How cocrystals of weakly basic drugs and acidic coformers might modulate solubility and stability

Kuminek, Gislaine; Rodrı́guez-Hornedo, Naı́r; Siedler, Sana; Rocha, Helvécio Vinícius Antunes; Cuffini, Silvia Lucía; Cardoso, Simone Gonçalves

doi:10.1039/c6cc00898d

Cited by 55 publications

(56 citation statements)

References 17 publications

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“…A reversal in cocrystal and drug solubilities between pH 3 and 4 is also observed for all cocrystals, suggesting the existence of pH max . 8, 11, 12, 15–17 At pH 5, cocrystals are 10 to 20 times more soluble than drug. Drug is 1.5 to 3 times more soluble than cocrystal at pH 3.…”

Section: Resultsmentioning

confidence: 99%

“…Previous work by our laboratory has shown that cocrystals can exhibit different solubility-pH dependence from the parent drug, and this can sometimes lead to the existence of a pH max . 8–11, 15, 16 pH max is defined as the solubility transition point based on solution pH, at which the cocrystal and drug solubilities are equal, and both solid phases are thermodynamically stable and coexist in equilibrium with solution. 8, 11, 12, 17 The cocrystal solubility advantage over parent drug is therefore not a constant value, and it can be fine-tuned by changing solution pH.…”

Section: Introductionmentioning

confidence: 99%

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Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug

Chen

Rodrı́guez-Hornedo

2018

Crystal Growth & Design

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Weakly basic drugs are predisposed to order of magnitude decreases in solubility and dissolution as pH increases from 1 to 7 along the gastrointestinal tract. Such behavior is known to be detrimental to drug absorption. The work presented here shows how cocrystals of basic drugs with acidic coformers can mitigate these negative effects. Cocrystals of ketoconazole (KTZ) with adipic, fumaric, and succinic acids exhibit a parabolic solubility dependence on pH such that with increasing pH, solubility decreases, reaches a minimum, and increases. Cocrystals exhibit pHmax values between 3.6 and 3.8, above which they generate supersaturation with respect to drug. Cocrystal supersaturation index (SA), defined as Scocrystal/Sdrug, changes from 1 (pHmax) to 10–30 (pH 5) to 800 – 3,000 (pH 6.5). SA represents the driving force for cocrystal conversion to the less soluble drug during dissolution. SA is not expected to be equal to the observed supersaturation, but it is of great value to classify cocrystals in terms of their risk of conversion. Cocrystal dissolution behavior was analyzed in terms of Cmax, σmax (maximum KTZ concentration and supersaturation), AUCdiss (KTZ concentration area under the curve during dissolution-precipitation), and SA. The three cocrystals studied achieved σmax values between 5 and 15 and sustained supersaturation for 1 to 3 h, resulting in AUCdiss advantage over drug in the range of 2 to 12. SA values as high as 800 were associated with enhanced drug exposure. SA of 3,000 led to limited exposure, very rapid conversion, and no measurable supersaturation. Since cocrystals may be more soluble than needed and/or too soluble to be developed, there is great value in recognizing the relationship between supersaturation threshold, cocrystal solubility, and SA. This becomes more important as cocrystal SA is dependent on pH and other environmental conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug

Chen

Rodrı́guez-Hornedo

2018

Crystal Growth & Design

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“…(7), ‫ܭ‬ ,ଵ describes the dissociation equilibrium of the first step, whereas ‫ܭ‬ ,ଶ in Eq. (8) describes that of the second step. The two dissociation constants ‫ܭ‬ ,ଵ and ‫ܭ‬ ,ଶ , can be estimated analogous to ‫ܭ‬ in Eq.…”

Section: Solubility Calculations and Dissociation Equilibriamentioning

confidence: 98%

“…Pharmaceutical cocrystals (CCs) represent a promising class of solid forms as they can potentially improve the physicochemical properties of the solid active pharmaceutical ingredients (APIs) compared to their pure state [1][2][3][4][5][6][7][8] . These…”

Section: Introductionmentioning

confidence: 99%

Predicting the Effect of pH on Stability and Solubility of Polymorphs, Hydrates, and Cocrystals

Lange

Schleinitz

Sadowski

2016

Crystal Growth & Design

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Cocrystal-formation processes from aqueous solutions are often affected by pH-dependent dissociation, polymorphic transitions, as well as by formation of hydrates and salts. To enhance the efficiency of those processes, the aqueous stability and solubility of pharmaceutical cocrystals were predicted in this study using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). The solubilities in the binary systems caffeine/water and oxalic acid/water were modeled including hydrate formation and polymorphic transitions between the corresponding anhydrate forms I and II. Moreover, pH-dependent solubilities of these hydrate-forming components, their 2:1 cocrystal as well as for all appearing salts were measured and modeled at 298.15 K. It was found, that the pH-dependent acid-base equilibria of caffeine and oxalic acid directly influence the stability and solubility of their cocrystal, their hydrates and salts. In consideration of the thermodynamic non-ideality of the components in the cocrystal system, PC-SAFT enables the solubility predictions of the before-mentioned components as well as if any cocrystal is formed at given conditions of pH and temperature.

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“…9 Neste caso, a adição de agentes solubilizantes do fármaco, para diminuir a vantagem da solubilidade, bem como de inibidores de cristalização, podem ser introduzidos ao meio ou à formulação a fim de evitar ou reduzir as conversões. 8 Outro fator interessante é que a solubilidade dos cocristais pode ser modulada de modo que fique dentro ou fora da região de estabilidade dos cocristais, dependendo da composição do meio como pH, [10][11][12][13] presença de aditivos, [14][15][16][17] concentração de coformador, 18 entre outras.…”

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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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How cocrystals of weakly basic drugs and acidic coformers might modulate solubility and stability

Cited by 55 publications

References 17 publications

Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug

Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug

Predicting the Effect of pH on Stability and Solubility of Polymorphs, Hydrates, and Cocrystals

Cocristais: uma estratégia promissora na área farmacêutica

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