Cocrystallization of Dolutegravir Sodium via Liquid-Assisted Grinding: Preparation, Characterization, and Ex vivo Evaluation

Rajendra Mogal; Moreshwar Patil

doi:10.30827/ars.v67i2.34754

Autores/as

Rajendra Mogal MET's Institute of Pharmacy https://orcid.org/0000-0002-5662-8580
Moreshwar Patil Department of Pharmaceutics, MET’s Institute of Pharmacy, Affiliated to Savitribai Phule Pune University, Bhujbal Knowledge City, Adgaon, Nashik 422003, India https://orcid.org/0000-0002-8060-1687

DOI:

https://doi.org/10.30827/ars.v67i2.34754

Palabras clave:

Dolutegravir sódico; Cocristales; Molienda asistida por líquido; Ácido sórbico; Estudio ex vivo

Resumen

Introducción: El dolutegravir sódico es un fármaco antirretroviral de segunda línea recomendado por la Organización Mundial de la Salud para el tratamiento de personas con el virus de la inmunodeficiencia humana (VIH) que no han respondido a un régimen de primera línea. Presenta baja solubilidad en agua y está clasificado como fármaco de Clase II según el Sistema de Clasificación Biofarmacéutica. Además, presenta una baja biodisponibilidad oral (<50%). La cocristalización es un método prometedor para mejorar la solubilidad y la biodisponibilidad mediante la formación de sintones supramoleculares con coformadores adecuados.

Método: Se prepararon cocristales de dolutegravir sódico utilizando xilitol, nicotinamida y ácido sórbico mediante el método de molienda asistida por líquido con acetato de etilo como disolvente. Se evaluaron los cocristales preparados para determinar su solubilidad, disolución, FTIR, DSC, PXRD y un estudio ex vivo mediante el método de intestino evertido.

Resultados: La solubilidad se incrementó 2,38; 2,91 y 5,01 veces con xilitol, nicotinamida y ácido sórbico, respectivamente. A los 60 minutos, las tasas de disolución fueron del 27,99 ± 2,5 % (fármaco puro), 49,06 ± 2,56 % (xilitol), 61,97 ± 3,24 % (nicotinamida) y 96,54 ± 4,61 % (ácido sórbico). Los cocristales de dolutegravir:ácido sórbico (1:1) mostraron un pico endotérmico distintivo a 177,22 °C en DSC y picos intensos de PXRD a 4,55 °C, junto con picos únicos a 10,61 °C, 12,61 °C, 12,23 °C, 15,09 °C, 16,24 °C, 21,56 °C, 24,76 °C y 25,27 °C. Los estudios ex vivo mostraron un transporte intestinal del 29,59 ± 4,93 % para el fármaco puro y del 72,51 ± 5,70 % para el cocristal.

Conclusión: Se prepararon y evaluaron con éxito cocristales de dolutegravir sódico con ácido sórbico. La solubilidad y la velocidad de disolución de los cocristales preparados aumentaron significativamente. Los análisis de FTIR, DSC y PXRD confirmaron la formación de una nueva estructura cristalina. Además, el estudio ex vivo demostró una mejora significativa en el transporte del fármaco a través de la membrana intestinal.

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