New Hydrophilic Matrix Tablets for the Controlled Released of Chlorzoxazone.

The modified release of active substances such as chlorzoxazone from matrix tablets, based on Kollidon®SR and chitosan, depends both on the drug solubility in the dissolution medium and on the matrix composition. The aim of this study is to obtain some new oral matrix tablet formulations, based on Kollidon®SR and chitosan, in order to optimize the low-dose oral bioavailability of chlorzoxazone, a non-steroidal anti-inflammatory drug of class II Biopharmaceutical Classification System. Nine types of chlorzoxazone matrix tablets were obtained using the direct compression method by varying the components ratio as 1:1, 1:2, and 1:3 chlorzoxazone/excipients, 20-40 w/w % Kollidon®SR, 3-7 w/w % chitosan while the auxiliary substances: Aerosil® 1 w/w %, magnesium stearate 0.5 w/w % and Avicel® up to 100 w/w % were kept in constant concentrations. Pharmaco-technical characterization of the tablets included the analysis of flowability and compressibility properties (flow time, friction coefficient, angle of repose, Hausner ratio, and Carr index), and pharmaco-chemical characteristics (such as mass and dose uniformity, thickness, diameter, mechanical strength, friability, softening degree, and in vitro release profiles). Based on the obtained results, only three matrix tablet formulations (F1b, F2b, and F3b, containing 30 w/w % KOL and 5 w/w % CHT, were selected and further tested. These formulations were studied in detail by Fourier-transform infrared spectrometry, X-ray diffraction, thermogravimetry, and differential scanning calorimetry. The three formulations were comparatively studied regarding the release kinetics of active substances using in vitro release testing. The results were analyzed by fitting into four representative mathematical models for the modified-release oral formulations. In vitro kinetic study revealed a complex mechanism of release occurring in two steps of drug release, the first step (0-2 h) and the second (2-36 h). Two factors were calculated to assess the release profile of chlorzoxazone: f1-the similarity factor, and f2-the factor difference. The results have shown that both Kollidon®SR and chitosan may be used as matrix-forming agents when combined with chlorzoxazone. The three formulations showed optima pharmaco-technical properties and in vitro kinetic behavior; therefore, they have tremendous potential to be used in oral pharmaceutical products for the controlled delivery of chlorzoxazone. In vitro dissolution tests revealed a faster drug release for the F2b sample.

Development of Solid Lipid Nanoparticles for Controlled Amiodarone Delivery.

In various drug delivery systems, solid lipid nanoparticles are dominantly lipid-based nanocarriers. Amiodarone hydrochloride is an antiarrhythmic agent used to treat severe rhythm disturbances. It has variable and hard-to-predict absorption in the gastrointestinal tract because of its low solubility and high permeability. The aims of this study were to improve its solubility by encapsulating amiodarone into solid lipid nanoparticles using two excipients-Compritol® 888 ATO (pellets) (C888) as a lipid matrix and Transcutol® (T) as a surfactant. Six types of amiodarone-loaded solid lipid nanoparticles (AMD-SLNs) were obtained using a hot homogenization technique followed by ultrasonication with varying sonication parameters. AMD-SLNs were characterized by their size distribution, polydispersity index, zeta potential, entrapment efficiency, and drug loading. Based on the initial evaluation of the entrapment efficiency, only three solid lipid nanoparticle formulations (P1, P3, and P5) were further tested. They were evaluated through scanning electron microscopy, Fourier-transform infrared spectrometry, near-infrared spectrometry, thermogravimetry, differential scanning calorimetry, and in vitro dissolution tests. The P5 formulation showed optimum pharmaco-technical properties, and it had the greatest potential to be used in oral pharmaceutical products for the controlled delivery of amiodarone.

Study on Acute Toxicity of Amiodarone New Complexes With Cyclodextrin.

Amiodarone low solubility and high permeability is the limiting step for its bioavailability, therefore new formulations are needed to improve the solubility of amiodarone either to increase its oral bioavailability or to reduce its toxic effects. Complexation of amiodarone with cyclodextrin results in improved dissolution rate, solubility, and allows for a more controlled drug release. We characterized the acute toxicity of a new amiodarone 2-hydroxypropyl-ß-cyclodextrin complex (AMD/HP-ß-CD) as powdered form and as a matrix based on Kollidon® and chitosan, administered intraperitoneally in laboratory animals. There were developed two formulations of matrix: one containing only pure AMD as a control sample (Fc) and one containing the inclusion complex with the optimal solubility (F). AMD was equitoxic with HP-ß-CD after intraperitoneal administration (289.4 mg/kg for AMD and 298.3 mg/kg for AMD/HP-ß-CD), with corresponding histopathological changes. The matrix based formulations presented higher LD50 values for acute toxicity, of 347.5 mg/kg for Fc and 455.6 mg/kg for F10, conducting to the idea of a safer administration because KOL and CHT matrix modified the solubility and controlled the AMD release. The LD50 is 1.5 higher for AMD/HP-ß-CD included in a KOL and CHT based matrix compared to the pure AMD, administered intraperitoneally.

