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“DEVELOPMENT OF NEW ANALYTICAL METHODS AND THEIR VALIDATION FOR THE DETERMINATION OF METOCLOPRAMIDE HYDROCHLORIDE AND LORATADINE IN BULK AND MARKETED FORMULATIONS” MASTER OF PHARMACY DISSERTATION PROTOCOL SUBMITTED TO THE RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE BY SOLANKI MEGHABEN JAGDISHBHAI Under The Guidance of DR. E.V.S. SUBRAHMANYAM. M.PHARM. Ph.D P.G. DEPARTMENT OF QUALITY ASSURANCE, SRINIVAS COLLEGE OF PHARMACY, MANGALORE – 574143 2011 – 2013 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA ANNEXURE – II REGISTRATION OF SUBJECT FOR DISSERTATION 1.0 NAME OF THE CANDIDATE SOLANKI MEGHABEN JAGDISHBHAI ADDRESS DEPARTMENT OF Q.A., SRINIVAS COLLEGE OF PHARMACY, VALACHIL,POST PARENGIPETE, MANGALORE TQ-574143 2.0 NAME OF THE INSTITUTION SRINIVAS COLLEGE OF PHARMACY, VALACHIL, MANGALORE. COURSE OF STUDY & MASTER OF PHARMACY SUBJECT (QUALITY ASSURANCE) 4.0 DATE OF ADMISSION 31st OCTOBER,2011 5.0 TITLE OF THE TOPIC: 3.0 “DEVELOPMENT OF NEW ANALYTICAL METHODS AND THEIR VALIDATION FOR THE DETERMINATION OF METOCLOPRAMIDE HYDROCHLORIDE AND LORATADINE FORMULATIONS” IN BULK AND MARKETED 6.0 BRIEF RESUME OF THE INTENDED WORK: 6.1 NEED FOR STUDY: Analytical Method Development for Pharmaceutical Formulations: Analytical methods are essential to characterize drug substances and drug products composition during all stages of pharmaceutical development. For routine analytical purpose it is always necessary to establish methods capable of analyzing large number of samples in a short time period with high accuracy and precision The number of drugs, which may be either new entities or partial structural modification of the existing ones, introduced into the market is increasing every year. Very often there is a time lag from the date of introduction of a drug into the market to the date of its inclusion in pharmacopoeias. Hence, standards and analytical procedures for these drugs may not be available in the pharmacopoeias. It becomes necessary, therefore to develop new analytical methods for such drugs. These products can present challenges to the analytical chemist responsible for the development and validation of analytical methods. Basic criteria for new method development of drug analysis: The drug or drug combination may not be official in any pharmacopoeias. A proper analytical procedure for the drug may not be available in the literature due to patent regulations. Analytical methods may not be available for the drug in the form of a formulation due to the interference caused by the formulation excipients. Analytical methods for a drug in combination with other drugs may not be available. The existing analytical procedures may require expensive reagents and solvents. It may also involve cumbersome extraction and separation procedures and these may not be reliable. Analytical method development provides the support to track the quality of the product from batch to batch. Estimation can be performed by the following two methods: Titrimetric methods and Instrumental methods. Spectrophotometric Methods Chromatographic Methods Methods for analyzing drugs in dosage forms can be developed, provided one has knowledge about the nature of the sample, its molecular weight, polarity, ionic character and the solubility parameter. Method development involves considerable trial and error procedures. The most difficult problem usually is where to start, what type of column is worth trying with what kind of mobile phase. Method development scheme for a typical HPLC-UV related substance describe below. 1. To define the goals for method development (e.g., what is the intended use of the method?), and to understand the chemistry of the analytes and the drug product. 2. To develop preliminary HPLC conditions to achieve minimally acceptable separations. These HPLC conditions will be used for all subsequent method development experiments. 