Formulation and pharmaceutical development of quetiapine fumarate sustained release matrix tablets using a QbD approach

The main objective of the present study was to apply QbD methodology in the development of once-a-day sustained release quetiapine tablets. The quality target product profile (QTPP) was defined after the pharmaceutical properties and kinetic release of the innovator product, Seroquel XR 200 mg. For the D-optimal experimental design, the level and ratio of matrix forming agents and the type of extragranular diluent were chosen as independent inputs, which represented critical formulation factors. The critical quality attributes (CQAs) studied were the cumulative percentages of quetiapine released after certain time intervals. After the analysis of the experimental design, optimal formulas and the design space were defined. Optimal formulas demonstrated zero-order release kinetics and a dissolution profile similar to the innovator product, with f2 values of 74.53 and 83.74. It was concluded that the QbD approach allowed fast development of sustained release tablets with similar dissolution behavior as the innovator product

Piecewise function parameters as responses of the design of experiment in development of a pulsatile release chronopharmaceutical system

The aim of this work was to develop a pulsatile release system with metoprolol for chronotherapeutical use by coating swellable mini-tablets with Eudragit RS. To study the influence of the formulation factors (amount of coating polymer, plasticizer percentage in film coating and swelling agent percentage in mini-tablets), a Box-Behnken design of experiment (DoE) was used. To evaluate the influence of the studied factors on the sigmoid shape of the dissolution profile, piecewise function parameters were used as the responses of DoE. The results show that higher concentrations of coating polymer and higher concentrations of plasticizer polymer led to a thicker and more elastic polymeric film, which led to a delay in drug release. Using the parameters of the piecewise function as DoE responses, an optimum formulation with a sigmoid shape dissolution profile and a 2.5-h lag time followed by rapid drug release were obtained

Quantification of ascorbic acid and sodium ascorbate in powder blends for tableting and in vitamin C chewable tablets by NIR-chemometry

The paper proposes a near infrared methodable to directlyand simultaneously quantify ascorbic acid and sodium ascorbate in powder blends for tableting and in vitamin C chewable tablets without any sample preparation.In the first step, calibration models for the quantification of ascorbic acid and sodium ascorbate in powder blends for tabletingand subsequently in chewable vitamin C tablets (corresponding to 80–120 % active substance) were developed according to an experimental design with 2 variables and 5 levels. Then, using the best calibration models, the methods were fully validatedin terms of recovery, precision and accuracyfor both powder blends and vitamin Cchewable tablets.The validated concentration range was 15.14–18.51 % for ascorbic acid and 12.06–14.49 % for sodium ascorbate in powder blends and 91.85–111.03 mg per tablet for ascorbic acid and 71.01–84.50 mg per tablet for sodium ascorbate in tablets. Validation results showed good precision and accuracy

Piecewise function parameters as responses of the design of experiment in the development of a pulsatile release chronopharmaceutical system

The aim of this work was to develop a pulsatile release system with metoprolol for chronotherapeutical use by coating swellable mini-tablets with Eudragit RS. To study the influence of the formulation factors (amount of coating polymer, plasticizer percentage in film coating and swelling agent percentage in mini-tablets), a Box-Behnken design of experiment (DoE) was used. To evaluate the influence of the studied factors on the sigmoid shape of the dissolution profile, piecewise function parameters were used as the responses of DoE. The results show that higher concentrations of coating polymer and higher concentrations of plasticizer polymer led to a thicker and more elastic polymeric film, which led to a delay in drug release. Using the parameters of the piecewise function as DoE responses, an optimum formulation with a sigmoid shape dissolution profile and a 2.5-h lag time followed by rapid drug release were obtained

A quality by design approach for the development of lyophilized liposomes with simvastatin

Lyophilization is used to ensure an increased shelf-life of liposomes, by preserving them in dry state, more stable than the aqueous dispersions. When stored as aqueous systems, the encapsulated drugs are released and the liposomes might aggregate or fuse. The aim of this study was to develop and optimize a lyophilized formulation of simvastatin (SIM) loaded into long circulating liposomes using the Quality by Design (QbD) approach. Pharmaceutical development by QbD aims to identify characteristics that are critical for the final product quality, and to establish how the critical process parameters can be varied to consistently produce a product with the desired characteristics. In the case of lyophilized liposomes, the choice of the optimum formulation and technological parameters has to be done, in order to protect the integrity of the liposomal membrane during lyophilization. Thus, the influence of several risk factors (3 formulation factors: PEG proportion, cholesterol concentration, the cryoprotectant to phospholipids molar ratio, and 2 process parameters: the number of extrusions through 100 nm polycarbonate membranes and the freezing conditions prior lyophilization) over the critical quality attributes (CQAs) of lyophilized long circulating liposomes with simvastatin (lyo-LCL-SIM), i.e. the size, the encapsulated SIM concentration, the encapsulated SIM retention, the Tm change and the residual moisture content, was investigated within the current study using the design of experiments tool of QbD. Moreover, the design space for lyo-LCL-SIM was determined, in which the established quality requirements of the product are met, provided that the risk factors vary within the established limits

