Investigation of the Dissolution Profile of Gliclazide Modified-Release Tablets Using Different Apparatuses and Dissolution Conditions.

In the absence of an official dissolution method for modified-release tablets of gliclazide, dissolution parameters, such as apparatuses (1, 2, and 3), rotation speeds, pH, and composition of the dissolution medium were investigated. The results show that although the drug presents a pH-mediated solubility (pH 7.0 > 6.8 > 6.4 > 6.0 > 5.5 > 4.5), the in vitro release of the studied tablets was not dependent on this parameter, despite of the apparatus tested. On the other hand, the rotation speed demonstrated a greater influence (100 rpm >50 rpm). Using similar hydrodynamic conditions, the three different apparatuses were compared in pH 6.8 and provided the following trend: apparatus 1 at 100 rpm >2 at 50 rpm ≈3 at 10 dpm. As a complete, but slow release is expected from modified-release formulations, apparatus 2, in phosphate buffer pH 6.8 and 100 rpm, were selected as the optimized dissolution method. In comparison to apparatus 1 under the same conditions, the paddle avoids the stickiness of formulation excipients at the mesh of the basket, which could prejudice the release of gliclazide. Results obtained with biorelevant medium through the developed dissolution method were similar to the buffer solution pH 6.8. The application of the optimized method as a quality control test between two different brands of gliclazide modified-release tablets showed that both dissolution profiles were considered similar by the similarity factor (f2 = 51.8). The investigation of these dissolution profiles indicated a dissolution kinetic following first-order model.

How cocrystals of weakly basic drugs and acidic coformers might modulate solubility and stability.

Cocrystals of a weakly basic drug (nevirapine) with acidic coformers are shown to alter the solubility dependence on pH, and to exhibit a pHmax above which a less soluble cocrystal becomes more soluble than the drug. The cocrystal solubility advantage can be dialed up or down by solution pH.

Avaliação da qualidade e equivalência farmacêutica de comprimidos contendo 10mg de sinvastatina / Assessment of quality and pharmaceutical equivalence of 10 mg simvastatin tablets

A sinvastatina, pertencente à classe das estatinas, é um importante fármaco redutor do colesterol e é encontrada comercialmente como medicamentos referência, genéricos e similares em diferentes dosagens, sendo a de 10 mg a mais comum. Este trabalho tem como objetivo avaliar a qualidade e a equivalência entre comprimidos de sinvastatina 10 mg comercializados no mercado brasileiro. Foram selecionados dois medicamentos similares, um genérico e referência. Os ensaios de controle de qualidade aplicados foram: determinação do peso médio, dureza, friabilidade, desintegração, teor de princípio ativo, uniformidade de conteúdo e dissolução in vitro. Para tanto, foi necessário desenvolvimento e validação de metodologia por espectrofotometria na região do ultravioleta (UV). As formulações apresentaram-se dentro dos limites preconizados para todas as análises. No entanto, quando analisou-se estatisticamente os perfis de dissolução, verificou-se a não equivalência entre os medicamentos similares e o de referência. Porém, através dos resultados obtidos, podemos evidenciar a equivalência entre o genérico e o de referência, sugerindo sua intercambialidade...

Simvastatin, a well-known medicine of the statin class, is used therapeutically for the reduction of cholesterol and is commercially available in reference, similar and generic forms, in various doses, the tablet of 10 mg being the commonest in prescriptions. The purpose of this study was to test the quality and the pharmaceutical equivalence of tablets containing 10 mg of simvastatin available on the Brazilian market. One generic, one reference and two similar dosage forms were selected. The quality-control variables used were: weight variation, hardness, friability, disintegration, content of the active principle, content uniformity and dissolution in vitro. A UV-spectrophotometric method was developed and validated. All formulations were approved in the quality analysis. By using mathematical and statistical models, it was observed that the dissolution profiles of the similar dosage forms were not equivalent to that of the reference. On the other hand, when the generic medicine was compared with the reference, their interchangeability was confirmed...

Dissolution enhancement of Deflazacort using hollow crystals prepared by antisolvent crystallization process.

