NMR imaging of high-amylose starch tablets. 1. Swelling and water uptake

Pharmaceutical tablets made of modified high-amylose starch have a hydrophilic polymer matrix into which water can penetrate with time to form a hydrogel. Nuclear magnetic resonance imaging was used to study the water penetration and the swelling of the matrix of these tablets. The tablets immersed in water were imaged at different time intervals on a 300 MHz NMR spectrometer. Radial images show clearly the swelling of the tablets and the water concentration profile. The rate constants for water diffusion and the tablet swelling were extracted from the experimental data. The water diffusion process was found to follow case II kinetics at 25 degrees C. NMR imaging also provided spin density profiles of the water penetrating inside the tablets.     

Imaging of high-amylose starch tablets. 3. Initial diffusion and temperature effects

The penetration of water into cross-linked high amylose starch tablets was studied at different temperatures by nuclear magnetic resonance (NMR) imaging, which follows the changes occurring at the surface and inside the starch tablets during swelling. It was found that the swelling was anisotropic, whereas water diffusion was almost isotropic. The water proton image profiles at the initial stage of water penetration were used to calculate the initial diffusion coefficient. The swelling and water concentration gradients in this controlled release system show significant temperature dependence. Diffusion behavior changed from Fickian to Case II diffusion with increasing temperature. The observed phenomena are attributed to the gelatinization of starch and the pseudo-cross-linking effect of double helix formation.     

Bio-fluid uptake and release of Indomethacin of direct-compressed HPMC tablets

Tablets of three different grades of hydroxypropyl methyl cellulose (HPMC), having different viscosity, were prepared using the direct-compression technique with no additive or binder. The fluid uptake behavior of these HPMC tablets was studied in three types of bio-media – water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF). The amount of fluid uptake by the tablets followed a power law relationship with time for all three media. Variants such as pH value, type of salts and salt concentration in the media were found to have little influence on the swelling process for the tablet. On the contrary, viscosity and molecular weight of HPMC were the controlling parameters for the swelling process. Subsequently, Indomethacin was added in certain percentage to the tablets as a model drug. It was to examine and elucidate drug releasing properties of the HPMC tablets. The possible mechanisms involved in the process of drug dispersion are proposed and discussed.     

The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets

The purpose of this study was to investigate the efficiency of superdisintegrants in promoting tablet disintegration and drug dissolution under varied media pH. Significant reductions in the rate and extent of water uptake and swelling were observed for both sodium starch glycolate (Primojel) and croscarmellose sodium (Ac-Di-Sol) in an acidic medium (0.1 N HCl) but not for crospovidone NF (Polyplasdone XL10), a nonionic polymer. When Primojel and Ac-Di-Sol were incorporated in model formulations, a significant increase in tablet disintegration time was observed for slowly disintegrating tablets (lactose-based tablets) but not for the rapidly disintegrating tablets (dicalcium phosphate-based tablets). The dissolution rate of the model drug, hydrochlorothiazide, was found highly dependent on both tablet disintegration efficiency and the solubility of base material(s) in the testing medium. A laser diffraction particle size analyzer proved to be an effective tool for determining the intrinsic swelling of disintegrant particles in different media. Water uptake and swelling were confirmed as 2 important functions of superdisintegrants. The reduced water uptake and swelling capacity of disintegrants containing ionizable substituents in an acidic medium can potentially jeopardize their efficiency in promoting tablet disintegration and the drug dissolution rate. Published: September 20, 2005     

Membrane formation and drug loading effects in high amylose starch tablets studied by NMR imaging

Cross-linked high amylose starch is used as an excipient in the preparation of pharmaceutical tablets for the sustained release of drugs. NMR imaging with contrast enhanced by proton density and by self-diffusion coefficient was used to follow the water uptake and swelling, two critical parameters controlling the drug release of the cross-linked starch tablets containing 10 wt % of ciprofloxacin and of acetaminophen, respectively. The drug-loaded tablets were studied in a H2O/D2O mixture at 37 degrees C in comparison to the tablets without any drug loading. The diffusion of water in the tablets all showed a Fickian behavior, but the kinetics of water uptake was faster in the case of the drug-loaded tablets. The formation of a membrane at the water/tablet interface was observed.     

