197,004 research outputs found
Design of pharmaceutical tablet formulation for a low water soluble drug : search for the critical concentration of starch based disintegrant applying percolation theory and F-CAD (Formulation-Computer Aided Design)
No full textThe topic of this PhD work is to search the critical concentration of starch based disintegrant applying percolation theory and F-CAD (Formulation-Computer Aided Design) in order to design a pharmaceutical tablet formulation for a low water soluble drug. Critical concentration of maize starch (MS) for a ternary mefenamic acid (MA) tablet formulation with respect to a minimum disintegration time is investigated. Additionally implemented application of F-CAD to compute the disintegration time of MA tablet formulation is presented. This topic is related to push forward the idea of Quality by Design (QbD) of FDA (Food and Drug Administration) / EMEA (European Medicines Agency) / PMDA (Pharmaceuticals and Medical Devices Agency) and the exploration of the design space according to ICH (International Conference of Harmonization) Q8.
The results of this work shows that the application of percolation theory is not limited to binary tablet formulation. The critical concentration of MS described by the renormalized MS concentration, MS/(MS+MA) applying the renormalization technique is always equal 0.198 (dimensionless). Moreover the critical concentration of MS is optimized using the spline approximation with the dataNESIA software. It is leading to a minimum disintegration time at 0.206, dimensionless, renormalized, which is very close to the experimental value of 0.198. According to the percolation theory, a minimum disintegration time corresponds to the formation of a continuous water-conducting cluster through the entire tablet. The critical volume fraction of an ‘infinite cluster’ that water can diffuse through the entire MA tablets are calculated with taking into account for the geometrical considerations between MS and MA particles based on random close packed (RCP) spheres system. The critical volume fraction of MS is calculated by the multiplication of critical concentration of MS and the solid fraction of MA tablets; which is within the range of 0.16 ± 0.01 (v/v). It is concluded that the critical volume fraction for three dimensional lattices is equal to 0.16 ± 0.01 (v/v); which is useful for the calculation of the critical concentration of starch based disintegrant in order to design the pharmaceutical tablet formulation based on scientific approach proposed by ICH Q8 guidance.
In addition, the disintegration behavior in the neighborhood of the percolation threshold is explained mathematically by the basic equation of the percolation theory, yielding a critical exponent q equal to 0.28 ± 0.06 (Quality of fit: r2 = 0.84). This value is close to the critical exponent for three dimensional lattices (q = 0.4). Thus, it is important, within a planned experimental design to optimize the disintegrant to take into account the percolation theory. However it has to be kept in mind that the determination of the percolation threshold and critical exponent does not give an answer about the absolute value of the disintegration time. Dissolution Simulation (DS) module, which is the one of F-CAD based on cellular automata algorithm is used to simulate the disintegration time of a MA tablet. Disintegration time of tablet is assumed as the time elapsed till the water is detected at the geometric center of the virtual tablet. Comparison of experimental disintegration time of MA tablet and computed specific time point for water to reach the geometric center of the tablet by using F-CAD software has been carried out and shown an acceptable correlation (Correlation coefficient: r = 0.81). The detailed evaluation of the data shows that there is still a need for optimization of F-CAD for the calculation of the disintegration time in order to achieve a similar or the same performance like in the prediction of the dissolution profile of a tablet formulation. It is concluded that F-CAD software is the only software so far, which is capable of computing the disintegration time of tablets. The software has a great potential to be improved and to be not only used for the safe prediction of the dissolution profile of a tablet formulation but also for a safe prediction of the disintegration time. Thus, such a software is one of the tools for the substitution of laboratory experiments for the purpose of the design and development of new pharmaceutical solid dosage forms. The replacement of expensive laboratory experiments by in-silico experiments is an important issue to reduce development costs and to comply with the requirements of ICH Q8 exploring the design space with response surface methodology. The results of this thesis show in addition that the application of percolation theory is a must in order to detect percolation thresholds. It is important to know the response surfaces close to the percolation threshold of sensitive tablet properties such as the disintegration time to get information about the robustness of the selected formulation. In this context one has to put the question forward if the application of percolation theory should be an integral part of the guidelines of ICH Q8 exploring the formulation design space
Search for technological reasons to develop a capsule or a tablet formulation
No full textThe following work should be understood as an approval to the FDA’s new concept of quality
assurance in the 21st century, i.e. to understand the process and the formulation, to build in and not to
test in quality.
There are a number of reasons from the economic and marketing point of view to prefer a capsule or a
tablet formulation. The aim of this work, however, was to find specific technological reasons to develop
a robust capsule or tablet formulation with special respect to physical properties of model drugs and
excipients such as wettability, solubility as well as compressibility and compactibility.
Formulations nowadays are usually developed under high-time pressure on the basis of “trial and
error” experiments. They are complex, variable systems consisting not only of an active substance but
also of a number of excipients. An in-depth and science based knowledge, whether to formulate a
drug as a robust capsule or tablet formulation, would help to shorten the developing process and as a
consequence, time and money could be saved.
In early clinical trials for example when the dose is increased in order to find the optimal therapeutic
effect with a minimum of side effects, the whole amount of drug should be released at the same time
independently of the drug load. No decrease of the bioavailability has then to be expected from a
technological point of view. In such a case, however, normally there is at first a capsule formulation
because the developing time is in most cases not as complex as for a tablet formulation: a powder
mixture can be filled directly into a capsule shell without a granulation and a compression process
(Leuenberger et al., 2005).
In the case of the well soluble and well wettable model drug caffeine such an approach would have
been successful. The standard capsule formulation consisting of caffeine, lactose and
magnesiumstearate turned out to be entirely robust in the dissolution test independently of the drug
load. The poorly soluble and poorly wettable model drug proquazone, however, showed a dramatically
prolonged release in the dissolution test when it was found in high concentrations. It became clear that
proquazone needs to be formulated as a granulate or a tablet to achieve a robust formulation
regarding dissolution. With the poorly soluble but well wettable model drug diclofenac sodium neither
the capsule nor the corresponding tablet formulation turned out to be robust.
It was therefore decided to introduce a novel excipient as all formulations mentioned above had all the
same compositions. This excipient, UICEL, was developed at the University of Iowa. It is said to have
excellent direct compressing properties, which could also be confirmed in this work. Furthermore it
turned out to be a very good excipient in the capsule filling process leading to fast dissolution rates in
combination with all model drugs because of its excellent wetting and disintegration properties. After a
direct compression of all model drugs in combination with UICEL it also caused fast dissolution rates
with the model drugs caffeine and proquazone. In combination with the model drug diclofenac sodium,
however, no fast releases could be achieved.
When the disintegration of all formulation was investigated, in the case of the model drug proquazone
no correlation between dissolution behaviour and the disintegration time has been observed. When
the different systems were evaluated from the point of view of sorption of water, which indicates the
wettability behaviour of the different systems, a clear difference between the formulations could be
observed having a correlation with the results found in the dissolution experiment. It is therefore
strongly recommended for preformulation studies to include water sorption experiments, especially in
the case of a high drug content.
As a good compressibility and compactibility of different system are important in the production of
tablet formulations in contrast to capsule formulations where the powder or granulate can be filled
directly into the capsule shell without any compression, it was decided to find a fast but science based
screening approach to discriminate between systems with poor compression properties that could be
candidates for a capsule filling approach and systems with good compression properties that could be
compressed to tablets. Therefore the physical model of powder compression proposed by
Leuenberger (1980), which connects the parameters compressibility and compactibility, was chosen.
In contrast to earlier studies, just five different compression forces for each sample were applied and
the crushing strength was determined with a common tablet tester. This approach turned out to be
very useful giving a clear discrimination between the different systems.
