DEVELOPMENT OF STABILITY INDICATING HPLC METHOD FOR NAFTOPIDIL IN NAFTOPIDIL TABLETS
M. PHARM DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIV GANDHI UNIVERSITY OF HEALTH
SCIENCES, KARNATAKA, BANGALORE
BY
MR. SAYAJI W. PATIL
b. pharm
UNDER THE GUIDANCE OF
HEDGAPURE RAMESH
M. Pharm (Ph.D).
Professor and H.O.D
P. G. DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
R.R.K’S COLLEGE OF PHARMACY,
NAUBAD,BIDAR-585402
2011-12
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidate & Address(In block letters) / : / MR. SAYAJI W. PATIL
Ratan Park, phase 1, A1/10, Sus road, Pashan, Pune-411021
2. / Name of the Institution / : / R.R.K’s COLLEGE OF PHARMACY, BIDAR-585401
3. / Course of Study and Subject / : / M. Pharm. in
(PHARMACEUTICAL CHEMISTRY)
4. / Date of Admission to Course / : / 10 – 12 - 2011
5. / Title of the Topic / : / DEVELOPMENT OF STABILITY INDICATING METHOD FOR NAFTOPIDIL IN NAFTOPIDIL TABLETS
6.
8.
/ Brief resume of intended work :
6.1 Need for the study:
Analytical branch gives the selectivity of the drug. It involves the more sensitive, simple and specific data for the bulk drug powders and its dosage form. It is an easy for the detection of sample purity and standardization with accurate result for pharmaceutical uses1. We have selected Naftopidil for present study.
Naftopidil, approved only in Japan, is an α1-adrenergic receptor antagonist (α1-blocker) used to treat lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Different from tamsulosin hydrochloride and silodosin, in that it has higher and extremely higher affinity respectively, for the α1A-adrenergic receptor subtype than for the α1D type, naftopidil has distinct characteristics because it has a three times greater affinity for the α1D-adrenergic receptor subtype than for the α1A subtype.2
The drug is used as an anti hypertensive and in the treatment of benign prostate hypertrophy.
6.2 Review of literature:
The literature review reveals that a less amount of work has been done on Naftopidil and its Tablets formulation. There is no stability indicating method reported for the same in its tablets dosage form. The drug is non pharmacopoeial and hence more and more research is welcome on it. There are few methods reported in the literature.
· F. Behn et.al. Report an HPLC method for Carvedilol in plasma of small children, where Naftopidil is used as an internal standard. The two drugs were analyzed by solid phase extraction and were eluted using Acetonitrile: Acetate Buffer (0.1M, pH 5.0). Further the extracts were analyzed on fluorescence detection.3
· Mu Yuan et.al. Have reported a method for the separation of enantiomers of Naftopidil. They developed a chiral HPLC method for the separation and analysis of naftopidil enantiomers. The two enantiomers of Naftopidil were separated using a Chiralpak AD-H (250 mm×4.6 mm, 5 μm) column and monitored at the wavelength of 283 nm. The isocratic mobile phase consisting of hexane–isopropanol–Diethylamine (85:15:0.1, v/v/v) was pumped at a flow rate of 1.0 mL/min. Under these chromatographic conditions, R-Naftopidil and S-Naftopidil were well separated and had good linearity in the ranges of 0.78–50 μg/mL (r = 0.9999) and 0.84–54 μg/mL (r = 0.9998), respectively. The relative standard deviations (RSD) of intra- and inter-day assays were no more than 0.5% and 0.7%, respectively. This improved method for the separation and quantitative determination of Naftopidil enantiomers can be used for the quality control of synthesized Naftopidil product.4
· ZHAO Xia et.al. Have reported a fluorescence method of HPLC- fluorescence to determine the plasma concentration in plasma. A single of 50 mg naftopidil tablet was given to 10 healthy male volunteers. The concentration of naftopidil in human serum was determined by HPLC-fluorescence detection method. The main pharmacokinetic parameters were analyzed by 3P87 program. Results. The assay of naftopidil in human serum was linear over the range of 0.5～100 ng·mL-1,the
within-day RSD was less than 7.83% and the between-day RSD was less than 9.08%; the recovery was 98.04%~99.22%.The pharmacokinetic parameters after a single oral administration of 50 mg naftopidil tablets were as follows: Cmax was (97.65±16.91) ng·mL-1,tmax was (0.53±0.13) h,t1/2Kewas (3.42±0.80) h, AUC0-16was (123.64±31.98) ng·h·mL-1.Conclusion The assay method is sensitive, accurate and usable for pharmacokinetic studies of naftopidil.5
· Townshend et.al. Have reported chemiluminescence method based on potassium permanganate oxidation in the presence of formaldehyde or formic acid.6
· Nishimo et.al. Have compared the therapeutic potential of Naftopidil with other alpha1 adrenoceptor antagonists like tamsulosin for Lower Urinary tract infections and benign prostate hyperplasia. The two agents provided similar efficacy in the treatment of LUTS with BPH. However, Naftopidil was better than tamsulosin for nocturia. The disappearance of involuntary contraction and the greater increase in first-desire volume with Naftopidil may be associated with the relief of nocturia. The alpha (1D)-adrenoceptor antagonist is effective in alleviating both voiding and storage symptoms. The alpha(1D)-adrenoceptor antagonist may be more effective than the alpha(1A)-adrenoceptor antagonist in LUTS with BPH.7
· M.J.G. et.al. Studied the pharmacokinetics of naftopidil, a novel alpha-1 adrenoceptor-blocking antihypertensive, in ten patients (9M/1F) with hepatic dysfunction after oral administration (50 mg, tablet) and after an intravenous infusion of 5.0 mg over 2 minutes. Results were compared to a control group of 12 healthy subjects (6M/6F) of a previous investigation, which was carried out according to the identical study protocol. The pharmacokinetic findings suggest that in patients with severe hepatic impairment or evidence for marked changes in hepatic blood flow the dose of naftopidil may require adjustment to the lower end of the therapeutic range and/or may be limited to once daily. However, before definite conclusions can be drawn, further steady-state studies were required. Despite the pharmacokinetic discrepancies no difference in drug tolerability was seen between patients and healthy subjects.8
6.3 Objectives of the study:
· To develop a simple, accurate, precise analytical method for the determination of Naftopidil in pharmaceutical formulations.