Organo hydrogel hybrids. Formation of reservoirs for protein delivery

A biodegradable organo hydrogel hybrid material is presented, which is formed through the water uptake of a phosphoryl choline zwitterionomer (PC ionomer). The water uptake and subsequent swelling is induced by the phosphoryl choline (PC) end group functionality. The nonfunctional poly(trimethylene carbonate) is hydrophobic and as such does not absorb any water. Disks of the PC ionomer showed significant water uptake, typically above 90 wt % when fully swollen. This high water uptake triggered us to utilize the material for drug and protein loading and subsequent release. Fluorescein and fluorescein-labeled proteins were used as simple models for the loading and release characteristics of the material which was studied by fluorescence spectroscopy. The rate of release of the loaded molecules was compared, and it was shown that the release rate was similar for FITC and insulin but slightly slower for albumin. These results suggest that the PC ionomer may be used as a biodegradable and low elastic modulus material with an additional drug and/or protein release capacity. Such materials are of particular interest for use in a variety of applications in vivo, for example as drug eluting stents.     

Ion transport in heart mitochondria. XIII. The effect of ethylenediaminetetraacetate on monovalent ion uptake

1. Ethylenediaminetetraacetate (EDTA) markedly activates the accumulation of Na⁺ and Li⁺ and the swelling which accompanies the ion uptake by isolated heart mitochondria. This activation is reflected in the removal of limited amounts of endogenous Mg²⁺ and extensive loss of K⁺. The removal of these cations requires the presence of Na⁺, a source of energy, and a permeant anion as well as EDTA. The effects of EDTA on the activation of Na⁺ uptake and cation removal are duplicated by chelators with a high affinity for Mg²⁺, but not by ethyleneglycol-bis-(β-aminoethylether)-N, N′-tetraacetic acid. Mg²⁺ at concentrations 5 to 6 times less than EDTA prevents both activation of Na⁺ uptake and cation removal.

2. EDTA does not appear to be bound by heart mitochondria. At neutral pH the chelator penetrates into the mitochondrial water volume to the same extent as sucrose and mannitol. At pH 8.1 where the removal of mitochondrial Mg²⁺ by EDTA is more effective, EDTA penetrates virtually the entire water volume. This penetration requires the presence of a source of energy, a transported cation such as Na⁺, and a permeant anion. It appears possible that the oscillations in ion uptake and swelling observed in the presence of EDTA at pH 8.1 may be related to the presence of the chelator in the interior compartment under these conditions.     

An Epichlorohydrin-Crosslinked Semi-Interpenetrating GG-PEO Network as a Xerogel Matrix for Sustained Release of Sulpiride

The current study involved the development of a novel sustained release crosslinked semi-IPN xerogel matrix tablet prepared by chemical crosslinking of poly(ethylene) oxide (PEO) and gellan gum (GG) employing epichlorohydrin (EPI) as crosslinker. A Box–Behnken design was employed for the statistical optimization of the matrix system to ascertain the ideal combination of native polymeric and crosslinking agents. Characterization studies were performed by employing standard polymer characterization techniques such as Fourier transform infrared spectrometry, differential scanning calorimetry, and scanning electron microscopy. Formulated matrix tablets displayed zero-order release kinetics, extending over 24 h. The mechanism of drug release was primarily by swelling and surface erosion. Crosslinked semi-IPN xerogel matrix tablets were compared to non-crosslinked polymer blends; results from the study conducted showed that the physiochemical properties of the PEO and GG were sufficiently modified to allow for sustained release of sulpiride with a 100% drug release at 24 h in a controlled manner as compared to non-crosslinked formulations which displayed further release beyond the test period. Crosslinked formulations displayed water uptake between 450 and 500% indicating a controlled rate of swelling and erosion allowing for sustained release. Surface morphology of the crosslinked system depicted a porous structure formed by interpenetrating networks of polymers, allowing for a greater degree of controlled penetration into the system affording it the ability to sustain drug release. Therefore, conclusively, based on the study performed, crosslinked PEO-GG allows for the sustained release of sulpiride from a hydrophilic semi-IPN xerogel matrix system.KEY WORDS: epichlorohydrin, matrix tablet, semi-interpenetrating polymer network, sustained release, sulpiride     

