Environmentally sustainable DRS-FTIR probe assisted by chemometric tools for quality control analysis of cinnarizine and piracetam having diverged concentration ranges: Validation, greenness, and whiteness studies.

A novel diffuse reflectance fourier transform infrared spectroscopic method accompanied by chemometrics was optimized to fulfill the white analytical chemistry and green analytical chemistry principles for the quantification of cinnarizine and piracetam for the first time without any prior separation in their challenging pharmaceutical preparation, which has a pretty substantial difference in the concentration of cinnarizine/piracetam (1:16). Furthermore, the suggested method was used for cinnarizine/piracetam dissolution testing as an effective alternative to traditional methods. For the cinnarizine/piracetam dissolution tests, we used a dissolution vessel with 900 mL of phosphate buffer pH 2.5 at 37 °C ± 0.5 °C, then the sampling was carried out by frequent withdrawal of 20 µl samples from the dissolution vessel at a one-minute interval, over one hour, then representative fourier transform infrared spectra were recorded. To create a partial-least-squares regression model, a fractional factorial design with 5 different levels and 2 factors was used. This led to the creation of 25 mixtures, 15 as a calibration set and 10 as a validation set, with varying concentration ranges: 1-75 and 16-1000 µg/mL for cinnarizine/piracetam, respectively. Upon optimization of the partial-least-squares regression model, in terms of latent variables and spectral region, root mean square error of cross-validation of 0.477 and 0.270, for cinnarizine/piracetam respectively, were obtained. The optimized partial-least-squares regression model was further validated, providing good results in terms of recovery% (around 98 to 102 %), root mean square error of prediction (0.436 and 3.329), relative root mean square error of prediction (1.210 and 1.245), bias-corrected mean square error of prediction (0.059 and 0.081), and limit of detection (0.125 and 2.786) for cinnarizine/piracetam respectively. Ultimately, the developed method was assessed for whiteness, greenness, and sustainability using five assessment tools. the developed method achieved a greener national environmental method index and complementary green analytical procedure index quadrants with higher eco-scale assessment scores (91), analytical greenness metric scores (0.87), and red-greenblue 12 algorithm scores (89.7) than the reported methods, showing high practical and environmental acceptance for quality control of cinnarizine/piracetam.

Versatile TLC-Densitometric Methods for the Synchronous Estimation of Cinnarizine and Acefylline Heptaminol in The Presence of Potential Impurity and Their Reported Degradation Products.

From evolution, thin-layer chromatography (TLC) attracts attention as a versatile technique for efficient separation and identification of many drug substances and chemicals. Owing to its simplicity and other outstanding advantages, TLC is extensively used by chromatographers in quantification and purity profiling objectives. In the present study two TLC-Densitometric methods are established and validated for the synchronous estimation of Cinnarizine (Cinn) and Acefyline Heptaminol (Acef) in the presence of Cinn/Acef reported degradation products and Thoephylline (Theo) as Acef potential impurity. The proposed methods are based on densitometric measurements of the spots of Cinn and Acef after separation from their degradation products. Separation is attained on silica gel sheet with dichloromethane: methanol: formic acid as a developing system in ratio: (15, 1, 0.5, by volume) and (15, 0.75, 0.4, by volume) for Cinn (method 1) and Acef (method 2) degradation, consecutively. Quantification is done at 254 nm over concentration ranges of 0.2-1.8 and 2-18 µg/spot for Cinn and Acef; respectively, with mean percentage recoveries of 99.18 ± 0.60/99.84 ± 0.53 and 99.19 ± 0.93/99.66 ± 0.58 for method 1 and method 2; consecutively. The two methods are fully validated and proven to be selective, robust and retained their accuracy in up to 50% of Cinn/Acef reported degradation products and Theo. Moreover, the two methods are applied to a coformulated drug product comprising Cinn and Acef showing satisfactory results. Comparison of the obtained results by the proposed methods with that of the reference ones statistically shows no significant differences.

