Acta Crystallographica Section B

Structural Science, Crystal Engineering and Materials

Volume 70, Part 1 (February 2014)

crystal engineering

Acta Cryst. (2014). B70, 81-90    [ doi:10.1107/S2052520613026917 ]

Tuning solubility and stability of hydrochloro­thiazide co-crystals

P. Sanphui and L. Rajput

Abstract: Hydrochlorothiazide (HCT), C7H8ClN3O4S2, is a diuretic BCS (Biopharmaceutics Classification System) class IV drug which has primary and secondary sulfonamide groups. To modify the aqueous solubility of the drug, co-crystals with biologically safe co-formers were screened. Multi-component molecular crystals of HCT were prepared with nicotinic acid, nicotin­amide, succinamide, p-aminobenzoic acid, resorcinol and pyrogallol using liquid-assisted grinding. The co-crystals were characterized by FT-IR spectroscopy, powder X-ray diffraction (PXRD) and differential scanning calorimetry. Single crystal structures were obtained for four of them. The N-H...O sulfonamide catemer synthons found in the stable polymorph of pure HCT are replaced in the co-crystals by drug-co-former heterosynthons. Isostructural co-crystals with nicotinic acid and nicotinamide are devoid of the common sulfonamide dimer/catemer synthons. Solubility and stability experiments were carried out for the co-crystals in water (neutral pH) under ambient conditions. Among the six binary systems, the co-crystal with p-aminobenzoic acid showed a sixfold increase in solubility compared with pure HCT, and stability up to 24 h in an aqueous medium. The co-crystals with nicotinamide, resorcinol and pyrogallol showed only a 1.5-2-fold increase in solubility and transformed to HCT within 1 h of the dissolution experiment. An inverse correlation is observed between the melting points of the co-crystals and their solubilities.

CCDC references: 949302, 949303, 949304 and 949305

Keywords: diuretic drug; solubility; heterosynthons.

hkldisplay filedownload file

Structure factor file (CIF format) (175.8 kbytes)
[ doi:10.1107/S2052520613026917/bi5011HCT-NICsup2.hkl ]
Contains datablock HCT-NIC

hkldisplay filedownload file

Structure factor file (CIF format) (182.9 kbytes)
[ doi:10.1107/S2052520613026917/bi5011HCT-NCTsup3.hkl ]
Contains datablock HCT-NCT

hkldisplay filedownload file

Structure factor file (CIF format) (150.6 kbytes)
[ doi:10.1107/S2052520613026917/bi5011HCT-SAMsup4.hkl ]
Contains datablock HCT-SAM

hkldisplay filedownload file

Structure factor file (CIF format) (269.6 kbytes)
[ doi:10.1107/S2052520613026917/bi5011HCT-PABAsup5.hkl ]
Contains datablock HCT-PABA


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