(M1030-10-54) Use of Povidones and Copovidones as Solubility Enhancers for Itraconazole Using Hot Melt Extrusion

Purpose: Preparation of Amorphous solid dispersions (ASDs) by Hot Melt Extrusion (HME) are increasingly getting attraction to enhance the solubility and bioavailability of insoluble actives. Kollidon^® VA 64 (Copovidone) has been widely studied and used for both HME and Spray drying. However there has been a rise in evaluation of the low/medium molecular weight povidones in HME for solubility enhancement due to avoid patent infringement issues and to create product differentiation. Therefore, the aim of the work was to generate the data on different Povidone grades and Copovidone to evaluate the formulation performance and extrusion parameters along with technical know how’s for HME. Furthermore, the performance of the solid dispersion was measured by carrying out dissolution under non-sink conditions. Additionally, the impact of addition of a non-ionic solubilizer- Kolliphor^® 40 on the selected ratio was studied for its dissolution performance.

Methods: Itraconazole, a weakly basic low solubility drug was selected as model API with melting point of around 165°C. Different grades of povidone: Kollidon^® 12 PF, Kollidon^® 17PF, Kollidon^® 25 and Kollidon^® 30; and Kollidon^® VA 64 was selected as a source of copovidone. Hot melt extrusion Trials: Binary Solid Dispersions (Drug +Polymer): Itraconazole (ITZ) and the selected polymers, in the ratio of 1:2 and 1:4 were passed through 30 mesh and mixed to ensure uniformity of the blend. The mixture was fed to a twin screw extruder (Thermo scientific™ Pharma 11 HME), and extrusion was carried out to ensure the formation of clear transparent extrudes. The formulation and parameters for extrusion has been summarized in Table 1. Based on the T_g of the polymer and Itraconazole melting point, the extruder parameters were adjusted to achieve transparent extrudes, indicating the formation of glassy solid solution. Ternary Solid Dispersion (Drug +Polymer+ Solubilizer): After the selection of the Drug and polymer ratio, Kolliphor^® RH 40 (4% w/w and 6%w/w to the polymer) was combined with the drug-polymer blend. The blend was sifted with a #30 mesh and extruded via HME. Characterization: DSC Studies: Samples were analyzed using DSC (Mettler Toledo, USA) using gold crucibles from 0°C to 200 °C at the heating rate 5 K/ minute. Dissolution studies: The dissolution studies were carried out in two discriminatory media: 0.1 N HCl without SLS (to maintain non-sink conditions) and pH 6.8 phosphate buffer, using direct addition method. Itraconazole is almost insoluble in the pH 6.8 phosphate buffer. USP II (paddle) dissolution apparatus was used, using 75 rpm, and maintained at 37 C. Extrudes were directly added to the dissolution vessel to avoid the false data due to gel formation in the capsules.

Results: Figure 1. summarizes the extrusion parameters for all the binary mixtures. For the binary ASDs, the clear endotherm of pure Itraconazole was either shifted or merged with the polymeric endotherms in the DSC thermographs of various extrudes under evaluations. For the ternary system with Kolliphor^® RH 40, no endotherm transition was observed indicating complete miscibility of the drug. For all the studied polymers in binary ASDs, the release profiles with the ratio of 1:4 (drug:polymer) in 0.1 N HCL media were higher compared to the ratio (1:2) (Figure 2) and also when compared against the marketed product release profile, Sporanox^®, an HPMC-based amorphous solid dispersion. The inclusion of Kolliphor^® RH40 in the binary ASD system of Drug: Polymer (1:4) significantly increased the dissolution of ITZ with all the studied polymers compared to their respective binary SD mixtures, when studied under non-sink condition of pH 6.8 as well.

Conclusion: All the Povidone grades and copovidone effectively formed the SDs of Itraconazole using HME process. The processing parameters were established to achieve the desired extrudes quality. Solubility enhancement was achieved with all the studied povidones and copovidones, indicating that povidones can also be used as alternatives for ASDs. Addition of Kolliphor^® RH 40 to the ASDs leads to significant increase in drug dissolution in the discriminatory media.

Figure 1. Extrusion parameters for different formulations

Figure 2. Dissolution of Binary SD in 0.1 N HCl, 900 mL, USP-II, 75 RPM