Estudo da eficácia de encapsulação da Cinarizina em cubossomos não-iônicos: caracterização estrutural e citotóxica / Study of the encapsulation efficacy of Cinnarizine in non-ionic cubosomes: structural and cytotoxic characterization

Os cubossomos são partículas nanoestruturadas em forma de bicamada lipídica, bicontínuas e altamente curvadas, as quais devem ser estabilizadas por um polímero não-iônico, neste caso o Pluronic® F-127. Podem ser compostos por alguns tipos de lipídios específicos que possuem a capacidade de se auto associar em estruturas cúbicas quando estão em excesso de água, como o fitantriol (PHY) e a monoleína (GMO). Devido a sua estrutura única, cubossomos possuem um grande potencial para serem considerados como sistemas drug delivery. Os sistemas drug delivery são amplamente utilizados na pesquisa farmacêutica e em contextos clínicos para aumentar a eficácia de compostos utilizados para diagnóstico e de fármacos. No caso da cinarizina (CNZ), fármaco já aprovado para o tratamento de náuseas, vômitos e vertigens causadas pela doença de Ménière, existem inúmeros efeitos colaterais associados a sua baixa solubilidade. Desta forma, a encapsulação em cubossomos se torna uma abordagem promissora para resolver os problemas de atividade farmacológica relacionados ao fármaco. Neste trabalho, realizamos uma caracterização biofísica da interação da CNZ em cubossomos (contendo PHY ou myverol, MYV, sendo este composto por 80% de GMO). As técnicas biofísicas utilizadas foram: espalhamento de raios-X em baixos ângulos (SAXS), espalhamento dinâmico de luz (DLS), microscopia eletrônica de transmissão (TEM), crio microscopia eletrônica de transmissão (Crio-TEM), análise de rastreamento de nanopartículas (NTA) e potencial zeta. A cromatografia líquida de alta eficiência (HPLC) foi realizada para verificar a porcentagem de eficiência de encapsulação (%EE) da CNZ nos cubossomos, enquanto que a citotoxicidade foi avaliada em eritrócitos através da análise da atividade hemolítica. Inicialmente, a influência de diferentes solventes (acetona, clorofórmio, etanol e octano) nas propriedades estruturais de cubossomos de PHY foi investigada, a fim de se minimizar os efeitos do solvente utilizados para a encapsulação da CNZ. Para amostras com acetona, descobriu-se que apenas altas concentrações tiveram influência na estrutura cristalográfica das nanopartículas, sendo o resultado foi totalmente reversível após 24h. O etanol fez com que o parâmetro de rede aumentasse de 10-15%. O clorofórmio e o octano tiveram efeitos diferentes sobre cubossomos de PHY em comparação com a acetona e o etanol; ambos induziram uma transição cúbico-hexagonal-micelar. Posteriormente, constatamos que as nanopartículas de PHY e MYV apresentaram diferentes estruturas cristalográficas, sendo elas Pn3m e Im3m, respectivamente. Devido a problemas com a baixa solubilidade de CNZ em PHY os estudos para esse lipídio foram suspensos. Nos testes para cubossomos de MYV ao incorporar a CNZ foi observado uma alteração da estrutura cúbica de Im3m para Pn3m e os valores dos parâmetros de rede se alteraram de acordo com a estrutura cristalina encontrada, porém os valores não apresentaram diferenças significativas de tamanho quando se trata da mesma estrutura, sugerindo que a CNZ não interferiu no parâmetro de rede. Os tamanhos das nanopartículas apresentaram uma população monodispersa com ~200 nm. DLS mostrou uma interferência da CNZ no tamanho dos cubossomos, variando de forma diretamente proporcional a concentração de CNZ na amostra, enquanto as técnicas de NTA e microscopia apresentaram nanopartículas de tamanhos bastante variados, mas independente da interferência da CNZ. A encapsulação de CNZ também foi dosada por HLPC em cubossomos de MYV, obtendo um limite superior de 0,6 mg/mL. A atividade citotóxica dos cubossomos foi testada em eritrócitos, revelando uma taxa de hemólise bastante inferior em cubossomos com CNZ em relação a cubossomos puros. Acreditamos que os cubossomos podem sim ser utilizados como sistemas carreadores de CNZ

