Amorphous solid dispersions of amphiphilic polymer excipients and indomethacin prepared by hot melt extrusion

Improving the solubility of poorly water-soluble drugs is essential for enhancing bioavailability, formulation flexibility and reducing patient-to-patient variability. The preparation of amorphous solid dispersions (ASDs) is an attractive strategy to formulate such drugs, leading to higher apparent water solubility and therefore higher bioavailability. For such ASDs, water-soluble polymer excipients, such as poly(vinyl pyrrolidone) (PVP) or poly(vinyl pyrrolidone-co-vinyl acetate) (P(VP-co-VA)), are employed to solubilize and stabilize the drug against crystallization. We posit that polymers bearing tertiary amides are particularly well suited to stabilizing drugs containing H-bond donors, as they offer strong H-bonding potential between the polymer and drug.

The aim of this study was to compare new and established polymers with tertiary amides as excipients for ASDs. Experimental amphiphilic ABA triblock copolymers comprising poly(2-methyl-2-oxazoline) (pMeOx), poly(2-butyl-2-oxazoline) (pBuOx) and poly(2-butyl-2-oxazine) (pBuOzi) blocks, were compared with the established excipients, PVP and P(VP-co-VA). ASDs with indomethacin as the model drug were prepared at high drug loadings via hot melt extrusion. The extrudates were studied with DSC and PXRD, revealing the ASDs to be fully amorphous up to 75wt% indomethacin, independent of the polymer used.

13C CPMAS NMR provided insights into intermolecular associations as a function of drug loading, and suggested the presence of drug dimers at 75wt% drug loading in pMeOx-pBuOzi-pMeOx and pMeOx-pBuOx-pMeOx, which could affect physical stability. Independent of the polymers, the solid-state form of the drug in the ASD was found to affect the dissolution profile of the samples, insofar as the samples containing crystalline indomethacin showed slower dissolution than the fully amorphous ones. This study shows that the polymers comprising poly(2-oxazoline) and poly(2-oxazine) are effective polymers for ASD preparation, similar to PVP and P(VP-co-VA) which merits futher investigations into these novel polymers for formulating ASDs.

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Materials and Methods

Indomethacin (IND) was purchased from TCI chemicals (Zwijndrecht, Belgium), 3-aminopropanol, 2-aminoethanol, valeronitrile, 2-methyl-2-oxazoline, benzonitrile, calcium hydride, phosphorus pentoxide, methyl triflate and zinc acetate dihydrate were obtained from SigmaAldrich (Helsinki, Finland). Poly(vinyl pyrrolidone) (PVP) and poly(vinyl pyrrolidone-co-vinyl acetate) (P(VP-co-VA)) were purchased from BASF (Ludwigshafen, Germany). All materials were used as received unless otherwise stated. The monomer 2-methyl-2-oxazoline was dried by stirring over CaH2 under inert atmosphere,followed by distillation prior to use. Benzonitrile was dried by refluxing over P2O5 under inert atmosphere, followed by distillation prior to use.

Keßler L, Mishra R, Hietala S, Lammens M, Rades T, van Veen B, et al. Amorphous solid dispersions of amphiphilic polymer excipients and indomethacin prepared by hot melt extrusion. ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-45fhm This content is a preprint and has not been peer-reviewed.

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