Track: Formulation and Delivery - Chemical - Formulation - Amorphous and Co-crystal Systems
Category: Poster Abstract
Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions Formulated with Neutral and Enteric Polymers
Purpose: Amorphous solid dispersions (ASDs) comprise of an amorphous drug molecularly dispersed in a hydrophilic polymer matrix. This formulation is typically used to confer bioavailability advantages in comparison to the crystalline drug. The dissolution of the higher energy amorphous form of the drug enables the formation of a supersaturated solution, which is maintained by the aid of a polymer acting as the crystallization inhibitor. Recent studies with neutral polymers have shown that on top of its role as a crystallization inhibitor, the polymer in the ASD plays an additional role in controlling the rate of drug dissolution in congruently release formulations, where both the drug and polymer have similar dissolution rates. However, as the drug loading (DL) increases, a transition from polymer-controlled to drug-controlled dissolution results in an abrupt decrease in the drug dissolution rate. In this case, the drug and polymer release are incongruent. The precise nature of this transition from congruent to incongruent release remains poorly understood. Additionally, the role of other polymers (e.g., enteric polymers) in controlling the dissolution rate of ASDs is not well studied. Herein, the suitability of enteric polymers as candidates to formulate ASDs in comparison to copovidone (PVPVA, a neutral polymer) was evaluated with lumefantrine as the model drug. This study aims to compare the solid-state stability and dissolution performance of ASDs when formulated using neutral and enteric polymers. Methods: One neutral (PVPVA) and four enteric polymers (hypromellose acetate succinate, HPMCAS; hypromellose phthalate, HPMCP; cellulose acetate phthalate, CAP and methacrylic acid–methyl methacrylate copolymer, Eudragit L 100) were used to formulate binary ASDs of different DLs with lumefantrine. The ASDs were prepared using solvent evaporation. The Wood’s intrinsic dissolution apparatus was used to monitor the release of lumefantrine and the polymer. The surface of the compacts after dissolution was characterized using Fourier transform infrared (FTIR) spectroscopy. Solid-state stability of the ASDs under accelerated stability conditions was monitored using powder X-ray diffraction. Results: The drug and polymer dissolution rates of lumefantrine–PVPVA ASDs up to 35% DL were rapid and similar. No drug release from PVPVA systems was detected when DL was increased to 40% (Figure 1a). In contrast, ASDs formulated with enteric polymers showed a DL-dependent decrease in the dissolution rates of both the drug and polymer. The surface normalized dissolution rate of both HPMCAS and HPMCP showed a gradual decrease as DL increased (Figure 1b and c). Drug release from CAP and Eudragit L 100 systems was slow and amorphous solubility was not achieved even at 5% DL. Drug release from 25 and 50% DL was below the quantification limit (Figure 1d and e). Likewise, the polymer release from the ASDs at these DLs was also below the quantification limit.
When the dispersions were stored in open dish accelerated stability conditions of 40 °C/ 75% RH, ASDs formulated with HPMCP and Eudragit L 100 were found to be stable under these conditions for up to 40 weeks. ASDs formulated with PVPVA were least stable under the accelerated stability conditions (Figure 2). Small peaks were also observed in HPMCAS ASD with 50% DL after 1 week. For lumefantrine–CAP ASDs, peaks were observed in 5% DL ASDs after 1 week of storage, while ASDs with 10 and 25% DL also showed crystalline peaks after 4 and 16 weeks, respectively.
The carbonyl region of the ASDs was monitored after 2 h dissolution. As shown in Figure 3, samples obtained from 40, 45, and 50% DL PVPVA-based compacts after 2 h dissolution showed a red shift in the vinylpyrrolidone peak when compared to 50% DL ASD. The intensities of the characteristic peaks of PVPVA were also substantially diminished. Additionally, new bands attributable to the –C=C– aromatic carbons in lumefantrine were observed. Together, these observations strongly suggest a change in the chemical composition of the compact surface after dissolution, and the appearance of new bands similar to those of amorphous lumefantrine further suggests that the compact surface was enriched with the drug while polymer concentration was markedly reduced. In contrast, the similarity between the spectra before and after dissolution in terms of peak shape and position for ASDs formulated with the enteric polymers suggests that the surface composition of these ASD compacts in terms of drug and polymer ratio did not change drastically during dissolution. Conclusion: The release of lumefantrine from PVPVA-based ASDs was found to be more rapid compared to binary ASDs formulated with enteric polymers HPMCAS, HPMCP, CAP, and Eudragit L 100. Diminished dissolution performance in PVPVA systems was attributed to the enrichment of lumefantrine at the compact surface during dissolution. Additionally, PVPVA systems were susceptible to crystallization when stored under accelerated storage conditions. This study highlights the importance of polymer selection in the formulation of ASDs, as a balance between physical stability and dissolution performance must be achieved.