Although hydrochlorothiazide (HCTZ) drug substance is known for its excellent solid-state stability, it can undergo hydrolysis with the formation of formaldehyde and 4-amino-6-chloro-1,3 benzenedisulfonamide (free amine). The degradation of HCTZ in a dosage form is undesirable due to the tight limits that need to be set for the free amine content. In a combination wet granulated tablet formulation of an antihypertensive drug A and HCTZ containing povidone K-30 NF (PVP) as a binder and poloxamer 188 NF (Pluronic F68) as a wetting agent, a progressive increase in the free amine level was seen after only 2 months storage at various conditions. Binary mixtures of HCTZ with PVP, pregelatinized starch (Starch 1500), and lactose (control) were incubated at elevated temperatures after adding an amount of water to simulate wet granulation conditions. Analysis of these mixtures showed more free amine formation in the HCTZ:PVP binary mixtures than the HCTZ:Starch 1500 or HCTZ:lactose binary mixtures. Replacement of PVP with Starch 1500 in the tablet formulation resulted in comparatively lower free amine levels on storage. The free amine formation in tablets was further reduced and dissolution of both drugs was not significantly affected when Pluronic F68 was removed from the formulation. It was hypothesized that the mechanism of degradation of HCTZ in the presence of PVP and/or Pluronic F68 was due to solubilization of the HCTZ by these excipients in the moisture present in tablets, followed by its hydrolysis.