Producción, caracterización y propiedades funcionales de un nuevo excipiente coprocesado a partir de sorbitol y fosfato de calcio anhidro

Abstract

RESUMEN: ANTECEDENTES: En la actualidad, la metodología preferida para la fabricación de formas farmacéuticas sólidas es la compresión directa debido a su gran versatilidad. La ejecución de esta tecnología hace necesaria la utilización de excipientes multifuncionales de alto desempeño. Este tipo de materiales pueden ser obtenidos por coprocesamiento. OBJETIVO: Desarrollar un excipiente multifuncional por aglomeración in-situ de sorbitol y fosfato de calcio anhidro. MÉTODOS: Se evaluaron cuatro métodos de coprocesamiento: secado por aspersión, aglomeración, coprecipitación y granulación por fusión utilizando niveles de fosfato de calcio anhidro del 5 al 95%. La funcionalidad del nuevo excipiente se comparó con excipientes coprocesados comerciales como Prosolv SMCC 90®, Ludipress® y Cellactose 80®. Las pruebas empleadas fueron: sensibilidad al lubricante, capacidad de reproceso, potencial de dilución, densificación, compresibilidad, compactabilidad, friabilidad, desintegración, mecanismo de deformación y pruebas de disolución in-vitro utilizando como fármaco modelo el gemfibrozilo. RESULTADOS: El análisis multivariado indicó la aglomeración in-situ como la tecnología más eficiente de producción del excipiente. Entre las proporciones de fosfato de calcio anhidro y sorbitol ensayados, la proporción 5:95 fue la de mejor desempeño farmacotécnico. CONCLUSIÓN: Se logró desarrollar un nuevo excipiente multifuncional por aglomeración in situ a partir de sorbitol y fosfato de calcio anhidro (95:5), el cual mostró adecuadas propiedades de compresión y puede ser utilizado en aplicaciones de compresión directa en formulaciones que contienen principios activos con propiedades farmacotécnicas muy pobres como el gemfibrozilo.

ABSTRACT: BACKGROUND: Currently, the preferred method for the manufacture of solid dosage forms is by direct compression, mainly due to its great versatility. The implementation of this technology requires the use of high-performance multi-functional excipients to improve efficiently the tableting behavior of active ingredients having poor mechanical properties. A great choice is co-processing, which involves the physical interaction to the microparticular level of compounds to create highly performing materials. OBJECTIVE: To develop a multifunctional excipient by in-situ agglomeration of sorbitol and anhydrous calcium phosphate. METHODS: Spray drying, agglomeration, hot-melt granulation and coprecipitation were used for co-processing employing calcium diphosphate levels from 5 to 95%. A multivariate analysis indicated in-situ agglomeration as the most efficient production technology. The calcium diphosphate and sorbitol ratio having the best tableting performance was 5:95. The functionality of this new in-situ agglomerated excipient was compared with commercial excipients named as Prosolv SMCC 90®, Cellactose 80® and Ludipress®. These materials were tested for lubricant sensitivity, reprocessing capacity, dilution potential, densification, compressibility, compactibility, friability, disintegration and deformation mechanism. Finally, direct compression of gemfibrozil, and in-vitro dissolution studies were conducted. RESULTS: A multivariate analysis indicated in-situ agglomeration as the most efficient production technology. The calcium diphosphate and sorbitol ratio having the best tableting performance was 5:95. Except for the in-situ agglomeration, most technologies required long processing times, were very tedious to implement and produced very low yields. Moreover, the agglomerate obtained with this novel excipient having the best tableting characteristics contained 5% of calcium diphosphate. This material showed a high plasticity and good compressibility and flow. Furthermore, its compactibility was superior to that of Cellactose 80® and Ludipress® but less than that obtained for Prosolv SMCC 90®. The dilution potential was similar to that obtained for the other commercial materials. However, the agglomerate showed a high reworking susceptibility and was less lubricant sensitive than Prosolv SMCC 90® and Ludipress®. Furthermore, formulations containing 600 mg of gemfibrozil had the highest percentage of dissolution fulfilling the S2 criterion of the USP 38. CONCLUSION: It was possible to develop a new multifunctional excipient by in-situ agglomeration of sorbitol and anhydrous calcium phosphate (95: 5). It showed adequate tableting properties and can be used in direct compression applications with formulations containing active ingredients having poor mechanical properties such as gemfibrozil. Keywords: