Compression and compaction properties of plasticised high molecular weight hydroxypropylmethylcellulose (HPMC) as a hydrophilic matrix carrier.

The compression and compaction properties of plasticised high molecular weight USP2208 HPMC were investigated with the aim of improving tablet formation in HPMC matrices. Experiments were conducted on binary polymer-plasticiser mixtures containing 17 wt.% plasticiser, and on a model hydrophilic matrix formulation. A selection of common plasticisers, propylene glycol (PG) glycerol (GLY), dibutyl sebacate (DBS) and triacetin (TRI), were chosen to provide a range of plasticisation efficiencies. T(g) values of binary mixtures determined by Dynamic Mechanical Thermal Analysis (DMTA) were in rank order PG>GLY>DBS>TRI>unplasticised HPMC. Mean yield pressure, strain rate sensitivity (SRS) and plastic compaction energy were measured during the compression process, and matrix properties were monitored by tensile strength and axial expansion post-compression. Compression of HPMC:PG binary mixtures resulted in a marked reduction in mean yield pressure and a significant increase in SRS, suggesting a classical plasticisation of HPMC analogous to that produced by water. The effect of PG was also reflected in matrix properties. At compression pressures below 70 MPa, compacts had greater tensile strength than those from native polymer, and over the range 35 and 70 MPa, lower plastic compaction values showed that less energy was required to produce the compacts. Axial expansion was also reduced. Above 70 MPa tensile strength was limited to 3 MPa. These results suggest a useful improvement of HPMC compaction and matrix properties by PG plasticisation, with lowering of T(g) resulting in improved deformation and internal bonding. These effects were also detectable in the model formulation containing a minimal polymer content for an HPMC matrix. Other plasticisers were largely ineffective, matrix strength was poor and axial expansion high. The hydrophobic plasticisers (DBS, TRI) reduced yield pressure substantially, but were poor plasticisers and showed compaction mechanisms that could be attributed to phase separation. The effect of different plasticisers suggests that the deformation characteristics of this HPMC in the solid state is dominated by hydroxyl mediated bonding, rather than by hydrophobic interactions between methoxyl-rich regions.

A simple, high throughput method for the quantification of sodium alginates on oesophageal mucosa.

Sodium alginate is a potential bioadhesive, but the lack of a convenient and suitable method for its quantification on the mucosal surface complicates the evaluation of its mucosal retentive properties. This paper develops and evaluates a spectrophotometric method for the rapid quantification of a range of sodium alginates differing in chemical composition, and investigates how quantification was influenced by the presence of oesophageal mucosa. The method, based on dye complexation with 1,9-dimethyl methylene blue (DMMB) was sensitive to alginate molecular weight and uronic acid composition, however, no significant correlations between assay performance and alginate molecular characteristics were demonstrated. The assay was also influenced by complexation time, calcium ions and mucin, but was unaffected by the presence of oesophageal tissue scrapings. The assay proved to be capable of quantifying sodium alginate with excellent linearity (r = 0.999), reproducibility (CV < 3%) and sensitivity (0.3 g l(-1)) and proved to be a precise, high-throughput method that may be used for quantifying the retention of sodium alginate on oesophageal mucosa.

A novel application of NMR microscopy: measurement of water diffusion inside bioadhesive bonds.

The self-diffusion coefficient of water (D) inside bioadhesive bonds formed by dry and prehydrated hydrophilic matrices has been spatially resolved using nuclear magnetic resonance (NMR) microscopy. One-dimensional profiles showing the variation of D inside bioadhesive bonds were calculated from nine diffusion-weighted profiles obtained immediately after bond formation and every 5 min for 30 min. The resulting data indicated that the hydration state of a hydrophilic matrix can significantly and dramatically influence the dynamics of water movement inside a bioadhesive bond.

First order release rate from porous PLA microspheres with limited exit holes on the exterior surface.

We applied the finite element method (FEM) to calculate release profiles from computer simulated slabs, one with a limited number of exit holes on the exterior surface, and the other with uniform structure. The former slab showed a first order release rate, and a nearly uniform drug concentration distribution within the device during the release process. It was concluded that circulation of the drug molecules within the slab resulted in the uniform concentration and consequently first order release rate. This theoretical work was used to explain the first order release rate of an active ingredient (flourescin-4-isothiocyanate-dextran, M(W)=71000 Da) from porous PLA (poly(D,L)-lactic acid) microspheres, which by canning electron microscopy (SEM) examination showed only a few exit holes on their exterior surface. Calculations indicated that the internal surface adsorption of the active ingredient, or the pore size distribution of the microspheres, could not influence the mechanism for the first order release rate, and the small number of exit holes on the exterior surface was likely to be the rate-determining factor. The exit holes could be observed by SEM and their size and number is consistent with our interpretations.

