No abstract

Vortioxetine hydrobromide (VOR), is a novel antidepressant used for the treatment of major depressive disorder. It has a chemical structure susceptible to degradation, therefore it is important to have suitable analytical methods to determine VOR in presence of its main degradation products (DP), because if the compound degrades, this could result in diminution of the therapeutic activity and safety. A simple HPLC method with photodiode array detection was developed and validated for determination of VOR in bulk and tablets, in the presence of its major DP. The drug was subjected to oxidative, hydrolytic, and photolytic stress conditions, showing significant degradation under oxidation with the formation of one DP, which was identified by ESI-MS/MS. A C 18 column was used, with mobile phase consisting of acetonitrile and water with acetic acid and triethylamine in isocratic elution mode, with detection at 228 nm and 1.0 mL/min flow rate. The assay was linear in the 25-125 μg/mL concentration range. For precision, the RSD was <1.8%, the recovery was 100.0-101.6%, and the method demonstrated adequate selectivity. The method was successfully applied to quantify VOR in tablets. The results showed that the method is useful for routine analysis and for quality control purposes.

Abstract:In this work, microparticles were prepared by spray-drying using albumin, chondroitin sulfate, and hyaluronic acid as excipients to create a controlled-release methylprednisolone system for use in inflammatory disorders such as arthritis. Scanning electron microscopy demonstrated that these microparticles were almost spherical, with development of surface wrinkling as the methylprednisolone load in the formulation was increased. The methylprednisolone load also had a direct influence on the mean diameter and zeta potential of the microparticles. Interactions between formulation excipients and the active drug were evaluated by x-ray diffraction, differential scanning calorimetry, and thermal gravimetric analysis, showing limited amounts of methylprednisolone in a crystalline state in the loaded microparticles. The encapsulation efficiency of methylprednisolone was approximately 89% in all formulations. The rate of methylprednisolone release from the microparticles depended on the initial drug load in the formulation. In vitro cytotoxic evaluation using THP-1 cells showed that none of the formulations prepared triggered an inflammatory response on release of interleukin-1β, nor did they affect cellular viability, except for the 9.1% methylprednisolone formulation, which was the maximum test concentration used. The microparticles developed in this study have characteristics amenable to a therapeutic role in inflammatory pathology, such as arthritis.

Due to their crystalline nature, the encapsulation of hydrophobic corticosteroids within polymeric nanoparticles by o/w solvent evaporation method is often difficult to achieve. The aim of this study was to evaluate the effect of both process and formulation parameters on the encapsulation of a model corticosteroid: methylprednisolone (MP). For this purpose, a 3(2)factorial design was performed evaluating the effects of the concentration of emulsifiers and sonication time on the manufactured nanoparticles, followed by a multiresponse optimization. The study also included the evaluation of other parameters such as the type of organic solvent used, polymer characteristics and the initial mass of drug. The optimal nanoparticle formulation using 0.25% (w/v) of emulsifying agent (Polyvinyl-alcohol, PVA) and 5 min of sonication was then characterized. The highest encapsulation was obtained with an organic phase consisting of acetone: dichloromethane (1:1), polyD,L-lactide-co-glycolide (PLGA) 50:50 as polymer and an initial mass of 6.6 mg of methylprednisolone. Nanoparticles size and ζ potential of optimized formulation were respectively around 230 nm and -14 mV. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) demonstrated that the drug was molecularly dispersed within the nanoparticles. Release study showed that MP-loaded nanoparticles sustained drug release for up to 120 h. This study reflects the importance of factorial design to optimize the manufacture of nanoparticles encapsulating hydrophobic drugs.

Development, validation and comparison of two stability-indicating LC methods, one with photodiode array detector (DAD) and the other with evaporative light scattering detector (ELSD), were performed for simultaneous determination of candesartan cilexetil (CANC) and hydrochlorothiazide (HCTZ), in pharmaceutical samples. A RP-18 column (125 mm × 4 mm, 5 μm) was used for separation of CANC, HCTZ and its major degradation products, using acetonitrile and phosphate buffer (pH 6.0) for DAD method and acetonitrile and water with acetic acid and triethylamine (pH 4.1) for ELSD method, as mobile phase in a gradient mode. The response with ELSD was fitted to a power function and the DAD response by a linear model over a range of 32-160 μg/mL for CANC and 25-125 μg/mL for HCTZ. The precision and accuracy of the methods were similar, with RSD below 3.0% and recovery between 98.1% and 103.9%. The drugs were subjected to stress conditions of hydrolysis, oxidation, photolysis, humidity and temperature. The degradation products were satisfactory separated from the main peaks and from each other. Both drugs mainly degrade by hydrolysis, showing the formation of one degradation product for HCTZ and two for CANC; its identification was conducted by LC/MS/MS. The methods were successfully applied to the analysis of CANC and HCTZ in combined commercial tablets. The performance of DAD and ELSD methods are comparable, therefore both methods are suitable for stability study and determination of CANC and HCTZ in pharmaceutical samples.