Herman Vromans

Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs

In this study the gastrointestinal absorption and P-glycoprotein (Pgp) efflux transport of heterocyclic drugs was investigated with the Caco-2 cell model. Based on the calculation of the physico-chemical properties a good oral absorption was predicted for all the drugs tested in this study which corresponded well with the measured Caco-2 permeabilities (Papp). Generally a high permeability of the tested heterocyclic drugs was measured being in agreement with earlier published human in vivo absorption data. Based on the transport data of domperidone and verapamil it was found that the Pgp efflux transporter was expressed in the Caco-2 cells. Many of the drugs tested were indicated to be potential Pgp efflux substrates. Since Pgp is expressed at the Blood Brain Barrier (BBB) as well, it was expected that CNS penetration will be impaired if a drug is a Pgp substrate. However, no correlation could be found between brain penetration in rats and the Pgp efflux ratio as measured with the Caco-2 cells. From the data it is concluded that Pgp efflux ratios as determined in in vitro High Throughput Screening (HTS) tests, where the transport conditions are fixed (pH gradient, concentration, etc.), cannot routinely be used to predict a possible limited brain penetration.

Growth mechanisms of high-shear pelletisation

Two high-shear mixers, Gral 10 and Gral 25, were used to prepare pellets of microcrystalline cellulose and lactose, using water as binder liquid. Growth of pellets was investigated by measuring the pellet size distribution during the process. On the basis of the experiments the destructive nucleation growth mechanism was defined. Pelletisation was started with the formation of large primary nuclei. Small secondary nuclei were formed due to break-up of the primary nuclei. This nucleation process could be described by the comparison of the theoretical tensile strength of the nuclei and the dynamic impact pressure. Due to densification, the secondary nuclei became stronger and growth proceeded exponentially by coalescence. During the kneading stage, net growth was diminished until a steady state was observed. The mean pellet size did not change during the final stage of the kneading phase which resulted in a well-defined product.

Porosity expansion of tablets as a result of bonding and deformation of particulate solids

Abstract This paper describes the tabletting process of y-sorbitol on the basis of the stress-deformation curve. This curve distinguishes between small, elastic deformation and large, viscous deformation. Small deformations can be quantified by the dynamic Youngs modulus. The results demonstrated an effect of both rate of strain and initial particle size on the Youngs modulus. The yield strength of compacts is a quantification of large deformations. There appeared to be an effect of strain rate on yield strength, but no clear relation between initial particle size and yield strength. The study relates elastic deformation with storage of elastic energy. The amount of stored energy was found to increase with compaction speed, and is postulated to be the driving force for changes of tablet porosities after compression. The attraction between particles causes resistance against porosity expansion, and is defined as expansion capacity. The expansion capacity showed no relation to compaction speed. It is therefore concluded that the effect of compaction speed on tablet properties is purely an effect of the amount of stored energy. The reciprocal value of expansion capacity demonstrated a direct relation with the constant that fits the relation between tablet strength and porosity. The expansion capacity is hence a quantification of bonding.

Head-to-head comparison of four nonadjuvanted inactivated cell culture-derived influenza vaccines: Effect of composition, spatial organization and immunization route on the immunogenicity in a murine challenge model

In order to study the influence of antigen composition, spatial organization of antigen and the route of administration, four cell culture-derived, inactivated, nonadjuvanted influenza vaccine formulations, i.e. whole inactivated virus (WIV), split, subunit and virosome vaccines were prepared from a single antigen batch. We directly compared the immunogenicity and efficacy of these vaccine formulations after intramuscular (i.m.) or intranasal (i.n.) administration in mice. Prime and boost vaccination were followed by a potentially lethal homologous aerosol challenge. For all vaccines, the i.m. route induced higher serum humoral immune responses as compared to the i.n. route and protected all mice against challenge at a dose of 5 microg. Upon i.n. immunization only WIV and split vaccines induced detectable IgG titers and partial protection against challenge but only very low HI titers were induced in almost all mice. WIV induced mainly IgG2a/c titers via both routes, whereas split vaccine induced exclusively IgG1 titers via both routes. Subunit and virosome vaccines induced exclusively IgG1 via the i.m. route. Mucosal sIgA levels were only detected after i.n. vaccination with WIV. Furthermore, vaccines containing all viral components (WIV and split vaccine) induced higher serum HI titers and serum antibody titers than subunit and virosome vaccines. The differences in magnitude and quality of immune responses of split and WIV, having the same composition, are likely related to their distinct spatial organization. In conclusion, the direct comparison between WIV, split, subunit and virosomes, shows that the differences in immune responses between these well known influenza vaccines can be explained by both the composition and particulate structure of these vaccine formulations.

