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Impact of Polymer Type and Relative Humidity on the Long-Term Physical Stability of Amorphous Solid Dispersions.
Mol Pharm. 2017 12 04; 14(12):4374-4386.MP

Abstract

The purpose of this work is to compare the long-term physical stability of amorphous solid dispersion (ASD) formulations based on three different commercially used excipients, namely, poly(vinylpyrrolidone) K25 (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxypropyl methylcellulose acetate succinate 126G (HPMCAS), at standardized ICH storage conditions, 25 °C/0% relative humidity (RH), 25 °C/60% RH, and 40 °C/75% RH. Acetaminophen (APAP) and naproxen (NAP) were used as active pharmaceutical ingredients (APIs). 18 month long stability studies of these formulations were analyzed and compared with the API/polymer phase diagrams, which were modeled and predicted by applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor or Kwei equation. The study showed that, at dry storage, the solubility of the APIs in the polymers and the kinetic stabilizing ability of the polymers increase in the following order: HPMCAS < PVPVA64 < PVP. RH significantly reduces the kinetic stabilization as well as NAP solubility in the polymers, while the impact on APAP solubility is small. The impact of RH on the stability increases with increasing hydrophilicity of the pure polymers (HPMCAS < PVPVA64 < PVP). The experimental stability results were in very good agreement with predictions confirming that PC-SAFT and the Kwei equation are suitable predictive tools for determining appropriate ASD compositions and storage conditions to ensure long-term physical stability.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

29050468

Citation

Lehmkemper, Kristin, et al. "Impact of Polymer Type and Relative Humidity On the Long-Term Physical Stability of Amorphous Solid Dispersions." Molecular Pharmaceutics, vol. 14, no. 12, 2017, pp. 4374-4386.
Lehmkemper K, Kyeremateng SO, Heinzerling O, et al. Impact of Polymer Type and Relative Humidity on the Long-Term Physical Stability of Amorphous Solid Dispersions. Mol Pharm. 2017;14(12):4374-4386.
Lehmkemper, K., Kyeremateng, S. O., Heinzerling, O., Degenhardt, M., & Sadowski, G. (2017). Impact of Polymer Type and Relative Humidity on the Long-Term Physical Stability of Amorphous Solid Dispersions. Molecular Pharmaceutics, 14(12), 4374-4386. https://doi.org/10.1021/acs.molpharmaceut.7b00492
Lehmkemper K, et al. Impact of Polymer Type and Relative Humidity On the Long-Term Physical Stability of Amorphous Solid Dispersions. Mol Pharm. 2017 12 4;14(12):4374-4386. PubMed PMID: 29050468.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impact of Polymer Type and Relative Humidity on the Long-Term Physical Stability of Amorphous Solid Dispersions. AU - Lehmkemper,Kristin, AU - Kyeremateng,Samuel O, AU - Heinzerling,Oliver, AU - Degenhardt,Matthias, AU - Sadowski,Gabriele, Y1 - 2017/11/07/ PY - 2017/10/21/pubmed PY - 2018/7/28/medline PY - 2017/10/21/entrez KW - amorphous solid dispersion KW - excipient KW - phase behavior KW - physical stability KW - polymer KW - thermodynamic model SP - 4374 EP - 4386 JF - Molecular pharmaceutics JO - Mol Pharm VL - 14 IS - 12 N2 - The purpose of this work is to compare the long-term physical stability of amorphous solid dispersion (ASD) formulations based on three different commercially used excipients, namely, poly(vinylpyrrolidone) K25 (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxypropyl methylcellulose acetate succinate 126G (HPMCAS), at standardized ICH storage conditions, 25 °C/0% relative humidity (RH), 25 °C/60% RH, and 40 °C/75% RH. Acetaminophen (APAP) and naproxen (NAP) were used as active pharmaceutical ingredients (APIs). 18 month long stability studies of these formulations were analyzed and compared with the API/polymer phase diagrams, which were modeled and predicted by applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor or Kwei equation. The study showed that, at dry storage, the solubility of the APIs in the polymers and the kinetic stabilizing ability of the polymers increase in the following order: HPMCAS < PVPVA64 < PVP. RH significantly reduces the kinetic stabilization as well as NAP solubility in the polymers, while the impact on APAP solubility is small. The impact of RH on the stability increases with increasing hydrophilicity of the pure polymers (HPMCAS < PVPVA64 < PVP). The experimental stability results were in very good agreement with predictions confirming that PC-SAFT and the Kwei equation are suitable predictive tools for determining appropriate ASD compositions and storage conditions to ensure long-term physical stability. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/29050468/Impact_of_Polymer_Type_and_Relative_Humidity_on_the_Long_Term_Physical_Stability_of_Amorphous_Solid_Dispersions_ L2 - https://doi.org/10.1021/acs.molpharmaceut.7b00492 DB - PRIME DP - Unbound Medicine ER -