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Formulation intervention to overcome decreased kinetic solubility of a low Tg amorphous drug

Bordawekar, Mangesh, Pudipeddi, Madhu, Ruegger, Colleen and Dhareshwar, Sundeep (2023) Formulation intervention to overcome decreased kinetic solubility of a low Tg amorphous drug. Formulation intervention to overcome decreased kinetic solubility of a low Tg amorphous drug, 24.

Abstract

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 (Tg 76°C). After 6 m at 40°C/75%RH, dissolution of NVS-1 was
≤40% of initial value. Scanning electron microscope characterization of the undissolved capsule contents from samples stored
at 50°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 (Tg) of the amorphous salt
(i.e., smaller Tg-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°C (± 75%RH); how�ever, 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
eforts will focus on the addition of water scavengers, reducing drug load by ~50% to physically separate drug particles by
water-insoluble excipients, and optimizing disintegrant levels.

Item Type: Article
Keywords: Low glass transition temperature (Tg), Amorphous salt, Surface agglomeration (sintering), Dissolution failure, Formulation optimization
Date Deposited: 07 Oct 2023 00:45
Last Modified: 07 Oct 2023 00:45
URI: https://oak.novartis.com/id/eprint/49807

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