Taste Masking of Dexketoprofen Trometamol Orally Disintegrating Granules by High-Shear Coating with Glyceryl Distearate.

Orally disintegrating granules (ODGs) are a pharmaceutical form commonly used for the administration of NSAIDs because of their easy assumption and fast dispersion. The development of ODGs is not easy for drugs like dexketoprofen trometamol (DXKT), which have a bitter and burning taste. In this work, high-shear coating (HSC) was used as an innovative technique for DKXT taste masking. This study focused on coating DXKT granules using the HSC technique with a low-melting lipid excipient, glyceryl distearate (GDS). The HSC technique allowed for the coating to be developed through the thermal rise resulting from the friction generated by the granules movement inside the equipment, causing the coating excipient to soften. The design of the experiment was used to find the best experimental coating conditions in order to gain effective taste masking by suitably reducing the amount of drug released in the oral cavity. The influence of the granule dimensions was also investigated. Coating effectiveness was evaluated using a simulated saliva dissolution test. It was found that low impeller speed (300 rpm) and a 20% coating excipient were effective in suitably reducing the drug dissolution rate and then in taste masking. The coated granules were characterized for their morphology and solid-state properties by SEM, BET, XRPD, DSC, and NIR analyses. A human taste panel test confirmed the masking of DXKT taste in the selected batch granules.

Development of a Near Infrared Spectroscopy method for the in-line quantitative bilastine drug determination during pharmaceutical powders blending.

The Food and Drug Administration (FDA)'s guidelines and the Process Analytical Technology (PAT) approach conceptualize the idea of real time monitoring of a process, with the primary objective of improvement of quality and also of time and resources saving. New instruments are needed to perform an efficient PAT process control and Near Infrared Spectroscopy (NIRS), thanks to its rapid and drastic development of last years, could be a very good choice, in virtue of its high versatility, speed of analysis, non-destructiveness and absence of sample chemical treatment. This work was aimed to develop a NIR analytical method for bilastine assay in powder mixtures for direct compression. In particular, the use of NIR instrumentation should allow to control the bilastine concentration and the whole blending process, assuring the achievement of a homogeneous blend. The commercial tablet formulation of bilastine was particularly suitable for this purpose, due to its simple composition (four excipients) and direct compression manufacturing process. Calibration and validation set were prepared according to a Placket-Burman experimental design and acquired with a miniaturized NIR in-line instrument (MicroNIR by Viavi Solution Inc.). Chemometric was applied to optimize information extraction from spectra, by subjecting them to a Standard Normal Variate (SNV) and a Savitzky-Golay second derivative pre-treatment. This spectra pre-treatment, combined with the most suitable wavelength interval (resulted between 1087 and 1217 nm), enabled to obtain a Partial Least Square (PLS) model with a good predictive ability. The selected model, tried on laboratory and production batches, provided in both cases good assay predictions. Results were confirmed by traditional HPLC (High Performance Liquid Chromatography) API (Active Pharmaceutical Ingredient) content uniformity test on the final product.

Development and Characterization of Liquisolid Tablets Based on Mesoporous Clays or Silicas for Improving Glyburide Dissolution.

The aim of this work was to evaluate the effectiveness of mesoporous clays or silicas to develop fast-dissolving glyburide tablets based on a liquisolid approach. Selected clay (Neusilin®US2) and silica (Aeroperl®300) allowed preparation of innovative drug liquisolid systems containing dimethylacetamide or 2-pyrrolidone as drug solvents, without using coating materials which are necessary in conventional systems. The obtained liquisolid powders were characterized for solid-state properties, flowability, compressibility, morphology, granulometry, and then used for directly compressed tablet preparation. The developed liquisolid tablets provided a marked drug dissolution increase, reaching 98% dissolved drug after 60 min, compared to 40% and 50% obtained from a reference tablet containing the plain drug, and a commercial tablet. The improved glyburide dissolution was attributed to its increased wetting properties and surface area, due to its amorphization/solubilization within the liquisolid matrix, as confirmed by DSC and PXRD studies. Mesoporous clay and silica, owing to their excellent adsorbent, flow, and compressibility properties, avoided use of coating materials and considerably improved liquid-loading capacity, reducing the carrier amount necessary to obtain freely flowing powders. Neusilin®US2 showed a superior performance than Aeroperl®300 in terms of the tablet's technological properties. Finally, simplicity and cost-effectiveness of the proposed approach make it particularly advantageous for industrial scale-up.

A new crystal form of the NSAID dexketoprofen.