3. To develop a suitable sample preparation scheme for the drug product 4. To determine an appropriate standardization method and the use of relative response factors in calculations. 5. To identify the “weaknesses” of the method and optimize the method through experimental design. Understand the method performance with different conditions, different instrument set ups and different samples. 6. To complete method validation according to ICH guidelines as mentioned in Q2 (R1). 6.2 A BRIEF INTRODUCTION ABOUT METOCLOPRAMIDE HYDROCHLORIDE[1] MOLECULAR STRUCTURE: IUPAC NAME: 4-amino- 5-chloro-N-(2-(diethylamino)ethyl)-2- methoxybenzamide Hydrochloride MOLECULAR FORMULA: C14H22ClN3O2·HCl MOLECULAR WEIGHT: 336.26 g/mol CATEGORY: Antiemetic and gastroprokinetic agent PHYSICAL APPEARANCE: white, crystalline, odourless powder SOLUBILITY: very soluble in water, freely soluble in alcohol, sparingly soluble in methylene chloride MELTING POINT: 147˚C (297˚F) BIOAVAILABILITY: 80±15%(oral) PROTEIN BINDING : 30% METABOLISM: Hepatic HALF-LIFE: 5 to 6 Hours EXCRETION: 70-85% renal, 2% faecal ROUTE: Oral, Intravenous, Intramuscular PHARMACOLOGY:[1] MEDICAL USES: Metoclopramide hydrochloride is commonly used to treat nausea including that which is due to chemotherapy and that occurring post operatively. Evidence also supports its use for gastroparesis (poor stomach emptying) and gastroesophageal reflux disease. Antiemetic: Metoclopramide hydrochloride commonly treats nausea and vomiting associated with conditions such as uremia, radiation sickness, malignancy, labor, infection, migraine headaches, and emetogenic drugs. In the setting of painful conditions such as migraine headaches, Metoclopramide hydrochloride may be used in combination with paracetamol (acetaminophen) (available in the UK as Paramax, and in Australia as (Metomax) or in combination with aspirin (Migramax). Gastroprokinetic: Metoclopramide hydrochloride increases peristalsis of the jejunum and duodenum, increases tone and amplitude of gastric contractions, and relaxes the pyloric sphincter and duodenal bulb. These gastroprokinetic effects make Metoclopramide useful in the treatment of gastric stasis (e.g. after gastric surgery or diabetic gastroparesis ), as an aid in gastrointestinal radiographic studies by accelerating transit through the gastrointestinal system in barium studies, and as an aid in difficult intubation of the small intestine. It is also used in gastroesophageal reflux disease (GERD). Other Indications: By inhibiting the action of dopamine, Metoclopramide hydrochloride has sometimes been used to stimulate lactation. It can also be used in the treatment of migraines in the setting of allodynia, where it is more effective than triptans. Veternary Use: Metoclopramide hydrochloride is also use in animals. It is commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits. MECHANISM OF ACTION: Metoclopramide hydrochloride appears to bind to dopamine D2 receptors where it is a receptor antagonist, and is also a mixed 5-HT3 receptor antagonist / 5HT4 receptor agonist. The antiemetic action of Metoclopramide hydrochloride is due to its antagonist activity at D2 receptors in the chemoreceptor trigger zone (CTZ) in the central nervous system (CNS)this action prevents nausea and vomiting triggered by most stimuli. At higher doses, 5-HT3 antagonist activity may also contribute to the antiemetic effect. The gastroprokinetic activity of Metoclopramide hydrochloride is mediated by muscarinic activity, D2 receptor antagonist activity and 5-HT4 receptor agonist activity. The gastroprokinetic effect itself may also contribute to the antiemetic effect. Metoclopramide hydrochloride also increases the tone of the lower esophageal sphincter. ADVERSE EFFECTS: Common adverse drug reaction (ADRs) associated with Metoclopramide hydrochloride