Beatrice Perissutti

Processing of carbamazepine–PEG 4000 solid dispersions with supercritical carbon dioxide: preparation, characterisation, and in vitro dissolution

The purpose of this study was to apply the attractive technique of the supercritical fluid to the preparation of solvent-free solid dispersions. In particular, the gas antisolvent crystallisation technique (GAS), using supercritical carbon dioxide as processing medium, has been considered to prepare an enhanced release dosage form for of the poorly soluble carbamazepine, employing PEG 4000 as a hydrophilic carrier. The physical characterisation of the systems using laser granulometer, powder X-ray diffraction, thermal analyses, and scanning electron microscopy was carried out in order to understand the influence of this technological process on the physical status of the drug. The results of the physical characterisation attested a substantial correspondence of the solid state of the drug before and after treatment with GAS technique, whereas a pronounced change in size and morphology of the drug crystals was noticed. The dramatic reduction of the dimensions and the better crystal shape, together with the presence of the hydrophilic polymer determined a remarkable enhancement of the in vitro drug dissolution rate.

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.

Controlled release of verapamil hydrochloride from waxy microparticles prepared by spray congealing

In this work, the potential of waxes for preparing with the ultrasonic spray congealing technique microparticles for controlling the in vitro release of verapamil HCl was investigated. The first part of the study encompassed the optimisation of the formulation to achieve an efficient drug incorporation together with a satisfactory in vitro drug release rate. In particular, microcrystalline wax, stearyl alcohol and mixtures of the two were used. Also a surfactant (soya lecithin) was added to the formulations. After the particle size analysis, the characterisation of the microparticles involved the study of the solid state of drug and carriers in the systems (DSC, HSM and XRD) and the morphological and chemical analyses of the microparticle surface (SEM and XPS). Finally, the drug release mechanism from these devices was evaluated using the statistical moment analysis. The results of this study show that by selecting the type and the amount of the carriers, microparticles with a spherical shape and a good encapsulation efficiency were observed. These particles showed a zero-order release for 8 h, without modifying the solid state properties of the drug. Therefore, waxy microparticles prepared by the ultrasonic spray congealing technique are promising solvent-free devices for controlling the release of verapamil HCl.

Preparation in high-shear mixer of sustained-release pellets by melt pelletisation.

The preparation of sustained-release pellets by melt pelletisation was investigated in a 10-l high shear mixer and ternary mixtures containing stearic acid as a melting binder, anhydrous lactose as a filler and theophylline as a model drug. A translated Doehlert matrix was applied for the optimisation of process variables and quality control of pellets characteristics. After determination of size distribution, the pellets were characterised with scanning electron microscopy, X-ray photoelectron spectroscopy and porosimetric analysis. Finally, the in vitro release from every single size fraction was evaluated and the release mechanism was analysed. Since the drug release rate decreased when enhancing the pellet size fraction, the 2000-microm fraction, exhibiting a substantially zero-order release, was selected for further in vivo biovailability studies. These data demonstrated that pellets based on the combination of stearic acid and lactose can be used to formulate sustained release pellets for theophylline.

Studies in dissolution enhancement of atenolol. Part I

Abstract The objective of this study was to design atenolol tablets with fast in vitro release rates. Different polymers were screened as possible carriers to enhance atenolol dissolution. Binary systems using povidone (PVP), crospovidone (PVP-CL), polyvinilpyrrolidone/vinylacetate (PVP/VA), and Eudragit ® E were prepared. The physical properties of solid dispersions, compared to physical mixtures, were analysed using X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The solubility and the release rate of atenolol from solid dispersions were compared to the drug alone. The influence of various parameters (type of polymer, drug to polymer ratio, pH) on the solubility and dissolution rate of the drug was also evaluated. The results of DSC and X-ray analyses of solid dispersions attested that the drug was always present in a crystalline form in the PVP-CL and Eudragit ® E systems, while with the high content of PVP and PVP/VA an amorphisation of the atenolol was detectable. On the other hand, the diffraction patterns and the DSC thermograms of the physical mixtures revealed that to some extent the drug was always present in a crystalline form. An improvement in solubility and dissolution rate of atenolol with PVP and PVP-CL was obtained.

