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A Novel Analytical Method for the Simultaneous Estimation of Remogliflozin and Metformin Hydrochloride by Uplc / Pda in Bulk and Formulation

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A Novel Analytical Method for the Simultaneous Estimation of Remogliflozin and Metformin Hydrochloride by Uplc / Pda in Bulk and Formulation TJPS-39699: ORIGINAL ARTICLE DOI: 10.4274/tjps.galenos.2020.39699 A NOVEL ANALYTICAL METHOD FOR THE SIMULTANEOUS ESTIMATION OF REMOGLIFLOZIN AND METFORMIN HYDROCHLORIDE BY UPLC / PDA IN BULK AND FORMULATION. APPLICATION TO THE ESTIMATION OF PRODUCT TRACES MOHANRAO TAMMISETTY1*, BALASEKHARA REDDY CHALLA 2, SRINIVASA BABU PUTTAGUNTA 3 1 Jawaharlal Nehru Technological University, Kakinada–533003, Andhra Pradesh, India. 2 Vagdevi college of Pharmacy, Gurajala-526415, Guntur (Dt.), Andhra Pradesh, India. 3 Vignan Pharmacy College, Vadlamudi, Guntur (Dt.), Andhra Pradesh, India. * Corresponding Author. proof MOHANRAO TAMMISETTY E-mail:[email protected] (M.R.T),Tel:+91-7997545957 orcid.org/0000-0002-2977-673X 04.03.2020 08.06.2020 1. ABSTRACT Selective and novel method has been optimized for evaluation of remogliflozin and metformin hydrochloride in bulk and formulation and cleaning samples by UPLC-PDA. The principle analytes were eluted with the conditions of mobile phase having the phosphate buffer (pH: 4.5): acetonitrile (60:40%, v/v) using the Spherisorb C18, 5 µ.m, 4.6 mm x 150mm analytical column with the 1.0 ml/min flow rate and 10 µl sample volume at 245 nm in photodiode array detector. The retention times of remogliflozin and metformin hydrochloride were 3.017 min and 5.011 min with the total run time of 8 min. The curve indicates correlation coefficient (r2) was superior by having the value 1.000 with linear range of 10 ng/ml- 100.0 ng/ml for remogliflozin and for metformin hydrochloride 50 ng/ml-500.0 ng/ml. The correlation coefficient (r2) for metformin hydrochloride found 1.000. The LOQ and LOD for the remogliflozin and metformin hydrochloride found 10 ng/ml and 50 ng/ml and 5 ng/ml and 10 ng/ml. The developed method was applied for the bulk and formulation and cleaning sample. Keywords: Remogliflozin, Metformin hydrochloride, Bulk drug, Formulation, Cleaning samples, UPLC-PDA. 2.uncorrected INTRODUCTION Remogliflozin etabonate (5-Methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3- yl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside) is a pro-drug of remogliflozin. It belongs to the class of glifozin category. Mainly this drug will use in the case of non-alcoholic steato hepatitis and type-2 diabetes. Remogliflozin inhibits the sodium-glucose transport proteins (SGLT), which are responsible for glucose reabsorption in the kidney. Metformin (N,N–Dimethylimido 1 dicarbonimidicdiamide). Metformin is used to lower the blood sugar in those with type 2 diabetes. It is also used on the polycystic ovary syndrome. Metformin is a dimethyl biguanide that reduces elevated blood glucose levels primarily through its effects on reducing hepatic glucose production and improving peripheral tissue sensitivity to insulin(3). Based on the literature survey there was no analytical method for this new formulation i.e. remogliflozin and metformin hydrochloride. There are several methods were developed for the other gliflozin drugs like dapagliflozin, empagliflozin, canagliflozin with other combination of gliptins like saxagliptin and linagliptin and with biguanides like metformin[4-20]. For the remogliflozin and metformin hydrochloride combination there was lack of sensitive analytical method for the identification and quantification in bulk and formulation. And there was no sensitive analytical method having the 10 ng/ml detectability to quantify the product traces of manufacturing area when the product change over. 3. MATERIALS AND METHODS Remogliflozin (Figure1), metformin hydrochloride (Figure 2) high purity acetonitrile (J.T.Baker, Phillipsburg, NJ, USA), water (Milli - Q system, Millipore, Bedford, MA, USA), potassium dihydrogen phosphate, sodium dihydrogen phosphate (Merck Pvt. Ltd, Worli, Mumbai), ortho phosphoric acid (Merck Pvt. Ltd, Worli, Mumbai). Formulation was provided by the Yountus Life Sciences, Andhra Pradesh, India. Preparation of standard solution Metformin hydrochloride and remogliflozin etabonate standards stock solution prepared by taking 25.38 mg and 126.92 mg in 25 ml volumetric flask then added 10 ml diluent andproof sonicated for 3 minutes. Then make up to 25 ml with the diluent. From the stock 25 ml taken 1 ml to 1000 ml volumetric flask and make up with the diluent. From 1000 ml taken 1 ml to 10 ml volumetric flask and make up to the mark with the diluent to get the 100 ng/ml of remogliflozin and 500 ng/ml of metformin hydrochloride. Preparation of Buffer (pH: 4.5) Precisely weighed 13.9 g of potassium dihydrogen phosphate and 35.04 g of disodium hydrogen phosphate and taken into 1000 ml beaker. Added 500 ml water and stirred with the glass rod up to complete dissolving the salts then make up to 1000 ml with water. Adjusted prepared buffer solution pH to 4.5 with