Sultana N, Naveed S and Arayne MS (2013) Facile and Manifest Liquid Chromatographic Method for the Simultaneous Determination of Enalpril maleate and NSAIDs in API and Pharmaceutical Formulations Pharmaceutica Analytica Acta S2 004 http://dx.doi.org/10.4172/2153-2435.S2-004

Pharmaceutica Sultana et al., Pharm Anal Acta 2013, S2 http://dx.doi.org/10.4172/2153-2435.S2-004 Analytica Acta Research Article Open Access Facile and Manifest Liquid Chromatographic Method for the Simultaneous Determination of Enalpril Maleate and NSAIDs in API and Pharmaceutical Formulations Najma Sultana1, Saila Naveed2,3* and M Saeed Arayne1 Research Institute of Pharmaceutical Sciences Faculty of Pharmacy, University of Karachi, Karachi, Pakistan Jinnah University for Women, Karachi, Pakistan 3 Department of Chemistry, University of Karachi, Karachi, Pakistan 1 2 Abstract Patients diagnosed with hypertension are prescribed an large number of medications for appropriate therapy, increasing risk of side effects or drug interactions. Enalapril, ACE inhibitor is commonly used as a drug of choice for the treatment of hypertension. On the other hand, NSAIDs are generally used for the treatment of pain, fever and inlammation, particularly in arthritis. A simple, eficient, economical and least time consuming isocratic method for the simultaneous determination of enalapril (ENP) and non-steroidal anti-inlammatory drugs (lurbiprofen, diclofenac sodium, ibuprofen and mefanamic) in bulk, pharmaceutical formulations and human serum using high performance liquid chromatography (HPLC) has been developed and validated. ENP was separated from NSAIDs using a Purospher STAR C18 column (250×4.6 mm, 5 μm) and a mobile phase consisting of methanol, water (80:20, v/v, pH was adjusted by ortho phosphoric acid to 2.8 at a low rate of 1.8 mL min-1 and at ambient temperature. Efluents from the column were monitored at 225 nm. The retention time of ENP was 4.1 minute and that for lurbiprofen, diclofenac sodium, ibuprofen and mefanamic acid was 5.4, 5.9, 6.4 and 8.7 mins respectively. LLOD and LLOQ of enalapril were 0.7 and 2.2 ng ml-1 respectively and that of lurbiprofen, diclofenac sodium, ibuprofen and mefanamic were 0.24, 0.07, 0.1, 0.1 and 0.7, 0.2, 0.3 and 0.4 ng ml-1 respectively. The method was validated according to ICH guidelines. Linearity of the method was studied in the concentration range 2.5-100 µg mL-1 for ENP and 0.625-25 µg mL-1 for (NSAIDs) where it demonstrated good linearity with r=0.9995, 0.9979, 0.9995, 0.9967, 0.9967 and 0.9995 (n=6), respectively, recovery was >97.8%. The developed method may successfully be applied for the quantitative analysis of ENP and NSAIDs alone or in combination from raw materials, in bulk drugs, dosage formulations and in serum. Keywords: Enalpril maleate; Flurbiprofen; Diclofenac sodium; Ibuprofen, Mefenamic acid, RP-HPLC CH2CH2CHNHCH Introduction Enalapril maleate is chemically described as (S)-1-[N-[1(ethoxycarbonyl) -3-phenylpropyl]-L-alanyl] -L-proline, (Z)-2butenedioate salt (Figure 1) [1]. It is an ester prodrug which is hydrolyzed to pharmacologically active enalaprilate, a speciic competitive inhibitor of ACE, It inhibits the active sites of a zinc glycoprotein, the angiotensin converting enzyme (ACE) blocking the conversion of angiotensin I to angiotensin II, whose levels are elevated in patients with hypertension [2]. Hypertension and musculoskeletal are two common coexisting problems for which antihypertensive and analgesics as nonsteroidal anti-inlammatory drugs (NSAIDs) are most commonly prescribed together [3]. Over the last two decades, concern about probable drug interactions between NSAIDs and antihypertensive agents has been grown. Cases with hypertensive emergency have been reported ater taking NSAIDs in patients with previously well-controlled hypertension [4,5]. Various HPLC methods have been reported for estimation of enalapril maleate [6-7]. Several methods have also been reported for determination of NSAIDs [8-10]. Our research group has developed and validated