Cubosomes are nanostructured particles in the form of a lipid bilayer, bicontinuous and highly curved, which must be stabilized by a non-ionic polymer, in this case Pluronic® F-127. They can be composed of some types of specific lipids that have the ability to self-associate in cubic structures when they are in excess of water, such as phytantriol (PHY) and monolein (GMO). Due to their unique structure, cubosomes have a great potential to be considered as drug delivery systems. Drug delivery systems are widely used in pharmaceutical research and clinical settings to increase the efficacy of compounds used for diagnostics and drugs. In the case of cinnarizine (CNZ), a drug already approved for the treatment of nausea, vomiting and vertigo caused by Ménière's disease, there are numerous side effects associated with its low solubility. Thus, cubosomal encapsulation becomes a promising approach to solve drug-related problems of pharmacological activity. In this work, we performed a biophysical characterization of the CNZ interaction in cubosomes (containing PHY or myverol, MYV, which is composed of 80% GMO). The biophysical techniques used were: low angle X-ray scattering (SAXS), dynamic light scattering (DLS), transmission electron microscopy (TEM), cryo transmission electron microscopy (Crio-TEM), nanoparticle tracking analysis (NTA) and zeta potential. High performance liquid chromatography (HPLC) was performed to verify the percentage of encapsulation efficiency (%EE) of CNZ in cubosomes, while cytotoxicity was evaluated in erythrocytes by analyzing the hemolytic activity. Initially, the influence of different solvents (acetone, chloroform, ethanol and octane) on the structural properties of PHY cubosomes was investigated in order to minimize the effects of the solvent used for the encapsulation of CNZ. For samples with acetone, it was found that only high concentrations had an influence on the crystallographic structure of the nanoparticles, with the result being fully reversible after 24h. Ethanol caused the network parameter to increase by 10-15%. Chloroform and octane had different effects on PHY cubosomes compared to acetone and ethanol; both induced a cubic-hexagonal-micellar transition. Later, we found that PHY and MYV nanoparticles presented different crystallographic structures, being Pn3m and Im3m, respectively. Due to problems with the low solubility of CNZ in PHY, studies for this lipid were suspended. In the tests for MYV cubosomes when incorporating CNZ, a change in the cubic structure from Im3m to Pn3m was observed and t he lattice parameters changed according to the crystal structure found, but the differences observed were not significant when it comes to the same structure, suggesting that the CNZ did not interfere with the network parameter. The nanoparticle sizes showed a monodisperse population with ~200 nm. DLS showed an interference of CNZ in the size of the cubosomes, varying directly proportionally to the concentration of CNZ in the sample, while NTA and microscopy techniques showed nanoparticles of widely varying sizes, but independent of CNZ interference. CNZ encapsulation was also dosed by HLPC in MYV cubosomes, obtaining an upper limit of 0.6 mg/ml. The cytotoxic activity of cubosomes was tested in erythrocytes, revealing a much lower rate of hemolysis in cubosomes with CNZ compared to pure cubosomes. We believe that cubosomes can indeed be used as CNZ carrier systems

Full spectrum and selected spectrum based chemometric methods for the simultaneous determination of Cinnarizine and Dimenhydrinate in laboratory prepared mixtures and pharmaceutical dosage form.

Three chemometric methods namely, concentration residual augmented classical least squares (CRACLS), spectral residual augmented classical least squares (SRACLS) and partial least squares (PLS) were applied for the simultaneous quantitative determination of Cinnarizine and Dimenhydrinate in their binary mixtures. All techniques were applied with and without variable selection using genetic algorithm (GA) resulting in six models (CRACLS, GA-CRACLS, SRACLS, GA-SRACLS, PLS, GA-PLS). These models were applied for the simultaneous determination of the drugs in their laboratory prepared mixtures and pharmaceutical dosage form via handling their UV spectral data. It was found that GA based models are simpler and more robust than those built with the full spectral data. The proposed models were found to be simple, fast and require no preliminary separation steps; so they can be used for the routine analysis of this binary mixture in quality control laboratories.

Optimization of self-nanoemulsifying formulations for weakly basic lipophilic drugs: role of acidification and experimental design

ABSTRACT Formulators face great challenges in adopting systematic approaches for designing self-nanoemulsifying formulations (SNEFs) for different drug categories. In this study, we aimed to build-up an advanced SNEF development framework for weakly basic lipophilic drugs, such as cinnarizine (CN). First, the influence of formulation acidification on CN solubility was investigated. Second, formulation self-emulsification in media with different pH was assessed. Experimentally designed phase diagrams were also utilized for advanced optimization of CN-SNEF. Finally, the optimized formulation was examined using cross polarizing light microscopy for the presence of liquid crystals. CN solubility was significantly enhanced upon external and internal acidification. Among the various fatty acids, oleic acid-based formulations showed superior self-emulsification in all the tested media. Surprisingly, formulation turbidity and droplet size significantly decreased upon equilibration with CN. The design was validated using oleic acid/Imwitor308/Cremophor El (25/25/50), which showed excellent self-nanoemulsification, 43-nm droplet size (for CN-equilibrated formulations), and 88 mg/g CN solubility. In contrast to CN-free formulations, CN-loaded SNEF presented lamellar liquid crystals upon 50% aqueous dilution. These findings confirmed that CN-SNEF efficiency was greatly enhanced upon drug incorporation. The adopted strategy offers fast and accurate development of SNEFs and could be extrapolated for other weakly basic lipophilic drugs.