In Vitro Dissolution Studies of Amiodarone Hydrochloride From Hydroxy-Propyl-ß-Cyclodextrin/Amiodarone Inclusion Complex Formulated Into Modified-Release Tablets.

Aim: Drug release from modified-release matrix tablets made of Kollidon® SR and Chitosan is dependent on its degree of solubility in the dissolution medium as well as on the matrix forming polymer. By complexing hydrochloride amiodarone with hydroxypropyl-ß-cyclodextrin, an inclusion complex was obtained, which showed an increase in solubility by more than 200%. The complex was used to obtain modified-release matrix tablets based on Kollidon® SR and Chitosan. Materials and Methods: Matrix tablets were obtained through direct compression method of non-complexed amiodarone and inclusion complex, and they were marked F1 and F10, respectively. The two formulations were studied comparatively in terms of release kinetics of the active substance through in vitro drug release tests. Those tests were conducted using a paddle apparatus II for 12 hours and two gastrointestinal simulation liquids with different pH values relevant for oral administration - 2 hours at pH 1.2 and 10 hours at pH 6.8. The release of hydrochloride amiodarone was quantified using a validated HPLC method. Two factors were calculated to assess the release profile of amiodarone: the similarity factor f1 and difference factor f2. Results: The increase in Kollidon® SR concentration resulted in a slower release of amiodarone at both pH values. The use of Chitosan resulted in a decrease of AMD release only at pH 6.8. Conclusions: The similarities between the two release profiles of AMD were confirmed by the values of the similarity factor (f1 = 43.697) and difference factor f2 (f2 = 68.263).

Fast RP-HPLC Method for the Determination of Bisoprolol.

Aim: To develop and validate a fast, robust, isocratic reversed-phase high performance liquid chromatographic method for the determination of bisoprolol in bulk and pharmaceutical formulations. Material and Method: Optimum separation of bisoprolol was achieved using as stationary phase a Zorbax SB-C18 column (100×3 mm; 5µm). The mobile phase was a mixture of phosphate buffer (pH = 3.5) and acetonitrile (70:30) with a flow rate of 1mL/min. The UV detection was performed at 225nm. The temperature of the column and autosampler was 25°C. The specificity was assessed by using metoprolol as internal standard. The method was validated in accordance with the current ICH guidelines in terms of linearity, limit of detection, limit of quantification, precision, accuracy, recovery and system suitability. Results: The retention time for bisoprolol was 1.158 minute. The calibration graph was linear in the concentration range 5-90 µg/mL. The LOD and LOQ of bisoprolol were 1.63 µg/mL and 4.94 µg/mL, respectively. The intra and interday precision of measurements were lower than the accepted criteria (RSD ≤ 2%). The recovery values of HPLC determination of bisoprolol from tablets proved that none of the excipients influenced the results of the analysis. Conclusions: The assay it was found to be accurate, reproducible, sensitive and less time consuming. The proposed method can be successfully applied to quality control studies of pharmaceutical products.

OPTIMIZATION OF THE PREPARATION OF KOLLIDON SR-BASED AMIODARONE HYDROCHLORIDE TABLETS WITH SUSTAINED RELEASE.

AIM: The formulation of sustained release tablets of AMD-HCl using KOLLIDON SR as matrix-forming agent. Chitosan, a natural polysaccharide with superior hydrating and absorbing properties was used in the formulation stage to optimize the release characteristics of those matrix tablets. MATERIAL AND METHODS: Nine formulations of sustained release matrix tablets of AMD x HCl (200 mg/tablet) were prepared through direct compression. The concentrations of matrix forming agents were included as independent variables of a type 2(3) mixed factorial plan in order to develop formulations of AMD-HCl with optimal release characteristics. The dependent variables of that plan were the amount of AMD released from the tablets studied by using in vitro dissolution testing. The test was carried out in the paddle apparatus II for 12 hours in two pH media that were relevant to oral delivery: 2 hours at pH 1.2 and 10 hours at pH 6.8. The released AMD-HCl was quantitatively determined through a validated HPLC method. RESULTS: The increase in KOL concentration leads to a decrease in AMD release rate at both pH values. The use of CHT resulted in a decrease of AMD release only at pH 6.8 in formulations with the lowest concentration of KOL. CONCLUSIONS: The retarding effect on the release of AMD-HCl in the tablets developed in this study was directly proportional to the KOL concentration in the formulation.

