An overview of pharmaceutical cocrystals as intellectual property.

This review article focuses on the interaction among certain scientific, legal, and regulatory aspects of pharmaceutical crystal forms. The article offers an analysis of pharmaceutical cocrystals as patentable inventions by drawing upon recent scientific developments in the field. Several potential commercial advantages of pharmaceutical cocrystals are highlighted, and a number of recent court decisions involving salient issues are summarized.

Solid-state acid-base interactions in complexes of heterocyclic bases with dicarboxylic acids: crystallography, hydrogen bond analysis, and 15N NMR spectroscopy.

A cancer candidate, compound 1, is a weak base with two heterocyclic basic nitrogens and five hydrogen-bonding functional groups, and is sparingly soluble in water rendering it unsuitable for pharmaceutical development. The crystalline acid-base pairs of 1, collectively termed solid acid-base complexes, provide significant increases in the solubility and bioavailability compared to the free base, 1. Three dicarboxylic acid-base complexes, sesquisuccinate 2, dimalonate 3, and dimaleate 4, show the most favorable physicochemical profiles and are studied in greater detail.

Physical stability enhancement of theophylline via cocrystallization.

The crystal form adopted by the respiratory drug theophylline was modified using a crystal engineering strategy in order to search for a solid material with improved physical stability. Cocrystals, also referred to as crystalline molecular complexes, were prepared with theophylline and one of several dicarboxylic acids. Four cocrystals of theophylline are reported, one each with oxalic, malonic, maleic and glutaric acids.

Investigating the latent polymorphism of maleic acid.

The unexpected appearance of a new polymorph of maleic acid is reported and a computational study addresses the predictability of this new polymorph and future potential polymorphism.

Screening for crystalline salts via mechanochemistry.

Neat grinding and solvent-drop grinding methods are found to be effective screening tools for indicating the potential for crystalline salt formation involving a given acid-base pair, as demonstrated with two model pharmaceuticals.

Selective polymorph transformation via solvent-drop grinding.

A method of inducing specific polymorph transformations is exemplified with two single-component systems, whereby a given crystal form undergoes conversion when subjected to solid state grinding in the presence of a minor quantity of a certain solvent.

Solvent-drop grinding: green polymorph control of cocrystallisation.

By grinding with a minimal addition of a solvent of appropriate polarity, control over the polymorphic outcome of a novel cocrystallisation involving the model pharmaceutical compound caffeine may be achieved.