Quantitative analysis of solid samples using modified specular reflectance accessory.

Diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS) is a fast, reliable and cost effective analytical method, requiring minimal or no sample preparation. It is commonly used in the course of qualitative and quantitative analysis of pharmaceutical ingredients and food. We demonstrate that simpler and cheaper specular reflectance (SR) accessory working in a DRIFTS like mode (SR-DL) can be an alternative for DIRFTS attachment. An application of a modified SR accessory for quantitative analysis of solids samples is presented. As a case study the concentration of cinnarizine in commercial tablets has been determined from DRIFTS and SR-DL infrared (IR) and near-infrared (NIR) spectra recorded using DTGS (deuterated triglicine sulphate) detector in the IR and NIR regions and InGaAs (indium-gallium arsenide) detector in the NIR range. Based on these spectra Partial Least Squares (PLS) models were constructed and relative standard errors of prediction (RSEP) were calculated for the calibration, validation and analysed data sets. They amounted to 2.4-2.5%, 2.1-2.7% and 2.0-2.6% for the DRIFTS attachment while 2.1-2.2%, 2.0-2.3% and 1.9-2.6%, respectively, for the modified SR accessory. Obtained error values indicate that modified SR accessory can be effectively used for quantification of solid pharmaceutical samples in the mid- and near-infrared regions.

Simultaneous Determination of Cinnarizine and Dimenhydrinate in Binary Mixture Using Chromatographic Methods.

Two accurate and sensitive chromatographic methods have been developed and validated for simultaneous determination of cinnarizine (CIN) and dimenhydrinate (DIM). The first method uses simultaneous quantitative thin layer chromatography (TLC) spectrodensitometric evaluation of them, using ethyl acetate:methylene chloride (8 : 2 by volume) as a mobile phase. Chromatograms are scanned at 254 nm. This method analyzes CIN in a concentration range of 0.5-6 µg per band with mean percentage recovery of 99.78 ± 1.001 and DIM in a concentration range of 1-6 µg per band with mean percentage recovery of 99.87 ± 1.319. The second method is high-performance liquid chromatography using methanol:acetonitrile:water [85 : 10 : 5, by volume +0.5% tri ethyl amine (TEA)] as a mobile phase. The linearity was found to be in the range of 10-60 and 5-60 µg mL(-1) for CIN and DIM, respectively. The methods were successfully applied to the simultaneous determination of CIN and DIM in bulk powder, laboratory-prepared mixtures and pharmaceutical dosage forms. The validity of results was assessed by applying standard addition techniques. The results obtained are found to agree statistically with those obtained by a reported method, showing no significant difference with respect to accuracy and precision.

Development of normalized spectra manipulating spectrophotometric methods for simultaneous determination of Dimenhydrinate and Cinnarizine binary mixture.

Simultaneous determination of Dimenhydrinate (DIM) and Cinnarizine (CIN) binary mixture with simple procedures were applied. Three ratio manipulating spectrophotometric methods were proposed. Normalized spectrum was utilized as a divisor for simultaneous determination of both drugs with minimum manipulation steps. The proposed methods were simultaneous constant center (SCC), simultaneous derivative ratio spectrophotometry (S(1)DD) and ratio H-point standard addition method (RHPSAM). Peak amplitudes at isoabsorptive point in ratio spectra were measured for determination of total concentrations of DIM and CIN. For subsequent determination of DIM concentration, difference between peak amplitudes at 250 nm and 267 nm were used in SCC. While the peak amplitude at 275 nm of the first derivative ratio spectra were used in S(1)DD; then subtraction of DIM concentration from the total one provided the CIN concentration. The last RHPSAM was a dual wavelength method in which two calibrations were plotted at 220 nm and 230 nm. The coordinates of intersection point between the two calibration lines were corresponding to DIM and CIN concentrations. The proposed methods were successfully applied for combined dosage form analysis, Moreover statistical comparison between the proposed and reported spectrophotometric methods was applied.

