4.4 Article

Formulation Intervention to Overcome Decreased Kinetic Solubility of a Low Tg Amorphous Drug

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AAPS PHARMSCITECH
卷 24, 期 6, 页码 -

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SPRINGER
DOI: 10.1208/s12249-023-02601-z

关键词

amorphous salt; dissolution failure; formulation optimization; low glass transition temperature (T-g); surface agglomeration (sintering)

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This technical note investigated the reduction of dissolution rate in a dry blend capsule formulation containing an amorphous salt of drug NVS-1 during accelerated stability studies. It was observed that at elevated temperature and humidity conditions, sintering of the amorphous drug particles occurred, resulting in slower dissolution rate. Formulation intervention improved dissolution performance, but sintering was still observed at high humidity. Future formulation efforts will focus on reducing the impact of moisture and optimizing disintegrant levels.
This technical note investigated the loss of dissolution rate during accelerated stability studies with a dry blend capsule formulation containing an amorphous salt of drug NVS-1 (T-g 76 degrees C). After 6 m at 40 degrees C/75%RH, dissolution of NVS-1 was & LE;40% of initial value. Scanning electron microscope characterization of the undissolved capsule contents from samples stored at 50 degrees C/75%RH for 3 weeks showed agglomeration with a distinct melt and fuse morphology of particles. At elevated temperature and humidity conditions, undesired sintering among the amorphous drug particles was observed. Humidity plasticizes the drug as the stability temperature (T) gets closer to the glass transition temperature (T-g) of the amorphous salt (i.e., smaller T-g-T); a decreased viscosity favors viscoplastic deformation and sintering of drug particles. When moisture is adsorbed onto agglomerated drug particles, partial dissolution of the drug forms a viscous surface layer, further reducing the rate of dissolution media penetration into the bulk solid, hence the slower dissolution rate. Formulation intervention focused on the use of L-HPC and fumed silica as disintegrant and glidant and the removal of the hygroscopic crospovidone. Reformulation improved dissolution performance at short-term accelerated stability conditions of 50 degrees C (& PLUSMN; 75%RH); however, sintering to a lesser extent was still observed at high humidity, impacting the dissolution rate. We infer reducing the impact of moisture at high humidity conditions in a formulation with a 34% drug load is challenging. Future formulation efforts will focus on the addition of water scavengers, reducing drug load by similar to 50% to physically separate drug particles by water-insoluble excipients, and optimizing disintegrant levels.

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