Gislaine Ribeiro Pereira

Multivariate optimization and validation of an analytical methodology by RP-HPLC for the determination of losartan potassium in capsules

This paper describes the optimization and validation of an analytical methodology for the determination of losartan potassium in capsules by HPLC using 2(5-1) fractional factorial and Doehlert designs. This multivariate approach allows a considerable improvement in chromatographic performance using fewer experiments, without additional cost for columns or other equipment. The HPLC method utilized potassium phosphate buffer (pH 6.2; 58 mmol L(-1))-acetonitrile (65:35, v/v) as the mobile phase, pumped at a flow rate of 1.0 mL min(-1). An octylsilane column (100 mm x 4.6mm i.d., 5 microm) maintained at 35 degrees C was used as the stationary phase. UV detection was performed at 254 nm. The method was validated according to the ICH guidelines, showing accuracy, precision (intra-day relative standard deviation (R.S.D.) and inter-day R.S.D values <2.0%), selectivity, robustness and linearity (r=0.9998) over a concentration range from 30 to 70 mg L(-1) of losartan potassium. The limits of detection and quantification were 0.114 and 0.420 mg L(-1), respectively. The validated method may be used to quantify losartan potassium in capsules and to determine the stability of this drug.

Analysis of chlorthalidone polymorphs in raw materials and tablets and the effect of forms I and II on the dissolution properties of drug products

Chlorthalidone (CTD) is an antihypertensive drug and exhibits four crystalline forms: I, II, III and IV. In this paper, the incidence of CTD polymorphs in raw materials and in tablets as well as the solubility and dissolution properties of forms I and II have been studied. Raw materials were named as A, B, C, D, and E and tablets as Reference, G1, G2 and S. Using powder X-ray diffraction and infrared spectroscopy analyses we found that A, B, E, Reference and G1 contain CTD form I; C, D and S contain predominantly form II; and G2 contain a mixture of both forms. Solubility experiments showed that form II is up to 49% more soluble than form I and dissolution studies showed a significantly effect of the polymorphism on the dissolution of CTD from tablets. Based on these results, it was concluded that only the CTD form I is acceptable for preparation of tablet form. Moreover, we proposed the polymorphic quality control of CTD raw materials and tablets.

In vitro evaluation of transdermal nicotine delivery systems commercially available in Brazil

The aim of this study was to develop and validate a method for evaluating the release and skin permeation from transdermal nicotine patches using the vertical diffusion cell (VDC). The VDC is an experimental apparatus employed in research, development, and the pharmaceutical field because it can simulate conditions closest to those established in clinical trials. Two transdermal nicotine delivery systems marketed in Brazil to release 14 mg over 24 hours were evaluated. Release studies were carried out using a regenerated cellulose dialysis membrane and permeation studies were carried out using excised porcine ear skin. The results indicated that nicotine release from both evaluated patches follows Higuchis release kinetics, while skin permeation studies indicated zero-order release kinetics. Nicotine release rates were different between both evaluated patches, but drug permeation rates were not significantly different. According to validation studies, the method was appropriate for evaluating in vitro performance of nicotine patches. The proposed method can be applied to in vitro comparative studies between different commercial nicotine patches and may be used as an auxiliary tool in the design of new transdermal nicotine delivery systems.

Desenvolvimento e validação de um método analítico rápido por cromatografia líquida de alta eficiência para determinação de nimesulida em estudos de liberação in vitro

A high performance liquid chromatography (HPLC) method has been developed for a rapid determination of nimesulide in dissolution studies. Nimesulide was analyzed using 5 µm Lichrospher® RP-18 column (125 x 4 mm i.d.) and mobile phase acetonitrile: phosphate buffer pH=6.0 (55:45) at a flow-rate of 1.0 mL min-1. Detection was carried out at 300 nm at 25 oC. The method was applied to analysis of nimesulide in in vitro release studies and showed a rapid and efficient analytical alternative for evaluation of dissolution profile of nimesulide.