Comparative study of spectrophotometric methods manipulating ratio spectra: an application on pharmaceutical binary mixture of cinnarizine and dimenhydrinate.

Four simple, specific, accurate and precise spectrophotometric methods are developed and validated for simultaneous determination of cinnarizine (CIN) and dimenhydrinate (DIM) in a binary mixture with overlapping spectra, without preliminary separation. The first method is dual wavelength spectrophotometry (DW), the second is a ratio difference spectrophotometric one (RD) which measures the difference in amplitudes between 250 and 270 nm of ratio spectrum, the third one is novel constant center spectrophotometric method (CC) and the fourth method is mean centering of ratio spectra (MCR). The calibration curve is linear over the concentration range of 4-20 and 10-45 µg/ml for CIN and DIM, respectively. These methods are tested by analyzing synthetic mixtures of the above drugs and they are applied to commercial pharmaceutical preparation of the subjected drugs. The validity of results was assessed by applying standard addition technique. The results obtained were found to agree statistically with those obtained by a reported method, showing no significant difference with respect to accuracy and precision.

Simultaneous determination of Cinnarizine and Domperidone by area under curve and dual wavelength spectrophotometric methods.

Accurate, selective and sensitive spectrophotometric methods have been developed and validated for simultaneous determination of Cinnarizine and Domperidone, a binary mixture with overlapping spectra, without preliminary separation. These methods include area under the curve (AUC) and dual wavelength spectrophotometry. For the AUC method, the area under curve of mixture solutions in the wavelength ranges 241-258 nm and 280-292 nm were selected for determination of Cinnarizine and Domperidone and by applying Cramer's rule, concentration of each drug was obtained. In dual wavelength method, two wavelengths were selected for each drug in a way so that the difference in absorbance is zero for another drug. Domperidone shows equal absorbance at 240.2 nm and 273.2 nm, where the differences in absorbance were measured for the determination of Cinnarizine. Similarly, differences in absorbance at 230.8 nm and 259.2 nm were measured for determination of Domperidone. The proposed methods were applied for determination of Cinnarizine and Domperidone over the concentration ranges of 2-20 and 2-22 µg mL(-1), respectively. The suggested methods were validated as per USP guidelines and the results revealed that they are reliable, reproducible and precise for routine use with short analysis time. The results obtained by the proposed methods were statistically compared to the reported method, and there was no significant difference between them regarding both accuracy and precision.

Smart stability-indicating spectrophotometric methods for determination of binary mixtures without prior separation.

Ratio subtraction and isosbestic point methods are 2 innovating spectrophotometric methods used to determine vincamine in the presence of its acid degradation product and a mixture of cinnarizine (CN) and nicergoline (NIC). Linear correlations were obtained in the concentration range from 8-40 microg/mL for vincamine (I), 6-22 microg/mL for CN (II), and 6-36 microg/mL for NIC (III), with mean accuracies 99.72 +/- 0.917% for I, 99.91 +/- 0.703% for II, and 99.58 +/- 0.847 and 99.83 +/- 1.039% for III. The ratio subtraction method was utilized for the analysis of laboratory-prepared mixtures containing different ratios of vincamine and its degradation product, and it was valid in the presence of up to 80% degradation product. CN and NIC in synthetic mixtures were analyzed by the 2 proposed methods with the total content of the mixture determined at their respective isosbestic points of 270.2 and 235.8 nm, and the content of CN was determined by the ratio subtraction method. The proposed method was validated and found to be suitable as a stability-indicating assay method for vincamine in pharmaceutical formulations. The standard addition technique was applied to validate the results and to ensure the specificity of the proposed methods.

Second-derivative synchronous fluorescence spectroscopy for the simultaneous determination of cinnarizine and nicergoline in pharmaceutical preparations.

A rapid, simple, and highly sensitive second-derivative synchronous fluorometric method has been developed for the simultaneous analysis of binary mixtures of cinnarizine (CN) and nicergoline (NIC). The method is based upon measurement of the native fluorescence of these drugs at constant wavelength difference (Deltalambda) = 80 nm in aqueous methanol (50%, v/v). The different experimental parameters affecting the native fluorescence of the studied drugs were carefully studied and optimized. The fluorescence-concentration plots were rectilinear over the range of 0.025-1.5 and 0.25-5.5 microg/mL for CN and NIC, respectively, with lower detection limits of 0.58 and 0.82 ng/mL and quantitation limits of 1.93 and 2.73 ng/mL for CN and NIC, respectively. The proposed method was successfully applied for the determination of the studied compounds in synthetic mixtures and in commercial tablets. The results obtained were in good agreement with those obtained with reference methods. The high sensitivity attained by the proposed method allowed the determination of CN in real and spiked human plasma. The mean recovery in the case of spiked human plasma [number of trials (n) = 3] was 102.82 +/- 2.17%, while that in real human plasma (n = 3) was 105.25 +/- 2.05.

