Purpose: Investigate the influence of particle size on the dissolution and recrystallization behavior of amorphous solid dispersions (ASDs) with various polymer loading.
Methods: Amorphous Griseofulvin (GF) and GF ASDs were prepared via the melt-quench method. For GF ASDs formulations, Kollidon® VA 64 was selected as a crystallization inhibitor; its content varied between 10% to 50%. Amorphous GF and GF ASDs were first milled via mortar and pestle. Then series of sieves with mesh sizes between 45 and 355 μm were used to obtain various particle sized samples. Finally, effect of particle size and crystallization inhibitor loading on the dissolution behavior of GF ASDs were examined in deionized water.
Results: Results demonstrated that the simultaneous dissolution and recrystallization behavior of GF ASDs is highly dependent on particle size. The final solution concentrations of GF ASDs at 2 hours for the 45-75 μm group were 1.5-7 and 1.3-4 times higher than those for the 250-355 μm group under non-supersaturation and supersaturation conditions respectively. The dissolution rate of GF ASDs with 50% polymer loading for the 45-75 μm group was 27 mg/L*h under supersaturating condition, which was far higher than 10.1 mg/L*h for the 250-355 μm group. Dissolution behavior also relies on Kollidon® VA 64 loading. For the samples with particles in the size range of 45-75 μm, the final solution concentration of GF ASDs with 30% and 50% polymer loading were 26.1 and 27.0 mg/L at 2 hours respectively, which were almost 2 times the solubility of crystalline GF. However, the final solution concentration of amorphous GF (without any polymer addition) was only 6.9 mg/L at 2 hours. The recrystallization of amorphous GF was proven to be an important mechanism responsible for the worse dissolution behavior.
Conclusion: Smaller particle size fractions of ASDs could enhance the dissolution behavior by increasing both apparent solution concentration and dissolution rate. According to the dissolution profiles, smaller particle size fractions could dissolve more drug in amorphous form before recrystallization, even though recrystallization rates for smaller particles are faster than larger particles. Kollidon® VA 64 could improve the dissolution behavior of GF ASDs by inhibiting the recrystallization of API, and keeping it in the amorphous state under supersaturation conditions for a period of time. A minimum of 30% Kollidon® VA 64 loading was found to be necessary to enhance the stability of GF in the solution. The judicious combination of particle size reduction and polymer loading was demonstrated to be an effective way to improve dissolution behavior of GF ASDs.
Zhixing Lin– New Jersey Institute of Technology, New Jersey
Kuriakose Kunnath– New Jersey Institute of Technology, New Jersey
Liang Chen– Research Assistant, New Jersey Institute of Technology, Harrison
Rajesh Dave– Distinguished Professor, New Jersey Institute of Technology, New Jersey