Colin D. Melia

Structure and behaviour in hydrophilic matrix sustained release dosage forms: 2. NMR-imaging studies of dimensional changes in the gel layer and core of HPMC tablets undergoing hydration

Abstract The swelling of hydrating HPMC tablets has been studied by NMR microscopy. The technique is non-invasive and has allowed both dimensional changes in the core and in the developing surface hydrated layer to be studied. Hydration at the edges of the tablet occurred to a greater extent than in the centre of the table surfaces, giving rise to a convex shaped hydrated layer. Gel layer development occurred to the same extent in both axial and radial directions, and was similar in all HPMC types. The predominantly axial swelling reported for all HPMC types, was shown to result almost equally from growth of the hydrated surface gel layer and expansion of the ungelled tablet core. The smaller axial expansion observed in E4M tablets was not a result of slower gel layer growth, but was entirely due to a smaller expansion of the core.

Structure and behaviour in hydrophilic matrix sustained release dosage forms: 3. The influence of pH on the sustained-release performance and internal gel structure of sodium alginate matrices

Abstract The effect of pH and drug solubility on the release kinetics of sodium alginate matrices has been studied. Release of a highly soluble model drug, chlorpheniramine maleate, was significantly faster in simulated gastric fluid (SGF) than in simulated intestinal fluid (SIF), whereas the opposite effect was observed for hydrochlorothiazide, a drug of poor solubility. These results could be explained in terms of the internal microscopic structure of the hydrated surface layer formed on matrix hydration and by the different hydration kinetics of the polymer in these two media. Cryogenic electron microscopy revealed the hydrated surface layer formed by alginate matrices in SGF to be particulate and porous in nature, in contrast to the highly hydrated continuous gel layer formed in SIF. Drug release mechanisms were discussed with respect to drug solubility and the structure and properties of the surface layers formed by alginate matrices when hydrated in different pH media.

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

AbstractPurpose. 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.

Xanthan/locust bean gum interactions at room temperature

Abstract Rheological and ultracentrifugation studies have been conducted on heated and unheated mixtures of xanthan with whole locust bean gum, and temperature fractions of the latter possessing different mannose: galactose ratios. The results suggest that xanthan and galactomannans may interact by two distinct mechanisms. One takes place at room temperature, gives weak elastic gels, and has little dependence upon the galactose content of the galactomannan, whilst the second requires significant heating of the polysaccharide mixture, gives stronger gels, and is highly dependent upon galactomannan composition. The results are discussed with reference to existing models proposed for the xanthan/galactomannan interaction.

The transit rate of different-sized model dosage forms through the human colon and the effects of a lactulose-induced catharsis

Gamma scintigraphy has been used to compare the colonic transit rate of different sizes of radiolabelled model dosage forms in healthy human subjects. Studies simultaneously compared the ascending colon residence time of 111In-labelled 0.2 mm ion-exchange resin particles and 99mTc-labelled 5 or 8.4 mm non-disintegrating tablets. Under normal conditions, no difference was observed between the rate of transit through the ascending colon of 0.2 mm particlesvs 5 mm tablets (n = 11) or 0.2 mm particles vs 8.4 mm tablets (n = 10). The mean period of residence of 50% of the administered 0.2 mm particles in the ascending colon was 11.0 ± 4.0 h (n = 21). Coadministration of the laxative, lactulose, to subjects receiving the 0.2 and 5 mm particles significantly accelerated colonic transit. Under these conditions, the ascending colon residence of the 0.2 mm resin was significantly shorter than for the 5 mm tablets, although the magnitude of the effect was small.

Mechanisms of drug release in citrate buffered HPMC matrices

Few studies report the effects of alkalizing buffers in HPMC matrices. These agents are incorporated to provide micro-environmental buffering, protection of acid-labile ingredients, or pH-independent release of weak acid drugs. In this study, the influence of sodium citrate on the release kinetics, gel layer formation, internal gel pH and drug release mechanism was investigated in HPMC 2910 and 2208 (Methocel E4M and K4M) matrices containing 10% felbinac 39% HPMC, dextrose and sodium citrate. Matrix dissolution at pH 1.2 and pH 7.5 resulted in complex release profiles. HPMC 2910 matrices exhibited biphasic release, with citrate increasing the immediate release phase (<60min) and reducing the extended release. HPMC 2208 matrices were accelerated, but without the loss of extended release characteristics. Studies of early gel layer formation suggested gel barrier disruption and enhanced liquid penetration. pH modification of the gel layer was transitory (<2h) and corresponded temporally with the immediate release phase. Results suggest that in HPMC 2910 matrices, high initial citrate concentrations within the gel layer suppress particle swelling, interfere with diffusion barrier integrity, but are lost rapidly whereupon drug solubility reduces and the diffusion barrier recovers. These Hofmeister or osmotic-mediated effects are better resisted by the less methoxylated HPMC 2208.

Magnetic resonance imaging of controlled release pharmaceutical dosage forms

Magnetic resonance imaging offers us a powerful non-invasive method for picturing events inside controlled-release dosage forms. It allows us to observe, follow and measure important processes, such as hydration and diffusion, that can contribute directly to the process of drug release. The potential of this technique for increasing our understanding of drug release mechanisms, and the behaviour of dosage forms in vitro and in vivo is only beginning to be exploited. The unique information obtained from MRI studies will provide important detailed knowledge in problem solving and formulation development.

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.

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.

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.