therapy include restlessness, drowsiness, dizziness, fatigue, and focal dystonia. Infrequent ADRs include hypertension, hypotension, hyperprolactinaemia, leading to galactorrhea, constipation, depression, headache, and extrapyramidal effects such as oculogyric crisis. Rare but serious ADRs associated with therapy include agranulocytosis, supraventricular tachycardia, hyperaldosteronism, neuroleptic malignant syndrome, akathisia and tardive dyskinesia. Recent research suggests that Metoclopramide hydrochloride may be the most common cause of drug-induced movement disorders. The risk of extrapyramidal effects is increased in people under 20 year of age and with high dose of prolonged therapy. Tardive dyskinesia may be persistent and irreversible in some patients. The majority of reports of tardive dyskinesia occur in people who have used Metoclopramide hydrochloride for more than three months. Consequently, the USFDA recommends that Metoclopramide hydrochloride be used for short term treatment, preferably less than 12 weeks. In 2009, the USFDA required all manufacturers of Metoclopramide hydrochloride to issue a black box warning regarding the risk of tardive dyskinesia with chronic or high-dose use of the drug. Dystonic reactions may be treated with benztropine, diphenhydramine, trihexyphenidyl or procyclidine. CONTRAINDICATIONS AND PRECAUTION: Metoclopramide hydrochloride is contraindicated in phaeochromocytoma. It should be used with caution in Parkinson’s disease since, as a dopamine antagonist, it may worsen symptoms. Long-term use should be avoided in patients with clinical depression as it may worsen mental state. Also contraindicated with a suspected bowel obstruction. Use in pregnancy: Metoclopramide hydrochloride has long been used in all stages of pregnancy with no evidence of harm to the mother or unborn baby. A large cohort study of babies born to Israeli women exposed to Metoclorpamide hydrochloride during pregnancy found no evidence that the drug increases the risk of congenital malformations, low birth weight, preterm birth, or perinatal mortality. Metoclopramide hydrochloride is excrete into milk. 6.3 REVIEW OF LITERATURE: A literature survey was carried out for the estimation of Metoclopramide hydrocloride in bulk and marketed dosage forms. It was found that a very few methods have been reported for this drug. The collection of references are reproduced below: 1. Hosakere D. Revanasiddappa and Malligere A. Veena[2] have developed sensitive spectrophotometric determination of Metoclopramide hydrochloride and Dapsone in bulk sample and dosage forms. The method is based on the diazo – coupling reaction of the studied drugs with a new coupling agent, imipramine hydrochloride, in an acid medium. The resulting violet – colored azo dyes exhibit maximum absorption at 570 nm for both Metoclopramide hydrochloride and Dapson. 2. N. P. Dudhane, M. J. Umekar, R. T. Lohiya,[3] have developed a validated RPHPLC method for estimation of Metoclopramide hydrochloride and Paracetamol in solid dosage form. RP-HPLC estimation of drugs in selected combination was done using Phenomenex ODS 5μ, C18 column (250×4.6mm) and Acetonitrile: Methanol: (0.5%) TEA Buffer (18.5:6.5:75) as mobile phase which shows sharp and resolved peak when detected at 273nm. 3. Dudhane N.P., Vidhate S.S., Borkar B.H., Lohiya R.T., Umekar M.J[4]. have developed simultaneous UV spectrophotometric estimtion of Metoclopramide hydrochloride and Paracetamol in solid dosage form. Method I: Simultaneous Equation method, wavelengths selected were 243.0 nm and 273.5 nm for estimation of Metoclopramide hydrochloride (MET) and Paracetamol (PAR) respectively. Method II: Absorbance Ratio method, wavelengths selected were 243.0 nm, 262.0nm Isoabsorptive point of Paracetamol and Metoclopramid hydrochloride. Method III: Correction method,309.0 nm 4. Vinay Wamorkar, Manjunath S.Y., M.Mohan Varma[5], have done development and validation of UV spectroscopic method for determination of Metoclopramide hydrochloride in bulk and tablet formulation. Drug concentrations in various tests were determined spectrophotometrically (SL‐164 Double beam UV spectrophotometer, Elico, India.) at 272 nm using 1 cm quartz match cells. 