Stability Indicating Method for a Thiazolylhydrazone Derivative with Antifungal Activity and Experimental/Theoretical Elucidation of Its Degradation Products

Silva, Iara R.; Maltarollo, Vinícius G.; Protti, Ícaro F.; Oliveira, Renata B.; César, Isabela C.

doi:10.21577/0103-5053.20220131

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Journal of the Brazilian Chemical Society

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Article • J. Braz. Chem. Soc. 34 (4) • 2023 • https://doi.org/10.21577/0103-5053.20220131 copy

Stability Indicating Method for a Thiazolylhydrazone Derivative with Antifungal Activity and Experimental/Theoretical Elucidation of Its Degradation Products

Authorship SCIMAGO INSTITUTIONS RANKINGS

RN104 (2-[2-(cyclohexylmethylene)hydrazinyl]-4-phenylthiazole) is a thiazolylhydrazone derivative with promising in vitro and in vivo antifungal activity. A stability indicating highperformance liquid chromatography with diode-array detection (HPLC-DAD) method was carried out using C18 end-capped column (250 × 4.6 mm, 5 μm) and a mobile phase composed of water and acetonitrile (15:85 v/v) at a flow rate of 1.2 mL min^-1, injection volume 25 μL and DAD detection at 240 nm. The method showed to be selective, linear in the range of 20 to 240 μg mL^-1, precise, accurate and robust. RN104 forced degradation study under different stress conditions (acidic, alkaline and neutral hydrolysis, oxidation, photolysis and thermolysis) was performed using the validated analytical method. The results showed that RN104 underwent significant degradation when subjected to alkaline hydrolysis and oxidation by metallic ions. Quantum mechanics calculations were carried out to assist in the structural elucidation of the formed degradation products. The obtained data may be useful for the development of future formulation based on RN104.

Keywords:
stability indicating method; HPLC; forced degradation; quantum mechanics calculations

Level	Recovery / %	Recovery mean / %	RSD / %
Low (20 μg mL^-1)	101.4	103.4	1.7
	104.4
	104.4
Middle (120 μg mL^-1)	99.9	99.7	0.6
	100.2
	99.0
High (240 μg mL^-1)	100.7	100.1	1.1
	100.7
	98.8
Mean	–	101.0	2.0

Parameter	Nominal and variable	Influence in the percentage content (X – x)^a a Difference in RN104 content (%) between nominal and varied condition.
Detection wavelength / nm	A = 240; a = 260	0.99
Column temperature / °C	B = 30; b = 35	–0.63
Mobile phase flow rate / (mL min^-1)	C = 1.2; c = 1.0	–0.51
Mobile phase composition	D = 85:15; d = 80:20	0.34
Brand of chromatographic column	E = Macherey Nagel; e = Merck	–1.46
Brand of acetonitrile	F = Lichrosolv Merck; f = PRQUÍMIOS	–0.38
Chromatograph model	G = Agilent 1100; g = Agilent 1200	–0.50

Condition	Degradation / %
Condition	24 h	48 h	72 h
NaOH (1 M), 23 °C	100.0	100.0	100.0
NaOH (1 M), 50 °C	100.0	100.0	100.0
HCl (1 M), 23 °C	46.3	46.5	46.6
HCl (1 M), 50 °C	69.2	67.3	71.5
Water, 23 °C	12.8	18.2	22.0
Water, 50 °C	27.9	31.0	33.2
Light, 23 °C	1.5	12.8	19.3
Dry heat (105 °C)	10.8	12.3	12.0
H₂O₂ (0.3% v/v), 23 °C	100.0	100.0	100.0
FeCl₃ (0.01 M), 23 °C	100.0	100.0	100.0

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