Spectrophotometric and atomic absorption determination of ramipril, enalapril maleate and fosinopril through ternary complex formation with molybdenum (V)-thiocyanate (Mo(V)-SCN).

Three different sensitive and accurate spectroscopic procedures were developed for the determination of three angiotensin-converting enzyme inhibitors, namely, ramipril, enalapril maleate and fosinopril. The first two spectrophotometric (extractive and non-extractive) procedures were based on ternary complex formation with molybdenum(V) thiocyanate. The formed complex can be determined by extraction with chloroform measured at lambdamax 517 nm Beer's law was obeyed in the concentration range from (10--90 microg ml(-1)) for ramipril and fosinopril and (4--36 microg ml(-1)) for enalapril maleate with molar absorptivity 1.2x10(4), 2x10(4) and 3.4x10(4) l mol(-1) cm(-1), respectively, or by direct measurement after addition of benzalkonium chloride as surfactant and measuring the formed ternary complex at lambdamax 545 nm with a linear relationship in the concentration range from (8-7-2 microg ml(-1)), (3--27 microg ml(-1)) and (8--72 microg ml(-1)) for ramipril, enalapril maleate and fosinopril with molar absorptivity 1.5x10(4), 5x10(4) and 2.1x10(4) l mol(-1) cm(-1), respectively. The third procedure is atomic absorption measurement through the quantitative determination of molybdenum content of the complex. These methods hold their accuracy and precision well when applied to the determination of ramipril, enalapril maleate and fosinopril in their dosage forms.

Monitoring of fosinopril sodium impurities by liquid chromatography-mass spectrometry including the neural networks in method evaluation.

In this paper, the mass spectrometry (MS) detection has been applied for screening of fosinopril sodium impurities which arise during forced stress study. Before MS analysis, liquid chromatographic method with suitable mobile phase composition was developed. The separation was done on SunFire 100 mm x 4.6 mm 3.5 microm particle size column. The mobile phases which consisted of methanol-ammonium acetate buffer-acetic acid, in different ratios, were used in a preliminary study. Flow rate was 0.3 mL min(-1). Under these conditions, percent of methanol, concentration of ammonium acetate buffer and acetic acid content were tested simultaneously applying central composite design (CCD) and artificial neural network (ANN). The combinations of experimental design (ED) and ANN present powerful technique in method optimization. Input and output variables from CCD were used for network training, verification and testing. Multiple layer perceptron (MLP) with back propagation (BP) algorithm was chosen for network training. When the optimal neural topology was selected, network was trained by adjusting strength of connections between neurons in order to adapt the outputs of whole network to be closer to the desired outputs, or to minimize the sum of the squared errors. From the method optimization the following mobile phase composition was selected as appropriate: methanol-10 mM ammonium acetate buffer-acidic acid (80:19.5:0.5 v/v/v). This mobile phase was used as inlet for MS. According to molecular structure and literature data, electrospray positive ion mode was applied for analysis of fosinopril sodium and its impurities. The proposed method could be used for screening of fosinopril sodium impurities in bulk and pharmaceuticals, as well as for tracking the degradation under stress conditions.

Método de cromatografía líquida de alta resolución para la determinación simultánea de fosinopril sódico e hidroclorotiazida en formulaciones de comprimidos / High performance liquid chromatographic method for simultaneous determination of fosinopril sodium and hydrochlorothiazide in tablets formulation

