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Long-term stability of clopidogrel solid dispersions—Importance of in vitro dissolution test

Formulation of solid dispersions (SDs), in which the drug substance is dissolved or dispersed inside a polymer matrix, is one of the modern approaches to increase the solubility and dissolution rate of poorly soluble active pharmaceutical ingredients (APIs), such as clopidogrel. In the form of a fre...

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Autores principales: Osmanović Omerdić, Ehlimana, Alagić-Džambić, Larisa, Krstić, Marko, Pašić-Kulenović, Maja, Medarević, Đorđe, Ivković, Branka, Vasiljević, Dragana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979437/
https://www.ncbi.nlm.nih.gov/pubmed/35377908
http://dx.doi.org/10.1371/journal.pone.0266237
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author Osmanović Omerdić, Ehlimana
Alagić-Džambić, Larisa
Krstić, Marko
Pašić-Kulenović, Maja
Medarević, Đorđe
Ivković, Branka
Vasiljević, Dragana
author_facet Osmanović Omerdić, Ehlimana
Alagić-Džambić, Larisa
Krstić, Marko
Pašić-Kulenović, Maja
Medarević, Đorđe
Ivković, Branka
Vasiljević, Dragana
author_sort Osmanović Omerdić, Ehlimana
collection PubMed
description Formulation of solid dispersions (SDs), in which the drug substance is dissolved or dispersed inside a polymer matrix, is one of the modern approaches to increase the solubility and dissolution rate of poorly soluble active pharmaceutical ingredients (APIs), such as clopidogrel. In the form of a free base, clopidogrel is unstable under increased both high moisture and temperature, so it is most often used as its salt form, clopidogrel hydrogen sulfate (CHS).The aim of this study was the formulation, characterization, and long-term stability investigation of CHS solid dispersions, prepared with four different hydrophilic polymers (poloxamer 407, macrogol 6000, povidone, copovidone) in five API/polymer ratios (1:1, 1:2, 1:3, 1:5, 1:9). SDs were prepared by the solvent evaporation method, employing ethanol (96% v/v) as a solvent. Initial results of the in vitro dissolution test showed an increase in the amount of dissolved CHS from all prepared SD samples compared to pure CHS, corresponding physical mixtures (PMs), and commercial tablets. SDs, prepared with poloxamer 407, macrogol 6000, and copovidone, at CHS/polymer ratios 1:5 and 1:9, notably increased the amount of dissolved CHS (> 80%, after 60 min), thus they were selected for further characterization. To assess the SDs long-term stability, in vitro dissolution studies, clopidogrel content determination, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) were performed initially and after 12 months of long-term stability studies under controlled conditions (25°C, 60% RH) meeting the ICH guideline Q1A (R2) requirements. The clopidogrel content in the selected samples was very similar at the beginning (96.13% to 99.93%) and at the end (95.98% to 99.86%) of the conducted test. DSC curves and FT-IR spectra of all SD samples after 12 months of stability study, showed the absence of CHS crystallization, which is an indication of good stability. However, the in vitro dissolution test showed a considerable reduction in CHS released from SDs with macrogol 6000. The amount of dissolved CHS from SDs with macrogol 6000 was initially 94.02% and 92.01%, and after 12 months of stability study, only 65.13% and 49.62%. In contrast, the amount of dissolved CHS from SDs prepared with poloxamer 407 and copovidone was very similar after 12 months of the stability study compared to the initial values. Results obtained indicated the great importance of the in vitro dissolution test in determining the long-term stability and quality of SDs.
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spelling pubmed-89794372022-04-05 Long-term stability of clopidogrel solid dispersions—Importance of in vitro dissolution test Osmanović Omerdić, Ehlimana Alagić-Džambić, Larisa Krstić, Marko Pašić-Kulenović, Maja Medarević, Đorđe Ivković, Branka Vasiljević, Dragana PLoS One Research Article Formulation of solid dispersions (SDs), in which the drug substance is dissolved or dispersed inside a polymer matrix, is one of the modern approaches to increase the solubility and dissolution rate of poorly soluble active pharmaceutical ingredients (APIs), such as clopidogrel. In the form of a free base, clopidogrel is unstable under increased both high moisture and temperature, so it is most often used as its salt form, clopidogrel hydrogen sulfate (CHS).The aim of this study was the formulation, characterization, and long-term stability investigation of CHS solid dispersions, prepared with four different hydrophilic polymers (poloxamer 407, macrogol 6000, povidone, copovidone) in five API/polymer ratios (1:1, 1:2, 1:3, 1:5, 1:9). SDs were prepared by the solvent evaporation method, employing ethanol (96% v/v) as a solvent. Initial results of the in vitro dissolution test showed an increase in the amount of dissolved CHS from all prepared SD samples compared to pure CHS, corresponding physical mixtures (PMs), and commercial tablets. SDs, prepared with poloxamer 407, macrogol 6000, and copovidone, at CHS/polymer ratios 1:5 and 1:9, notably increased the amount of dissolved CHS (> 80%, after 60 min), thus they were selected for further characterization. To assess the SDs long-term stability, in vitro dissolution studies, clopidogrel content determination, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) were performed initially and after 12 months of long-term stability studies under controlled conditions (25°C, 60% RH) meeting the ICH guideline Q1A (R2) requirements. The clopidogrel content in the selected samples was very similar at the beginning (96.13% to 99.93%) and at the end (95.98% to 99.86%) of the conducted test. DSC curves and FT-IR spectra of all SD samples after 12 months of stability study, showed the absence of CHS crystallization, which is an indication of good stability. However, the in vitro dissolution test showed a considerable reduction in CHS released from SDs with macrogol 6000. The amount of dissolved CHS from SDs with macrogol 6000 was initially 94.02% and 92.01%, and after 12 months of stability study, only 65.13% and 49.62%. In contrast, the amount of dissolved CHS from SDs prepared with poloxamer 407 and copovidone was very similar after 12 months of the stability study compared to the initial values. Results obtained indicated the great importance of the in vitro dissolution test in determining the long-term stability and quality of SDs. Public Library of Science 2022-04-04 /pmc/articles/PMC8979437/ /pubmed/35377908 http://dx.doi.org/10.1371/journal.pone.0266237 Text en © 2022 Osmanović Omerdić et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Osmanović Omerdić, Ehlimana
Alagić-Džambić, Larisa
Krstić, Marko
Pašić-Kulenović, Maja
Medarević, Đorđe
Ivković, Branka
Vasiljević, Dragana
Long-term stability of clopidogrel solid dispersions—Importance of in vitro dissolution test
title Long-term stability of clopidogrel solid dispersions—Importance of in vitro dissolution test
title_full Long-term stability of clopidogrel solid dispersions—Importance of in vitro dissolution test
title_fullStr Long-term stability of clopidogrel solid dispersions—Importance of in vitro dissolution test
title_full_unstemmed Long-term stability of clopidogrel solid dispersions—Importance of in vitro dissolution test
title_short Long-term stability of clopidogrel solid dispersions—Importance of in vitro dissolution test
title_sort long-term stability of clopidogrel solid dispersions—importance of in vitro dissolution test
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979437/
https://www.ncbi.nlm.nih.gov/pubmed/35377908
http://dx.doi.org/10.1371/journal.pone.0266237
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