(M0930-08-52) Improving Solubility of Poorly Soluble Active Pharmaceutical Ingredients:The Impact of Plasticizers in Melt-Based Amorphous Solid Dispersions with Polyvinyl Alcohol

Purpose: Amorphous solid dispersions (ASDs) are a proven approach to enhance the solubility of Active Pharmaceutical Ingredients (API)¹. ASDs can be produced using a variety of technologies. In recent years, spray drying and hot melt extrusion (HME) have emerged as the most utilized methods. The selection of an appropriate excipient is crucial for the formulation of ASDs. Particularly for the HME process, the range of suitable thermoplastic polymers that are pharmaceutically approved is limited². A well-suited polymer is polyvinyl alcohol (PVA), which has demonstrated promising results as an HME carrier matrix for ASDs, particularly in terms of enhancing solubility and inhibiting precipitation³. A limiting factor for its use in HME is the viscosity of the melt, which defines the temperature-dependent process range. Various plasticizer combinations have already been described to expand this process window. In this work, the plasticizer sorbitol, mannitol, glycerol, triacetin, triethyl citrate, and PEG 300 are investigated in combination with polyvinyl alcohol with focus on how these plasticizers influence the release kinetics of melt‑processed PVA systems and using ketoconazole as a model drug to demonstrate their impact on ASD performance

Methods: Mixtures were produced by cryo-milling. Drug load was 20% for the Ketoconazole samples an 1% for the Fluorescein-Sodium samples. For the ternary systems, binary mixtures were first prepared with 10% (w/w) plasticizer and the PVA. Mixtures were produced by cryo-milling, SPEX 6875D Large Freezer/Mill^® (SPEX SamplePrep LLC, NJ, USA). Pre-cool time: 5 min followed by two milling cycles run time: 5 minutes, impact rate: 15 CPS. The preparation of the ASDs was conducted using a Vacuum Compression Molding tool (VCM) 20mm (MeltPrep GmbH, Graz, Austria). The samples were prepared with 400 mg of the physical mixture. The samples were melted at 210°C for 6 minutes. X-ray diffraction was measured using a Miniflex 600 X-ray diffractometer from Rigaku Corporation (Tokyo, Japan). CuKα radiation (λ = 1.54 Å), range: 3–50° 2θ, step size: 0.02° 2θ, scan speed: 0.8° 2θ/min. Voltage: 45 kV, current: 15 mA. The dissolution trials were conducted using the Sotax AT Xtend (Sotax AG, Lörrach, Germany), equipped with a Specord 200 Plus UV-VIS spectrophotometer (Analytik Jena GmbH+Co.KG, Jena, Germany). Paddle speed: 50 rpm, temperature: 37°C. Wire sinker applied. Each 400 mg sample body was measured in 900 ml of 0.1N HCl. For the non-sink dissolution, 40 mg of the ground sample was mixed with 10 ml of FaSSIF. The dissolution tests were conducted in centrifuge tubes, which were placed in a test tube rack on a shaking platform (TiMix 5, Edmund Bühler GmbH, Bodelshausen, Germany) inside an incubator (TH 15, Edmund Bühler GmbH) shaking at 350 rpm at a temperature of 37°C. At each sampling point, 500 µl of the sample was taken and filtered through a 0.45 µm PTFE filter. Subsequently, 250 µl of the filtrate was diluted 1:1 with the mobile phase. HPLC method Ketoconazole: the eluent consisted of 70% Eluent A (Diisopropylamine in MeOH, 10 ml/5 L) and 30% Eluent B (Ammonium acetate in Milli-Q water, 5 g/L). Flow rate: 2.0 ml/min, injection volume: 5 μl. Column: Supelcosil LC-18. Wavelength: 225 nm.

Results: The PXRD data indicate that ketoconazole was successfully incorporated into the PVA matrix through melting under vacuum. PVA exhibits a partially crystalline character, which is reflected in the PXRD pattern. The combination with the examined plasticizers showed no negative effects on the system's ability to form amorphous solid dispersions with ketoconazole. Release experiments conducted with 1% (w/w) fluorescein-sodium demonstrate the influence of the plasticizer on the release behavior of PVA. Specifically, the combinations with glycerol and triacetin accelerated the release, achieving 100% release after approx. 60 minutes, which is about 30 minutes earlier than the pure PVA formulation. In contrast, triethyl citrate and PEG 300 sustained the release, reaching 100% after about 120 minutes. The formulations containing mannitol and sorbitol exhibited similar release kinetics, being slightly faster than pure PVA. In the non-sink dissolution conditions, ketoconazole with PVA showed a maximum concentration of approx. 500 µg/ml after 20-minutes. After reaching the maximum concentration, a delayed precipitation (parachute effect) was observed. The use of plasticizers had an impact on the maximum concentration. Combinations with mannitol, sorbitol, glycerol, triacetin, and triethyl citrate exhibited an increase in concentration, reaching nearly 600 µg/ml. However, the concentration also decreased much more rapidly compared to the binary KTZ-PVA mixture. The mixture with PEG300 showed a lower maximum concentration of 380 µg/ml.

Conclusion: The incorporation of ketoconazole into the PVA matrix through melting has proven effective. The release trials demonstrated that the release kinetics can be modified by the addition of plasticizers. These changes have a direct impact on the solubility-enhancing properties of the ASD formulation. Overall, these findings suggest that the careful selection of plasticizers can optimize the release profile of an API like ketoconazole from PVA matrices, potentially improving its therapeutic efficacy.

References: 1. Newman, A.; Knipp, G; Zografi, G; Assessing the performance of amorphous solid dispersions. J. of Pharm. Sc. X 2012, 4, 1001, 1355-1377 https://doi.org/10.1002/jps.23031
2. Moseson, D. E.; Tran, T. B.; Karunakaran, B.; Ambardekar, R.; Hiew, T. N.; Trends in Amorphous Solid Dispersion Drug Products Approved by the U.S. Food and Drug Administration between 2012 and 2023. Int. J. Pharm. X 2024, 7, 100259. https://doi.org/10.1016/j.ijpx.2024.100259.
3. Wlodarski, K; Zhang, F; Liu, T; Sawicki, W; Kipping, T; Synergistic Effect of Polyvinyl Alcohol and Copovidone in Itraconazole Amorphous Solid Dispersions. Pharm. Res. 2018, 35, 16. https://doi.org/10.1007/s11095-017-2313-1