Deflazacort (DFZ), a derivate of prednisolone, is a poorly soluble drug which has been proposed to have major advantages over other corticosteroids. Poorly soluble drugs present limited bioavailability due to their low solubility and dissolution rate and several strategies have been developed in order to find ways to improve them. In general, pharmaceutical laboratories use a micronized process to reduce the particle size in order to increase the dissolution of the drugs. However, this process causes changes such as polymorphic transitions, particle agglomeration and a reduction in fluidity and wettability. These solid-state properties affect the dissolution behavior and stability performance of drugs. Crystallization techniques are widely used in the pharmaceutical industry and antisolvent crystallization has been used to obtain ultrafine particles. In this study, DFZ was investigated in terms of its antisolvent crystallization in different solvents and under various preparation conditions (methanol/water ratio, stirring and evaporation rate, etc.), in order to compare the physicochemical properties between crystallized samples and raw materials available on the Brazilian market with and without micronization. Crystalline structure, morphology, and particle size, and their correlation with the Intrinsic Dissolution Rate (IDR) and dissolution profile as relevant biopharmaceutical properties were studied. Crystallization conditions were achieved which provided crystalline samples of hollow-shaped crystals with internal channels, which increased the dissolution rate of DFZ. The antisolvent crystallization process allowed the formation of hollow crystals, which demonstrated a better dissolution profile than the raw material (crystalline and micronized), making this a promising technique as a crystallization strategy for improving the dissolution and thus the bioavailability of poorly soluble drugs.

Isolation and characterization of a degradation product of deflazacort.

Deflazacort (DFZ) is an oxazoline derivative of prednisolone with anti-inflammatory and immunosuppressive activity. The aim of this study was to investigate and to identify the main degradation product of DFZ, and to evaluate the anti-inflammatory effect of both DFZ and its major degradation product (namely DDP1). DFZ was subjected to alkaline and acid degradation. In 0.1 N NaOH, DFZ was immediately degraded and 99.0% of product DDP1 was detected by high performance liquid chromatography (HPLC). The HPLC method was ideal to separate the primary and other minor degradation products and was carried out using C18 column, mobile phase consisting of water: acetonitrile: (60:40, v/v) with flow rate of 1.0 mL/min and detection at 244 nm. DDP1 was isolated and identified as 21-hydroxy deflazacort (21-OH-DFZ) by NMR, IR and LCMS. The in vivo pharmacological assays showed that both DFZ as 21-OH-DFZ are active in in vivo and in vitro inflammatory models, but 21-OH-DFZ is more potent than DFZ.

Determination of tacrolimus in pharmaceutical formulations by validated spectrophotometric methods

Two simple, rapid and sensitive spectrophotometric methods were developed for the determination of tacrolimus in pharmaceutical dosage forms. The methods, based on the sulphuric acid reaction and on thei odine charge-transfer reaction, gave absorption peaksat 295 nm and 365 nm, respectively. The calibrationcurves were linear in the concentration range of 30-55 miug mL-1 for the sulphuric acid method (r² equal 0.9999)and 5-10 miug mL-1 (r² equal 0.9999) for the charge-transfer method. The specificity was assessed, showing that there was no interference from the excipients. The accuracyof both of the methods was higher than 99.44%, witha bias lower than 2%, and high precision was also demonstrated. The limits of quantitation for the two methods were 30 miug mL-1 and 5 miug mL-1. The proposed methods were applied to the determination of tacrolimusin capsule dosage forms, and the results compared statistically with the validated reversed-phase liquid chromatography (RP-LC) method, showing significant correlation (p smaller that 0.05) and demonstrating either method to be an excellent alternative to LC. The application of these simple methods to routine quality control analysisof pharmaceuticals could contribute to their safety and therapeutic efficacy.

Direct spectrophotometric determination of diacerhein in capsules.

A simple, rapid and precise ultraviolet spectrophotometric method using 0.1 N sodium hydroxide has been developed and validated for the assay of diacerhein. The drug can be estimated at 277 nm (ultraviolet region, UV) as well as at 502 nm (visible region, VIS). The absorbances were linearly correlated with concentration in the 6.0-24 microg mL(-1) range (r = 0.9999) and 10-34 microg mL(-1) range (r = 0.9998), respectively at 277 and at 502 nm. The relative standard deviation values for intra (n = 6) and inter-day (n = 3) precision were <2%. Recoveries ranged between 99.0 and 101.7%. The method has been successfully applied to the drug assay in capsules. It was also found that the excipients in the commercial capsules did not interfere with the method. Statistical analysis showed no significant difference between the results obtained at two wavelengths (277 nm or 502 nm).

