“DEVELOPMENT OF NEW ANALYTICAL METHODS FOR …



“DEVELOPMENT OF NEW ANALYTICAL   METHODS FOR QUANTITATIVE ESTIMATION OF A NEW DRUG”

M. Pharm. Dissertation Protocol

Submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka.

Bangalore.

by

NAMRATA BASNET

B. Pharm.

Under the guidance of

Dr. SYEDA HUMAIRA

M Pharm. Ph.D

P.G. Dept. of Quality Assurance.

[pic]

DEPARTMENT OF QUALITY ASSURANCE

LUQMAN COLLEGE OF PHARMACY, GULBARGA

2012-2013

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

| | | |

| |Name of the candidate And |NAMRATA BASNET |

| |address |Luqman college of pharmacy, |

| | |old jewargi road, |

| | |gulbarga-585102 |

| | | |

| |Name of the institution |Luqman college of pharmacy, old jewargi road, |

| | |gulbarga-585102 |

| | | |

| |Course of study and subject |m.PHARM |

| | |(QUALITY ASSURANCE) |

| | | |

| |Date of Admission of course |9-05-2012 |

| | | |

| |Title of the Topic: |“DEVELOPMENT OF NEW ANALYTICAL   METHODS FOR QUANTITATIVE ESTIMATION OF A NEW |

| | |DRUG” |

|6 |Brief Resume of the intended work: |

| |6.1 Need for study: |

| |Chemically Terbinafine Hydrochloride is (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1- naphthalenemethanamine hydrochloride. [1] [2] [3]. |

| |Terbinafine hydrochloride is a new potent orally and topically active drug of allylamine derivative with antifungal [4] activity. It is found to |

| |be potent inhibitor of squalene epoxidase, an important enzyme required in ergosterol biosysnhesis. The drug is indicated for both oral and |

| |topical treatment of mycoses [5][6][7]. The raw material of Terbinafine Hydrochloride is official in British Pharmacopoeia.[3]. |

| |Considering basic drugs capacity to generate ion-pairs with azoic dyes, there have been investigated the experimental conditions in order to |

| |develop new Spectrophotometric method for the assay of Terbinafine Hydrochloride in bulk and in dosage forms. Simple, rapid Spectrophotometric |

| |method and HPLC method may be useful for day to day routine analysis of the product. They are recommended for quality control and routine analysis|

| |where time, cost effectiveness and high specificity of analytical techniques are of great importance. Investigations of some new instrumental |

| |methods are in need for the quantitative estimation of Terbinafine Hydrochloride in bulk drug and its pharmaceutical dosage forms with high |

| |sensitivity, accuracy, precision and economic too. |

| |Few simple new validated analytical methods are required for the quantitative estimation of Terbinafine Hydrochloride in various pharmaceutical |

| |dosage forms. |

| | |

| |Review of Literature: |

| |Literature survey revealed that, chemically Terbinafine Hydrochloride is (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine |

| |hydrochloride.[1] [2] [3] |

| |Molecular formula- C21H26CIN HCl |

| |Molecular weight - 327.90 |

| |Characteristic -A white to off-white fine crystalline powder. |

| |Solubility -Freely soluble in methanol and dichloromethane, freely soluble in anhydrous ethanol, soluble in ethanol, slightly and very slightly |

| |soluble in water, and slightly soluble in acetone[2],[3],[4] |

| | |

| |Melting Point- 204°C to 208°C. [2] |

| | |

| |[pic] |

| | |

| |Chemical structure of Terbinafine Hydrochloride .[1] |

| |Literature Survey reveals that previously, the drug has been determined in various dosage forms using Spectrophotometric |

| |methods[8],[9],[10],11],[12],[13], Microbiological assay [14] in tablets and creams and by HPLC[15],[16],[17],[18]. HPTLC methods, RP-HPLC methods|

| |[19],[20][21] have also been developed. The drug has also been determined in biological fluids (plasma, urine), tissues, nails and hair by HPLC |

| |mathod [22],[23],[24].   |

| |1. Pritam S Jain, Amar J Chaudhari, Stuti A Patel, Zarana N Patel, Dhwani T Patel (2011)[8] |

