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

Abstract

Understanding the dissolution mechanisms of amorphous solid dispersions (ASDs) and being able to link enhanced drug exposure with process parameters are key when formulating poorly soluble compounds. Thus, in this study, ASDs composed by itraconazole (ITZ) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were formulated with different polymer grades and drug loads (DLs) and processed by spray drying with different atomization ratios and outlet temperatures. Their in vitro performance and the ability to form drug-rich colloids were then evaluated by a physiologically relevant dissolution method. In gastric media, drug release followed a diffusion-controlled mechanism and drug-rich colloids were not formed since the solubility of the amorphous API at pH 1.6 was not exceeded. After changing to intestinal media, the API followed a polymer dissolution-controlled release, where the polymer rapidly dissolved, promoting the immediate release of API and thus leading to liquid–liquid phase separation (LLPS) and consequent formation of drug-rich colloids. However, the release of API and polymer was not congruent, so API surface enrichment occurred, which limited the further dissolution of the polymer, leading to a drug-controlled release. ASDs formulated with M-grade showed the highest ability to maintain supersaturation and the lowest tendency for AAPS due to its good balance between acetyl and succinoyl groups, and thus strong interactions with both the hydrophobic drug and the aqueous dissolution medium. The ability to form colloids increased for low DL (15%) and high specific surface area due to the high amount of polymer released until the occurrence of API surface enrichment. Even though congruent release was not observed, all ASDs formed drug-rich colloids that were stable in the solution until the end of the dissolution study (4 h), maintaining the same size distribution (ca. 300 nm). Drug-rich colloids can, in vivo, act as a drug reservoir replenishing the drug while it permeates. Designing ASDs that are prone to form colloids can overcome the solubility constraints of Biopharmaceutics Classification System (BCS) II and IV drugs, posing as a reliable formulation strategy.

Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers

“…Indeed, despite the low polymer solubility at pH 1.6, a notable amount of drug was released at this pH for all ASDs (Figures and ). The observation of drug release from enteric polymer ASDs at low pH has been reported for other weakly basic compounds including posaconazole, clotrimazole, ketoconazole, and itraconazole . For posaconazole, maximum concentrations achieved by ASDs with HPMCAS 10–50% DL in FaSSGF were below the crystalline solubility at that pH .…”

“…The observation of drug release from enteric polymer ASDs at low pH has been reported for other weakly basic compounds including posaconazole, 27 clotrimazole, 26 ketoconazole, 68 and itraconazole. 69 For posaconazole, maximum concentrations achieved by ASDs with HPMCAS 10−50% DL in FaSSGF were below the crystalline solubility at that pH. 27 However, high DL ASDs exhibited more drug leaching in gastric conditions and achieved supersaturation.…”

Investigation on the use of fused deposition modeling for the production of IR dosage forms containing Timapiprant

“…t 80% ≤ 30 min) via extrusion-based hot-processing techniques would be particularly challenging, because these are well-known to provide high density products characterized by slow penetration of aqueous fluids [ Casati et al, 2020 ; Fuenmayor et al, 2019 ; Tanaka et al, 2021 ; Van Renterghem et al, 2018 ; Verstraete et al, 2016 ; Zema et al, 2012 ]. A screening program for the identification of thermoplastic carriers suitable for FDM of solid units having a dissolution performance comparable to that of reference tablets was undertaken, taking into account a variety of polymers already deemed suitable for hot-processing [ Hardung et al, 2010 ; Melocchi et al, 2016 ; Nunes et al, 2022 , Tanno et al, 2004 ]. The polymers chosen were hydrophilic in nature, either promptly soluble ( i.e.…”

Stable amorphous solid dispersion of flubendazole with high loading via electrospinning

“…However, limited research is put into drug loading capability, for both immediate release as for sustained release formulations. [35,[40][41][42][43][44].…”