Stability order of caffeine co-crystals determined by co-crystal former exchange reaction and its application for the validation of in silico models.
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.
Asahi Kasei Pharma Corporation; 632–1 Mifuku Izunokuni, Shizuoka 410–2321, Japan; Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.  mukaida.mb@om.asahi-kasei.com.jp
Makoto
M
Mukaida
Kiyohiko
K
Sugano
Katsuhide
K
Terada
D002110:Caffeine / Q000737:chemistry*; D019343:Citric Acid / Q000737:chemistry; D003460:Crystallization; D000431:Ethanol / Q000737:chemistry; D006860:Hydrogen Bonding; D008314:Malonates / Q000737:chemistry; D008958:Models, Molecular; D019815:Oxalic Acid / Q000737:chemistry; D010226:Parabens / Q000737:chemistry; D014961:X-Ray Diffraction
D008314:Malonates; D010226:Parabens; D019343:Citric Acid; D002110:Caffeine; D000431:Ethanol; D019815:Oxalic Acid; C030290:malonic acid; C038193:4-hydroxybenzoic acid