This work demonstrates a pH-dependent dissolution in vitro and absorption in vivo for the weak bases ketoconazole and dipyridamole independent of food effects. This model is useful to examine pH-dependent effects on oral drug absorption and for screening formulations to overcome the pH dependency.

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.

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The objective of this study is to recover Active Pharmaceutical Ingredients (APIs) from tablets via green engineering technology to meet material requirements for downstream formulation development. A separation train, using water as the separation media, includes dissolution, centrifugal phase separation, diafiltration and reverse osmosis and has been developed based on the physical properties of the API and excipients. These properties include solubility, multiphase behaviors, particle densities, and size differences between API and excipients. The recovered API both meets purity specifications and contains no polymer. It is suitable for reuse in formulation process development. The recovery of the API from tablets is over 90%. A green engineering technology using water and separation methods is successfully developed and used to recover API from tablets.

We describe the synthesis, chromatographic purification, and isolation of the epothiloneÀfolic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10À30 g) of cGMP quality BMS-753493.