5. Nawal. A. Al-Arfaj[6] determination of has developed flow-injection chemiluminescent Metoclopramide hydrochloride in pharmaceutical formulations and biological fluids using the [ru(dipy)32+]–permanganate system. The method is based on the CL reaction of Metoclopramide with Ru(dipy)32+ and KMnO4 in a sulfuric acid medium. Under the optimum conditions, a calibration graph was obtained over the concentration range 0.005–3.5 _gml−1 with a limit of detection (S/N = 2) of 1 ngml−1. The correlation coefficient was 0.99993 (n = 8) with a relative standard deviation of 0.48% for 10 determinations of 1 _gml−1 of drug. The method was successfully applied to the determination of Metoclopramide in pharmaceutical preparations and biological fluids after IP administration of 25 mg kg−1 dose to rats. The elimination half-life was 2.5 ± 0.4 h. 6. Ahmad Khan, Syed Baqir Shyum Naqvi, Muhammad Harris Shoaib, Rabia Ismail Yousaf, Jallat Khan, Muhammad Hanif and Asadullah Madni [7] have done validation and application of RP-HPLC method for the quantification of Metoclopramide hydrochloride in oral formulations prepared for IVIVC studies. A reverse chromatographic method was used with the mobile phase of Acetonitrile, 20m M.Potassium dihydrogen phosphate buffer solution (pH 3 adjusted with orthophosphoric acid) in the ratio of 40:60.The column used was Waters C18 3.9×300mm μBondapak (RP). The flow rate of the mobile phase was 2ml/minute. The detector was set at the wavelength of 275nm. 7. S R Patel, Dr. L J Patel[8] have done development and validation of first derivative spectroscopy method for simultaneous determination of Ondansetron and Metoclopramide in combined dosage form. The first derivative spectroscopy was performed on a double beam UV Visible spectrophotometer using methanol as a solvent. Absorbances were recorded at 266 nm (ZCP of ONDA) and 253 nm (ZCP of METO) for Metoclopramide hydrochloride and Ondancetron, respectively. 8. Gaikwad Shubhangee, Kondawar Manish, Nazarkar Swapnil, Phase Sheetal and Narkhede Harshal[9] have developed RPHPLC method for the simultaneous determination of Metoclopramide hydrochloride and Paracetamol in tablet dosage form. The method was carried out on a HiQsil C8, (4.6×250mm) column with a mobile phase consisting of acetonitrile:acetate buffer (pH 6.78) (50:50v/v) at a flow rate of 1ml/min. Detection was carried out at 308 nm. The retention time of Paracetamol and Metoclopramide hydrochloride was 3.2 and 5.5 min respectively. 6.4 A BRIEF INTRODUCTION ABOUT LORATADINE[10][11] MOLECULAR STRUCTURE: IUPAC NAME: ethyl 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin11-ylidene)-1-piperidinecarboxylate MOLECULAR FORMULA: C22H23ClN2O2 MOLECULAR WEIGHT: 382.88 g/mol CATEGORY: H1 histamine antagonist ,drug used to treat allergies PHYSICAL APPEARANCE: white to off white powder SOLUBILITY: insoluble in water, soluble in acetone, alcohol and chloroform BIOAVAILABILITY: Almost 100% PROTEIN BINDING: 97-99% METABOLISM: Hepatic(CYP2D6 and 3A4 mediated) HALF LIFE: 8 Hours EXCRETION: 40% as conjugated metabolites into urine, similar amount into the feces ROUTES: ORAL PHARMACOLOGY:[11][12] MECHANISM OF ACTION: Loratadine competes with free histamine and exhibits specific, selective peripheral H1 antagonistic activity. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms (eg. nasal congestion, watery eyes) brought on by histamine. Loratadine has low affinity for chlolinergic receptors and does not exhibit any appreciable alpha-adrenergic blocking activity in-vitro. Loratadine also appears to suppress the release of histamine and leukotrienes from animal mast cell, and the release of leukotrienes from human lung fragments, although the clinical importance of this is unknown. ADVERSE EFFECTS: As a“non sedative” antihistamine, Loratadine causes less (but still significant, in some cases) sedation and psychomotor retardation than the older antihistamines because it penetrates the blood brain barrier to smaller extent. Although drowsiness is rare at the common 10 mg dose, patients should, nevertheless, be advised that it can occur and may affect performance of skilled task (eg. driving). Patients should also avoid the use of alcohol as it can increase the central nervous system depressing effects of Loratadine. Other possible side effects include headache and antimuscarinic effects such as urinary retention, dry mouth, blurred vision, and gastrointestinal disturbances. DRUG INTERACTIONS: Substances that act as inhibitors of the CYP3A4 enzyme such as ketoconazole, erythromycin, cimetidine and furanocoumarin derivates (found in grapefruit) lead to increased plasma levels of Loratadine. This had clinically significant effects in controlled trials of higher than usual doses of Loratadine (20 mg). Antihistamines should be discontinued approximately 48 hours prior to skin allergy tests since these drugs may prevent to diminish otherwise positive reactions to dermal activity indicators. CAUTION AND CONTRAINDICATIONS: Patients with severe hepatic (liver) disorders may need to start with a lower dose. No dose adaptation is necessary for elderly or renally impaired patients. Loratadine is usually compatible with breast feeding (classified category L-2 by the American Academy of Pediatrics). In the U.S., it is classified as category B in pregnancy, meaning that animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well controlled studies in pregnant women. 6.5 REVIEW OF LITERATURE: A literature survey was carried out for the estimation of Loratadine in bulk and marketed dosage forms. It was found that a very few methods have been reported for this drug. The collection of references are reproduced below: 1. Krishna Veni Nagappan, Meyyanathan SN, Rajinikanth B Raja, Suresh Reddy, Jeyaprakash MR, Arunadevi S Birajdar and Suresh Bhojraj[13] have developed RP-HPLC method for simultaneous estimation of Ambroxol Hydrochloride and Loratidine in pharmaceutical formulation. The method was carried out on a Phenomenex Gemini C18 (25 cm x 4.6 mm i.d., 5 μ) column with a mobile phase consisting of acetonitrile: 50mM ammonium acetate (50:50v/v) at a flow rate of 1.0 mL/min. Detection was carried out at 255 nm. Hydrochlorthiazide was used as an internal standard. 2. K Basavaiah and V S Charan[14] have developed spectrophotometric determination of Astemizole and Loratadine based on charge-transfer complex formation with chloranilic acid. The determination was based on the formation of charge transfer complexes between chloranilic acid as a p - acceptor and the studied drugs as n-donors in acetonitrile solvent. The spectra, various experimental parameters, composition and formation constant of the complexes were studied. The formation constant (K) values of CT complex with Astemizole were 0.9x103 and 1.06x103 calculated from Benesi-Hildebrand plot and from Turner and Anderson plot, respectively, whereas the corresponding values for Loratadine were 4.50x103 and 4.19x103, respectively. The charge-transfer complexes formed were found to absorb at 520 nm. 3. Georgeta Pavalache, Vasile Dorneanu And Antoanela Popescu[15] have developed validation of UV molecular absorption spectrophotomertric method for Loratadine determination. Loratadine and potassium tetraiodomercuriate form a macromolecule which can be detected by molecular absorption spectrometry in well determined working conditions: reaction environment, the optimal amount of reagent, time reaction. Detection wavelength was established at λ = 380 nm (at this wavelength the compound shows maximum absorption in methanol in comparison with maximum absorption Loratadine, which is at 288 nm). 