Method development and validation for the simultaneous determination of cinnarizine and co-formulated drugs in pharmaceutical preparations by capillary electrophoresis.

Rapid and simple capillary electrophoresis (CE) methods were developed for the simultaneous determinations of cinnarizine and domperidone (CN/DOM) and cinnarizine and nicergoline (CN/NIC) in their co-formulated tablets. The optimized CE conditions were as follows: running buffer, methanol-acetate buffer (pH 3.0, 10 mM) (80:20 and 85:15 (v/v) for CN/DOM and CN/NIC, respectively); applied voltage, 20 kV; UV detection wavelengths, 215 and 227 nm for CN/DOM and CN/NIC, respectively; hydrodynamic injection was performed at a height of 25 mm for 30 s. Quinine hydrochloride and nicardipine hydrochloride were used as internal standards for the determination of CN/DOM and CN/NIC, respectively. Calibration curves were linear over the ranges 0.25-20/0.375-15 microg/ml (CN/DOM) and 0.25-25/0.4-10 microg/ml (CN/NIC) in each optimized condition. Detection limits were 0.074/0.119 microg/ml and 0.072/0.116 microg/ml for CN/DOM and CN/NIC, respectively. The proposed methods were successfully applied for the simultaneous determination of both CN/DOM and CN/NIC in their co-formulated tablets without interfering peaks due to the excipients present in the pharmaceutical tablets. The estimated amounts of CN/DOM and CN/NIC were almost identical with the certified values, and their percentage relative standard deviation values (%R.S.D.) were found to be < or =2.34% (n=3).

Second-derivative synchronous fluorometric method for the simultaneous determination of cinnarizine and domperidone in pharmaceutical preparations. Application to biological fluids.

A rapid, simple and highly sensitive second derivative synchronous fluorometric method has been developed for the simultaneous analysis of binary mixture of cinnarizine (CN) and domperidone (DOM). The method is based upon measurement of the native fluorescence of these drugs at Deltalambda=80 nm in aqueous methanol (50% V/V). The different experimental parameters affecting the native fluorescence of the studied drugs were carefully studied and optimized. The fluorescence-concentration plots were rectilinear over the range of 0.1 to 1.3 microg mL(-1) and 0.1-3.0 microg mL(-1) for CN and DOM, respectively with lower detection limits of 0.017 and 5.77 x 10(-3) microg mL(-1) and quantification limits of 0.058 and 0.02 microg mL(-1) for CN and DOM. The proposed method was successfully applied for the determination of the studied compounds in synthetic mixtures and in commercial tablets. The results obtained were in good agreement with those obtained with reference methods. The high sensitivity attained by the synchronous fluorometric method allowed the determination of CN in real and spiked human plasma. The mean % recoveries in case of spiked human plasma (n=3) were 96.39+/-1.18 while that in real human plasma (n = 3) was 104.67+/-4.16.

Optimización del sistema gastrorretentivo para la administración oral controlada de cinarizina mediante la metodología de superficie de respuesta / Optimization of gastroretentive system for oral controlled delivery of cinnarizine using response surface methodology

