Capillary electrophoresis in the enantioseparation of modern antidepressants: An overview.

Chirality is a key subject in modern drug research as well as in the pharmaceutical industry and drug development. Almost all second-generation modern antidepressants are chiral substances; however in therapy some are used as racemic mixtures while others are used as pure enantiomers. The development of enantioseparation methods of chiral antidepressants and their metabolites is one of the keys in understanding their enantioselective drug action. For this purpose, efficient and reliable analytical methods are needed, and capillary electrophoresis has proved to be an interesting and advantageous alternative to the more frequently used chromatographic techniques. In this review electrodriven methods available for the chiral discrimination of selective serotonin reuptake inhibitors (fluoxetine, citalopram, sertraline) and selective serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine) are presented and discussed.

Pharmacokinetics of praziquantel and pyrantel pamoate combination following oral administration in cats.

Objectives The pharmacokinetics of praziquantel and pyrantel pamoate has never been reported in cats. The present study was designed to establish the plasma concentration-time profile and to derive pharmacokinetic data for a combined formulation of praziquantel and pyrantel in cats, after a single, oral administration. Methods Twenty-two clinically healthy adult cats were used, each receiving a single oral dose of praziquantel (8.5 mg/kg) and pyrantel (100 mg/kg). Blood samples were collected at regular time points up to 48 h post-dosing. Plasma concentrations of praziquantel and pyrantel were measured using a liquid chromatography-mass spectrometry-high-throughput screening method. Results Clinical examination of all cats did not reveal any side effects after oral administration of these medications. The terminal half-life for praziquantel and pyrantel was 1.07 and 1.36 h, respectively. Praziquantel peak concentration (Cmax) was 1140 µg/ml, reached at 1.22 h. The plasma concentrations of pyrantel after oral administration were low with a mean Cmax of 0.11 µg/ml, reached at a Tmax of 1.91 h. Pyrantel showed a very limited absorption as pamoate salt, suggesting permanence and efficacy inside the gastrointestinal tract, where the adult stages of most parasitic nematodes reside. Conclusions and relevance Pyrantel showed a very limited absorption as pamoate salt. Praziquantel was rapidly absorbed following oral administration and the concentrations achieved suggest that praziquantel could be an effective and safe medication in cats. Although some resistance problems are arising as a result of their long use, these anthelminthic products can still play a major role in parasitic control, especially in geographical areas where the high cost of newer treatments or necessity of parenteral administration could decrease the number of treated animals.

Enantioselective analysis of fluoxetine in pharmaceutical formulations by capillary zone electrophoresis.

Fluoxetine is an antidepressant, a selective serotonin reuptake inhibitor (SSRI) used primarily in the treatment of major depression, panic disorder and obsessive compulsive disorder. Chiral separation of racemic fluoxetine is necessary due to its enantioselective metabolism. In order to develop a suitable method for chiral separation of fluoxetine, cyclodextrin (CD) modified capillary electrophoresis (CE) was employed. A large number of native and derivatized, neutral and ionized CD derivatives were screened to find the optimal chiral selector. As a result of this process, heptakis(2,3,6-tri-O-methyl)-ß-CD (TRIMEB) was selected for enantiomeric discrimination. A factorial analysis study was performed by orthogonal experimental design in which several factors are varied at the same time to optimize the separation method. The optimized method (50 mM phosphate buffer, pH = 5.0, 10 mM TRIMEB, 15 °C, + 20 kV, 50 mbar/1 s, detection at 230 nm) was successful for baseline separation of fluoxetine enantiomers within 5 min. Our method was validated according to ICH guidelines and proved to be sensitive, linear, accurate and precise for the chiral separation of fluoxetine.

Simultaneous quantification of related substances of perindopril tert-butylamine using a novel stability indicating liquid chromatographic method.

A novel stability indicating gradient reverse-phased high-performance liquid chromatographic method has been developed for the quantification of impurities of perindopril tert-butylamine (PER) in pharmaceutical dosage form. Separation of the active substance and its known (Impurities B, C, D, E, F) and unknown impurities was achieved on a BDS Hypersil C18 column (250 mm × 4.6 mm, 5 µm), thermostated at 70°C, using a mobile phase comprised of aqueous solution of sodium 1-heptanesulfonate adjusted to pH 2 with perchloric acid and acetonitrile. The flow rate was maintained at 1.5 mL min(-1), injection volume of 20 µL was utilized and detection of analytes was performed at 215 nm. The developed method was validated in accordance with current ICH Guidelines for all suggested parameters, including forced degradation studies and proved to be linear, accurate, precise and suitable for the impurity testing of PER, being subsequently applied during on-going stability studies of a newly developed generic formulation.

Role of chemical structure in stereoselective recognition of beta-blockers by cyclodextrins in capillary zone electrophoresis.

Most of the beta-blocking drugs for treating diseases of the cardiovascular system are chiral aryloxy-propanolamine derivatives. Tipically, the S(-) enantiomers are more active than the R(+) enantiomers. Only some of them (for example timolol) are used as single enantiomers, the others are employed as racemates. For the determination of the enantiomeric purity of timolol European Pharmacopoeia prescribes an HPLC method using chiral stationary phase. However, the use of chiral capillary zone electrophoresis for the determination of the enantiomeric purity is of pharmaceutical interest. This study describes the application of various cyclodextrin derivatives, hydroxypropyl-beta-cyclodextrin, randomly methylated beta-cyclodextrin, sulphated beta-cyclodextrin and sulphated alpha-cyclodextrin for the stereoselective analyses of beta-blockers. Baseline separation was obtained for bopindolol, carvedilol, mepindolol, pindolol and alprenolol, while only partial separation was observed for sotalol, propranolol, oxprenolol, atenolol, bisoprolol, bupranolol, and metoprolol. The uneven molecular recognition of the enantiomers of the beta-blockers, especially of the optical isomers of labetalol and nadolol, showed the importance of the chemical nature of the separators and the analytes.

Role of chemical structure in stereoselective recognition of beta-blockers and H1-antihistamines by human serum transferrin in capillary zone electrophoresis.

Studies on chiral resolution of beta-blocker and H1-antihistamine drugs by CZE using human serum transferrin are described. The drugs with different structures passed a pseudostationary protein zone in a coated capillary applying the partial filling method for the chiral separation. In this study we screened 15 compounds; most of them showed longer migration time, indicating an interaction with transferrin. Stereoselective interaction was observed only for five beta-blockers (celiprolol, talinolol, mepindolol, bopindolol, and oxprenolol) and for one H1-antihistamine (brompheniramine). The most important finding was that very small differences in the chemical structure of the drug resulted in significant changes in the stereoselective recognition. Resolution of mepindolol enantiomers was observed showing the essential role of one methyl group compared to pindolol, which is not resolved by transferrin. Bopindolol, also a derivative of pindolol having bigger difference in the structure, showed more experienced separation. The very slight difference between alprenolol and oxprenolol was also revealed with these methods, since only oxprenolol enantiomers, having an extra oxygen in the structure, are resolved. Determining the migration order of the eutomers and distomers (chlorpheniramine, brompheniramine) we can deduct conclusions about the role of serum proteins in the delivery of drugs within the body.