| |had developed and validated UV-spectrophotometric method for determination of Terbinafine Hydrochloride in bulk and in formulation using water as |

| |the solvent. The spectrum was recorded at 283 nm. |

| | |

| |2. Marinela Florea, Crina-Maria Monciu,(2008)[9] had developed Spectrophotometric |

| |determination of Terbinafine through ion-pair complex formation with Methyl Orange . |

| | |

| |3. Abdel-Moety EM, Kelani KO, Abou al-Alamein AM (2003)[10] carried out |

| |Spectrophotometric methods for the quantitative determination of Terbinafine Hydrochloride in |

| |presence of its photodegradation products. The methods make use of the first spectral derivation |

| |(1D) and the first derivative of the ratio spectra (1DD) of the named drug and its photodegradants |

| |at different justified wavelengths. The proposed methods showed good linearity, precision and |

| |reproducibility. |

| | |

| |4. Karuna T., Neelima K., Venkateshwarlu G., Swamy P.Y.(2006)[11] had developed |

| |Spectrophotometric determination of drugs with iodine. |

| | |

| |5. Cardoso SG, Schapoval EE (1999)[12] had worked on Ultraviolet Spectrophotometric and a |

| |non aqueous volumetric method of analysis for determining Terbinafine Hydrochloride in |

| |pharmaceutical formulations.( raw materials, tablets, and creams) The method was tested for |

| |linearity (0.8-2.8 micrograms/mL, r = 0.9997), recovery (102.00% for creams and 99.90% for tablets) and precision (101.3%, CV = 0.96%, n = 9, for |

| |creams; 100.25%, CV = 1.08%, n = 9, for tablets). |

| |The volumetric method involves titration of Terbinafine with 0.05M Perchloric Acid with Crystal |

| |Violet as indicator. This method was used for quantitative determination of Terbinafine in raw |

| |materials and tablets. Mean recovery and precision were, respectively, 100.41 and 101.18% (CV = 1.64%, n = 9) for Terbinafine tablets. |

| | |

| | |

| |6. EL-Saharty YS, Hassan NY, Metwally FH:(2002)[13] had developed Simultaneous determination of Terbinafine Hydrochloride and Triamcinolone |

| |Acetonide by UV Derivative Spectrophotometry and Spectrodensitometry . A binary mixture of Terbinafine Hydrochloride and Triamcinolone Acetonide |

| |was determined by three different methods. The first one concerned with determination of both drugs using first derivative (D(1)) |

| |Spectrophotometric technique at 297 and 274 nm over concentration ranges of 5-30 and 4-24µg/ml, with mean percentage accuracies 99.90±0.67 and |

| |100.25±0.49, respectively. The second method depends on ratio-spectra 1st derivative (RSD(1)) Spectrophotometry at 298 and 248 nm over the same |

| |concentration ranges with mean percentage accuracies 100.22±0.51 and 99.93±0.56, respectively. |

| | |

| |7. Simone Goncalves Cardoso and Elfrides ES Schapoval (2000) [14] had developed Microbiological assay of Terbinafine Hydrochloride in tablet and |

| |cream applying Cylinder Plate method using strain of Aspergillus Flavous ATCC 15546 as the test organism., Terbinafine  Hydrochloride at |

| |concentrations ranging from 0.125 to 0.5 µg/ml could be measured in tablets and creams. |

| | |

| |Monika P. Tagliari; Gislaine Kuminek; Sílvia H. M. Borgmann; Charise D. Bertol; Simone G. Cardoso; Hellen K. Stulzer (2010)[15] had developed a|

| |simple Liquid Chromatographic method optimized for the quantitative determination of Terbinafine in pharmaceutical hydroalcoholic solutions and |

| |tablets, and was also employed for a tablet dissolution test. The analysis was carried out using a RP-C18 (250 mm × 4.6 mm, 5 μm) Vertical® |

| |column, UV-Vis detection at 254 nm, and a methanol-water (95:5, v/v) mobile phase at a flow-rate of 1.2 ml/ min. Validation parameters like |

| |linearity, precision, accuracy, robustness and specificity were investigated. |

