Tuning solubility and stability of hydrochlorothiazide co-crystals.
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.
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India.
Palash
P
Sanphui
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India.
Lalit
L
Rajput
D010129:4-Aminobenzoic Acid / Q000737:chemistry; D003460:Crystallization; D018360:Crystallography, X-Ray; D004232:Diuretics / Q000737:chemistry*; D004355:Drug Stability; D006801:Humans; D006852:Hydrochlorothiazide / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D009525:Niacin / Q000737:chemistry; D009536:Niacinamide / Q000737:chemistry; D011748:Pyrogallol / Q000737:chemistry; D012118:Resorcinols / Q000737:chemistry; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013449:Sulfonamides / Q000737:chemistry; D044366:Transition Temperature
D004232:Diuretics; D012118:Resorcinols; D013449:Sulfonamides; D011748:Pyrogallol; D006852:Hydrochlorothiazide; D009536:Niacinamide; D009525:Niacin; D010129:4-Aminobenzoic Acid; C031389:resorcinol
diuretic drug; heterosynthons; solubility