Dissolution Behavior of an Amorphous Solid Dispersion in Surfactant Containing Media
G. Ma, B. S. Levine, D. J. Lavrich
Merck & Co., Inc.
Purpose
Amorphous solid dispersions have been increasingly used to enhance the bioavailability for poorly soluble drugs. Dissolution method
development for these formulations has faced challenges due to their unstable super saturation state in aqueous media. Whether the
dissolution sink condition should be based on API crystalline solubility or amorphous solubility is debatable. In this work the
dissolution behavior of a poorly soluble API in a HPMCAS spray dried formulation and the function of surfactant in dissolution media
were studied in order to develop an appropriate QC dissolution method.
Methods
Equilibrium solubility of the drug substance in crystalline form and apparent solubility of the spray dried intermediate (SDI) in media
containing 0% to 5% of polysorbate 80 was measured by HPLC. Crystalline API solubility was also mapped with varying levels of
polysorbate 80 and HPMCAS at room temperature and 37°C by HPLC. 60 minutes and 24 hours dissolutions of tablets containing the
SDI were performed at 0% to 3% of polysorbate 80. The tendency of the API precipitation was evaluated at room temperature and
5°C by seeding different forms of the crystalline API in the dissolution vessels.
Results
Solubility measurement shows that polysorbate 80 increases solubility for both crystalline and amorphous API. However the API
crystalline equilibrium solubility (0.09 mg/mL) is still a little lower than target dissolution concentration (0.11mg/mL) even at 5%
polysorbate 80 while the amorphous solubility reaches sink condition (3x target concentration) at 3% polysorbate 80 (0.40 mg/mL).
On the other hand API solubility mapping shows HPMCAS almost does not increase API crystalline solubility (Figure 1).
The dissolution profiles in Figure 2 show that the SDI solution is stable within 24 hours at 3% polysorbate 80. The supersaturated
solutions were seeded with different forms of the crystalline API and no precipitation was observed. The solutions with crystalline
seeds were stored at room temperature and 5°C for 4 days and no assay drop was observed. On the other hand, solutions without
polysorbate 80 showed precipitation overtime during the dissolution and crystalline seeding trigger more precipitation.
Conclusion
This study demonstrated that for the API evaluated, a sink condition based on crystalline equilibrium solubility is not necessary for a
QC dissolution method for tablets containing amorphous solid dispersion materials. With adequate amount of surfactant, solution at
super saturation state can have sufficient stability for dissolution testing. This allows the use of lower level of surfactant, potentially
providing better discrimination.
The study also confirmed that HPMCAS alone does not increase the crystalline solubility of the API and the API precipitated from the
SDI solution overtime. Surfactant stabilized the supersaturated SDI solution. No API precipitation were triggered by low temperature
storage and seeding of crystalline API. With this finding the sink condition can be determined based on amorphous solubility instead
of crystalline solubility and surfactant level in dissolution can be significantly reduced.