It was found for a future continuation of this work that the wettability as a physical property for the
decision whether to formulate a drug as a capsule or a tablet should be investigated in-depth and
more specifically. Formulations with other excipients or other poorly wettable model drugs should be
analysed at the same time than the sorption of water. The future compressibility or compactibility
studies could be carried out with the PressterTM compaction simulator and with other model drugs
having very poor compressibilities and compactibilities
Lectotypification and correct author citation of Ipheion uniflorum (Amaryllidaceae), with a new synonym
No full textThe type of the generic name Ipheion Rafinesque is Milla uniflora Graham but the same specific epithet had been used in Triteleia by Lindley a few years earlier for the same species with a different type. Confusion ensued concerning the correct author citation for the species under Ipheion. A taxonomic history of the name Ipheion uniflorum (Graham) Raf., a new synonym for this species, and a lectotype for Milla uniflora are presented herein.Fil: Sassone, Agostina Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; Argentina. Freie Universität Berlin; AlemaniaFil: Giussani, Liliana Mónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: Arroyo Leuenberger, Silvia. Freie Universität Berlin; Alemani
Evidence of synergistic/additive effects of sildenafil and erythropoietin in enhancing survival and migration of hypoxic endothelial cells
No full textEndothelial cell dysfunction is a common event to several pathologies including pulmonary hypertension (PH), which is often associated with hypoxia. As the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction, this cell type is fundamental in the development of vascular remodelling and increased vascular resistance.
We investigated the protective effects of sildenafil, a phosphodiesterase type 5 inhibitor, given in combination with erythropoietin (Epo) as it has been demonstrated that both drugs have anti-apoptotic effects on several cell types. Specifically, we examined the viability and angiogenetic properties of rat pulmonary artery endothelial cells upon exposure to either 21% or 1% oxygen, in presence of sildenafil (1 and 100 nM) and Epo (5 and 20 U/ml) alone or in combination (1 nM and 20 U/ml). Cell proliferation and viability were analysed by trypan blue staining, MTT assay and annexin V/PI stainings. In all assays the ability of the combination treatment in improving cell viability was superior to that of either drug alone. The angiogenetic properties were studied using a migration and a 3D collagen assay and the results revealed increases in the migration potential of endothelial cells as well as the ability to form tube-like structures in response to sildenafil and the combination treatment. We therefore conclude that both drugs exert protective effects on endothelial cells upon hypoxia, and that sildenafil enhances the migratory and angiogenetic properties, especially in hypoxic conditions. Furthermore, we present evidence of possible additive or synergistic effects of both drugs
Bryozoan stable carbon and hydrogen isotopes: relationships between the isotopic composition of zooids, statoblasts and lake water
No full textWe explored the extent to which δ13C and δD values of freshwater bryozoan statoblasts can provide information about the isotopic composition of zooids, bryozoan food and surrounding water. Bryozoan samples were collected from 23 sites and encompassed ranges of nearly 30‰ for δ13C and 100‰ for δD values. δ13C offsets between zooids and statoblasts generally ranged from −3 to +4.5‰, with larger offsets observed in four samples. However, a laboratory study with Plumatella emarginata and Lophopus crystallinus demonstrated that, in controlled settings, zooids had only 0–1.2‰ higher δ13C values than statoblasts, and 1.7‰ higher values than their food. At our field sites, we observed a strong positive correlation between median δ13C values of zooids and median δ13C values of corresponding statoblasts. We also observed a positive correlation between median δD values of zooids and statoblasts for Plumatella, and a positive correlation between median δD values of statoblasts and δD values of lake water for Plumatella and when all bryozoan taxa were examined together. Our results suggest that isotope measurements on statoblasts collected from flotsam or sediment samples can provide information on the feeding ecology of bryozoans and the H isotopic composition of lake water
Soft tabletting of MCC 102 and UICEL-A/102 pellets into multiple unit pellet systems
