Synchronous LC-MS/MS determination of pantoprazole and amitriptyline in rabbit plasma: application to comparative in vivo pharmacokinetic study of novel formulated effervescent granules with its marketed tablet dosage form

Abstract

In the present study the bioavailability and pharmacokinetics properties of pantoprazole (proton pump inhibitor)/amitriptyline (tricyclic antidepressant) in novel formulated effervescent granules was estimated in rabbit plasma using a validated, selective and rapid LC-MS/MS method. Separation and detection of pantoprazole, amitriptyline and internal standards namely omeprazole and dothiepin, respectively, were achieved at ambient column temperature on C 18 . Acetonitrile: 4mM ammonium acetate solution (comprising 0.05 % formic acid) (40:60, v/v) was used as mobile phase and the flow rate of 0.6 mLmin -1 was applied. Liquid-liquid extraction technique with diethyl ether: dichloromethane (70:30, v/v) was used to extract the cited drugs from rabbit plasma. Multiple reactions monitoring (MRM) in the positive ionization mode was carried out for quantification. The method was validated over linear concentration range of 0.01-4μgmL −1 and 0.001–0.1 μgmL −1 for Pan and Ami respectively, with regression coefficient (r 2 ) ≥ 0.9961. The intra- and inter-run precisions (%CV) were ≤4.03. The extraction recoveries were in the range of 95.92%–100.24 %. Pan and Ami were stable during three freeze-thaw cycle and post-preparative stability. The work also aimed to formulate immediate release novel effervescent granules by melt granulation technique. Nine formulae were assessed by validated dissolution test for their micrometric properties and dissolution profile. Experimental design was applied to select formula that fulfilled the desired criteria of optimum release of pantoprazole and amitriptyline with optimum micrometric properties for the study. A single period randomized open-label parallel design was applied on Chancellor's rabbit. The selected formula showed superior pharmacokinetic parameters for pantoprazole and amitriptyline than that of marketed products.

Intragastric Carbon Dioxide Release Prolongs the Gastric Residence Time of Postprandially Administered Caffeine

“…Hot melt extrusion has already been used to manufacture granules by other work groups [ 21 ]. Zaher et al also produced effervescent granules containing pantoprazole and amitriptyline using PEG 4000 [ 22 ]. As PEG 4000 has a relatively low melting point (54 °C), the granulation process could be carried out at low temperatures.…”

Formulation of Dosage Forms with Proton Pump Inhibitors: State of the Art, Challenges and Future Perspectives

“…In other studies, the LC-MS/MS method was used for the simultaneous determination of esomeprazole and naproxen in human plasma [ 65 ], as well as pantoprazole and amitriptyline in rabbit plasma [ 66 ].…”

Polystyrene‐Coated Magnetite Nanoparticles Based Dispersive Micro‐Solid Phase Extraction of Active Pharmaceutical Ingredients of Antidepressant Drugs and Determination by GC‐MS

“…Several chromatographic methods such as gas chromatography‐mass spectrometry (GC‐MS), [8–10] gas chromatography‐flame ionization detection (GC‐FID), [11] gas chromatography tandem mass spectrometry (GC‐MS/MS), [12] liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) [13,14] and ultra‐high performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) [15–17] have been extensively used for the qualification and quantification of antidepressant drugs in different matrices. Among these instruments, GC‐MS offers simplicity and low operational cost, making it ideal for the separation, qualification and quantification of volatile organic compounds that have peculiar mass‐to‐charge (m/z) ratios [18] .…”