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Phase behavior of pharmaceutically relevant polymer/solvent mixtures.
Int J Pharm. 2020 Mar 15; 577:119065.IJ

Abstract

In the pharmaceutical industry, polymers are used as excipients for formulating poorly water-soluble active pharmaceutical ingredients (APIs) in so-called "amorphous solid dispersions" (ASDs). ASDs can be produced via solvent-based processes, where API and polymer are both dissolved in a solvent, followed by a solvent evaporation step (e.g. spray drying). Aiming at a homogeneous API/polymer formulation, phase separation of the components (API, polymer, solvent) during solvent evaporation must be avoided. The latter is often determined by the phase behavior of polymer/solvent mixtures used for ASD processing. Therefore, this work investigates the polymer-solvent interactions in these mixtures. Suitable polymer/solvent combinations investigated in this work comprise the pharmaceutically relevant polymers poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxyppropyl methylcellulose acetate succinate 126G (HPMCAS) as well as the solvents acetone, dichloromethane (DCM), ethanol, ethyl acetate, methanol, and water. Based on vapor-sorption experiments demixing of solvents and polymers were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These were found to be correct for all investigated solvent/polymer mixtures. Acetone, DCM, ethanol, methanol, and water were found to be completely miscible with PVPVA64. DCM, ethanol, methanol, and water were found to be completely miscible with PVP K90, while none of the investigated solvents was appropriate for avoiding immiscibility with HPMCAS. In addition, the impact of temperature, polymer molecular weight, and solvent-mixture composition on miscibility was successfully predicted using PC-SAFT. Thus, the proposed methodology allows identifying suitable solvents or solvent mixtures relevant for solvent-based preparations of pharmaceutical ASD formulations with low experimental effort.

Authors+Show Affiliations

Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.AbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraβe, D-67061 Ludwigshafen am Rhein, Germany.AbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraβe, D-67061 Ludwigshafen am Rhein, Germany. Electronic address: samuel.kyeremateng@abbvie.com.AbbVie Deutschland GmbH & Co. KG, Global Pharmaceutical R&D, Knollstraβe, D-67061 Ludwigshafen am Rhein, Germany.Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund University, Emil-Figge-Str. 70, D-44227 Dortmund, Germany. Electronic address: gabriele.sadowski@tu-dortmund.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31988034

Citation

Dohrn, Stefanie, et al. "Phase Behavior of Pharmaceutically Relevant Polymer/solvent Mixtures." International Journal of Pharmaceutics, vol. 577, 2020, p. 119065.
Dohrn S, Luebbert C, Lehmkemper K, et al. Phase behavior of pharmaceutically relevant polymer/solvent mixtures. Int J Pharm. 2020;577:119065.
Dohrn, S., Luebbert, C., Lehmkemper, K., Kyeremateng, S. O., Degenhardt, M., & Sadowski, G. (2020). Phase behavior of pharmaceutically relevant polymer/solvent mixtures. International Journal of Pharmaceutics, 577, 119065. https://doi.org/10.1016/j.ijpharm.2020.119065
Dohrn S, et al. Phase Behavior of Pharmaceutically Relevant Polymer/solvent Mixtures. Int J Pharm. 2020 Mar 15;577:119065. PubMed PMID: 31988034.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase behavior of pharmaceutically relevant polymer/solvent mixtures. AU - Dohrn,Stefanie, AU - Luebbert,Christian, AU - Lehmkemper,Kristin, AU - Kyeremateng,Samuel O, AU - Degenhardt,Matthias, AU - Sadowski,Gabriele, Y1 - 2020/01/24/ PY - 2019/11/07/received PY - 2020/01/16/revised PY - 2020/01/17/accepted PY - 2020/1/29/pubmed PY - 2020/11/26/medline PY - 2020/1/29/entrez KW - Amorphous solid dispersion KW - HPMCAS KW - Liquid-liquid phase separation KW - Miscibility gap KW - PC-SAFT KW - PVP KW - PVPVA64 KW - Solvent selection SP - 119065 EP - 119065 JF - International journal of pharmaceutics JO - Int J Pharm VL - 577 N2 - In the pharmaceutical industry, polymers are used as excipients for formulating poorly water-soluble active pharmaceutical ingredients (APIs) in so-called "amorphous solid dispersions" (ASDs). ASDs can be produced via solvent-based processes, where API and polymer are both dissolved in a solvent, followed by a solvent evaporation step (e.g. spray drying). Aiming at a homogeneous API/polymer formulation, phase separation of the components (API, polymer, solvent) during solvent evaporation must be avoided. The latter is often determined by the phase behavior of polymer/solvent mixtures used for ASD processing. Therefore, this work investigates the polymer-solvent interactions in these mixtures. Suitable polymer/solvent combinations investigated in this work comprise the pharmaceutically relevant polymers poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxyppropyl methylcellulose acetate succinate 126G (HPMCAS) as well as the solvents acetone, dichloromethane (DCM), ethanol, ethyl acetate, methanol, and water. Based on vapor-sorption experiments demixing of solvents and polymers were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These were found to be correct for all investigated solvent/polymer mixtures. Acetone, DCM, ethanol, methanol, and water were found to be completely miscible with PVPVA64. DCM, ethanol, methanol, and water were found to be completely miscible with PVP K90, while none of the investigated solvents was appropriate for avoiding immiscibility with HPMCAS. In addition, the impact of temperature, polymer molecular weight, and solvent-mixture composition on miscibility was successfully predicted using PC-SAFT. Thus, the proposed methodology allows identifying suitable solvents or solvent mixtures relevant for solvent-based preparations of pharmaceutical ASD formulations with low experimental effort. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/31988034/Phase_behavior_of_pharmaceutically_relevant_polymer/solvent_mixtures_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(20)30049-1 DB - PRIME DP - Unbound Medicine ER -