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Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination.
Int J Pharm. 2016 Dec 30; 515(1-2):114-124.IJ

Abstract

The purpose of this work was to increase the solubility and the dissolution rate of itraconazole, which was chosen as the model drug, by obtaining an amorphous solid dispersion by hot melt extrusion. Therefore, an initial preformulation study was conducted using differential scanning calorimetry, thermogravimetric analysis and Hansen's solubility parameters in order to find polymers which would have the ability to form amorphous solid dispersions with itraconazole. Afterwards, the four polymers namely Kollidon® VA64, Kollidon® 12PF, Affinisol® HPMC and Soluplus®, that met the set criteria were used in hot melt extrusion along with 25wt.% of itraconazole. Differential scanning confirmed that all four polymers were able to amorphize itraconazole. A stability study was then conducted in order to see which polymer would keep itraconazole amorphous as long as possible. Soluplus® was chosen and, the formulation was fine-tuned by adding some excipients (AcDiSol®, sodium bicarbonate and poloxamer) during the hot melt extrusion process in order to increase the release rate of itraconazole. In parallel, the range limits of the hot melt extrusion process parameters were determined. A design of experiment was performed within the previously defined ranges in order to optimize simultaneously the formulation and the process parameters. The optimal formulation was the one containing 2.5wt.% of AcDiSol® produced at 155°C and 100rpm. When tested with a biphasic dissolution test, more than 80% of itraconazole was released in the organic phase after 8h. Moreover, this formulation showed the desired thermoformability value. From these results, the design space around the optimum was determined. It corresponds to the limits within which the process would give the optimized product. It was observed that a temperature between 155 and 170°C allowed a high flexibility on the screw speed, from about 75 to 130rpm.

Authors+Show Affiliations

Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liege, Belgium. Electronic address: jthiry@ulg.ac.be.Arlenda SA, Chaussée Verte 93, 4470, Saint-Georges-sur-Meuse, Belgium.Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liege, Belgium.Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liege, Belgium.Laboratory of Analytical Chemistry, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liege, Belgium.Laboratory of Analytical Chemistry, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liege, Belgium.Laboratory of Analytical Chemistry, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liege, Belgium.Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liege, Belgium.Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000 Liege, Belgium.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27720874

Citation

Thiry, Justine, et al. "Continuous Production of Itraconazole-based Solid Dispersions By Hot Melt Extrusion: Preformulation, Optimization and Design Space Determination." International Journal of Pharmaceutics, vol. 515, no. 1-2, 2016, pp. 114-124.
Thiry J, Lebrun P, Vinassa C, et al. Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination. Int J Pharm. 2016;515(1-2):114-124.
Thiry, J., Lebrun, P., Vinassa, C., Adam, M., Netchacovitch, L., Ziemons, E., Hubert, P., Krier, F., & Evrard, B. (2016). Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination. International Journal of Pharmaceutics, 515(1-2), 114-124. https://doi.org/10.1016/j.ijpharm.2016.10.003
Thiry J, et al. Continuous Production of Itraconazole-based Solid Dispersions By Hot Melt Extrusion: Preformulation, Optimization and Design Space Determination. Int J Pharm. 2016 Dec 30;515(1-2):114-124. PubMed PMID: 27720874.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination. AU - Thiry,Justine, AU - Lebrun,Pierre, AU - Vinassa,Chloe, AU - Adam,Marine, AU - Netchacovitch,Lauranne, AU - Ziemons,Eric, AU - Hubert,Philippe, AU - Krier,Fabrice, AU - Evrard,Brigitte, Y1 - 2016/10/05/ PY - 2016/07/18/received PY - 2016/09/30/revised PY - 2016/10/01/accepted PY - 2016/11/5/pubmed PY - 2017/4/19/medline PY - 2016/11/6/entrez KW - Amorphous solid dispersions KW - Design of experiments KW - Design space determination KW - Itraconazole KW - Solubility enhancement SP - 114 EP - 124 JF - International journal of pharmaceutics JO - Int J Pharm VL - 515 IS - 1-2 N2 - The purpose of this work was to increase the solubility and the dissolution rate of itraconazole, which was chosen as the model drug, by obtaining an amorphous solid dispersion by hot melt extrusion. Therefore, an initial preformulation study was conducted using differential scanning calorimetry, thermogravimetric analysis and Hansen's solubility parameters in order to find polymers which would have the ability to form amorphous solid dispersions with itraconazole. Afterwards, the four polymers namely Kollidon® VA64, Kollidon® 12PF, Affinisol® HPMC and Soluplus®, that met the set criteria were used in hot melt extrusion along with 25wt.% of itraconazole. Differential scanning confirmed that all four polymers were able to amorphize itraconazole. A stability study was then conducted in order to see which polymer would keep itraconazole amorphous as long as possible. Soluplus® was chosen and, the formulation was fine-tuned by adding some excipients (AcDiSol®, sodium bicarbonate and poloxamer) during the hot melt extrusion process in order to increase the release rate of itraconazole. In parallel, the range limits of the hot melt extrusion process parameters were determined. A design of experiment was performed within the previously defined ranges in order to optimize simultaneously the formulation and the process parameters. The optimal formulation was the one containing 2.5wt.% of AcDiSol® produced at 155°C and 100rpm. When tested with a biphasic dissolution test, more than 80% of itraconazole was released in the organic phase after 8h. Moreover, this formulation showed the desired thermoformability value. From these results, the design space around the optimum was determined. It corresponds to the limits within which the process would give the optimized product. It was observed that a temperature between 155 and 170°C allowed a high flexibility on the screw speed, from about 75 to 130rpm. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/27720874/Continuous_production_of_itraconazole_based_solid_dispersions_by_hot_melt_extrusion:_Preformulation_optimization_and_design_space_determination_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(16)30937-1 DB - PRIME DP - Unbound Medicine ER -