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Insights into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance.
Mol Pharm. 2019 03 04; 16(3):1327-1339.MP

Abstract

The aim of this study was to probe the dissolution mechanisms of amorphous solid dispersions (ASDs) of a poorly water-soluble drug formulated with a hydrophilic polymer. Ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) were used as the model drug and polymer, respectively. ASDs with drug loadings (DLs) from 10 to 50 wt % were prepared by solvent evaporation. Surface-normalized dissolution experiments were carried out using Wood's intrinsic dissolution apparatus, and both drug and polymer release were quantified. ASDs at or below 25% DL showed rapid, complete, and congruent (i.e., simultaneous) release of the drug and polymer with dissolution rates similar to that of the polymer alone. The highest drug loading at which congruent release was observed is termed the limit of congruency (LoC) and occurred at 25% DL for RTV-PVPVA. The ASD with 30% DL showed an initial lag time, followed by a period of congruent release. At later times, the release of drug and polymer became incongruent with polymer releasing faster than drug. Higher DL ASDs (40 and 50%) showed slow release of both drug and polymer, whereby the drug release rate was similar to that of the neat amorphous drug. In cases where the release of the ASD components was congruent or close to congruent, the drug concentration exceeded the amorphous solubility, and liquid-liquid phase separation (LLPS) occurred with the formation of colloidal, drug-rich species. Solid state analyses of the ASD tablet surface by infrared spectroscopy and scanning electron microscopy revealed that the partially dissolved tablet surface remains smooth, and drug-polymer miscibility is retained at low DLs; whereas, at a very high DL, the surface is porous and enriched with amorphous drug. In concert, these observations suggest that ASD dissolution and drug release at low DLs is governed primarily by hydrophilic polymer; whereas, at high DLs, amorphous drug controls dissolution. Fluorescence microscopy images of thin ASD films suggested that ASDs at or below the LoC remain homogeneous even after exposure to water. In contrast ASDs with DL above LoC undergo, to various extents, water-induced amorphous-amorphous phase separation (AAPS) leading to demixing of the drug and polymer. Correlating the observations of the dissolution study with the solid state data suggest that the ASDs with DLs higher than the LoC undergo AAPS in the hydrating matrix on the surface of the dissolving solid during dissolution, leading to separation of drug and polymer, the formation of a drug-rich interface, and hence, incongruent and/or slow release of the components. In contrast, low DL ASDs dissolve before AAPS occurs. The competition between these two parallel and competing processes on the surface of ASD solids, i.e., dissolution and AAPS, thus dictates the overall release characteristics of the ASD formulations, which is one of the most important considerations in designing formulations with superior dissolution and absorption.

Authors+Show Affiliations

Drug Product Development, Research and Development , AbbVie Inc. , North Chicago , Illinois 60064 , United States. Department of Industrial and Physical Pharmacy, College of Pharmacy , Purdue University , West Lafayette , Indiana 47907 , United States.Drug Product Development, Research and Development , AbbVie Inc. , North Chicago , Illinois 60064 , United States.Drug Product Development, Research and Development , AbbVie Inc. , North Chicago , Illinois 60064 , United States.Department of Industrial and Physical Pharmacy, College of Pharmacy , Purdue University , West Lafayette , Indiana 47907 , United States.

Pub Type(s)

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

Language

eng

PubMed ID

30669846

Citation

Indulkar, Anura S., et al. "Insights Into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance." Molecular Pharmaceutics, vol. 16, no. 3, 2019, pp. 1327-1339.
Indulkar AS, Lou X, Zhang GGZ, et al. Insights into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance. Mol Pharm. 2019;16(3):1327-1339.
Indulkar, A. S., Lou, X., Zhang, G. G. Z., & Taylor, L. S. (2019). Insights into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance. Molecular Pharmaceutics, 16(3), 1327-1339. https://doi.org/10.1021/acs.molpharmaceut.8b01261
Indulkar AS, et al. Insights Into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance. Mol Pharm. 2019 03 4;16(3):1327-1339. PubMed PMID: 30669846.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Insights into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance. AU - Indulkar,Anura S, AU - Lou,Xiaochun, AU - Zhang,Geoff G Z, AU - Taylor,Lynne S, Y1 - 2019/02/05/ PY - 2019/1/24/pubmed PY - 2019/12/18/medline PY - 2019/1/24/entrez KW - amorphous solid dispersion KW - dissolution KW - drug release KW - liquid−liquid phase separation KW - polymer release SP - 1327 EP - 1339 JF - Molecular pharmaceutics JO - Mol Pharm VL - 16 IS - 3 N2 - The aim of this study was to probe the dissolution mechanisms of amorphous solid dispersions (ASDs) of a poorly water-soluble drug formulated with a hydrophilic polymer. Ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) were used as the model drug and polymer, respectively. ASDs with drug loadings (DLs) from 10 to 50 wt % were prepared by solvent evaporation. Surface-normalized dissolution experiments were carried out using Wood's intrinsic dissolution apparatus, and both drug and polymer release were quantified. ASDs at or below 25% DL showed rapid, complete, and congruent (i.e., simultaneous) release of the drug and polymer with dissolution rates similar to that of the polymer alone. The highest drug loading at which congruent release was observed is termed the limit of congruency (LoC) and occurred at 25% DL for RTV-PVPVA. The ASD with 30% DL showed an initial lag time, followed by a period of congruent release. At later times, the release of drug and polymer became incongruent with polymer releasing faster than drug. Higher DL ASDs (40 and 50%) showed slow release of both drug and polymer, whereby the drug release rate was similar to that of the neat amorphous drug. In cases where the release of the ASD components was congruent or close to congruent, the drug concentration exceeded the amorphous solubility, and liquid-liquid phase separation (LLPS) occurred with the formation of colloidal, drug-rich species. Solid state analyses of the ASD tablet surface by infrared spectroscopy and scanning electron microscopy revealed that the partially dissolved tablet surface remains smooth, and drug-polymer miscibility is retained at low DLs; whereas, at a very high DL, the surface is porous and enriched with amorphous drug. In concert, these observations suggest that ASD dissolution and drug release at low DLs is governed primarily by hydrophilic polymer; whereas, at high DLs, amorphous drug controls dissolution. Fluorescence microscopy images of thin ASD films suggested that ASDs at or below the LoC remain homogeneous even after exposure to water. In contrast ASDs with DL above LoC undergo, to various extents, water-induced amorphous-amorphous phase separation (AAPS) leading to demixing of the drug and polymer. Correlating the observations of the dissolution study with the solid state data suggest that the ASDs with DLs higher than the LoC undergo AAPS in the hydrating matrix on the surface of the dissolving solid during dissolution, leading to separation of drug and polymer, the formation of a drug-rich interface, and hence, incongruent and/or slow release of the components. In contrast, low DL ASDs dissolve before AAPS occurs. The competition between these two parallel and competing processes on the surface of ASD solids, i.e., dissolution and AAPS, thus dictates the overall release characteristics of the ASD formulations, which is one of the most important considerations in designing formulations with superior dissolution and absorption. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/30669846/Insights_into_the_Dissolution_Mechanism_of_Ritonavir_Copovidone_Amorphous_Solid_Dispersions:_Importance_of_Congruent_Release_for_Enhanced_Performance_ L2 - https://doi.org/10.1021/acs.molpharmaceut.8b01261 DB - PRIME DP - Unbound Medicine ER -