simultaneous methods for the co-adminstered drugs as rosuvastatin with NSAIDs [11] and with alprazolam and diclofenac [12]. Lisinopril, captopril [13,14] and metformin [15] have also been simultaneously determined with NSAIDs. Sultana and Arayne et al., have also developed methods for the simultaneous determination of various co-administered drugs as calcium channel blockers with NSAIDS [16,17] and many other drugs [18-23] in raw materials, pharmaceutical formulations Pharm Anal Acta . CH3 CO COOCH2CH3 N COOH CHCOOH CHCOOH Enalapril AR R O C C Where R=H, CH3 or alkyl AR= aryl or Heteroaryl OH H aryl alkanoic acid Figure 1: Aryl alkanoic acid. *Corresponding author: Saila Naveed, Jinnah University for Women, Karachi, Pakistan, E-mail: saila117@yahoo.com Received May 06, 2013; Accepted May 25, 2013; Published May 27, 2013 Citation: Sultana N, Naveed S, Arayne MS (2013) Facile and Manifest Liquid Chromatographic Method for the Simultaneous Determination of Enalpril Maleate and NSAIDs in API and Pharmaceutical Formulations. Pharm Anal Acta S2: 004. doi:10.4172/2153-2435.S2-004 Copyright: © 2013 Sultana N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Pharmaceutical Formulations: Regulatory updates ISSN: 2153-2435 PAA, an open access journal Citation: Sultana N, Naveed S, Arayne MS (2013) Facile and Manifest Liquid Chromatographic Method for the Simultaneous Determination of Enalpril Maleate and NSAIDs in API and Pharmaceutical Formulations. Pharm Anal Acta S2: 004. doi:10.4172/2153-2435.S2-004 Page 2 of 5 and serum. All these developed and validated methods follow ICH guidelines [23] are economical, short time consuming and could be applied to quantitate drugs upto nano gram levels and thus ind applications not only in pharma industry but also in clinical and forensic laboratories as well as for pharmacokinetic studies. So keeping in mind the above facts and as no RP-HPLC method is reported for simultaneous estimation of enalapril and NSAIDs we made an attempt to develop and validate a simple economical and time efective method for the simultaneous quantiication of enalapril and four NSAIDs in raw material, pharmaceutical formulations and serum. As the LLOD is quite low and the drug could be detected in nano amounts in serum this method is applicable for clinical and forensic laboratories. concentrations of 2.5, 5, 10, 25, 50, 100 μg ml-1 of EM and 0.625, 1.25, 2.5, 6.25, 12.5 and 25 μg ml-1 of NSAIDs. Standard solutions (n=6) were injected through 20 μl loop system and chromatograms were obtained using 1.0 ml min-1 low rate. he eluent was monitored at 225 nm. Calibration curve was constructed by plotting average peak area against concentration and regression equation was computed, chromatogram is depicted in igure 2. Materials and Methods Sample preparation Chemicals and reagents To determine the content of the drugs in pharmaceutical formulations, 20 tablets of each formulation were powdered and an amount equivalent to 10 mg of EM and 2.5 mg of NSAIDs was transferred to 100 mL volumetric lask, 50 ml of mobile phase was added and the lask was kept in an ultrasonic bath for 10 mins. he resulting solutions were iltered through a 0.45 μm ilter paper and diluted to the desired concentration and analyzed for the drug content, chromatogram is depicted in igure 3. HPLC grade methanol and phosphoric acid were obtained from Merck, Germany. Enalapril was a git from Brooks Pharmaceutical Laboratories Pakistan. he NSAIDs used were diclofenac sodium from Yung Shin Pharmaceutical Ind. Co. Ltd, lurbiprofen and ibuprofen, Abbott Laboratories (Pakistan) Ltd and mefenamic acid from Parke Davis and Co. Ltd. Dosage forms of diclofenac sodium (Voren 50 mg), lurbiprofen (NSAID 100mg), ibuprofen (Brufen 200 mg) and mefenamic acid (Ponstan 250 mg) were purchased from the local pharmacy. All these drugs had an expiry of not less than one year at the time of study. Validation of the method he developed method was validated in terms of linearity, accuracy, speciicity, limit of detection, limit of quantiication, intra-day