Azilsartan piperazine salt solvate and monohydrate: preparation, crystal structure, enhanced solubility and oral bioavailability

Xu, Jingyi; Du, Rongkai; Wu, Lvying; Zhang, Xianrui; Guan, Su; Zhang, Lei; Ning, Lifeng; Li, Shan

doi:10.1039/c9nj05042f

Cited by 9 publications

(7 citation statements)

References 39 publications

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“…46−52 Therefore, the higher solubility of FPV-PP might be a result of the higher solubility of PP. 53,54 On the other hand, as shown in Figure S3, the special crystal structure of the FPV-PP salt has many cavities, with the primary hydrophilic amino groups stretching inward. 55,56 Due to the solvent inclusion of cavities and their internal hydrophilic environment, the solubility of the FPV-PP salt has been enhanced in comparison with that of FPV.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The solubility of the FPV-PP salt was significantly improved by 1.6-fold in comparison with that of FPV. Many examples have also shown that the solubility of drug salts could be effectively improved due to the higher solubility of the salt-forming reagent. − Therefore, the higher solubility of FPV-PP might be a result of the higher solubility of PP. , On the other hand, as shown in Figure S3, the special crystal structure of the FPV-PP salt has many cavities, with the primary hydrophilic amino groups stretching inward. , Due to the solvent inclusion of cavities and their internal hydrophilic environment, the solubility of the FPV-PP salt has been enhanced in comparison with that of FPV . Above all, the higher solubility of FPV-PP salt might be a result of the high solubility of PP, the special cavity structure of the salt, or both.…”

Section: Resultsmentioning

confidence: 99%

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Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Wang

Yao

et al. 2021

Crystal Growth & Design

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Recently, favipiravir, as a broad-spectrum antiviral drug, has gain more attention because it might be a candidate to remedy the coronavirus disease 2019 (COVID-19). To improve its poor permeability and tabletability, four multicomponent crystals of favipiravir (FPV) were prepared by a slow evaporation or liquidassisted grinding method, including three cocrystals (FPVtheophylline, 1:1; FPV-saccharin, 1:1; FPV-5-fluorouracil, 1:1) and one salt (FPV-piperazine, 2:1). All of the crystal structures were solved by single-crystal X-ray diffraction. Interestingly, FPVtheophylline has a crystal structure similar to that of FPV, leading to similar properties, such as solubility, permeability, and tabletability. Except for FPV-theophylline, all of the other multicomponent crystals exhibit an enhanced permeability and tabletability. Our studies provide a new insight in overcoming the shortcomings of the important antiviral drug FPV.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Wang

Yao

et al. 2021

Crystal Growth & Design

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“…PXRD performs as an effective tool to judge the solid-substance states, including salt, polymorphs, and physical mixture, and check the phase purity of the bulk samples based on the line profile. , The PXRD patterns of seven HAM salts (experimental-exp and simulation-sim), HAM, and the corresponding acidic counterions are shown in Figure S1(a–g). It can be seen that the PXRD patterns of prepared HAM salts were different from that of either HAM or acidic counterions, indicating that the new solid forms were produced.…”

Section: Resultsmentioning

confidence: 99%

Insight into the Relationship of Aqueous Solubility and Single-Crystal Structure of Harmine’s New Organic Salt Forms