THE RELATIONSHIP BETWEEN BULK-DENSITY AND COMPACTIBILITY OF LACTOSE GRANULATIONS

The relationship between the bulk density and the compactibility of lactose granulations was studied. The granulations were prepared from different α-lactose monohydrate and roller dried β-lactose powders by wet granulation, using different techniques with only water as a binder, or by slugging. The results demonstrate that by the process of granulation of one lactose powder, granules with different bulk densities and different compactibilities can be prepared. In addition to the type of lactose used, the compactibility of the granule fractions is dependent on the bulk density of the granule fraction. Generally, with an increase of the bulk density, the compactibility of a granule fraction decreases. Little variation is observed between the intergranular porosities of the granule fractions. More differences are found between the intragranular porosities of the granule fractions. However, the compactibility of granule fractions of one lactose type is mainly determined by the total porosity of the granule powder bed. Mercury porosimetry determinations on tablets compacted from the granule fractions show a relationship between the tablet pore system and the compact strength: compression of granulations with a low bulk density results into tablets with a small average pore diameter and a high crushing strength. Obviously, the possibility to deform a granule fraction during compression, the deformation potential, is determined by the total porosity of the powder bed. A high deformation potential, i.e., a high compactibility, can be obtained by using a granulation procedure in which granulations with a low bulk density are produced.

Studies on tableting properties of lactose. Part 2. Consolidation and compaction of different types of crystalline lactose

Lactose is available in several crystalline forms, which differ in binding properties. A new method of estimating the fragmentation propensity was applied to investigate the consolidation and compaction behaviour of this excipient for direct compression. Mercury porosimetry was used to demonstrate that crystalline lactose fragments during compaction. Tablet strength was found to be dependent on the degree of fragmentation only. This finding indicates that the nature of the actual binding must be the same for the different types of crystalline lactose.

Studies on upscaling parameters of the Gral high shear granulation process

Abstract Granulation of lactose in three high shear mixers of the type Gral (Gral 10, 75 and 300) is compared. An attempt is made to identify scale-up parameters. It is concluded that an equal Froude-number results in a comparable process concerning temperature and particle size distribution. A constant relative swept volume and a constant impeller tip speed appeared not to result in a comparable process. Monitoring the temperature rise during the process might be an interesting process control.

Granule characterization during fluid bed drying by development of a near infrared method to determine water content and median granule size

PurposeWater content and granule size are recognized as critical process and product quality parameters during drying. The purpose of this study was to enlighten the granule behavior during fluid bed drying by monitoring the major events i.e. changes in water content and granule size.MethodsNIR spectra collected during drying and water content of sampled granules were correlated by principal component analysis (PCA) and partial least squares regression (PLSR). NIR spectra of dried granules were correlated to median granule size in a second PCA and PLSR.ResultsThe NIR water model discriminates between various stages in fluid-bed drying. The water content can be continuously predicted with errors comparable to the reference method. The four PLS factors of the granule size model are related to primary particle size of lactose, median granule size exceeding primary particle size and amorphous content of granules. The small prediction errors enable size discrimination between fines and granules.ConclusionFor product quality reasons, discrimination between drying stages and end-point monitoring is highly important. Together with the possibilities to determine median granule size and to distinguish fines this approach provides a tool to design an optimal drying process.

Stress relaxation of compacts produced from viscoelastic materials

Stress relaxation of tablets is a phenomenon that is known to be related to elastic deformation of particles. Expressions of stress relaxation are tablet expansion and capping. It has been shown that there is a direct relation between the changes in volume of the tablet and the amount of stored energy, calculated from the elastic modulus and the yield strength of the material. The relations are, however, different for the different materials. On the basis of the assumption that the increase in tablet volume is an expression of stress relaxation and stored energy is the driving force for it, there should be a counteracting force that prevents a compact from expansion. This paper shows that the counteracting force is determined by particle bonding, quantified by the Ryshkewitch-Duckworth relation and friction of the tablet with the die wall, quantified by the ejection pressure. The data presented here suggest that the final tablet porosity is unequivocally determined by stored energy, particle attraction and friction of the tablet with the die wall. All tablets that were capped showed both high stored energies and large particle bonding. From this observation it is concluded that porous and capped tablets suffer from the same problem, but the expression stress relaxation is different for the different materials.

The effect of dry granulation on the consolidation and compaction of crystalline lactose

Abstract The consolidation and compaction properties of granule fractions prepared by dry granulation (slugging) of α-lactose monohydrate and roller dried β-lactose, respectively, were studied. The results showed that the compactibility of the granule fractions was determined by the type of lactose used and the granule size. The tablets compacted from the granule fractions show a lower compressibility resulting into almost equal crushing strength but a higher specific BET-surface area as compared to the surface area of the slugs. Influence of granule size on tablet strength points to a relation between outside surface area of granules and tablet strength. Obviously, granule particles sustain their integrity to some extent during compaction. Air permeability and mercury porosimetry showed that in tablets with equal strength different pore systems can exist. Generally, tablets compacted from fine granule size fractions exhibited finer pore sizes and higher strengths compared to the tablets compacted from coarse size fractions. Furthermore, mercury porosimetry revealed that the whole pore system determines tablet strength. This means that granule particles deform during consolidation. The influence of the starting materials on tablet strength can not be explained by permeametry surface area measurements and mercury porosimetry. It is suggested that differences in the internal structure between the granules of the two lactose types are responsible.