Amoxicillin chewable tablets intended for pediatric use: formulation development, stability evaluation and taste assessment.

To cover the unpleasant taste of amoxicillin (250 mg), maize starch (baby food) and milk chocolate were co-formulated. The raw materials and the final formulations were characterized by means of Dynamic Light Scattering (DLS), Differential Scanning Calorimetry (DSC) and Fourier-Transform Infrared (FT-IR) spectroscopy. To evaluate the taste masking two different groups of volunteers were used, according to the Ethical Research Committee of the Aristotle University of Thessaloniki. The optimization of excipients' content in the tablet was determined by experimental design methodology (crossed D-optimal). Due to the matrix complexity, amoxicillin was extracted using liquid extraction and analyzed isocratically by HPLC. The developed chromatographic method was validated (%Recovery 98.7-101.3, %RSD = 1.3, LOD and LOQ 0.15 and 0.45 µg mL-1 respectively) according to the International Conference on Harmonization (ICH) guidelines. The physicochemical properties of the tablets were also examined demonstrating satisfactory quality characteristics (diameter: 15 mm, thickness: 6 mm, hardness <98 Newton, loss of mass <1.0%, disintegration time ∼25min). Additionally, dissolution (%Recovery >90) and in vitro digestion tests (%Recovery >95) were carried out. Stability experiments indicated that amoxicillin is stable in the prepared formulations for at least one year (%Recovery <91).

Assessment of mefenamic acid polymorphs in commercial tablets using chemometric coupled to MIR and NIR spectroscopies. Prediction of dissolution performance.

Mefenamic Acid (MFA) is a widely-used non-steroidal anti-inflammatory drug. MFA presents four possible crystal forms; Form I and Form II being the only two pure crystals that have been isolated and fully characterized. Both Form I and Form II were prepared following the literature and completely characterized by middle (MIR) and near (NIR) infrared spectroscopy, digital optical microscopy, differential scanning calorimetry, melting point and dissolution properties. In order to develop quantitative models to assess Form I in formulated products, two sets of samples, training (n=10) and validation (n=8) sets, were prepared by mixing both polymorphs and the matrix of excipient (simulating commercial tablets). The particle size of the samples was homogenized by sieving and samples were mechanically mixed. A batch of commercial tablets was gently disaggregated, sieved and mechanically mixed for further analysis. For each sample, full MIR and NIR spectra were acquired and used as input of partial least squares (PLS) algorithm separately. Method optimization and internal validation were performed by leave one out procedure. Full spectra and 5 PLS-factors were used for MIR; while, 5 PLS-factors and mean center spectra of full spectra were the optimal conditions for NIR. Accuracy and precision were assessed by evaluation of the actual vs. predicted curve of validation set; and by calculating validation set recoveries and deviations (104.3±8.2% and 100.4±1.0% for MIR and NIR respectively). Only NIR-PLS yielded acceptable results and low deviations during commercial samples evaluation (102.8±0.1%). The same behavior was observed when spiked tablets were analyzed (103.5±0.5%). Additionally, for the calibration set ten dissolution profiles (average of 6 curves each), were obtained under optimized test conditions (900 ml of buffer phosphate pH 9 with surfactant, apparatus II USP, 100rpm, detection at 342nm). A multiple linear regression (MLR) was carried out using dissolution profiles and Form I content. The developed MLR model could correlate dissolution profiles and polymorphic richness. This approach, coupled to previously developed NIR-PLS, may act as a valid tool to estimate dissolution profiles from solid forms.

Torsemide Fast Dissolving Tablets: Development, Optimization Using Box-Bhenken Design and Response Surface Methodology, In Vitro Characterization, and Pharmacokinetic Assessment.

The present study planed to develop new fast dissolving tablets (FDTs) of torsemide. Solid dispersions (SDs) of torsemide and sorbitol (3:1) or polyvinylpyrrolidone (PVP) k25 were prepared. The prepared SDs were evaluated for in-vitro dissolution. Fourier transform infrared spectroscopy and differential scanning calorimetry for SDs revealed no drug/excipient interactions and transformation of torsemide to the amorphous form. Torsemide/sorbitol SD was selected for formulation of torsemide FDTs by direct compression method. Box-Bhenken factorial design was employed to design 15 formulations using croscarmellose sodium and crospovidone at different concentrations. The response surface methodology was used to analyze the effect of changing these concentrations (independent variables) on disintegration time (Y1), percentage friability (Y2), and amount torsemide released at 10 min. The physical mixtures of torsemide and the used excipients were evaluated for angle of repose, Hausner's ratio, and Carr's index. The prepared FDTs tablets were evaluated for wetting and disintegration time, weight variation, drug content, percentage friability, thickness, hardness, and in vitro release. Based on the in-vitro results and factorial design characterization, F10 and F7 were selected for bioavailability studies following administration to Albino New Zealand rabbits. They showed significantly higher C max and (AUC0-12) and shorter T max than those obtained after administration of the corresponding ordinary commercial Torseretic ® tablets. Stability study was conducted for F10 that showed good stability upon storage at 30°C/75% RH and 40°C/75% RH for 3 months.

