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A Validated Stability-Indicating LC Method for Fluocinonide in The American Journal of Analytical Chemistry, 2010, 1, 113-126 doi:10.4236/ajac.2010.13015 Published Online November 2010 (http://www.SciRP.org/journal/ajac) A Validated Stability-Indicating LC Method for Fluocinonide in the Presence of Degradation Products, Its Process-Related Impurities and Identification of Degradation Products Prabha Srinivasu1,2, Devarakonda V. SubbaRao1, Raju V. K. Vegesna1, K. Sudhakar Babu2 1Versapharm Incorporated, Warminister, USA 2Department of Chemistry, Sri Krishnadevaraya University, Anantapur, India E-mail: {sreenu_ind, drdvsubbarao}@yahoo.com Received July 26, 2010; revised October 14, 2010; accepted October 27, 2010 Abstract The objective of the current study was to develop a validated, specific and stability-indicating reverse phase liquid chromatographic method for the quantitative determination of fluocinonide and its related substances. The determination was done for active pharmaceutical ingredient and its pharmaceutical dosage forms in the presence of degradation products, and its process-related impurities. The drug was subjected to stress condi- tions of hydrolysis (acid and base), oxidation, photolysis and thermal degradation per International Confer- ence on Harmonization (ICH) prescribed stress conditions to show the stability-indicating power of the method. Significant degradation was observed during acid, base hydrolysis, and peroxide degradation. The major degradants were identified by LC-MS, FTIR and 1H/13C NMR spectral analysis. The chromatographic conditions were optimized using an impurity-spiked solution and the samples generated from forced degra- dation studies. In the developed HPLC method, the resolution between fluocinonide and its process-related impurities, (namely imp-1, imp-2, imp-3, imp-4, imp-5, imp-6, imp-7 and imp-8) and its degradation products was found to be greater than 2.0. The chromatographic separation was achieved on a C18, 250 mm × 4.6 mm, 5 µm column. The LC method employed a linear gradient elution and the detection wavelength was set at 240 nm. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.3%. The developed RP-LC method was validated with respect to linearity, accuracy, precision and robustness. Keywords: Fluocinonide, RP-LC, LC-MS, Forced Degradation, Validation, Stability-Indicating 1. Introduction a “high-potency” (second-highest rank) topical cortico- steroid [1]. Corticosteroids have multiple actions, in- Fluocinonide, pregna-1, 4-diene-3, 20-dione, 21-(acety- cludeing anti-inflammatory and anti-proliferative effects. loxy)-6, 9-difluoro-11-hydroxy-16, 17-[(1-methylethyli- When applied topically for at least one week, fluocinon- dene)bis(oxy)]-, (6α, 11β, 16α)-, is a potent glucorticoid ide is effective in the treatment of inflammation and steroid used topically as anti-inflammatory agent for the itching caused by a number of skin conditions such as treatment of skin disorders such as eczema. It relieves allergic reactions, eczema and psoriasis. Minimal amounts itching, dryness, redness, crusting, scaling, inflammation should be used for a minimal length of time to avoid the and discomfort. Fluocinonide is a white or almost white occurrence of adverse effects. Fluocinonide is also used crystalline powder. It is practically insoluble in water; in veterinary medicine. It is used for treatment of aller- slightly soluble in absolute ethanol. There are seven gies in dogs. Natural systemic cortisol concentrations can classes of topical corticosteroids ranked according to be suppressed for weeks after one week of topical expo- their potency based vasoconstrictor assays. Fluocinonide sure. is a fluorinated, highly potent, corticosteroid. It ranks as A chromatographic assay method has appeared in US Copyright © 2010 SciRes. AJAC 114 P. SRINIVASU ET AL. pharmacopeia for the quantification of fluocinonide in Fluocinonide drug substance and its pharmaceutical topical dosage O forms [2]. Few analytical methods were available in lit- O 22 erature for the quantification of fluocinonide and fluclo- 21 23 cortisone acetate. Shek E. et al. has described an HPLC 25 20 procedure to chromatograph fluocinonide as well as tri- 19 O 12 amcinolone acetonide and diflorasone diacetate [3-6]. In HO 17 O 24 addition, Shek E. et al. reported the stability indicating 11 13 18 26 16 O LC method for triple corticoid integrated system in a 1 9 14 cream. [3] in which Shek. E. et al. described the quanti- 2 8 10 15 fication