and inter-day precision and repeatability of measurement. mV 40 Instrumentation Two identical LC systems of two diferent labs were used for the separation in order to ensure ruggedness of the method. Shimadzu HPLC system consisted of LC-10 AT VP pump, DGU-14 AM on-line degasser, rheodyne manual injector itted with a 20 μL loop, and SPD10 A VP UV–VIS detector and a Purospher star C18 (5 µm, 25×0.46 cm) column was utilized for separation. Chromatographic system was integrated via Shimadzu model CBM-102 Communication Bus Module to P-IV computer loaded with CLASS-GC sotware (Version 5.03) for data acquisition and mathematical calculations. a b 20 c he mobile phase containing methanol: water (80:20), pH was adjusted to pH 2.5 with orthophosphoric and iltered through 0.45 micron membrane ilter and then ultrasonicated for 10 mins. he low rate was set to 1.0 ml min-1. 5 10 15 min Figure 2: A representative chromatogram of (a) enalapril (b) lurbiprofen (c) diclofenac sodium (d) ibuprofen and (e) mefanimic acid in raw material. mV Preparation of stock solutions Stock solutions of 100 μg mL-1 of enalapril, ibuprofen, lurbiprofen, diclofenac sodium and mefenamic acid were prepared individually by dissolving 10 mg of each drug in 100 mL volumetric lask using mobile phase as a diluent. Aliquots were diluted in the range of 0.62525 μg mL-1 for ibuprofen, diclofenac sodium, mefenamic acid and lurbiprofen and for enalapril 2.5-100 μg mL-1 for. hese solutions were stored at 20ºC, they were prepared once and analyzed daily for inter-day and inter-operator variations of the method, 20 µL of these solutions were injected into LC system and chromatographed. e 0 0 Chromatographic conditions d a 100 b c d e 0 Calibration curve Calibration curves were prepared by taking appropriate aliquots of standard EM and NSAIDs stock solutions in diferent 10 ml volumetric lask and diluted up to the mark with mobile phase to obtain inal Pharm Anal Acta 0 5 10 mn Figure 3: A representative chromatogram of (a) enalapril (b) lurbiprofen (c) diclofenac sodium (d) ibuprofen and (e) mefanamic acid in formulation. Pharmaceutical Formulations: Regulatory updates ISSN: 2153-2435 PAA, an open access journal Citation: Sultana N, Naveed S, Arayne MS (2013) Facile and Manifest Liquid Chromatographic Method for the Simultaneous Determination of Enalpril Maleate and NSAIDs in API and Pharmaceutical Formulations. Pharm Anal Acta S2: 004. doi:10.4172/2153-2435.S2-004 Page 3 of 5 Results and Discussion his work was designed to develop an isocratic method based on RP-HPLC separation combined with UV detection for ENP and NSAIDs assay in API and pharmaceuticals dosage formulations. he goal of this study was to develop a rapid, more accurate, precise, reliable, least time consuming HPLC method for the drugs individually as well as simultaneously. his analytical method was developed taking in account the therapeutic concentrations range and overdose concentrations range, has been validated and holds well for the determination of drug in raw materials and dosage formulations. Our research group has been involved in the developments of new and eicient RP-HPLC methods for the determination of drugs alone as well as simultaneous determination of co-adminstered drugs. As in these methods the drug could be quantitated upto nanogram levels so they can also be applied for clinical laboratories, serums as well as forensic medicines. To develop a precise, accurate and suitable RP- HPLC method for the simultaneous estimation of EM and NSAIDs, diferent mobile phases ratios (50:50, 60:40, 70:30, 80:20 v/v) of methanol: water were tried and the best selected mobile phase was 80:20 methanol: water. he pH of the mobile phase was adjusted with orthophosphoric acid and tried in the range 2 to 3 where the best tailing results were obtained with pH 2.8. he proposed chromatographic conditions were found to be appropriate for the quantitative determination. he short analysis time (<10 min) also enables its application in routine and qualitycontrol analysis of inished