High drug-loaded amorphous solid dispersions of a poor glass forming drug: The impact of polymer type and cooling rate on amorphous drug behaviour

Enhancing the aqueous solubility via amorphization of crystalline poor glass-forming drugs represents a challenge, particularly when drug dosing is high. In such scenarios, there is often a need for high polymer loadings leading to an increase in the dosage form mass and less patient acceptability. This work investigated the role that polymer type and after-melt cooling rate had upon the amorphicity of solid dispersions (SDs) containing high levels of naproxen and three commonly used polymeric excipients: Eudragit® EPO, Kollidon® VA64, and Soluplus®.

Using a combination of thermogravimetry, conventional and fast-scan DSC, oscillatory rheology, in silico Hansen solubility parameter computation, FTIR, and PXRD, we have shown that amorphicity could be affected by the cooling rate with the specific polymer type and amount playing a significant role in the degree of this impact. The amorphous drug content, evident at higher cooling rates, was found to be dependent on drug-polymer interaction and polymer melt viscosity. Higher polymer concentration and faster cooling produced less melt crystallization upon cooling, which was attributed to a shift in nucleation to lower temperatures where it could be inhibited by polymer matrix viscosity. Amorphous drug content, which contained drug nuclei, was evidenced by cold crystallization upon reheating.

After 4 weeks of ‘gentle’ storage, cold crystallization increased if nucleation was the dominant process, whereas cold crystallization decreased if crystal growth prevailed. Storage at elevated temperature and humidity resulted in the absence of cold crystallization, and increased melt crystallisation. Thus, faster cooling could serve as an additional tool to improve amorphous yield and stability of high drug-loaded SDs, however, intermolecular polymer-drug interaction, melt viscosity of the drug-polymer matrix, and storage conditions are of critical importance to achieve this goal.

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