Two Modes of Cell Death Caused by Exposure to Nanosecond Pulsed Electric Field

High-amplitude electric pulses of nanosecond duration, also known as nanosecond pulsed electric field (nsPEF), are a novel modality with promising applications for cell stimulation and tissue ablation. However, key mechanisms responsible for the cytotoxicity of nsPEF have not been established. We show that the principal cause of cell death induced by 60- or 300-ns pulses in U937 cells is the loss of the plasma membrane integrity (“nanoelectroporation”), leading to water uptake, cell swelling, and eventual membrane rupture. Most of this early necrotic death occurs within 1–2 hr after nsPEF exposure. The uptake of water is driven by the presence of pore-impermeable solutes inside the cell, and can be counterbalanced by the presence of a pore-impermeable solute such as sucrose in the medium. Sucrose blocks swelling and prevents the early necrotic death; however the long-term cell survival (24 and 48 hr) does not significantly change. Cells protected with sucrose demonstrate higher incidence of the delayed death (6–24 hr post nsPEF). These cells are more often positive for the uptake of an early apoptotic marker dye YO-PRO-1 while remaining impermeable to propidium iodide. Instead of swelling, these cells often develop apoptotic fragmentation of the cytoplasm. Caspase 3/7 activity increases already in 1 hr after nsPEF and poly-ADP ribose polymerase (PARP) cleavage is detected in 2 hr. Staurosporin-treated positive control cells develop these apoptotic signs only in 3 and 4 hr, respectively. We conclude that nsPEF exposure triggers both necrotic and apoptotic pathways. The early necrotic death prevails under standard cell culture conditions, but cells rescued from the necrosis nonetheless die later on by apoptosis. The balance between the two modes of cell death can be controlled by enabling or blocking cell swelling.     

Fabrication of Triple-Layer Matrix Tablets of Venlafaxine Hydrochloride Using Xanthan Gum

The objective of present investigation was to develop venlafaxine hydrochloride-layered tablets for obtaining sustained drug release. The tablets containing venlafaxine hydrochloride 150 mg were prepared by wet granulation technique using xanthan gum in the middle layer and barrier layers. The granules and tablets were characterized. The in vitro drug dissolution study was conducted in distilled water. The tablets containing two lower strengths were also developed using the same percentage composition of the middle layer. Kinetics of drug release was studied. The optimized batches were tested for water uptake study. Radar diagrams are provided to compare the performance of formulated tablets with the reference products, Effexor XR capsules. The granules ready for compression exhibited good flow and compressibility when xanthan gum was used in the intragranular and extragranular fractions. Monolayer tablets failed to give the release pattern similar to that of the reference product. The drug release was best explained by Weibull model. A unified Weibull equation was evolved to express drug release from the formulated tablets. Lactose facilitated drug release from barrier layers. Substantial water uptake and gelling of xanthan gum appears to be responsible for sustained drug release. The present study underlines the importance of formulation factors in achieving same drug release pattern from three strengths of venlafaxine hydrochloride tablets.     

Water potential,glycerol synthesis,and water content of germinating Phycomyces spores

During early germination, the sporangiospores of Phycomyces blakesleeanus synthesized large amounts of glycerol. Glycerol started leaking out of the spores after some 20 min germination. Simultaneously the water content of the spores greatly increased. Water uptake was accompanied by disapperance of the phase contrast halo and an increase in spore cross-sectional area which all occurred during the same period between 10 and 30 min germination. When spores were incubated in 0.5 or 1 M sucrose, glycerol accumulated in the spores to much higher concentrations and the increase in cellular water content was greatly reduced and retarded. Glycerol synthesis and the concomitant lowering of spore osmotic potential was not the only mediator of spore swelling since equally important glycerol concentrations loaded into dormant spores did not cause spore water uptake or swelling. Also the swelling of the spores was less affected than water uptake by decreases in ambient water potential. Apparently also cell wall loosening was involved in the swelling phenomenon which might have important implications for cellular metabolism.     

