Fulvio Rubessa

Formulation design of carbamazepine fast-release tablets prepared by melt granulation technique

This work describes a new approach to prepare a fast-release dosage form for carbamazepine (CBZ), involving the use of melt granulation process in high shear mixer for the production of tablets. In particular, the granules containing CBZ were prepared using polyethylene glycol (PEG) 4000 as a melting binder and lactose monohydrate as a hydrophilic filler. The potential of the intragranular addition of crospovidone as a dissolution enhancer and a disintegrant agent was also evaluated. After the analysis of their solid state performed by means of X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC), the granules were characterised from the technological and dissolution point of view. The subsequent step encompassed the preparation and the evaluation of the tablets, including the effect of the extragranular introduction of crospovidone. Besides the remarkable enhancement of drug dissolution rate of the granulates in comparison to physical mixtures and pure drug, no significant differences were found between the dissolution profiles of the granulates containing lactose or crospovidone. However, the difficult disintegration and bad dissolution performance of the tablets not containing intragranular crospovidone highlight the necessity of this disintegrant in the granulating mixture. Moreover, the extragranular addition of a small amount of crospovidone gave rise to a further amelioration of the disintegration and dissolution performances.

Preparation of extruded carbamazepine and PEG 4000 as a potential rapid release dosage form.

The aim of this research was to use a ram extruder to prepare directly a fast release dosage form with uniform shape and density, containing carbamazepine (C) as a water-insoluble drug and polyethylene glycol 4000 (PEG) as a low melting binder. The potential inclusion of lactose (L) as a hydrophilic filler was also considered. The temperature suitable to ensure a successful extrusion process of several formulations containing PEG in different percentages was found to be below the melting point of the PEG. The influence of composition on the extrusion process of different ram speeds was checked by measuring the pressure at the steady state, the apparent shear rate and the apparent shear stress of a range of mixtures of drug, lactose and PEG. The physical-mechanical properties of extrudates, including tensile strength and Youngs modulus, prepared with different ram velocities were also determined. The solid-state physical structure by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) was established. The dissolution of the extrudates and their corresponding physical mixtures were compared. The mixtures were found to be shear thinning when extruded; the tensile strength of extrudates was dependent on the composition but not the extrusion rate, while the value of Youngs modulus was strongly influenced by the rate of extrusion, but less affected by the composition of the extrudates. The results of DSC and XRD indicated that the solid structure of the extrudates corresponded to that of a physical mixture of the components, hence there had been no change in the physical form of the drug induced by extrusion. In terms of dissolution, the rate of the extrusion process did not influence the performance of the products, whereas the composition did. The extruded mixtures of an equivalent composition exhibited a more rapid release than a simple physical mixture. The addition of lactose reduced the dissolution rate.

Effect of ageing on the release of indomethacin from solid dispersions with Eudragits

Abstract The effect of ageing on the release of indomethacin from coprecipitates with Eudragit RS, Eudragit E and blends of these polymers was studied. DSC thermograms were carried out to control the glass transition temperature (Tg) of polymers and the physical state of indomethacin after 2 and 3 years of storage in closed containers at room temperature. The rotating disk method was used on compressed powders in order to test drug release under controlled conditions. Data treatments were carried out in order to verify modifications in the diffusion coefficient and mechanism of drug release. Results indicated that, for all the systems investigated, randomness was reduced within the polymeric network during storage, and this observation was confirmed by the appearance of a peak at the polymeric Tg. The drug diffusion coefficient from Eudragit RS was not influenced by storage, while, in the case of Eudragit E and a blend of polymers, a significant reduction of the diffusion coefficient was noticed after 3 years, probably due to an interaction between the drug and Eudragit E.

Experimental Design for a Granulation Process with “Priori” Criterias

AbstractOptimization techniques representr analytical tools available for the best solution to a particular problem.Pharmaceutical product and process design problems were structured as constrained optimization problems and subsequently solved by the “a priori” optimality approach using an exchange algorithm.The effect of the amount of added water plus granulation time and impeller speed on two properties of the granulates were investigated.Experimental results obtained for the optimal formulation agreed well with the predictions.

Simultaneaus Optimization of Several Response Variables in a Granulation Process

AbstractWet granulation of lactose and corn starch in a 10 litre high shear mixer was examined. The optimal combination of three indipendendent variables (moisture level, impeller speed and granulation time) on four properties of the granules was investigated by simultaneaus optimization method.The optimun zone determined in 10 litre high shear mixer was analyzed for scaling-up study. The same product was manufacted at 50 L scale and optimum theoretical results were obtained for the four response variables and are comparable with the experimental results.

Dissolution Rate of Griseofulvin from Solid Dispersions with Poly(Vinylmethylether/Maleic Anhydride)

AbstractA solid dispersion technique with poly(vinylmethylether/ maleic anhydride) (PVM/MA) and its half esters has been used to enhance griseofulvin dissolution.A marked increase of the dissolution rate and solubility of griseofulvin contained in these solid dispersions was observed compared with that of drug alone and that of physical mixture with the carrier.Differences in dissolution rates resulted from the molecular weight and the chemical structure of the carrier.X-Ray powder diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the nature of the studied forms.

Wet Granulation in a Small Scale High Shear Mixer

AbstractWet granulation of lactose and corn starch in a 10 litre high shear mixer was examined. The effect of the amount of water added, granulation time and impeller speed on five properties of the granules was investigated by a response surface design.It was shown that moisture level as a major effect on geometric mean diameter and flow rate of the granules. The impeller speed markedly influences the geometric mean diameter, geometric standard deviation, compactability index and percentage of granules smaller than 1250 μm. Finally the granulation time has an evident influence on compactability index.Theoretical optimum conditions were obtained for the five response variables and are comparable with the experimental results.

Optimization of granulates in a high shear mixer by mixture design

AbstractOptimization of wet granulation in a 10 litre high shear mixer was examined by mixture design. Lactose, corn starch and cellulose microcrystalline were used as eccipients of the granules. Mixing ratios of these eccipients were selected as formulation factors. In addition, the impeller speed and granulation time was employed as independent process variables. A two-phase experimental strategy was drawn up: one phase for the percentages of the three eccipients and the other phase for the determination of the influence of process variable on geometric mean diameter. The percentages were studied using a Scheffe simplex-centroid design, and the other phase was examined using a Doehlert experimental matrix.

The release rate of indomethacin from solid dispersions with Eudragit E

AbstractThe coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.

Formulation and evaluation of vinylpyrrolidone/vinylacetate copolymer microspheres with griseofulvin

Regular spherical microspheres of 220-260 microns average size have been prepared from vinylpyrrolidone/vinylacetate copolymer using a solvent evaporation method. Griseofulvin has been incorporated into these microspheres and its physical characterization has been carried out by differential scanning calorimetry (DSC), X-ray diffractometry and X-ray photoelectron spectroscopy. An increase of solubility was observed only with the 1:3 drug/polymer microspheres and the comparison of the dissolution profiles of microspheres with pure griseofulvin resulted in an enhancing effect. Furthermore the release rate of griseofulvin, incorporated into the microspheres, was shown to be biphasic and dependent upon the penetration of water into the microspheres, hydration and dissolution of the polymer and finally dissolution of the drug.