PREFORMULATION STUDIES FOR A PARENTERAL SOLUTION OF MEMANTINE

Abstract Preformulation studies regarding a physico-chemical evaluation of memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, are presented in this work. This characterization of memantine is pre-required for the formulation of a parenteral solution. The water solubility, the thermal behavior and the chemical stability in aqueous solution, depending on the pH, temperature, UV light and the presence of oxidizing or isotonising agents were determined. A LC/MS/MS analytical method for memantine hydrochloride quantification was developed and validated. It was determined that memantine hydrochloride has a water solubility of 47.035 mg/mL (20 o C). Thermal analysis revealed that it is an anhydrous substance, presenting a crystalline form, with the melting point at 297.16 o C. In aqueous solution memantine hydrochloride is stable at room temperature (20 o C), regardless the pH of medium, UV light, isotonising agent or oxidizing agent and at 80ºC, at acidic pH value. These results indicate that memantine hydrochloride has appropriate physico-chemical properties for a parenteral solution formulation. Rezumat În această lucrare sunt prezentate studii de preformulare constând într-o evaluare fizico-chimică a memantinei, un antagonist necompetitiv al receptorilor N-metil-D-aspartat (NMDA). Această caracterizare a memantinei este necesară în vederea formulării unei soluţii parenterale. S-a urmărit determinarea solubilităţii în apă, a comportamentului termic şi a stabilităţii chimice în soluţie apoasă, în funcţie de pH, temperatură, lumină UV şi prezenţa unor agenţi oxidanţi sau izotonizanţi. S-a dezvoltat şi validat o metodă analitică LC/MS/MS pentru dozarea clorhidratului de memantină. S-a determinat o solubilitate în apă de 47.035 mg/mL (20 o C). Analiza termică a relevat faptul că memantina clorhidrat este o substanţă anhidră, cristalină, cu punctul de topire la 297.16 o C. În soluţie apoasă, clorhidratul de memantină este stabil la temperatura camerei, indiferent de pH, lumină UV, prezenţa unor agenţi oxidanţi sau izotonizanţi, ca şi la 80 o C, la pH acid. Aceste rezultate indică faptul că memantina are proprietăţi fizico-chimice adecvate pentru formularea unei soluţii parenterale

The pharmaceutical applications of a biopolymer isolated from Trigonella foenum-graecum seeds: Focus on the freeze-dried matrix forming capacity

The aim of the present study was to evaluate the funtion of fenugreek seed mucilage (FSM) as potential matrix forming agent for orodispersible pharmaceutical lyophilisates. The FSM was isolated and characterized. FSM colloidal dispersions were prepared and the rheological evaluation was performed. Oral lyophilisates (OLs) with different FSM concentrations, containing meloxicam as model drug were prepared by freeze drying method. The OLs were characterized and compared to gelatin containing tablets, prepared under the same conditions.The FSM dispersions revealed shear thinning flow type. Based on colloidal dispersions' rheological properties, five FSM concentrations were taken forward to the lyophilization step. Completely dry and elegant tablets were obtained. Texture analysis indicated highly porous structures, confirmed by SEM analysis, which explain the fast disintegration properties. All the prepared tablets disintegrated in less than 47 s. The disintegration process was prolonged by the increase in FSM content, due to the high viscosity the polymer creates in aqueous media. FSM tablets presented longer disintegration times, as compared to gelatin tablets, but also higher crushing strength. Considering the fast disintegration and the high crushing strength, FSM is a good candidate as matrix forming agent for fast disintegrating dosage forms or other freeze-dried preparations. Keywords: Meloxicam, Oral lyophilisates, Matrix forming agent, Galactomannan, Lyophilizatio

Antiproliferative and Antimicrobial Effects of Rosmarinus officinalis L. Loaded Liposomes

Rosmarinus officinalis L. is a species that is widely known for its culinary and medicinal uses. The purpose of the present study consisted of the evaluation of the antiproliferative and antimicrobial effects of R. officinalis-loaded liposomes (L-R). Characterization of the liposomes was performed by establishing specific parameters. The load of the obtained liposomes was analyzed using an LC-MS method, and antiproliferative assays evaluated the cell viability on a liver adenocarcinoma cell line and on a human hepatic stellate cell line. Antimicrobial assays were performed by agar–well diffusion and by broth microdilution assays. The obtained liposomes showed high encapsulation efficiency, suitable particle size, and good stability. High amounts of caffeic (81.07 ± 0.76), chlorogenic (14.10 ± 0.12), carnosic (20.03 ± 0.16), rosmarinic (39.81 ± 0.35), and ellagic (880.02 ± 0.14) acids were found in their composition, together with other polyphenols. Viability and apoptosis assays showed an intense effect on the cancerous cell line and a totally different pattern on the normal cells, indicating a selective toxicity towards the cancerous ones and an anti-proliferative mechanism. Antimicrobial potential was noticed against all tested bacteria, with a better efficacy towards Gram-positive species. These results further confirm the biological activities of R. officinalis leaf extract, and proposes and characterizes novel delivery systems for their encapsulation, enhancing the biological activities of polyphenols, and overcoming their limitations