A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate

Žegarac, Miroslav; Lekšić, Edislav; Šket, Primož; Plavec, Janez; Bogdanović, Maja Devčić; Bučar, Dejan‐Krešimir; Dumić, Miljenko; Meštrović, Ernest

doi:10.1039/c3ce42013b

Cited by 63 publications

(36 citation statements)

References 21 publications

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“…[63][64][65][73][74][75] O teor lipídico presente nos alimentos e a presença de sais biliares também podem melhorar o desempenho de um fármaco lipofílico/hidrofóbico in vivo. [111][112][113][114][115] No entanto, o efeito destes agentes de solubilização na solubilidade do cocristal geralmente não é tão simples.…”

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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Section: Agentes Solubilizantesunclassified

Cocristais: uma estratégia promissora na área farmacêutica

et al. 2016

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“…Indexing of PXRD data for 1' revealed a monoclinic unit cell strongly resembling that of 1, with a=13.770(1) Å b=8.0432 (5) Å, c=18.949(1) Å, β=107.419(4) o and V=2002.48(21) Å 3 .…”

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“…2 bioavailability, 3 compressibility, 4 dissolution rate, 5 taste, 6 colour 7 ) and establishing new intellectual property. Mechanochemical 9 techniques, e.g.…”

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Mechanochemistryvs.solution growth: striking differences in bench stability of a cimetidine salt based on a synthetic method

et al. 2018

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“…K n was estimated by Eq. (13). In the simulations in Figure 12, all cases were based on 100 mg/mL CC added to water, with pH adjusted using either 1 M HCl or NaOH.…”

Section: Atazanavir:pterostilbene 1:1 Cocrystal -Exploratory Simulatimentioning

confidence: 99%

Cocrystal solubility-pH and drug solubilization capacity of sodium dodecyl sulfate – mass action model for data analysis and simulation to improve design of experiments

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2018

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This review discusses the disposition of the anionic surfactant, sodium dodecyl sulfate (SDS; i.e., sodium lauryl sulfate), to solubilize sparingly-soluble drugs above the surfactant critical micelle concentration (CMC), as quantitated by the solubilization capacity (k). A compilation of 101 published SDS k values of mostly poorly-soluble drug molecules was used to develop a prediction model as a function of the drug’s intrinsic solubility, S0, and its calculated H-bond acceptor/donor potential. In almost all cases, the surfactant was found to solubilize the neutral form of the drug. Using the mass action model, the k values were converted to drug-micelle stoichiometric binding constants, Kn, corresponding to drug-micelle equilibria in drug-saturated solutions. An in-depth case study (data from published sources) considered the micellization reactions as a function of pH of a weak base, B, (pKa 3.58, S0 52 μg/mL), where at pH 1 the BH.SDS salt was predicted to precipitate both below and above the CMC. At low SDS concentrations, two drug salts were predicted to co-precipitate: BH.Cl and BH.SDS. Solubility products of both were determined from the analysis of the reported solubility-surfactant data. Above the CMC, in a rare example, the charged form of the drug (BH+) appeared to be strongly solubilized by the surfactant. The constant for that reaction was also determined. At pH 7, the reactions were simpler, as only the neutral form of the drug was solubilized, to a significantly lesser extent than at pH 1. Case studies also featured examples of solubilization of solids in the form of cocrystals. For many cocrystal systems studied in aqueous solution, the anticipated supersaturated state is not long-lasting, as the drug component precipitates to a thermodynamically stable form, thus lowering the amount of the active ingredient available for intestinal absorption. Use of surfactant can prevent this. A recently-described method for predicting the solubility product of cocrystals (coupled with predicted k values described here) allowed for simulations of solubility-pH speciation profiles of cocrystal systems in the presence of SDS. Well in advance of any actual measurements, these simulations can be used to probe conditions favorable to the design of cocrystal experiments where SDS stabilizes cocrystal suspensions against drug precipitation over a predicted range of pH values.

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A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate

Cited by 63 publications

References 21 publications

Cocristais: uma estratégia promissora na área farmacêutica

Cocristais: uma estratégia promissora na área farmacêutica

Mechanochemistryvs.solution growth: striking differences in bench stability of a cimetidine salt based on a synthetic method

Cocrystal solubility-pH and drug solubilization capacity of sodium dodecyl sulfate – mass action model for data analysis and simulation to improve design of experiments

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