A method for quantifying differential expansion within hydrating hydrophilic matrixes by tracking embedded fluorescent microspheres.

A method is described for quantifying the pattern of deformation within a matrix and is demonstrated by analyzing the expansion of polymer hydrophilic matrix tablets. The fundamental features of the method are the incorporation of nondiffusing markers into the matrix and the subsequent tracking of these markers during deformation. Since the markers are too large to diffuse, their individual movement reflects the translocation of the surrounding matrix, and the separation between pairs of markers reveals any perturbation in the intervening area. By tracking many markers, the pattern of deformation within a matrix can be ascertained. The method was demonstrated on hydrating hydrophilic matrix tablets, using fluorescent microspheres as nondiffusing markers which were observed with a confocal laser scanning microscope. Analysis of the tracks showed a wave of expansion moving from the exterior toward the core, with the greatest and earliest expansion found in the outer regions. The results also showed that even as deeper layers started to expand the outer layers continued to swell.

Determination of the internal morphology of poly (D,L-lactide) microspheres using stereological methods.

The morphological characteristics of the internal structure of poly (D,L-lactide) microspheres have been determined by stereological methods in two different formulations of microspheres, with different internal structures, prepared by using a double emulsion method. In one formulation the internal emulsion was produced by homogenisation at 3000 rpm, whilst the other was prepared at 11000 rpm. As expected the formulation prepared at the lower speed contained larger and more broadly distributed pores than that prepared at the higher speed. The porosity, pore size distribution and total internal surface area of the microspheres were obtained by stereological methods from electron microscopic measurements of the sectioned microspheres. It was found that whilst the porosity of the microspheres was 0.6 in both formulations, the preparation method gave rise to large differences in their pore size distribution characteristics. The pore size distribution was simulated by computer modelling to validate and compare alternative stereological algorithms. It was found that the Saltykov unfolding method predicts the measured pore size distribution more accurately than the Cruz-Orive unfolding method (at significance level alpha=0.1). This finding was attributed to the violation of one of the basic assumptions of the Cruz-Orive unfolding method.

Self-diffusion and molecular mobility in PVA-based dissolution-controlled systems for drug delivery.

Nuclear magnetic resonance (NMR) microscopy has been used to monitor the hydration of poly(vinyl alcohol) (PVA) samples of varying molecular weight. One-dimensional profiles weighted to predominantly show the variation of water concentration were acquired every 3 min during the first 30 min of hydration and subsequently at 1 and 2 h. Diffusion-weighted profiles obtained after 30 min and 1 and 2 h were used to calculate the spatial variation of the water self-diffusion coefficient. The resulting data provide supporting evidence for the hypothesis that phenomena such as reptation are important near the glassy/rubbery interface of polymers during dissolution, while the diffusion gradually changes to Zimm type near the rubbery/solvent interface.

Starch granule surface imaging using low-voltage scanning electron microscopy and atomic force microscopy.

High resolution imaging of wheat and potato starch granule surfaces has been performed using low-voltage scanning electron microscopy and atomic force microscopy. The complimentary images of uncoated granules demonstrate that the two starch types possess substantially different surface topologies; potato starch has many protrusions (100-300 nm in diameter), above a flatter surface containing 20-50 nm structures, whilst wheat starch possesses far fewer protrusions and generally has a smoother surface composed of approximately 20 nm structures. The protrusions are believed to be carbohydrate in nature and thus represent the ends of amylopectin side-chain clusters at the granule surface.

Uptake of drugs by catheters: the influence of the drug molecule on sorption by polyurethane catheters.

The sorption of drugs by indwelling intravenous catheters may have clinical consequences both by alteration of the dose received by the patient and by physically affecting the catheter materials themselves which may lead to changes in mechanical properties and biocompatibility. Studies of drug sorption to new catheter materials are therefore important. Pellethane, a polyurethane increasingly used in vascular access catheters, is as yet little studied in terms of its capacity for drug sorption. In this work a range of drugs known to be sorbed by PVC infusion sets were studied with respect to their sorption by Pellethane catheters. Standard lengths of catheter were incubated with solutions of drugs and samples of the solution were taken at intervals, assayed spectrophotometrically and compared with control solutions incubated without catheter. Losses from solution of up to 93% were found after 24 h. A series of highly sorbing and clinically relevant drugs was identified and their uptake was studied until equilibrium had been reached. A correlation was evident between the octanol/water partition coefficient and the fraction of drug taken up from solution at equilibrium, with the more hydrophobic drugs being taken up to a greater extent by the catheter.

Structure and behavior in hydrophilic matrix sustained release dosage forms: 4. Studies of water mobility and diffusion coefficients in the gel layer of HPMC tablets using NMR imaging.