A NEW SPECTROPHOTOMETRIC METHOD FOR THE ASSAY OF LISINOPRIL.

AIM: A new spectrophotometric method for the assay of lisinopril using 2,4-dinitrophenol as reagent is described. MATERIAL AND METHODS: The method involved the addition of 2,4-dinitrophenol to lisinopril in methanol followed by absorbance measurement at 400 nm. Experimental conditions that provide wide linear range, maximum sensitivity, selectivity, accuracy and precisions were optimized. RESULTS AND DISCUSSIONS: Beer's law was obeyed in the concentration range 2.0-14.0 µg/mL. Linear regression equation of calibration graph was A = 0.005 + 0.045 x concentration, with a regression coefficient (r) of 0.9995 (n = 8). The limits of detection (LOD) and quantification (LOQ) calculated according to the ICH guidelines were 0.42 and 1.42 µg/mL, respectively. Accuracy and precision of the assays were determined by computing the intra-day and inter-day variations at three different lisinopril concentrations; the intra-day and inter-day RSD was < 1.43% and accuracy was better than 1.72%. CONCLUSIONS: The proposed method is simple, easy to perform, sensitive, linear, precise, accurate and robust.

ANTINFLAMMATORY ACTIVITY OF AN N, N'-DISALICYLIDENEMETHYLENDIAMINE-DERIVED SCHIFF BIS BASE AND ITS COPPER(II) COMPLEX.

AIM: The cooper(II) complex combination of N, N'-disalicylidenemethylenediamine and the Schiff bis base were investigated for anti-inflammatory activity. MATERIAL AND METHODS: In vivo, the anti-inflammatory activity of the metallic complex in comparison with the activity of the Schiff bis base was tested by the method of Winter and co-workers using the Levy technique. RESULTS AND DISCUSSIONS: Our study on the anti-inflammatory activity of a new Schiff bis base and its complex cooper(II) combination showed that the Schiff bis bases exhibited significant anti-inflammatory action in acute experimental inflammation when compared to the control group. The copper cation from the complex combination enhanced the anti-inflammatory effect of the Schiff bis base, the effect being stronger at doses of 10 mg/kg cooper(II) complex. CONCLUSIONS: The Schiff bis base and its cooper(II) complex had an anti-inflammatory effect comparable to that of indomethacin.

Spectrophotometric method for estimation of bisoprolol fumarate in tablets.

UNLABELLED: Bisoprolol fumarate is prescribed for the treatment of hypertension and angina pectoris. AIM: The purpose of this study was to develop a simple, sensitive, accurate, and reproducible method for estimation of bisoprolol fumarate in tablets. MATERIAL AND METHODS: The proposed method was based on a yellow colored complex formed with tropaeolin 00, extractable in dichloromethane with maximum absorbance at 412 nm. The method was validated statistically. RESULTS: The linearity domain was observed in the concentration of 5-30 microg/ml. The recovery studies confirmed the accuracy of the proposed method. CONCLUSIONS: The proposed method can be applied for the routine analysis of bisoprolol from formulations.

Validation of spectrophotometric method for Se(IV) determination: analytical applications.

As selenium is an important part of the antioxidant enzymes and also because there are several studies suggesting a possible link between cancer and selenium deficiency, this paper presents a spectrophotometric method for the assay of Se(IV), using N,N-diethyl-p-phenylenediamine monohydrochloride as reagent. The proposed method is based on the reaction between the selenium and potassium iodide in low acidic medium, when iodine is released. This last product will further oxidise the new reagent. The final obtained product is strongly coloured in red and has an absorption maximum at 552 nm and molar extinction coefficient (ε) of 6.1 × 10(4) L mol(-1) cm(-1). The optimum working conditions were established, and the developed method was validated, being characterised by a good linearity (in the range of 0.5-3.0 µg/mL), a limit of detection (0.0573 µg/mL) and a limit of quantification (0.1737 µg/mL). At the same time, the repeatability, the precision of the method and the accuracy were established. The proposed and validated method was applied with good results for the determination of Se(IV) in spring and bottled water from Iasi and also in pharmaceutical and cosmetic products.

