Cocrystallization screening for “drug-drug” type of cocrystals
Cocrystallization became well known bottom-up approach starting from intermolecular interactions among, either selected neutral, ionic or zwitterionic molecules to design and control the properties of the multicomponent crystals. [1] In the scope of interest for drug design and formulation, the main...
Main Authors: | , , |
---|---|
Format: | Conference Object |
Language: | unknown |
Published: |
2014
|
Subjects: | |
Online Access: | http://eprints.ugd.edu.mk/15670/ http://eprints.ugd.edu.mk/15670/14/Programma%20definitivo.pdf http://eprints.ugd.edu.mk/15670/3/Cvetkovski%20A.,%20Poster,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf http://eprints.ugd.edu.mk/15670/1/Cvetkovski%20A.,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf http://ecs1.azuleon.org/welcome.php |
id |
ftunivgocedelcev:oai:eprints.ugd.edu.mk:15670 |
---|---|
record_format |
openpolar |
institution |
Open Polar |
collection |
Goce Delchev University Stip: UGD Repository |
op_collection_id |
ftunivgocedelcev |
language |
unknown |
topic |
Chemical sciences |
spellingShingle |
Chemical sciences Cvetkovski, Aleksandar Bertolasi, Valerio Gilli, Paola Cocrystallization screening for “drug-drug” type of cocrystals |
topic_facet |
Chemical sciences |
description |
Cocrystallization became well known bottom-up approach starting from intermolecular interactions among, either selected neutral, ionic or zwitterionic molecules to design and control the properties of the multicomponent crystals. [1] In the scope of interest for drug design and formulation, the main advantage for designing Pharmaceutical Cocrystals (PCCs) is, through their modulating properties, to improve the performance of the native Active Pharmaceutical Ingredients (APIs) such are: biopharmaceutical profile (solubility and dissolution rate), thermodynamical stability (phase transition of polymorphs, solvate/ hydrate formation, decomposition) or bulk powder processability (flowability, compressibility, particle size and shape control). [2,3] Many debates regarding semantic and classification in cocrystals (CCs) based on accomplishments in research of supramolecular chemistry, highlighted the complex reality of multi-component systems, and the wide scope associated between salts and cocrystals in the salt-cocrystal continuum. [4] N,N-dimethylbiguanide is used as oral antidiabetic drug, well known as Metformin (MET). It directlyimproves insulin action and is the only approved hypoglycemic drug of the biguanide class. Because of the biguanide π-conjugated system, MET can exist in three resonance-stabilized forms, i.e. as neutral molecule (MET), monoprotonated (METH+) or diprotonated (METH2+) cation, with dissociation constants in water typical of biguanides (pKa112.40 and pKa2 2.96). A search of the MET fragment in the structural literature, both in the CCDC database and in patents, shows that in crystals it exists as METH+ or METH2+ but never in its neutral form MET. We have undertaken a systematic study of the crystal chemistry of MET with the aim of understanding its properties in the solid state and finding relationships with its biopharmaceutical profile. We have obtained 29 PCCs of quality suitable for crystal structure determination by single crystal X-ray diffraction with the CFs listed below. Inorganic acids: nitric, phosphoric and carbonic acid; Organic NH-type acids: saccharine and acesulfame; Organic OH-type acids: squaric and picric acid; Monocarboxylic acids: fumaric, acetic, trifluoroacetic, trichloroacetic, dichloroacetic, monochloroacetic, glycolic, salicylic, dichlofenac; Dicarboxylic acids: oxalic, malonic, maleic, fumaric, succinic, adipic. In the poster are presented structures analyses for “drug-drug” type of PCCs where both API and CF exhibit pharmacological effect: MET/ Dichloroacetic acid 1:1 and 1:2 molar ratio, MET/ Diclofenac 1:1, MET/ Glycolic 1:1 acid and MET/ Salicylic acid 1:1 molar ratio. Literature: [1] Braga D., Crystal Engineering, Chem Comm, 2003, 2751-2754, [2] Good J. D., et al. N Cryst Growth Des., 2009, 9 (5), pp 2252–2264 [3] Cheney ML, et al. .,J.PharmSci. 2011Jun;100(6):2172-81 [4] Childs, S.L., Stahly, G.P., Park, A., 2007. Mol. Pharm. 4, 323–338 |
format |
Conference Object |
author |
Cvetkovski, Aleksandar Bertolasi, Valerio Gilli, Paola |
author_facet |
Cvetkovski, Aleksandar Bertolasi, Valerio Gilli, Paola |
author_sort |
Cvetkovski, Aleksandar |
title |
Cocrystallization screening for “drug-drug” type of cocrystals |
title_short |
Cocrystallization screening for “drug-drug” type of cocrystals |
title_full |
Cocrystallization screening for “drug-drug” type of cocrystals |
title_fullStr |
Cocrystallization screening for “drug-drug” type of cocrystals |
title_full_unstemmed |
Cocrystallization screening for “drug-drug” type of cocrystals |
title_sort |
cocrystallization screening for “drug-drug” type of cocrystals |
publishDate |
2014 |
url |
