Crystal engineering approach to improve the solubility of mebendazole

Chen, Jiamei; Wang, Zizhou; Wu, Chuanbin; Li, Song; Lu, Tong‐Bu

doi:10.1039/c2ce25724f

Cited by 73 publications

(65 citation statements)

References 39 publications

(41 reference statements)

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“…Both salts exhibit an important increase in solubility and dissolution rate as compared with MBZ forms A and C; in addition, they are even more soluble than the MBZ-oxalate monohydrate and the MBZ-maleate salts reported by Chen et al, 17 with reference to the corresponding form C solubility values in all cases.…”

Section: Solubility Studiesmentioning

confidence: 72%

“…16 Structural and thermal information as well as stability and dissolution studies were recently reported for some MBZ salts and cocrystals involving dicarboxylic acids as coformers. 17 Two new MBZ solvates with N,N-dimethyl acetamide (MBZ-DMA) and N,N-dimethyl formamide (MBZ-DMF) were obtained as microcrystalline forms, and other techniques such as optical and polarized microscopy, Fourier transformed infrared (FTIR) spectroscopy, thermal analysis, and PXRD were applied to their characterization. 18 In an attempt to increase the solubility and subsequent bioavailability of not only MBZ C form but also the nonpharmaceutically preferred MBZ polymorph A, we have synthesized a new salt by incorporating a pharmaceutically acceptable coformer.…”

Section: Mebendazolementioning

confidence: 99%

See 1 more Smart Citation

Mebendazole Mesylate Monohydrate: A New Route to Improve the Solubility of Mebendazole Polymorphs

Paula

Camí

Brusau

et al. 2013

Journal of Pharmaceutical Sciences

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Section: Solubility Studiesmentioning

confidence: 72%

Section: Mebendazolementioning

confidence: 99%

Mebendazole Mesylate Monohydrate: A New Route to Improve the Solubility of Mebendazole Polymorphs

Paula

Camí

Brusau

et al. 2013

Journal of Pharmaceutical Sciences

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“…[6][7][8] Crystal engineering has been used extensively in tuning the physicochemical properties of the drug candidates. [9][10][11][12][13] The method has been shown to be effective in addressing problems of low aqueous solubility/permeability of drug like substances. 9 It is known that highly soluble coformers may lead to solubility enhancement in the cocrystal form of a poorly soluble drug.…”

Section: Introductionmentioning

confidence: 99%

Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/Permeability Enhancements through Drug–Coformer Interactions

et al. 2015

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Hydrochlorothiazide (HCT) is a diuretic and a BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption. The present study attempts to improve the physicochemical properties of the drug using a crystal engineering approach with cocrystals. Such multicomponent crystals of HCT with nicotinic acid (NIC), nicotinamide (NCT), 4-aminobenzoic acid (PABA), succinamide (SAM), and resorcinol (RES) were prepared using liquid-assisted grinding, and their solubilities in pH 7.4 buffer were evaluated. Diffusion and membrane permeability were studied using a Franz diffusion cell. Except for the SAM and NIC cocrystals, all other binary systems exhibited improved solubility. All of the cocrystals showed improved diffusion/membrane permeability compared to that of HCT with the exception of the SAM cocrystal. When the solubility was high, as in the case of PABA, NCT, and RES cocrystals, the flux/permeability dropped slightly. This is in agreement with the expected interplay between solubility and permeability. Improved solubility/permeability is attributed to new drug-coformer interactions. Cocrystals of SAM, however, showed poor solubility and flux. This cocrystal contains a primary sulfonamide dimer synthon similar to that of HCT polymorphs, which may be a reason for its unusual behavior. Hirshfeld surface analysis was carried out in all cases to determine whether a correlation exists between cocrystal permeability and drug-coformer interactions.

