Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution

Jagia, Moksh; Kale, Dnyaneshwar P; Bansal, Arvind K.; Patel, Sarsvatkumar

doi:10.1208/s12249-021-02182-9

Cited by 8 publications

(9 citation statements)

References 40 publications

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“…32,53 Therefore, the microenvironmental pH can influence the solubility, dissolution, permeability, and oral bioavailability of drugs having pH-dependent solubility. Previous works have demonstrated the impact of microenvironmental pH on the solubility and dissolution behavior of salts, 54 cocrystals, 55 and eutectics. 56 In the present study, the impact of PIP on the microenvironmental pH of the SMX−PIP salt and its effect on speciation profile, solubility, and IDR of SMX from the SMX− PIP salt in comparison to pure SMX was investigated.…”

Section: Microenvironmental Ph and Effect On Speciationmentioning

confidence: 99%

Study on Sulfamethoxazole–Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties

Roy,

Chakraborty,

Pandey

et al. 2023

Mol. Pharmaceutics

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Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole−piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole−piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole−piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.

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Section: Microenvironmental Ph and Effect On Speciationmentioning

confidence: 99%

Study on Sulfamethoxazole–Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties

Roy,

Chakraborty,

Pandey

et al. 2023

Mol. Pharmaceutics

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“…Thus, the research is being conducted on the solubilization of poorly soluble drugs using various substances and methods. Drug solubilization methods include solid dispersion ( Sohn and Choi, 2022 , Sohn et al, 2021a , Sohn et al, 2021b , Zaki et al, 2023 ), complexation ( Aung et al, 2022 , Kamel et al, 2017 , Volkova et al, 2021 ), self-micro and nano-emulsifying formulations ( Al-Amodi et al, 2020 , Habib et al, 2021 , Rangaraj et al, 2019 ), micelles ( Choi et al, 2020 ), and co-crystals ( Jagia et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…The model drug, febuxostat (Febux), which is commercial product as Uloric®, is a new bipurine-selective xanthine oxidase inhibitor. It is approved for treatment of hyperuricemia in gout patients ( Davoodi et al, 2020 , Jagia et al, 2022 ). Uloric® (40 and 80 mg) tablets consist of various excipients such as mannitol, lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, and sodium croscarmellose in RxList.…”

Section: Introductionmentioning

confidence: 99%

“…The most recent research trends of Febux were SD formulations ( Amin et al, 2020 , El Shenawy et al, 2019 , Kaur et al, 2020 , Moinuddin et al, 2020 , Patel et al, 2021 ), as well as self-micro and nano-emulsifying formulations ( Al-Amodi et al, 2020 , Habib et al, 2021 , Rangaraj et al, 2019 ), nanostructure lipid carriers ( Varia et al, 2022 ), and co-crystal ( Jagia et al, 2022 ). Among them, the SD manufacturing method was selected owing to the reason that our group has established a drug solubilization method with an SD manufacturing method, and has an approach and manufacturing technology accordingly.…”

Section: Introductionmentioning

confidence: 99%

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Development and evaluation of febuxostat solid dispersion through screening method

Sohn,

Choi

2023

Saudi Pharmaceutical Journal

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“…Although FBX form-A is still used in drug formulation, the co-crystallization of FBX was widely attempted due to the low aqueous solubility and slow absorption rate of FBX as a restriction of BCS class II drugs [ 1 , 14 , 18 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Many cases to enhance the solubility of FBX were reported in numerous FBX cocrystals with isonicotinamide, arginine, pyridine, 4-hydroxy benzoic acid, or salicylic acid as a co-former [ 22 , 24 , 34 ], but these cocrystals of FBX exhibited unstable properties in the buffered solutions of pH 4–7 [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice

Yu,

You,

Bae

et al. 2023

Pharmaceutics

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Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX- and FBX-PG-treated rats and mice was compared in this study. The results showed that the bioavailability (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration–time curve from time zero to infinity (AUC0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (Cmax,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (Cmax,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC0-inf of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and a 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value.

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Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution

Cited by 8 publications

References 40 publications

Study on Sulfamethoxazole–Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties

Study on Sulfamethoxazole–Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties

Development and evaluation of febuxostat solid dispersion through screening method

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice

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