| | |

| |9. Majumdar T. K., Bakthiar R., Tse F. L.(2000)[16] carried out a method for determination |

| |of Terbinafine (Lamisil) in human hair by microbore liquid chromatography / tandem mass |

| |spectrometry. |

| | |

| |10. Marinela Florea, Corina-Cristina (2009) [17] had developed an Ion-Pair Reversed Phase Liquid Chromatographic method (IP-RP-HPLC) for the assay|

| |of Terbinafine. A C18 column was used as stationary phase, and the mobile phase consisted of an aqueous acid solution. |

| | |

| |11. R Ramesh Raju, N Bujji Babu (2011) [18] had developed High Performance Reverse Phase Liquid Chromatographic method for Terbinafine and |

| |Bezafibrate using C 18 column. |

| | |

| |12. Suma, B,V., Kannan. K, Madhavan V., Chandini R Nayar (2011) [19] had developed and validated HPTLC method for development of Terbinafine in |

| |bulk and tablet dosage form using pre coated silica gel 60F 254 aluminium foil TLC plates as stationary phase. |

| | |

| |13. K.K Patel , V.V Karkhanis (2012)[20] had recently validated HPTLC method for determination |

| |of Terbinafine Hydrochloride The method had proved to be reproducible and selective for the |

| |analysis of Terbinafine Hydrochloride in bulk and in pharmaceutical dosage form. |

| | |

| |14. Patel Krupa K (2012) [21] had developed a validated RP-HPLC method for determination of |

| |Terbinafine Hydrochloride in pharmaceutical solid dosage form. Terbinafine Hydrochloride was chromatographed on a reverse phase C18 column with a|

| |mobile phase consisting of methanol: water in the ratio of 80:20% v/v. The mobile phase was pumped at a flow rate of 1ml/min. The detection is |

| |carried out at 282 nm. The retention time of the drug was 5.84 min. The linearity curved showed a correlation coefficient (r2) of 0.9974 with |

| |concentration range of 80-160μg/ml. The method was validated with respect to linearity, precision, accuracy and sensivity (LOQ and LOD). |

| | |

| |15. Denouel J, Keller HP, Schaub P, Delaborde C,Humbert H(1995)[22] had developed the |

| |method for determination of Terbinafine and its desmethyl metabolite in human plasma by |

| |high-performance liquid chromatography. |

| | |

| |16. Zehender H, Denouel J, Roy M, Saux L Le, Schaub P(1995)[23] developed simultaneous determination of Terbinafine (Lamisil®) and five |

| |metabolites in human plasma and urine by |

| |high-performance liquid chromatography using on-line solid-phase extraction |

| | |

| |17. Kuzne J, Kozuh Erzen N, Drobnic-Kosorok M(2001) [24] had developed the method for |

| |determination of the Terbinafine Hydrochloride Levels in Cat’s Plasma and Hair using a New |

| |developed Isocratic HPLC Method. |

| | |

| |6.3 Objective of the study: |

| |The objective of the present study is to develop an accurate, precise, selective sensitive and reproducible method to quantify Terbinafine |

| |Hydrochloride in bulk and pharmaceutical dosage forms. |

| |Litrature survey reveals a few Spectrophotometric methods for estimation of Terbinafine Hydrochloride but there may be chance of excipients |

| |interference. Certain groups present in the drug molecule when treated with chromogenic agent produce a colour. Therefore visible |

| |Spectrophotometric analysis is suitable for estimation. Of those cited in literature Spectrophotometric methods have been utilized for assay of |

| |drug in pharmaceutical dosage form. Hence on the basis of literature survey it was thought to develop a precise, accurate, simple, reliable, |

| |economical, sensitive, validated and less time consuming UV- Visible Spectrophotometric and Chromatographic methods for estimation of drugs in |

| |bulk and pharmaceutical dosage form. The objectives of the present work are: |

| |To develop validated analytical UV- Visible Spectrophotometric method for estimation of Terbinafine Hydrochloride in bulk drugs and various |

| |pharmaceutical dosage forms. |

| |To develop RP-HPLC method to estimate Terbinafine Hydrochloride in bulk drug and dosage forms. |

