Quantitative Proton Magnetic Resonance Spectroscopic Determination of Nifedipine and Its Photodecomposition Products from Pharmaceutical Preparations

Quantitative Proton Magnetic Resonance Spectroscopic Determination of Nifedipine and Its Photodecomposition Products from Pharmaceutical Preparations G.s. SADANAX AND A. B. GHOGARE Received February 12, 1990, from the Departmenf of Chemisfry, G. N. Khalsa College, Sombay 400 019, India. December 6 , 1990.

Accepted for publication

acquired by a 45"pulse (pulse width of 18 pi),with a 4-s pulse delay and 1.6-sacquisition time. The offset was set at 54.51 kHz, and the spectra were recorded with 900-Hzspectral width. Chemical shifts and its photodecomposition products in pharmaceutical preparations is are reported in 6 (ppm) with respect to tetramethylsilane as an described. Analysis of commercial samples by 'H NMR and USP NFXVll internal reference. procedures has indicated a maximum difference of 1.0%. The 'H NMR Procedure-With a dissecting scalpel, the capsules were cut method is recommended for analysis of nifedipine since it provides cleanly in half and carefully emptied out into a small conical flask (10 sufficiently accurate results, together with a unique spectrum as a mL). The average weight of the content per capsule was calculated confirmatory identification of nifedipine, its photodecomposition products, and other impurities. from the contents of 20 such capsules. The content equivalent to 8 mg of nifedipine was accurately weighed into a tared, stoppered vial (Pears), and 0.8 mL of a solution of deuterochloroform in carbon tetrachloride (40%) containing 8 x M t-butyl alcohol (w/v)was added to the vial. The vial was then stoppered and shaken on a vortex Nifedipine [ 1; dimethyl 1,4-dihydro-2,6-dimethyl-4-(2'- stirrer for 2 min, and 0.4 mL of the solution was filtered into a 5-mm nitrophenyl)-3,5-pyridinedicarboxylatel belongs to a class of 'H NMR analytical tube. The spectrum was recorded, using described drugs having calcium antagonist properties.1 Pharmaceutical experimental conditions, and integrated (n 2 5) from 1.2 to 3.8 ppm preparations containing nifedipine have been widely used (see Table I). The integral of the methoxyl signal (3.58 ppm) of clinically as coronary vasodilators. The drug is usually adnifedipine was compared with the integral of the intense singlet of t-butyl alcohol (1.26 ppm). In some formulations, where there was ministered orally or iv, and the therapeutic range in plasma interference observed with the methoxyl protons (3.58 ppm) from is 25-100 pg/L. The drug is highly light sensitive, especially excipients and impurities, the integral value of methyl protons (2.32 in solution. When exposed to visible light, it is converted to ppm) was used for calculation. From this integral ratio of analyte the 4-(2'-nitrosophenyl)pyridine (21, whereas on exposure to to the internal standard protons, the percent content of UV light, it changes to the 4-(2'-nitropheny1)pyridine (3).*4 protons nifedipine was calculated using the following equation: Abstract 0 A rapid (5 min), accurate, and precise (SD 0.51%) analytical method involving 'H NMR spectroscopy for determination of nifedipine

Because of its instability to light, special care must be taken in its determination. Various methods such as HPLC,3.5 GC,6.7 GC-MS,S fluorimetry,g polarography,2,10and colorimetry" have been reported for the determination of nifedipine in biological fluids and pharmaceutical preparations. Most of these methods, however, are time consuming and involve tedious derivatization or chemical modification. The present communication describes a simple and fast 'H NMR spectroscopicmethod for quantitative determination of nifedipine and its photodecomposition products in pharmaceutical preparations.

Experimental Section Materials-Nifedipine reference standard was obtained from Cipla Chemicals (Bombay, India), and capsule and tablet preparations of nifedipine were collected from different commercial sources. t-Butyl alcohol, (AR grade; Glaxo India, Bombay, India), carbon tetrachloride (spectroscopy grade; E. Merck India, Bombay, India), and deuterated chloroform (99.80%;Fluka Chemie AG, Switzerland) were used in this study. Instruments-A Jeol FX-SOQ Fourier transform NMW spectrometer with a 5-mm C/H dual switchable probe and a deuterium internal lock operating at 30 " c constant temperature was used. The data was analyzed bY a Hewlett-Packard computer with 16K memow and

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Results and Discussion The 1H NMR spectra ofnifedipine are simple (Figures 1-3). Signals due to the two symmetrical methyls (2.32ppm) and the methoxyls (3.58ppm) are very intense, and their integral values are large and can be measured with sufficient accuracy and precision. The impurities that are normally observed in nifedipine samples are photodecomposition products 2 and 3. The methyl and the methoxyl signals of these impurities are distinct and do not interfere with the corresponding nifedipine signals (Table I). They are also very intense and, hence, can be measured accurately. These observations are the basis Journal of Pharmaceutical Sciences / 895 Vol. 80, No. 9, September 7997

Table CSpectral Data of Nlfedlplne and Its Photodecomposltlon Products Type of Proton

Number of Protons

Nifedipine (1)

Nitrosophenylpyridine (2)

Nitrophenylpyridine(3)

2x-CH3 2x-OCH3 4-H

6H 6H 1H 1H 4H

2.32 3.58 5.62 5.82 7.1-7.7

2.66 3.37

2.63 3.68

6.5-7.7

7.1-8.2

N-H

Arom-H a

NMR shift, ppm"

-

-

-

40% CDCI, in CCI, as a solvent and all shifts are compared with TMS referenced as 0 ppm.

