(T1330-10-57) Material Sparing Approaches for Preparation of Amorphous Solid Dispersions

Purpose: This study aimed to investigate the capability of material-sparing approaches to generate amorphous solid dispersions (ASDs) of poorly water-soluble drugs with limited amounts ( < 1 gram) of an active ingredient. The key objectives were to: i) prepare ASDs of a new chemical entity (NCE) on a small scale ( < 1 gram) using material-sparing approaches, ii) evaluate the ASDs, iii) prepare >10 gram scale spray-dried dispersions (SDDs) using a mini spray dryer, and iv) verify the feasibility of these material-sparing approaches for the spray drying process.

Methods: Potential ASDs with different drug loadings (DLs) were prepared on a < 1 gram scale using various methods: 1) rotary evaporation (RE), 2) centrifugal evaporation (CE), 3) co-precipitation (CP), 4) direct vacuum drying (DVD), and 5) physical mixing-grinding. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) was used to confirm the amorphous state of the active pharmaceutical ingredient (API). Subsequently, 10-gram scale SDDs with different percentages of DLs were manufactured using a mini spray dryer and evaluated for amorphous formulation stability and solubility in biorelevant media.

Results: Prototype ASDs containing 20% to 75% of the NCE Compound A (BCS II class) were generated and evaluated. The material-sparing approaches demonstrated the feasibility of formulating the NCE into ASDs on a small scale. While RE, CP, and DVD successfully generated ASDs with up to 75% DL without drug recrystallization, the ASD with 75% DL prepared by CE showed recrystallization. Physical mixing-grinding did not generate ASDs at any drug loading level. Based on the evaluation of prototype ASDs, SDDs up to 60% DL with 10 g scale were generated using a mini spray dryer. These SDDs were assessed for amorphous formation, solubility enhancement, stability, and two-stage dissolution in biorelevant media. SDDs with 20% to 60% DLs maintained amorphous forms and physicochemical stability for 4 weeks under stressed conditions of 40°C/75% RH, with a glass transition temperature (Tg) >90°C. The Direct Compression (DC) Immediate Release (IR) tablet containing 50% DL SDD showed a three-fold higher release amount in an in vitro 2-stage dissolution test compared to the tablet with the crystalline API.

Conclusion: Material-sparing techniques such as RE and CP proved effective for rapid ASD development, showing performance comparable to spray-dried dispersions. These methods are highly beneficial for working with scarce and expensive NCEs.

Acknowledgements: There is no conflict of interest.