A Stratified Analysis of Supersaturation and Precipitation Effects Based on the Refined Developability Classification System (rDCS).

Supersaturation and precipitation within the gastrointestinal tract can influence oral absorption of active pharmaceutical ingredients (APIs). Supersaturation of weakly basic APIs upon transfer from the stomach into the small intestine may enhance their absorption, while salt forms of poorly soluble weak acids may generate supersaturated solutions in both stomach and intestine. Likewise, APIs with solubility-limited absorption may be developed as enabling formulations intended to produce supersaturated solutions of the API in the gut. Integrating the supersaturation/precipitation characteristics of the API into the biopharmaceutical risk classification enables comprehensive mapping of potential developability risks and guides formulation selection towards optimizing oral bioavailability (BA). The refined Developability Classification System (rDCS) provides an approach for this purpose. In this work, the rDCS strategy is revisited and a stratified approach integrating the in vitro supersaturation and precipitation behavior of APIs and their formulations is proposed.

Projection of Target Drug Particle Size in Oral Formulations Using the Refined Developability Classification System (rDCS).

Dissolution limitations to oral absorption can occur if the time required for dissolution is longer than the transit time across the small intestine and/or if dissolution is slower than the drug's permeation through the gut wall. These limitations most often occur for poorly soluble drugs. A standard method for overcoming dissolution issues is to reduce the particle size of the (solid) drug. Building on the refined Developability Classification System (rDCS), this work establishes a novel set of equations with which the appropriate degree of particle size reduction needed to mitigate dissolution limitations to absorption can be calculated. According to the type of data available, the appropriate equation(s) for each situation can be applied. Three case examples are used to illustrate implementation of the equations: voriconazole, lemborexant and istradefylline. Although for voriconazole (rDCS Class I) target radius (rtarget) estimates indicate that particle size reduction is unnecessary, for lemborexant (rDCS Class I) a radius of ≤20 µm would be required to improve absorption. For istradefylline (rDCS Class IIb) the rtarget was approximately 12 µm. Results are commensurate with literature information for these three drugs, signaling that the equations are suitable for application to a wide variety of drug substances.

Increasing the Robustness of Biopharmaceutical Precipitation Assays - Part I: Derivative UV Spectrophotometric Method Development for in-line Measurements.

In vitro precipitation assays are often applied to support drug and formulation development. Current methods applied to quantify the amount of dissolved drug, in particular (U)HPLC, require time-consuming sample preparation. Furthermore, small precipitates formed during the nucleation phase may not be removed quantitatively by filtration or centrifugation of the sample. Given the drawbacks of standard (U)HPLC analyses during the application in transfer experiments, it was the aim of this work to develop a robust and simple to implement in-line UV spectrophotometric method which accurately reflects the precipitation profile obtained from in vitro transfer assays. Based on the three model compounds cinnarizine, dipyridamole, and ketoconazole, the manuscript describes the development of a design of experiments (DoE) based approach to develop derivative UV spectrophotometric methods accounting for the change in media composition over time due to the dilution of simulated intestinal with simulated gastric fluid. An R script was developed which automatically identifies suitable wavelengths for in-line measurements. As an outcome of this study, a fast, robust, accurate, and specific derivative UV spectrophotometric methodology for measuring the concentration of dissolved drugs in in vitro transfer experiments was successfully developed. This method can flexibly be applied to multi-compartmental precipitation assays.