Multiple effects of mercuric chloride on hexose transport in Xenopus oocytes.

HgCl(2) had both stimulatory and inhibitory effects on [(3)H]2-deoxyglucose (DG) uptake in Xenopus laevis oocytes. The Hg dose response was complex, with 0.1-10 microM Hg increasing total DG uptake, 30-50 microM Hg inhibiting, and concentrations >100 microM increasing uptake. Analyses of the effects of Hg on DG transport kinetics and cell membrane permeability indicated that low concentrations of Hg stimulated mediated uptake, intermediate concentrations inhibited mediated uptake, but high Hg concentrations increased non-mediated uptake. 10 microM Hg increased the apparent V(max) for DG uptake, but caused little or no change in apparent K(m). Phenylarsine oxide prevented the increase in DG uptake by 10 microM Hg, suggesting that the increase was due to transporter recruitment. Microinjecting low doses of HgCl(2) into the cell increased mediated DG uptake. Higher intracellular doses of Hg increased both mediated and non-mediated DG uptake. Both insulin and Hg cause cell swelling in isotonic media and, for insulin, this swelling has been linked to the mechanism of hormone action. Osmotically swelling Xenopus oocytes stimulated DG transport 2-5-fold and this increase was due to an increased apparent V(max). Exposing cells to 10 microM Hg or 140 nM insulin both increased cellular water content by 18% and increased hexose transport 2-4-fold. These data indicate that low concentrations of Hg and insulin affect hexose transport in a similar manner and that for both an increase cellular water content could be an early event in signaling the increase in hexose transport.     

Matrix Tablets: The Effect of Hydroxypropyl Methylcellulose/Anhydrous Dibasic Calcium Phosphate Ratio on the Release Rate of a Water-Soluble Drug Through the Gastrointestinal Tract I. In Vitro Tests

Different hydroxypropyl methylcellulose (HPMC)/anhydrous dibasic calcium phosphate (ADCP) matrix tablets have been developed aiming to evaluate the influence of both components ratio in the control release of a water-soluble drug (theophylline). In order to characterise the matrix tablets, swelling, buoyancy and dissolution studies have been carried out in different aqueous media (demineralised water, progressive pH medium, simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid). The HPMC/ADCP ratio has turned out to be the determinant in the matrix behaviour: the HPMC characteristic swelling behaviour was modulated, in some cases, by the ADCP characteristic acidic dissolution. When the HPMC/ADCP ratio was ≥0.69, buoyancy, continuous swelling and low theophylline dissolution rate from the matrices (H1, H2 and H3) were observed in all dissolution media. Consequently, these formulations could be adequate as gastro-retentive drug delivery systems. Additionally, HPMC/ADCP ratio ≤0.11 (H5 and H6) induces a pH-dependent drug release which could be applied to design control drug release enteric formulations (with a suitable enteric coating). Finally, a HPMC/ADCP ratio between 0.11 and 0.69 (H4) yield a gastrointestinal controlled drug release, due to its time-dependent buoyancy (7 h) and a total drug delivery in 17 h in simulated colonic fluid.Key words: anhydrous dibasic calcium phosphate, hydroxypropyl methylcellulose, matrix tablets, oral controlled release, theophylline     

