Biomedical subjects

Herman Vromans

Publications and source records attributed to Herman Vromans.

10 recordsLinked to original sources

PubMed2006

Granule breakage during drying processes.

The drying of wet granules often involves an unwanted and uncontrolled size reduction. Current FDA PAT guidance stresses importance of process control and understanding. The aim of this study is to determine and understand the breakage phenomena during drying processes in order to control these processes. High shear granulated lactose granules with water as binding liquid were dried during variable periods. Subsequently the (partially) dried granules were exposed to agitation by the impeller and chopper in the granulator. Granule characterization revealed that the change in granule size of (partially) dried granules is dependent on water content and follows a three phase system characterized by a growth, plateau and breakage phase. The derived yield stress of the granules is a function of velocity. From this it is concluded that in the plateau phase above minimum water content, stress behavior of granules can be described with Rumpfs' dynamic granule strength, whereas below minimum water content (breakage phase) granule strength is determined by the solid bridges. The extent and velocity of stress and water content of the granules during the process determine the size reduction phenomena.

Drug Compounding↗

PubMed2006

The effect of crystal imperfections on particle fracture behaviour.

Micronisation of active pharmaceutical ingredients is a process which is sometimes difficult to control. The main purpose of this study was to assess the effect of the pre-existing flaws in the material to be milled. The rate of breakage of four samples of a model compound (sodium chloride), originating from different sources, was determined in a jet mill. It appeared that each type of sodium chloride has a distinct particle rate of breakage and breakage pattern. The numbers of flaws in the different types of sodium chloride have been determined by immersing the sodium chloride particles in a liquid with the same refractive index. This makes the cracks better visible. Microphotographs were made and flaws were counted manually. The study shows that the flaw density has an impact on the fracture behaviour of particles. The degree of fracture tends to increase with increasing flaw density. The paper shows however that the mechanical properties of the material as well as the starting particle size dominate the significance of the impact of flaws on fracture behaviour.

Crystallization↗

PubMed2005

The use of 13C labeling to enhance the sensitivity of 13C solid-state CPMAS NMR to study polymorphism in low dose solid formulations.

(13)C labeling was used to enhance the sensitivity of (13)C solid-state NMR to study the effect of tabletting on the polymorphism of a steroidal drug. The steroidal drug Org OD 14 was (13)C labeled and formulated into tablets containing only 0.5-2.5% active ingredient. The tablets were subsequently studied by solid-state (13)C CPMAS NMR. The crystalline form present in tablets could readily be analyzed in tablets. No change in crystalline form was observed as a result of formulation or in subsequent stability studies. Solid-state NMR in combination with (13)C labeling can, in suitable cases, be used as a strategy to study the effect of formulation on the polymorphism of low dose drugs.

Carbon Isotopes↗

PubMed2004

Milling of agglomerates in an impact mill.

Milling of agglomerates is one of the common unit operations during preparation of oral dosage forms like capsules and tablets. In literature the breakage of granules is mostly determined after single impact at an ideally formed granule or of single particles. In this paper the breakage behavior of agglomerates after milling with multiple impacts has been studied. It investigates the effects of the formulation and the influences of the mill settings. With respect to the formulation it has been found that both the size of the particles before granulation and the amount of binder used determine the breakage behavior. Both parameters have an influence on the strength of the granule to be milled, where initial particle size has the largest effect. A relation has been found between the strength of granules and the degree of size reduction. Regarding the mill settings, there are no mill parameters which influence the formation of fines independently. Formation of fines is always the result of the total degree of size reduction. It is not possible to achieve a large degree of size reduction without intensive fines formation. The results indicate that it is possible to achieve every desired average particle size. However, when formation of dust has to be reduced, multiple milling steps with separation of in-size particles is necessary.

Administration, Oral↗

PubMed2004

Qualitative proof of liquid dispersion and penetration-involved granule formation in a high shear mixer.

The origination of granules in the early seconds is an important aspect of high shear granulation. To elucidate these mechanisms, a substandard amount (1.5% w/w) of an aqueous hydroxypropyl cellulose solution was added to four different lactose mixtures: (1) lactose 100 M (d(4,3) approximately 170 microm), (2) lactose 200 M (d(4,3) approximately 50 microm), and (3, 4) 10% magnesium stearate/lactose 100 or 200 M. Between 1 and 15 s after binder addition samples were taken, which were immediately frozen in liquid nitrogen. The frozen sample was sieved into granular (> 280 microm) and non-granular-material (< 280 microm). The binder distribution in these fractions was determined. The observed binder distribution behaviour revealed that three different nucleation mechanisms can occur: (I) For lactose 100 M holds that all the binder is initially located in the granules. These granules are subsequently broken again. (II) The lactose 200 M granules also contain 100% of the added binder liquid. Contrary to lactose 100 M the lactose 200 M granules remain intact during the process. It is argued that in both cases liquid penetration is responsible for the accumulation of all liquid in the granules. A theoretical evaluation also confirmed that liquid penetration leads to the formation of the primary granules (III) No liquid penetration is possible in the hydrophobic magnesium stearate/lactose mixtures and the binder is completely dispersed in the non-granular material.

Chemistry, Pharmaceutical↗

PubMed2004

Influence of spinline stress on release properties of a coaxial controlled release device based on EVA polymers.

