Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

Meng, Yuanyuan; Tan, Fangyun; Yao, Jiaxin; Cui, Yanan; Feng, Yumiao; Li, Zhiping; Wang, Yuli; Yang, Yang; Gong, Wenbin; Yang, Meiyan; Kong, Xiaolong; Gao, Chunsheng

doi:10.1016/j.ijpx.2022.100119

Cited by 7 publications

(8 citation statements)

References 46 publications

(62 reference statements)

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“…Therefore, a hydrophobic drug may require a fugacious inhibition of precipitation or delayed cocrystallization via pharmaceutical excipients or other components that intervene with nucleation or growth of crystals (“parachute”) to maintain a sufficient period for absorption. Some studies have shown that crystallization induces rapid precipitation, thus inhibiting the effects of crystallization on solubility and dissolution. , The powder dissolution profiles showed that the S max value of ENR-2,6-DHBA·1/2H 2 O was 0.65 mg/mL (1.9-fold that of ENR), and the concentration remained unchanged even after reaching S max . Notably, the crystal form of ENR-2,6-DHBA·1/2H 2 O was not changed before and after dissolution, as confirmed by PXRD analysis (Figure b).…”

Section: Resultsmentioning

confidence: 99%

“…Some studies have shown that crystallization induces rapid precipitation, thus inhibiting the effects of crystallization on solubility and dissolution. 52,53 The powder dissolution profiles showed that the S max value of In addition, the more hydrogen bonds formed between the API and the cocrystal former, the more stable it was. 55 There are more Hbonds that were formed in ENR-2,6-DHBA•1/2H 2 O (Table S2).…”

Section: Resultsmentioning

confidence: 99%

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Enhancing the Bioavailability of a Novel Enrofloxacin Salt by Inhibiting Precipitation via a Crystallization Inhibitor

Mao,

Wang,

Liu

et al. 2024

Crystal Growth & Design

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Highly soluble cocrystals can improve the bioavailability of poorly soluble drugs by inducing supersaturation when absorption is limited by drug dissolution. Enrofloxacin (ENR) is a concentration-dependent fluoroquinolone antibacterial with poor solubility. In this study, two new ENR salts, 3,5-dihydroxybenzoic acid (ENR-3,5-DHBA) and 2,6-dihydroxybenzoic acid (ENR-2,6-DHBA•1/2H 2 O), were prepared, and their physicochemical properties were evaluated for suitability in formulation development.Results showed that the solubility of the two new salts enhanced. Although ENR-3,5-DHBA had a much higher solubility than ENR, it underwent rapid precipitation during dissolution, forming the poorly soluble ENR•6H 2 O in aqueous form. This negated the potential high-solubility advantage of the new salt, which might have enhanced its dissolution rate and in vivo bioavailability. To solve this problem, we systematically evaluated suitable crystallization inhibitors that could maintain the supersaturation generated by cocrystal/salt dissolution for a prolonged period. At 37 °C, the solubility and mean AUC 0−24h of ENR-3,5-DHBA increased by about 4.7 and 1.5 times, respectively (compared with ENR), when ENR-3,5-DHBA was dosed with 2.0 mg/mL methacrylic acidethyl acrylate copolymer (ME) solution instead of an active pharmaceutical ingredient. This study demonstrates that using a highly soluble salt and an appropriate crystallization inhibitor is a potentially effective formulation strategy for improving the oral bioavailability of poorly soluble drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Enhancing the Bioavailability of a Novel Enrofloxacin Salt by Inhibiting Precipitation via a Crystallization Inhibitor

Mao,

Wang,

Liu

et al. 2024

Crystal Growth & Design

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“…By introducing a more soluble coformer into the crystal lattice, which results in a lower solvation barrier, significant attempts have been undertaken in recent decades to increase the solubility, permeability, or bioavailability of poorly water-soluble medicines. The ultimate aim of using the coformer is to improve the solubility and dissolution rate of a poorly aqueous soluble drug by introducing the coformers into the BCS class-II drugs [18,92,142].…”

