Cocrystal dissociation in the presence of water: a general approach for identifying stable cocrystal forms.
In previous studies, cocrystals have been shown to be susceptible to dissociation at high humidity because of differences in the solubilities of the two coformer molecules, especially when these molecules can form hydrates. Contrastingly, however, the propensity of the pharmaceutically active compound caffeine to hydrate formation is reduced by cocrystallization with oxalic acid. Here, the stability of the oxalic acid cocrystal of caffeine is investigated from a thermodynamic perspective through the use of aqueous slurries of caffeine hydrate and oxalic acid dihydrate. Conversion to the anhydrous caffeine-oxalic acid cocrystal occurred under these conditions confirming that this form is thermodynamically stable in an aqueous environment. The slurry methodology was further developed as a general approach to screening for cocrystals that are not susceptible to dissociation at high humidity. In this manner, cocrystals of the hydrate-forming molecules theophylline, carbamazepine, and piroxicam that are stable at high humidity, indefinitely avoiding hydrate formation, were identified.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom. Electronic address: mde32@cam.ac.uk.
Mark D
MD
Eddleston
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Nadeesh
N
Madusanka
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
William
W
Jones
D002110:Caffeine / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D004355:Drug Stability; D006813:Humidity; D019815:Oxalic Acid / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013806:Theophylline / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
D004364:Pharmaceutical Preparations; D014867:Water; D002110:Caffeine; D019815:Oxalic Acid; D013806:Theophylline
cocrystals; hydrates/solvates; physical stability; powder X-ray diffraction; solid state; solubility