of–fluocinonide, procinonide and ciprocinonide F and expected the major degradation product under hy- 3 5 7 6 drolytic conditions would be fluocinolone acetonide. O 4 Further study was not carried out to confirm this impu- rity. The present study was carried out to describe de- F tailed degradation studies as per ICH guidelines and de- (a) pregna-1, 4-diene-3, 20-dione, 21-(acetyloxy)-6, 9-difluoro-11- hydroxy-16, 17-[(1-methylethylidene)bis(oxy)]-, (6α, 11β, 16α)-. Mo- veloped a suitable LC method for the separation and es- lecular weight: 494.52. timation of both process related impurities and degrada- tion impurities. Interestingly author observed two major Imp-1 degradation products in acid, base hydrolysis and perox- OH ide degradation of fluocinonide. The major degradation 21 products of fluocinonide were isolated using preparative HPLC and structure elucidation was performed for the 19 O same using advanced spectral techniques such as NMR, 20 12 17 OH LC-MS and IR. The purpose of the present research HO 11 13 work was to develop a suitable single stability-indicating 18 16 LC method for the determination of fluocinonide and its OH 1 9 related substances and structure elucidation of major 14 2 8 degradation products. The developed LC method was 10 15 validated with respect to specificity, LOD, LOQ, linear- F 3 5 ity, precision, accuracy and robustness. Forced degrada- 7 6 tion studies were performed on the drug substance and O 4 drug products to show the stability-indicating nature of the method [7-13]. These studies were performed in ac- F cordance with established ICH guidelines [14-15]. (b) pregna-1, 4-diene-3, 20-dione, -6, 9-difluoro-11, 16, 17, 21- tetrahydroxy-, (6α, 11β, 16α)-. Molecular weight: 412.42. 2. Experimental Imp-2 OH H3CO 2.1. Chemicals 22 21 24 Samples of fluocinonide and its related impurities were 19 20 O 12 23 received from Versapharm Incorporated, Warminister, HO 17 O PA, USA. (Figure 1). All of the impurities and the fluo- 11 13 18 25 cinonide standard were of > 90% purity and are as fol- 16 O lows:-, fluocinonide (99.6%), imp-1 (95.9%), imp-2 1 9 2 8 14 (99.3%), imp-3 (93.7%), imp-4 (99.5%) imp-5 (96.7%), 10 15 imp-6 (98.5%), imp-7 (97.8%) and imp-8 (99.2%). F 3 5 Commercially available fluocinonide ointment and fluo- 7 O 6 cinonide solution (LIDEX) were purchased for this study. 4 In addition, HPLC grade acetonitrile and methanol were F purchased from Merck, (Darmstadt, Germany). Analyti- (c) pregna-1, 4-diene-3, 20-dione, -6, 9-difluoro-11, 21-dihydroxy- cal reagent grade sodium dihydrogen phosphate mono- 21methoxy-16, 17-[(1-methylethylidene)bis(oxy)]-(6α, 11β, 16α) Mo- hydrate, phosphoric acid and acetic acid were purchased lecular weight: 482.51. Copyright © 2010 SciRes. AJAC P. SRINIVASU ET AL. 115 Imp-3 Imp-6 O OH O 21 22 23 23 21 19 20 O 25 22 19 20 HO 12 17 O O 12 24 HO 17 O 18 11 13 16 24 O 11 13 18 16 26 1 9 O 1 9 2 8 14 10 15 8 14 2 15 F 10 3 5 F 6 7 3 5 7 O 6 4 O 4 F F (d) pregna-1, 4-diene-3, 20-dione, -6, 9-difluoro-11, 21-dihydroxy-16, (g) pregna-1, 4-diene-3, 20-dione, 21-(acetyloxy)-6, 9-difluoro-11- 17-[(1-methylethylidene)bis(oxy)]-, (6β, 11β, 16α)-. Molecular weight: hydroxy-16, 17-[(1-methylethylidene)bis(oxy)]-, (6β, 11β, 16α)-. Mo- 452.49. lecular weight: 494.52. Imp-7 Imp-4 O OH O 21 22 23 23 21 19 20 O 25 22 19 20 12 17 O O 12 24 11 HO 17 O 18 O 13 16 24 O 11 13 18 16 26 1 O 1 9 8 14 9 2 14 10 15 2 8 10 15 3 5 F 6 7 3 5 O 4 7 4 O 6 F F (e) pregna-1, 4-diene-3, 20-dione, -6-fluoro-9, 11 epoxy, -21- (h) pregna-1, 4-diene-3, 20-dione, 21-(acetyloxy)-4, 9-difluoro-11- hydroxy-16, 17-[(1-methylethylidene)bis(oxy)]-, (6α, 11β, 16α)-. Mo- hydroxy-16, 17-[(1-methylethylidene)bis(oxy)]-, (4α, 11β, 16α)- Mo- lecular weight: 432.48. lecular weight: 496.54. Imp-8 Imp-5 O OH O 21 23 21 19 20 O 25 22 19 20 HO 12 17 O O 12 24 HO 17 O 18 11 13 16 24 O 11 13 18 16 26 1 9 O 8 14 1 9 2 15 10 2 8 14 F 10 15 3 5 F 6 7 3 5 7 O 6 4 O 4 Cl Cl (f) pregna-1, 4-diene-3, 20-dione, -6 chloro, 9-fluoro-11, 21-dihydroxy- (i) pregna-1, 4-diene-3, 20-dione, 21-(acetyloxy)-6-Chloro, 9-fluoro- 16, 17-[(1-methylethylidene)bis(oxy)]-, (6α, 11β, 16α)-. Molecular 11-hydroxy-16, 17-[(1-methylethylidene)bis(oxy)]-, (6α, 11β, 16α)-. Mo- weight: 468.94. lecular weight: 510.18. Copyright © 2010 SciRes. AJAC 116 P. SRINIVASU ET AL. Degradation (Base degradation) impurity at RRT 0.54 2.3. Chromatographic Conditions O O A Waters symmetry C18 250 mm × 4.6 mm, 5 µm col- 22 21 umn was used with a mobile phase containing a gradient 23 of solvents A and B.
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