Table Il-Percent Recovery and Statistical Evaluatlon of the Method Level

Added, mgb

Found, mg

0.82 0.82 0.82 0.82 0.82

0 1.36 2.72 4.08 5.44

6.12 7.46 8.82 10.22 11.51

la 2 3 4 5 a

Nifedipine

Internal Standard, mg

Recovery, '10

SD (n = 5)

98.53 99.26 100.49 99.08

0.61 0.47 0.43 0.51

-

Preanalyzed sample. Amount of standard drug added in preanalyzed sample.

Table IlCDetermInation of Nlfediplne in Commercial Formulations Sample

Claimed, mgldosage

Hard gelatin capsules

5 10 5 10 10 20 10 20

Soft gelatin capsules Tablets Sustained-releasetablets a

Results are expressed as mean

2

'H NMR

Procedure

4.98 2 0.034 10.02 5 0.049 4.93 2 0.038 9.87 2 0.057 10.03 2 0.028 19.89 2 0.034 9.79 -t 0.041 19.86 2 0.058

Found, mgldosagea Percent NF XVll Procedure 99.60 100.20 98.60 98.70 100.30 99.45 97.90 99.30

4.96 3: 0.028 10.01 2: 0.026 4.97 ?: 0.042 9.82 2 0.039 9.98 If. 0.036 19.82 +. 0.028 9.89 ? 0.033 19.87 ? 0.041

Percent 99.20 100.10 99.40 98.20 99.80 99.10 98.90 99.43

SD.

for the quantitative analysis of nifedipine and its photodecomposition products in pharmaceutical preparations involving the 'H NMR technique. Due to the light sensitive nature of nifedipine, the use of Fourier transform-NMR (FT-NMR)for quantitative analysis of nifedipine from pharmaceutical preparations offers a number of advantages, such as rapidity, simplicity, and specificity, compared with other reported analytical techniques, including the USP procedure. Using a nifedipine solution of 10mg/mL concentration, a signal-to-noise (SN) ratio >10 was observed within 10 transients, with storage of the spectrum in the computer memory accomplished in <1 min. Sample preparation and data analysis are also comparatively simple. Therefore, the total time required to analyze a sample is <5 min. This eliminates the possibility of any decomposition during the analysis and, hence the results are more reliable, reproducible, and accurate. The potential value of the proposed 'H NMR technique was established by the measurement of the nifedipine in commercial pharmaceutical preparations. The sharp singlet a t 3.58 ppm due to the methoxyl protons (spin lattice relaxation time, T, = 0.73 s)'2 was used for the quantitation with respect to an intense signal of t-butyl alcohol as an internal standard appearing at 1.26 ppm (T, = 1.17 s)12 in most of the formulations. For comparative purposes, the same formulations were analyzed by the USP NF XVII procedure and the results are presented in Table 111. The results were statistically validated by the F and t tests. For capsules, tcal was tteb at the 5%level, indicating that the difference in mean results of the two methods is insignificant. In tablet formulations, 896 I Journal of Pharmaceutical Sciences Vol. SO,No. 9, September 1991

however, tcalwas
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Thus, the proposed method is recommended for the quantitative analysis of the drug since it provides a rapid and stability

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Flgun2-The ‘H NMR spectrum of nifedipine (1) solution exposed to room light for 8 h, indicatingformation of the nitrosophenylhomologue (2,4.2%) of nifedipine. Journal of Pharmaceutical Sciences I 897 Vol. 80, No. 9, September 7997

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References and Notes 1. Henry, P. Am. J. Cardiol. 1980,46, 1047-1053. 2. Ebel, S.; Shutz, H.; Hornitschek, A. Anneim.-Forsch. 1978, 28, 218a2193. 3. Pietta, P.; Rava, A.; Biondi, P. J. Chromatogr. 1981, 210, 516-521. 4. Testa, R.; Dolfini, E.; Roschiotti, C.; Secchi, C.; Biondi, P. Farmaco. Ed. Pmt. 1979.34.463-465. 5. Chem. Sadanga, Phurm. T.; Hikida, Bull. K.; 1982,30,3807-3809. Tameto, K.; Matsuchima, Y.; Ohkura, Y. 6. Jacobson, P.; Pederaon, Co.; Mikkelsen, 162,8147.

898 I Journal of Pharmaceutical Sciences Vol. 80, No. 9, September 7997

E.J. Chromatogr. 1979,

7. Kondo, S.; Kuchiki, A.; Yamamoto, K.; Akimoto, K.; Takahashi, K.; Awata, N.; Sugimoto, I. Chem.Phurm. Bull. 1980,28,1-7. 8. Hi chi S.; Shiobara, Y. Bwmed. M a s . Spectrum. 1978, 5, 22r224. 9. Schlossmann, S. Aneim.-Forsch. 1972,22, 60-62. 10. Squella, J.; Barnafi, E.; Perna, S.; Nunez-Vergara, L. Talanta 1989,36,363-366. 11. Agrawal, Y.; Shah, K.Zndiun J.Pharma. Sci. 1989,51(2), 17-18. 12. The TIvalue was determined by use of inversion recovery pulse sequence (180” - Y - 90”).The values of T,were measured for the analyte protons and the internal standard rotom at 10 mg/mL concentrations of nifedi ine in 40% C6Cl in CCl, M t-butyl arcohol as an internafstandard. containing 0.8 x

Acknowledgments The authors thank the management of Hoechst India Limited, Bombay, India, for providing instrumental facilities for this work.