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Conference Paper: Design and Characterization of a New Drug-Herb Isoniazid-Curcumin Cocrystal for Potentially improving Tuberculosis Treatment

TitleDesign and Characterization of a New Drug-Herb Isoniazid-Curcumin Cocrystal for Potentially improving Tuberculosis Treatment
Authors
Issue Date2019
PublisherAmerican Association of Pharmaceutical Scientists.
Citation
American Association of Pharmaceutical Scientists (AAPS) 2019 PharmSci 360 Annual Meeting, San Antonio, Texas, 3-6 November 2019 How to Cite?
AbstractPurpose: Cocrystallization engineering is a promising technology with the potential to improve the physicochemical property of an active pharmaceutical ingredient (API), for example, solubility, dissolution performance and hygroscopicity [1]. Tuberculosis (TB) is the most common lethal infectious disease caused by Mycobacterium tuberculosis, and its first-line therapy efficacy is limited by a high rate of multi-drug resistance tuberculosis (MDR-TB) [2]. Isoniazid (ISO) is one of four first-line antitubercular drugs in fixed-dose combination therapy, while it could accelerate the degradation of another first-line drug called rifampicin [3] and thus lead to questionable treatment efficacy and possible drug-resistance. Curcumin (CUR), a natural polyphenolic compound derived from Curcuma longa Linn has been reported for various properties, such as immunomodulatory anti-TB [4] and hepato-protective effect on antitubercular drug-induced hepatotoxicity [5]. Incorporating isoniazid and curcumin together has the possibility to decrease the rapid decomposition of rifampicin with the existence of isoniazid, contributing to shortening regimen duration and lower hepatotoxicity. This study aimed to design, prepare and characterize a new drug-herb cocrystal by rapid solvent removal for potentially improve tuberculosis treatment. Methods: The cocrystal was synthesized by dissolving 128 mg ISO and 172 mg CUR in a 2:1 molar ratio in 100 mL ethanol via rapid solvent removal. The resulting products were collected, oven-dried at 60 ℃ overnight to remove residual solvent and characterized by various solid-state characterization methods. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were utilized for crystallinity, phase purity and thermal properties, respectively. Binary Temperature-Composition phase diagram confirmed eutectic points and stoichiometry ratio of ISO-CUR cocrystal. Moreover, Fourier transform infrared spectroscopy (FTIR) illustrated the change of intermolecular interactions. Results: Phase-pure 2:1 ISO-CUR cocrystal was synthesized by rapid solvent removal and confirmed of formation by PXRD (Figure 1), DSC (Figure 2) and FTIR results. The PXRD pattern of ISO-CUR cocrystal showed two characteristic diffraction peaks at 2θ = 12.82° and 19.97°, revealing that a new crystalline phase formed. The DSC result illustrated that ISO-CUR 2:1 cocrystal possessed a melting endotherm at 156 ℃ lower than both ISO (175 ℃) and CUR (183 ℃). In addition, the fusion enthalpy of ISO-CUR cocrystal (ΔHf = 90.17 kJ/mol) was larger than both of ISO (ΔHf = 33.17 kJ/mol) and CUR (ΔHf = 49.02 kJ/mol), suggesting a stronger crystal lattice has formed. Interestingly, different rotary evaporation speed corresponded to different purity of cocrystals in Figure 2(B), which implied the impact of solvent evaporation rate on ISO-CUR cocrystal phase purity. In the phase diagram (Figure 3), two eutectic points occurred at 142.1 ℃ and 141.1 ℃, indicating the cocrystal only existed a 2:1 stoichiometry ratio. FTIR spectra demonstrated that phenolic O-H stretching frequency of CUR was shifted from 3506 to 3423 cm-1for the cocrystal along with other spectral shifts, suggesting the formation of intermolecular hydrogen bonds. Conclusion: The ISO-CUR 2:1 cocrystal with unique melting point and diffraction