A review of analytical methods for the determination of four new phosphodiesterase type 5 inhibitors in biological samples and pharmaceutical preparations

The introduction of oral phosphodiesterase type 5 inhibitor therapy in 1998 revolutionized the treatment of erectile dysfunction. Erectile dysfunction is the most common sexual problem in men. It often has a profound effect on intimate relationships and quality of life. The analysis of pharmaceuticals is an important part of the drug development process as well as for routine analysis and quality control of commercial formulations. Whereas the determination of sildenafil citrate, vardenafil and tadalafil are well documented by a variety of methods, there are few publications about the determination of udenafil, lodenafil carbonate, mirodenafil and avanafil. The paper presents a brief review of the action mechanism, adverse effects, pharmacokinetics and the most recent analytical methods that can determine drug concentration in biological matrices and pharmaceutical formulations of these four drugs.A introdução da terapia oral com inibidores da fosfodiesterase tipo 5, em 1998, revolucionou o tratamento da disfunção erétil. A disfunção erétil é o problema sexual mais comum em homens. Muitas vezes tem um efeito profundo nas relações íntimas e na qualidade de vida. A análise de produtos farmacêuticos é uma parte importante do processo de desenvolvimento de fármacos, bem como para a análise de rotina e controle de qualidade das formulações comerciais. Enquanto a determinação do citrato de sildenafila, vardenafila e tadalafila está bem documentada por uma variedade de métodos, existem poucas publicações sobre a determinação de udenafila, carbonato de lodenafila, mirodenafila e avanafila. O artigo apresenta uma breve revisão do mecanismo de ação, efeitos adversos, farmacocinética e os mais recentes métodos analíticos, que podem determinar a concentração do fármaco em matrizes biológicas e formulações farmacêuticas destes quatro fármacos

Treatment of invasive fungal infections: stability of voriconazole infusion solutions in PVC bags

Voriconazole is a novel broad-spectrum antifungal drug, employed in the treatment of invasive fungal infections, and represents an alternative to amphotericin B treatment. The manufacturer recommends that any unused reconstituted product should be stored at 2ºC to 8ºC, for no more than 24 h, but no recommendations about i.v. infusion solutions are given. Previous works have reported on the stability of voriconazole in polyolefin bags and just one in 5% dextrose polyvinyl chloride (PVC) bags, at a 4 mg.mL-1 concentration. In this work, the stability of voriconazole as an i.v. infusion solution in 0.9% sodium chloride and in 5% dextrose, in PVC bags, at 0.5 mg.mL-1, stored at 4 ºC and at room temperature, protected from light, was evaluated. These infusion solutions were analyzed for a 21-day period. Chemical stability was evaluated by HPLC assay. Visual inspection was performed and pH of the solutions was measured. No color change or precipitation in the solutions was observed. The drug content remained above 90% for 11 days in 0.9% sodium chloride and for 9 days in 5% dextrose solutions. The i.v. infusion solutions stored at room temperature were not stable. At room temperature, the voriconazole content dropped down to 88.3 and 86.6%, in 0.9% sodium chloride or 5% dextrose solutions, respectively, two days after admixture. Assays performed at the end of the study suggest the sorption of voriconazole by the PVC bags. The results of this study allow cost-effective batch production in the hospital pharmacy

Main Degradation Products of Dabigatran Etexilate Evaluated by LC-UV and LC-ESI-MS, Degradation Kinetics and in vitro

The present study reports the stability profile of an antithrombotic drug: dabigatran etexilate (DAB). The drug was subjected to thermal degradation at 60 ºC and products formed were investigated by liquid chromatography-UV (LC-UV) and liquid chromatography-mass spectrometry (LC-ESI-MS). Chromatographic separation of the degradation products was performed on a GL Sciences Inc. Inertsil ODS-2 column (250 mm × 4.6 mm i.d., with a particle size of 5 µm and pore size of 110 Å) with mobile phase consisting of acetonitrile and ammonium acetate buffer (pH 5.5; 10 mmol L−1) (65:35, v/v) pumped at 1.0 mL min−1 flow rate. Column temperature was set at 30 ºC and detection at 225 nm using a UV detector. LC-UV method previously validated was extended to LC-ESI-MS for the characterization of the degradation products (DP-01 and DP-02) formed, without complicated isolation or purification processes, based on retention times and confirmation of molecular weight. Degradation kinetics of DAB was also evaluated and could be described as a first-order process (R2= 0.9900). Furthermore, no evidence of cytotoxicity in human mononuclear cells was observed for DAB degraded samples

