An investigation of the disintegration of tablets in biorelevant media.

The purpose of the study was to examine the disintegration of tablets in media designed to simulate conditions pertaining in the stomach. Although many studies have been performed to determine dissolution rates in these media, little work has been undertaken on the preliminary step in dissolution, namely disintegration. Two tablet formulations were prepared. One disintegrated rapidly (under 25 s in water) and the other more slowly (8 min in water). The disintegration times were measured by the BP 2000 test using discs. For the rapidly disintegrating tablets, disintegration times were similar in all media except for whole milk. This media is used to simulate the fed stomach and disintegration times were over five times longer than in the other media (P < 0.05). A similar effect was seen with the poorly disintegrating tablets in milk, and prolonged times were also observed in some of the other media. For these latter media, there was a good correlation between the penetration rate of the fluid into the tablet and the disintegration time. Penetration rates for milk were also slow which may be a reflection of its relatively high viscosity and low surface tension.

The potential use of mixed films of pectin, chitosan and HPMC for bimodal drug release.

Polyelectrolyte complex (PEC) formation between pectin USP and chitosan was investigated by examining the viscosities of supernatant solutions after removal of the precipitated complex. The amount of pectin, relative to chitosan, required for optimal PEC formation increased as the pH of the solution was reduced. At pH values of less than 1.3, there was no evidence for the formation of the PEC. Swelling studies conducted on pectin/chitosan films, showed minimal swelling occurring when the pectin:chitosan weight ratio was optimal for PEC formation, suggesting the formation of the PEC in situ. The permeability of the films to paracetamol as a model compound was dependent on film composition and was markedly increased after exposure to pectinolytic enzymes, used to mimic conditions in the colon. It may be implied from the results that similar formulations, applied as a film coat to tablets, could be used to achieve bimodal drug release with colonic conditions acting as a trigger for an increased rate of release.

Floating dosage forms: an in vivo study demonstrating prolonged gastric retention.

Gastroretentive dosage forms have potential for use as controlled-release drug delivery systems. The use of floating dosage forms (FDFs) is one method to achieve prolonged gastric residence times (GRTs), providing opportunity for both local and systemic drug action. Multiple-unit systems avoid the 'all-or-nothing' gastric emptying nature of single-unit systems. A freeze-dried calcium alginate multiple-unit FDF has been developed which demonstrated favourable in vitro floating characteristics. The aim of this study was to investigate the in vivo behaviour of this system compared to a multiple-unit non-floating dosage form manufactured from identical material. The study was performed in seven healthy volunteers, who swallowed the radiolabelled formulations after a standard breakfast. Transit was monitored by gamma-scintigraphy and subjects were maintained in the fed state. Prolonged GRTs of over 5.5 h were achieved in all subjects for the floating formulations, which remained high up in the stomach for the whole of the test period. In contrast, the non-floating beads displayed short GRTs, with a mean onset emptying time of 1 h. The results of this study suggest that, in the fed state, this FDF has potential for sustained drug delivery for either local or systemic purposes.

Targeting drugs to the colon: delivery systems for oral administration.

The oral delivery of drugs to the colon has applications in a variety of therapeutic areas. This review is concerned with the approaches taken to achieve a universal system for delivery. The design of such a system requires the identification and exploitation of a unique feature of the colonic environment. The use of transit times, pH and bacterial enzymes are critically assessed. In addition, the system must provide protection for the drug during transit to the colon. Upper gastro-intestinal physiology and the transit of pharmaceuticals through these regions are reviewed with reference to their relevance in achieving site specificity.

Effect of aging on physical properties of phenylbutazone tablets.

A study was made of the influence of age on the physical properties of phenylbutazone tablets BP, with special reference to in vitro dissolution rates. Past batches of tablets showed a progressive decrease in dissolution rate with age. This effect could be simulated in short periods by using elevated temperatures. The effect appears to be connected with the subcoat layer of the sugar coating of the tablet which adheres more strongly to the tablet core and slows down its disintegration.

Stability of phenylbutazone in presence of pharmaceutical colors.

The degradation of phenylbutazone was studied in the presence of lakes suitable for coloring the sugar coats of phenylbutazone tablets. The drug was degraded, in light, in the presence of erythrosine sodium. The degradation probably proceeds via singlet oxygen generated by the light-exicited dye. The degradation may be important in some quality control procedures and can lead, for example, to unusual results in dissolution rate testing.

Contact angles and wetting of pharmaceutical powders.

