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Four simple, specific, accurate and precise spectrophotometric methods manipulating ratio spectra were developed and validated for simultaneous determination of simvastatin (SM) and ezetimibe (EZ) namely; extended ratio subtraction (EXRSM), simultaneous ratio subtraction (SRSM), ratio difference (RDSM) and absorption factor (AFM). The proposed spectrophotometric procedures do not require any preliminary separation step. The accuracy, precision and linearity ranges of the proposed methods were determined, and the methods were validated and the specificity was assessed by analyzing synthetic mixtures containing the cited drugs. The four methods were applied for the determination of the cited drugs in tablets and the obtained results were statistically compared with each other and with those of a reported HPLC method. The comparison showed that there is no significant difference between the proposed methods and the reported method regarding both accuracy and precision., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aim: To evaluate the non-invasive collection of bile from healthy human subjects for the qualitative characterization of the biliary disposition of a drug, using spectrometric techniques., Methods: Twenty subjects underwent non-invasive bile capture using a peroral string test (Entero-Test) device prior to and following a single oral dose of simvastatin (80 mg). The device, consisting of a weighted gelatin capsule containing a highly absorbent nylon string, was swallowed by each subject with the proximal end of the string taped to the face. Once the weighted string was judged to have reached the duodenum, gallbladder contraction was stimulated in order to release bile. The string was then retrieved via the mouth, and bile samples were analysed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction., Results: Numerous metabolites of simvastatin were detected, and the major metabolites were consistent with those reported from studies where bile was collected using invasive techniques from patients dosed with [(14) C]-simvastatin., Conclusions: The results from this study demonstrate the utility of deploying the Entero-Test in human studies to provide structural information on biliary metabolites. This can be readily applied in drug development studies, including those in the target patient population and may eliminate the need for more invasive sampling techniques., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Simple, accurate, sensitive, and precise UV spectrophotometric, chemometric, and HPLC methods were developed for simultaneous determination of a two-component drug mixture of ezetimibe (EZ) and simvastatin (SM) in laboratory-prepared mixtures and a combined tablet dosage form. Four spectrophotometric methods were developed, namely, ratio spectra derivative, ratio subtraction, isosbestic point, and mean centering of ratio spectra. The developed chemometric-assisted spectrophotometric method was the concentration residual augmented classical least-squares method; its prediction ability was assessed and compared to the conventional partial least-squares method. The developed HPLC method used an RP ZORBAX C18 column (5 microm particle size, 250 x 4.6 mm id) with isocratic elution. The mobile phase was acetonitrile-pH 3.5 phosphate buffer (40 + 60, v/v) at a flow rate of 1.0 mL/min, with UV detection at 230 nm. The accuracy, precision, and linearity ranges of the developed methods were determined. The developed methods were successfully applied for determination of EZ and SM in bulk powder, laboratory-prepared mixtures, and a combined dosage form. The results obtained were compared statistically with each other and to those of a reported HPLC method; there was no significant difference between the proposed methods and the reported method regarding both accuracy and precision.

Simple, accurate and precise colorimetric method for the determination of simvastatin and lovastatin in tablets is described. The method is based on the reaction of simvastatin or lovastatin with hydroxylamine in alkaline medium to form the corresponding hydroxamic acid derivatives which, on treatment with ferric ion in acid medium, yield highly colored ferric-chelate complex with maximum absorption at 513nm. Beer's law is obeyed in the concentration ranges 0.04-0.4mgml(-1) for both simvastatin and lovastatin, respectively. Molar absorptivity values, as calculated from Beer's law data, were found to be 1.15x10(3) and 1.09x10(3)lmol(-1)cm(-1) for simvastatin and lovastatin, respectively. Optimal experimental parameters for the reaction have been studied. The validity of the described procedures was assessed. Statistical analysis of the results reflects that the proposed procedures are precise, accurate and easily applicable for the determination of simvastatin and lovastatin in pure form and in pharmaceutical preparation., (Copyright 2010 Elsevier B.V. All rights reserved.)

A micellar electrokinetic capillary chromatography method was developed and validated for the simultaneous determination of ezetimibe and simvastatin in pharmaceutical preparations. The influence of buffer concentration, buffer pH, sodium dodecyl sulphate (SDS) concentration, organic modifier, capillary temperature, applied voltage, and injection time was investigated, and the method validation studies were performed. The optimum separation for these analytes was achieved in less than 10 min at 30 degrees C with a fused-silica capillary column (56 cm x 50 microm i.d.) and a 25mM borate buffer at pH 9.0 containing 25mM SDS and 10% (v/v) acetonitrile. The samples were injected hydrodynamically for 3 s at 50 mbar, and the applied voltage was +30.0 kV. Detection wavelength was set at 238 nm. Diflunisal was used as internal standard. The method was suitably validated with respect to stability, specificity, linearity, limits of detection and quantification, accuracy, precision, and robustness. The limits of detection and quantification were 1.0 and 2.0 microg/mL for both ezetimibe and simvastatin, respectively. The method developed was successfully applied to the simultaneous determination of ezetimibe and simvastatin in pharmaceutical preparations.