peaks was successfully produced by rapid solvent removal but failed through slow evaporation, indicating the high degree of supersaturation was crucial to overcome the kinetic energy obstacle. Moreover, the solvent evaporation rate is likely to be a critical parameter when determining whether thermally unstable cocrystals could form or not. When screening cocrystals, rapid solvent removal is a reliable and robust approach to screen some cocrystals unlikely to be produced by traditional cocrystallization methods. We plan to further investigate the pharmacological performance of ISO-CUR cocrystal and the exact impact of evaporation rate on cocrystal phase purity. References: Chow SF, Chen M, Shi L, Chow AH, Sun CC. Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide.Pharm Res 29(7), 1854-1865 (2012). Pham DD, Fattal E, Tsapis N. Pulmonary drug delivery systems for tuberculosis treatment.Int J Pharm 478(2), 517-529 (2015). Singh S, Mariappan TT, Sharda N, Kumar S, Chakraborti AK. The Reason for an Increase in Decomposition of Rifampicin in the Presence of Isoniazid under Acid Conditions.Pharmacy and Pharmacology Communications 6(9), 405-410 (2000). Bai X, Oberley‐Deegan RE, Bai Aet al. Curcumin enhances human macrophage control of Mycobacterium tuberculosis infection.Respirology 21(5), 951-957 (2016). Singh M, Sasi P, Gupta VH, Rai G, Amarapurkar DN, Wangikar PP. Protective effect of curcumin, silymarin and N-acetylcysteine on antitubercular drug-induced hepatotoxicity assessed in an in vitro model.Human & Experimental Toxicology 31(8), 788-797 (2012).
DescriptionPoster Presentation - no. M0930-04-26
Persistent Identifierhttp://hdl.handle.net/10722/280114

 

DC FieldValueLanguage
dc.contributor.authorXuan, B-
dc.contributor.authorZhang, Y-
dc.contributor.authorChow, SF-
dc.date.accessioned2020-01-06T02:01:10Z-
dc.date.available2020-01-06T02:01:10Z-
dc.date.issued2019-
dc.identifier.citationAmerican Association of Pharmaceutical Scientists (AAPS) 2019 PharmSci 360 Annual Meeting, San Antonio, Texas, 3-6 November 2019-
dc.identifier.urihttp://hdl.handle.net/10722/280114-
dc.descriptionPoster Presentation - no. M0930-04-26 -
dc.description.abstractPurpose: Cocrystallization engineering is a promising technology with the potential to improve the physicochemical property of an active pharmaceutical ingredient (API), for example, solubility, dissolution performance and hygroscopicity [1]. Tuberculosis (TB) is the most common lethal infectious disease caused by Mycobacterium tuberculosis, and its first-line therapy efficacy is limited by a high rate of multi-drug resistance tuberculosis (MDR-TB) [2]. Isoniazid (ISO) is one of four first-line antitubercular drugs in fixed-dose combination therapy, while it could accelerate the degradation of another first-line drug called rifampicin [3] and thus lead to questionable treatment efficacy and possible drug-resistance. Curcumin (CUR), a natural polyphenolic compound derived from Curcuma longa Linn has been reported for various properties, such as immunomodulatory anti-TB [4] and hepato-protective effect on antitubercular drug-induced hepatotoxicity [5]. Incorporating isoniazid and curcumin together has the possibility to decrease the rapid decomposition of rifampicin with the existence of isoniazid, contributing to shortening regimen duration and lower hepatotoxicity. This study aimed to design, prepare and characterize a new drug-herb cocrystal by rapid solvent removal for potentially improve tuberculosis treatment. Methods: The cocrystal was synthesized by dissolving 128 mg ISO and 172 mg CUR in a 2:1 molar ratio in 100 mL ethanol via rapid solvent removal. The resulting products were collected, oven-dried at 60 ℃ overnight to remove residual solvent and characterized by various solid-state characterization methods. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were utilized for crystallinity, phase purity and thermal properties, respectively. Binary Temperature-Composition phase diagram confirmed eutectic points and stoichiometry ratio of ISO-CUR cocrystal. Moreover, Fourier transform infrared spectroscopy (FTIR) illustrated the change of intermolecular interactions. Results: Phase-pure 2:1 ISO-CUR cocrystal was synthesized by rapid solvent removal and confirmed of formation by PXRD (Figure 1), DSC (Figure 2) and FTIR results. The PXRD pattern of ISO-CUR cocrystal showed two characteristic diffraction peaks at 2θ = 12.82° and 19.97°, revealing that a new crystalline phase formed. The DSC result illustrated that ISO-CUR 2:1 cocrystal possessed a melting endotherm at 156 ℃ lower than both ISO (175 ℃) and CUR (183 ℃). In addition, the fusion enthalpy of ISO-CUR cocrystal (ΔHf = 90.17 kJ/mol) was larger than both of ISO (ΔHf = 33.17 kJ/mol) and CUR (ΔHf = 49.02 kJ/mol), suggesting a stronger crystal lattice has formed. Interestingly, different rotary evaporation speed corresponded to different purity of cocrystals in Figure 2(B), which implied the impact of solvent evaporation rate on ISO-CUR cocrystal phase purity. In the phase diagram (Figure 3), two eutectic points occurred at 142.1 ℃ and 141.1 ℃, indicating the cocrystal only existed a 2:1 stoichiometry ratio. FTIR spectra demonstrated that phenolic O-H stretching frequency of CUR was shifted from 3506 to 3423 cm-1for the cocrystal along with other spectral shifts, suggesting the formation of intermolecular hydrogen bonds. Conclusion: The ISO-CUR 2:1 cocrystal with unique melting point and diffraction peaks was successfully produced by rapid solvent removal but failed through slow evaporation, indicating the high degree of supersaturation was crucial to overcome the kinetic energy obstacle. Moreover, the solvent evaporation rate is likely to be a critical parameter when determining whether thermally unstable cocrystals could form or not. When screening cocrystals, rapid solvent removal is a reliable and robust approach to screen some cocrystals unlikely to be produced by traditional cocrystallization methods. We plan to further investigate the pharmacological performance of ISO-CUR cocrystal and the exact impact of evaporation rate on cocrystal phase purity. References: Chow SF, Chen M, Shi L, Chow AH, Sun CC. Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide.Pharm Res 29(7), 1854-1865 (2012). Pham DD, Fattal E, Tsapis N. Pulmonary drug delivery systems for tuberculosis treatment.Int J Pharm 478(2), 517-529 (2015). Singh S, Mariappan TT, Sharda N, Kumar S, Chakraborti AK. The Reason for an Increase in Decomposition of Rifampicin in the Presence of Isoniazid under Acid Conditions.Pharmacy and Pharmacology Communications 6(9), 405-410 (2000). Bai X, Oberley‐Deegan RE, Bai Aet al. Curcumin enhances human macrophage control of Mycobacterium tuberculosis infection.Respirology 21(5), 951-957 (2016). Singh M, Sasi P, Gupta VH, Rai G, Amarapurkar DN, Wangikar PP. Protective effect of curcumin, silymarin and N-acetylcysteine on antitubercular drug-induced hepatotoxicity assessed in an in vitro model.Human & Experimental Toxicology 31(8), 788-797 (2012).-
dc.languageeng-
dc.publisherAmerican Association of Pharmaceutical Scientists. -
dc.relation.ispartofAAPS PharmSci 360 Annual Meeting-
dc.rightsAAPS PharmSci 360 Annual Meeting. Copyright © American Association of Pharmaceutical Scientists.-
dc.rightsThe original publication is available at www.springerlink.com-
dc.titleDesign and Characterization of a New Drug-Herb Isoniazid-Curcumin Cocrystal for Potentially improving Tuberculosis Treatment-
dc.typeConference_Paper-
dc.identifier.emailChow, SF: asfchow@hku.hk-
dc.identifier.authorityChow, SF=rp02296-
dc.identifier.hkuros308891-
dc.publisher.placeUnited States-

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