Improving the Solubility and Bioavailability of Apixaban via Apixaban–Oxalic Acid Cocrystal

Chen, Yong; Li, Long; Yao, Jia; Ma, Yuyu; Chen, Jiamei; Lu, Tong‐Bu

doi:10.1021/acs.cgd.6b00266

Cited by 106 publications

(79 citation statements)

References 40 publications

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“…Dissolution methods under non-sink conditions are commonly used for evaluating the ability of poorly soluble APIs to generate and to maintain a supersaturation state in solution [24,39]. Additionally, Pharmaceutics 2020, 12, 23 3 of 18 powder dissolution experiments are a good alternative to intrinsic dissolution tests for cocrystals undergoing rapid transformation to a less soluble phase of the drug [24], as recently found in the biopharmaceutical characterization of cocrystals with meloxicam, indomethacin, apixaban and myricetin [40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

et al. 2019

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The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel ® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others.

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Section: Introductionmentioning

confidence: 99%

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

et al. 2019

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“…Thus, higher solubility of drug was obtained by cocrystals as compared to salt formation [37] . The solubility of apixaban cocrystals was increased about two times and cocrystals showed faster dissolution as compared to pure drug [38] . Six times enhancement of solubility was measured by formulating cocrystals of pterostilbene with piperazine whereas drug was precipitated rapidly in pterostilbene-glutaric acid cocrystals due to high solubility of glutaric acid [39] .…”

Section: Solubilitymentioning

confidence: 99%

“…Many approaches have been used to improve the solubility of drugs such as salt formation, solid dispersion, particle size reduction, and so on [23] , amongst which cocrystallization has been used by several researchers [37][38][39][40][41] . Solubility of antifungal drug ketoconazole was increased 53 and 100 times by synthesizing salts and cocrystals respectively as compared to ketoconazole.…”

Section: Solubilitymentioning

confidence: 99%

“…Crystal engineering is mainly used to design and synthesize the pharmaceutical cocrystals with enhanced aqueous solubility and oral bioavailability. Pharmacokinetics study of apixaban-oxalic acid cocrystals in beagle dogs showed that oral bioavailability was increased by 2.7 times as compared to pure drug [38] . Oral bioavailability of baicalein was increased by formation of cocrystals with nicotinamide and showed that cocrystals had 2.49 times higher peak plasma concentration (C max ) and 2.80 times higher area under the curve (AUC) as compared to pure drug in rats [55] .…”

Section: Bioavailabilitymentioning

confidence: 99%

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Pharmaceutical Cocrystals: An Overview

Kumar¹,

Nanda²

2017

pharmaceutical-sciences

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“…Co-crystallizing agents are also well known to influence crystal structure formation [90], and it is estimated that roughly half of all commercially available drugs use salt as a co-crystallizer to control the synthesized crystal form [91].…”

Section: Improving Materials Performance Through Crystal Polymorphismmentioning

confidence: 99%

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Dybeck

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AcknowledgementsI would like to acknowledge the guidance and support provided by my advisor MichaelShirts. I would also like to thank Levi Naden, Natalie Schieber, Nate Abraham and the entire Shirts group for their help and technical support during my research. I also would like to acknowledge the UVA high performance computing team for the computational resources necessary to complete this work. Finally, I would like to acknowledge the endless love and support that my friends and family provided me during this challenging Ph.D. journey.iii AbstractThe presence of multiple stable crystal structures in solid organic materials can limit their commercial viability when two or more observable polymorphs exhibit markedly different physical properties. Unintended restructuring events have hindered pharmaceutical solid form development in numerous therapeutic candidates and have led to costly market recalls.Conversely, intentional synthesis of a metastable form has led to significantly more favorable performance in numerous materials.Current computational methods for predicting polymorphic behavior evaluate candidate crystal structures based on the minimized lattice energy. However, these static lattice energybased approaches generate far more lattice energy minima than there are experimentally observed structures. Thermal motion of the crystals under working conditions has the potential to explain why many of these lattice minima are not observed experimentally. Lattice minima that are identified from a static crystal structure prediction can ultimately be unstable at experimental conditions through either temperature-mediated stability reranking, kinetic interconversion of multiple minima, or inaccuracies of the energy function in producing the real crystal ensemble.In this work, we explore the role of thermal motion in eliminating candidate crystal structures using fully atomistic molecular dynamics simulations. Enthalpically favorable structures with low entropy will become unfavorable at high temperatures through temperaturemediated stability reranking. Our simulations correctly identify the high temperature solid form as having a larger entropy than the low temperature form in twelve small molecule organic systems with known temperature-mediated transformations. The estimated entropy differences in the classical point-charge potential are significantly closer to experimental measurements than estimated enthalpy differences. This result suggests that entropy difference estimates are less sensitive to the complexity of the simulation potential than the corresponding enthalpy estimates. We additionally find that a cheaper harmonic approximation provides a sufficient estimate of entropic contributions in small rigid molecules. However, entropies with iv the harmonic approximation diverge from molecular dynamics-derived entropies in systems with multiple rotatable degrees of freedom or dynamically disordered crystalline structures.We additionally probe the sensitivity of the stability estimates to the energy function ...

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Improving the Solubility and Bioavailability of Apixaban via Apixaban–Oxalic Acid Cocrystal

Cited by 106 publications

References 40 publications

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

Pharmaceutical Cocrystals: An Overview

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

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