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

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.

Development of an automated microfluidic reaction platform for multidimensional screening: reaction discovery employing bicyclo[3.2.1]octanoid scaffolds.

An automated, silicon-based microreactor system has been developed for rapid, low-volume, multidimensional reaction screening. Use of the microfluidic platform to identify transformations of densely functionalized bicyclo[3.2.1]octanoid scaffolds will be described.

Solder-based chip-to-tube and chip-to-chip packaging for microfluidic devices.

Constructing a microsystem compatible with a large variety of chemistries requires a system design that will be robust in the presence of different compounds and at a wide range of conditions. Although microreactors themselves can accommodate a great span of conditions, few packaging schemes are compatible with cryogenic temperatures, high pressures, and aggressive organic solvents. Solder-based connections are designed and implemented on silicon-based microreactors and are demonstrated to withstand elevated pressures (up to 200 atm), a wide range of temperatures (-78 to 160 degrees C) and a variety of solvent systems. Through the deposition of metal bonding pads directly onto silicon and glass surfaces, solder-based chip-to-tube connections can be reliably formed using handheld soldering tools. Packaging techniques are also described for fluidic chip-to-chip bonds, facilitating direct connection of microfluidic modules. This method greatly expands the utility of microfluidic reactors while enabling easy and reproducible fluidic packaging.