Amino acid based pharmaceutical cocrystals and hydrate cocrystals of the chlorothiazide: Structural studies and physicochemical properties

Cocrystals can be formed with a pair of carefully selected organic molecules, which may present novel structures that are not available for individual molecule. Pharmaceutical cocrystals may offer synergetic physicochemical properties of the drugs. In this paper, we aimed to screen chlorothiazide(CTZ) cocrystals under the structural resemblance strategy to investigate the correlation between the structure of CTZ cocrystals and their physicochemical properties. Four new cocrystals of CTZ were synthesized and characterized, namely CTZ−Sarcosine (CTZ−SAR), CTZ−DL-proline (CTZ−DL-PRO), CTZ−L-proline hydrate (CTZ−L-PRO-H2O) and CTZ−D-proline hydrate (CTZ−D-PRO-H2O). Single crystal data indicate the CTZ molecule attractively interacts with the amino acids through the amine−carboxylate interactions. CTZ−SAR and CTZ−DL-PRO exhibit very similar crystal structures due to the structural similarity between SAR and PRO. In the two PRO hydrate cocrystals, PRO molecule is in favor to form the hydrogen bonding with the CTZ molecule but not with other neighboring PRO molecules while water is strongly hydrogen bonded to both the CTZ (Sulfonyl O) and the PRO (Amino N–H) as a bridge link. Thermal analysis of hydrate cocrystals shows high thermal stability (∼156 °C). Dissolution kinetic measurements reveal that CTZ−SAR and CTZ−DL-PRO cocrystals exhibit improved solubility in water. [Display omitted] •Four chlorothiazine cocrystals were synthesized using Amino acid as coformers.•Designing cocrystals based on structural resemblance strategy.•CTZ−SAR cocrystal and CTZ−DL-PRO cocrystal exhibit very similar crystal structures.•Describing the crystal environment of a molecule quantitatively by Hirshfeld surface analysis.