Mechanistic Models for USP2 Dissolution Apparatus, Including Fluid Hydrodynamics and Sedimentation

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pharmaceutical Sciences
• Biopharmaceutics

Background:

• Accurate in vitro dissolution is crucial for physiologically based biopharmaceutics models (PBBMs) to predict in vivo drug performance.
• Existing PBBMs require mechanistic integration of in vitro dissolution, capturing key determinants and batch-specific parameters for immediate-release products.

Purpose of the Study:

• To develop and validate new hydrodynamic (HD) models for predicting drug product dissolution.
• To integrate product particle size distribution (P-PSD) with factors like USP2 apparatus paddle speed and medium viscosity.
• To model the impact of formulation and drug sedimentation (coning) on dissolution.

Main Methods:

• Proposed new hydrodynamic (HD) models, including HDC-1 (with excipients) and HDC-2 (drug substance only), to predict coning.
• Parameterized and validated models using 166 dissolution experiments across 18 different drugs.
• Assessed predictive power using average fold error (AFE) and absolute average fold error (AAFE).

Main Results:

• HD model demonstrated satisfactory predictive power for dissolution rate (AFE: 0.85-1.15, AAFE: 1.08-1.28).
• HDC-1 model improved prediction precision by 2.46-fold compared to the HD model in cases of suspected coning.
• Validated models integrate USP2 paddle rotation, medium viscosity, and coning effects into P-PSD calculations.

Conclusions:

• The developed HD and HDC models enhance the accuracy of in vitro dissolution prediction for immediate-release formulations.
• Improved P-PSD calculations integrating hydrodynamic factors and coning will refine PBBM predictions.
• These advancements facilitate better prediction of prandial state effects on human drug exposure through in silico tools.