PURPOSE: To investigate the influence of the extrusion parameters on the polymeric structure and release properties of polyethylene vinyl acetate (EVA) coaxial fibers, used for controlled release of steroids. METHODS: Coaxial fibers were prepared under various extrusion conditions. Both spinline stress and release properties were determined. The polymeric structure of the membrane was investigated with wide angle X-ray scattering (WAXS). RESULTS: Upon leaving the spinneret, the polymeric fiber exhibits a large die swell. As a consequence, it is necessary to apply a force to draw the fiber to its desired diameter. A larger drawing force is needed at lower extrusion temperature, at a smaller air gap, or at a higher spinning velocity. It was found that the release rate of a steroid from the coaxial fiber increases, when the fibers are prepared at a higher spinline stress. X-ray measurements reveal that at higher spinline stress, the crystalline volume fraction of the membrane decreases. As a result of a decreasing crystallinity, the permeability of the polymer increases. CONCLUSIONS: It is demonstrated that the extrusion parameters and spinline stress have a significant influence on the polymeric structure of the membrane and hence the release properties. Higher spinline stress results in a higher release rate.

Algorithms↗

PubMed2004

Biowaivers for oral immediate-release products: implications of linear pharmacokinetics.

Bioequivalence of drug formulations plays an important role in drug development. Recently, the Biopharmaceutical Classification System (BCS) has been implemented for the purpose of waiving bioequivalence studies on the basis of the solubility and gastrointestinal permeability of drug substance. Using the rationale of the BCS, it can be argued that biowaivers can, however, also be granted on the basis of standard pharmacokinetic data. If a drug exhibits dose-linear pharmacokinetics and a sufficiently fast dissolution profile, it can be concluded that this drug appears to pose no problem with respect to absorption. It should be noted that a change of an immediate-release tablet formulation can only lead to a deviating rate and/or extent of absorption when release of the drug from the formulation is altered. Logically, the dissolution profiles of the different formulations should be equal to guarantee bioequivalency. Thus, both BCS and the alternative linear pharmacokinetics approach require an evaluation of dissolution profiles. The justification of BCS is found in the permeability classification of the compound, while those of the linear pharmacokinetics lie in the apparent lack of a permeability problem. For example, in this context P-glycoprotein-transported drugs form an interesting class of compounds, which may be treated likewise when complying to the aforementioned requirements. Furthermore, poorly soluble compounds may be less troublesome than expected. It is shown that linear kinetics can be explained by the solubilising activity of, for example, bile salts. In this instance, linear pharmacokinetics shows that elevated doses do not appear to exhibit a limiting role on the dissolution. Hence, a change in formulation without any effect on the dissolution profile is not expected to cause a change in availability. It is clear that the formulations to be compared should not contain excipients that display an effect on (presystemic) drug metabolism.

Administration, Oral↗

PubMed2003

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 ratio's 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.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Experimental and modelistic approach to explain granulate inhomogeneity through preferential growth.

Wet granulation of a powder mixture often leads to accumulation of the smallest particles in the large granules. The preferential uptake of these particles results in an inhomogeneous granulate. The aim of this study was to investigate the mechanism of preferential growth. For that purpose the growth of one single granule was followed by adding a droplet of binder liquid to a rotating powder mixture of paracetamol and lactose. The particle sizes of both components were varied. At various time points mass and paracetamol content of the granule was determined. The results showed in all cases that the fine particles have a relatively higher presence in the granule than the coarse particles. These observations were independent of the fact whether the fine particles consists of lactose or paracetamol. During layering growth of the granule, caused by radial penetration of the liquid, fine particles appear to have a higher affinity for growth than coarse particles. It was argued that small particles penetrate the pores of the granule more easily than large particles, leading to the preferential absorption of the fine constituents. A model based on this growth mechanism, was able to predict the experimental results. It was concluded that this non-random growth process underlies the formation of inhomogeneous granules.

Acetaminophen↗

PubMed2003

Physicochemical properties and transport of steroids across Caco-2 cells.

PURPOSE: The purpose of this work was to study the relevant physicochemical properties for the absorption of steroids. METHODS: Various physicochemical properties of steroids were calculated (molecular weight, ClogP, static polar surface area [PSA], etc.). Within this series of steroids, different pharmacological groups were defined. Based on the outcome of this survey, steroids were selected for the Caco-2 permeability study. The apparent permeability coefficients (Papp) were related to the calculated and measured physicochemical properties. RESULTS: Between the defined groups of steroids, ClogP was the most discriminative descriptor. The steroids were well transported over the cell monolayers and the Papp was independent of the concentration and the transport direction. No relationship was found with the PSA; however, the Papp showed a weak inverse correlation with ClogP. CONCLUSIONS: The molecular descriptors and Papp values showed that all steroids are well transported. The small differences in the Papp values showed a weak inverse correlation with ClogP: the hydrophilic steroids (ClogP approximately 0-2) tend to diffuse faster over the cell monolayers compared with the more hydrophobic steroids (ClogP approximately 5). The relationship with ClogP suggests that partitioning of steroids between the biologic membrane and the surrounding aqueous phase is one of the main mechanisms for absorption.

Biological Transport↗