Contact angles of pharmaceutical powders were determined by the h-epsilon method, which consists essentially of measuring the maximum height of a drop of liquid fomed on a presaturated compact of the material. Determinations with aspirin as the test material indicate that the measured value is independent of the particle size of the powder and the porosity of the cake. The method was extended to include determinations on mixed powder systems. The results show that the hydrophobic material dominates with large particle-size powders; with small particle sizes, a linear relationship between the cosine of the contact angle of the mixed system and the proportion of the components is obtained. Results are presented for a wide variety of materials of pharmaceutical interest.

Effect of hydrophilization of hydrophobic drugs on release rate from capsules.

The release of poorly soluble hydrophobic drugs from capsules can be improved significantly by the creation of a hydrophilic surface by intensive mixing of the hydrophobic drug with a small amount of a solution of a hydrophilic excipient. This technique was introduced previously for the production of microgranules. The data presented indicate that the hydrophilic material is mechanically distributed over the hydrophobic surface. The creation of hydrophilic capillaries in a capsule or tablet allowed the rapid penetration of the dissolution fluid, resulting in a dispersion of well-wetted particles, so that the maximum surface area of the powder was exposed to the dissolution medium. Moreover, hydrophilization of hydrophobic drugs has the important benefit that the release rate from capsules is independent of the surface tension of the dissolution medium.

Biphasic drug release: the permeability of films containing pectin, chitosan and HPMC.

The permeabilities of mixed films of pectin/chitosan/HPMC have been studied to assess their value in producing a dosage form with biphasic drug release characteristics. The inclusion of chitosan enhanced the properties of the films, rendering them stable at all physiological pH values. Pectin/HPMC films were soluble at pH values above 3.0. All pectin/chitosan/HPMC films were permeable to a model drug, paracetamol. HPMC initially increased the permeability of the films and subsequently reduced it at higher concentrations. The minimum permeability was obtained at pH 3 and at an HPMC level of 5% where the potential for polyelectrolyte complex formation between pectin and chitosan exists. The permeabilities of the films increased when they were exposed to pectinolytic enzymes, a system designed to mimic conditions in the colon. The film formulation thus show the potential for biphasic delivery with an initial, controllable slow phase that can be manipulated by changes in the formulation followed by a faster phase under conditions pertaining in the colon.

Amoxycillin release from a floating dosage form based on alginates.

Floating alginate beads have been prepared from alginate solutions containing either dissolved or suspended amoxycillin. The beads were produced by the dropwise addition of the alginate into calcium chloride solution, followed by removal of the gel beads and freeze drying. Drug release studies showed that beads prepared with the drug in solution provided some sustained release characteristics and that these could be improved by the addition of amylose. In all cases, the drug release was consistent with release of a dissolved solute from a granular or porous matrix. The beads retained their buoyancy when amylose and amoxycillin were incorporated, exhibiting resultant weight values greater than zero after 20 h. Preparation of the beads from alginate solutions containing the drug in suspension allowed higher drug loadings, at the expense of faster release and lower buoyancy.

The influence of additives on the spreading coefficient and adhesion of a film coating formulation to a model tablet surface.

The surface energies of film coating formulations based on hydroxypropyl methylcellulose and containing microcrystalline cellulose, lactose and Tween 20, respectively, have been assessed. The approach taken allowed the components of the surface energy, in terms of the Lifshitz-van der Waals and the acid-base contributions, to be determined. Spreading coefficients of these coating formulations were determined on a model tablet surface whose surface energy had been similarly characterised. The determined spreading coefficients were high and positive indicating that spreading and wetting would not be a controlling factor in the formation of an adequate film coat. The adhesion of the coats to the core was measured and showed that the inclusion of additives influenced the adhesion of the film. Maximum adhesion was obtained when microcrystalline cellulose was included in the coating formulation that presumably allowed a strong interaction with the same component in the tablet core. Adhesion was enhanced when the tablet cores were made at a higher compaction force. Atomising air pressure had little influence on the adhesion.

An in vitro investigation into the potential for bimodal drug release from pectin/chitosan/HPMC-coated tablets.