Se propone un sistema fl otante efervescente de liberación controlada para la administración gastrorretentiva de cinarizina. Para producir comprimidos de cinarizina fl otantes de liberación controlada mediante compresión directa se utilizó un diseño de Box-Behnken 33. Se estudiaron los efectos de variables de formulación como los niveles de HPMC K4M (X1), bicarbonato sódico (X2) y ácido cítrico (X3) en las características de fl otabilidad del comprimido y la liberación de fármaco. Los parámetros de respuesta como el tiempo de fl otabilidad total (TFT), la liberación al cabo de 10 h (Rel10), el tiempo necesario para la liberación del 50% del fármaco (t50) y el exponente de difusión de Korsemeyer y Peppas (n), se analizaron mediante la metodología de superfi cie de respuesta. Los parámetros se analizaron mediante el test F, y se generaron modelos matemáticos para cada parámetro de respuesta mediante análisis de regresión lineal múltiple (MLRA) y análisis de varianza (ANOVA). Las tres variables de formulación estudiadas tuvieron un efecto signifi cativo (P < 0,05) en el TFT, mientras que los niveles de HPMC K4M y ácido cítrico infl uyeron signifi cativamente en la liberación de fármaco. Para desarrollar una formulación optimizada se utilizó la optimización numérica con enfoque de deseabilidad, estableciendo restricciones en las variables dependientes e independientes. La formulación optimizada presentó una liberación de fármaco del 82,37 % durante el TFT de 8,5 h en modo de orden cero un valor de t50 de 5,30 h. Los valores experimentales del TFT, t50 y Rel10 observados concordaban con los predichos por los modelos matemáticos, confi rmando la predictabilidad de MLRA y ANOVA

A controlled release effervescent fl oating system is proposed for gastroretentive delivery of cinnarizine. A 33 box-behnken design was employed to produce controlled release fl oating tablets of cinnarizine by direct compression method. The effect of the formulation variables such as levels of HPMC K4M (X1), sodium bicarbonate (X2) and citric acid (X3) on the tablet fl oating characteristics and drug release was studied. The response parameters like total fl oating time (TFT), release at the end of 10 h (Rel10), time taken for 50% of the drug to release (t50) and Korsemeyer and Peppas diffusion exponent (n) were analyzed using response surface methodology. The parameters were analyzed using the F test and mathematical models were generated for each response parameter using multiple linear regression analysis (MLRA) and analysis of variance (ANOVA). All the three formulation variables studied had a signifi cant effect (P < 0.05) on the TFT whereas the levels of HPMC K4M and citric acid signifi cantly infl uenced the drug release. Numerical optimization employing desirability approach was used to develop an optimized formulation by setting constraints on the dependent and independent variables. The optimized formulation showed 82.37 % drug release during the TFT of 8.5 h in a zero order fashion with a t50 of 5.30 h. The experimental values of the TFT, t50 and Rel10 were found to agree with those predicted by the mathematical models confi rming the fore casting ability of MLRA and ANOVA

New methods for determination of cinnarizine in mixture with piracetam by spectrodensitometry, spectrophotometry, and liquid chromatography.

Four new methods were developed and validated for the determination of cinnarizine HCl in its binary mixture with piracetam in pure and pharmaceutical preparations. The first one was a densitometric analysis that provides a simple and rapid method for the separation and quantification of cinnarizine HCI. The method depends on the quantitative densitometric evaluation of thin-layer chromatograms of cinnarizine HCI at 252 nm over concentration range of 1-6 microg/spot, with a mean accuracy of 100.05 +/- 0.91%. The second method was determination of the drug using a colorimetric method that utilizes the reaction of 3-methyl-benzothiazolin-2-one in the presence of FeCl3 as an oxidant. The green color of the resulting product was measured at 630 nm over concentration range 10-40 microg/mL, with a mean accuracy of 100.10 +/- 1.13%. The third method was a direct spectrophotometric determination of cinnarizine HCI at 252 nm over the concentration range 7-20 microg/mL, while piracetam was determined by derivative ratio spectrophotometry at 221.6 nm over concentration range 5-30 microg/mL, with a mean accuracy of 100.14 +/- 0.79 and 100.26 +/- 1.24% for cinnarizine HCI and piracetam, respectively. The last method was a liquid chromatography analysis of both cinnarizine HCI and piracetam, depending on quantitative evaluation of chromatograms of cinnarizine HCI and piracetam at 252 and 212 nm, respectively, over the concentration range 10-200 microg/mL for cinnarizine HCI and 20-500 microg/mL for piracetam, with a mean accuracy of 100.03 +/- 0.89 and 100.40 +/- 0.94% for cinnarizine HCI and piracetam, respectively. The proposed procedures were checked using laboratory-prepared mixtures and successfully applied for the analysis of their pharmaceutical preparations. The validity of the proposed procedures was further assessed by applying the standard addition technique. Recoveries were quantitative, and the results obtained agreed with those obtained by other reported methods.

Simultaneous determination of domperidone and cinnarizine in a binary mixture using derivative spectrophotometry, partial least squares and principle component regression calibration.