Dexketoprofen [(2S)-2-(3-benzoylphenyl)propanoic acid], C16H14O3, is the S-enantiomer of ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID) that has analgesic, antipyretic and anti-inflammatory properties, and finds applications for the short-term treatment of mild to moderate pain. A new crystalline phase of dexketoprofen is reported. Its solid-state structure was determined by single-crystal X-ray diffraction (SCXRD). The molecular structure of the two independent molecules found in the asymmetric unit of this new phase (DXKP-ß) were compared to those of the already known crystal form of dexketoprofen (DXKP-α) and with the S-enantiomer of the racemic compound. The three different conformers of dexketoprofen found in DXKP-α and DXKP-ß were then investigated by computational methods. The optimized structures are very close to the corresponding starting geometries and do not differ significantly in energy. The crystal packing of DXKP-ß was studied by means of Hirshfeld surface (HS) analysis; interaction energies were also calculated. A comparison with DXKP-α shows close similarities between the two crystal forms, i.e. in both cases, molecules assemble through the catemer O-H...O synthon of the carboxylic acid stabilized by additional C-H...O contacts and, accordingly, the interaction energies, as well as the contributions to the HS area, are very similar. Finally, the thermal behaviour of the two polymorphs of dexketoprofen was assessed by means of XRD (both from single crystal and microcrystalline powder) and differential scanning calorimetry (DSC); both crystal forms are stable under the experimental conditions adopted (air, 300-350 K for DXKP-α and 300-340 K DXKP-ß) and no solid-solid phase transition occurs between the two crystal forms in the investigated temperature range (from 100 K up to ca 350 K).

Characterization and evaluation of the performance of different calcium and magnesium salts as excipients for direct compression.

The performance of a series of inorganic salts as direct compression excipients was systematically evaluated. The physical-chemical and technological properties of the different salts were investigated in terms of crystalline/amorphous state, morphology, granulometry, apparent/tapped density, specific surface area, flowability, compressibility, dilution and distribution coefficients. To achieve a comprehensive evaluation of the performance of the different salts, the data obtained by the various analyses were normalized, giving a score to each excipient for each evaluated property/parameter. Statistical elaboration (JMP software) of the full dataset provided a final ranking of the powders based on their effectiveness as direct compression excipients. The salt emerged as the best was used to prepare direct-compression tablets, using cefixime as model drug, by modifying the composition of marketed tablets. A significant improvement of the mechanical properties of the new tablets was observed, compared to the marketed ones, with a crushing strength increase of over 30%, without variations of the drug dissolution profile. Even though the resulted ranking cannot have an absolute value, being the behavior of the different excipients susceptible to the kind of drug and other formulation excipients, the proposed approach can provide a useful model for a systematic evaluation and comparison of potentially similar excipients.

Characterization and evaluation of different mesoporous silica kinds as carriers for the development of effective oral dosage forms of glibenclamide.

This work evaluated the suitability of various mesoporous silicas as carriers for developing an oral formulation endowed with improved dissolution properties of glibenclamide, hypoglycemic agent poorly water-soluble. The different silicas were examined for solid-state, morphology, and technological and physical-chemical properties (granulometry, specific surface area, wettability, water content, water activity, apparent density, flowability, compactability). A pairwise comparison allowed a ranking, by importance order, of the parameters examined and, for each parameter, a score was assigned to each silica type. Data statistical treatment (JMP software) indicated Neusilin®US2 and Syloid®XDP3150 as the best materials. Different loading methods were tested: physical mixing; addition of drug dissolved in a volatile solvent, subsequently evaporated; addition of drug dissolved in a solvent. Methods involving drug dissolution enabled drug amorphization and intimate dispersion within the silica porous structure. Dissolution tests indicated Syloid®XDP3150 as the most effective silica in enhancing drug dissolution properties, providing a release rate clearly faster than from commercial tablets. Drug amorphization, improved wettability, increased surface area of the drug, finely dispersed into the highly porous silica, were the main factors responsible for this finding. Moreover, the obtained results suggested that drug dissolution rate can be properly tuned, based on the suited choice of the silica type.

Development and characterization of fast-dissolving tablet formulations of glyburide based on solid self-microemulsifying systems.

The aim of this work was to develop effective fast-dissolving tablet formulations of glyburide, endowed with improved dissolution and technological properties, investigating the actual effectiveness of the Solid-Self MicroEmulsifying Drug Delivery System (S-SMEDDS) approach. An initial screening aimed to determine the solubility of the drug in different oils, Surfactants and CoSurfactants allowed the selection of the most suitable components for liquid SMEDDS, whose relative amounts were defined by the construction of pseudo-ternary phase diagrams. The selected liquid SMEDDS formulations (Capyol 90 as oil, Tween 20 as Surfactant and Glycofurol or Transcutol as CoSurfactant) were converted into Solid-SMEDDS, by adsorbing them onto Neusilin (1:1 and 1:0.8w/w S-SMEDDS:carrier), and fully characterized in terms of solid state (DSC and X-ray powder diffraction), morphological (ESEM) and dissolution properties, particle size and reconstitution ability. Finally, the 1:1 S-SMEDDS containing Glycofurol as CoSurfactant, showing the best performance, was selected to prepare two final tablet formulations. The ratio test (t10 min ratio and DE60 ratio) and pair-wise procedures (difference (f1) and similarity (f2) factors) highlighted the similarity of the new developed tablets and the marked difference between their drug dissolution profiles and those of formulations based on the micronized drug. The S-SMEDDS approach allowed to develop fast-dissolving tablets of glyburide, endowed with good technological properties and able to achieve the complete drug dissolution in a time ranging from 10 to 15min, depending on the formulation composition.

