Hydrochlorides, hydrates, hydronitrate, and an unanticipated hydrolysis product of famotidine

This article contributes to the development of Paper-Based Analytical Devices (PADs), a low-cost field-friendly platform for screening low-quality medicines. Our investigation focuses on famotidine, the active pharmaceutical ingredient (API) in Pepcid AC [an over-the-counter medicine used to treat gastroesophageal reflux disease (GERD)]. We report the successful isolation and characterization of several new crystalline forms of famotidine, focusing on the API itself rather than its PAD-activated colored complex. These forms include a famotidine hydrochloride polymorph, C₆H₁₄N₇O₂S⁺·Cl⁻ (I), a famotidine hydrochloride hemihydrate salt, C₆H₁₄N₇O₂S⁺·Cl⁻·0.5H₂O (II), and a famotidine nitrate salt, C₆H₁₄N₇O₂S⁺·NO₃⁻ (III). Unexpectedly, we also characterized a hydrolyzed famotidine complex, N-(diaminomethylene)-4-({[3-oxo-3-(sulfamoylamino)propyl]sulfanyl}methyl)thiazol-2-aminium chloride sesquihydrate, C₈H₁₅N₆O₃S₃⁺·Cl⁻·1.5H₂O (IV). The crystal structures reveal significant solid-state diversity: hemihydrate salt II exhibits two symmetry-independent famotidine hydrochloride molecules per asymmetric unit, while sesquihydrate salt IV shows four crystallographically-independent hydrochloride molecules and six symmetry-independent water molecules per standard unit. All four complexes display extensive hydrogen-bonded networks in the solid state. The detailed structural characterization of these crystalline complexes generates fundamental solid-state chemistry data; this knowledge is essential for predicting and controlling the drug performance and formulation stability of famotidine and crucially informs our development of PADs.