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Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions by Hot-Melt Extrusion.
Mol Pharm. 2020 02 03; 17(2):554-568.MP

Abstract

The aim of this study was to develop a fast, effective, and material sparing screening method to design amorphous solid dispersions (ASDs) of etravirine to drive more effectively the development process, leading to improved bioavailability (BA) and stability. A systematic step-by-step approach was followed by combining theoretical calculations with high-throughput screening (HTS) and software-assisted multivariate statistical analysis. The thermodynamic miscibility and interaction of the drug in several polymers were predicted using Hansen solubility parameters (δ). The selected polymers were evaluated by HTS, using solvent evaporation. Binary compositions were evaluated by their solubilization capacity and physical stability over 2 months. JMP 14.0 was used for multivariate statistical analysis using principal components analysis. Extrusion was performed in Thermo Scientific HAAKE MiniLab II, and extrudates were characterized by assay, related substances, dissolution, and physical state (polarized light microscopy (PLM), Raman spectroscopy, and X-ray powder diffraction (XRPD)). A short stability study was performed where milled extrudates were exposed to 25 °C/60%RH and 40 °C/75%RH for 3 months. Through thermodynamic predictions, five main polymers were selected. The HTS enabled the evaluation of 42 formulations for solubilization capacity and physical stability. The three most promising compositions were selected for hot-melt extrusion (HME) tests. In general, a good correlation was found among the results of theoretical predictions, HTS, and HME. Poly(vinylpyrrolidone) (PVP)-based formulations were shown to be easily extrudable, with low degradation and complete amorphicity, whereas in Soluplus, the drug was not miscible, leading to a high crystalline content. The drug release rate was improved more than two times with PVP, and the manufactured ASD was demonstrated to be stable physically and chemically. A fast and effective screening technique to develop stable ASDs for a poorly soluble drug was successfully developed as applied to etravirine. The given method is easy to use, requires a low amount of drug, and is fairly accurate in predicting the amorphization of the drug when formulated. The success of HME formulation development of etravirine was undoubtedly enhanced with this high-throughput tool, which led to the identification of extrudates with improved biopharmaceutical properties. The structural characterization performed by PLM, XRPD, and Raman spectroscopy demonstrated that the HME prototype was essentially amorphous. The unexpected stability at 40 °C/75%RH was correlated with the presence of molecular interaction characterized by Raman spectroscopy.

Authors+Show Affiliations

Bluepharma - Indústria Farmacêutica , São Martinho do Bispo , 3045-016 Coimbra , Portugal. Faculty of Pharmacy , University of Coimbra , Azinhaga de Santa Comba , 3000-548 Coimbra , Portugal.Bluepharma - Indústria Farmacêutica , São Martinho do Bispo , 3045-016 Coimbra , Portugal.Bluepharma - Indústria Farmacêutica , São Martinho do Bispo , 3045-016 Coimbra , Portugal.Midas Pharma GmbH , Rheinstrasse 49 , 55218 Ingelheim , Germany.Midas Pharma GmbH , Rheinstrasse 49 , 55218 Ingelheim , Germany.Bluepharma - Indústria Farmacêutica , São Martinho do Bispo , 3045-016 Coimbra , Portugal.Bluepharma - Indústria Farmacêutica , São Martinho do Bispo , 3045-016 Coimbra , Portugal. Faculty of Pharmacy , University of Coimbra , Azinhaga de Santa Comba , 3000-548 Coimbra , Portugal.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31774685

Citation

Simões, Marta F., et al. "Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions By Hot-Melt Extrusion." Molecular Pharmaceutics, vol. 17, no. 2, 2020, pp. 554-568.
Simões MF, Pereira A, Cardoso S, et al. Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions by Hot-Melt Extrusion. Mol Pharm. 2020;17(2):554-568.
Simões, M. F., Pereira, A., Cardoso, S., Cadonau, S., Werner, K., Pinto, R. M. A., & Simões, S. (2020). Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions by Hot-Melt Extrusion. Molecular Pharmaceutics, 17(2), 554-568. https://doi.org/10.1021/acs.molpharmaceut.9b00996
Simões MF, et al. Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions By Hot-Melt Extrusion. Mol Pharm. 2020 02 3;17(2):554-568. PubMed PMID: 31774685.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions by Hot-Melt Extrusion. AU - Simões,Marta F, AU - Pereira,Alexandra, AU - Cardoso,Sara, AU - Cadonau,Stephanie, AU - Werner,Karl, AU - Pinto,Rui M A, AU - Simões,Sérgio, Y1 - 2020/01/23/ PY - 2019/11/28/pubmed PY - 2019/11/28/medline PY - 2019/11/28/entrez KW - BCS class IV KW - Etravirine KW - amorphous solid dispersions KW - hot-melt extrusion KW - principal component analysis KW - solubility enhancement SP - 554 EP - 568 JF - Molecular pharmaceutics JO - Mol Pharm VL - 17 IS - 2 N2 - The aim of this study was to develop a fast, effective, and material sparing screening method to design amorphous solid dispersions (ASDs) of etravirine to drive more effectively the development process, leading to improved bioavailability (BA) and stability. A systematic step-by-step approach was followed by combining theoretical calculations with high-throughput screening (HTS) and software-assisted multivariate statistical analysis. The thermodynamic miscibility and interaction of the drug in several polymers were predicted using Hansen solubility parameters (δ). The selected polymers were evaluated by HTS, using solvent evaporation. Binary compositions were evaluated by their solubilization capacity and physical stability over 2 months. JMP 14.0 was used for multivariate statistical analysis using principal components analysis. Extrusion was performed in Thermo Scientific HAAKE MiniLab II, and extrudates were characterized by assay, related substances, dissolution, and physical state (polarized light microscopy (PLM), Raman spectroscopy, and X-ray powder diffraction (XRPD)). A short stability study was performed where milled extrudates were exposed to 25 °C/60%RH and 40 °C/75%RH for 3 months. Through thermodynamic predictions, five main polymers were selected. The HTS enabled the evaluation of 42 formulations for solubilization capacity and physical stability. The three most promising compositions were selected for hot-melt extrusion (HME) tests. In general, a good correlation was found among the results of theoretical predictions, HTS, and HME. Poly(vinylpyrrolidone) (PVP)-based formulations were shown to be easily extrudable, with low degradation and complete amorphicity, whereas in Soluplus, the drug was not miscible, leading to a high crystalline content. The drug release rate was improved more than two times with PVP, and the manufactured ASD was demonstrated to be stable physically and chemically. A fast and effective screening technique to develop stable ASDs for a poorly soluble drug was successfully developed as applied to etravirine. The given method is easy to use, requires a low amount of drug, and is fairly accurate in predicting the amorphization of the drug when formulated. The success of HME formulation development of etravirine was undoubtedly enhanced with this high-throughput tool, which led to the identification of extrudates with improved biopharmaceutical properties. The structural characterization performed by PLM, XRPD, and Raman spectroscopy demonstrated that the HME prototype was essentially amorphous. The unexpected stability at 40 °C/75%RH was correlated with the presence of molecular interaction characterized by Raman spectroscopy. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/31774685/Five_Stage_Approach_for_a_Systematic_Screening_and_Development_of_Etravirine_Amorphous_Solid_Dispersions_by_Hot_Melt_Extrusion_ L2 - https://doi.org/10.1021/acs.molpharmaceut.9b00996 DB - PRIME DP - Unbound Medicine ER -