Hofmann rearrangement of primary carboxamides and cyclic imides using DCDMH and application to the synthesis of gabapentin and its potential peptide prodrugs

Two protocols for the efficient transformation of aromatic as well as aliphatic primary carboxamides to the corresponding carbamates and aromatic as well as aliphatic cyclic imides to the corresponding anthranilic acid derivatives & amino acid derivatives, respectively, are described. We also developed a novel methodology to the multigram scale synthesis of gabapentin and (S)-pregabalin. The gabapentin methyl carbamate was converted to novel potential peptide prodrugs of gabapentin.     

An improved synthesis of a fluorescent gabapentin-choline conjugate for single molecule detection

Voltage-gated calcium ion channels comprise pore-forming α₁ and auxiliary α₂δ, β, and γ subunits. They are important molecular devices involved in a variety of cell functions. Fluorescently labeled acylcholine analogues are important in studies such as ion channel regulation. Cy3-3-acetylcholine has recently been synthesized for single molecule detection studies; albeit in an extremely low overall yield (0.06%). In this work, an alternative route to that used in the previous Cy3-3-acetylcholine synthesis was developed with a 90% yield at a significantly lower material cost.     

Piezoelectric pumping in flow analysis: Application to the spectrophotometric determination of gabapentin

Solutions propelling devices are fundamental components of a flow-based analytical manifold. In this work different manifold configurations were implemented to evaluate the performance of multiple piezoelectric micro-pumps used as solutions insertion and propulsion devices. The micro-pumps are piezo-actuated micro-diaphragm pumps with passive check valves characterised by a small compact size and low power demands, and are able to produce reproducible flow rates of up to 4 mL min⁻¹. The flow rate is controlled by the frequency of the piezoelectric actuator (up to 20 Hz). As an additional feature, piezoelectric micro-pumps actuation generates a pulsed flowing stream that ensures a faster sample/reagent mixing contributing to improved reaction development.

The developed flow approach was assessed in the spectrophotometric determination of gabapentin in pharmaceutical preparations upon reaction with 1,2-naphthoquinone-4-sulfonate in alkaline medium. Distinct flow manifold configurations were designed for achievement of different solutions management. Linear calibrations plots for gabapentin concentrations of up to 150 mg L⁻¹, with relative standard deviations of less than 1.50% (n = 10) and a sample throughput of about 28 determinations per hour, were obtained.     

Voltammetric Determination of Trace Antiepileptic Gabapentin with a Silver‐Nanoparticle Modified Multiwalled Carbon Nanotube Paste Electrode

For the first time, a novel carbon nanotube bed electrode impregnated with silver–nanoparticles (AgNPs) for the determination of trace amounts of gabapentin (GBP) is described. We synthesized the AgNPs via a new procedure. The voltammetric behavior of the electrode was investigated by cyclic voltammetry. There were linear relationships in the ranges from 3.1×10^?9 to 2.9×10^?2 M and from 1.0×10^?8 to 1.0×10^?2 GBP with square wave and differential pulse voltammetric peak currents, respectively. The detection limits were 5.6×10^?10 and 9.7×10^?9 M, respectively. The electrode showed excellent response over a period of 2 months and was successfully applied in human plasma and pharmaceutical capsular products.     

Generic Automated Fluorimetric Assay for the Quality Control of Gamma Aminobutyric Acid-Analogue Anti-Epileptic Drugs Using Sequential Injection

The first sequential injection assay for the generic determination of gabapentin and pregabalin is reported. The analytes react with o-phthalaldehyde in the presence of N-acetylcysteine as a nucleophilic reagent in alkaline medium under flow conditions to form highly fluorescent derivatives. The effect of the main instrumental and chemical variables on the assay was examined. The proposed method was validated for both analytes in terms of linearity, detection, and quantitation limits (c _L  = 160 μg L^?1, c _Q  = 480 μg L^?1 for gabapentin, and c _L  = 70 μg L^?1, c _Q  = 210 μg L^?1 for pregabalin), precision (s _r  < 1.0% in both cases), selectivity, and accuracy. The applicability of the assay was demonstrated by successfully analyzing commercially available formulations. The experimental percent recoveries were in the range of 97.9–102.0% for gabapentin and 98.3–102.3% for pregabalin.     

Hollow fiber-based liquid phase microextraction combined with high-performance liquid chromatography for the analysis of gabapentin in biological samples

Three-phase hollow fiber microextraction technique combined with high performance liquid chromatography-ultra violet (HPLC-UV) was applied for the extraction and determination of gabapentin in biological fluids. Gabapentin (GBP) was derivatized with 1-fluoro-2,4-dinitrobenzene, as a UV absorbent agent in borate buffer (pH 8.2) before extraction. The derivative product of GBP was extracted from the 8.5 mL of acidic solution (source phase) into an organic phase (dihexyl ether) impregnated in the pores of a hollow fiber and finally back-extracted into 24 μL of the basic solution (pH 9.1) located inside the lumen of the hollow fiber (receiving phase). The extraction took place due to pH gradient between the inside and outside of the hollow fiber membrane. In order to achieve maximum extraction efficiency, different parameters affecting the extraction conditions were optimized. Under the optimized conditions, preconcentration factor of 95 and detection limit (LOD) of 0.2 μg L⁻¹ were obtained. The calibration graph was linear within the range of 0.6-5000 μg L⁻¹. Finally, the feasibility of the proposed method was successfully confirmed by extraction and determination of GBP in human urine and plasma samples in the range of microgram per liter and suitable results were obtained (RSDs < 6.3%).     

Comparison of two aerosol-based detectors for the analysis of gabapentin in pharmaceutical formulations by hydrophilic interaction chromatography

Comparison of hydrophilic interaction chromatography (HILIC) columns coupled with an evaporative light scattering detector (ELSD) or charged aerosol detector (CAD) was done for the detection of gabapentin in pharmaceutical formulations. The chromatographic separations were achieved on four HILIC columns: ZIC HILIC, ZIC pHILIC, Luna HILIC, and Atlantis HILIC. Experimental factors such as mobile phase composition, acetonitrile content, and mobile phase pH were evaluated. Validation of method was done in terms of linearity, sensitivity, accuracy, and precision. The performance of ELSD detection method is comparable to that of CAD. The intra-day and inter-day variations were below 1.7% and 3.2% for CAD and 2.8%, and 3.4% for ELSD, respectively. In addition, detection sensitivities of ELSD, CAD, and UV detectors were also compared for HILIC and reversed phase (RP) modes and the highest sensitivities were obtained in the HILIC mode when connected with CAD and ELSD. The developed HILIC aerosol based detection methods were successfully applied to the analysis of gabapentin in commercial tablets and capsules.     

The synthesis of baclofen and GABOB via Rh(II) catalyzed intramolecular C-H insertion of α-diazoacetamides

The synthesis of baclofen and GABOB is reported via hydrolysis of the corresponding N-tert-butyl γ-lactams, which were obtained from Rh(II) catalyzed intramolecular C-H insertion of α-diazoacetamides.