A simple, precise and rapid high-performance liquid chromatography (HPLC) method has been developed and validated for the simultaneous determination of ezetimibe (EZE) and simvastatin (SIM) from their combination drug products. The applicability of monolithic LC phases in the field of quantitative analysis has been evaluated. The existing method with UV detection set at 240 nm was successfully transferred from a conventional silica column to a 10 cm x 4.6 mm i.d. monolithic silica column. By simply increasing the mobile phase flow rate, run time was about five-fold reduced and the consumption of mobile phase was about two-fold decreased, while the chromatographic resolution of the analytes remain unaffected. Ranitidine (RAN) was used as internal standard to guarantee a high level of quantitative performance. The method used a mobile phase consisted of acetonitrile-ammonium acetate (50 mM pH 5.0) (65:35, v/v). It was validated with respect to system suitability, specificity, limit of quantitation (LOQ) and detection (LOD), linearity, precision, accuracy, and recovery, respectively. The described method was linear over the range of 40-1200 ng ml(-1) (r=0.999) for both drugs. The LOD for EZE and SIM were 13.2+/-0.4029 and 13.3+/-0.4772 ng ml(-1), respectively. The LOQ were found to be 39.9+/-1.221 and 39.5+/-1.446 ng ml(-1) for EZE and SIM, respectively. The method is fast (less than 2.0 min) and is suitable for high-throughput analysis of the drug and ones can analyze 700 samples per working day, facilitating the processing of large-number batch samples.

A fast and novel sample preparation procedure: ultrasound assisted ionic liquid (IL) dispersive liquid extraction for the concentration of lovastatin and simvastatin in aqueous samples was developed. An IL ([C(6)MIM][PF(6)]) was used as the extraction solvent, and the factors affecting the extraction efficiency such as initial temperature, the volume of IL, pH of water samples, cooling time, and salt concentration were optimized. In combination with HPLC-UV, both lovastatin and simvastatin exhibited a good linear range of 1-100 ng/mL. The limits of detection (LODs) of lovastatin and simvastatin were 0.17 and 0.29 ng/mL, respectively. Precisions of the proposed method (RSDs, n = 9) were 4.12 and 4.52%, respectively. This method has been successfully applied for the analysis of target compounds in three real water samples and good spiking recoveries were obtained in the range of 90.0-102.2% for lovastatin and 80.5-112.0% for simvastatin. These results indicated that ultrasound assisted IL dispersive liquid phase extraction would have good application prospect in the pretreatment of environmental samples.

A reversed-phase liquid chromatographic (LC) method was developed and validated for the simultaneous determination of ezetimibe and simvastatin in pharmaceutical dosage forms. The LC method was carried out on a Synergi fusion C18 column (150 mm x 4.6 mm id) maintained at 45 degrees C. The mobile phase consisted of phosphate buffer 0.03 M, pH 4.5-acetonitrile (35 + 65, v/v) run at a flow rate of 0.6 mL/min, and detection was made using a photodiode array detector at 234 nm. The chromatographic separation was obtained within 15.0 min, and calibration graphs were linear in the concentration range of 0.5-200 microg/mL. Validation parameters such as specificity, linearity, precision, accuracy, and robustness were evaluated, giving results within the acceptable range for both compounds. Moreover, the proposed method was successfully applied for the routine quality control analysis of pharmaceutical products.

A spectrophotometric method has been developed and applied to the determination of simvastatin and fluvastatin in human serum and in tablets. Simvastatine and fluvastatin were determined by measurement of their first derivative signals at 241.6, 245.9, 249.1 nm (for simvastatin) and 259.6 nm (for fluvastatin), respectively. Calibration curves were linear and the ranges of quantification were 12.0-28.0 micrograms.ml-1 for simvastatin and 10.0-28.0 micrograms.ml-1 for fluvastatin. The procedure was successfully applied to the determination of these compounds in pharmaceutical formulations as well as in human serum with a high percentage of recovery, good accuracy and precision, and without measurable interference by the excipients.

A micellar electrokinetic chromatographic (MEKC) method was developed for the quantification of lovastatin and simvastatin, cholesterol lowering agents in pharmaceutical dosage forms. Lovastatin and simvastatin were separated using an electrolyte system consisting of 12% acetonitrile (v/v) in 25 mM sodium borate buffer pH 9.3 containing 25 mM sodium dodecyl sulphate (SDS) with an extended light path capillary (48.5 cm x 50 microm i.d, 40 cm to detector). The method has been validated and proven to be rugged. Calibration curves were linear over the studied ranges with correlation coefficients greater than 0.996. A limit of detection of 3.2 microg/ml and a limit of quantitation of 10.6 microg/ml were estimated for both the drugs. The proposed method was found to be suitable and accurate for the determination of these drugs in commercial formulations.

Simvastatin, a highly effective cholesterol-lowering agent, has been widely used for the treatment of hypercholesterolemia. During the development of simvastatin solid dosage form, formulation compositions were constantly varied to define a suitable matrix. A fast and reliable method for the dissolution and release testing of simvastatin was highly desirable to support formulation screening. A second derivative UV spectroscopic method was developed for determination of simvastatin in the tablet dosage form. After carefully choosing a zero-crossing technique of second derivative UV measurement at 243 nm, the selectivity and sensitivity of simvastatin was comparable to the previously developed HPLC method. In comparison with the direct UV method, second derivative UV spectroscopy eliminates the interference from UV absorbing excipients such as ascorbic acid, which often results in a bias of 2-10%. This method is also fast and economical in comparison to the more time-consuming HPLC method regularly used for formulation screening. Finally, this method has been validated to be precise and accurate, and is demonstrated to be an excellent alternative to HPLC method for the dissolution and release testing of simvastatin in the solid dosage form.