Preparation of sustained release co-extrudates by hot-melt extrusion and mathematical modelling of in vitro/in vivo drug release profiles

Aim of this work was to develop a cylindrical co-extrudate characterised by an in vivo sustained release profile by means of a hot-melt extrusion process. Co-extrudate was made up of two concentric extruded matrices: an inner one having a hydrophilic character, based on polyethylene glycol, and an outer one with lipophilic character, based on microcrystalline wax. Both segments contained theophylline as a model drug. A screening between several devices differing for dimensions (diameter and length) and relative proportions of the inner and outer part was carried out on the basis of their in vitro drug release and the release mechanism was studied by means of a mathematical model. The co-extrudate exhibiting the desired sustained release was selected for in vivo bioavailability studies. In vivo studies confirmed the achievement of the purpose of the research, demonstrating the desired release of theophylline on four healthy volunteers. Accordingly, hot-melt extrusion process is a viable method to produce in a single step co-extrudates showing a sustained release. In addition, the developed mathematical model proved to be a reliable descriptor of the both in vitro and in vivo experimental data.

Bi-layered self-emulsifying pellets prepared by co-extrusion and spheronization: Influence of formulation variables and preliminary study on the in vivo absorption

The aim of this work was to produce by co-extrusion-spheronization pellets with two cohesive layers, one of them containing a self-emulsifying system for vinpocetine, a poorly water soluble model drug. Two layers were prepared: an inert layer of microcrystalline cellulose, lactose and water and a second one wetted with the self-emulsifying system. Different formulations of both layers were tested, evaluating the effects of formulation variables with an experimental design. The screening amongst formulations was performed preparing rod extrudates and using the extrusion profiles to assess their suitability for extrusion and to anticipate quality of the spheronized extrudates. Tubular extrudates and co-extrudates/spheronized pellets were then produced. Two types of bi-layered pellets were prepared: type I with the self-emulsifying system internally and the inert matrix externally, whereas type II vice versa. The pellets were characterized for sizing and shape, density, hardness, in vitro dissolution and disintegration and released droplets size and in vivo tests. Although both types of pellets demonstrated adequate morphological and technological characteristics, pellets type II revealed an improved drug solubility and in vivo bioavailability. These preliminary technological and pharmacokinetic data demonstrated that co-extrusion/spheronization is a viable technology to produce bi-layered cohesive self-emulsifying pellets of good quality and improved in vivo bioavailability.

Spray-dried chitosan/ethylcellulose microspheres for nasal drug delivery: swelling study and evaluation of in vitro drug release properties.

The aim of this study was to develop spray-dried chitosan-based microspheres, suitable for nasal delivery of loratadine, and to evaluate their potential of modifying loratadine release. The microspheres were composed with ethylcellulose (EC) and chitosan (CM) in two different weight ratios, 1:2 and 1:3. One-phase systems (dispersions) and two-phase systems (emulsions and suspensions) were subjected to spray-drying, resulting in conventional and composed microspheres, respectively. The microspheres were evaluated with respect to the yield, particle size, encapsulation efficiency, physical state of the drug in the polymer matrix, swelling properties and in vitro drug release profile. It was shown that particle size, swelling ability and loratadine release from spray-dried microspheres were significantly affected by the polymeric composition and feed concentration in spray-drying process. Emulsifying method to produce composed EC/CM microspheres resulted in improved loratadine entrapment and moderate swelling, when compared to conventional chitosan microspheres. It seems like better formation of EC cores and chitosan coating were obtained when higher feed concentration and ultrasonic homogenization were employed in the preparation of emulsion systems and when EC to CM weight ratio was 1:3.

Oral bioavailability of silymarin phytocomplex formulated as self-emulsifying pellets.

The objective of this study was to develop new solid self-emulsifying pellets to deliver milk thistle extract (silymarin). These pellets were prepared via extrusion/spheronisation procedure, using a self-emulsifying system or SES (Akoline MCM®, Miglyol®, Tween 80®, soy lecithin and propylene glycol), microcrystalline cellulose and lactose monohydrate. To select the most suitable formulations for extrusion and spheronisation, an experimental design of experiences was adopted. The screening amongst formulations (13 different blends) was performed preparing pellets and evaluating extrusion profiles and quality of the spheronised extrudates. The pellets were characterised for size and shape, density, force required to crush them. Although more than one type of pellets demonstrated adequate morphological and technological characteristics, pellets prepared from formulation 7 revealed the best properties and were selected for further biopharmaceutical investigations, including in vitro dissolution and in vivo trials on rats to study serum and lymph levels after oral administration of the pellets. These preliminary technological and pharmacokinetic data demonstrated that extrusion/spheronisation is a viable technology to produce self-emulsifying pellets of good quality and able to improve in vivo oral bioavailability of main components of a phytotherapeutic extract of more than 100 times by enhancing the lymphatic route of absorption.