Danielle Guimarães Almeida Diniz

A High Performance Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method Using Solid Phase Extraction for the Simultaneous Determination of Plasma Concentrations of Enalapril and Enalaprilate in Hypertensive Patients Treated With Different Pharmaceutical Formulations

Enalapril maleate, available on the market in a variety of different pharmaceutical formulations, is commonly used for the control of systemic arterial hypertension. Many therapeutical failures have been reported thus far in clinical practice with respect to switching between different pharmaceutical formulations of the same product during pharmacological therapy. In the present study, plasma concentrations of enalapril and enalaprilate were measured in hypertensive patients undergoing treatment with different pharmaceutical formulations. Materials and methods: Pharmaceutical formulations studied included the reference brand product, a generic formulation, and a third drug product marketed as “similar”; plasma samples were obtained from 30 hypertensive volunteer patients. Drug was extracted from the plasma by solid phase extraction and determined by liquid chromatography-tandem mass spectrometry. The method was validated for the main analytical parameters. Results: The analytical method developed in this study, using liquid chromatography-tandem mass spectrometry, was confirmed as suitable for application in the determination of plasma concentrations in patients and subsequently revealed statistically significant differences in plasma concentrations between the 3 treatment groups. Conclusions: Such differences reinforce the hypothesis that the bioequivalence tests currently proposed by the regulatory authorities to promote interchangeability between pharmaceutical formulations may not in fact represent a definitive parameter for guaranteeing similar plasma concentrations.

Validation of an LC Method for Polyphenol Assay in Extractive Solutions from Ilex paraguariensis (Mate)

Abstract A liquid chromatography (LC) method was developed and validated for identification and quantification of polyphenols in aqueous extractive solution from Ilex paraguariensis (erva‐mate), in agreement with the ICH requirements for analytical methods. The analysis was performed using a RP 18 column, in gradient solvent. Chlorogenic acid (CLOA) and rutin (RU) were used as external standards. The standard curves for CLOA and RU were linear with correlation coefficients higher than 0.9980. The LC method showed excellent performance in separating seven peaks. The method showed excellent repeatability (R.S.D.<2.0%) and accuracy (CLOA=97.4 and RU=104.0%). Besides CLOA and RU, six other constituents were detected, which were identified by LC‐MS/MS based on their mass spectra in full scan mode and retention times compared with those available in the literature data. The analytical method was successfully applied for quantifying polyphenols in four different extractive solutions from erva‐mate, a decoction (ES), an infusion (ESI), and an extractive solution obtained by turbo extraction with water (TE1) or ethanol 40% (v/v) (TE2). The last one presented the highest polyphenol concentration.

Improvement of enalapril maleate chemical stability by high shear melting granulation

Abstract Enalapril maleate is a widely used drug, which is chemically unstable when mixed with excipients resulting in enalaprilat and diketopiperazine as the main degradation products. The preparation of enalapril sodium salt has been used to improve drug stability in solid dosage forms; however, product rejection is observed when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. In this study, granules were prepared by melting granulation using stearic acid or glyceryl monostearate, with a view to developing more stable enalapril maleate solid dosage forms. The granules were prepared in a laboratory-scale high shear mixer and compressed in a rotary machine. Size distribution, flow properties, in vitro drug release and enalapril maleate chemical stability were evaluated and compared with data obtained from tablets prepared without hydrophobic binders. All formulations showed good physical properties and immediate drug release. The greatest improvement in the enalapril maleate stability was observed in formulations containing stearic acid. This study showed that hot melting granulation could be successfully used to prepare enalapril maleate granules which could substitute the in situ formation of enalapril sodium salt, since they provided better enalapril stability in solid dosage forms.

Effect of Stearic Acid on Enalapril Stability and Dissolution from Multiparticulate Solid Dosage Forms

Enalapril maleate (EM) is a widely used anti-hypertensive drug which is unstable when mixed with excipients. Enalaprilate and diketopiperazine (DPK) are the main degradation products of enalapril. The in situ preparation of enalapril sodium salt (NaE) has been used to improve drug stability in dosage forms; however, gas release and product rejection ensue when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. This study evaluated the effect of stearic acid (SA) on enalapril stability in microcrystalline cellulose (MCC) pellets containing EM or NaE. MCC pellets containing SA were prepared by the extrusion–spheronization technique and characterized. Enalapril stability and dissolution were then evaluated. DPK and enalaprilate formation were reduced by the addition of SA in pellets containing EM. The overall enalapril degradation in these formulations was lower when compared with pellets containing EM or even NaE prepared without SA. The immediate-release characteristic was maintained by the addition of 5% crospovidone to all the formulations tested. The incorporation of SA into NaE pellets resulted in unexpected enalapril degradation, caused by the interaction of these compounds, as suggested by a thermal analysis of the SA–NaE binary mixture. The findings presented here showed that formulations containing SA could substitute the formation of NaE, since they provide better enalapril stability in solid dosage forms. In addition, it is suggested that the stabilization effects would be observed for other N-carboxyalkyl dipeptide analogs with angiotensin converting enzyme inhibition activity, since these new entities share the same degradation pathway of enalapril.

Isotretinoína: perfis farmacológico, farmacocinético e analítico

Isotretinoin, or 13-cis-retinoic acid, is one of the vitamin A related compounds. Isotretinoin is used for the treatment of severe cystic acne and also shows inhibitory activity over the proliferation of neoplasic cells, due to its efficiency in regulating cell diferentiation. Side effects are related to skin and mucous membranes, central nervous system, muscles, lymphatic, gastrintestinal, pulmonary and genitourinary systems. Isotretinoin is a highly thermal and photolabile compound. Stability studies require several analytical methods such as HPLC, GC, thermal analysis, mass spectrometry, microcalorimetry and X-Ray difratometry.

Preparation and characterization of solid oral dosage forms containing soy isoflavones

Soy isoflavones have been extensively used for menopausal symptoms and prevention of hormone-related cancer, osteoporosis and cardiovascular diseases. Commercially available forms of isoflavones include supplements, capsules and tablets. However, the non-standardization of soy isoflavones extracts and different dissolution profiles of these solid dosage forms highlight the need of additional studies on the development of well characterized pharmaceutical dosage forms of isoflavones. In this work, immediate release oral tablets of soy isoflavones were obtained and evaluated. Genistein and daidzein, were the main constituents of the dried soy extract. Preparation of the tables was accomplished in a rotary tableting machine following either a dry mixture for direct compression or wet granulation with different excipients. Powder, granules and tablets were evaluated for several parameters, including flow properties, Carr and Hausner indexes, hardness, friability, disintegration time and drug release profile. Also, a fast and validated HPLC analytical method for both genistein and daidzein was developed. Formulations containing sodium croscarmellose and sodium dodecyl sulfate resulted in better flowability as indicated by the flow rate and angle of repose, faster disintegration time and immediate release dissolution profile.