Spectrophotometric determination of carvedilol in pharmaceutical formulations through charge-transfer and ion-pair complexation reactions.

Simple extraction-free spectrophotometric methods have been developed for the determination of carvedilol (CAR). The methods were based either on charge-transfer reaction of the drug with the sigma-acceptor iodine, in acetonitrile, or on ion-pair formation with the acidic sulphophthalein dyes bromothymol blue (BTB) and bromocresol green (BCG), in chloroform. The obtained complexes showed absorbance maxima at 363, 411 and 414 nm, respectively for iodine, BTB and BCG. Beer's law validation, accuracy, precision, and other aspects of analytical merit are presented in the text. The proposed methods were applied for the determination of CAR in tablets and compounded capsules. The results were in good agreement with those obtained by an established UV spectrophotometric method.

Desenvolvimento de teste de dissolução e estudo comparativo de comprimidos e cápsulas magistrais contendo anlodipino / Development of dissolution test and comparative study of tablets and compounded capsules containing amlodipine

O anlodipino é um fármaco amplamente utilizado para o tratamento da hipertensão arterial e da angina, e encontra-se disponível, no mercado brasileiro, sob a forma de comprimidos e cápsulas magistrais.O presente estudo objetivou desenvolver as condições para o teste de dissolução, bem como realizar estudo comparativo visando avaliar a intercambiabilidade de alguns produtos contendo o fármaco por meio de testes físicos e físico-químicos, tais como:variação de peso, desintegração, dureza, friabilidade, identificação, teor, uniformidade de conteúdo, teste e perfil de dissolução.No desenvolvimento do método de dissolução, diversas condições foram testadas e os seguintes parâmetros foram considerados satisfatórios:ácido clorídrico 0,01N (500 mL, a 37graus C mais ou menos 0,5 graus C) como meio de dissolução, aparato cesta e pá, respectivamente para cápsulas e comprimidos, e rotação de 50 rpm.Realizou-se estudo comparativo de cápsulas manipuladas por cinco diferentes farmácias, denominadas de A, B, C, D e E;bem como de comprimidos obtidos de cinco laboratórios produtores diferentes, denominados de F, G, H, I e J. Os produtos B (cápsula) e H (comprimido) foram reprovados nos teste de uniformidade de conteúdo e dureza, respectivamente.Todos os demais produtos apresentaram resultados satisfatórios nos testes a que foram submetidos.

Microbiological assay for terbinafine hydrochloride in tablets and creams.

The optimization of a microbiological assay, applying the cylinder-plate method, for the determination of the antifungal terbinafine hydrochloride is described. Using a strain of Aspergillus flavus ATCC 15546 as the test organism, terbinafine hydrochloride at concentrations ranging from 0.125 to 0.5 microg ml(-1) could be measured in tablets and creams. A prospective validation of the method showed that the method was linear (r=0. 9999), precise (intra-day: CV=0.48%-tablets and 0.43%-creams; inter-day: CV=0.98%-tablets and 0.64%-creams) and accurate (it measured the added quantities). The method shows results that confirm its precision, not differing significantly the others methods described in the literature. We conclude that the microbiological assay is satisfactory for quantitation of in vitro antifungal activity of terbinafine.

UV spectrophotometry and nonaqueous determination of terbinafine hydrochloride in dosage forms.

An ultraviolet spectrophotometric and a nonaqueous volumetric method for determining terbinafine hydrochloride (TH) in pharmaceutical formulations are presented. The UV spectrophotometric procedure was developed for assay of TH in raw materials, tablets, and creams. The method was tested for linearity (0.8-2.8 micrograms/mL, r = 0.9997), recovery (102.00% for creams and 99.90% for tablets) and precision (101.3%, CV = 0.96%, n = 9, for creams; 100.25%, CV = 1.08%, n = 9, for tablets). The volumetric method involves titration of TH with 0.05M perchloric acid with crystal violet as indicator. This method was used for quantitative determination of TH in raw materials and tablets. Mean recovery and precision were, respectively, 100.41 and 101.18% (CV = 1.64%, n = 9) for TH tablets. There were no significant differences between the proposed methods and a previously described high-performance liquid chromatographic method. The UV spectrophotometric and titrimetric methods are potentially useful for a routine laboratory because of their simplicity, rapidity, and accuracy.