| | |

| |PLAN OF WORK |

| |The work has been planned to carry out on following lines: |

| |Estimation of Terbinafine Hydrochloride by UV Spectroscopy: |

| |By selecting some common solvents and studying the solubility of raw material and |

| |selecting the solvent. |

| |Study of Spectra and selection of method and wavelengths. |

| |Analysis of marketed formulation by proposed method. |

| |i. Terbinafine Hydrochloride is slightly soluble in water soluble in water, freely soluble in methanol, soluble in ethanol and a number of |

| |UV-Spectrophotometric methods can be developed by using buffer with acidic pH or organic solvents including chloroform for its quantitative |

| |estimation in bulk drug and pharmaceutical dosage forms.[8] |

| | |

| |Calorimetric methods for estimation of Terbinafine Hydrochloride. |

| |Selection of suitable solvent and reagents. |

| |Optimization of solvent system, reagent concentration etc. |

| |Selection of method and wavelength. |

| |Study of effect of pH, temperature, colour stability. |

| |Analysis of market formulation by proposed method. |

| | |

| |i. Since Terbinafine Hydrochloride contains tertiary amino group which is protonated in acid medium it can react with the dyes containing |

| |sulphonic groups. The dyes containing sulphonic groups dissociate in pH range 1-5. The protonated Terbinafine Hydrochloride forms ion complex with|

| |the dissociated dyes which may be quantified by extraction in chloroform by Visible Spectrophotometry. Considering basic drugs capacity to |

| |generate ion-pairs with azoic dyes, Spectrophotometric method for the assay of Terbinafine Hydrochloride in bulk and in dosage forms can be |

| |developed based on ion-pair formation..[25] |

| | |

| |ii. A number of organic acid anhydrides are capable of forming colored products with tertiary amines; malonic, citric, and aconitic acids are |

| |representative examples. A citric/acetic anhydrides can be used for the Spectrophotometric determination.[25] |

| | |

| |iii. The amino group present in the drug allows the oxidative coupling reaction with 3-methyl-2-benzothiazolinone hydrazone (MBTH) in presence |

| |of Ferric chloride / Cerric ammonium sulphate and forms colored chromogen (VI) by which drug can be estimated quantitatively by colorimetry. |

| | |

| | |

| | |

| | |

| |Estimation of Terbinafine by RP- HPLC |

| |The method involving following steps: |

| |1.Selection of mobile phase and wavelengths |

| |2. Selection of Chromatographic Conditions. |

| |3. Analysis of marketed formulation by the proposed method. |

| |RP- HPLC method can be developed by using either isocratic or gradient system with |

|7. |stationary phase of C18 or C8 column. |

| | |

| |7.1 Materials and Methods |

| |In the present investigation we are in need of following Materials: |

| |i. Raw Material: |

| |Working Standard of Terbinafine Hydrochloride, |

| |Raw material of Terbinafine Hydrochloride |

| |ii. Reagents: Water, Alcohol, Methanol, Dyes: Bromo Thymol blue, Bromo Cresol Purple. |

| |iii. Market samples of Terbinafine Tablets. |

| |iv. Instruments: |

| |Double Beam UV Visible Spectrophotometer, (1700) Shimadzu, Japan. |

| |High Performance Liquid Chromatography with pump. |

| |Chromatogrphic instruments and volumetric glass apparatus, Vacuum filter, Sonicator, Stirrer. |

| |Analytical Balance. |

| |All the above mentioned will be made available from Luqman College of Pharmacy, Gulbarga. |

| | |

| |7.2. Source of Data: |

| |Data will be obtained from |

| |i Pubmed , Science Direct Medline, and other internet facilities. |

| |ii Literature search and related articles from library of Luqman College of |

| |Pharmacy Gulbarga etc. |

| | |

| |Method of Collection of Data(Including Sampling Procedures if any) |

| |The research work that will be carry out in the laboratory by various experimental technique |

| |includes: |

| |Analysis of reference raw material and their physical constant, solubility, assay analysis data will be done. |

| |Spectroscopic data will be obtained for identification of the drug molecule compound. |