Section: Succinic Acid (Sa)mentioning

confidence: 99%

“…Pharmaceutics 2023, 15, x FOR PEER REVIEW 30 of 45 solubility, permeability, or bioavailability of poorly water-soluble medicines. The ultimate aim of using the coformer is to improve the solubility and dissolution rate of a poorly aqueous soluble drug by introducing the coformers into the BCS class-II drugs [18,92,142].…”

Section: Succinic Acid As a Coformermentioning

confidence: 99%

Cocrystals by Design: A Rational Coformer Selection Approach for Tackling the API Problems

et al. 2023

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Active pharmaceutical ingredients (API) with unfavorable physicochemical properties and stability present a significant challenge during their processing into final dosage forms. Cocrystallization of such APIs with suitable coformers is an efficient approach to mitigate the solubility and stability concerns. A considerable number of cocrystal-based products are currently being marketed and show an upward trend. However, to improve the API properties by cocrystallization, coformer selection plays a paramount role. Selection of suitable coformers not only improves the drug’s physicochemical properties but also improves the therapeutic effectiveness and reduces side effects. Numerous coformers have been used till date to prepare pharmaceutically acceptable cocrystals. The carboxylic acid-based coformers, such as fumaric acid, oxalic acid, succinic acid, and citric acid, are the most commonly used coformers in the currently marketed cocrystal-based products. Carboxylic acid-based coformers are capable of forming the hydrogen bond and contain smaller carbon chain with the APIs. This review summarizes the role of coformers in improving the physicochemical and pharmaceutical properties of APIs, and deeply explains the utility of afore-mentioned coformers in API cocrystal formation. The review concludes with a brief discussion on the patentability and regulatory issues related to pharmaceutical cocrystals.

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“…Since then, the drug has been approved for use in a variety of other medical settings, including the treatment of deep vein thrombosis and pulmonary embolism. Recently, RXB has been used to prevent disease progression in hospitalized patients with Coronavirus disease (Covid- 19), as well as to prevent thrombosis in non-valvular atrial fibrillation (NVAF) patients and obese patients [5,6].…”

Section: Introductionmentioning

confidence: 99%

Bioavailability Enhancement Strategies for Rivaroxaban: A Noteworthy Review

AL-SHOUBKI,

H. TEAIMA,

ABDELMONEM

et al. 2023

Int J App Pharm

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This review article discusses Rivaroxaban (RXB), an anticoagulant that has gained much attention due to its ability to prevent blood clots from forming in the body. However, one of the major challenges pharmaceutical companies face is the low water solubility of RXB, which can lead to difficulties in formulating the drug for oral administration and affect the drug's bioavailability. However, to the best of our knowledge, limited studies have explored enhancing the bioavailability of the RXB. Most of these studies have been purely academic and impractical for industrial use. Therefore, this review article aims to discuss successful studies that have increased the bioavailability of RXB. The goal is to inspire researchers to develop this new drug further. The article covers seven strategies for enhancing the bioavailability of RXB, including microspheres, liposomes, self-nano emulsifying drug delivery system, solid lipid nanoparticles, cocrystals, sustained release, and solid dispersion. The studies discussed in this review offer valuable insights into developing novel drug delivery systems that can help overcome the limitations of existing drugs.

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Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

Cited by 7 publications

References 46 publications

Enhancing the Bioavailability of a Novel Enrofloxacin Salt by Inhibiting Precipitation via a Crystallization Inhibitor

Enhancing the Bioavailability of a Novel Enrofloxacin Salt by Inhibiting Precipitation via a Crystallization Inhibitor

Cocrystals by Design: A Rational Coformer Selection Approach for Tackling the API Problems

Bioavailability Enhancement Strategies for Rivaroxaban: A Noteworthy Review

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