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Water-Induced Phase Separation of Spray-Dried Amorphous Solid Dispersions
Na Li1,2, Jonathan L Cape3, Bharat R Mankani1,4
1Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
Molecular Pharmaceutics
|September 15, 2020
Summary
Spray drying amorphous solid dispersions (ASDs) with mixed solvents can lead to phase separation. Even small changes in water content significantly impact ASD properties and drug dissolution rates, affecting manufacturing.
Area of Science:
- Pharmaceutical Sciences
- Materials Science
- Chemical Engineering
Background:
- Spray drying is a key technique for producing amorphous solid dispersions (ASDs), crucial for enhancing drug solubility and bioavailability.
- Solvent composition during spray drying critically influences the physical properties and stability of ASDs.
- Understanding phase behavior is essential for controlling ASD formation and preventing drug crystallization.
Purpose of the Study:
- To investigate the impact of methanol-water solvent mixtures on the phase behavior and properties of ritonavir-copovidone ASDs.
- To correlate spray-drying conditions with ASD characteristics and dissolution performance.
- To assess the risk of phase separation in ASDs manufactured using mixed organic solvents.
Main Methods:
- Preparation of ASDs using ritonavir and copovidone (PVPVA) via spray drying with varying methanol-water ratios.
- Characterization using differential scanning calorimetry (DSC), fluorescence spectroscopy, X-ray photoelectron spectroscopy (XPS), and surface-normalized dissolution rate (SNDR) measurements.
- Calculation of quaternary phase diagrams using a four-component Flory-Huggins model.
Main Results:
- Addition of water to the methanol solvent system induced phase separation during spray drying, with heterogeneity increasing with water content.
- A 10:90 H2O/MeOH system showed minor phase separation, detectable by DSC at higher drug loadings, impacting dissolution rates.
- A 60:40 H2O/MeOH system resulted in significant phase heterogeneity across all analytical techniques, with notable surface drug enrichment.
Conclusions:
- Solvent composition, particularly water content, profoundly affects ASD phase behavior and properties during spray drying.
- Phase separation can lead to compromised dissolution rates due to drug-rich phase formation.
- Predictive phase diagrams and drying trajectories align with experimental findings, aiding in process development and risk assessment for ASD manufacturing.
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