Exploring the Phase Behavior of Monoolein/Oleic Acid/Water Systems for Enhanced Donezepil Administration for Alzheimer Disease Treatment

Donepezil is a drug usually administered by oral route for Alzheimer disease treatment, but several gastric side effects have been reported as diarrhea, nausea, and anorexia. We explored the phase behavior of lyotropic liquid crystalline (LLC) mesophases composed by monoolein/oleic acid/water for enhanced administration of donepezil. Polarized light microscopy suggested that these systems ranged from isotropic inverse micellar solutions (L2) to viscous and birefringent reverse hexagonal (HII) mesophases according to the amount of water in the ternary systems. Phase transition was observed from a L2 phase to HII mesophase after swelling studies, an interesting property to be explored as a precursor of LLC mesophases for mucosal administration that increases its viscosity in situ. Mucoadhesive properties of LLC mesophases were characterized using a texture analyzer indicating that these systems can have an increased residence time in the site of absorption. Donepezil-free base was incorporated in the evaluated formulations, and their in vitro release was controlled up to 24 h. The phase behavior of the systems demonstrated a great potential for enhanced donepezil administration once these mucoadhesive-controlled release formulations can incorporate the drug and prolong its release, possibly reducing its side effects.

Comparative study of analytical methods by direct and first-derivative UV spectrophotometry for evaluation of losartan potassium in capsules

Losartan potassium is an antihypertensive non-peptide agent, which exerts its action by specific blockade of angiotensin II receptors. The aim of the present study was the validation and application of analytical methods for the quality control of losartan potassium 50 mg in pharmaceutical capsules, using direct and first-derivative UV spectrophotometry. Based on losartan potassium spectrophotometric characteristics, a signal at 205 nm of the zero-order spectrum and a signal at 234 nm of the first-derivative spectrum, were found adequate for quantification. The results were used to compare these instrumental techniques. The linearity between the signals and concentrations of losartan potassium in the ranges of 3.0-7.0 mg L-1 and 6.0-14.0 mg L-1 for direct and first-derivative spectrophotometry in aqueous solutions, respectively, presented a correlation coefficient (r) of 0.9999 in both cases. The methods were applied for losartan potassium in capsule dosage obtained from local pharmacies, and were shown to be efficient, easy to apply and low cost. These methods do not use polluting reagents and require relatively inexpensive equipment.

A Dissolution Test for Finasteride in Immediate-Release Capsules

In vitro dissolution tests for solid oral dosage forms are extremely important to ensure the quality of these products. However, no dissolution test has been reported for finasteride (FNS) in immediate-release capsules. The aims of this work were to optimize a dissolution method for FNS capsules, validate the analytical method, and evaluate three different commercial products. The best in vitro dissolution profile was achieved using water as the dissolution medium with a basket stirrer at 100 rpm. The quantitative determination was performed by high performance liquid chromatography (HPLC) at 210 nm. All validation parameters were satisfactory. The application of the method to commercial products showed the discriminatory power of the dissolution method. Because there is no monograph for FNS in capsules, this study illustrates the importance of an official dissolution test for FNS in capsules and the need to standardize the composition of the excipients contained in these commercial products. INTRODUCTION In vitro dissolution tests for immediate-release solid oral dosage forms, such as tablets and capsules, are extremely important because these tests are essential to evaluate the lot-to-lot quality of a drug product, to guide the development of new formulations, and to ensure continuing product quality and performance after certain changes (e.g., formulation, manufacturing process, site of manufacture, and scale-up of the manufacturing process) (1). For these reasons, progressively more emphasis has been placed on dissolution testing within the pharmaceutical industry and by regulatory authorities (2). Despite the importance of dissolution tests in ensuring the quality of medicines, several drug products that are widely commercialized throughout the world lack official dissolution tests. Finasteride (FNS) is a relevant example because no dissolution test is reported in the literature or in pharmacopeias for immediate-release capsules of this medication. FNS capsules are widely marketed and are prepared for medical reasons (e.g., avoiding an excipient to which a patient is allergic or obtaining a dosage level that is not marketed). FNS is N-(1,1-dimethylethyl)-3-oxo-4-aza-5α-androst1-ene-17β-carboxamide (Figure 1), a specific competitive inhibitor of steroid type-II 5α-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT) and is widely used for the treatment of benign prostatic hyperplasia (BPH) (3), prostate cancer (4), and androgenetic alopecia (5–8). A daily dose of 5 mg has been used for the treatment of BPH and prostate cancer, and a 1-mg dose has been used for the treatment of androgenetic alopecia. FNS has a molecular formula of C23H36N2O2, a molecular weight of 372.6, and a log Po/w of 3.03. According to the Biopharmaceutics Classification System (BCS), FNS is a Class 2 drug having low solubility and high permeability (9). Multiple analytical procedures have been reported for the analysis of FNS in pharmaceutical preparations when it is present as a single active ingredient or in combination dosage forms, using spectrophotometry (10–12), thin-layer chromatography (13, 14), infrared spectrophotometry (15), polarography (16), voltammetry (17), gas chromatography (18), gas chromatography–mass spectrometry (19), high performance liquid chromatography (HPLC) (20–23), and ultra-high performance liquid chromatography (UHPLC) (24, 25). Because of the importance of in vitro dissolution tests for immediate-release solid oral dosage forms and the lack of a dissolution test for FNS compounded capsules, the aims of this work were to optimize a dissolution method *Corresponding author. e-mail: olimpia_martins@yahoo.com.br Figure 1. Chemical structure of finasteride. dx.doi.org/10.14227/DT200313P25

