Stability Order of Caffeine Co-crystals Determined by Co-crystal Former Exchange Reaction and Its Application for the Validation of in Silico Models

• Published in: Chemical & pharmaceutical bulletin Vol. 63; no. 1; pp. 18 - 24
• Main Authors: Mukaida, Makoto, Sugano, Kiyohiko, Terada, Katsuhide
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.01.2015; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: caffeine; Caffeine - chemistry; Citric Acid - chemistry; co-crystal; co-crystal former; Crystallization; Ethanol - chemistry; exchange reaction; hydrogen bond energy; Hydrogen Bonding; Malonates - chemistry; Models, Molecular; Oxalic Acid - chemistry; Parabens - chemistry; X-Ray Diffraction
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c14-00480

The purpose of the present study was to determine the thermodynamic stability orders of co-crystals by co-crystal former (CCF) exchange reactions. Caffeine (CA) was employed as a model drug. The CCF exchange reaction was performed by liquid-assisted grinding using ethanol. When oxalic acid (OX) was added to CA–citric acid co-crystal (CA–CI), CA–CI converted to CA–OX, suggesting that CA–OX is more stable than CA–CI. The stability orders of other co-crystals were determined in the same manner. The stability order of CA co-crystals was determined as CA–OX≈CA–p-hydroxybenzoic acid (HY)>CA–CI>CA–malonic acid>CA–maleic acid. The stability order correlated with the difference in hydrogen bond energy estimated in silico, except for CA–HY. The π–π stacking in CA–HY was suggested as a reason for this discrepancy. The CCF exchange reaction was demonstrated as a useful method to determine the stability order of co-crystals, which can be used for the validation of in silico parameters to predict co-crystal formation.