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Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt
Acemetacin (ACM) is a non-steroidal anti-inflammatory drug (NSAID), which causes reduced gastric damage compared with indomethacin. However, acemetacin has a tendency to form a less soluble hydrate in the aqueous medium. We noted difficulties in the preparation of cocrystals and salts of acemetacin...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
International Union of Crystallography
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062091/ https://www.ncbi.nlm.nih.gov/pubmed/25075330 http://dx.doi.org/10.1107/S2052252514004229 |
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author | Sanphui, Palash Bolla, Geetha Nangia, Ashwini Chernyshev, Vladimir |
author_facet | Sanphui, Palash Bolla, Geetha Nangia, Ashwini Chernyshev, Vladimir |
author_sort | Sanphui, Palash |
collection | PubMed |
description | Acemetacin (ACM) is a non-steroidal anti-inflammatory drug (NSAID), which causes reduced gastric damage compared with indomethacin. However, acemetacin has a tendency to form a less soluble hydrate in the aqueous medium. We noted difficulties in the preparation of cocrystals and salts of acemetacin by mechanochemical methods, because this drug tends to form a hydrate during any kind of solution-based processing. With the objective to discover a solid form of acemetacin that is stable in the aqueous medium, binary adducts were prepared by the melt method to avoid hydration. The coformers/salt formers reported are pyridine carboxamides [nicotinamide (NAM), isonicotinamide (INA), and picolinamide (PAM)], caprolactam (CPR), p-aminobenzoic acid (PABA), and piperazine (PPZ). The structures of an ACM–INA cocrystal and a binary adduct ACM–PABA were solved using single-crystal X-ray diffraction. Other ACM cocrystals, ACM–PAM and ACM–CPR, and the piperazine salt ACM–PPZ were solved from high-resolution powder X-ray diffraction data. The ACM–INA cocrystal is sustained by the acid⋯pyridine heterosynthon and N—H⋯O catemer hydrogen bonds involving the amide group. The acid⋯amide heterosynthon is present in the ACM–PAM cocrystal, while ACM–CPR contains carboxamide dimers of caprolactam along with acid–carbonyl (ACM) hydrogen bonds. The cocrystals ACM–INA, ACM–PAM and ACM–CPR are three-dimensional isostructural. The carboxyl⋯carboxyl synthon in ACM–PABA posed difficulty in assigning the position of the H atom, which may indicate proton disorder. In terms of stability, the salts were found to be relatively stable in pH 7 buffer medium over 24 h, but the cocrystals dissociated to give ACM hydrate during the same time period. The ACM–PPZ salt and ACM–nicotinamide cocrystal dissolve five times faster than the stable hydrate form, whereas the ACM–PABA adduct has 2.5 times faster dissolution rate. The pharmaceutically acceptable piperazine salt of acemetacin exhibits superior stability, faster dissolution rate and is able to overcome the hydration tendency of the reference drug. |
format | Online Article Text |
id | pubmed-4062091 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
spelling | pubmed-40620912014-07-24 Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt Sanphui, Palash Bolla, Geetha Nangia, Ashwini Chernyshev, Vladimir IUCrJ Research Papers Acemetacin (ACM) is a non-steroidal anti-inflammatory drug (NSAID), which causes reduced gastric damage compared with indomethacin. However, acemetacin has a tendency to form a less soluble hydrate in the aqueous medium. We noted difficulties in the preparation of cocrystals and salts of acemetacin by mechanochemical methods, because this drug tends to form a hydrate during any kind of solution-based processing. With the objective to discover a solid form of acemetacin that is stable in the aqueous medium, binary adducts were prepared by the melt method to avoid hydration. The coformers/salt formers reported are pyridine carboxamides [nicotinamide (NAM), isonicotinamide (INA), and picolinamide (PAM)], caprolactam (CPR), p-aminobenzoic acid (PABA), and piperazine (PPZ). The structures of an ACM–INA cocrystal and a binary adduct ACM–PABA were solved using single-crystal X-ray diffraction. Other ACM cocrystals, ACM–PAM and ACM–CPR, and the piperazine salt ACM–PPZ were solved from high-resolution powder X-ray diffraction data. The ACM–INA cocrystal is sustained by the acid⋯pyridine heterosynthon and N—H⋯O catemer hydrogen bonds involving the amide group. The acid⋯amide heterosynthon is present in the ACM–PAM cocrystal, while ACM–CPR contains carboxamide dimers of caprolactam along with acid–carbonyl (ACM) hydrogen bonds. The cocrystals ACM–INA, ACM–PAM and ACM–CPR are three-dimensional isostructural. The carboxyl⋯carboxyl synthon in ACM–PABA posed difficulty in assigning the position of the H atom, which may indicate proton disorder. In terms of stability, the salts were found to be relatively stable in pH 7 buffer medium over 24 h, but the cocrystals dissociated to give ACM hydrate during the same time period. The ACM–PPZ salt and ACM–nicotinamide cocrystal dissolve five times faster than the stable hydrate form, whereas the ACM–PABA adduct has 2.5 times faster dissolution rate. The pharmaceutically acceptable piperazine salt of acemetacin exhibits superior stability, faster dissolution rate and is able to overcome the hydration tendency of the reference drug. International Union of Crystallography 2014-02-28 /pmc/articles/PMC4062091/ /pubmed/25075330 http://dx.doi.org/10.1107/S2052252514004229 Text en © Palash Sanphui et al. 2014 http://creativecommons.org/licenses/by/2.0/uk/ This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. |
spellingShingle | Research Papers Sanphui, Palash Bolla, Geetha Nangia, Ashwini Chernyshev, Vladimir Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt |
title | Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt |
title_full | Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt |
title_fullStr | Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt |
title_full_unstemmed | Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt |
title_short | Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt |
title_sort | acemetacin cocrystals and salts: structure solution from powder x-ray data and form selection of the piperazine salt |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062091/ https://www.ncbi.nlm.nih.gov/pubmed/25075330 http://dx.doi.org/10.1107/S2052252514004229 |
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