4. Ilangovan Ponnilavarasan, Chebrolu.Sunil Narendra Kumar, And P.Asha [16] have developed simultaneous estimation of Ambroxol hydrochloride and Loratadine in tablet dosage form by using UV Spectrophotometric method. The method employs measurement of absorbance at two wavelengths, 308nm and 245nm, of Ambroxol and Loratadine respectively. Beer´s law obeyed in the concentration range of 10-50&g/ml and 10-50&g/ml for Ambroxol and Loratadine respectively. 5. F.J. Rupe´rez, H. Ferna´ndez, C. Barbas[17] have developed LC determination of Loratadine and related impurities. A HPLC method employing a Symmetry Shield RP8 column has been developed and validated for Loratadine and related compounds measurement, the last ones under the 0.1% level. The mobile phase consisted of methanol-buffer A (65:35, v/v), being buffer A: H3PO4 10 mM (H2O) brought up to pH 7.00 with triethylamine. UV detection was performed at 244 nm.. 6. Radhakrishna T., Narasaraju A.,Ramakrishna M.,Satyanarayana[18] studied high performance liquid chromatography (HPLC) and second derivative spectrophotometry for the simultaneous determination of Montelukast and Loratadine in pharmaceutical formulations, HPLC separation was achieved with a Symmetry C18 column and sodium phosphate buffer (pH adjusted to 3.7):acetonitrile (20:80, v/v) as eluent, at a flow rate of 1.0 ml/min. UV detection was performed at 225 nm. In the second-order derivative spectrophotometry, for the determination of Loratadine the zero-crossing technique was applied at 276.1 nm, but for Montelukast peak amplitude at 359.7 nm (tangent method) was used. Both methods were fully validated and a comparison was made for assay determination of selected drugs in formulations. 6.6 OBJECTIVES OF THE STUDY: In the proposed work, attempt shall be made : To develop a new instrumental method for estimation of Metoclopramide hydrochloride and Loratadine To develop a validated method according to ICH guidelines. To apply validated method for the estimation of Metoclopramide hydrochloride and Loratadine in pharmaceutical formulation. 7.0 7.1 Materials And Methods: All experiments will be carried out in the Department of Quality Assurance. Srinivas college of Pharmacy, Valachil, Mangalore. Pure sample of Metoclopramide hydrochloride and Loratadine will be procured from Industries involved in bulk manufacture of this drug. Dosage formulation will be procured from local market. The methods will be developed and validated in Q.A. lab of Srinivas college of Pharmacy. The methods will be first developed, then Validated as per ICH guidelines, then the method will be applied to the formulations. UV spectrophotometer Shimadzu-UV1700 with spectral band width of 2nm and 10nm and matched quartz shall be used for measuring absorbance for Metoclopramide hydrochloride and Loratadine solutions. Reagents supposed to use for the estimation. 3-methyl,2-benzothiazolinehydrazone,(MBTH) 1,10-phenanthroline, 4-amino phenazene, Para dimethyl amino benzaldehyde (PDAB) Folin Ciocaltaeau reagent In combinations 3-methyl 2-benzothiazoline hydrazine and cerric ammonium sulphate 3-methyl 2-benzothiazoline hydrazineand and ferric ammonium sulphate etc. can be used as reagents for Spectrophotometric method development. 