Development and Application of a Dissolution-Transfer-Partitioning System (DTPS) for Biopharmaceutical Drug Characterization.

A variety of in vitro dissolution and gastrointestinal transfer models have been developed aiming to predict drug supersaturation and precipitation. Further, biphasic, one-vessel in vitro systems are increasingly applied to simulate drug absorption in vitro. However, to date, there is a lack of combining the two approaches.

Screening for Differences in Early Exposure in the Fasted State with in Vitro Methodologies can be Challenging: Experience with the BioGIT System.

The Biorelevant Gastrointestinal Transfer (BioGIT) system is a useful screening tool for assessing the impact of dose and/or formulation on early exposure after administration of immediate release or enabling drug products with a glass of water in the fasted state. The objective of this study was to investigate potential limitations. BioGIT experiments were performed with five low solubility active pharmaceutical ingredients with weakly alkaline characteristics: mebendazole (tablet and chewable tablet), Compound E (aqueous solutions, three doses), pazopanib-HCl (Votrient™ tablet, crushed Votrient™ tablet and aqueous suspension), Compound B-diHCl (hard gelatin capsule, three doses) and Compound C (hard gelatin capsule containing nanosized drug and hard gelatin capsule containing micronized drug).

Challenges and Strategies for Solubility Measurements and Dissolution Method Development for Amorphous Solid Dispersion Formulations.

This manuscript represents the view of the Dissolution Working Group of the IQ Consortium on the challenges of and recommendations on solubility measurements and development of dissolution methods for immediate release (IR) solid oral dosage forms formulated with amorphous solid dispersions. Nowadays, numerous compounds populate the industrial pipeline as promising drug candidates yet suffer from low aqueous solubility. In the oral drug product development process, solubility along with permeability is a key determinant to assure sufficient drug absorption along the intestinal tract.

Impact of amorphization and GI physiology on supersaturation and precipitation of poorly soluble weakly basic drugs using a small-scale in vitro transfer model.

Formulation of amorphous solid dispersions (ASD) is one possibility to improve poor aqueous drug solubility by creating supersaturation. In case of weakly basic drugs like ketoconazole (KTZ), supersaturation can also be generated during the gastrointestinal (GI) transfer from the stomach to the intestine due to pH-dependent solubility. In both cases, the supersaturation during dissolution can be stabilized by polymeric precipitation inhibitors.

Improved Prediction of in Vivo Supersaturation and Precipitation of Poorly Soluble Weakly Basic Drugs Using a Biorelevant Bicarbonate Buffer in a Gastrointestinal Transfer Model.

The characterization of intestinal dissolution of poorly soluble drugs represents a key task during the development of both new drug candidates and drug products. The bicarbonate buffer is considered as the most biorelevant buffer for simulating intestinal conditions. However, because of its complex nature, being the volatility of CO, it has only been rarely used in the past.

Application of an automated small-scale in vitro transfer model to predict in vivo precipitation inhibition.

The majority of NCEs are weakly basic drugs. Consequently, their solubility is highly pH-dependent, with higher solubility in the acidic stomach and poor solubility in the neutral intestinal environment. The gastric emptying of dissolved drug can lead to the intestinal precipitation of the drug.

Automated small-scale in vitro transfer model as screening tool for the prediction of in vivo-dissolution and precipitation of poorly solubles.

Precipitation testing, especially for weakly basic APIs, represents a key parameter in drug substance characterization during early development stages, where the amount of API available is limited. Therefore, it was the aim of this study to develop an automated small-scale in vitro transfer model to characterize the supersaturation and precipitation behavior of two poorly water-soluble drugs. Following automation and scale-down of the standard transfer model, the developed small-scale model was used to assess the impact of gastrointestinal variability, i.

In-line derivative spectroscopy as a promising application to a small-scale in vitro transfer model in biorelevant supersaturation and precipitation testing.

Objectives: Dissolution testing of poorly soluble and precipitating drugs is of great importance for pharmaceutical industry. As offline HPLC analytics is time-consuming and labour-intensive, the development of suitable in-line analytics to measure drug concentration allows better predictions of drug dissolution and precipitation. The purpose of this study was to develop an in-line derivative spectroscopic method which facilitates drug concentration measurements in suspensions without additional sample preparation.