PURPOSE: The purpose of this study was to characterise the water mobility in the gel layer of hydrating HPMC tablets. Water mobility in the gel layer of different HPMCs was studied. METHODS: NMR imaging, a non-invasive technique, has been used to measure the spatial distribution of self-diffusion coefficient (SDC) and T2 relaxation times across the gel layer. RESULTS: It has been shown that there is a water mobility gradient across the gel layer of HPMC tablets. Although SDC and T2 relaxation times in the outer parts of the gel layer approached that of free water, in the inner parts they decreased progressively. Water mobility and SDC in the gel layer of different HPMCs appeared to vary with degree of substitution of the polymer and the lowest values were obtained across the gel layer of K4M tablets. CONCLUSIONS: Water mobility varies across the gel layer of hydrating HPMC tablets and it is dependent on the degree of substitution of the polymer.

NMR microscopy of hydrating hydrophilic matrix pharmaceutical tablets.

NMR microscopy has been used to monitor the formation of the gel layer in hydrating hydrophilic polymer tablets. Such tablets are used in the controlled delivery of drugs, where it has been found that the rate and extent of the swelling of the outer gel layer critically influences the kinetics of drug release. Tablets were hydrated in distilled water at 37 degrees C and then imaged at discrete time intervals using a 500 MHz microscope. The growth of the gel layer was clearly observed in time sequences of radial and axial sections. Axial images showed some interesting dimensional changes, with the gel at the flat surface of the tablet developing a concave shape. This is probably a reflection of the occurrence of uni-axial stress relaxation as hydration proceeds. Diffusion- and T2-weighted images provided evidence that the water in the gel layer is more strongly bound close to the dry core of the tablet than at the more fully hydrated outer surface. In images of tablets containing diclofenac, disruption of the gel layer was shown to occur primarily from the flat surfaces of the tablet, whilst the distribution of particles could be seen in tablets doped with insoluble calcium phosphate.

The qualitative and quantitative analysis of chlorpropamide polymorphic mixtures by near-infrared Fourier transform Raman spectroscopy.

We analyzed binary mixtures of polymorphs A and B of chlorpropamide ((1-[4-chlorobenzenesulphonyl]-3-propyl urea)) by near-infrared Fourier transform Raman spectroscopy (FTRS). The individual polymorphs were prepared and characterized by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) microscopy, and physical appearance. The FTR spectra of the two polymorphs showed distinct differences which result from "crystal splitting" effects. A series of 13 different mixtures of polymorph A and B was prepared by geometric mixing and their FTR spectra statistically analysed by factor analysis programming. Predictions of the A/B polymorphic composition of mixtures were made and compared with the theoretical values. The results demonstrate that FTRS combined with factor analysis programming may be successfully applied to the in situ monitoring of the A/B polymorphic nature of a chlorpropamide sample.

Quantitative, noninvasive assessment of antidiarrheal actions of codeine using an experimental model of diarrhea in man.

Enteric coating of a capsule has been used to deliver a bolus of radioisotope to the ileocecal region. This has allowed quantitative assessment of regional colonic transit in a group of healthy subjects whose proximal colonic transit was accelerated by lactulose 20 ml thrice daily. In this experimental model of diarrhea, codeine delayed transit from mouth to terminal ileum and also delayed transit through the ascending colon from 5.3 +/- 2.5 hr to 7.4 +/- 2.5 hr, N = 11, P < 0.05. Furthermore, codeine delayed whole colon transit, as assessed by geometric center analysis, which showed the delay to be most marked in the right colon with little effect noted in the left colon. In addition, codeine significantly reduced the number of retrograde movements observed and reduced the colonic response to eating. The antidiarrheal effect of codeine appears to be due to a combination of delayed mouth-cecum transit plus an additional delay in the ascending colon. This colonic delay may be partially explained by a reduction in postprandial propulsive movements that were seen in this model of diarrhea.

Decontamination methods for cytotoxic drugs. 1. Use of a bioluminescent technique to monitor the inactivation of methotrexate with chlorine-based agents.

A new microbial bioluminescence assay has been used to monitor the loss of mutagenicity on inactivation of methotrexate by active chlorine-based agents. The drug was degraded to products that were non-active in this mutagen detection system, in agreement with previously described work. Presept granules appear to be a suitable alternative to sodium hypochlorite for inactivating solutions and surface spills of methotrexate. The bioluminescence assay appears to have potential for monitoring clean-up and decontamination procedures in areas where cytotoxic agents are used.

Scintigraphic demonstration of lactulose-induced accelerated proximal colon transit.