No full textMultiple Unit Pellet Systems, widely known as MUPS, are tablets consisting of spherical, granular subunits (pellets). Thanks to their prompt disintegration into the single subunits immediately after administration, they transit shortly in stomach and promptly disperse across the huge surface area of the small intestine stabilizing the overall bioavailability and reducing the risk of dose dumping and local irritations. If until two decades ago pellets were exclusively filled into hard gelatine capsules, they represent nowadays the ideal subunits for multiparticulate tablets. In fact, MUPS present all the advantages of the production of tablets compared to capsules: lower production costs, higher production rates, reduced risk of tampering, lower tendency of adhering to oesophagus during swallowing and better patient compliance. Despite this, the compaction of pellets into tablets is a complex technology: MUPS must be robust enough but still disintegrate into their subunits within short time, and, not less importantly, they should retain the dissolution profile of the original subunits. At this scope, the pellets should undergo a soft compaction, without breakage of the pellet coating layer nor formation of matrix tablets. Such ideal MUPS may be strived optimizing the proportions between three crucial factors: the pellet cores, the coating materials and the embedding excipients. Not many studies have focused so far on the simultaneous optimization of these three variables. Cellulose, and in particular microcrystalline cellulose, is one of the major excipients in solid dosage formulations. It presents four polymorphic forms, out of which the form I and II have pharmaceutical relevance. The form I, which behaves plastically when compressed, is extremely widespread as a filler-binder for MUPS. Unfortunately, it does not possess prevalent disintegration properties, so that a disintegrant must be added if prompt disintegration is strived. Kumar et al. developed a new Cellulose II pharmaceutical aid named UICEL-A/102 through alkali treatment of Avicel PH 102 and successive hydrolysis with ethanol and oven dry. So far, UICEL-A/102 has been extensively studied as potential multifunctional excipients (filler and disintegrant) in tablet formulations, whereas its employing as a multifunctional excipient in MUPS has been not yet investigated. The aim of this study was on the one hand the multifactorial investigation of crucial parameters involved in the compaction of pellets into MUPS, on the other hand the evaluation of the suitability of UICEL-A/102 as filler in two different kind of pellets formulations for MUPS (homogeeous pellets from direct pelletization, inhomogeneous pellets from dry powder layering). In the end, a robust technology for UICEL-A/102 MUPS production was suggested and discussed. To this scope, MCC 102 (Cellulose I) and UICEL-A/102 (Cellulose II) were compared as pellet filler and embedding excipients in MUPS for controlled release. In the first part of the study, MCC 102 and UICEL-A/102 were separately mixed with Sodium Diclofenac, directly pelletized, coated with Kollicoat® SR 30 D to 20% w/w weigth gain and compacted into MUPS. In the second part of the study, a binary mixture of MCC 102 or UICEL-A/102 and Sodium Diclofenac was layered on neutral cores (Suglets® or Cellets®), in order to produce inhomogeneous pellets by means of dry powder layering technology. These pellets were then coated and compacted into MUPS according to the same procedure employed for the previous pellet batches. In the case of homogeneous pellets of either MCC 102 or UICEL-A/102, the MUPS formulations overcame compaction deformed rather than ruptured, as proved by comparison between the dissolution profiles and the SEM and CLSM images before and after compaction. Both MCC 102 and UICEL-A/102 MUPS resulted to be mechanically robust (crushing strength of 70-100 N), fast disintegrating in water (≤ 3 min) and maintained the same release profile and almost the same superficial and inner morphology of their uncompressed subunits. Compared with MCC pellets, UICEL-A/102 pellets proved to be generally less spherical and more porous. Nonetheless, they could be homogenously coated and also retained their dissolution profile after compaction into MUPS. The fact that UICEL-A/102 pellets and MUPS presented shorter dissolution times than their MCC counterparts is to ascribe to the prevalent swelling properties of UICEL-A/102. In fact, UICEL-A/102 contained in pellets sped up their dissolution independently of the amount and homogeneity of their coating layer. The multifactorial evaluation of selected parameters (drug loading amount in pellets, type and quantity of filler in pellets, type of disintegrant in MUPS) on response variables (disintegration and dissolution time) brought to an interesting conclusion: UICEL-A/102 was on the one hand favourable filler and disintegrant for immediate disintegration, on the other hand it proved to be unsuited as filler in pellets for extended release. MCC 102 MUPS, conversely, were appropriately delayed formulations, mainly due to retention of their subunits characteristics. In the case of inhomogeneous pellets, only UICEL-A/102 pellets proved to be favourable subunits; in fact, MUPS made of UICEL-A/102 pellet featured pretty good robustness (crushing strength of 90-120 N) and rapid