Validation of a spectrophotometric assay method for bisoprolol using picric acid.

UNLABELLED: Bisoprolol is a drug belonging to beta blockers drugs used primarily for the treatment of cardiovascular diseases. AIM: A spectrophotometric method for quantitative determination of bisoprolol was developed based on the formation of a complex combination between bisoprolol and picric acid. MATERIAL AND METHODS: The complex combination of bisoprolol and picric acid has a maximum absorbance peak at 420 nm. Optimum working conditions were established and the method was validated. RESULTS: The method presented a good linearity in the concentration range 5-120 microg/ml (regression coefficient r2 = 0.9992). The RSD for the precision of the method was 1.74 and for the intermediate precision 1.43, and recovery values ranged between 98.25-101.48%. CONCLUSIONS: The proposed and validated spectrophotometric method for the determination of bisoprolol is simple and cost effective.

Visible spectrophotometric method for amiodarone.

Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmia, both ventricular and supraventricular (atrial) arrhythmia. A spectrophotometric method for the assay of amiodarone was established. Based on the reduction of potassium ferricyanide in hydrochloric acid medium to potassium ferrocyanide forming a blue colored complex ferric ferrocyanide with Fe (III) ions. The compound was most stable in a mixture of ethylic alcohol and water (2:1, v/v) and it had an absorption maximum at 725 nm. The data were according to the Lambert-Beer Law in the concentration range of 0.5-5.0 microg/sample: correlation and coefficient R = 0.99977, R2 = 0.999541, slope of the line 0.12775, intercept 0.042077. The detection limit (DL) was 0.1032 microg/sample and the quantification limit (QL) 0.344 microg/ sample.

Spectrometric method for the assay of ramipril using molybdophosphoric acid.

UNLABELLED: Ramipril is a drug of the angiotensin converting enzyme inhibitor class. AIM: A new molecular absorbance spectrometric method was developed for the assay of ramipril using molybdophosphoric acid in acidic medium. MATERIAL AND METHODS: The reaction product showed a maximum absorbance at 361 nm. The optimum conditions of the reaction were established. The developed method was validated. RESULTS: The method showed a good linearity in the range of 8 - 36 microg/ml (correlation coefficient r = 0.9996). The detection limit (LD) was 0.86microg/ml and the quantification limit (LQ) 2.88 pg/ml. Precision and accuracy were determined (RSD = 1.15%); mean recovery was 98.90% in the 97.13-101.03% concentration range. CONCLUSIONS: The proposed method is simple, easy to perform, sensitive, linear, precise, accurate and robust.

[Construction and characterisation of a selective membrane electrode for the assay of lisinopril]. / Constructia si caracterizarea unui electrod membrana selectiv pentru determinarea lisinoprilului.

UNLABELLED: In order to analyze lisinopril using a selective membrane electrode, the electro-active compound was obtained and included in the selective membrane. The new analysis method was developed and validated. MATERIAL AND METHOD: The electro-active compound was obtained through the precipitation of lisinopril in acidic media using silicowolframic acid solution. The membrane was obtained by mixing the electro-active compound with polyvinylchloride using tetrahydrofurane as solvent. The solution was evaporated in order to obtain a thick membrane, which was then attached at one end of a polyvinylchloride tube. The internal Ag/AgCl reference electrode was inserted in that tube. The assembly was filled with a lisinopril internal solution. The electrode was characterized by establishing the following characteristics: electrode slope, selectivity, optimal pH range, response time and life-time period. The developed method was validated. RESULTS: The method showed a good linearity in the range of 10(-7) and 10(-2)M (the correlation coefficient r = 0.9991). The detection limit (LD) was 8,66 x 10(-8)M and the quantification limit (LQ) was 7,8 x 10(-7)M. There were established the precision (RSD = 1.73%) and the accuracy (mean recovery was 99.92%) CONCLUSIONS: The experimental results demonstrated a good sensibility.

[Erythromycin ethylsuccinate obtaining possibilities]. / Posibilitati de obtinere a etil-succinatului de eritromicina.

