Mechanochemistry and co-crystal formation: effect of solvent on reaction kineticsElectronic supplementary information (ESI) available for PXRD profiles showing the grinding results for CTA + Bipy with and without solvent as well as CTA + 2fPh with different solvents. See http://www.rsc.org/suppdata/cc/b2/b207369m/

Shan, Ning; Toda, Fumio; Jones, William

doi:10.1039/b207369m

Cited by 429 publications

(245 citation statements)

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“…[33][34][35][36][37][38][39] In liquid-assisted grinding, a few drops of solvent are added to the dry mixture to catalyze or mediate co-crystal or salt formation. [40][41][42] Besides its 'green' nature in that there is no waste of crystallization solvent, solid-state grinding allows for nearly quantitative yields with a common particle size while solubility problems are avoided. …”

Section: Introductionmentioning

confidence: 99%

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine

McHugh

Erxleben

2011

Crystal Growth & Design

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Co-crystal and salt formation of the kinetin analogue N 6 -benzyladenine with the pharmaceutically acceptable co-crystal and salt formers maleic acid, oxalic acid, glutaric acid, succinic acid, benzoic acid and fumaric acid has been studied by solid-state and solvent-drop grinding in combination with X-ray powder diffraction. In all cases salt or co-crystal formation was observed. Single crystals of (bzadeH + )(mal -) (1) and (bzadeH + )2(ox 2-) (2) were obtained by solution crystallization and the X-ray structures are reported along with that of (adeH + )2(mal -)2 . ade . 2H2O (3) (bzadeH + = N 6 -benzyladeninium, adeH + = adeninium, ade = adenine, mal -= hydrogen maleate, ox 2-= oxalate). The hydrogen-bonding motifs in 1 -3 are discussed. The salts contain a robust bzadeH + -carboxylate or ade-carboxylate R2 2 (9) heterosynthon involving the protonated Hoogsteen sites (N6-H, N7-H) of bzadeH + and ade. Molecular recognition between the protonated Hoogsteen site and the carboxylate group stabilizes the unusual 7H,9H tautomer of bzadeH + in 2 and the non-canonical 7H-adenine tautomer in 3.* To whom correspondence should be addressed. ABSTRACT Co-crystal and salt formation of the kinetin analogue N 6 -benzyladenine with the pharmaceutically acceptable co-crystal and salt formers maleic acid, oxalic acid, glutaric acid, succinic acid, benzoic acid and fumaric acid has been studied by solid-state and solvent-drop grinding in combination with X-ray powder diffraction. In all cases salt or co-crystal formation was observed. Single crystals of (bzadeH + )(mal -) (1) and (bzadeH + )2(ox 2-) (2) were obtained by solution crystallization and the X-ray structures are reported along with that of (adeH + )2(mal -)2 . ade . 2H2O (3) (bzadeH + = N 6 -benzyladeninium, adeH + = adeninium, ade = adenine, mal -= hydrogen maleate, ox 2-= oxalate). The hydrogen-bonding motifs in 1 -3 are discussed. The salts contain a robust bzadeH + -carboxylate or ade-carboxylate R2 2 (9) heterosynthon involving the protonated Hoogsteen sites (N6-H, N7-H) of bzadeH + and ade. Molecular recognition between the protonated Hoogsteen site and the carboxylate group stabilizes the unusual 7H,9H tautomer of bzadeH + in 2 and the non-canonical 7H-adenine tautomer in 3.3

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Section: Introductionmentioning

confidence: 99%

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine

McHugh

Erxleben

2011

Crystal Growth & Design

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“…39,69,[76][77][78][79][80][81][82] Em alguns casos, fármaco e coformador apresentam uma fase intermediária amorfa. 83 Desta forma, a temperatura de transição vítrea (T g ) e a temperatura de fusão dos componentes são propriedades importantes para qualquer método mecanoquímico que induz transformação de fase e, portanto, devem ser consideradas.…”

Section: Estratégias De Formação De Cocristaisunclassified

“…A moagem assistida por solvente emprega pequenos volumes de solvente durante a moagem e pode levar à formação do cocristal por processos mediados por: (1) alteração da mobilidade molecular da fase sólida e/ou (2) interações em solução. 81,82 Além dos métodos mencionados, outro método que têm sido aplicado com sucesso na triagem e processos de obtenção de cocristais em grande escala é o método de fusão. 5,71 A aplicação de fusão seguida de extrusão parece ser uma alternativa promissora para a formação de cocristais onde a instabilidade química não é um problema.…”

