Combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, in order to improve clofazimine aqueous solubility and 4-aminosalicylic acid thermal stability

Laurie Bodart; Amélie Derlet; Xavier Buol; Tom Leyssens; Nikolay Tumanov; Johan Wouters

doi:10.1016/j.xphs.2020.09.024

Combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, in order to improve clofazimine aqueous solubility and 4-aminosalicylic acid thermal stability

Laurie Bodart, Amélie Derlet, Xavier Buol, Tom Leyssens, Nikolay Tumanov, Johan Wouters (Supervisor)

Research output: Contribution to journal › Article › peer-review

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Abstract

Four forms of a salt combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, are reported and the crystal structure of two of these forms are described. TG/DSC analysis of all four forms demonstrate an increase in the temperature at which degradation (upon decarboxylation) occurs in comparison to pure 4-aminosalicylic acid. Water solubility evaluation indicates a significant increase of the amount of clofazimine detected in water (10.26 ± 0.52 µg/mL for form I, 12.27 ± 0.32 µg/mL for form II, 7.15 ± 0.43 µg/mL for form III and 8.50 ± 1.24 µg/mL for form IV ) in comparison to pure clofazimine (0.20 ± 0.03 µg/mL).

Translated title of the contribution	Combiner deux antituberculeux, la clofazimine et l'acide 4-aminosalicylique pour améliorer la solubilité aqueuse de la clofazimine et la stabilité thermique de l'acide 4-aminosalicylique
Original language	English
Pages (from-to)	3645-3652
Number of pages	8
Journal	Journal of Pharmaceutical Sciences
Volume	109
Issue number	12
Early online date	22 Sept 2020
DOIs	https://doi.org/10.1016/j.xphs.2020.09.024
Publication status	Published - Dec 2020

Keywords

4-Aminosalicylic acid
Clofazimine
Differential scanning calorimetry
Polymorph
Salts
Solid-state
Solubility
Thermogravimetric analysis

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10.1016/j.xphs.2020.09.024

Accepted_manuscript_PUREAccepted author manuscript, 1.77 MB

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title = "Combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, in order to improve clofazimine aqueous solubility and 4-aminosalicylic acid thermal stability",

abstract = "Four forms of a salt combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, are reported and the crystal structure of two of these forms are described. TG/DSC analysis of all four forms demonstrate an increase in the temperature at which degradation (upon decarboxylation) occurs in comparison to pure 4-aminosalicylic acid. Water solubility evaluation indicates a significant increase of the amount of clofazimine detected in water (10.26 ± 0.52 µg/mL for form I, 12.27 ± 0.32 µg/mL for form II, 7.15 ± 0.43 µg/mL for form III and 8.50 ± 1.24 µg/mL for form IV ) in comparison to pure clofazimine (0.20 ± 0.03 µg/mL).",

keywords = "4-Aminosalicylic acid, Clofazimine, Differential scanning calorimetry, Polymorph, Salts, Solid-state, Solubility, Thermogravimetric analysis",

author = "Laurie Bodart and Am{\'e}lie Derlet and Xavier Buol and Tom Leyssens and Nikolay Tumanov and Johan Wouters",

note = "Funding Information: L.B. thanks the FRS-FNRS for the funding (research fellow grant) and Lionel Pochet for his help for the elaboration of the HPLC method. X. B. thanks the Fonds Europ{\'e}en de D{\'e}veloppement R{\'e}gional, European Union and the “Walloon Region” for their financial support in the operational framework Wallonie2020.EU. This work was performed on XRD and TA equipments from the PC2 platform at the University of Namur.This research used resources of the “Plateforme Technologique de Calcul Intensif (PTCI){"} ( http://www.ptci.unamur.be ) located at the University of Namur, Belgium, which is supported by the FNRS-FRFC, the Walloon Region, and the University of Namur (Conventions No. 2.5020.11, GEQ U.G006.15, 1610468, and RW/GEQ2016). The PTCI is member of the “Consortium des {\'E}quipements de Calcul Intensif (C{\'E}CI){"} ( http://www.cecihpc.be ). Publisher Copyright: {\textcopyright} 2020 American Pharmacists Association{\textregistered}",

