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Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions.
Mol Pharm. 2017 01 03; 14(1):157-171.MP

Abstract

The preparation of amorphous solid dispersion (ASD) formulations is a promising strategy to improve the bioavailability of an active pharmaceutical ingredient (API). By dissolving the API in a polymer it is stabilized in its amorphous form, which usually shows higher water solubility than its crystalline counterpart. To prevent recrystallization, the long-term physical stability of ASD formulations is of big interest. In this work, the solubility of the APIs acetaminophen and naproxen in the excipient polymers poly(vinylpyrrolidone) (PVP K25) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was calculated with three models: the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the Flory-Huggins model (FH), and an empirical model (Kyeremateng et al., J. Pharm. Sci, 2014, 103, 2847-2858). PC-SAFT and FH were further used to predict the influence of relative humidity (RH) on the API solubility in the polymers. The Gordon-Taylor equation was applied to model the glass-transition temperature of dry ASD and at humid conditions. The calculations were validated by 18 months-long stability studies at standardized storage conditions, 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH. The results of the three modeling approaches for the API solubility in polymers agreed with the experimental solubility data, which are only accessible at high temperatures in dry polymers. However, at room temperature FH resulted in a lower solubility of the APIs in the dry polymers than PC-SAFT and the empirical model. The impact of RH on the solubility of acetaminophen was predicted to be small, but naproxen solubility in the polymers was predicted to decrease with increasing RH with both, PC-SAFT and FH. At 25 °C/60% RH and 40 °C/75% RH, PC-SAFT is in agreement with all results of the long-term stability studies, while FH underestimates the acetaminophen solubility in PVP K25 and PVPVA64.

Authors+Show Affiliations

AbbVie Deutschland GmbH & Co. KG , Global Pharmaceutical R&D, Knollstraβe, D-67061 Ludwigshafen am Rhein, Germany. TU Dortmund , Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, 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.AbbVie Deutschland GmbH & Co. KG , Global Pharmaceutical R&D, Knollstraβe, D-67061 Ludwigshafen am Rhein, Germany.TU Dortmund , Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge-Str. 70, D-44227 Dortmund, Germany.

Pub Type(s)

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

Language

eng

PubMed ID

28043133

Citation

Lehmkemper, Kristin, et al. "Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions." Molecular Pharmaceutics, vol. 14, no. 1, 2017, pp. 157-171.
Lehmkemper K, Kyeremateng SO, Heinzerling O, et al. Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions. Mol Pharm. 2017;14(1):157-171.
Lehmkemper, K., Kyeremateng, S. O., Heinzerling, O., Degenhardt, M., & Sadowski, G. (2017). Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions. Molecular Pharmaceutics, 14(1), 157-171. https://doi.org/10.1021/acs.molpharmaceut.6b00763
Lehmkemper K, et al. Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions. Mol Pharm. 2017 01 3;14(1):157-171. PubMed PMID: 28043133.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-Term Physical Stability of PVP- and PVPVA-Amorphous Solid Dispersions. AU - Lehmkemper,Kristin, AU - Kyeremateng,Samuel O, AU - Heinzerling,Oliver, AU - Degenhardt,Matthias, AU - Sadowski,Gabriele, Y1 - 2016/12/07/ PY - 2017/1/4/entrez PY - 2017/1/4/pubmed PY - 2017/10/27/medline KW - Flory−Huggins KW - PC-SAFT KW - acetaminophen KW - amorphous solid dispersion KW - long-term stability studies KW - naproxen KW - phase behavior KW - polymer KW - relative humidity KW - thermodynamic model SP - 157 EP - 171 JF - Molecular pharmaceutics JO - Mol Pharm VL - 14 IS - 1 N2 - The preparation of amorphous solid dispersion (ASD) formulations is a promising strategy to improve the bioavailability of an active pharmaceutical ingredient (API). By dissolving the API in a polymer it is stabilized in its amorphous form, which usually shows higher water solubility than its crystalline counterpart. To prevent recrystallization, the long-term physical stability of ASD formulations is of big interest. In this work, the solubility of the APIs acetaminophen and naproxen in the excipient polymers poly(vinylpyrrolidone) (PVP K25) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) was calculated with three models: the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the Flory-Huggins model (FH), and an empirical model (Kyeremateng et al., J. Pharm. Sci, 2014, 103, 2847-2858). PC-SAFT and FH were further used to predict the influence of relative humidity (RH) on the API solubility in the polymers. The Gordon-Taylor equation was applied to model the glass-transition temperature of dry ASD and at humid conditions. The calculations were validated by 18 months-long stability studies at standardized storage conditions, 25 °C/0% RH, 25 °C/60% RH, and 40 °C/75% RH. The results of the three modeling approaches for the API solubility in polymers agreed with the experimental solubility data, which are only accessible at high temperatures in dry polymers. However, at room temperature FH resulted in a lower solubility of the APIs in the dry polymers than PC-SAFT and the empirical model. The impact of RH on the solubility of acetaminophen was predicted to be small, but naproxen solubility in the polymers was predicted to decrease with increasing RH with both, PC-SAFT and FH. At 25 °C/60% RH and 40 °C/75% RH, PC-SAFT is in agreement with all results of the long-term stability studies, while FH underestimates the acetaminophen solubility in PVP K25 and PVPVA64. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/28043133/Long_Term_Physical_Stability_of_PVP__and_PVPVA_Amorphous_Solid_Dispersions_ L2 - https://doi.org/10.1021/acs.molpharmaceut.6b00763 DB - PRIME DP - Unbound Medicine ER -