Se ha desarrollado un método HPLC de fase inversa con detección de UV sencillo, específi co, exacto y preciso para la determinación de fosinopril sódico e hidroclorotiazida en formulaciones farmacéuticas. La solución de fármaco se preparó en fase móvil y se inyectó en una columna C18 con detección de UV a 208 nm. La fase móvil era una mezcla de 0,2% p/v de ácido fosfórico en agua y acetonitrilo (30:70) añadida a una velocidad de fl ujo de 0,5 ml/min a 29 0C. Los gráfi cos de calibración fueron lineales en el rango de 10-50 μg/ml (r2 > 0,99) para el fosinopril sódico y de 6,25-31,35 μg/ml para la hidroclorotiazida (r2 > 0,99). El límite de detección fue de 0,5 μg/ml para el fosinopril sódico y de 1,0 μg/ml para la hidroclorotiazida, con un límite de cuantifi cación de 10 μg/ml y 6,25 μg/ml para el fosinopril sódico y la hidroclorotiazida, respectivamente. La evaluación estadística del método se examinó mediante calibración intradía (n=5) e interdía (n=5) y resultó satisfactoria, con una exactitud y precisión elevadas. El método sugerido se aplicó con éxito en la determinación simultánea de fosinopril sódico e hidroclorotiazida en formulaciones de comprimidos, con un elevado porcentaje de recuperación, buena exactitud y precisión

A simple, specifi c, accurate and precise reversed phase HPLC method with UV detection for the simultaneous determination of fosinopril sodium and hydrohclorthiazide in pharmaceutical formulations was developed. The drug solution was prepared in mobile phase and was injected into a C18 column with UV detection at 208 nm. The mobile phase was a mixture of 0.2%w/v phosphoric acid in water and acetonitrile (30:70) delivered at a fl ow rate of 0.5 ml/min at 29 0C. The calibration graphs were linear in the range of 10-50 μg/ml (r2 > 0.99) for fosinopril sodium and 6.25- 31.35 μg/ml for hydrochlorthiazide (r2 > 0.99). The detection limit was 0.5μg/ml for fosinopril sodium and 1.0 μg/ml for hydrochlorthiazide with quantitation limit of 10 μg/ml and 6.25 μg/ml for fosinopril sodium and hydrochlorthiazide, respectively. The statistical evaluation of the method was examined by performing intra-day (n=5) and inter-day calibration (n=5) and was found to be satisfactory, with high accuracy, and precision results. Application of the suggested method was successfully applied to the simultaneous determination of fosinopril sodium and hydrochlorthiazide in tablets formulation, with high percentage of recovery, good accuracy with precision

Microemulsion liquid chromatographic method for characterisation of fosinopril sodium and fosinoprilat separation with chemometrical support.

The properties of the eluent are the essential factors governing the efficiency in the high-performance liquid chromatography (HPLC) method. A novel approach in retention modelling in the liquid chromatographic separation of fosinopril sodium and its degradation product, fosinoprilat, applying a microemulsion as the mobile phase, was used. The modifications of the mobile phase included the changes to the type of the lipophilic phase, the type and concentration of co-surfactant and surfactant, as well as the pH of the mobile phase. In this study, a full factorial 2(3) design, as the optimal method for screening of the experiment, was applied for selecting factors which had an influence on separation. Optimisation was done by a central composite design. An appropriate resolution with reasonable retention times was obtained with a microemulsion containing 0.9% w/w of cyclohexane, 2.2% w/w of sodium dodecyl sulphate (SDS), 8.0% w/w of n-butanol and 88.9% of aqueous 25 mM disodium phosphate, the pH of which was adjusted to 2.8 with 85% orthophosphoric acid. Separations were performed on an X-Terra 50-mmx4.6-mm, 3.5-mum particle size column at 30 degrees C. UV detection was performed at 220 nm and with a flow rate of 0.3 mL min(-1). The established method was validated and applied for analysis of appropriate tablets. The proposed chromatographic procedure for the separation of fosinopril sodium and its degradation product is less expensive compared with the conventional reversed-phase HPLC method, as well as being simple and rapid. The optimised and validated method can be used for separation, identification and simultaneous determination of fosinopril sodium and fosinoprilat in bulk drug and in pharmaceutical dose forms.

Synthesis of optically active trans 4-cyclohexyl-L-proline as an intermediate product in the preparation of fosinopril.

