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Co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers

INTRODUCTION: Strategies to address the problem of poorly water-soluble drugs encompass the conversion of a crystalline drug into an amorphous form to promote its apparent solubility and dissolution. Co-amorphous systems (CAMs) incorporate low molecular mass molecules (co-formers), which are mixed w...

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Autores principales: Bastos, Ana C., Santos, Inês A., Pinto, João F., Fernandes, Ana I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480635/
http://dx.doi.org/10.1080/07853890.2021.1896099
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author Bastos, Ana C.
Santos, Inês A.
Pinto, João F.
Fernandes, Ana I.
author_facet Bastos, Ana C.
Santos, Inês A.
Pinto, João F.
Fernandes, Ana I.
author_sort Bastos, Ana C.
collection PubMed
description INTRODUCTION: Strategies to address the problem of poorly water-soluble drugs encompass the conversion of a crystalline drug into an amorphous form to promote its apparent solubility and dissolution. Co-amorphous systems (CAMs) incorporate low molecular mass molecules (co-formers), which are mixed with the drug to form one single phase [1,2]. The aim of this study is to understand the capability of different co-formers (amino, carboxylic and sulphonic acids), in the production of CAMs with olanzapine by ball milling, solvent evaporation and quench cooling. MATERIALS AND METHODS: Mixtures (2 g) of olanzapine (OLZ) and each co-former [l-aspartate (ASP); l-tryptophan (TRY); l-arginine (ARG); l-proline (PRO); citric acid (CIT); tartaric acid (TAR); oxalic acid (OXA); saccharine (SAC); potassium acessulfame (ACE); cyclamic acid (CYC)] in 1:1 molar ratios were submitted to ball milling (BM), solvent evaporation (SE) and quench cooling (QC). CAMs were evaluated for the OLZ solubility increase, co-formability and storage stability over time, by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and Fourier-transform infra-red spectroscopy (FTIR). RESULTS: The BM technique presented the most promising results followed by QC and SE (Table 1), since more CAMs were produced. All the sulphonic acids (SAC, CYC and ACE) formed CAMs regardless of the technique used, presenting complete amorphization probably due to their higher ability to produce intermolecular interactions, like hydrogen-bonding, thus increasing the stability of CAMs (more than 8 weeks at 25 °C/11 and 53% RH). Conversely, amino acids were the least efficient in producing CAMs. Crystalline OLZ presented low solubility (40.1 mg/L) in water and a general increase in the solubility of the CAMs was observed. Carboxylic acids (TAR, CIT, OXA) achieved the biggest increase (up to 269 times, BM with TART) followed by sulphonic acids (up to 199 times, SE with SAC), unveiling the possibility of improved dissolution profiles and bioavailability. Discussion and conclusions: The study has shown the possibility of converting a crystalline drug into an amorphous entity, particularly when in presence of co-formers which stabilise the amorphous structures formed. In fact, with sulphonic acids, both SE and BM, achieved complete amorphization and successfully stabilised the CAMs obtained. Due to the noteworthy increase in solubility, resulting from co-amorphization, this technique is considered to be adequate to process active compounds with poor water solubility, such as OLZ.
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spelling pubmed-84806352022-03-03 Co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers Bastos, Ana C. Santos, Inês A. Pinto, João F. Fernandes, Ana I. Ann Med Abstract 100 INTRODUCTION: Strategies to address the problem of poorly water-soluble drugs encompass the conversion of a crystalline drug into an amorphous form to promote its apparent solubility and dissolution. Co-amorphous systems (CAMs) incorporate low molecular mass molecules (co-formers), which are mixed with the drug to form one single phase [1,2]. The aim of this study is to understand the capability of different co-formers (amino, carboxylic and sulphonic acids), in the production of CAMs with olanzapine by ball milling, solvent evaporation and quench cooling. MATERIALS AND METHODS: Mixtures (2 g) of olanzapine (OLZ) and each co-former [l-aspartate (ASP); l-tryptophan (TRY); l-arginine (ARG); l-proline (PRO); citric acid (CIT); tartaric acid (TAR); oxalic acid (OXA); saccharine (SAC); potassium acessulfame (ACE); cyclamic acid (CYC)] in 1:1 molar ratios were submitted to ball milling (BM), solvent evaporation (SE) and quench cooling (QC). CAMs were evaluated for the OLZ solubility increase, co-formability and storage stability over time, by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and Fourier-transform infra-red spectroscopy (FTIR). RESULTS: The BM technique presented the most promising results followed by QC and SE (Table 1), since more CAMs were produced. All the sulphonic acids (SAC, CYC and ACE) formed CAMs regardless of the technique used, presenting complete amorphization probably due to their higher ability to produce intermolecular interactions, like hydrogen-bonding, thus increasing the stability of CAMs (more than 8 weeks at 25 °C/11 and 53% RH). Conversely, amino acids were the least efficient in producing CAMs. Crystalline OLZ presented low solubility (40.1 mg/L) in water and a general increase in the solubility of the CAMs was observed. Carboxylic acids (TAR, CIT, OXA) achieved the biggest increase (up to 269 times, BM with TART) followed by sulphonic acids (up to 199 times, SE with SAC), unveiling the possibility of improved dissolution profiles and bioavailability. Discussion and conclusions: The study has shown the possibility of converting a crystalline drug into an amorphous entity, particularly when in presence of co-formers which stabilise the amorphous structures formed. In fact, with sulphonic acids, both SE and BM, achieved complete amorphization and successfully stabilised the CAMs obtained. Due to the noteworthy increase in solubility, resulting from co-amorphization, this technique is considered to be adequate to process active compounds with poor water solubility, such as OLZ. Taylor & Francis 2021-09-28 /pmc/articles/PMC8480635/ http://dx.doi.org/10.1080/07853890.2021.1896099 Text en © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Abstract 100
Bastos, Ana C.
Santos, Inês A.
Pinto, João F.
Fernandes, Ana I.
Co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers
title Co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers
title_full Co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers
title_fullStr Co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers
title_full_unstemmed Co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers
title_short Co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers
title_sort co-formability, solubility enhancement and stability of olanzapine co-amorphous systems produced with different co-formers
topic Abstract 100
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480635/
http://dx.doi.org/10.1080/07853890.2021.1896099
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