Section: Estratégias De Formação De Cocristaisunclassified

Cocristais: uma estratégia promissora na área farmacêutica

et al. 2016

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COCRYSTALS: A PROMISING STRATEGY IN PHARMACEUTICAL SCIENCES. Pharmaceutical cocrystals have emerged as a useful strategy to improve the aqueous solubility of poorly water soluble drugs by aiming to enhance their oral absorption and bioavailability. Aqueous cocrystal solubility can be orders of magnitude higher than that of the constituent drug and this solubility advantage can be fine-tuned based on environmental conditions such as pH and the presence of drug solubilizing agents. This review presents a brief overview of pharmaceutical cocrystals regarding cocrystal design, obtainment methods, with particular focus on cocrystal solubility, and the solubility modulation by solution phase chemistry.Keywords: cocrystals; drug; solubility; transition point; thermodynamic stability. INTRODUÇÃOO setor de fármaco-medicamentos representa uma área estratégica sob o ponto de vista tecnológico/produtivo nacional. Vários são os desafios da produção de medicamentos competitivos e de qualidade no Brasil, como a oferta de insumos, a pesquisa de novas moléculas ativas e a sua inserção no mercado. Neste sentido, a utilização de inovações incrementais surge como alternativa à problemática do setor, destacando-se a manipulação da forma cristalina dos fármacos, síntese de polimorfos, sais, complexos e, mais recentemente, os cocristais. 1 Cocristais são materiais cristalinos homogêneos, compostos por dois ou mais compostos em proporção estequiométrica definida e que são sólidos em condições ambientes (25 ºC/1 atm). 2,3 Ao longo das últimas décadas, os cocristais têm recebido atenção significativa por parte da indústria farmacêutica, e diversos cocristais farmacêuticos têm sido relatados. Cocristais farmacêuticos, por sua vez, são compostos por um ingrediente farmacêutico ativo (IFA) e uma molécula não tóxica ou outro IFA, chamado de coformador. Ligações de hidrogênio entre as moléculas neutras do fármaco e do coformador orientam a formação do cocristal. 2,4 A síntese de cocristais tem sido uma estratégia cada vez mais utilizada para melhorar a solubilidade, a taxa de dissolução in vitro, e consequentemente, a biodisponibilidade de fármacos pouco solúveis, sem a necessidade de mudar a estrutura molecular e/ou a interação farmacológica. [5][6][7] No entanto, a avaliação da solubilidade e estabilidade dos cocristais em solução ainda não está consolidada. Um levantamento realizado no período de 1999 a 2015 (Figura 1) revelou um crescente número de publicações envolvendo a síntese e a caracterização dos cocristais, mas um reduzido número de publicações envolvendo outros aspectos essenciais no desenvolvimento de formulações contendo cocristais, como estudos de solubilidade, química em solução, estabilidade e a influência de excipientes.Considerando que a baixa solubilidade aquosa é um dos principais problemas associados às entidades químicas farmacêuticas, os

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“…4,5 Cocrystals are crystal forms where two or more neutral molecules are present in the unit cell, 6,7 and can be prepared by a variety of approaches including solution crystallisation, solid state grinding, thermal methods, freeze-drying and slurrying. [8][9][10][11][12][13] An important consideration with cocrystallisation is that not every pair of molecules has the propensity to form a cocrystal. In fact, identifying species (coformers) which will cocrystallise with a given compound can sometimes be an arduous process.…”

Section: Introductionmentioning

confidence: 99%

“…The cocrystals with formamide (T:1), acetamide (T:2) and benzamide (T:5), and one polymorph of the cocrystal with pyrazinamide (T:6-I), contain an R 2 (9) hydrogen bonding motif between the amide cocrystal formers and the HN-C-C=O moiety of the theophylline molecule (an amide-pseudo amide synthon). This motif was, however, absent from the other polymorph of the pyrazinamide cocrystal (T:6-II), and also from the N-methylformamide cocrystal (T:3) (and is not possible in the N,N-dimethylformamide cocrystal (T:4)).…”

mentioning

confidence: 99%

Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

Eddleston

Arhangelskis

Fábián

et al. 2015

Crystal Growth & Design

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The pharmaceutically active compound theophylline (T) was cocrystallized with the amides formamide (1), acetamide (2), N-methylformamide (3), N,N-dimethylformamide (4), benzamide (5), and pyrazinamide (6), with systems T:1, T:5, and T:6 displaying polymorphic behavior. The cocrystals with formamide (T:1), acetamide (T:2), and benzamide (T:5), and one polymorph of the cocrystal with pyrazinamide (T:6-I), contain an R 2 2 (9) hydrogen bonding motif between the amide cocrystal formers and the HN−C−CO moiety of the theophylline molecule (an amide-pseudo amide synthon). This motif was, however, absent from the other polymorph of the pyrazinamide cocrystal (T:6-II) and also from the N-methylformamide cocrystal (T:3) (and is not possible in the N,N-dimethylformamide cocrystal (T:4)). These observations are rationalized using hydrogen bond propensity calculations, although limitations of using such calculations for predicting cocrystallization are noted. The amide-pseudo amide synthon is favored when theophylline cocrystallizes with both primary amides and with secondary amides which are locked in a cis configuration. On heating, all cocrystals were found to dissociate before melting due to loss of the amide, making stability to dissociation a more meaningful measure of cocrystal stability than melting point for these systems. On dissociation of the cocrystals, theophylline typically crystallizes as the commonly observed polymorph Form II. In the case of the acetamide cocrystal (T:2), however, the rarely observed metastable polymorph, Form V, crystallizes concomitantly with Form II suggesting that cocrystal dissociation on heating could be a strategy for identifying novel polymorphic forms of compounds.

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Abstract: We demonstrate that significant improvements in kinetics of co-crystal formation by grinding can be achieved by the addition of minor amounts of appropriate solvent.

Cited by 429 publications

References 9 publications

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine

Cocristais: uma estratégia promissora na área farmacêutica

Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

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Abstract: We demonstrate that significant improvements in kinetics of co-crystal formation by grinding can be achieved by the addition of minor amounts of appropriate solvent.

Cited by 429 publications

References 9 publications

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N6-Substituted Adenine

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N6-Substituted Adenine

Cocristais: uma estratégia promissora na área farmacêutica

Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

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Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine

Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N⁶-Substituted Adenine