POVIDONE-MEDIATED AND POLOXAMER-MEDIATED DEGRADATION OF HYDROCHLOROTHIAZIDE IN AN ANTIHYPERTENSIVE COMBINATION TABLET PRODUCT

Although hydrochlorothiazide (HCTZ) drug substance is known for its ex cellent solid-state stability, it can undergo hydrolysis with the form ation of formaldehyde and 4-amino-6-chloro-1,3 benzenedisulfonamide (f ree amine). The degradation of HCTZ in a dosage form is undesirable du e to the tight limits that need to be set for the free amine content. In a combination wet granulated tablet formulation of an antihypertens ive drug A and HCTZ containing povidone K-30 NF (PVP) as a binder and poloxamer 188 NF (Pluronic(R) F68) as a wetting agent, a progressive i ncrease in the free amine level was seen after only 2 months storage a t various conditions. Binary mixtures of HCTZ with PVP, pregelatinized starch (Starch(R) 1500), and lactose (control) were incubated at elev ated temperatures after adding an amount of water to simulate wet gran ulation conditions. Analysis of these mixtures showed more free amine formation in the HCTZ:PVP binary mixtures than the HCTZ:Starch(R) 1500 or HCTZ:lactose binary mixtures. Replacement of PVP with Starch(R) 15 00 in the tablet formulation resulted in comparatively lower free amin e levels on storage. The free amine formation in tablets was further r educed and dissolution of both drugs was not significantly affected wh en Pluronic F68 was removed from the formulation. It was hypothesized that the mechanism of degradation of HCTZ in the presence of PVP and/o r Pluronic(R) F68 was due to solubilization of the HCTZ by these excip ients in the moisture present in tablets, followed by its hydrolysis.