UNLABELLED: In this study we tried to improve the erythromycin ethylsuccinate obtaining, having in view to separate the erythromycin ester by crystallization in water. MATERIAL AND METHODS: The erythromycin acylation and the erythromycin ethylsuccinate crystallization were realized, following the next steps: 1. the acylation of the erythromycin with a methylene chloride solution of monoethylsuccinyl chloride, at 25-28 degrees C for 3 hours in the presence of NaHCO3; 2. the transfer of the erythromycin ethylsuccinate from methylene chloride solution in acetone solution by distillation of mixture methylene chloride: acetone 1:1 at 25-28 degrees C; 3. erythromycin ethylsuccinate separation by crystallization in water at pH = 8-8.5 and 5 degrees C for 90 minutes. The quality control for the erythromycin ester was performed according to the Xth edition of Romanian Pharmacopoeia standards using national standard for erythromycin ethylsuccinate and national standard for erythromycin with an activity of 1: 937 U and 2.02% humidity. The Micrococcus luteus ATCC 9341 was used as a test microorganism and a thin layer cromatography was performed for qualitative control. RESULTS: 13.1 g of erythromycin ethylsuccinate were obtained with an output of the process of 82.02%. Using water for the separation of erythromycin ethylsuccinate the output of the process is greater (82.02%) than in case of using petroleum ether (74.14%) or hexane (80.25%). The thin layer cromatography revealed an Rf = 0.56 and the microbiological activity of the erythromycin ethylsuccinate was 98.7% compared with the standard. CONCLUSIONS: Using water instead of hexane or petroleum ether is gainful for the separation of erythromycin ethylsuccinate from the reaction medium. The obtained erythromycin ethylsuccinate corresponds to the Xth edition of Romanian Pharmacopoeia standards. So, the raw materials consumption is decreased, the costs are cut down, the obtained product purity is high and the output of the process is greater.

[Schiff base type onno spectrophotometric determination of magnesium]. / Determinarea spectrofotometrîca a Mg (II) folosind CA reactiv o baza Schiff tip ONNO.

By condensing hydrazide salicylic acid with o-hydroxy carbonilic compounds it was obtained 2--hydroxy acetophenon--salicyl hidrazina, Schiff base--type ONNO. These Schiff bis bases present a good capacity of complexing the Mg (II) ions. The above mentioned Schiff base forms complex with Mg (II) cation, with maximum absorbance at 386 nm, and molar absorbtivity (epsilon) = 6.27 x 10(4) mol-1.L.cm-1. The complex with Mg (II) presents a maximum stability at pH = 9.6 - 10.0. The calculated apparent stability constant is K = 3.18 x 10(3). The absorbance is proportional to Mg (II) concentration in the range of 10-60 mg/mL. In this range, the Lambert--Beer law is respected, the linearity coefficient being 0.9818, SD = 0.83, RSD = 0.84 (n = 6). The results obtained for spectrophotometric determination of Mg (II) using this Schiff base as reagent were successfully applied to pharmaceutical products containing Mg (II) cation.

[Membrane-selective electrode for atropine assay]. / Electrod membrana-selectiv pentru determinarea cantitativa a atropinei.

One membrane-selective electrode with PVC matrix for atropine is described, with atropine tetraphenylborate as electroactive material. This electrode has a linear response in the concentration range of 10(-2)-10(-5) M atropine sulphate, with a detection limit of 3.29 x 10(-6) M. This electrode was used with good results for quantitative assay by direct potentiometry and potentiometric titration of atropine sulphate from pharmaceutical formulations.

Schiff bis bases: analytical reagents. II. Spectrophotometric determination of manganese from pharmaceutical forms.

By condensing ethyl-o-hydroxybenzene with ethylene diamine, and 1-ethyl-salicylidene bis ethylene diamine, a Salen-type Schiff bis base is obtained. These Schiff bis bases present a good capacity of complexing the Mn(II) ions, resulting brown complexes. In this paper, the results of a study concerning the use of the Schiff bis base as reagent in spectrophotometric determination of the Mn(II) is presented. The above mentioned Schiff bis base forms a brown complex with Mn(II) cation, with maximum absorbance at 460 nm, and molar absorbtivity (epsilon)=9.8 x 10(4). The complex with Mn(II) presents a maximum stability at pH 6.0. The combination ratio was established by isomolar series method, and it is 1:2 (metal:ligand). The calculated apparent stability constant is beta(n)=2.943 x 10(-5). The absorbance is proportional to Mn(II) concentration in the range of 10-70 microg ml(-1). In this range, the Lambert-Beer law is respected, the linearity coefficient being 0.9989, S.D.=0.83, R.S.D.=0.88 (n=7). In these conditions, the complexation reaction of Mn(II) is interfered by other cations, Fe(II); Fe(III); Ni(II). The results obtained for spectrophotometric determination of Mn(II) using this Schiff base as reagent were successfully applied to pharmaceutical products containing Mn(II) cation.