· To prove the method to be stability indicating by carrying out forced degradation studies.
· To validate the proposed method as per ICH guidelines.
Materials and Methods:
7.1 Source of data:
· Standard Bulk drugs will be obtained from bulk drug manufacturers as gift samples and different dosage forms will be procured from the market.
· All the reagents & solvents of analytical grade will be used.
· Data will be collected using instruments like UV spectrophotometer, HPLC instrument having UV detector.
7.2 Method of collection of data.
· Strategy: The estimation of Naftopidil will be carried out by recent techniques like spectrophotometry and HPLC.
The authenticated gift samples of pure bulk drug will be collected from pharmaceutical industries. The procured formulations will be analyzed and estimated for purity as per vendor’s standards.
For developing an analytical method, the most appropriate sample and instrument condition will be selected as described below:
1)Sample conditions:
The selection of the solvent system is purely based on the solubility, polarity & other physicochemical properties of sample. The solvents of analytical grade will be used.
2)Instrumental conditions:
· UV spectrophotometer model SHIMADZU 1700 using quartz cell will be used.
· HPLC model LC-6600 HPLC, CHEMITO Detector, with C18 and C8 RP HPLC columns will be used.
3)Statistical analysis:
The Statistical analysis will be carried out for the calculation by applying statistical techniques.
7.3 Does the study require any investigation or intervention to be conducted on
Patients or other humans or animals?
NOT APPLICABLE
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
NOT APPLICABLE
LIST OF REFERENCES:
1. Sethi PD. “Quantitative Analysis of Drug in Pharmaceutical Formulation”.
2nd ed. CBS Publication 1993.
2. Masumori N, ‘Naftopidil for the treatment of urinary symptoms in patients with benign prostatic hyperplasia’, DOI: http://dx.doi.org/10.2147/TCRM.S13883, June 2011, Volume 2011:7, Pages 227 – 238.
3. F.Behn et.al.,”HPLC quantification of Carvedilol in small volumes of plasma in small children”, Chromatographia Journal, 2001, 641-644.
4. Mu Yuan et.al , Development of a chiral HPLC method for the analysis of naftopidil enantiomers, (http://www.jcps.ac.cn/qikan/epaper/zhaiyao.asp?bsid=12227
5. ZHAO Xia, SUN Pei-hong, ZHOU Ying, LIU Yu-wang, ZHAO Dong-fang, CUI Yi-min, SUN Zhong-min, “Determination of naftopidil in human serum by HPLC-fluorescence and study on its pharmacokinetics in healthy volunteers”, The Chinese Journal of Clinical Pharmacology, CNKI:ISSN:1001-6821.0.2007-03-015.
6. Townshend, Alan1; Pulgarín, José A. Murillo2; Pardo, M. Teresa Alañón2
Analytical and Bioanalytical Chemistry, Volume 381, issue 4 (February 2005), p. 925 - 931.ISSN: 1618-2642 DOI: 10.1007/s00216-004-2998-Springer-Verlag, Berlin/Heidelberg.
7. Nishino Y, Masue T, Miwa K, Takahashi Y, Ishihara S, Deguchi T, “Comparison of two alpha1-adrenoceptor antagonists, Naftopidil and tamsulosin hydrochloride, in the treatment of lower urinary tract symptoms with benign prostatic hyperplasia: a randomized crossover study” , BJU Int. 2006 Apr;97(4):747-51, discussion 751.
8. M.J. Farthering, E.M. Alstead, S.M.L. Abrams, G. Haug, A. Johnson, R. Hermann, G. Niebch, P. Russ, K.H. Molz, “Pharmacokinectics of naftopidil, a novel antihypertensive drug, in patients with hepatic dysfunction”, Postgrad Med J (I 994) 70, 363 366.
9. / Signature of candidate / : /
Mr. Sayaji Patil
10. / Remark of the guide / :
11. / Name and Designation of
11.1 Guide:
11.2 Signature:
11.3 Head of Department:
11.4 Signature: / : / H.RAMESH
M. Pharm. (Ph.D)
Professor and HOD
Department of Pharmaceutical Chemistry
RRK’s College of Pharmacy, Bidar -585 401.
H.RAMESH
M. Pharm. (Ph.D)
Professor and HOD
Department of Pharmaceutical Chemistry
RRK’s College of Pharmacy, Bidar -585 401
12. / 12.1 Remarks of the chairman and principal: / :
12.2 Signature: / : / DR. K. SREENIVASA RAO