Potential Anti-Tumor Drug: Co-Crystal 5-Fluorouracil-nicotinamide

Zhang, Zhu-Yan; Ye, Nan; Xue, Chang; Gao, Shan; Deng, Zhao‐Peng; Li, Min; Liu, Cong; Castellot, John J.; Han, Siying

doi:10.1021/acsomega.9b03574

Cited by 21 publications

(8 citation statements)

References 20 publications

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“…Figure a displays the cumulative amount of ABC and its salt/cocrystals permeated in 480 min, which followed the order ABC-GLA (22.97 mg cm –2 ) > ABC-OXA (22.01 mg cm –2 ) > ABC-AZA (21.14 mg cm –2 ) > ABC-SUA (16.92 mg cm –2 ) > ABC (6.17 mg cm –2 ) . In comparison with ABC, the cumulative amounts of ABC-GLA, ABC-OXA, ABC-AZA, and ABC-SUA permeated increased by 272%, 256%, 242%, and 174%, respectively, indicating that the formation of the salt and cocrystals could effectively improve the permeability of ABC.…”

Section: Resultsmentioning

confidence: 99%

“…According to the literature, permeability is positively correlated with lipophilicity. Therefore, the partition coefficients of ABC and its salt/cocrystals were determined, 67 (calculation details and results are given in Table S15). The order of the partition coefficient (log P) at pH 6.8 and 298.15 K was ABC-AZA (−1.01) > ABC-SUA (−1.03) > ABC (−1.06) > ABC-OXA (−1.13) > ABC-GLA (−1.16), indicating that the improvement in the permeability of ABC-AZA and ABC-SUA was related to their increased lipophilicity, while the permeability of ABC-OXA and ABC-GLA could be influenced by other factors.…”

Section: Powder Dissolutionmentioning

confidence: 99%

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Enhanced Solubility, Dissolution, and Permeability of Abacavir by Salt and Cocrystal Formation

Chang

et al. 2021

Crystal Growth & Design

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Abacavir (ABC) is a carbocyclic 2′-deoxyguanosine nucleoside reverse transcriptase inhibitor specifically prescribed for the treatment of HIV infection. However, as a BCS class III drug, the poor permeability seriously limits its absorption in the body. This study attempts to improve the permeability of ABC through the crystal engineering method of salt/cocrystal formation. Herein, four multicomponent crystals of ABC with dicarboxylic acids were prepared: namely, the salt ABC-oxalic acid (ABC-OXA) and the cocrystals ABC-glutaric acid (ABC-GLA), ABC-suberic acid (ABC-SUA), and ABC-azelaic acid (ABC-AZA). The salt/cocrystals were characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FT-IR) spectroscopy. In comparison with ABC, the synthesized salt/cocrystals showed significant improvement in the aqueous solubility, dissolution rate, and permeability. In addition, a correlation of permeability revealed that the permeability of abacavir and its salt and cocrystals was mainly determined by the concentration gradient in the donor chamber and influenced by multiple factors, including the partition coefficient (lipophilicity). This study is another successful example of improving the solubility and permeability of drugs through crystal engineering of salt and cocrystal formation.

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Section: Resultsmentioning

confidence: 99%

Section: Powder Dissolutionmentioning

confidence: 99%

Enhanced Solubility, Dissolution, and Permeability of Abacavir by Salt and Cocrystal Formation

Chang

et al. 2021

Crystal Growth & Design

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“…It was shown that the 5-FU-nicotinamide co-crystal had enhanced inhibitory activity and better anticancer effect in comparison to 5-FU. The authors attributed this decrease to be possibly from nicotinamide possessing antioxidant activity Lastly, a conclusion was made that 5-FU-nicotinamide had enhanced solubility compared to the 5-FU alone, the logP value of 5-FU was higher than that of the co-crystal [61]. This showed that the co-crystal was more hydrophilic and had lower membrane permeability than the API.…”

Section: Anticancer Api Co-crystalsmentioning

confidence: 99%

“…A summary of available co-crystals, their composition, indication and status as depicted in Table 4. Formulations such as Suglat ® (Ipragliflozin L-Proline) (Astellas Pharma and Kotobuki Pharmaceutical, Japan), Entresto ® (sacubitril and valsartan) (Novartis, Switzerland), Steglatro ® (ertugliflozin) (Merck Sharp and Dohme B.V, Netherlands), and Steglujan ® (ertugliflozin and sitagliptin) (Pfizer, USA) were marketed between the years 2014 to 2017 [61,97]. Some products were identified as co-crystals at a later stage, while already being on the market, such as Lexapro ® (Escitalopram oxalate oxalic acid) (Lundbeck, Denmark) and Beta-chlor ® (Chloral hydrate and betaine) (Franklin Laboratories, India) [26,60,101].…”

