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May 1, 2020

Amorphous Solid Dispersions in Early Stage of Formulation Development: Predicting Excipient Influence on Dissolution Profiles Using DDDPlus


Excipients play an important role in the formulation of dosage forms and can be used to improve the bioavailability of a drug through physical interactions that alter the rate of dissolution of a drug. The objective of this study was to predict the effect of formulation on the dissolution rate of a poorly soluble drug using computer simulations. Solid dispersion of ritonavir was prepared. Dissolution test results of direct compressed tablets with and without disintegrant in various media with physiologically relevant pH were compared with simulations. Solubilizer and disintegrant effect were evaluated on the Dose, Disintegration, and Dissolution Plus (DDDPlus) simulation software (version 5.0.0011, Simulations Plus, Inc., Lancaster, CA, USA) using previously published solubility data on ritonavir. Observed and predicted dissolution profiles similarity tests and drug release mechanisms were assessed. Optimization of the solubilizer effect coefficient (SEC) on the program gives good estimations of the effect of copovidone in the solid dispersion in the dissolution profiles of all tablets. The SEC is dependent on the solubility of the active pharmaceutical ingredient (API) at the local pH and the dissolved concentration of the solubilizer. Disintegrant concentration in the program has no effect on simulations, rather the disintegration time was the predictive factor. Drug release was formulation controlled in the tablets without disintegrant and in the tablets with disintegrant was via drug diffusion and polymer surface erosion. DDDPlus has the potential to estimate the effect of excipients in a formulation on in vitro dissolution at an early stage in the drug development process. This could be useful in decisions on formulation strategies to enhance bioavailability in poorly soluble drugs.

By Juliet Obianuju Njoku, Dwaipayan Mukherjee, Gregory K. Webster, and Raimar Löbenberg

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