Toxicological assessment of Anionic Methacrylate Copolymer: I. Characterization, bioavailability and genotoxicity.

Anionic Methacrylate Copolymer (AMC) is a fully polymerized copolymer used in the pharmaceutical industry as an enteric/delayed-release coating to permit the pH-dependent release of active ingredients in the gastrointestinal tract from oral dosage forms. This function is of potential use for food supplements. Oral administration of radiolabeled copolymer to rats resulted in the detection of chemically unchanged copolymer in the feces, with negligible absorption (<0.1%). AMC is therefore determined not to be bioavailable. Within a genotoxicity test battery AMC did not show any evidence of genotoxicity in bacteria and mammalian cells. Furthermore, no genotoxic effects occurred in vivo within a micronucleus test. There would therefore appear to be no safety concerns under intended conditions of oral use for the discussed toxicological endpoints.

Industrial perspective of gastroretentive drug delivery systems: physicochemical, biopharmaceutical, technological and regulatory consideration.

INTRODUCTION: Gastroretentive drug delivery systems (GRDDS) can overcome drawbacks associated with oral drug delivery, by defeating natural physiological principles. Various gastroretentive technologies have been developed in the past, but few of them achieved success on the market. AREAS COVERED: This review is focused on the key concepts required to make a high-quality drug product available in a timely and economical manner. EXPERT OPINION: Pharmacotherapy of various disease states can be amended by drug repurposing through GRDDS. Assessment of the effect of the fed and fasted condition on product performance should be necessary during initial development phases. Dual working technology would be a possible way to overcome drawbacks associated with different GRDDS. Before development of a drug product, the principles of scale up and process validation must be considered to improve the quality and market availability of GRDDS. Knowledge of all regulatory aspects will help to deliver a product to the market within a reasonable timeframe and in a cost-effective manner.

Release of indomethacin from ultrasound dry granules containing lactose-based excipients.

Physical mixtures were prepared containing indomethacin and beta-lactose and alpha-lactose-based excipients (Ludipress and Cellactose). The mixtures were compacted with the aid of ultrasound, obtaining tablets, which were milled and sieved. Granules thus obtained were examined by optical microscopy and differential scanning calorimetry. The intense yellow color of the granules and the absence of indomethacin peak in thermograms suggest important modifications of indomethacin physical state; the drug thus modified appears to be spread on the excipient particle surface as a thin film, giving a lustrous appearance. No influence of ultrasound was observed on phase transition concerning lactose; only loss of water was important under high energy ultrasound. Dissolution profiles suggest an increased release of the drug from the systems treated with ultrasound at high energy, with respect to a traditional compaction; while no difference could be evidenced among the three excipients that, however, appear all suitable for this ultrasound-aided direct compression process.

The formulation of Halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: physical stability and absolute bioavailability assessment.

A non-solubilizing solid dispersion formulation (polyethylene glycol 6000) and two solubilizing solid dispersions (Vitamin E TPGS and a Gelucire 44/14/Vitamin E TPGS blend) containing the antimalarial, Halofantrine (Hf), were formulated for bioavailability assessment in fasted beagles to determine if the oral absorption of Hf can be enhanced by these delivery systems. Solid dispersions comprising varying proportions of drug to carrier were prepared by the fusion method. Whilst the non-solubilizing formulation was assessed according to its dispersion characteristics, the solubilizing solid dispersions were assessed by their ability to form microemulsions upon dispersion. Studies in fasted beagles showed that the solid dispersions afforded a five- to seven-fold improvement in absolute oral bioavailability when compared with the commercially available tablet formulation. The delivery of Hf in either a solubilizing or non-solubilizing solid dispersion did not result in significant differences in oral bioavailability. The physical stability of the solid dispersions was studied using differential scanning calorimetry and X-ray powder diffraction.