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Published on: September 20, 2017
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Overcoming drug impurity challenges in amorphous solid dispersion with rational development of biorelevant
T Huzjak1, O Jakasanovski2, K Berginc2
1Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, Ljubljana 1000, Slovenia; Product Development, Lek Pharmaceuticals d.d., Verovškova 57, Ljubljana 1526, Slovenia.
Summary
This study optimized hot-melt extrusion (HME) parameters for amorphous solid dispersions, establishing an in vitro-in vivo correlation for drug release relevant to patient bioavailability.
Area of Science:
- Pharmaceutical Sciences
- Drug Delivery Systems
- Materials Science
Background:
- Hot-melt extrusion (HME) is crucial for creating amorphous solid dispersions (ASDs) to enhance the bioavailability of poorly soluble drugs (BCS Class II/IV).
- Optimizing HME process parameters (temperature, feed rate, screw speed) is essential for achieving drug amorphization and desired release profiles.
- Drug properties, including its initial form (anhydrous vs. hydrate) and impurity profile, significantly influence ASD performance.
Purpose of the Study:
- To evaluate the impact of HME process parameters, drug form, and supplier on the biorelevant drug release of ASDs.
- To develop and validate in vitro dissolution and dissolution-permeation methods for assessing ASD performance.
- To establish an in vitro-in vivo correlation (IVIVC) linking in vitro supersaturation and precipitation behavior to in vivo bioavailability in patients.
Main Methods:
- Preparation of ASDs using a BCS II/IV model drug and PVP/VA polymer via HME.
- Development of a small-volume paddle dissolution method and a side-by-side dissolution-permeation method using the MicroFlux™ apparatus.
- In vivo studies in dogs and clinical studies in patients to confirm biorelevance and establish IVIVC.
Main Results:
- The study established a relationship between in vitro supersaturation/precipitation and in vivo outcomes.
- The developed in vitro methods demonstrated high discriminatory power and biorelevance.
- IVIVC was confirmed, validating the predictive capability of the in vitro models for patient bioavailability.
Conclusions:
- Optimized HME processing is critical for consistent ASD quality and performance.
- In vitro testing must consider supersaturation and colloidal species formation for accurate prediction of ASD behavior.
- The established IVIVC supports the use of these in vitro methods for generic drug product development and quality assurance.
Keywords:
Biorelevant dissolution-permeationHot-melt extrusionIn vitro – in vivo correlationLiquid-liquid phase separationSolid dispersionSupersaturationMore Related Videos
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