Although lactulose, a widely used cathartic, is known to increase stool frequency, details of its site of action in the colon are obscure. In the present study a noninvasive scintigraphic technique was used to closely follow the movements of proximal colonic contents. Lactulose, 10-20 mL three times daily, significantly accelerated mean transit through the ascending colon from 12.9 +/- 3.7 to 7.0 +/- 2.5 hours (n = 11; P less than 0.01). This was associated with the occurrence of mass movements, with six such events seen during lactulose treatment whereas only one was seen during the control study (P less than 0.05). Lactulose also accelerated movement through the rest of the colon so that at 24 hours after dosing the geometric center of the isotope bolus was distal to that seen during the control study (6.6 +/- 1.2 vs. 4.7 +/- 1.3; n = 11, P less than 0.001). This model of diarrhea in otherwise normal subjects was subsequently used to study the effects of viscous gels in diarrhea. The viscous and relatively poorly fermented gel ispaghula, 3.5 g three times daily, abolished mass movements and was associated with a small but significant increase in proximal colonic transit time, which increased from 6.1 +/- 2.1 to 7.7 +/- 1.5 hours (n = 8; P less than 0.05). By contrast, the viscous but readily fermentable gelling agent guar gum, 5 g three times daily, further accelerated the cathartic effect of lactulose, with the mean transit time decreasing from 6.4 +/- 2.3 to 4.7 +/- 1.7 hours (n = 8; P less than 0.05). The acceleration of proximal colonic transit by lactulose may be a useful model to study diarrhea and its modification by therapy.

Fourier transform-Raman spectroscopy for the qualitative and quantitative characterization of sulfasalazine-containing polymeric microspheres.

FT-Raman spectroscopy (FTRS) has been used to characterize microspheres produced from the pharmaceutical polymer Eudragit RS containing a range of concentrations of the drug sulfasalazine. While pure sulfasalazine produced an intense and complex Raman spectrum, the spectrum of drug-free Eudragit RS microspheres was considerably weaker in intensity and contained only a few prominent Raman scattering peaks. In spectra of the drug-polymer microspheres, peaks arising from the individual components could be identified. This enabled a quantitative analysis to be undertaken by calculating the ratio between the area of a sulfasalazine peak and the area of a Eudragit RS peak for each microsphere spectrum. A correlation was shown between the peak area ratio and the microsphere sulfasalazine content. FTRS was then applied to a series of microsphere samples which had been dissoluted into pH 7 buffer for 1, 3, 6, 9, 12, or 24 hr. For each spectrum, the drug-polymer peak area ratio was determined and this in turn enabled calculation of the residual drug content of the microsphere sample. FTRS-calculated data showed good agreement with microsphere drug content values determined spectrophotometrically.

Characterisation of the in vivo behaviour of a controlled-release formulation of levodopa (Sinemet CR).

The gastrointestinal transit and systemic absorption of Sinemet CR (50-200) controlled-release tablets and standard Sinemet (25-100) immediate-release (IR) tablets have been studied in fasted and fed healthy human subjects. Both formulations were labelled with a gamma-emitting radionuclide and their gastric emptying, colon arrival and in vivo disintegration profiles monitored using gamma scintigraphy. The IR dosage forms were found to disperse soon after administration and to empty rapidly from both fasted and fed stomachs. Erosion of the CR system was independent of food or stomach pH. The CR tablet was observed to disintegrate fully in the gastrointestinal (GI) tract, resulting in complete release of levodopa over a 3-4 h time period. Considerable intersubject variation was found to exist for levodopa absorption. Absorption was more protracted with Sinemet CR than with standard Sinemet, due to the controlled release characteristics of the tablet matrix. There was no rapid initial absorption phase and instead, a gradual build-up in the absorption profile occurred.

A simple and rapid method for the quantification of Eudragit RS100 and RL100 poly(methacrylates) in sustained-release dosage forms.

A colorimetric ion-pair complexation method has been developed which provides a simple and rapid way of quantifying Eudragit RS100 and RL100 in pharmaceutical dosage forms. The quaternary ammonium groupings in these polymers appear to form an ion-pair complex with the dye tropaeolin OOO. When extracted into an organic phase, the optical density at 484 nm is linearly related to polymer concentration. Control of pH is important, and it should be maintained within the range 4.5 to 9.0. A wide range of pharmaceutical excipients commonly used in tablet, pellet, and film-coating formulations did not interfere with formation of the complex, but certain drugs were found to significantly enhance or decrease the assay response. Good reproducibility, precision, and accuracy were demonstrated when the method was applied to a film-coated pellet formulation containing an interfering drug (promethazine hydrochloride). However, removal of interfering substances must be optimized. The method was sufficiently sensitive for the determination of polymer on a single dose unit of encapsulated beads.

Hydrophilic matrix sustained release systems based on polysaccharide carriers.

The hydrophilic matrix (HM) continues to be a popular and widely used strategy for sustained-release drug delivery, with polysaccharides and their derivatives being the polymers of choice as the rate-controlling carriers for these systems. This review provides an appraisal of the more recent developments in the design and in our understanding of the behavior of HM systems. It also focuses on areas of current interest not encompassed by previous reviews.