disintegration (disintegration time ≤ 12 min), whereas MUPS made of MCC 102 were too compact (200-300 N) and did not disintegrate before 50 min. This dichotomy was put in relation with the fact that UICEL-A/102 coated and uncoated pellets were less compact and more porous than their MCC 102 counterparts. In addition, the choice of Cellets® rather than Suglets® as basic neutral cores in dry powder layering had a significant impact on the characteristics of UICEL-A/102 MUPS. In fact, UICEL-A/102 MUPS whose subunits had Cellets® cores retained the release profile of their uncompressed subunits more then their counterparts having Suglets® as subunit cores. This suggests that subunits with a MCC core contributed significantly to the softness of the compaction, this difference being associable with a plastic behaviour of Cellets® in contrast with the rather elastic behaviour of Suglets® during compaction. On the one hand, it can be claimed that dry powder layering produced UICEL-A/102 pellets with less prevalent disintegration properties, which were therefore more suitable for controlled release MUPS. On the other hand, the presence of a hard core in those pellets favored the partial rupture of their coating layer during compaction, resulting in a faster drug release after compaction, especially in the case of Suglets® as non pareils. Actually, the pellets produced via dry powder layering contained proportionally less UICELA/102 than their homologous prepared via direct pelletization (20% vs. 60% w/w). This means that the use of UICEL-A/102 as unique multifunctional excipients is rather suggested in pellets and MUPS for immediate release, while its employing as layering excipients on neutral core is very promising in the development of MUPS for extended release
GdN thin films: Bulk and local electronic and magnetic properties
No full textA study of high-quality thin films of the ferromagnet gadolinium nitride, GdN, is reported. The films, prepared by reactive ion-beam sputtering, show good stoichiometry and the lattice parameter, Curie temperature T-C, and saturation magnetization of the bulk material. The electrical conductivity is thermally activated down to the onset of magnetic ordering where there is evidence of a transition to metallic behavior. The transition can be tuned by a magnetic field, as reflected by a giant negative magnetoresistance. The ordered 4f moment extracted from the spectra of x-ray magnetic circular dichroism at the gadolinium M-4,M-5 edges is consistent with the S-8(7/2) configuration of Gd3+; it varies with temperature as the macroscopic magnetization of the GdN layers. The experimental K-edge photoabsorption spectra of nitrogen in this compound indicate the presence of N p character of the low-lying unoccupied conduction-band states, pointing to hybridization of the N 2p and Gd (5d,6s) states. However, a comparison of the spectra with the theoretical partial density of vacant N p states shows considerable disparities that are not well understood. The exchange field generated by the Gd f electrons in the ferromagnetic phase of GdN induces a magnetic polarization of the N p band states, as can be concluded from the observation of strong magnetic circular dichroism at the K edge of nitrogen. It indicates the presence of an important spin-orbit interaction in the final N p states
Compression behavior of the enzyme ß-galactosidase
No full textThis thesis is based on the investigation of the compression behavior of a solid model enzyme. It
was the scope of this work to characterize the behavior of the enzyme powder under pressure to
gain on the one hand information about the behavior of powder during the compression process
and on the other hand to get more knowledge about the behavior of enzyme powder in
pharmaceutical formulations. An important aspect was the influence of excipients because their
deformation character may change the properties of pharmaceutical formulations. For that reason
the physical influences of a plastic and a brittle model excipient, respectively on the enzyme
powder in binary mixtures was investigated. Critical mixture ratios should be defined where the
behavior of the binary mixtures shows sudden changes. If critical mixture ratios are known, they
can be avoided in the development of dosage forms to get robust formulations. Since the direct
compaction of powders may be difficult, the compression behavior of enzyme granulates and
enzyme coated pellets was investigated as well. For that reason powders and pellets from different
raw materials were layered with an enzyme binding agent solution. The enzyme activity of the
various granulates, pellets and compacts was detected and the preparations were judged based on
this property. The investigated model enzyme was a solid β-galactosidase preparation from Aspergillus oryzae,
which was chosen for its stability, the molecular weight of 105 kDa, which is an average value
compared to other enzymes and the reliable and relatively simple enzyme activity assay.
