Physical stability and release properties of lumefantrine amorphous solid dispersion granules prepared by a simple solvent evaporation approach

Abstract

Amorphous solid dispersions (ASDs) of lumefantrine, which has low aqueous solubility, have been shown to improve bioavailability relative to crystalline formulations. Herein, the crystallization tendency and release properties of a variety of lumefantrine ASD granules, formed on a blend of microcrystalline cellulose and anhydrous lactose, prepared using a simple solvent evaporation method, were evaluated. Several polymers, a majority of which contained acidic moieties, and different drug loadings were assessed. Crystallinity as a function of time following exposure to stress storage conditions of 40 °C and 75% relative humidity was monitored for the various dispersions. Release testing was performed and ASD characteristics were further evaluated using infrared and X-ray photoelectron spectroscopy (XPS). A large difference in stability to crystallization was observed between the various ASDs, most notably depending on polymer chemistry. This could be largely rationalized based on the extent of drug-polymer interactions, specifically the degree of lumefantrine-polymer salt formation, which could be readily assessed with XPS spectroscopy. Lumefantrine release from the ASDs also varied considerably, whereby the best polymer for promoting physical stability did not lead to the highest extent of drug release. Several formulations led to concentrations above the amorphous solubility of lumefantrine, with the formation of nano-sized drug-rich aggregates. A balance between the ability of a given polymer to promote physical stability and drug release may need to be sought.

Physical Stability and Dissolution of Lumefantrine Amorphous Solid Dispersions Produced by Spray Anti-Solvent Precipitation

“…The ASDs having a higher extent of lumefantrine protonation exhibiting better stability. 39 However, in this study at the 4:6 drug:polymer ratio, the extent of protonation in lumefantrine in the ASDs with different polymers was ranked HPMCP > EL100 > CAP > HPMCAS > amorphous lumefantrine, while the order of lumefantrine stability was HPMCP > HPMCAS > CAP > EL100 > amorphous lumefantrine. From these results, a correlation is not observed between the degree of protonation in lumefantrine and ASD stability.…”

“…However, it is noteworthy that both CAP- and EL100-based systems, which both exhibited higher degrees of lumefantrine protonation, also had higher moisture contents or were exposed to moisture for a longer time due to slow drying rates. When no aqueous solvent was involved in the preparation process, EL100 and CAP based lumefantrine ASDs exhibited much higher stability (>30 days under accelerated storage conditions), 39 than when the aqueous solvent was involved like in this study. A high moisture content or prolonged exposure to moisture could have been a cause of instability in these ASDs.…”

“…However, if the nitrogen is protonated due to the presence of the acidic polymers, a second N1s peak emerges with a binding energy of 402 eV. 38 , 39 This higher binding energy is consistent with the greater energy required to remove electrons in the presence of a positive charge. Peak fitting was performed on the XPS data to calculate the percentage of protonation.…”

“…They also discovered that decreasing drug loads below 40% in the CAP-based ASDs achieved greater lumefantrine release. 39 This poor drug release from the CAP-based ASDs could be related to the stronger drug-polymer interactions as seen from the high degree of protonation observed for this system. However, more studies are warranted to better understand this phenomenon.…”

Comparison of Amorphous Solid Dispersions of Spironolactone Prepared by Spray Drying and Electrospinning: The Influence of the Preparation Method on the Dissolution Properties

“… 9 The preparation method can influence the dissolution, 10 − 12 the bioavailability, 13 the downstream processing, 14 and the stability of the ASDs. 15 , 16 Furthermore, the properties of the APIs can also determine the applied downstream methods and used excipients. 17 − 19 …”