New solid self-microemulsifying systems to enhance dissolution rate of poorly water soluble drugs.

CONTEXT: An adequate drug dissolution behavior is essential for the therapeutic effectiveness of all solid dosage forms. OBJECTIVE: To develop a new solid self-micro-emulsifying drug delivery system (S-SMEDDS) to improve the dissolution properties of poorly water-soluble drugs, such as glyburide. METHODS: Liquid self-micro-emulsifying drug delivery systems (SMEDDS) consisted of Labrafac-Hydro(®), Tween(®) 20, Transcutol(®), and drug. S-SMEDDS were prepared by adsorption of SMEDDS onto different adsorbents; the obtained powders were evaluated for flow, compactability and liquid-retention potential. The reconstitution ability of S-SMEDDS into SMEDDS by re-dispersion in water was assessed. Tablets, prepared by direct compression of selected S-SMEDDS, were characterized for technological properties and dissolution behavior. RESULTS: Neusilin US2 was selected as the most effective adsorbent, based on its better flow and compacting properties, greater surface area and mesoporosity. The significantly higher (P < 0.001) drug dissolution rate from S-SMEDDS-based tablets than from commercial tablets was ascribed to enhanced wetting and surface area of drug, finely distributed onto the hydrophilic adsorbent, and, above all, to the already drug dissolved form in the SMEDDS system. Properties, drug content and dissolution from S-SMEDDS tablets were unchanged after 25°C and 60% RH six-month storage. CONCLUSIONS: The developed tablets showed the advantages of SMEDDS, allowing a strong improvement of drug dissolution, together with increased physical and chemical stability.

Development of glyburide fast-dissolving tablets based on the combined use of cyclodextrins and polymers.

Commercial tablets of glyburide exhibit unsatisfactory dissolution profiles and, consequently, problems of bioinequivalence and poor bioavailability. The aim of this work was to develop glyburide fast-dissolving tablets by exploiting the solubilizing effect of different cyclodextrins (CDs), alone or in combination with hydrophilic polymers. Drug-CD and drug-CD-polymer systems, prepared by different techniques, were characterized by differential scanning calorimetry (DSC), X-ray diffractometry, and Fourier transform infra-red (FT-IR) spectroscopy. Tablets containing binary and ternary systems were prepared by direct compression and evaluated for technological properties and dissolution behavior in comparison with a reference formulation containing the plain drug. A significant improvement of the drug dissolution profile was achieved from tablets containing drug-CD systems (coevaporated products doubled drug dissolution efficiency [DE]), but 100% drug dissolution was never reached. Better results were obtained with ternary systems. In particular, polyvinylpyrrolidone (PVP) emerged as the most effective polymer, and tablets with drug-PVP-hydroxypropyl-betaCD coevaporated products showed the best dissolution profiles, reaching 100% dissolved drug within only 15 min.

Validation of an HPLC-MS method for rociverine tablet dissolution analysis.

The aim of this work was to develop and validate a method to assess the dissolution behaviour of rociverine sugar-coated tablets. In our laboratories, an HPLC-MS in reverse phase method of analysis was developed for the dosage of unknown rociverine solution. This analytical method was applied to determine the dissolution rate of rociverine tablets produced by the industrial procedure, because there is no official method description. Dissolution tests were carried out in sink conditions as follows: dissolution medium HCl 0.01 N, paddle rotation speed 50 rpm and vessel volume 1000 ml. The dissolution test gave satisfactory results: 95% of the drug was dissolved within 30 min and drug dissolution was concluded after 60 min. The method was demonstrated to be adequate for Quality Control of rociverine tablets. Validation was inferred from specificity, linearity, precision, accuracy and robustness.

Fast-dissolving tablets of glyburide based on ternary solid dispersions with PEG 6000 and surfactants.

Marketed glyburide tablets present unsatisfying dissolution profiles that give rise to variable bioavailability. With the purpose of developing a fast-dissolving tablet formulation able to assure a complete drug dissolution, we investigated the effect of the addition to a reference tablet formulation of different types (anionic and nonionic) and amounts of hydrophilic surfactants, as well as the use of a new technique, based on ternary solid dispersions of the drug with an hydrophilic carrier (polyethylene glycol [PEG] 6000) and a surfactant. Tablets were prepared by direct compression or previous wet granulation of suitable formulations containing the drug with each surfactant or drug:PEG:surfactant ternary dispersions at different PEG:surfactant w/w ratios. The presence of surfactants significantly increased (p<0.01) the drug dissolution rate, but complete drug dissolution was never achieved. On the contrary, in all cases tablets containing ternary solid dispersions achieved 100% dissolved drug within 60 min. The best product was the 10:80:10 w/w ternary dispersion with PEG 6000 and sodium laurylsulphate, showing a dissolution efficiency 5.5-fold greater than the reference tablet formulation and 100% drug dissolution after only 20 min.