(T1430-09-60) Solubility Enhancement of a Poorly Water-Soluble Drug Using Hypromellose Phthalate HP-50 by the Hot Melt Extrusion Process

Purpose: Most new drugs are approved for solid dispersion by the spray-drying or hot-melt extrusion methods. Hypromellose phthalate is widely explored in solid dispersion applications using the spray-drying approach. HME has not been extensively explored because of the polymer properties that lead to the generation of free phthalic acid at higher temperatures. Thus, considering this as a requirement to make the polymer feasible for the hot-melt extrusion process, this study was initiated for solid dispersion applications

Methods: This study was divided into two strategies: the first strategy was to make Hypromellose Phthalate feasible for the HME process, and the second strategy was to check the formulation for solid dispersion applications. In this study, itraconazole was used as a model API at a dose of 65 mg. To make Hypromellose Phthalate feasible for the HME process, sugar alcohol derivatives were evaluated while performing the hot-melt extrusion process at different die temperatures (150°C-170°C), die sizes (2 and 3 mm), and screw rpm (190–250). The formulation that resulted in the minimum free phthalic acid generation, along with the model API, was evaluated for solid dispersion application in a capsule dosage form. The analytical part was divided into two parts: first, free phthalic acid was evaluated in the formulation, and then the formulation with the least free phthalic acid was evaluated for the second part, that is, in vitro dissolution studies, XRD, and DSC analysis.

Results: Free phthalic acid was analysed according to the USP method. Dissolution studies of the solid dispersion-prepared capsules were carried out in the water +0.5% SLS system for 2 h. Fig 1. Comparative data of free phthalic analysis with Hypromellose Phthalate HP-50 with different sugar alcohol derivatives from the capsules. Fig 2. Comparative in vitro dissolution studies of the solid dispersion in the capsule dosage form. Fig 3. DSC graphs of API Itraconazole Plain and Solid dispersion with Hypromellose Phthalate alone and Hypromellose Phthalate with sugar alcohol in the capsule dosage form.

Conclusion: When Hypromellose Phthalate HP 50 was evaluated for solid dispersion by the hot-melt extrusion process, it led to the generation of free phthalic acid. This phenomenon occurs because of the high processing temperature required in HME, which leads to the de-esterification of the phthalate groups. The formation of free phthalic acid can cause instability in the formulation, which is a major challenge in the use of HP 50 in HME. The Model API i.e. Itraconazole has a melting point between 160 °C and 165°C. Thus, the API and Hypromellose Phthalate HP 50 combination could not be processed at temperatures lower than 160 °C, which led to the generation of free phthalic acid and impacted the in vitro dissolution release. When sugar alcohol derivatives were incorporated into the formulation, they behaved as melting point depressants and enhanced the polymer miscibility. Of all the sugar alcohol derivatives evaluated, erythritol resulted in a formulation that generated less than 1% free phthalic acid even under accelerated stability conditions (40°C and 75% RH). Formulation with erythritol also helped in achieving an appreciable improvement in the release profile of itraconazole. The other positive outcome from the study was the solid dispersion that allowed the conversion of the crystalline nature of the API to the amorphous form.

Fig 1. Comparative data of free phthalic analysis with Hypromellose Phthalate HP-50 with different sugar alcohol derivatives from the capsules

Fig 2. Comparative In-vitro dissolution studies of the Solid dispersion in the capsule dosage form.

Fig 3. DSC graphs of API Itraconazole Plain and Solid dispersion with Hypromellose Phthalate alone and Hypromellose Phthalate with sugar alcohol in the capsule dosage form.