Eutectic binary phase diagram and kinetically stable homogeneous co-amorphous mixtures of two imidazole drugs
Amorphous multicomponent formulations allow improving the solubility and thus the bioavailability of active pharmaceutical ingredients (APIs) that are poorly soluble in water, provided that the molecular mobility in such formulations does not promote crystallization in the amorphous (glassy) state d...
| Autores: | , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universitat Politècnica de Catalunya (UPC) |
| Repositorio: | UPCommons. Portal del coneixement obert de la UPC |
| Idioma: | inglés |
| OAI Identifier: | oai:upcommons.upc.edu:2117/427472 |
| Acceso en línea: | https://hdl.handle.net/2117/427472 https://dx.doi.org/10.1016/j.molliq.2024.126518 |
| Access Level: | acceso abierto |
| Palabra clave: | Amorphous solid solutions Glass transition temperature Conformational dynamics Dielectric spectroscopy Physical stability of glasses Formulation pre-development Àrees temàtiques de la UPC::Física |
| Sumario: | Amorphous multicomponent formulations allow improving the solubility and thus the bioavailability of active pharmaceutical ingredients (APIs) that are poorly soluble in water, provided that the molecular mobility in such formulations does not promote crystallization in the amorphous (glassy) state during their shelf life. Multi component formulations may involve a single API mixed with excipients, but also two mutually compatible APIs. Here, we describe kinetically stable amorphous binary mixtures of two commercial antifungal imidazole APIs, bifonazole and clotrimazole, which have similar melting points and glass transition temperatures. The equilib rium phase diagram of this binary system, as determined by differential scanning calorimetry, follows the Schroeder-van Laar-LeChatelier predictions, as typically found for compounds that are miscible as liquids but immiscible in the crystalline form, and is characterized by an experimental eutectic composition close to equi molar composition (xbifonazole = 0.45) and eutectic melting point Te = 392 K. The glass transition temperature Tg varies linearly with composition, as found in ideal liquid mixtures. Dielectric spectroscopy characterization is carried out to investigate the relaxation dynamics of each amorphous API separately, and of the amorphous mixtures (both in the supercooled liquid and glass state). A single structural a relaxation is observed in all supercooled liquid mixtures, confirming their homogeneity. Both pure amorphous APIs display conformational secondary relaxations: the one of bifonazole stems from the torsional rotation of the imidazole ring; the one of clotrimazole is significantly slower than that of bifonazole, and is related to small-angle librations of the imid azole and chlorobenzene rings. Conformational relaxation processes are observed also in binary mixtures, which display also a Johari-Goldstein relaxation as pure clotrimazole. Despite the presence of both primary and sec ondary relaxations, the binary mixtures are observed to remain amorphous for at least twelve months both at Tg and slightly above it. |
|---|