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“…It has been demonstrated that excipients have significant influence on drug dissolution and oral bioavailability, which can be altered by drug−excipient interactions. 46,47 As a complement to the mechanism study of drug dissolution, the application of crystal engineering provides an accurate and comprehensive understanding of drug−excipient interactions, 48 as well as drug binding and subsequent release from the complex, 49 which is expected to provide fundamental information for in vivo study.Herein, we used CB [7] as an excipient to improve the solubility and bioavailability of triamterene. Two polymorphs of triamterene@CB [7] were obtained, and their crystal structures were determined by single crystal X-ray diffraction to see the drug−excipient interactions at the molecular level.…”

mentioning

confidence: 99%

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

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In recent years, cucurbit [7]uril (CB [7]) has attracted great attention in drug delivery. Though the effect of CB [7] in enhancing the solubility of water insoluble drugs has been validated, the underlying mechanism remains poorly understood, particularly at a molecular level. This study is designed to evaluate a CB [7]-based pharmaceutical formulation to improve solubility and bioavailability of triamterene (a mild potassium-sparing diuretic). Two polymorphs of triamterene@CB [7] were obtained, and their crystal structures were determined by single crystal X-ray diffraction. The CB [7] molecule forms a stable host−guest complex with triamterene (K a = 1.69 ± 0.34 × 10 4 M −1 ) in aqueous solution (pH = 1.0). The results of dissolution study demonstrate that the apparent solubility value of triamterene@CB [7] complex in 0.1 M HCl is 1.6 times as large as that of triamterene, while free triamterene was released from triamterene@CB [7] complex in phosphate buffer of pH 6.8. Pharmacokinetic studies in rats reveal that the AUC 0−∞ value of triamterene@CB [7] complex increases 2.8-fold compared with that of free triamterene, and t 1/2 is prolonged from 1.42 to 2.61 h (P < 0.05) after oral administration. The increased solubility and oral bioavailability are attributed to the formation of a hydrophilic capsule composed of two CB [7] molecules, in which two insoluble triamterene molecules are encapsulated. These results demonstrate that triamterene@CB [7] complex is a stable and effective pharmaceutical formulation. KEYWORDS: cucurbit [7]uril, triamterene, crystal structure, solubility, pharmacokinetics ■ INTRODUCTIONPoor aqueous solubility is a major bottleneck in drug discovery and drug development: more than 40% of drug candidates are poorly water-soluble, and poor aqueous solubility is the main factor to restrict the bioavailability of drugs.1,2 Various approaches have been investigated to improve solubility of drugs, including cocrystal, 3,4 salts, 5 prodrugs, 6 solid dispersion, 7 macrocyclic hosts (e.g., cyclodextrins, cucurbiturils), 8,9 etc. Triamterene, 2,4,7-triamino-6-phenylpteridine (Scheme 1) is a mild potassium-sparing diuretic used either alone or in combination with potassium-wasting diuretics such as hydrochlorothiazide.10,11 It displays low oral bioavailability, and there exists wide intersubject variation because of its poor aqueous solubility (45 mg/L). 12,13 Though triamterene contains three primary amine groups, various methods to obtain soluble salts failed, probably due to its weak basicity. 12 To date, only a few formulations have been proposed to improve the solubility of triamterene, including cyclodextrins 14,15 and solid dispersions. 16,17 However, parenteral administration of β-cyclodextrin results in renal toxicity, 18 and solid dispersions are often physically unstable upon storage at elevated temperature and humidity, 19 and neither of the two triamterene formulations has been applied for clinical therapy. Therefore, the development of new pharmaceutical formulation of triam...

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Crystal engineering approach to improve the solubility of mebendazole

Cited by 73 publications

References 39 publications

Mebendazole Mesylate Monohydrate: A New Route to Improve the Solubility of Mebendazole Polymorphs

Mebendazole Mesylate Monohydrate: A New Route to Improve the Solubility of Mebendazole Polymorphs

Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/Permeability Enhancements through Drug–Coformer Interactions

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

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