This work is concerned with the simultaneous determination of domperidone maleate (DOM) and cinnarizine (CINN) in a binary mixture form, without previous separation, by two different techniques. The first method is the application of derivative spectrophotometry where the linearity range and percentage recoveries for DOM and CINN were 2.5-30 micro g mL(-1), 5-25 micro g mL(-1) and 100.06+/-1.157, 99.93+/-1.377, respectively. The second method depends on the application of partial least squares (PLS) and principle component regression (PCR) models. A training set consisting of 10 mixtures containing 5-20 micro g mL(-1) for each component was used for the construction of the PCR and PLS models. These models were used after their validation for the prediction of the concentration of DOM and CINN in their mixtures. The proposed procedures were successfully applied for the simultaneous determination of both drugs in laboratory prepared mixtures and in commercial tablet preparations. The validity of the proposed methods was assessed by applying the standard addition technique where the percentage recovery of the added standard was found to be 99.98+/-0.297 and 99.84+/-0.700 for DOM and CINN, respectively, using the derivative spectrophotometric method and 100.29+/-0.398 and 100.11+/-0.363 for DOM and CINN, respectively, using the PLS and PCR methods. The proposed procedures are rapid, simple, require no preliminary separation steps and can be used for routine analysis of both drugs in quality control laboratories.

Simultaneous determination of domperidone maleate and cinnarizine in a binary mixture using derivative ratio spectrophotometry and classical least squares calibration.

This work is concerned with the simultaneous determination of domperidone maleate (DOM) and cinnarizine (CINN) in a binary mixture form without previous separation by two different methods. The first method is the application of derivative ratio spectrophotometry where the linearity range was 2.5-30 micro g/ml, 2.5-25 micro g/ml for DOM and CINN, respectively, and percentage recoveries were 100.26+/-1.308 and 99.86+/-0.939 for DOM and CINN, respectively, in their laboratory prepared mixtures. The second method depends on the application of classical least squares (CLS) calibration model. Two training sets were constructed and the best model was used for the prediction of the concentrations of both drugs. The proposed procedures were successfully applied for the simultaneous determination of both drugs in laboratory prepared mixtures and in commercial tablet preparations. The validity of the proposed methods was assessed by applying the standard addition technique where the percentage recovery of the added standard was found to be 99.83+/-1.861 and 98.38+/-0.871 for DOM and CINN, respectively, using the derivative ratio method and 99.53+/-0.916 and 99.39+/-0.599 for DOM and CINN, respectively, using the CLS method. The proposed procedures are rapid, simple, require no preliminary separation steps and can, therefore, be used routine analysis of both drugs in quality control laboratories.

Simple spectrophotometric determination of cinnarizine in its dosage forms.

A direct, extraction-free spectrophotometric method has been developed for the determination of cinnarizine in pharmaceutical preparations. The method is based on ion-pair formation between the drug and three acidic (sulphonphthalein) dyes; namely bromocresol green (BCG), bromocresol purple (BCP) and bromophenol blue (BPB) which induces an instantaneous bathochromic shift of the maximum in the drug spectrum. Conformity to Beer's law enabled the assay of dosage forms of the drug. Compared with a reference method, the results obtained were of equal accuracy and precision. A more detailed investigation of the cinnarizine-BCG ion pair complex was made with respect to its composition, association constant and free energy change. In addition, this method was also found to be specific for the analysis of cinnarizine in the presence of some of the co-formulated drugs, such as pyridoxine hydrochloride and digoxin.

LC and TLC determination of cinnarizine in pharmaceutical preparations and serum.

New high performance liquid chromatography (HPLC) and thin layer densitometry (TLC) methods are developed for quantification of cinnarizine in dosage forms in the presence of its photo-degradation products and related substances and in the presence of its metabolites in serum. Mobile phases consisting of benzene-methanol-formic acid (80:17:3) and methanol-acetate buffer of pH 4 (70:30) are satisfactorily used for resolution of cinnarizine from associated substances by TLC and HPLC techniques, respectively. The lower detection limits are 16 and 10 ng microl(-1) of cinnarizine with standard deviations of 1.3 and 1.1% with TLC and HPLC, respectively. The methods are used for assessment of drug purity, stability, bioavailability, bioequivalency and tablet dissolution rate. Four cinnarizine related substances and six drug degradation products are isolated and identified by infrared and mass spectrometry. The results obtained by both techniques are in good agreement and offer the advantages of reproducibility and accuracy.