Molecularly imprinted microparticles in lipid-based formulations for sustained release of donepezil.

Donepezil is a drug administered for Alzheimers disease treatment, and it is a potential template molecule for imprinted microparticles. The precipitation polymerization technique allows the synthesis of spherical imprinted microparticles, and the intermolecular interactions among drug and molecularly imprinted polymers (MIPs) play a promising role for delineating drug delivery systems. Once that donepezil is a poorly-water soluble compound, lipid based-formulations (LBFs) may enhance its oral administration. Based on this, LBFs are useful vehicles to incorporate imprinted microparticles synthesized by precipitation polymerization. In these formulations, the drug dissolved in lipids is accessible to adsorbate in the polymers, and the hydrophobic environment of lipids increases the molecular recognition of MIPs. The formulations based on MIPs using pure oleic acid as vehicle prolong the in vitro release of donepezil up to several hours by a Fickian diffusion mechanism, and it provides a multiphasic release pattern related to the heterogeneity of the binding sites. The modulation of donepezil release from MIPs-based formulations using oil vehicles may contribute to decrease its side effects, possibly regulating its absorption rate in the gastrointestinal tract. These systems represent a novel technological platform to prolong the delivery not only for donepezil, but also for a variety of therapeutics.

LC-PDA and LC-MS studies of donepezil hydrochloride degradation behaviour in forced stress conditions

The aim of this work was to study the intrinsic stability of donepezil hydrochloride in conditions of forced degradation (acid stress, alkaline stress, oxidant stress, light exposure and dry heat). The degradation profile of donepezil was characterized by liquid chromatography-mass spectrometry (LC-MS) and high-performance liquid chromatography coupled with photodiode array detection (LC-PDA). According to the results, the degradation products were separated and detected in acid and alkaline solutions. After seven days at room temperature, the recovery of donepezil in alkaline solution (0.1 mol L-1 NaOH) was about 42%, and three degradation products were detected. In acid solution (0.1 mol L-1 HCl), the drug recovery was about 86%, and three degradation products were detected. Thus, it was possible to propose a rapid and selective stability-indicating assay method using reversed-phase liquid chromatography for analysis of donepezil and their degradation products.

Development and validation of a dissolution test for diltiazem hydrochloride in immediate release capsules

This work describes the development and validation of a dissolution test for 60 mg of diltiazem hydrochloride in immediate release capsules. The best dissolution in vitro profile was achieved using potassium phosphate buffer at pH 6.8 as the dissolution medium and paddle as the apparatus at 50 rpm. The drug concentrations in the dissolution media were determined by UV spectrophotometry and HPLC and a statistical analysis revealed that there were significant differences between HPLC and spectrophotometry. This study illustrates the importance of an official method for the dissolution test, since there is no official monograph for diltiazem hydrochloride in capsules.