year = "2020",

month = dec,

doi = "10.1016/j.xphs.2020.09.024",

language = "English",

volume = "109",

pages = "3645--3652",

journal = "Journal of Pharmaceutical Sciences",

issn = "0022-3549",

publisher = "John Wiley and Sons Inc.",

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Combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, in order to improve clofazimine aqueous solubility and 4-aminosalicylic acid thermal stability. / Bodart, Laurie; Derlet, Amélie; Buol, Xavier et al.
In: Journal of Pharmaceutical Sciences, Vol. 109, No. 12, 12.2020, p. 3645-3652.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, in order to improve clofazimine aqueous solubility and 4-aminosalicylic acid thermal stability

AU - Bodart, Laurie

AU - Derlet, Amélie

AU - Buol, Xavier

AU - Leyssens, Tom

AU - Tumanov, Nikolay

A2 - Wouters, Johan

N1 - Funding Information: L.B. thanks the FRS-FNRS for the funding (research fellow grant) and Lionel Pochet for his help for the elaboration of the HPLC method. X. B. thanks the Fonds Européen de Développement Régional, European Union and the “Walloon Region” for their financial support in the operational framework Wallonie2020.EU. This work was performed on XRD and TA equipments from the PC2 platform at the University of Namur.This research used resources of the “Plateforme Technologique de Calcul Intensif (PTCI)" ( http://www.ptci.unamur.be ) located at the University of Namur, Belgium, which is supported by the FNRS-FRFC, the Walloon Region, and the University of Namur (Conventions No. 2.5020.11, GEQ U.G006.15, 1610468, and RW/GEQ2016). The PTCI is member of the “Consortium des Équipements de Calcul Intensif (CÉCI)" ( http://www.cecihpc.be ). Publisher Copyright: © 2020 American Pharmacists Association®

PY - 2020/12

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N2 - Four forms of a salt combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, are reported and the crystal structure of two of these forms are described. TG/DSC analysis of all four forms demonstrate an increase in the temperature at which degradation (upon decarboxylation) occurs in comparison to pure 4-aminosalicylic acid. Water solubility evaluation indicates a significant increase of the amount of clofazimine detected in water (10.26 ± 0.52 µg/mL for form I, 12.27 ± 0.32 µg/mL for form II, 7.15 ± 0.43 µg/mL for form III and 8.50 ± 1.24 µg/mL for form IV ) in comparison to pure clofazimine (0.20 ± 0.03 µg/mL).

AB - Four forms of a salt combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, are reported and the crystal structure of two of these forms are described. TG/DSC analysis of all four forms demonstrate an increase in the temperature at which degradation (upon decarboxylation) occurs in comparison to pure 4-aminosalicylic acid. Water solubility evaluation indicates a significant increase of the amount of clofazimine detected in water (10.26 ± 0.52 µg/mL for form I, 12.27 ± 0.32 µg/mL for form II, 7.15 ± 0.43 µg/mL for form III and 8.50 ± 1.24 µg/mL for form IV ) in comparison to pure clofazimine (0.20 ± 0.03 µg/mL).

KW - 4-Aminosalicylic acid

KW - Clofazimine

KW - Differential scanning calorimetry

KW - Polymorph

KW - Salts

KW - Solid-state

KW - Solubility

KW - Thermogravimetric analysis

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DO - 10.1016/j.xphs.2020.09.024

M3 - Article

SN - 0022-3549

VL - 109

SP - 3645

EP - 3652

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

IS - 12

ER -

Combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, in order to improve clofazimine aqueous solubility and 4-aminosalicylic acid thermal stability

Abstract

Keywords

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CÉCI – Consortium of high performance computing centers

High Performance Computing Technology Platform

Physical Chemistry and characterization(PC2)

Drug-drug cocrystallization or salt formation as an alternative to combination drugs: A case study on clofazimine

Cite this

Combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, in order to improve clofazimine aqueous solubility and 4-aminosalicylic acid thermal stability

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Projects

CÉCI – Consortium of high performance computing centers

Equipment

High Performance Computing Technology Platform

Physical Chemistry and characterization(PC2)

Student theses

Drug-drug cocrystallization or salt formation as an alternative to combination drugs: A case study on clofazimine

Cite this