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Laser Microinterferometry for API Solubility and Phase Equilibria: Darunavir as a Case Example
Veronika Makarova1, Mark Mandrik1,2, Sergey Antonov1
1A.V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, Leninsky pr. 29, 119991 Moscow, Russia.
Pharmaceutics
|July 30, 2025
Summary
Laser microinterferometry accurately determines the thermodynamic solubility and phase behavior of amorphous active pharmaceutical ingredients (APIs). This method aids in selecting excipients and predicting formulation stability for drug development.
Area of Science:
- Pharmaceutical Science
- Physical Chemistry
- Materials Science
Background:
- Accurate determination of active pharmaceutical ingredient (API) solubility and phase behavior is critical for drug development and stability.
- Conventional methods often struggle with precise phase transition and solubility limit determination, particularly for poorly soluble compounds.
Purpose of the Study:
- To demonstrate the utility of laser microinterferometry for determining the thermodynamic solubility of APIs.
- To adapt a method traditionally used for polymer systems to pharmaceutical applications.
Main Methods:
- Laser microinterferometry was employed to measure the thermodynamic solubility and phase behavior of amorphous darunavir.
- Experiments were conducted across a temperature range of 25-130 °C in diverse pharmaceutical solvents, including oils, water, glycerol, alcohols, and glycols.
- Dissolution kinetics and Hansen solubility parameters were also assessed for comparative analysis.
Main Results:
- Darunavir exhibited practical insolubility in vaseline and olive oils.
- Amorphous equilibrium with an upper critical solution temperature was observed in water and glycerol, with phase diagrams constructed.
- High solubility and crystalline solvate formation were noted in alcohols, glycols, and ethoxylated castor oil derivatives.
- Dissolution rates varied significantly, with methanol showing a fourfold faster rate than ethanol and thirtyfold faster than isopropanol.
- A good correlation was found between experimental data and calculated solubility parameters.
Conclusions:
- Laser microinterferometry is a viable tool for determining API thermodynamic solubility and observing dissolution processes.
- The method facilitates direct detection of solubility limits and phase transitions, crucial for formulation development.
- These findings support informed excipient selection, prevention of undesirable solvates, and prediction of formulation stability in early drug development.
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