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Understanding the Influence of API Conformations on Amorphous Dispersion Formation Potential Predictions using the

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The R3m molecular descriptor aids in predicting amorphous solid dispersions (ASDs) with PVPVA. Incorporating conformational flexibility refines ASD prediction models for active pharmaceutical ingredients (APIs).

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Area of Science:

  • Physical Chemistry
  • Materials Science
  • Pharmaceutical Sciences

Background:

  • The R3m molecular descriptor (R-GETAWAY third-order autocorrelation index weighted by atomic mass) correlates with API properties relevant to amorphous solid dispersion (ASD) formation.
  • Previous models used single 3D conformations, potentially limiting accuracy for amorphous states.

Purpose of the Study:

  • To investigate the impact of molecular conformational flexibility on the R3m descriptor.
  • To refine ASD prediction models by incorporating a distribution of R3m values derived from molecular dynamics simulations.

Main Methods:

  • Molecular dynamics simulations were used to generate a distribution of probable conformations for APIs in the amorphous state.
  • The R3m descriptor was calculated for each conformation, yielding a distribution of R3m values per API.
  • A logistic regression model was developed using these R3m distributions to predict ASD formation with polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA).

Main Results:

  • While individual conformations showed R3m variations, the median R3m value closely matched single-conformation predictions for most APIs.
  • The distribution of R3m values, reflecting conformational flexibility, was successfully integrated into a logistic regression model.
  • This refined model demonstrated an improved classification boundary for predicting ASD formation compared to the single-conformation model.

Conclusions:

  • Accounting for molecular conformational distributions enhances the predictive power of the R3m descriptor for ASD formation.
  • The refined model offers a more robust approach to predicting API-PVPVA amorphous solid dispersion behavior.
  • This study highlights the importance of considering dynamic molecular properties in drug formulation development.