameters as in the structure generation step, coupled with an atomic multipole model for electrostatic interactions, deriving multipoles up to hexadecapole on each atom from a distributed multipole analysis (DMA)[52] of the B3LYP/6-311G** charge densities These crystal structure calculations were performed using DMACRYS.[51] All intermolecular interactions were summed to a 30 Acutoff, apart from charge–charge, charge–dipole and dipole–dipole interactions, for which Ewald summation was applied. Experimental details and Rietveld plots for all cocrystal structures are available in the ESI.†

Results and discussion

Conclusion and outlook

Developing Solid Oral Dosage Forms