CHEMOMETRIC TOOLS AND FTIR-ATR SPECTROSCOPY APPLIED IN MILK ADULTERATED WITH CHEESE WHEY

Brazilian law forbids the addition of cheese whey in milk. However, adulteration with cheese whey is one of the most applied fraud due to its low cost. The detection of this fraud is the quantification of Caseinomacropeptide (CMP). The CMP is a constituent of the whey that can be used as adulteration marker. Thus, an analytical method capable of identifying CMP by Fourier Transform Infrared Spectra (FTIR) was developed using chemometrics methods. Firstly, we attempted to develop an exploratory analysis model by Hierarchical Grouping Analysis (HCA) and Principal Component Analysis (PCA) that indicated similarity between samples of raw milk and semi-skimmed milk. Moreover, in the PCA scores, it was possible to observe a tendency of separation between samples with different concentrations of CMP. Afterwards, multivariate regression models were used for Partial Least Squares (PLS), Partial Least Square with Interval Synergism (siPLS) and Supporting Machines with Least Squares (LS-SVM) to quantify the adulteration in different types of milk by Cheese serum through the CMP. All the models were then compared to each other and the results of the official method with Liquid Chromatography Tandem mass spectrometry (LCMS/MS) analysis used by the Ministry of Livestock and Supply (MAPA). The model LS-SVM, employing the full spectrum, obtained the best result compared to the other models (PLS and siPLS) to quantify the CMP in the milk samples

Development of alternative methods for the determination of raloxifene hydrochloride in tablet dosage form

Three methods are proposed for the quantitative determination of raloxifene hydrochloride in pharmaceutical dosage form: ultraviolet method (UV) high performance liquid chromatography (HPLC) and micellar capillary electrophoresis (MEKC). These methods were developed and validated and showed good linearity, precision and accuracy. Also they demonstrated to be specific and robust. The HPLC and MEKC methods were tested in regards to be stability indicating methods and they showed to have this attribute. The UV method used methanol as solvent and optimal wavelength at 284 nm, obeying Lambert-Beer law in these conditions. The chromatographic conditions for the HPLC method included: NST column C18 (250 x 4.6 mm x 5 µm), mobile phase water:acetonitrile:triethylamine (67:33:0,3 v/v), pH 3.5, flow rate 1.0 mL min-1, injection volume 20.0 µl, UV detection 287 nm and analysis temperature 30 °C. The MEKC method was performed on a fused-silica capillary (40 cm effective length x 50 µm i.d.) using as background electrolyte 35.0 mmol L-1 borate buffer and 50.0 mmol L-1 anionic detergent sodium dodecyl sulfate (SDS) at pH 8.8. The capillary temperature was 32°C, applied voltage 25 kV, UV detection at 280 nm and injection was perfomed at 45 mBar for 4 s, hydrodimanic mode. In this MEKC method, potassium diclofenac (200.0 µg mL-1) was used as internal standard. All these methods were statistically analyzed and demonstrated to be equivalent for quantitative analysis of RLX in tablets and were successfully applied for the determination of the drug.</p

Development and Validation of a Discriminating In Vitro Dissolution Method for a Poorly Soluble Drug, Olmesartan Medoxomil: Comparison Between Commercial Tablets

A dissolution test for tablets containing 40 mg of olmesartan medoxomil (OLM) was developed and validated using both LC-UV and UV methods. After evaluation of the sink condition, dissolution medium, and stability of the drug, the method was validated using USP apparatus 2, 50 rpm rotation speed, and 900 ml of deaerated H2O + 0.5% sodium lauryl sulfate (w/v) at pH 6.8 (adjusted with 18% phosphoric acid) as the dissolution medium. The model-independent method using difference factor (f1) and similarity factor (f2), model-dependent method, and dissolution efficiency were employed to compare dissolution profiles. The kinetic parameters of drug release were also investigated. The obtained results provided adequate dissolution profiles. The developed dissolution test was validated according to international guidelines. Since there is no monograph for this drug in tablets, the dissolution method presented here can be used as a quality control test for OLM in this dosage form, especially in a batch to batch evaluation