7.2 Sources of data: References from library – Srinivas College of Pharmacy, Valachil, Mangalore. www.pharmainfo.net. www.google.com www.sciencedirect.com www.rxlist.com www.pubmed.com www.medline.com www.wikipedia.com 7.3 Does the study require any investigation to be conducted on patients or animals? No 7.4 Has the ethical clearance been obtained from your institution in case of 7.3 ? Not applicable 8.0 REFERENCES: 1. en.wikipedia.org/wiki/metoclopramide hydrochloride 2. Hosakere D. Revanasiddappa and Malligere A. Veena, sensitive spectrophotometric determination of Metoclopramide hydrochloride And Dapsone in Bulk Sample And Dosage Forms. ScienceAsia;2006;32:319-321 3. N. P. Dudhane, M. J. Umekar, R. T. Lohiya, a validated RP-HPLC method for estimation of Metoclopramide hydrochloride and Paracetamol in solid dosage form. JPR 2010, 3(12):3064-3066 4. Dudhane N.P., Vidhate S.S,. Borkar B.H., Lohiya R.T., Umekar M.J., simultaneous UV spectrophotometric estimtion of Metoclopramide hydrochloride and Paracetamol in solid dosage form.J. Pharm. Sci. & Res.2010;.2(1): 48-52 5. Vinay Wamorkar,Manjunath S.Y., M. Mohan Varma, development and validation of UV spectroscopic method for determination of Metoclopramide hydrochloride in bulk and tablet formulation. IJPRS, 2011; 3(3);171-174 6. Nawal. A. Al-Arfaj, flow-injection chemiluminescent determination of Metoclopramide hydrochloride in pharmaceutical formulations and biological fluids using the [ru(dipy)32+]–permanganate system, Talanta 2004;62: 255–263 7. Ahmad Khan, Syed Baqir Shyum Naqvi, Muhammad Harris Shoaib, validation and application of RP-HPLC method for the quantification of Metoclopramide hydrochloride in oral formulations prepared for IVIVC studies. Pak. J. Pharm. Sci.,2012January;25(1):135-140 8. S R Patel, Dr. L J Patel, development and validation of first derivative spectroscopy method for simultaneous determination of Ondansetron and Metoclopramide in combined dosage form. International Journal of Pharmacy and Pharmaceutical SciencesIJPRS 2011;3(4):85-88 9. Gaikwad Shubhangee, Kondawar Manish, Nazarkar Swapnil, Phase Sheetal and Narkhede Harshal, developed RPHPLC method for the simultaneous determination of Metoclopramide hydrochloride and Paracetamol in tablet dosage form. IJPLS 2010July;1(3):127-132 10. www.chemicalland21.com/lifescience/phar/LORATADINE.htm 11. en.wikipedia.org/wiki/loratadine 12. www.drugbank.ca/drugs/loratadine/DB00455 13. Krishna Veni Nagappan, Meyyanathan SN, Rajinikanth B Raja, Suresh Reddy, Jeyaprakash MR,Arunadevi S Birajdar and Suresh Bhojraj developed RP-HPLC method for simultaneous estimation of Ambroxol Hydrochloride and Loratidine in pharmaceutical formulation. Research J. Pharm. and Tech.2008 Oct-Dec;1(4):366369 14. K Basavaiah and V S Charan, Spectrophotometric determination of Astemizole and Loratadine based on charge-transfer complex formation with chloranilic acid. ScienceAsia 2002;28:359-364 15. Georgeta Pavalache,, Vasile Dorneanu and Antoanela Popescu, validation of UV molecular absorption spectrophotomertric method for Loratadine determination. Ovidius University Annals of Chemistry 2010;21(2): pp157-162, 16. Ilangovan Ponnilavarasan,Chebrolu.Sunil Narendrakumar, and P.Asha simultaneous estimation of Ambroxol hydrochloride and Loratadine in tablet dosage form by using UV spectrophotometric method.,Int J Pharma and Bio Sciences,2011 Apr-Jun;2(2):338-344 17. F.J. Rupe´rez, H. Ferna´ndez, C. Barbas.LC determination of Loratadine and related impurities. J. Pharm. Biomed. Anal.2002; 29:35–41 18. Radhakrishna T., Narasaraju A.,Ramakrishna M.,Satyanarayana studied high performance liquid chromatography (HPLC) and second derivative spectrophotometry for the simultaneous determination of Montelukast and Loratadine in pharmaceutical formulations.J Pharma Biomed Anal 2003;31:359368 9.0 SIGNATURE OF THE CANDIDATE 10.0 REMARKS OF THE GUIDE Solanki Meghaben Jagdishbhai Forwarded for Approval Dr. E.V.S. Subrahmanyam, 10.1 NAME AND DESIGNATION OF GUIDE Professor and Head, Dept of Quality Assurance 10.2 SIGNATURE Dr. E.V.S. Subrahmanyam, 11.0 HEAD OF THE DEPARTMENT Professor and Head, Dept of Quality Assurance 11.1 SIGNATURE 12.0 REMARKS OF THE PRINCIPAL Forwarded for approval Dr. Ramakrishna Shabaraya A. 12.1 SIGNATURE Principal, Srinivas college of pharmacy, Valachil, Mangalore