(T1430-12-81) Novel High Throughput Polymer Screening for Development of Amorphous Solid Dispersion

Purpose: Here, we discuss a case study of a DCS class IIb compound whose bioavailability was solubility limited. An enabling formulation platform based on Amorphous Solid Dispersions (ASD) by Spay drying was evaluated to improve the kinetic solubility. For this, bespoke high-throughput screening techniques were employed that used minimum quantities of API to help select optimum polymer and drug load for the compound.

Methods: The Active Pharmaceutical Ingredient (API) was a crystalline with a melting temperature above 250 °C. The API had a solubility of up to 0.01 mg/mL in Fasted State Simulated Gastric Fluid (FaSSGF, pH 1.6) and Fasted State Simulated Intestinal Fluid (FaSSIF, pH 6.5) respectively. Immediate and enteric polymers such as PVP, HPMC, HP-50, HP-55 and HPMCAS-LF were screened for their ability to form amorphous dispersions. This was performed using material sparing slow evaporation film casting method in a 96-well plate. This allowed to test various API loads ranging from 5 to 50% w/w whilst consuming minimum amount of API. Amorphous hits were confirmed by X-ray powder diffraction (XRPD) using the bespoke high throughput Bruker^® D8 Discover system, polarised light microscopy (PLM) and modulated differential scanning calorimetry (mDSC). Amorphous films were scaled up for two stage low volume dissolution testing under non-sink conditions in FaSSGF (pH 1.6) and FaSSIF (pH 6.5) at 37 ± 0.5 °C to help narrow down the best performing polymer and to select optimum API to polymer load for scale up. ASD at 20% w/w API load with HPMCAS-LF was scaled up by spray drying using ProCepT^® Spray Dryer (4M8-TriX) equipped with a bi-fluid nozzle. Physicochemical characterisation such as XRPD, mDSC, thermogravimetric analysis (TGA) and dynamic vapour sorption (DVS) was performed on the spray dried dispersion (SDD) followed by a two stage biorelevant dissolution under non-sink conditions in FaSSGF (pH 1.6) and FaSSIF (pH 6.5) at 37 ± 0.5 °C. This was followed by a 4 week physical and chemical stability under refrigerated and accelerated conditions.

Results: High-throughput screen successfully identified 20% w/w API-HPMCAS-LF as an optimum drug load for further SDD development. Subsequent biorelevant dissolution on the SDD showed 600 fold higher solubility as compared to the crystalline material.

Conclusion: High-throughput screening helped in identifying the best polymer along with optimum polymer load for development of ASD using minimum amount of API in rapid time.

High throughput XRPD stage

Bespoke 96 well plate

Dissolution profile API vs ASD film vs SDD