| |Data of estimation of reference raw material and market samples will be obtained spectrophotometrically and through HPLC graphs. |

| | |

| |Data Collected from |

| |Journals and articles: |

| |Journal of Pharmaceutical and Biomedical Analysis. |

| |Journal of AOAC International |

| |International Journal of Pharmacy and Technology |

| |Internet Browsing: |

| | |

| | |

| | |

| | |

| | |

| | |

| | |

| |The Drug sample will be collected from Panas Pharmaceutical Pvt. Ltd Nepal or from other reputed company. |

| | |

|8 | |

| |7.3 Does the study require any investigation or intervention to be conducted on patients or other |

| |humans ? if so please mention briefly. |

| | |

| |-NOT APPLICABLE |

| | |

| |7.4 Has ethical clearance been obtained from your institution in case of 7.3? |

| |-NOT APPLICABLE- |

| | |

| | |

| | |

| | |

| | |

| |List of References: |

| | |

| | |

| |Terbinafine Wikipedia, The free encyclopedia; |

| |British Pharmacopoeia 2012, Online, 2112. |

| | |

| | |

| |Budavari S. The Merck Index. 12 th ed. New Jersey, USA: Merck and Co., Inc., 1996, 1564.   |

| | |

| |Clinical Pharmacology/ Biopharmaceutics Review Nov.5 1999, Centre for Drug Evaluation and Research., Application Number 21-124 |

| | |

| |Martindale. The Complete Drug Reference. 32 nd ed. Great Britain: Council of Royal Pharmaceutical Society of Great Britain, 1999, 367-87. |

| | |

| |Delgodo JN, Remers WA. Wilson and Gisvold's, Text book of Organic Medicinal and Pharmaceutical Chemistry. 9 th ed. Philadelphia: J. B. Liipincott |

| |Company; 1991.145-53.   |

| | |

| |Pritam S, Jain, Amar J Chaudhari, Sruti A Patel, Zarana N Patel, Dhwani T Patel, Development and Validation of the UV- Spectrophotometric method |

| |for determination of Terbinafine Hydrochloride in bulk and in formulation. 2011, 2, ( 3),198-202. |

| | 2011/2/3/198/9364. |

| | |

| |Marinela Florea, Crina-Maria Monciu: Spectrophotometric Determination Of Terbinafine Through Ion-Pair Complex Formation With Methyl Orange, |

| |Farmacia, 2008, LVI, (4), 393. |

| | |

| |Abdel-Moety EM, Kelani KO, Abou al-Alamein AM: Spectrophotometric determination of Terbinafine in presence of its Photodegradation products. |

| |Boll Chim Farm 141 (4), 267-73(2003)PMID12426813. |

| | |

| | |

| |Karuna T., Neelima K., Venkateshwarlu G., Swamy P.Y., Spectrophotometric determination of drugs with iodine, Journal of Scientific & Industrial |

| |Research, 2006, 65(10), 808-811. |

| | |

| |Cardoso SG, Schapoval EE. UV Spectrophotometry and non aqueous determination of Terbinafine Hydrochloride in dosage forms. J AOAC Int |

| |1999,82:380-3.   |

| | |

| |EL-Saharty YS, Hassan NY, Metwally FH: Simultaneous determination of Terbinafine Hydrochloride and Triamcinolone Acetonide by UV derivative |

| |Spectrophotometry and Spectrodensitometry , Journal of Pharmaceutical and Biomedical Analysis, 2002 28, ( 3-4), 569-580. |

| | |

| |Simone Goncalves Cardoso and Elfrides ES Schapoval (2000); Microbiological assay for Terbinafine Hydrochloride in tablet and cream, International |

| |Journal of Pharmaceutics 203(2000), 109-113 |

| | |

| |Monika P. Tagliari; Gislaine Kuminek; Sílvia H. M. Borgmann; Charise D. Bertol; Simone G. Cardoso; Hellen K. Stulzer ;Terbinafine : Optimization|

| |of a LC method for quantitative analysis in Pharmaceutical formulations and its application for a tablet dissolution test. Quim, Nova, Sao Paulo,|