http://eprints.ugd.edu.mk/15670/ http://eprints.ugd.edu.mk/15670/14/Programma%20definitivo.pdf http://eprints.ugd.edu.mk/15670/3/Cvetkovski%20A.,%20Poster,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf http://eprints.ugd.edu.mk/15670/1/Cvetkovski%20A.,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf http://ecs1.azuleon.org/welcome.php |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_relation |
http://eprints.ugd.edu.mk/15670/14/Programma%20definitivo.pdf http://eprints.ugd.edu.mk/15670/3/Cvetkovski%20A.,%20Poster,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf http://eprints.ugd.edu.mk/15670/1/Cvetkovski%20A.,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf Cvetkovski, Aleksandar and Bertolasi, Valerio and Gilli, Paola (2014) Cocrystallization screening for “drug-drug” type of cocrystals. In: Giornata di Chimica dell'Emillia Romagna, 18 Dec 2014, Parma, Italy. |
_version_ |
1766388130186788864 |
spelling |
ftunivgocedelcev:oai:eprints.ugd.edu.mk:15670 2023-05-15T15:53:04+02:00 Cocrystallization screening for “drug-drug” type of cocrystals Cvetkovski, Aleksandar Bertolasi, Valerio Gilli, Paola 2014-12-18 text http://eprints.ugd.edu.mk/15670/ http://eprints.ugd.edu.mk/15670/14/Programma%20definitivo.pdf http://eprints.ugd.edu.mk/15670/3/Cvetkovski%20A.,%20Poster,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf http://eprints.ugd.edu.mk/15670/1/Cvetkovski%20A.,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf http://ecs1.azuleon.org/welcome.php unknown http://eprints.ugd.edu.mk/15670/14/Programma%20definitivo.pdf http://eprints.ugd.edu.mk/15670/3/Cvetkovski%20A.,%20Poster,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf http://eprints.ugd.edu.mk/15670/1/Cvetkovski%20A.,%20XIV%20Giornata%20di%20Chimica,%202014,%20Parma.pdf Cvetkovski, Aleksandar and Bertolasi, Valerio and Gilli, Paola (2014) Cocrystallization screening for “drug-drug” type of cocrystals. In: Giornata di Chimica dell'Emillia Romagna, 18 Dec 2014, Parma, Italy. Chemical sciences Conference or Workshop Item PeerReviewed 2014 ftunivgocedelcev 2020-08-21T19:04:42Z Cocrystallization became well known bottom-up approach starting from intermolecular interactions among, either selected neutral, ionic or zwitterionic molecules to design and control the properties of the multicomponent crystals. [1] In the scope of interest for drug design and formulation, the main advantage for designing Pharmaceutical Cocrystals (PCCs) is, through their modulating properties, to improve the performance of the native Active Pharmaceutical Ingredients (APIs) such are: biopharmaceutical profile (solubility and dissolution rate), thermodynamical stability (phase transition of polymorphs, solvate/ hydrate formation, decomposition) or bulk powder processability (flowability, compressibility, particle size and shape control). [2,3] Many debates regarding semantic and classification in cocrystals (CCs) based on accomplishments in research of supramolecular chemistry, highlighted the complex reality of multi-component systems, and the wide scope associated between salts and cocrystals in the salt-cocrystal continuum. [4] N,N-dimethylbiguanide is used as oral antidiabetic drug, well known as Metformin (MET). It directlyimproves insulin action and is the only approved hypoglycemic drug of the biguanide class. Because of the biguanide π-conjugated system, MET can exist in three resonance-stabilized forms, i.e. as neutral molecule (MET), monoprotonated (METH+) or diprotonated (METH2+) cation, with dissociation constants in water typical of biguanides (pKa112.40 and pKa2 2.96). A search of the MET fragment in the structural literature, both in the CCDC database and in patents, shows that in crystals it exists as METH+ or METH2+ but never in its neutral form MET. We have undertaken a systematic study of the crystal chemistry of MET with the aim of understanding its properties in the solid state and finding relationships with its biopharmaceutical profile. We have obtained 29 PCCs of quality suitable for crystal structure determination by single crystal X-ray diffraction with the CFs listed below. Inorganic acids: nitric, phosphoric and carbonic acid; Organic NH-type acids: saccharine and acesulfame; Organic OH-type acids: squaric and picric acid; Monocarboxylic acids: fumaric, acetic, trifluoroacetic, trichloroacetic, dichloroacetic, monochloroacetic, glycolic, salicylic, dichlofenac; Dicarboxylic acids: oxalic, malonic, maleic, fumaric, succinic, adipic. In the poster are presented structures analyses for “drug-drug” type of PCCs where both API and CF exhibit pharmacological effect: MET/ Dichloroacetic acid 1:1 and 1:2 molar ratio, MET/ Diclofenac 1:1, MET/ Glycolic 1:1 acid and MET/ Salicylic acid 1:1 molar ratio. Literature: [1] Braga D., Crystal Engineering, Chem Comm, 2003, 2751-2754, [2] Good J. D., et al. N Cryst Growth Des., 2009, 9 (5), pp 2252–2264 [3] Cheney ML, et al. .,J.PharmSci. 2011Jun;100(6):2172-81 [4] Childs, S.L., Stahly, G.P., Park, A., 2007. Mol. Pharm. 4, 323–338 Conference Object Carbonic acid Goce Delchev University Stip: UGD Repository |