Caffeine, cocrystals with carboxylic acids

Contents 1. Introduction 373 2. Screening for and Preparation of Cocrystal Systems 375 3. Cocrystal Systems Having Pharmaceutical Interest 377 3.1. Cocrystal systems formed by carbamazepine- type molecules 378 3.2. Cocrystal systems formed by nicotinamide with carboxylic acids 380 3.3. Cocrystal systems formed by caffeine and theophylline 382 3.4. Cocrystal systems formed by saccharin 384 3.5. Cocrystal systems formed by carboxylic acids 385 References 386... 

The structures of three cocrystals of caffeine having a 1 1 stoichiometry with various hydroxy-2-naphthoic acids have been reported [62], The anticipated imidazole-carboxylic acid supramolecular synthon was observed in caffeine cocrystals containing l-hydroxy-2-naphthoic acid and 3-hydroxy-2-naphthoic acid, while a hydrogen-bonded carboxylic acid dimer (and no hydroxyl-caffeine heterosynthon) was observed in the caffeine cocrystal with 6-hydroxy-2-naphthoic acid. 

The use of co-crystals to enhance the hydration stability of a solid API was first demonstrated for model APIs caffeine and theophylline by forming cocrystals with dicarboxylic acids. Co-crystallisation with oxalic, malonic, maleic and glutaric adds provided co-crystals based on the expected carboxylic acid-imidazole " heterosynthon. In both cases, the co-crystal with oxalic acid demonstrated enhanced hydration stability compared to the solid APIs and did not transform into a hydrate even after seven weeks exposure to 98% relative humidity. Similar observations were also made in the case of analogous co-crystals of theophylline. ... 

Pharmaceutical cocrystals generally consist of an API and one or more pharmaceutically acceptable molecules, known as the cocrystal formers or coformers. The coformers are typically compounds generally regarded as safe (GRAS compounds). The first examples were reported in 1993 by Caira and Etter, with the drug sulfadimidine and a variety of carboxylic acids such as acetylsalicylic acid (aspirin) [9]. A recent example is the use of cocrystals to enhance the hydration stability of a solid API, as in caffeine and theophylline by forming cocrystals with dicarboxylic acids [8c]. 

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