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Investigation into Intermolecular Interactions and Phase Behavior of Binary and Ternary Amorphous Solid Dispersions of Ketoconazole.
Mol Pharm. 2020 03 02; 17(3):787-801.MP

Abstract

Conventionally, amorphous solid dispersions (ASDs) have been formulated as a binary matrix, but in recent years a new class of ASDs has emerged, where generally a second polymer is also added to the formulation. Having the presence of a second polymer necessitates a comprehensive solid-state characterization to study the intermolecular interactions and phase behavior on a molecular level. With this goal in mind, ketoconazole (KET) was selected as a model drug, and hydroxypropyl methyl cellulose (HPMC) and poly(acrylic acid) (PAA) were chosen as polymeric carriers. The binary and ternary ASDs were characterized by differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, and powder X-ray diffraction (PXRD). The binary KET:HPMC dispersions lacked any specific interactions, whereas binary KET:PAA dispersions and ternary KET:PAA:HPMC dispersions showed evidence for ionic and hydrogen bonding interactions. The 13C SSNMR deconvolution study established a comparison for molecular interactions between the binary KET:PAA and ternary KET:PAA:HPMC dispersions, with the binary KET:PAA system showing higher prevalence of ionic and hydrogen bonds than the ternary KET:PAA:HPMC system. Moreover, individual binary and ternary ASDs were found to be homogeneous on a nanometric level, implying the presence of a second polymer did not impact the phase homogeneity. In addition, a stronger interaction in binary KET:PAA and ternary KET:HPMC:PAA systems translated to better physical stability at different storage conditions. Through this case study it is recommended that a comprehensive investigation is needed to study the impact of using two polymers in ASD formulations in terms underlying intermolecular interactions and physical stability.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536, United States.Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536, United States. Department of Chemistry, Allegheny College, Meadville, Pennsylvania 16335, United States.Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536, United States.

Pub Type(s)

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

Language

eng

PubMed ID

31860316

Citation

Sarpal, Kanika, et al. "Investigation Into Intermolecular Interactions and Phase Behavior of Binary and Ternary Amorphous Solid Dispersions of Ketoconazole." Molecular Pharmaceutics, vol. 17, no. 3, 2020, pp. 787-801.
Sarpal K, Tower CW, Munson EJ. Investigation into Intermolecular Interactions and Phase Behavior of Binary and Ternary Amorphous Solid Dispersions of Ketoconazole. Mol Pharm. 2020;17(3):787-801.
Sarpal, K., Tower, C. W., & Munson, E. J. (2020). Investigation into Intermolecular Interactions and Phase Behavior of Binary and Ternary Amorphous Solid Dispersions of Ketoconazole. Molecular Pharmaceutics, 17(3), 787-801. https://doi.org/10.1021/acs.molpharmaceut.9b00970
Sarpal K, Tower CW, Munson EJ. Investigation Into Intermolecular Interactions and Phase Behavior of Binary and Ternary Amorphous Solid Dispersions of Ketoconazole. Mol Pharm. 2020 03 2;17(3):787-801. PubMed PMID: 31860316.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigation into Intermolecular Interactions and Phase Behavior of Binary and Ternary Amorphous Solid Dispersions of Ketoconazole. AU - Sarpal,Kanika, AU - Tower,Cole W, AU - Munson,Eric J, Y1 - 2020/02/20/ PY - 2019/12/21/pubmed PY - 2021/5/27/medline PY - 2019/12/21/entrez KW - drug-polymer interactions KW - hydrogen bonding KW - ketoconazole KW - phase behavior KW - physical stability KW - solid-state NMR KW - ternary amorphous solid dispersions SP - 787 EP - 801 JF - Molecular pharmaceutics JO - Mol Pharm VL - 17 IS - 3 N2 - Conventionally, amorphous solid dispersions (ASDs) have been formulated as a binary matrix, but in recent years a new class of ASDs has emerged, where generally a second polymer is also added to the formulation. Having the presence of a second polymer necessitates a comprehensive solid-state characterization to study the intermolecular interactions and phase behavior on a molecular level. With this goal in mind, ketoconazole (KET) was selected as a model drug, and hydroxypropyl methyl cellulose (HPMC) and poly(acrylic acid) (PAA) were chosen as polymeric carriers. The binary and ternary ASDs were characterized by differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, and powder X-ray diffraction (PXRD). The binary KET:HPMC dispersions lacked any specific interactions, whereas binary KET:PAA dispersions and ternary KET:PAA:HPMC dispersions showed evidence for ionic and hydrogen bonding interactions. The 13C SSNMR deconvolution study established a comparison for molecular interactions between the binary KET:PAA and ternary KET:PAA:HPMC dispersions, with the binary KET:PAA system showing higher prevalence of ionic and hydrogen bonds than the ternary KET:PAA:HPMC system. Moreover, individual binary and ternary ASDs were found to be homogeneous on a nanometric level, implying the presence of a second polymer did not impact the phase homogeneity. In addition, a stronger interaction in binary KET:PAA and ternary KET:HPMC:PAA systems translated to better physical stability at different storage conditions. Through this case study it is recommended that a comprehensive investigation is needed to study the impact of using two polymers in ASD formulations in terms underlying intermolecular interactions and physical stability. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/31860316/Investigation_into_Intermolecular_Interactions_and_Phase_Behavior_of_Binary_and_Ternary_Amorphous_Solid_Dispersions_of_Ketoconazole_ L2 - https://doi.org/10.1021/acs.molpharmaceut.9b00970 DB - PRIME DP - Unbound Medicine ER -