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Determination of Residual Dimethyl Sulfate in Methoxsalen Drug Substance by Pre-Column Derivatization with Static Headspace Gas Chromatography

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Determination of Residual Dimethyl Sulfate in Methoxsalen Drug Substance by Pre-Column Derivatization with Static Headspace Gas Chromatography International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 10, Issue 8, 2018 Original Article DETERMINATION OF RESIDUAL DIMETHYL SULFATE IN METHOXSALEN DRUG SUBSTANCE BY PRE-COLUMN DERIVATIZATION WITH STATIC HEADSPACE GAS CHROMATOGRAPHY AJIT ANERAO*, BHUSHAN PATIL, NITIN PRADHAN R and D centre (API), Wanbury Ltd., EL-16, TTC Industrial Estate, Mahape, Navi Mumbai 400710, India Email: [email protected] Received: 01 Jun 2018 Revised and Accepted: 12 Jul 2018 ABSTRACT Objective: Dimethyl sulfate has been highlighted as potential genotoxic and carcinogenic impurity. A sensitive Headspace gas chromatography (HS- GC) method with pre-column derivatization was developed and validated for the determination of dimethyl sulfate impurity in methoxsalen active pharmaceutical ingredient. Methods: HS-GC method on the column Agilent DB-5, 30m X 0.53 mm, film thickness 1.5 µm, with flame ionization detector (FID) was used. Derivatization reagent concentration, time of reaction and pH of the solution were optimized during method development. This analytical method was evaluated by performing method validation as per ICH guideline. Results: The proposed method was specific, linear, accurate, rugged and precise. The calibration curves showed good linearity over the on (LOD) and limit of quantification (L – concentration range of 0.5 μg/ml to 3.0 μg/ml and the correlation coefficient was 0.999. Method had very low limit of detecti Conclusion: TheOQ) developed 2.0 μg/g method and 5.0 wasμg/g demonstrated respectively. Accuracyto be accurate, was observed robust andwithin sensitive 98.1% for104.5%. the determination of dimethyl sulfate impurity in methoxsalen drug substance. Keywords: , Dimethyl sulfate, GC-HS, Derivatization, Validation Methoxsalen http://creativecommons.org/licenses/by/4.0/) © 2018 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license ( DOI: http://dx.doi.org/10.22159/ijpps.2018v10i8.27670 INTRODUCTION methods are found reported of estimation of dimethyl sulfate. Dimethyl sulfate is checked at workplace atmosphere by GC with electrolytic conductivity detector (sulphur mode) at trace level using Methoxsalen is a naturally occurring photoactive substance found in group of compounds known as psoralens or furocoumarins [1]. The workplace atmosphere by thin layer chromatography (TLC) method chemicalthe seeds nameof the oAmmi majus (Umbelliferae)-methoxy plant.- -furo It belongs [3,2-g] to[1] a- derivatizingstainless steel with Chromosorb 4- WHP column [13]. DMS is estimated at -one. It has an empirical formula of C12H O4 and a which is very high because TLC technique has limitations in f methoxsalen is 9 1 7H g mole 8 sensitivity point of nitrophenol.view [14]. Quantification The LOQ of DMS of dimethylis reported sulfate 40 ppm by benzopyran7 − anmolecular exogenous weight of 216.19 [2]. Photochemotherapy report suggests that solution stability and diluent study need to be irradiation(PUVA) is treatment [3-5]. involving the use of psoralen, like methoxsalen, opGCMS is reported by derivatizing with pentafluorobenzenethiol. This photosensitizer followed by ultraviolet A (UVA) trace level [15]. Few more methods are reported by extracting the The manufacturing process of methoxsalen is seven step syntheses. timized and mass detector is necessary- to-20]. get DMS sensitivity at by ion chromatography technique with conductivity detector is also used as methylating agent. It is used mainly for converting active- reportedDMS in a solventby separating and tested ionic by GCcompoundsMS [16 usingDMS quantificationAllsep anion In synthetic stage five a key raw material dimethyl sulfate (DMS) is hydrogen compounds such as phenols, amines and thiols to the exchange column [21]. Literature suggests that to achieve such a low corresponding methyl derivatives. Dimethyl sulfate is probably level of limit of quantification hyphenated techniques with . It is a sophisticated instruments like GC- tor or potent genotoxic chemical which can directly alkylate DNA both in LC with conductivity detector is required. It might hardly possible vitrocarcinogenic and in vivoto humans - so IARC classified DMS in Group 2A for quality control laboratory of pharmaceuticalMS or sulphur industry specific detecto perform genotoxicity, the presence of residual dimethyl sulfate in the testing routinely with GC- methoxsalen drug[6 substance8]. Because must of bethe controlledknown carcinogenicity as per European and maintenance of a mass detector is very high. So in present research, MS because of the cost and drug substance with flame ionization detector. Due to low sensitivity Medicines Agency (EMA), International Conference on ofanalytical FID, premethod-column is developed derivatization to quantify was thetried DMS to in methoxsalenachieve the “thresholdHarmonization of toxicological [9] and Food concern” and (TTC)Drug conceptAdministration for the limit(FDA) of quantification of analyte at trace level. The proposed analytical genoguidelines [10, 11]. EMA and FDA guidelines proposed the use of the method was validated as per International conference on harmonization guidelines ICH Q2-R1 [22]. day totoxic/carcinogenic the expected dose impurities. of drug The substance concentration in a gram limit, per in ppm,day. of genotoxic impurity in drug substance, is the ratio of TTC in μg per MATERIALS AND METHODS methoxsalen per day [1, 12], dimethyl sulfate must be limited to less Considering the recommended daily maximum dose of 0.070 g Method of analysis sensitive, accurate and robust analytical method. Instrumentation than 21.4 μg/g in drug substance. So it is necessary to develop -500 GC with headspace auto sampler and flame ). Dimethyl sulphate is not controlled in the ionization detector (FID) using Total Chrome Navigator software. Methoxsalen is official drug substance in United State ReferPerkin chromatographic Clarus parameters as per given in table 1. Pharmacopoeia (USP USP monograph [2]. During literature survey several analytical Anerao et al. Int J Pharm Pharm Sci, Vol 10, Issue 8, 84-89 Table 1: Chromatography parameter Column DB-5, 30m X 0.53 mm, Film Thickness: 1.5 µm Oven Temperature 40 °C 40 - - hold for 5 minute, DetectorOven Program Flame°C hold Ionization for 8.0 Detectormin, ramp (FID)1 at 5 °C/min to 100 °C hold for 0 minute, ramp 2 at 20 °C/min to 250 °C Detector temperature 220 °C Carrier Gas Nitrogen280 °C CarrierInjector Gas temperature pressure 5.0 psi Run Time 32.50 min Headspace Conditions Oven Temperature Sample Line Temperature 110 °C Transfer line Temp 12090 °C °C 3.0 min Headspace Pressure 0.2016 psi min WithdrawPressurize timetime 0.5 min ThermostatInject time time 30.0 min GC Cycle Time 46.0 min Chemical and reagents followed by two test preparations. Run the chromatograph for 32.5 min and record the chromatogram. The retention time of dimethyl GC columns used of Agilent DB-5 of a dimension 30 meters, internal sulfate derivative i.e. anisole is 15.0 min. diameter 0.53 mm with film thickness 1.5 µm. Agilent DB-1 of a dimension 30 meters, internal diameter 0.53 mm with film thickness Acceptance criteria for system suitability 3 µm. Agilent DB- internal diameter 0.53 mm with film thickness 3 µm. Anisole standard was procured 624 of a dimension 30 meters, should not be more than 15.0. % RSD of area of dimethyl sulfate peak in six replicate injections methyl sulfoxide from Rankem, phenol from CALCULATION from AVRA synthesis of purity 99.5%, dimethyl sulfate from Finar waterLtd. of was purity used 99.0%, in the di experimentation. Calculated the content of dimethyl sulfate in ppm by formula given Rankem, sodium hydroxide from Merck and purified HPLC grade below Solution preparation – Diluent preparation: phenol and 5.0 g of sodium hydroxide into 500 ml volumetric flask (peak area of DMS6 in sample peak area DMS in blank) × Conc. of std. and diluted up to the markAccurately with premixed weighed dimethyl and transferred sulfoxide: 10.7 Water g of in mg/ml x P x 10 – minute again sonicated for two minutes. This solution is used as (Avg. peak area of DMS in std. peak area of DMS in blank) × Conc. of diluent(1:1 v/v) for mixture. preparation It was of blank,sonicated standard for two solution minutes; and shaketest solution. for one sampleRESULTS in mg/ml x 100 Analytical method development Standard stock solution A: Accurately weighed and transferred 0.10 g of dimethyl sulfate standard into 100 ml volumetric flask containing 40 ml of diluent and diluted up to the mark with diluent, has no chromophores. For analysis of such a ultr- shake it for two minutes again sonicated for five minutes. volatileDimethyl compoundsulfate is a volatilegas chromatography compound of boiling (GC) pointis a188 ⁰Csuitable and technology. To quantify the analyte at parts per millionviolet (UV)(ppm) inactive levels, Note: 1) Diluent should be ready before weighing of dimethyl sulfate standard. the concentration of test solution is required more. If the large 2) After transfer of dimethyl sulfate standard to 100 ml volumetric term usage so head space technique is preferable over liquid flask immediately dilute up to the mark with diluent. quantity of test solutionity of flame is injected ionization on GC detector column itis may not spoilsufficient in long to detect dimethyl sulphate at such a low concentration. So to enhance Accurately transferred 1.0 ml of Standard stock solution B: theinjection. response Sensitiv of dimethyl sulphate it was decided to perform pre- standard stock solution A in to 100 ml volumetric flask, added column derivatization technique. Considering all above properties of diluent and diluted up to the mark with diluent. Shake and mix well. the compound and purpose of the requirement of method Standard stock solution C: Accurately transferred 5.0 ml of development, GC headspace pre-column derivatization method is standard stock solution B in to 25 ml volumetric flask, added diluent developed with FID after optimizing chromatographic parameters. and diluted up to the mark with diluent.
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