Method Development Challenges and Regulatory Expectation in Nifedipine

Abstract

Aim: A novel and accurate high-throughput tandem mass spectroscopic method has been developed and validated for determination of nifedipine, a calcium-channel blocker. Materials & methods: Nifedipine was detected on a triple quadruple tandem mass spectrometer by multiple reactions monitoring mode via ESI source. Results: The selective and sensitive method was linear in the concentration range of 0.501 to 360.100 ng/ml and reported no matrix effect. The percent accuracy of the method was found to be between 99.7 and 102.80%, while percentage of RSD was in range of 1.77 to 4.73%. Conclusion: Validated method was used for bioavailability studies under fasting and fed conditions. Clinical pharmacokinetics of noncommunicable disease such as hypertension has interested the academicians and practitioners alike due to intricacies and limited knowledge of labile metabolites. Calciumchannel blocker drug slows down the progression of coronary artery calcification. Nifedipine (1,4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylic acid dimethyl ester), belonging to the group of 1,4-dihydropyridines is one of the highly prescribed calcium-channel blockers that selectively dilates peripheral arteries [1]. It is widely used in the treatment of cardiovascular diseases such as hypertension, angina pectoris and Raynaud's phenomenon [2][3][4]. It inhibits the influx of extracellular calcium through myocardial and vascular membrane pores as well as restricts contractile processes of smooth muscle cells thereby decreasing total peripheral resistance and systemic blood pressure [5,6]. However, developing a robust method for analysis of Nifedipine in plasma is highly challenging due to multiple reasons. Nifedipine is a photo-labile compound, undergoing oxidative biotransformation in human body into pharmacologically inactive metabolites, dehydronifedipine and hydroxydehydro nifedipine carboxylate [7].In recent past, several analytical methods were reported for the determination of nifedipine in biological matrix. These methods include HPLC [8][9][10][11][12][13][14] coupled with UV detectors or electrochemical detector, but tedious sample processing technique, lengthy analysis time and lack of sensitivity were major limitations in these methods. Diverse detection techniques like electron-capture detection [15][16][17][18][19][20], nitrogen phosphorus detection [21] and mass spectrometric (MS) detection [22,23] were reported. However, scope of thermal decomposition of nifedipine under gas chromatography conditions was a co ncern and MS methods are usually preferred.Nifedipine is metabolized by cytochrome P-450 IIIA4 enzymatic activity, in vivo. Nifedipine metabolism involves oxidative dehydrogenation to dehydronifedipine, followed

LC–MS/MS Method for Quantitation of Hydrochlorothia-zide and Nifedipine in Human Plasma

“…No cross-talk was observed between the MRMs of the analytes. In studies by Dipanjan et al, 2017, Wang et al, 2011and Xiangjun et al, 2014, the full scan product ions mass spectra for NFP and HCTZ have been shown, however, we report a more informative product ions mass spectra with the fragmentation patterns of the molecular ions.…”

“…Clinical therapeutic studies of non-communicable diseases such as hypertension has interested the practitioners and academicians alike due to intricacies and limited data among the Sub-Saharan Africa populations (Dipanjan et al, 2017). Monotherapy is also becoming increasingly ineffective at bringing the desired treatment outcomes due to the multifactorial etiology of hypertension, most practitioners have therefore resorted to combination therapy involving different classes of antihypertensive agents being administered as either fixed dose combination formulary or co-administered separate formulations as per recommendations of the European hypertension guidelines (Volpe et al, 2012;Takao et al, 2007).…”

LC–MS/MS Method for Quantitation of Hydrochlorothia-zide and Nifedipine in Human Plasma

“…The precursor→ product ion transitions of m/z 347.2→315.1 for NFP, m/z 296.1→205.2 for HCTZ and m/z 193.1→ 285.0 for IS were chosen for MRM. No cross-talk was observed between the MRMs of the analytes.In studies byDipanjan et al, 2017, Wang et al, 2011and Xiangjun et al, 2014, the full scan product ions mass spectra for NFP and HCTZ have been shown, however, we report a more informative product ions mass spectra with the fragmentation patterns of the molecular ions.…”