A nine-step synthesis of trans 4-cyclohexyl-L-proline has been developed on a laboratory scale. The product is an intermediate in the preparation of fosinopril--an effective hypotensive drug. The total yield of the synthesis was 25%. The final product was 99.7% pure. Analytical methods were developed for each step of the synthesis (HPLC, TLC, IR, 1H-NMR, 13C-NMR, GC-MS, [alpha]D).

Simultaneous determination of fosinopril and hydrochlorothiazide in pharmaceutical formulations by spectrophotometric methods.

Three new spectrophotometric procedures for the simultaneous determination of fosinopril and hydrochlorothiazide are described. The first method, derivative-differential spectrophotometry, comprised of measurement of the difference absorptivities derivatized in the first-order (DeltaD(1)) of a tablet extract in 0.1 N NaOH relative to that of an equimolar solution in methanol at wavelengths of 227.6 and 276.4 nm, respectively. The second method, depends on the application ratio spectra derivative spectrophotometric method to resolve the interferance due to spectral overlapping. The analytical signals were measured at 237.9, 243.8 nm for fosinopril and 262.4, 269.3 and 278.6 nm for hydrochlorothiazide in the binary mixture, in the first derivative of the ratio spectra of the mixture solutions in methanol. Calibration graphs were established for 4.0-50.0 microg ml(-1) fosinopril and 2.0-14.0 microg ml(-1) hydrochlorothiazide in binary mixture. The third method, absorbance ratio method, the determination of fosinopril and hydrochlorothiazide was performed by using the absorbances read at 210.0, 219.5 and 271.7 nm in the zero-order spectra of their mixture. The developed methods were compared with absorbance ratio method. Application of the suggested procedures were successfully applied to the determination of this compound in synthetic mixtures and in pharmaceutical preparations, with high percentage of recovery, good accuracy and precision.

Antioxidant power of angiotensin-converting enzyme inhibitors in vitro.

AIMS: There is controversy regarding the potential antioxidant effect of captopril, therefore this study was performed to compare the in vitro antioxidant power of captopril with other angiotensin-converting enzyme (ACE) inhibitors. METHODS: Antioxidant power of captopril, enalapril, fosinopril, perindopril, quinapril and ramipril in aqueous solution was measured using the ferric reducing (antioxidant) power (FRAP) assay; captopril was also measured in ethanolic solution. RESULTS: Only captopril showed significant antioxidant power, demonstrating a stoichiometric factor of 1.0 in this assay. Concentration-related antioxidant power was seen in both aqueous and ethanolic solutions. CONCLUSIONS: Captopril shows antioxidant activity in vitro. This property could be relevant in vivo if captopril is concentrated in membranes, lipoproteins or at other important sites.

Quantitative analysis of fosinopril sodium by capillary zone electrophoresis and liquid chromatography.

A capillary zone electrophoresis (CZE) method was developed for the quantitative analysis of fosinopril sodium. Validation parameters of the CZE method were evaluated and compared to an existing LC method. In terms of precision and sensitivity. LC performance was superior to that of the CZE method for this application. The CZE method achieved better selectivity for several degradants of interest within a much shorter analysis time than did the LC method. Effects of detection wavelength, applied voltage and buffer concentration on optimization of the CZE method are presented. Effects of diluent composition on capillary loading and peak behaviour are also discussed.

Solid-state NMR and IR for the analysis of pharmaceutical solids: polymorphs of fosinopril sodium.

The two polymorphic modifications of fosinopril sodium have been characterized as to their differences in melting behaviour, powder X-ray diffraction patterns, Fourier transform infrared spectra (FTIR), and solid-state 31P- and 13C-NMR spectra. The polymorphs were found to be enantiotropically related based upon melting point, heat of fusion, and solution mediated transformation data. Analysis of the solid-state FTIR and 13C-NMR data indicated that the environment of the acetal side chain of fosinopril sodium differed in two polymorphs, and that there might be cis-trans isomerization about the C6-N peptide bond. These conformational differences are postulated as the origin of the observed polymorphism.