The influence of disintegrant on the water uptake and subsequent disintegration force developed was investigated in a simple tablet formulation. The results indicated that a reasonable correlation existed between water uptake and disintegration force for the disintegrants screened with cross linked polyvinyl pyrrolidone (PVP XL) showing a proportionally higher disintegration force for the amount of water imbibed. Two tablet formulations, intended to promote accelerated drug release in the colon, were prepared, with and without PVP XL, and film coated with a mixture of pectin, chitosan and HPMC. The two systems showed different drug release rates which were influenced by the pH of the dissolution medium. In the presence of pectinolytic enzyme, drug release was faster when compared to release in buffer alone for both systems although the mechanism differed for each. Drug release in simulated gastrointestinal conditions showed a bimodal profile with the increased drug release rate being triggered by the action of pectinolytic enzymes.

Selective drug delivery to the colon using pectin:chitosan:hydroxypropyl methylcellulose film coated tablets.

A study has been carried out to assess the potential of pectin:chitosan:hydroxypropyl methylcellulose (HPMC) (P:C:H) films for colonic drug delivery. Radiolabelled (99mTc) tablets were coated with a 3:1:1, P:C:H film and administered to human volunteers. The gastro-intestinal transit of the tablets was assessed by gamma scintigraphy. The results showed that in all cases (n=4), the tablets were able to pass through the stomach and small intestine intact. Break up of the tablets commenced once they were in the colon, due to degradation of the coat by colonic bacteria. The study has highlighted the potential of this coating system for colonic drug delivery.

Representation of the path of a non-disintegrating capsule in the gastrointestinal tract using external scintigraphy and computer graphics.

The intestinal transit rate of a single non-disintegrating object has been measured using gamma scintigraphy. Using computer graphics, a three-dimensional visualization of the data has been developed. The display enables viewing from any angle and should be of value in assessing the effect of variables on the transit of pharmaceuticals and other materials.

The wetting of powders of acetylsalicylic acid, salicylic acid, phenacetin and paracetamol.

The wetting of powders of acetylsalicylic acid, salicylic acid, phenacetin and paracetamol has been assessed using methanol--water mixtures to give a range of surface tensions. The results have been interpreted in terms of the critical surface tension, adhesion tension and spreading coefficients. The critical surface tension values are surprisingly low which may be due to adsorption of the methanol at the solid surface, exposing its CH3 group to the liquid. The adhesion tension and spreading coefficient values could be useful guides in formulation.

The influence of initial packing on the compression of powders.

The influence of the initial packing density on the compression properties of lactose and sodium chloride has been studied. Differences in initial packing density are eliminated for both materials at relatively low pressures. The results have been analysed by the equations of Kawakita (1956), Heckel (1961), and Cooper & Eaton (1962). The constants derived from the Cooper & Eaton equation are dependent on the choice of low pressure data. The Kawakita constants are influenced by the initial packing of the powder. The Heckel treatment uses data at pressures above the point where the initial packing exerts an influence. Hence the constants are independent of the initial packing. If comparisons are to be made between processing treatments or mixtures which change the initial packing of the powder, the Heckel equation would appear to offer the most valid approach.

Simultaneous measurement of gastric emptying of the soluble and insoluble components of a formulation using a dual isotope, gamma scintigraphic technique.

The gastric emptying of a soluble and an insoluble component of a capsule formulation has been monitored by gamma scintigraphy using a dual isotope technique. There was no significant difference between the emptying rates for the two components or between fasting and non-fasting conditions (P greater than 0.01).

The mechanical strength of film-coated tablets.

The mechanical strength of film-coated tablets has been assessed using the diametral compression test. The results show that the influence of the film is more complex than that suggested by Stern (1976). The film may increase the breaking load of the core itself by acting as a padding material during the test and also by filling in surface irregularities. The film may also have enough intrinsic strength and elasticity to hold the core together once it has broken. The maximum breaking load to completely fracture the coated tablet is related to film properties, but the relation is not a simple one.

Bioavailability of griseofulvin from a novel capsule formulation.

The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non-treated powder.

In vivo behavior of hydrogel beads based on amidated pectins.

Radio-labeled hydrogel beads, based on amidated pectin, have been produced by adding droplets of an amidated pectin solution to calcium chloride. Incorporation of model drugs into the beads and measurement of the dissolution rate showed that the properties of the beads were unaffected by the incorporation of the radiolabel. The labeled beads were used to carry out an in vivo study of their behavior in the gastrointestinal tract using human volunteers. The volunteers were given the beads after an overnight fast and images were obtained at frequent intervals during transit through the upper gastrointestinal tract and the colon. The beads exhibited rapid gastric emptying and proceeded to pass through the small intestine individually before regrouping at the ileo-caecal junction. Once in the colon, the beads again proceeded as individuals and evidence of the degradation of the beads was observed.