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Iranian Journal of Pharmaceutical Research (2003) 111-115 Received: January 2002 Accepted: May 2003 Photostability Determination of Commercially Available
Nifedipine Oral Dosage Forms in Iran
Katayoun Javidnia *a,b, Ramin Miria,b, Ladan Movahedb, Shohreh Golrangib aMedicinal & Natural Products Chemistry Research Centre, Shiraz University of The Medical Sciences, Shiraz, Iran. bDepartment of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Abstract
Nifedipine (NIF) a 1, 4-dihydropyridine calcium channel antagonist, undergoes photodegradation to nitroso analogues of dehydronifedipine (NDNIF) when exposed to sunlight. Photodegradation products of NIF have no clinical activity, so different formulations of NIF must remain unchanged. If NIF preparations become unstable in exposure to light, they could cause therapeutic failure. The present study was carried out in order to investigate the photostability of commercially available NIF products, in Iran. Three oral NIF formulations available in Iran were studied using indirect sunlight (daylight) and continuous artificial light exposure extending over a period of 12 weeks. The extent of photodecomposition of NIF was determined using a specific reversed phase high performance liquid chromatography (HPLC) method. NIF photodegradation was measured using both pure NIF powder as well as a methanolic NIF solution to determine differences in the effectiveness of artificial light and natural indirect sunlight sources used in this study. All the tested NIF formulations were likely to be photostable up to at least 12 weeks of continuous artificial and natural day light exposure, compared with pure NIF powder and methanolic solution. Photodegradation of NIF powder and methanolic solution exposed to indirect sunlight was faster than the artificial light.
Keywords: Nifedipine; Photostability; HPLC; Daylight; Artificial light.
Introduction
important chemical changes, accompained by alternation in their activities and in some cases Nifedipine (NIF), 1,4-dihydro-2,6-dimethyl- total loss of their therapeutic activity (5). NIF is 4-(2-nitrophenyl)-3,5-pyridine dicarboxylic very highly sensitive to photooxidation. NIF acid dimethyl ester (Figure 1), is the prototype exposure to ultraviolet-visible irradiation compound of the dihydropyridine class of produces both aromatization in the calcium channel antagonists. Calcium dihydropyridine moiety (turning it into a antagonists inhibit the influx of calcium ion pyridine ring) and a reduction of nitro group in through plasma membrane channels and thus to nitroso groups (NDNIF). In addition, its dilate vascular smooth muscle contraction. NIF is a selective arterial dilator, and is used for the dehydronifedipine (DNIF) (6-9) (Figure 1). treatment of hypertension, angina pectoris, and other cardiovascular disorders (1-4). The pharmacological activity. Several studies exposure of some drugs to light leads to related to its photodecomposition have been photodecomposition. These drugs undergo reported (10-13) but to our knowledge this * Corresponding author: E-mail: javidniak@sums.ac.ir K Javidnia , R Miri , L Movahed , Sh Golrangi / IJPR 2003, 2: 111-115 solution was mixed with 1 ml of the tested concentrations of NIF (12.5–150 µg/ml) and 20 µl of the mixed solution was injected to HPLC. Melting point was determined on a kofler hot stage apparatus. 1H-NMR spectra was run on a Varian Unity Plus 400 MHz spectrometer. TMS was used as the internal standard. Mass spectra was measured with a Finnigan TSQ-70 Synthesis of Isopropyl-3-amido-2, 6-
dimethyl-4-(1-methyl 5-nitro 2-imidazolyl)-
1,4-dihydropyrinine-5-carboxylate (Internal
standard)
Figure 1. Structures of A: Nifedipine(NIF), B:
Dehydronifedipine(DNIF), C: Nitroso-analogue of
A solution of acetoacetamide (0.5g, 5mmol) dehydronifedipine (NDNIF), D: Internal standard
in MeOH (3 ml) was added to a solution of photostability of oral dosage forms used in our 1-methyl-5-nitro-imidazole-2-carboxaldehyde (0.77 g, 5 mmol) and isopropyl 3-amino crotonate (0.72 g , 5 mmol) in EtOH (4 ml) and stirred constantly for a period of 5 min. The resistant coating and/or packing to minimize reaction was heated at reflux temperature for 14 their photodegradation. Long term exposure to h, cooled to 25°C. The resulting precipitate was sunlight or artificial light may also occur if NIF filtered and purified by recrystalization from formulations are improperly stored by patients. MeOH (yield= 48%; mp = 217-219°C) (15). decrease clinical efficacy of NIF products (14). Differences in the degree of light protection 7.94 (s, 1H, imidazole H-4), 5.14(s, 1H, C4-H), may exist between different formulation types. 4.21(s, 3H, N-CH3), 4.12(m, 3H, CO2CH & In this paper, we report the photostability of NH2), 2.25(s, 6H, C2-CH3 & C6-CH3), 1.28 commercially available NIF products, in Iran. &1.18 (twod, J=7.2 Hz, 3H each, CH (CH3)2). photodegradation of authentic NIF powder and methanolic NIF solution obtained from three Irradiation test