Water uptake by dry beans observed by micro-magnetic resonance imaging

BACKGROUND AND AIMS: Water uptake by dry kidney beans (Phaseolus vulgaris 'Rajma') and adzuki beans (Vigna angularis) was traced using micro-magnetic resonance imaging in order to elucidate the channel of water entry, the manner of water delivery and the timing of swelling of the seeds. METHODS: Magnetic resonance images of beans absorbing water were continuously measured with the single-point imaging method for 16 h or 20 h at 15-min intervals. With this technique, it was possible to detect and visualize the location of water in the beans, at a low water content, in the initial stages of water entry. KEY RESULTS: Water was taken up through a specified tissue, the lens, near the hilum, and distributed primarily to the testa. When water reached the radicle, it began to be incorporated into cotyledons with considerable swelling of the seeds. Water uptake took place within a short time for kidney beans. The initial process of water entry was associated with mechanical vibration of the seed. Rapid hydration of the testa and the swelling of the cotyledons were then observed. Water was supplied to cotyledons through the adaxial epidermis. In contrast, it took a long time, approx. 7 h, to activate the water channel of the lens for adzuki beans which have a tightly fitting testa. Steeping of the testa was not uniform, which induced temporary slanting before enlargement of the seed. CONCLUSIONS: The activation of the lens as the sole water channel, the delivery of water to the radicle within the testa, the swelling of the cotyledons, and the further increment of water are physiologically different processes during imbibition, and were separated by locating water in various tissues and by analysing the time course of water uptake using magnetic resonance imaging with the single-point imaging method.     

Ouabain-insensitive salt and water movements in duck red cells. I. Kinetics of cation transport under hypertonic conditions

Duck red cells in hypertonic media experience rapid osmotic shrinkage followed by gradual reswelling back toward their original volume. This uptake of salt and water is self limiting and demands a specific ionic composition of the external solution. Although ouabain (10(-4)M) alters the pattern of cation accumulation from predominantly potassium to sodium, it does not affect the rate of the reaction, or the total amount of salt or water taken up. To study the response without the complications of active Na-K transport, ouabain was added to most incubations. All water accumulated by the cells can be accounted for by net salt uptake. Specific external cation requirements for reswelling include: sufficient sodium (more than 23 mM), and elevated potassium (more than 7 mM). In the absence of external potassium cells lose potassium without gaining sodium and continue to shrink instead of reswelling. Adding rubidium to the potassium- free solution promotes an even greater loss of cell potassium, yet causes swelling due to a net uptake of sodium and rubidium followed by chloride. The diuretic furosemide (10(-3)M) inhibits net sodium uptake which depends on potassium (or rubidium), as well as inhibits net sodium uptake which depends on sodium. As a result, cell volume is stabilized in the presence of this drug by inhibition of shrinkage, at low, and of swelling at high external potassium. The response has a high apparent energy of activation (15-20 kcal/mol). We propose that net salt and water movements in hypertonic solutions containing ouabain are mediated by direct coupling or cis-interaction, between sodium and potassium so that the uphill movement of one is driven by the downhill movement of the other in the same direction.     

Uptake of uric acid, xanthine and hypoxanthine by brush-border membrane vesicles from mouse small intestine

Using mouse small intestine brush-border membrane vesicles virtually free of xanthine oxidase (EC 1.2.3.2) and free of uricase (EC 1.7.3.3) the uptake of the purines uric acid, xanthine and hypoxanthine have been studied. The sodium-dependent overshoot phenomenon shown to exist for the uptake into the vesicles for d-glucose and l-phenylalanine was not observed with the purines. However, the uptake of the three purines in the presence of NaCl or KCl was greater than the uptake in the presence of either NaSCN or mannitol. Although 12.9% of the xanthine uptake and 17.6% of the hypoxanthine uptake was attributed to binding to the membranes, almost all the uric acid uptake was due to transport into an osmotically active space. The apparent intravesicular volume, calculated after 60 min incubation, for the three purines was consistently greater than the values obtained with d-glucose, l-phenylalanine equilibration, suggesting slow continuing penetration of purines associated with swelling or an apparent accumulation of purines within the vesicles associated with normal vesicle volume.     

Impact of Physicochemical Environment on the Super Disintegrant Functionality of Cross-Linked Carboxymethyl Sodium Starch: Insight on Formulation Precautions

The aim of this work is to improve the understanding of the physicochemical mechanisms involved in the functionality of cross-linked carboxymethyl sodium starch (CCSS) as a tablet super disintegrant (SD). The behavior and properties of this SD (medium uptake, disintegration times, particle size, and rheology) was investigated in a wetting medium of different physicochemical properties. In particular, the relative permittivity (dielectric constant) of these media was intentionally modified for evaluating its effect on CCSS properties. Results showed different swelling behaviors of CCSS particles according to the relative permittivity of the tested media and allow to propose two underlying mechanisms that explain CCSS functionality. Both the intra-particular swelling and the inter-particular repulsion are affected by the relative permittivity of the media. Finally, disintegration test performed on tablets specially formulated with mannitol (used commonly as an excipient and known to modify relative permittivity) confirmed that the functionality of CCSS and therefore the disintegration of the tablet can be altered according to the mannitol content.KEY WORDS: cross-linked carboxymethyl sodium starch, disintegrant functionality, orally disintegrating tablets, relative permittivity, repulsive layers     