products. Method validation he proposed HPLC method was validated as per ICH guidelines [21]. Where speciicity, linearity, accuracy, precision, robustness and ruggedness were studied which were well in accordance to ICH guidelines. Speciicity: he peak purity of EM and NSAIDs was assessed by comparing the retention time (RT) of standard EM and NSAIDs. Good correlation was obtained between the retention time of standard and sample of EM and NSAIDs. Linearity: Linearity was studied by preparing standard solutions at diferent concentration levels. he linearity range for EM and NSAIDs was found to be 2.5- 100 μg ml-1 and 0.625-25 μg ml-1, respectively. he regression equation for EM and NSAIDs is given in table 1. Accuracy (Recovery studies): To check the degree of accuracy of the method, recovery studies were performed in triplicate by standard addition method at 80%, 100% and 120%. Known amounts of standard EM and NSAIDs were added to pre-analyzed samples and were subjected to the proposed HPLC method. Results of recovery studies are shown in table 2. Precision: Precision was evaluated by carrying out six independent sample preparations of a single lot of formulation. he sample solution was prepared in the same manner as described in sample preparation. Percentage relative standard deviation (%RSD) was found to be less than 2% for within a day and day to day variations, which proves that method is precise. Results are shown in table 3. Sensitivity: he lower limit of quantitation (LLOQ) of the method as signal/noise of enalapril, diclofenac acid, mefenamic acid, lurbiprofen and ibuprofen was found to be 2.2, 0.7, 0.2, 0.3 and 0.4 Pharm Anal Acta ng mL-1 respectively. Similarly a signal/noise of 3, a LOD of enalapril, diclofenac acid, mefenamic acid,lurbiprofen and ibuprofen was determined to be 0.7, 0.24, 0.07, 0.1 and 0.1 ng mL-1, respectively. Ruggedness: Ruggedness of this method was evaluated in two diferent labs with two diferent instruments. Lab 1 was in the Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy University of Karachi, while Lab 2 was in the Department of Chemistry, Faculty of Science, University of Karachi. he method did not show any notable deviations in results from acceptable limits. Robustness of method: To evaluate the robustness of the developed RP-HPLC method, small deliberate variations in the optimized method parameters were done. he efect of change in low rate, pH and mobile phase ratio on the retention time and tailing factor were studied. he method was found to be unafected by small changes like ± 0.1 change in pH, ± 0.1 change in low rate and ± 1 change in mobile phase (Table 4). Conclusion he proposed RP-HPLC method allows for accurate, precise and reliable measurement of EM and NSAIDs simultaneously in combined dosage form within a short time. he developed RP-HPLC method was found to be simple, rapid, selective, accurate, precise and economical for the concurrent estimation of drugs in multiple drugs therapy of EM and NSAIDs. he RSD for all parameters was found to be less than one, which indicates the validity of method and assay results obtained by this method are in fair agreement. he developed method can be used for routine quantitative simultaneous estimation of EM and NSAIDs in multicomponent pharmaceutical preparation as well as in clinical laboratories. LLOQ** (ngmL-1) Regression equation Conc. (µgmL-1) 0.7 2.2 A= 2340.4x +3022.3 2.5-100 0.24 0.7 A=9368.9x +5785.8 0.625-25 0.07 0.2 A=18339x + 10493 0.625-25 Flurbiprofen 0.9967 0.1 0.3 A=12964x + 4896.7 0.625-25 Ibuprofen 0.1 0.4 A=9171.4x + 4741 0.625-25 Drugs r2 Enalapril 0.9995 Diclofenac sodium 0.9995 Mefanimic acid 0.9967 0.9995 *Lower limit of detection, **Lower limit of quantiication Table 1: Regression statistics LLOD and LLOQ. Drugs Enalapril Diclofenac sodium Mefanamic acid Flurbiprofen Ibuprofen Pharmaceutical Formulations: Regulatory updates Conc %RSD 80% 0.01 % Recovery 99.96 100% 0.00 100.00 120% 0.00 99.98 80% 0.01 99.94 100% 0.00 100.09 120% 0.00 100.00 80% 0.00 100.03 100% 0.00 100.00 120% 