the diluted ortho phosphoric acid. Preparation of mobile phase From the 1000 ml buffer taken 600 ml buffer in 1000 ml mobile phase bottle. Added 400 ml of acetonitrile to the buffer and degassed to prepare 1000 ml of mobile phase. Preparation of Diluent Prepared the diluent by taking 2000 ml of water in 4000 ml mobile phase bottle and added 2000 ml of methanol and degassed to get 4000 ml of diluent. Optimization of Chromatographic conditions:- After series of trials, the chromatographic conditions were accomplished with the buffer having the pH of 4.5 and acetonitrile (60:40% v/v) by utilizing the stationary phase Spherisorb C18, 5 µ.m, 4.6 mm x 150 mm to obtain the best peak shape. The remogliflozin and metformin hydrochloride separation was good at 245 nm with the column temperature 25°C and sample compartment temperature 10° C with the flow 1.0 ml/min with the sample volume 10µl. Assay Sample Preparation Taken one tablet (REMO-M) having remogliflozin 100 mg and metformin 500 mg into 1000 ml volumetric flask and dissolved in the diluent and make up to the 1000 ml. This preparation considered as stock solution. From the stock solution taken 1ml to 1000 ml volumetric flask and makeuncorrected up to the mark with the diluent to get 100 ng/ml of remogliflozin and 500 ng/ml of metformin hydrochloride. VALIDATION OF ANALYTICAL METHOD Validation was performed for the developed method with the stringent limit to prove the efficiency of this method [1-2]. 2 System suitability To verify the system producing the consistent results with the optimized method injected the standard for six times with the criteria of % RSD for retention time and area NMT 2.0%, theoretical plates NLT 3000 plates, tailing factor NMT 1.5 and resolution NLT 4. Selectivity To verify the method validation in terms of the selectivity and exactness injected triplicate preparations of 100 % concentration i.e. 100 ng/ml of remogliflozin and 500 ng/ml of metformin hydrochloride. Then injected one blank also to prove the method was not having the carryover issue. The limit for the specificity is, it should pass the system suitability criteria and there should not be RT shift for all the three preparations. Precision After passing the specificity and system suitability criteria the method was verified for the system precision and method precision with the limit of % RSD for the retention time and area NMT 2%. The intermediate precision was verified on the next day with another column by following the limit as % RSD for the retention time and area should be NMT 2%. Accuracy and Recovery To verify the method accuracy triplicate preparations were prepared at 80% and 100% and 120% level of 100 % concentration (100 ng/ml of remogliflozin and 500 ng/ml of metformin hydrochloride) by spiking the standard into the diluent. Calculated the recovery with the acceptance criteria 95-105%. Linearity proof The method linearity was verified with the five concentrations of 100% concentration as 10 ng/ml, 20 ng/ml, 50 ng/ml, 75 ng/ml, 100 ng/ml for the remogliflozin and 50 ng/ml, 100 ng/ml, 250 ng/ml, 375 ng/ml, 500 ng/ml for the metformin hydrochloride with the acceptance criteria of regression coefficient (R2) NLT 0.99. Robustness To verify the method efficiency when the minor changes happened in the optimized method parameters like mobile phase composition and column temperature and flow and buffer pH this parameter was performed with the criteria, it should pass the system suitability criteria. Lower level of Quantification By considering the 10% concentration of the target concentration injected the sample in to the system with the acceptance criteria S/N ration NLT 10. From the LOQ concentration injected the different concentration preparation to identify the detectability with the acceptance criteria 3:1 and minimum detectability five times out of six injections from the same concentration. Lower level of Quantification Precision LOQ precision verified with the limit NMT 2.0% for the RT and area. Assessment of stability of standard and Mobile phase The prepared mobile phase and standard preparations were verified up to 72 hours for the stability. Degradation Behavior To prove the developed method stability indicating method the formulation sample was subjected to aid and base and thermal, photo, peroxide degradation was carried with the aim of detection of degradants in the chromatogram. The acid degradation was carried by adding the 20ml of 0.1HCL to the stock solution and from that taken 1 ml to 1000 ml volumetric flask and make up to the mark. In the same way 1 N NaoH 2ml added in base degradation. In thermal degradation the sample was subjected to heat at 105° C for 3 hours and prepared the sample as per assay procedure, In photo degradation the sample exposed to UV light with the intensity not less than 2000 lux power for six hours and prepared the sample as per the assay procedure.For the peroxide degradation added H2O2 2uncorrected ml to the stock 1000 ml volumetric flask and taken one ml to 1000 ml and make up to the mark with the diluent and injected the sample.
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