Effect of Sorbed Water on Disintegrant Performance of Four Brands of Polacrilin Potassium NF

Polacrilin Potassium NF is a commonly used weak cation exchange resin disintegrant in pharmaceutical tablets. The objective of this research was to evaluate the effects of sorbed moisture on physical characteristics and disintegrant performance of four brands of Polacrilin Potassium NF. The disintegrants were stored in five different relative humidity chambers and their dynamic vapor adsorption–desorption analysis, effect of moisture on their compressibility, compactability, particle size, morphology, water uptake rate, and disintegration ability were studied. Moisture seemed to plasticize the disintegrants, reducing their yield pressures. However, certain optimum amount of moisture was found to be useful in increasing the compactablity of the tablets containing disintegrants. The tablets, however, lost their tensile strengths beyond this optimum moisture content. Moisture caused two brands of the disintegrants to swell; however, two other brands aggregated upon exposure to moisture. Swelling without aggregation increased the water uptake, and in turn the disintegrant performance. However, aggregation probably reduced the porosities of the disintegrants, reducing their water uptake rate and disintegrant performance. Different brands of Polacrilin Potassium NF differed in the abilities to withstand the effects of moisture on their functionality. Effect of moisture on disintegrant performance of Polacrilin Potassium NF needs to be considered before its use in tablets made by wet granulation.     

Influence of cations on spheroplasts of marine bacteria functioning as osmometers

Penetration of substrates into marine bacteria as influenced by cations has been demonstrated by the effects of increased osmotic pressure in spheroplasts of these cells. Spheroplasts of Pseudomonas natriegens, stabilized with lactose, underwent a metabolic swelling in the presence of a substrate to which they had been induced. Maximal and persistent swelling was achieved only by addition of catabolizable substrate and both Na(+) and K(+). Addition, along with substrate, of Na(+) alone or K(+) alone did not stimulate swelling; no metabolic swelling occurred in the presence of a sugar to which the cells had not been induced. Confirmation of rapid uptake by induced cells of the inducer sugar, l-arabinose, but not the d-isomer, was obtained with (14)C-labeled substrate. Addition of NaN(3) completely inhibited swelling, and 2, 4-dinitrophenol and ouabain each suppressed it by 50%, indicating requirement for energy metabolism and involvement of an adenosine triphosphatase in the penetration phenomena of these cells.     

<Emphasis Type="Italic">In Vitro</Emphasis> Release Kinetics and Bioavailability of Gastroretentive Cinnarizine Hydrochloride Tablet

An oral sustained release dosage form of cinnarizine HCl (CNZ) based on gastric floating matrix tablets was studied. The release of CNZ from different floating matrix formulations containing four viscosity grades of hydroxypropyl methylcellulose, sodium alginate or polyethylene oxide, and gas-forming agent (sodium bicarbonate or calcium carbonate) was studied in simulated gastric fluid (pH 1.2). CNZ release data from the matrix tablets were analyzed kinetically using Higuchi, Peppas, Weibull, and Vergnaud models. From water uptake, matrix erosion studies, and drug release data, the overall release mechanism can be explained as a result of rapid hydration of polymer on the surface of the floating tablet and formation of a gel layer surrounding the matrix that controls water penetration into its center. On the basis of in vitro release data, batch HP1 (CNZ, HPMC-K100LV, SBC, LTS, and MgS) was subjected to bioavailability studies in rabbits and was compared with CNZ suspension. It was concluded that the greater bioavailability of HP1 was due to its longer retention in the gastric environment of the test animal. Batch no. HP1 of floating tablet in rabbits demonstrated that the floating tablet CNZ could be a 24-h sustained release formulation.