US EPA

1620014 

Journal Article 

Solubility Advantage of Pharmaceutical Cocrystals 

Good, DJ; Rodriguez-Hornedo, N 

2009 

Yes 

Crystal Growth & Design
ISSN: 1528-7483
EISSN: 1528-7505 

9 

5 

2252-2264 

10.1021/cg801039j 

WOS:000265892200038 

Pharmaceutical cocrystals can improve solubility,
dissolution, and bioavailability of poorly water soluble drugs. However, true cocrystal
solubility is not readily measured for highly soluble cocrystals because they can transform to
the most stable drug form in solution. The objectives of this study are to develop a method to
estimate the cocrystal solubility in pure solvent and establish the influence of constituent drug
and ligand (i.e., coformer) properties. Cocrystal solubility and solubility product were derived
from transition concentration measurements where a solution is in equilibrium with solid drug and
cocrystal. Transition concentrations and solubilities are reported for carbamazepine cocrystals
in water, ethanol, isopropanol, and ethyl acetate. The aqueous solubility for seven carbamazepine
cocrystals was estimated to be 2-152 times greater than the solubility of the stable
carbamazepine dihydrate form. Cocrystal solubility is shown to be directly proportional to the
solubility of constituent reactants for carbamazepine, caffeine, and theophylline cocrystals. The
ligand transition concentration is also correlated with ligand solubility. Transition
concentration measurements reveal drug solubilization by ligand for several of the cocrystals
studied. The correlation established between constituent and cocrystal solubility was not
effectively predicted by fusion properties of the various crystal forms considered.