(M1530-07-38) Twin Screw Melt Granulation: Enhancing Solubility and Release Profile of Simvastatin Using Miscible and Immiscible Polymer Blends

Purpose: This study aims to assess the feasibility of employing twin-screw melt granulation (TSMG) as a continuous manufacturing method to produce simvastatin (SIM) granules, with enhanced solubility and dissolution properties. SIM, a cholesterol-lowering agent, falls under class II of the Biopharmaceutics Classification System (BCS) due to its poor solubility and limited gastrointestinal absorption. Furthermore, this research investigates the impact of various polymeric combinations, both miscible and immiscible with simvastatin, on the drug solubility, thermal profile, and release characteristics.

Methods: To produce SIM solid dispersion granules (SDGs) using TSMG, various polymeric combinations were investigated with a 30% w/w drug load and a 1:1 ratio of polymer binary blends, including Soluplus® (SOP), polyvinylpyrrolidone Kollidon® 12PF (K12), polyvinylpyrrolidone vinyl acetate Kollidon® VA64 (KVA), and Kollicoat® IR (KIR). The compositions of all the investigated formulations are outlined in (Table 1). Modulated- Differential Scanning Calorimetry (MDSC) was employed for the pure SIM and physical mixtures (PMs) to precisely determine the enthalpy and melting point depression of SIM, aiding in the classification of blends as miscible or immiscible. Furthermore, a solubility study of SIM in 1% binary polymer blend solutions was conducted to identify blends with the lowest and highest solubility. The ternary drug-polymer systems with the lowest and highest miscibility and solubility values were granulated using an 11 mm co-rotating twin-screw extruder (Thermo Fisher Scientific, Waltham, MA). Thermal characterization of the drug in the granules was performed using Differential Scanning Calorimetry (DSC) (TA DSC 25) and Powder X-Ray Diffraction Analysis (PXRD) (D/MAX-2500PC, Rigaku Corp., Tokyo, Japan). Dissolution studies of SIM (equivalent to 20 mg) were conducted using the pure drug, PMs, and the SDGs. The release study was carried out in a USP type II dissolution apparatus (Erweka, Korsh-Erweka GmbH, Germany) at 37°C ± 5°C, with 50 rpm, and 900 mL of monobasic sodium phosphate buffer (pH 7) with 0.2% sodium dodecyl sulfate (SDS). Samples were withdrawn at specified time intervals (5, 10, 15, 30, 45, 60 minutes), and SIM quantification was performed using a Waters High-Performance Liquid Chromatography (HPLC) with UV detection system (Waters Corporation, Milford, MA, USA).

Results: Among all the formulations, SIM-K12/KIR exhibited the highest miscibility, evidenced by the highest depression in the melting point of SIM, while SIM-KVA/SOP showed the least miscibility. Furthermore, SIM-SOP/KIR demonstrated the highest SIM solubility, achieving around a 6.3-fold enhancement over the pure drug, while SIM-K12/KIR had the lowest aqueous solubility (data not shown). It was found that blends with low miscibility had higher solubility and vice versa, indicating that high miscibility does not always correlate with improved solubility. The DSC heating curves (Figure 1) illustrate the thermal behavior of SIM, polymers, PMs, and the SDGs. Crystalline SIM is characterized by an endothermal process at 140 °C, with an enthalpy of fusion value of 73.5 J/g. The DSC curves of the granules demonstrated the absence of SIM peak which implies the amorphization of SIM within the binary polymeric blend under the extrusion temperature employed. This observation is corroborated by (PXRD) analysis, confirming SIM transition to the amorphous state (data not shown). The SIM-SOP/KIR granules demonstrated rapid dissolution rates compared to the physical mixture and the pure drug. Dissolution reached 76.1% ± 5.25% in 10 minutes, 95.3% ± 1.10% in 30 minutes, and 99.7% ± 1.53% in 45 minutes (Figure 2). The enhanced dissolution is attributed to the overall enhanced hydrophilicity of the system combined with the conversion of SIM to the amorphous form.

Conclusion: In this study, the application of TSMG utilizing a 1:1 polymeric blend of Soluplus® and Kollicoat® IR proved highly effective in producing SIM SDGs with significantly improved solubility and release profiles compared to the PM and the pure drug. This polymeric blend was immiscible with SIM yet demonstrated remarkable solubility properties. The ternary drug-polymer system achieved a rapid dissolution profile of over 80% drug release within 15 minutes and reaching complete release within 45 minutes. These findings underscore the potential of TSMG as a promising single-step continuous manufacturing technique for enhancing the solubility and dissolution kinetics of a poorly water-soluble drug.

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Table 1. Composition of the drug-polymer ternary systems

Figure 1. DSC thermograms for SIM, polymers, selected PMs, and SDGs

Figure 2. Dissolution profiles of crystalline SIM, PMs, and SDGs at 37 °C in pH 7 phosphate buffer and 0.2% w/v SD