Experimental
For artificial light irradiation, a 40 W tungsten lamp was used. NIF samples were Sigma-Aldrich placed 50 cm from the lamp in a cabinet Chemie GmbH (Deisenhofen, Germany). (1 m × 1 m × 0.75 m). Protected samples from Methanol and chloroform were obtained from extraneous light were placed in aluminum foils. Merck (Darmstadt, Germany). All reagents Exposure to indirect sunlight was also used were analytical or HPLC grade. during the spring months in Shiraz to compare Ten mg liquid filled immediate release the efficacy of artificial light and natural room capsules of NIF were obtained from Zahravi Co. (Tabriz, Iran) and Apotex Inc. (Toronto, Samples were irradiated from 0-12 weeks in Canada); and 10 mg tablets were obtained from artificial light and indirect sunlight. Samples Toliddarou Co. (Tehran, Iran). These three were collected at 0, 1, 2, 4, 6, 8, 10 and 12 formulations are the commercially available weeks intervals (n=3). NIF powder samples (10 NIF products in Iran. The NIF stock solution mg) were placed in 10 ml clean glass vials, irradiated from 0-12 days and samples were standard solutions were obtained by serial collected at 0, 1, 2, 3, 7, 10 and 12 days. Also a dilution. The Internal standard solution (IS) was total of 11 × 1 ml methanolic NIF solution prepared (40 µg/ml) in methanol. 1 ml of IS samples (10 µg/ml) were placed in 5 ml clear glass vials and irradiated for a period of 0-360 Photostability Determination of Commercially Available… min. Samples were taken at 0, 5, 10, 15, 20, 30, Statistical analysis
45, 60, 120, 240, 360 mins. The experiments were conducted at ambient temperature (14). Sample preparation
Nifedipine tablets: Three NIF tablets were Identification of the NDNIF
crushed into fine particles and a quantity 0.2 mg/ml of NIF methanolic solution was equivalent to 10 mg of NIF was placed in a exposed to indirect sunlight. At 5 min intervals centrifuge tube and 2 ml of chloroform was 10 µl of the solution were injected to HPLC 30 s and centrifuged for 5 min. Twenty µl of chromatogram (15 min). The solution was then supernatant was drawn by Hamiltonian syringe evaporated over nitrogen stream. The mass and added to a tube containing 100 µl of IS spectrum of the residue was obtained on a solution (40 µg/ml). This solution was Finnigan Mat at 70 eV ionization potential. evaporated to a dry residue under Nitrogen stream. Two hundred µl of mobile phase was Results and Discussion
added to the residue and vortexed for 10 s. Aliquots of 10 µl were injected to HPLC (14). In the present study photostability of NIF Nifedipine softgel capsules: a 20 µl volume formulations available in Iran was determined solution from each NIF capsule was withdrawn after exposure to indirect natural light and using a 25 µl Hamiltonian syringe and was continuous artificial light. NDNIF, NIF and IS diluted with 0.5 ml of chloroform. One hundred were eluted at approximately 5.5, 7.0 and 11.5 µl of IS solution (40 µg/ml) was added and min respectively. Resolution between NIF and mixed on a vortex for 30 s. Further sample NDNIF was adequate (R>1.5) and no buffer preparation and evaporation was as described and pH adjustment was required with this Nifedipine powder samples: each of the photodecomposition product produced major irradiated NIF powder samples were diluted fragments at 328 (M+, 28%), 298 (15%), 269 with 2 ml of chloroform and vortexed for 20 s. (100%) and 253 (50%), that confirmed the Twenty µl of this solution was mixed with 100 structure of NDNIF. Figure 2 shows a typical µl of IS solution (40 µg/ml), and dried over nitrogen stream, then 1 ml of mobile phase was methanolic solution irradiated with artificial added and vortexed for 10 s, Finally, 10 µl of methanolic solution irradiated with indirect Nifedipine methanolic solution: One natural sunlight for 1 min and c) a commercial hundred µl of IS was added to the vials 10 mg NIF tablet irradiated for 12 weeks with containing 1 ml of NIF (100 µg/ml) and indirect natural sunlight. vortexed, and then 10 µl of the solution was injected to HPLC.
