RESUMEN
Active pharmaceutical ingredients (API) can undergo an anhydrate to hydrate transformation during wet granulation and this transformation may either result in mixed crystalline forms or an unwanted form in the final drug product. Previous studies have shown that it may be possible to inhibit this transformation with polymeric excipients. In this study, three model compounds, caffeine (CAF), carbamazepine (CBZ), and sulfaguanidine (SGN), were subjected to high shear wet granulation and phase transformations were monitored using in-line Raman spectroscopy. Wet granulation was performed in the presence and absence of various polymeric excipients to determine the extent of the inhibitory effects. Although several polymers had some retardation effect, cross-linked poly(acrylic) acid was found to completely inhibit the CAF transformation and both hydroxypropyl methylcellulose and cross-linked poly(acrylic) acid completely inhibited the CBZ transformation. For SGN, transformation to the hydrate was rapid, even in the presence of the polymers. The observed inhibitory effects were attributed to either specific interactions between the polymer and the API crystal or substantial water absorption by the polymer. There was also evidence from physical property testing that the inclusion of a small amount of inhibitory polymer did not significantly change the compaction or flow behavior of the final granulation.
Asunto(s)
Composición de Medicamentos/métodos , Excipientes/química , Polímeros/química , Cafeína/administración & dosificación , Cafeína/química , Calibración , Carbamazepina/administración & dosificación , Carbamazepina/química , Química Farmacéutica , Cristalización , Derivados de la Hipromelosa , Cinética , Metilcelulosa/análogos & derivados , Tamaño de la Partícula , Polvos , Programas Informáticos , Espectrometría Raman , Sulfaguanidina/administración & dosificación , Sulfaguanidina/química , Sulfatiazol , Sulfatiazoles/administración & dosificación , Sulfatiazoles/químicaRESUMEN
Crystalline anhydrous active pharmaceutical ingredients (APIs) can potentially transform to the hydrate form during manufacturing processes involving water. The ability to understand and manipulate these transformations is important to maintain control of the solid state form of the API. The influence of various polymeric excipients on the anhydrate to hydrate transformation of caffeine, carbamazepine, and sulfaguanidine was investigated in this study. The transformation of the APIs in aqueous slurries was monitored using in-line Raman measurements and the resultant kinetic profiles provided insight into the inhibitory ability of the polymers investigated. The results showed that cross-linked poly(acrylic acid) inhibited the caffeine transformation and hydroxypropyl methylcellulose inhibited the carbamazepine transformation. None of the polymers tested were able to inhibit the sulfaguanidine transformation although some polymers were able to reduce the rate of the transformation with poly(vinylpyrrolidone) showing the greatest effect. It was found that the inhibitory polymers were able to either reduce crystal growth rates and/or increase the induction time preceding the nucleation event.