Comparison of HPMCAS Chemical Grades (L, M, and H) for Amorphous Solid Dispersion by Hot-Melt Extrusion. II: Polymer-Drug-Surfactant Miscibility and Drug Release with Itraconazole as a Model Drug

Abstract

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is commonly used to develop amorphous solid dispersions (ASDs), but its use is mostly limited to spray-dried preparations. Although hot-melt extrusion (HME) is a simpler, continuous method for preparing ASDs, it is rarely used with HPMCAS. To assess the application of the polymer in HME, we compared physicochemical attributes of three HPMCAS grades (L, M, and H) and, in Part I of the study, found no significant differences in complex viscosity or hot-melt extrudability among the three grades, with or without added drug and surfactants. In the current Part II of the study, the miscibility of the three HPMCAS grades with itraconazole (ITZ) and two surfactants, poloxamer 407 and TPGS, was evaluated, and drug release from melt extrudates of drug-polymer binary mixtures and drug-polymer-surfactant ternary mixtures with all three HPMCAS grades was compared. All HPMCAS grades exhibited similar miscibility with itraconazole and surfactants, and their ASDs showed comparable physical stability, with no evidence of crystallization after storage at 40Cº/75% RH for 30 days. The ASDs of drug-polymer binary mixtures with the three HPMCAS grades, however, showed different drug release profiles in a two-step dissolution test conducted initially at pH 1, followed by a change in pH to 6.8; the L grade showed complete release of ITZ from ASDs, whereas the M grade showed ~70% and the H grade only ~10% drug release at the end of the test. Incorporation of surfactants to produce ternary mixtures improved drug release compared to their binary counterparts. At pH 6.8, there was complete drug release (~100%) from the HPMCAS-ITZ-surfactant (65:20:15 w/w) ASDs of L and M grades with poloxamer 407 and TPGS as surfactants, but the drug release was still incomplete (<40%) from the H grade. These results show that while L and M grades of HPMCAS could be suitable for developing ASDs for poorly water-soluble drugs like itraconazole by HME with satisfactory drug release, HPMCAS-H did not provide complete drug release; therefore, the use of H grade for developing ASDs by HME for dissolution improvement of poorly water-soluble drugs should be considered on a case-by-case basis.

Introduction

Amorphous solid dispersion is a commonly used formulation strategy to improve the dissolution rate and bioavailability of poorly water-soluble drugs (1–4). Among various polymers available as carriers for ASDs, hydroxypropyl methylcellulose acetate succinate (HPMCAS) has gained popularity in recent years, as it has been demonstrated that HPMCAS is capable of maintaining the drug in a supersaturated state and inhibiting precipitation in aqueous media after dissolution (5–10). However, most marketed products with HPMCAS have been prepared using spray-drying (11,12), which presents manufacturing challenges due to the large volumes of organic solvent required to dissolve both the hydrophobic drug and the hydrophilic polymer in a single solvent system. In addition, after processing, all organic solvents must be collected and disposed of in an environmentally friendly manner, and testing is needed to confirm that any residual solvents in the ASD product meet specifications (13). Although hot melt extrusion (HME) can be used as a solvent-free, one-step, and continuous process for manufacturing ASDs (14), there has been limited use of HPMCAS in HME due to the polymer’s high complex viscosity, which makes it difficult to extrude at relatively low temperatures (15). It requires >170ºC to extrude the neat HPMCAS, but it may undergo degradation at such high temperatures, liberating acetic and succinic acids (16,17). These issues are probably responsible for the paucity of HPMCAS-based commercial ASD products manufactured using HME. Only one marketed product, posaconazole delayed-release tablet (Noxafil® Delayed-release Tablet, Merck), was produced by HME using HPMCAS as the polymeric matrix (11); however, this product was discontinued from marketing by its manufacturer in 2024 due to business reasons, although its generic versions manufactured by others remain available.

