Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?

Almarsson, Ӧrn; Zaworotko, Michael J.

doi:10.1039/b402150a

Cited by 977 publications

(745 citation statements)

References 52 publications

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“…Pharmaceutical co-crystals, combining an API and an acceptable co-former, 11 have the potential for enhancing the physical properties of the API, positively impacting its solubility, stability, oral bioavailability and processability, without compromising its biological function 1,9,[12][13][14][15][16][17][18][19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

Co-crystals of diflunisal and isomeric pyridinecarboxamides – a thermodynamics and crystal engineering contribution

et al. 2016

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This version is available at https://strathprints.strath.ac.uk/56947/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Strathprints administrator: strathprints@strath.ac.ukThe Strathprints institutional repository (https://strathprints.strath.ac.uk) is a digital archive of University of Strathclyde research outputs. It has been developed to disseminate open access research outputs, expose data about those outputs, and enable the management and persistent access to Strathclyde's intellectual output.1 To whom correspondence should be addressed. E-mail: antonio.evora@uc.pt Tel.: Co-crystals of diflunisal and isomeric pyridinecarboxamides a thermodynamics and crystal engineering contribution +351239854450 ABSTRACTDiflunisal is an anti-inflammatory non-steroidal drug, class II of the Biopharmaceutical Classification System, that has recently been the subject of renewed interest due to its potential use in the oral therapy of familial amyloid polyneuropathy. In this work, a thermodynamic based approach is used to investigate binary mixtures (diflunisal + picolinamide) and (diflunisal + isonicotinamide) in order to identify solid forms potentially useful to improve the biopharmaceutical performance of this active pharmaceutical ingredient.Special emphasis is put on the research of co-crystals and on the influence of structural changes in the pyridinecarboxamide co-former molecules on co-crystal formation with diflunisal. The thermodynamic based methodology described by ter Horst et al. in 2010 indicates that the formation of co-crystals is thermodynamically feasible for both systems. The binary solid-liquid phase diagrams are built and allow identifying unequivocally the formation of co-crystals of diflunisal with each of the two isomers and also their stoichiometry: 1:1, (diflunisal:co-former) in the case of pyridine-2-carboxamide, picolinamide, and 2

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Section: Introductionmentioning

confidence: 99%

Co-crystals of diflunisal and isomeric pyridinecarboxamides – a thermodynamics and crystal engineering contribution

et al. 2016

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“…Suitable cocrystals can enable the tuning of the crucial physical and chemical parameters such as the solubility, vapour pressure, crystal habit etc., of a an active ingredient in pharmaceutical, 35 agrochemical or other areas. 3 The prevailing model for cocrystal engineering is using a supramolecular synthon approach, where supramolecular synthons, which consist of intermolecular interactions (especially hydrogen bonds), are viewed as bonds for the construction of supermolecules, i.e. crystals.…”

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confidence: 99%

Comparison of the polymorphs and solvates of two analogous fungicides—a case study of the applicability of a supramolecular synthon approach in crystal engineering

et al. 2011

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The polymorphism and solvate formation of thiophanate-ethyl (TE), a fungicidal active, were investigated by solvent crystallization and compared to a close analogue, thiophanate-methyl (TM). Four polymorphs and seven solvates of TE were found and structurally compared with the previously found two polymorphs and fourteen solvates of TM by analyzing the hydrogen bonding patterns and using fingerprint plots, packing coefficients and lattice energies. TE and TM have the same functional groups that can build identical supramolecular synthons. Despite the strong similarities, the polymorphs and solvates of the two actives show significant differences in hydrogen bonding and packing. The results demonstrate the challenges in using a supramolecular synthon approach, and promote the importance in finding methods to also make use of packing effects and lipophilic interactions in crystal engineering.Scheme 1 Molecular structures of thiophanate-methyl (TM) and thiophanate-ethyl (TE).

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“…Synthons formados por interações entre dois grupos funcionais iguais são classificados como homosynthons, enquanto que as interações entre dois grupos funcionais diferentes são mais favoráveis e caracterizam os heterosynthons (Figura 6). 27 Além de interações baseadas em complementaridade molecular, cabe ressaltar que outros fenômenos podem estar envolvidos na formação de um cocristal. O empacotamento, a estereoquímica dos componentes e características intrínsecas do fármaco, como a polaridade e o pK a , também devem ser considerados durante a seleção do coformador para a síntese do cocristal.…”

Section: Desenho Do Cocristalunclassified

“…Desta forma, agentes solubilizantes podem induzir pontos de transição. [14][15][16]27,106,107 Um exemplo interessante é o cocristal de indometacina-sacarina (IND-SAC), cuja vantagem da solubilidade, 26 vezes maior do que a indometacina em pH 2, 11 é eliminada na presença de lauril sulfato de sódio, Brij 99 ou Tween 80, onde o cocristal apresenta menor solubilidade. 11,107 Os agentes solubilizantes podem, de fato, aumentar a solubilidade de ambos, cocristal e fármaco, porém a razão da solubilização (S cocristal /S fármaco ) é variável, dependendo da natureza e da concentração destes agentes.…”

Section: Agentes Solubilizantesunclassified

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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Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?

Cited by 977 publications

References 52 publications

Co-crystals of diflunisal and isomeric pyridinecarboxamides – a thermodynamics and crystal engineering contribution

Co-crystals of diflunisal and isomeric pyridinecarboxamides – a thermodynamics and crystal engineering contribution

Comparison of the polymorphs and solvates of two analogous fungicides—a case study of the applicability of a supramolecular synthon approach in crystal engineering

Cocristais: uma estratégia promissora na área farmacêutica

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