0.00 100.00 80% 0.01 99.89 100% 0.00 99.97 120% 0.00 99.95 80% 0.01 99.85 100% 0.00 99.96 120% 0.00 99.96 Table 2: Accuracy in formulations. ISSN: 2153-2435 PAA, an open access journal Citation: Sultana N, Naveed S, Arayne MS (2013) Facile and Manifest Liquid Chromatographic Method for the Simultaneous Determination of Enalpril Maleate and NSAIDs in API and Pharmaceutical Formulations. Pharm Anal Acta S2: 004. doi:10.4172/2153-2435.S2-004 Page 4 of 5 Drugs Enalapril Diclofenac sodium Mefanamic acid Flurbiprofen Ibuprofen Conc. injected Inter-day µg mL−1 %RSD %Recovery Intra-day %RSD %Recovery 2.5 0.0073 99.93 0.08 99.9 5 0.0078 100.02 0.09 100.0 10 0.0019 100.06 0.07 100.1 25 0.001 100.17 0.062 100.2 50 0.0005 99.99 0.059 100.0 100 0.0002 100.10 0.089 1001.7 0.625 0.0121 99.88 0.095 99.9 1.25 0.0067 99.94 0.64 99.9 2.5 0.0017 99.99 0.098 100.0 6.25 0.0008 99.99 0.12 100.0 12.5 0.0004 99.99 0.89 100.0 25 0.0002 100.00 0.032 100.0 0.625 0.004 101.12 0.48 101.1 1.25 0.0039 100.03 0.098 100.0 2.5 0.001 100.01 0.089 100.0 6.25 0 99.91 0.5 99.9 12.5 0.0002 100.01 0.045 100.0 25 0 100.00 0 100.0 0.625 0.0077 99.87 0.09 99.9 1.25 0.0106 99.86 0.01 99.9 2.5 0.0014 99.97 0.089 100.0 6.25 0.0012 99.99 0.089 100.0 12.5 0.0004 99.97 0.58 100.0 25 0.0004 100.00 0.99 100.0 0.625 0.0133 99.72 0.98 99.7 1.25 0.0069 99.86 0.00689 99.9 2.5 0.002 100.03 0.08 100.0 6.25 0.001 99.93 0.9 99.9 12.5 0.0005 100.02 0.089 100.0 25 0.0002 100.00 0.04 100.0 Table 3: Inter day and intraday precision of enalapril and NSAIDs. Level K’ T (Rs) A: pH of mobile phase 2.0 -0.2 4.8 1.39 2.4 2.5 0 4.5 1.43 2.3 3.0 0.2 4.2 1.4 2.2 4.5 ± 0.3 1.43 ± 0.020 2.3 ± 0.1 Mean ± S.D (n=6) B: Flow rate (mLmin-1) 0.8 -0.2 4.1 1.45 2.32 1 0 4.2 1.45 2.36 1.2 0.2 4.4 1.42 2.37 4.3 ± 0.212 1.44 ± 0.015 2.36 ± 0.026 Mean ± S.D (n=6) C: Percentage of water in mobile phase (V/V) 25 -5 4.6 1.42 2.38 20 0 4.3 1.43 2.36 15 5 4.5 1.46 2.33 4.36 ± 0.070 2.36 ± 0.025 2.36 ± 0.025 Mean ± S.D (n=6) C: Wavelength (nm) 220 -5 4.5 1.42 2.38 225 0 4.3 1.43 2.36 230 5 4.4 1.45 2.32 4.3 ± 0.070 1.43 ± 0.015 2.36 ± 0.030 Mean ± S.D (n=6) K’= Capacity factors, N = Theoretical plates, T = Tailing factor Rs=Resolution Table 4: Robustness of the method. Pharm Anal Acta References 1. Sweetman SC (2005) Martindale: The Complete Drug Reference. (34thedn) Pharmaceutical Press, London & Chicago 900-901. 2. Dominic PI, Gerald SB (1987) Analytical Proiles of Drug Substances. Academic Press, New York, pages 207-243. 3. 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Pharmaceutical Formulations: Regulatory updates ISSN: 2153-2435 PAA, an open access journal Citation: Sultana N, Naveed S, Arayne MS (2013) Facile and Manifest Liquid Chromatographic Method for the Simultaneous Determination of Enalpril Maleate and NSAIDs in API and Pharmaceutical Formulations. Pharm Anal Acta S2: 004. doi:10.4172/2153-2435.S2-004 Page 5 of 5 21. Arayne MS, Sultana N, Tabassum A, Ali SN, Saila Naveed S (2012) Simultaneous LC determination of rosuvastatin, lisinopril, captopril and enalapril in API, formulations and human serum by liquid chromatography. Medicinal Chemistry Research. 22. Arayne MS, Sultana N, Zuberi MH, Siddiqui FA (2013) Simultaneous RP-HPLC method for thedDetermination of metformin, captopril, lisinopril and enalapril: Its applications indDosage formulations and in human plasma. Medicinal Chemistry Research. 23. International Conference on the Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) Q2B 1996 Validation of Analytical Procedures, Methodology. Submit your next manuscript and get advantages of OMICS Group submissions Unique features: Citation: Sultana N, Naveed S, Arayne MS (2013) Facile and Manifest Liquid Chromatographic Method for the Simultaneous Determination of Enalpril Maleate and NSAIDs in API and Pharmaceutical Formulations. Pharm Anal Acta S2: 004. doi:10.4172/2153-2435.S2-004 This article was originally published in a special issue, Pharmaceutical Formulations: Regulatory updates handled by Editor(s). 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