(M1030-04-22) Control of Recrystallization in Tablets Containing Amorphous Solid Dispersion

Purpose: Formulation containing amorphous solid dispersion (ASD) has demonstrated effectiveness of enhancing the bioavailability of poorly soluble drugs. However, the drug in ASD may recrystallize during downstream manufacturing process and/or upon storage for extended time. The purpose of this study was to evaluate factors (from formulation and process) that may impact stability of the ASD in a tablet formulation and propose a strategy to control recrystallization of the amorphous drug in the tablets.

Methods: ASD of a BCS II drug and polymer hypromellose succinate acetate (HPMC-AS) was prepared by spray drying process in a 1:1 ratio. The spray drying process has been developed and optimized to form the ASD, which was then processed by blending, dry granulation, compression and aesthetic film coating with selected excipients into an immediate release tablet. Initial risk assessment was conducted, and four factors were determined to be potentially at higher risk of inducing ASD to recrystallize in the tablet. These four factors were further evaluated: 1) particle size of the ASD (Dv50 8.0µm vs. Dv50 23.0µm); 2) surfactant in the formulation (low vs. high); 3) main compression force (8kN vs 12kN); 4) coating process– “dry (T exhaust at 48-50°C)” vs. “standard (T exhaust at 45-48°C)” condition with Opadry II white coating system. Uncoated and coated tablets with these variations were stressed at 40°C/75% RH in an open dish protected from the light and tablets pulled at different stability time points were characterized for appearance, moisture content, amount of crystalline API if present via PXRD, and DSC.

Results: Crystallization of ASD particles depend on its specific surface area. Smaller amorphous drug particles tend to recrystallize faster due to increased surface area which may absorb more moisture when being exposed to elevated humidity. Coated tablets prepared with smaller ASD particle size showed recrystallization of the drug earlier than tablets prepared with larger particle size ASD after storing the tablets under 40°C/75% RH open. Surfactants and main compression force at two different levels studied did not induce recrystallization of ASD in the tablets after exposing to 40°C/75% RH in an open dish condition for 14 days and 29 days respectively based on PXRD and DSC results.  The aqueous based coating process was determined as the high-risk factor causing the drug to recrystallize in the tablets due to high moisture and temperature exposure. Based on stability study results, coated tablets using standard processing condition were found to be at relatively higher risk of recrystallization as compared to dry coating condition. It was determined that maintaining the “dry” coating environment for relatively shorter time can minimize recrystallization of the amorphous drug in the tablet coating.

Conclusion: This study explored different factors that may cause recrystallization of the drug from the ASD in a tablet formulation. Four factors were successfully evaluated based on risk assessment: ASD particle size, surfactant level, tablet main compression force, and the film coating process. ASD particle size and the film coating process conditions were most likely causing recrystallization of API from the tablets, thus these factors need to be controlled in manufacturing tablets containing ASD. Additional characterization of the tablets such as Raman Mapping on the cross-section area of tablets can also be a useful tool to evaluate the crystalline API present in the tablets.

Acknowledgments: No conflict of interest stated in this poster presentation. Study included is solely sponsored by Blueprint Medicines.