HPMCAS is a cellulosic polymer produced by adding various neutral, hydrophilic, and acidic substituents to the chain structure of cellulose. A detailed description of the structures of different grades of HPMCAS was given in Part I of this series of papers. HPMCAS comes in three chemical grades, L, M, and H, with differences in their succinoyl and acetyl contents. The succinoyl contents of the L, M, and H grades are 14-18%, 10-14%, and 4-8%, respectively, while their respective acetyl contents are 5-9%, 7-11%, and 10-14%, respectively. Thus, the L grade has the highest succinoyl-to-acetyl ratio, while the H grade has the lowest. HPMCAS is a pH-sensitive enteric polymer that dissolves at different intestinal pH conditions. The highest succinoyl-to-acetyl ratio in the L grade makes it the most hydrophilic among the three grades after ionization and enables it to dissolve at a relatively lower intestinal pH of 5.5. In contrast, M and H grades dissolve at pH 6.0 and 6.8, respectively, or higher.

While different HPMCAS grades have been used for decades as pH-sensitive enteric coating materials for oral dosage forms, there is no clear guidance in the literature regarding which grades of HPMCAS to select for the development of ASDs. Although there are a few reports on the use of different grades of HPMCAS to prepare ASDs by spray drying (18,19) and rotary evaporation from organic solutions (20,21), there are very limited studies on how the differences in chemical grades would influence the melt extrusion of ASDs and drug release from the ASDs produced (22). The successful development of ASDs by HME depends on several factors: (a) the complex viscosity of the polymers used must be such that they can be extruded at a temperature where both the polymer and drug are stable and the polymer should be fluid enough to dissolve the drug and/or additives during extrusion, (b) the polymer must be miscible with drug and any other additives, such as surfactants, plasticizers, etc., used, and (c) there must be relatively rapid and complete drug release from the extrudates under the desired pH conditions. In Part I of the study, we reported the comparative complex viscosity and extrudability of L, M, and H grades of HPMCAS by using itraconazole (ITZ) as the model drug and two different surfactants, poloxamer 407 (P407) and tocopheryl polyethylene glycol succinate (TPGS). Since the drug-polymer and drug-polymer surfactant miscibility, as well as drug release, are critically important for developing ASDs with HPMCAS (23–25), the following are the specific objectives of Part II of the study:

• Compare the miscibility of L, M, and H grades of HPMCAS with the model drug, itraconazole (ITZ), alone and in combination with two different surfactants, poloxamer 407 (P407) and TPGS.
• Compare ITZ release from melt extrudates produced with the three different grades of HPMCAS by two step dissolution testing, where dissolution was first conducted at micropH 1 to mimic the gastric pH condition, followed by a change to the intestinal pH condition of 6.8.
• Compare the effect of added surfactants on drug release from ASDs produced by HME with the three grades of HPMCAS.

Download the full article as PDF here Comparison of HPMCAS Chemical Grades (L, M, and H) for Amorphous Solid Dispersion by Hot-Melt Extrusion. II

or continue reading here

Materials

Itraconazole (ITZ) was purchased from Attix Pharmaceuticals (Toronto, Canada). Hydroxypropyl methylcellulose acetate succinate (HPMCAS, L, M, and H grades; trade name: AquaSolve®) was donated by Ashland Chemical (Delaware, USA). Each chemical grade of HPMCAS is available in two physical forms: fine (F) and granular (G). Since the polymers melted during HME, it was assumed that their particle size would not affect the extrudate’s performance; therefore, only the granular (G) materials were used in the present investigation, given their better powder flow and physical mixing with other formulation components before extrusion. Poloxamer 407 (Kolliphor® P407) and D-α-tocopherol polyethylene glycol succinate (Kolliphor® TPGS) were donated by BASF Corporation (Tarrytown, New York, USA).

Mufaddal H. Kathawala, Nayan G. Solanki, Abu T.M. Serajuddin, Comparison of HPMCAS Chemical Grades (L, M, and H) for Amorphous Solid Dispersion by Hot-Melt Extrusion. II: Polymer-Drug-Surfactant Miscibility and Drug Release with Itraconazole as a Model Drug, Vol. 3, Issue 1, 2026March 27, 2026 EDT, https://doi.org/10.66617/001c.159629

Read more interessting articles on Surfactants here:

• Nature Meets Science: The Role of Food-Grade Oils and Green Excipients in Pharmaceutical Nanoemulsion Formulation
• Carbohydrate-surfactant interplay: structural effects of Saccharides on Micellar Behavior of Kolliphor® EL and Kolliphor® HS15
• The Effect of Pharmaceutical Excipients on Protein Chemical Degradation Through Deamidation and Isomerization