Section: Regulatory Limitations Of Crystalline Productsmentioning

confidence: 99%

Nano- and Crystal Engineering Approaches in the Development of Therapeutic Agents for Neoplastic Diseases

et al. 2022

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Cancer is a leading cause of death worldwide. It is a global quandary that requires the administration of many different active pharmaceutical ingredients (APIs) with different characteristics. As is the case with many APIs, cancer treatments exhibit poor aqueous solubility which can lead to low drug absorption, increased doses, and subsequently poor bioavailability and the occurrence of more adverse events. Several strategies have been envisaged to overcome this drawback, specifically for the treatment of neoplastic diseases. These include crystal engineering, in which new crystal structures are formed to improve drug physicochemical properties, and/or nanoengineering in which the reduction in particle size of the pristine crystal results in much improved physicochemical properties. Co-crystals, which are supramolecular complexes that comprise of an API and a co-crystal former (CCF) held together by non-covalent interactions in crystal lattice, have been developed to improve the performance of some anti-cancer drugs. Similarly, nanosizing through the formation of nanocrystals and, in some cases, the use of both crystal and nanoengineering to obtain nano co-crystals (NCC) have been used to increase the solubility as well as overall performance of many anticancer drugs. The formulation process of both micron and sub-micron crystalline formulations for the treatment of cancers makes use of relatively simple techniques and minimal amounts of excipients aside from stabilizers and co-formers. The flexibility of these crystalline formulations with regards to routes of administration and ability to target neoplastic tissue makes them ideal strategies for effectiveness of cancer treatments. In this review, we describe the use of crystalline formulations for the treatment of various neoplastic diseases. In addition, this review attempts to highlight the gaps in the current translation of these potential treatments into authorized medicines for use in clinical practice.

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“…Cocrystals are orderly arranged multicomponent crystals composed of two or more neutral molecules at fixed stoichiometric ratios through various noncovalent interactions, such as hydrogen-bonding, π-stacking, and halogen-bonding interactions etc. − The formation of cocrystals provides an effective way to tailor the physicochemical properties of a given compound at the molecular level, and this strategy has been widely applied to pharmaceuticals. − Recently, charge transfer (CT) cocrystals, within which the donor (D) and acceptor (A) are combined by charge transfer interactions, have offered an opportunity to alter the optical properties of organic chromophores in the solid state. − In this context, the donor refers to an organic electron-rich molecule, and the acceptor is an organic electron-deficient molecule. CT cocrystals offer an excellent platform for the production of novel solid-state luminescent materials, which are otherwise hard to realize in a single-component system.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Solid-State Optical Properties of o-Hydroxynaphthoic Acids through Formation of Charge Transfer Cocrystals with TCNB

Hao

Dai

Huang

et al. 2020

Crystal Growth & Design

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Charge transfer cocrystals offer an opportunity to alter the photophysical characteristics of organic chromophores in the solid state. A set of new charge transfer cocrystals of three positional isomers of o-hydroxynaphthoic acid with 1,2,4,5-tetracyanobenzene (TCNB) as the electron acceptor was prepared and subjected to single-crystal and powder X-ray diffraction, thermal analysis, vibrational, and UV−vis absorption and fluorescence spectroscopic measurements. Crystal structure analyses reveal that the donor and acceptor molecules are combined in a 2:1 stoichiometric ratio and stacked alternately through a typical mixed face-to-face arrangement (DAD•••DAD), forming a columnlike charge transfer structure involving π-stacking interactions. All of the cocrystals exhibit distinct tunable emission colors and photoluminescence characteristics due to the charge transfer transition states. This research indicates that the cocrystal strategy can be applied to effectively modulate the optical properties of o-hydroxynaphthoic acid compounds, which have a great research value in optoelectronic applications.

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Potential Anti-Tumor Drug: Co-Crystal 5-Fluorouracil-nicotinamide

Cited by 21 publications

References 20 publications

Enhanced Solubility, Dissolution, and Permeability of Abacavir by Salt and Cocrystal Formation

Enhanced Solubility, Dissolution, and Permeability of Abacavir by Salt and Cocrystal Formation

Nano- and Crystal Engineering Approaches in the Development of Therapeutic Agents for Neoplastic Diseases

Modulation of Solid-State Optical Properties of o-Hydroxynaphthoic Acids through Formation of Charge Transfer Cocrystals with TCNB

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