First-Principles and Empirical Approaches to Predicting In Vitro Dissolution for Pharmaceutical Formulation and Process Development and for Product Release Testing

Abstract

This manuscript represents the perspective of the Dissolution Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) and of two focus groups of the American Association of Pharmaceutical Scientists (AAPS): Process Analytical Technology (PAT) and In Vitro Release and Dissolution Testing (IVRDT). The intent of this manuscript is to show recent progress in the field of in vitro predictive dissolution modeling and to provide recommended general approaches to developing in vitro predictive dissolution models for both early- and late-stage formulation/process development and batch release. Different modeling approaches should be used at different stages of drug development based on product and process understanding available at those stages. Two industry case studies of current approaches used for modeling tablet dissolution are presented. These include examples of predictive model use for product development within the space explored during formulation and process optimization, as well as of dissolution models as surrogate tests in a regulatory filing. A review of an industry example of developing a dissolution model for real-time release testing (RTRt) and of academic case studies of enabling dissolution RTRt by near-infrared spectroscopy (NIRS) is also provided. These demonstrate multiple approaches for developing data-rich empirical models in the context of science- and risk-based process development to predict in vitro dissolution. Recommendations of modeling best practices are made, focused primarily on immediate-release (IR) oral delivery products for new drug applications. A general roadmap is presented for implementation of dissolution modeling for enhanced product understanding, robust control strategy, batch release testing, and flexibility toward post-approval changes.

Comparative in Vitro Dissolution Study on Metformin Market Products Using Different Dissolution Apparatuses

“…During drug development, dissolution profiles have been utilized to comprehend the influence of formulation composition on the in vitro release of an active pharmaceutical ingredient (API). It plays as well an important role in the context of science and risk-based process development, validation and evaluation of post-approval formulation changes to drug product quality [6].…”

Physiologically Based Pharmacokinetic (PBPK) Modelling for In Vitro-In Vivo Extrapolation: Emphasis on the Use of Dissolution Data

“…Though these models have profound influence on the current methodology of drug development, they are limited within themselves in terms of incomplete mimicking of in vivo behavior of the drug dissolution kinetics. Thus, the empirical calculations are largely concentrated in the in vitro domain of dissolution modelling (18). On the other hand, the kinetics of drug dissolution have also seen vigorous and energetic alterations incorporating the rate processes in terms of surface area, distance, solvent layers, and partition coefficient data (19).…”

“…Though these classical kinetic models are not categorized as empirical modelling tools for dissolution data, they are used to fit the coefficients of the models to the experimental data and provide proof for the release mechanism and time-dependent observations. Advantages of these empirical methods for calculation of drug release kinetics can be extrapolated to the in vivo profiles (18,(20)(21)(22).…”

Biorelevant Dissolution Method Development for Dutasteride and Tamsulosin Hydrochloride Modified Release Capsule Simulating Post-prandial Condition

“…6 Generally, quality control test for dissolution is performed by using standard buffer, with or without surfactant based on solubility of drug, dissolution procedure is different for individual product. 7 Whereas, bio relevant dissolution media is based on human gastro-intestinal condition and transit time. Dissolution volume and agitation speed are required to be modulated based on in vivo performance product.…”