Hong,

Wu,

Wang

et al. 2024

Crystal Growth & Design

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Harmine (HAM) is a natural product with neuroprotective and antitumor activity. Its poor aqueous solubility is the major factor limiting its clinical application. In this work, seven new organic acid salts of HAM were prepared and systematically characterized. Their single crystals were obtained, and the structures were identified by a single-crystal X-ray diffractometer. The corresponding solubilities in water were determined in the temperature range of 20−35 °C by the HPLC method. All HAM salts showed significantly improved powder solubility profiles compared with the free base. The relationship between the aqueous solubility and the single-crystal structures of HAM organic salts was explored from several perspectives, including the basic properties of acidic counterions, the intermolecular force in crystals (type of lattice force, cohesive energy density, and lattice energy), the factors affecting the dissolution process (hydration energy and sublimation energy), and the external environmental factors (chemical hardness). The aqueous solubility of different HAM salts was dependent on the type of charge assistant hydrogen bonds; that is, the salts withbonds exhibited better solubility than the other salts with N + −H•••O − hydrogen bonds. In addition, the results revealed that HAM salts with higher acidic counterion intrinsic solubility (S ACID ) showed smaller cohesive energy density of the crystal; the larger the absolute value of hydration energy (ΔG hyd 0 ), the greater the chemical hardness (η) of acidic anions in the crystal and ultimately the better the equilibrium solubility in water. The rank order of the linear fitting accuracy of these four parameters regarding solubility was as follows: Δη > CED > ΔG hyd 0 . The solubility of HAM organic acidic salts is associated with several factors, even though the chemical hardness seems to play a central role.

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“…In addition, the piperazine ring is considered an important class of nitrogen heterocycles that can effectively regulate the lipid-water partition coefficient and acidbase equilibrium constants of drugs, which may have positive influences on improving the druggability of DAI [25]. What is more, a series of the literature on the cocrystals with PPZ demonstrates that the introduction of PPZ can significantly optimize the solubility and bioavailability of active pharmaceutical ingredients (APIs) [24,26,27]. Until now, there have been some studies on the cocrystal of DAI reported [14,28,29].…”

Section: Introductionmentioning

confidence: 99%

A Novel Cocrystal of Daidzein with Piperazine to Optimize the Solubility, Permeability and Bioavailability of Daidzein

Wang,

Li,

et al. 2024

Molecules

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It is well known that daidzein has various significant medicinal values and health benefits, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-diabetic, cholesterol lowering, neuroprotective, cardioprotective and so on. To our disappointment, poor solubility, low permeability and inferior bioavailability seriously limit its clinical application and market development. To optimize the solubility, permeability and bioavailability of daidzein, the cocrystal of daidzein and piperazine was prepared through a scientific and reasonable design, which was thoroughly characterized by single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. Combining single-crystal X-ray diffraction analysis with theoretical calculation, detailed structural information on the cocrystal was clarified and validated. In addition, a series of evaluations on the pharmacogenetic properties of the cocrystal were investigated. The results indicated that the cocrystal of daidzein and piperazine possessed the favorable stability, increased solubility, improved permeability and optimized bioavailability of daidzein. Compared with the parent drug, the formation of cocrystal, respectively, resulted in 3.9-, 3.1-, 4.9- and 60.8-fold enhancement in the solubility in four different media, 4.8-fold elevation in the permeability and 3.2-fold in the bioavailability of daidzein. Targeting the pharmaceutical defects of daidzein, the surprising elevation in the solubility, permeability and bioavailability of daidzein was realized by a clever cocrystal strategy, which not only devoted assistance to the market development and clinical application of daidzein but also paved a new path to address the drug-forming defects of insoluble drugs.

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Azilsartan piperazine salt solvate and monohydrate: preparation, crystal structure, enhanced solubility and oral bioavailability

Abstract: Two azilsartan–piperazine salt solvates and a monohydrate feature crystal structural diversity and improve the azilsartan solubility over that of the free Az form. Az–Pz·EtOH and Az–Pz·H2O improve the plasma azilsartan concentration Cmax and AUC over the free Az form.

Cited by 9 publications

References 39 publications

Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Novel Formulations of the Antiviral Drug Favipiravir: Improving Permeability and Tabletability

Insight into the Relationship of Aqueous Solubility and Single-Crystal Structure of Harmine’s New Organic Salt Forms

A Novel Cocrystal of Daidzein with Piperazine to Optimize the Solubility, Permeability and Bioavailability of Daidzein

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