| |2010, 33, (8). |

| | |

| |Majumdar TK, Bakhtiar R, Melamed D, Tse FL Determination of Terbinafine (Lamisil) in human hair by Microbore Liquid Chromatography/tandem Mass |

| |Spectrometry. Rapid Commun Mass Spectrom. 2000, 14(14),1214-9. |

| | |

| |Marinela Florea, Corina-Cristina Aramă, Crina-Maria Monciu : Determination of Terbinafine Hydrochloride by ion pair reverse phase liquid |

| |chromatography, Farmacia 2009, L VII,1. |

| | |

| |R. Ramesh Raju, N Bujji Babu : Simultaneous analysis of RPHPLC method development and validation of Terbinafine and Bezafibrate drugs in |

| |pharmaceutical dosage forms. Pharmacophore ( An international Research Journal) 2011, 2 (4), 232-238. |

| | |

| |Suma B.V, Kannan. K, Madhavan V., Chandini R. Nayar; HPTLC method for determination of Terbinafine in the bulk and tablet dosage form; |

| |International Journal of Chem. Tech. Research. CODEN (USA); IJCRGG ISSN: 0974-4290, 2011 3 (2), 742-748,. |

| | |

| |K.K Patel , V.V Karkhanis ; A validated HPTLC method for determination of Terbinafine |

| |Hydrochloride in pharmaceutical solid dosage form. International journal of Pharmaceutical |

| |Sciences and Research, UPSR 2012,3 (11), 4492-4495. |

| | |

| | |

| | |

| |21. Patel Krupa K; A validated RP-HPLC method for determination of Terbinafine |

| |Hydrochloride in pharmaceutical solid dosage form. International Journal Of |

| |Pharmacy &Technology IJPT , 2012 , 4 ,(3) , 4663-4669 |

| | |

| | |

| |22. Denouel J, Keller HP, Schaub P, Delaborde C,Humbert H: Determination of Terbinafine |

| |and its desmethyl metabolite in human plasma by High-Performance Liquid |

| |Chromatography. Journal of Chromatography B: Biomedical Sciences and Applications |

| |1995, 663(2), 353-359. |

| | |

| | |

| |23. Zehender H, Denouel J, Roy M, Saux L Le, Schaub P: Simultaneous determination of Terbinafine (Lamisil®) and five metabolites in human plasma |

| |and urine by High-Performance Liquid Chromatography using on-line solid-phase extraction. Journal of Chromatography B: Biomedical Sciences and |

| |Applications 1995,664(2),347-55. |

| | |

| |24. Kuzne J, Kozuh Erzen N, Drobnic-Kosorok M: Determination of the Terbinafine |

| |Hydrochloride Levels in Cat’s Plasma and Hair Using a New Developed Isocratic HPLC |

| |Method. Biomedical Chromatography BMC 2001,15(8),497-502. |

| | |

| |25. Website; research.cm.utexas.edu/nbauld/CHAPTER%2021.htm. Chapter 21: Amines. |

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|9 |SIGNATURE OF CANDIDATE | |

| | |( NAMRATA BASNET ) |

|10 |REMARKS OF THE GUIDE |The candidate is working under my direct supervision in laboratories of L.C.P |

| | |Gulbarga-585202 |

|11 |NAME AND DESIGNATION OF | Dr. SYEDA HUMAIRA M.Pharm, Ph.D |

| |11.1 GUIDE |PROFESSOR |

| |11.2 SIGNATURE | |

| |11.3 CO-GUIDE (IF ANY) | |

| |11.4 SIGNATURE | |

| |11.5 HEAD OF DEPARTMENT |Dr. SYEDA HUMAIRA M.Pharm, Ph.D |

| | |PROFESSOR |

| |11.6 SIGNATURE |DEPT. OF QUALITY ASSURANCE, |

| | |LUQMAN COLLEGE OF PHARMACY, |

| | |GULBARGA-585102 |

|12 |REMARKS OF THE CHAIRMAN AND PRINCIPAL |Recommended and Forwarded |

| | | |

| |12.1 SIGNATURE | |

| | |PROF. SYED SANAULLAH M. Pharm. Ph.D |

| | |(PRINCIPAL) |

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