(M1330-09-57) Dissolution Enhancement Technique of Amorphous Solid Dispersions by External Addition of HPMCAS

Purpose: Amorphous solid dispersions (ASDs) are a technology used to improve the dissolution of poorly water-soluble drugs. The carrier distributed within the solid dispersion contributes to the stabilization of the amorphous drug. Shin-Etsu AQOAT^® (hypromellose acetate succinate, HPMCAS) is known to exhibit a high dissolution-enhancing effect for a wide range of drugs when used as a carrier. However, due to the thermal properties during the manufacturing process of solid dispersions and the dissolution behavior in solvents, there are rare cases where the use of HPMCAS as a carrier is restricted. Therefore, in this study, we investigated the effect of externally adding HPMCAS separately from the carrier as a novel approach to improve dissolution.

Methods: Nifedipine (NIF) was used as a model drug, and ASDs were prepared by spray drying (SD) and hot melt extrusion (HME). HPMCAS (AS-MG), methyl cellulose (SM-4), Polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA) were selected as carriers and hypromellose phthalate (HP-55). For ASDs that did not contain HPMCAS as a carrier, HPMCAS was externally added. Additionally, commonly used excipients (microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and magnesium stearate) in ASDs formulations were further incorporated, and the powders were mixed thoroughly in a mortar. The mixed powder was weighed to contain 40 mg of NIF, and dissolution was evaluated in pH 6.8 phosphate buffer solution. Furthermore, using ASDs with SM-4 as the carrier, the effects of changing the external additive polymer on dissolution characteristics were compared (external additive polymer: AS-MF, SM-4, HP-55 and hypromellose (HPMC, Pharmacoat^® 603, P-603)).

Results: For ASDs prepared with any carrier and manufacturing method, the external addition of HPMCAS significantly improved dissolution compared to the original formulation without addition (Control). The amount of dissolved NIF increased to levels comparable to the target formulation using HPMCAS as the carrier. Furthermore, when dissolution tests were conducted using different external additive polymers, the highest dissolution amount of NIF was observed with HPMCAS, suggesting that HPMCAS is the most suitable external additive polymer. Since externally added HPMCAS dissolves similarly to the ASDs, it is considered to function pseudo-carrier-like, thereby contributing to the stabilization of the ASDs.

Conclusion: It was found that dissolution can be conveniently improved by incorporating HPMCAS through external addition, even without using HPMCAS as the carrier. The dissolution improvement technique by external addition is effective regardless of the carrier type or manufacturing method used for the ASD, and it may serve as a solution when HPMCAS cannot be incorporated as a carrier due to manufacturing issues of solid dispersions.

Table 1. Formulation of ASDs

Figure 1. Dissolution profiles (a) SM-4/SD, (b) PVPVA/SD, (c) HP-55/SD, (d) PVPVA/HME

Figure 2. Effect of polymer type used as external additive on the dissolution of NIF