Chromatography and instrumentation
Analytical separation was accomplished
using a Bondapack C18 (250×4.6 mm) column. Mobile phase flow rate was 1.5 ml/min and consisted of methanol/water (60/40). It was continuously degassed with Helium (60 ml/min). The HPLC system employed consisted of a model 604 solvent delivery system and a 486 tunable uv/vis absorbance detector set at Figure 2. Chromatograms of: (a) methanolic NIF solution
350 nm (Waters). Sample preparation and irradiated by artificial light for 120 min, and (b) methanolic NIF solution irradiated by natural sunlight for 1 min, and (c) a analysis were conducted under sodium lamp commercial 10 mg NIF tablet irradiated by natural sunlight for 12 weeks. Peak identification: (1) NDNIF; (2) NIF; (3) I.S. K Javidnia , R Miri , L Movahed , Sh Golrangi / IJPR 2003, 2: 111-115 Table 1. Risults obtained from the photodegradation of
Table 2. Results obtained from the photodegradation of
various nifedipine formulations by exposure to artificial Various nifedipine formulations by exposure to natural whether manufacturers in Iran can produce NIF formulations in a photoprotective condition. For tungsten artificial light have similar effects in this reason three formulations, two produced in the photodecomposition of NIF. But in our Iran, and another a commercially available form study NIF methanolic solution exposed to of NIF used in Iran (Apotex Inc.), as a control natural indirect sunlight was completely sample, were chosen. The percentage of NIF photodecomposed in 10 min. On the other hand content (w/w initial NIF content) was measured photodecomposition of NIF methanolic solution in all three tested formulations irradiated for up exposed to artificial light exceeded 7.3 % in to 12 weeks by artificial and natural light. Table approximately 10 min. This result shows that the efficacy of natural indirect sunlight in formulation after 0, 2 and 12 week exposure to photodecomposition of NIF is more than artificial light and Table 2 shows this artificial light in Iran and it can be due to the photodegradation data for each formulation fact that the intensity of natural light in Iran is after 0, 2 and 12 week exposure to natural more than Canada. Therefore, these results are indirect sunlight. Results obtained in this study evidence for that artificial light can not be used showed that differences between data obtained alone in photodecomposition studies. were not significant and none of the tested NIF Photodegradaition plots of NIF methanolic formulations underwent any appreciable solution (A) and NIF powder (B) after artificial decomposition (> 10%), even after 12 weeks light irradiation are shown in Figure 3. irradiation. Photodegradation of NIF powder measured as In conclusion, based on our results it is the loss percentage of NIF, exceeded 5.6 % and unlikely that a photostability degradation 16.8%, in approximately 24 h after artificial and would be the primary contributing factor, natural indirect light irradiation respectively. should therapeutic failure of the tested NIF Our major goal in this study was to find that Acknowledgment
Council of Medical Sciences, University of References
(1) Graham-Clarke EM and Herborn BS. Hypertention. In: Walker R and Edwards C. (Eds.) Clinical Pharmacy and Ttherapeutics. 2nd ed. Churchill (2) Roberstone RM and Roberstone D. Drugs Used for the Treatment of Myocardial Ischemia. In: Hardman JG Limbird LE and et al (Eds.) Goodman & Gilman's the Pharmocological Basis of Therapeutics. 9th ed. McGraw-Hill Companies, NewYork (1996) 1520- (3) Burnham TH, Bell WL and Schweain SL. Drug Facts Figure 3. NIF photodegradation curves of (A) NIF
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