Balancing Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions: The Role of Polymer Choice and Drug–Polymer Interactions

Abstract

Amorphous solid dispersions (ASDs) are of great interest due to their ability to enhance the delivery of poorly soluble drugs. Recent studies have shown that, in addition to acting as a crystallization inhibitor, the polymer in an ASD plays a role in controlling the rate of drug release, notably in congruently releasing formulations, where both the drug and polymer have similar normalized release rates. The aim of this study was to compare the solid-state stability and release performance of ASDs when formulated with neutral and enteric polymers. One neutral (polyvinylpyrrolidone−vinyl acetate copolymer, PVPVA) and four enteric polymers (hypromellose acetate succinate; hypromellose phthalate; cellulose acetate phthalate, CAP; methacrylic acid− methyl methacrylate copolymer, Eudragit L 100) were used to formulate binary ASDs with lumefantrine, a hydrophobic and weakly basic antimalarial drug. The normalized drug and polymer release rates of lumefantrine−PVPVA ASDs up to 35% drug loading (DL) were similar and rapid. No drug release from PVPVA systems was detected when the DL was increased to 40%. In contrast, ASDs formulated with enteric polymers showed a DLdependent decrease in the release rates of both the drug and polymer, whereby release was slower than for PVPVA ASDs for DLs < 40% DL. Drug release from CAP and Eudragit L 100 systems was the slowest and drug amorphous solubility was not achieved even at 5% DL. Although lumefantrine−PVPVA ASDs showed fast release, they also showed rapid drug crystallization under accelerated stability conditions, while the ASDs with enteric polymers showed much greater resistance to crystallization. This study highlights the importance of polymer selection in the formulation of ASDs, where a balance between physical stability and dissolution release must be achieved.

Dissolution Behavior of Weakly Basic Pharmaceuticals from Amorphous Dispersions Stabilized by a Poly(dimethylaminoethyl Methacrylate) Copolymer

“…Diluting to neutral pH (Figure b) did not result in precipitation of lumefantrine for the Eudragit EPO amorphous dispersion, and the concentration maintained >150 μg/mL. At neutral pH, the amorphous dispersion stabilized by HPMCAS began to dissolve and released ∼40 μg/mL API after 60 min of dissolution, in line with concentrations observed in other studies. , Similar to data for posaconazole, these results demonstrate that Eudragit EPO can enable supersaturated solutions of weak bases under gastric and neutral conditions, and significantly for lumefantrine, high supersaturation was maintained for an hour under neutral conditions, potentially representing an increase to in vivo exposure compared to the other ASDs studied.…”

“…At neutral pH, the amorphous dispersion stabilized by HPMCAS began to dissolve and released ∼40 μg/mL API after 60 min of dissolution, in line with concentrations observed in other studies. 38,63 Similar to data for posaconazole, these results demonstrate that Eudragit EPO can enable supersaturated solutions of weak bases under gastric and neutral conditions, and significantly for lumefantrine, high supersaturation was maintained for an hour under neutral conditions, potentially representing an increase to in vivo exposure compared to the other ASDs studied. The impact of gastric pH on dissolution performance was also investigated for amorphous dispersions of lumefantrine.…”

“…Posaconazole and lumefantrine were selected as prototypical weakly basic pharmaceuticals with varied physicochemical properties to understand the generalizability of this approach. Posaconazole is a BCS class II compound with moderate crystallization propensity and aqueous solubility highly sensitive to pH, , whereas lumefantrine is a more stable glass former and is highly insoluble in both acidic and neutral pH. , Co-precipitated dispersions were generated by precipitation into alkaline aqueous media to ensure low residual solubility of both the API and the stabilizing polymer. Amorphous dispersions containing Eudragit EPO showed rapid dissolution at low pH and supersaturation in neutral media.…”

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

“…IR and DSC are rapid methods to identify such solids. A complete understanding of the thermodynamics driving the components to achieve the amorphous state without transformation to the low-energy crystalline form is a topic of recent studies in pharmaceutical systems. − Coamorphous solids are a relatively recent entry to pharmaceutical formulation in contrast to salts, cocrystals, and eutectics. Broadly, two categories of techniques are reported to prepare coamorphous solids: the amorphous drug is formed as a melt followed by rapid cooling (quenching) or fast removal of solvent by rapid precipitation of the drug from solution.…”

Insights into the Release Mechanisms of ITZ:HPMCAS Amorphous Solid Dispersions: The Role of Drug-Rich Colloids

“…If the polymer fraction in the matrix is higher (for lower DL) and the polymer has a ratio of acetyl (hydrophobic groups) to succinoyl (hydrophilic groups) closer to 1 (0.8) (M-grade), it may be inferred that these ASDs will present both strong drug–polymer interactions (through hydrophobic regions) and strong polymer–water interactions (through hydrophilic regions), which will lead to both a fast dissolution and high concentration of colloids as well as lower precipitation tendency compared to L-grade. On the contrary, the more hydrophilic grade, with a lower acetyl/succinoyl ratio (0.4) (HPMCAS L), will tend to interact more with the water than with the drug, which may result in a higher tendency to precipitate, as previously observed for other APIs. ,, …”