Compacts were produced on a material testing machine and the activity was detected
spectophotometrically. The compression properties of the various formulations were characterized
by using Heckel equation and modified Heckel equation. Granulates and pellets as well as their
compacts were further characterized by scanning electron microscopy pictures. The extent of activity loss in the compacted brittle enzyme powder could not be decreased by the
addition of a plastic or a brittle excipient. With the diversity of the particles even a higher number of
shearing forces was built in the compacts during compression. The shearing forces seemed to
have negative influences on the activity of the enzyme. In the binary powder mixtures of the
enzyme powder with the plastic excipient there was found a sudden change in the behavior of the
system at a mixture ratio of 20% of enzyme powder. For the brittle-brittle binary mixtures of the
enzyme powder with an excipient, differences in the behavior were difficult to detect because the
two powders showed a very similar behavior. Tendencies towards a critical concentration at a ratio
of 60% (V/V) of enzyme powder could not be proved, although a comparison with a second brittle
enzyme powder preparation in mixtures with a brittle excipient showed similar tendencies. It was
found that a plastic compression character and regularity in shape and size of the compressed
particles was important to protect the enzyme activity under pressure. These properties could be
reached with the production of granulates and the coating of pellets by enzyme layering, whereas especially the compacted enzyme coated pellets showed no significant activity loss under pressure
due to the very regular shape and size distribution and the fact that the pellets did not break and
only slightly changed their shape to reduce the spaces between the individual pellets.
A lot of new aspects in the field of particle compression have been discussed in this work. It was
found that the shape and the size of the various particles may have big influences on friction and
shearing forces. Shearing forces can cause a reduction of enzyme activity during the compression
of an enzyme powder. The compression character of the particles showed influences on the extent
of activity loss under pressure, whereas plastic properties are favorable to protect the enzyme.
As a further step it would be important to test the transferability of the results on other enzyme
products and to take into consideration more practical aspects like the production on a rotary press,
the investigation of economic points of view or simply the attainment of a required dosage to define
an optimal formulation for an oral application of a pharmaceutical enzyme powder
The 8.2 ka BP event in north eastern North America: first combined oxygen and hydrogen isotopic data from peat in Newfoundland.
No full textFinding direct evidence for atmospheric circulation change in terrestrial records of Holocene climate variability remains a fundamental challenge. Here we present the first combined stable oxygen and hydrogen isotopic palaeorecord from a peatland core in Newfoundland, Canada. Sphagnum cellulose samples were isolated from a core from Nordan's Pond Bog, Newfoundland, and analysed for ?D values. Combined with existing ?18O data, the resulting ?D/?18O bi-plot correlates directly with existing measurements of the modern (late 20th century) isotopic composition of precipitation from GNIP stations in Nova Scotia and Labrador, implying a close relationship between the estimated isotopic composition of source water used by the mosses and that of the source precipitation. We use the relative variations between the two isotope records to test the hypothesis that atmospheric circulation changed in the millennium following the 8.2-ka BP climate event. The data reveal a secondary complex isotopic response ?200 years (8250–8050 a BP) after a primary oxygen isotopic event that is widespread in the north Atlantic region. This secondary event is characterized by a divergence in oxygen and hydrogen isotope records that can most plausibly be explained by the augmentation of precipitation moisture from a more distant and more continental vapour source
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