Effect of disintegrants on drug dissolution from capsules filled on a dosator-type automatic capsule-filling machine

Various levels of newer disintegrants were compared against 10% starch and 0% disintegrant in dicalcium phosphate-based hard gelatin capsules filled on an instrumented Zanasi machine at a constant compression force. Hydrochlorothiazide or acetaminophen were included for drug dissolution studies. Disintegration time, ejection force and overall running characteristics were also considered. In general, the modified celluloses were most effective in enhancing drug dissolution, followed, in order, by the modified starches, corn starch, cross-linked PVP and the control (0% disintegrant). Reducing the lubricant level (magnesium stearate) or using a more soluble drug (acetaminophen) required less modified cellulose (AcDiSol) to exert a similar effect on drug dissolution. Disintegration and dissolution data correlated best with the more soluble drug.     

Multiple tamping effects on drug dissolution from capsules filled on a dosing-disk type automatic capsule filling machine

The effects of number of tamps and tamping force on drug dissolution from capsules filled on an instrumented dosing-disk automatic capsule filling machine (Hofliger-Karg) were studied using hydrochlorothiazide as a model, low dose, poorly soluble drug. Generally, there was a trend toward slower dissolution rate with increasing numbers of tamps, the effect being most marked when insoluble dicalcium phosphate dihydrate was the filler. Higher compression forces improved drug release when anhydrous lactose was the filler, but adversely affected the dicalcium phosphate-based capsules. Inclusion of 4% croscarmellose sodium disintegrant tended to nullify the effects of number of tamps or tamping force with both fillers; however, the disintegrant also markedly enhanced drug dissolution from the dicalcium phosphate-based formulation. Hydrochlorothiazide dissolution from the latter formulation without disintegrant appeared to follow a "diffusion from insoluble matrix" model regardless of number of tamps or their intensity. Mercury intrusion pore size distribution data for some plugs suggested that for tamps of equal force (100 or 200 N), further powder consolidation after two tamps does not occur.     

The evaluation of an automatic system for filling liquids into hard gelatin capsules

A system is described in which an intermittent motion powder filling capsule machine is modified to fill liquids into hard gelatin capsules suitable for pilot scale or small production batches. The system is shown to be suitable for filling materials covering a wide range of viscosities and to give excellent fill weight uniformity which is largely independent of operating conditions. The process is clean and trouble-free.     

Cross-linking of hard gelatin carbamazepine capsules: effect of dissolution conditions on in vitro drug release.

The aim of this study was to determine if the use of both enzyme and surfactant in the dissolution medium changes the in vitro drug release from cross-linked hard gelatin capsules containing a water-insoluble drug. Hard gelatin capsules were cross-linked by a controlled exposure to formaldehyde resulting in different stressed capsules and carbamazepine (CBZ) was chosen as a drug model. In vitro dissolution studies were conducted using simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) with enzymes. Sodium lauryl sulfate (SLS) was added in the dissolution medium at a concentration of 2% m/v both in SGF and SIF with pepsin and pancreatin, respectively. The percentage of CBZ dissolved was reduced by increasing the degree of gelatin cross-linking. For unstressed hard gelatin capsules, 36% of the CBZ was released after 1 h, lowering to 5% for highly stressed hard gelatin capsules in the SGF. A similar effect was observed with SIF. In the case of moderately stressed hard gelatin capsules, addition of enzyme in the dissolution medium enhanced the percentage of CBZ dissolved. The dissolution level increased from 12% to 39% in SGF with pepsin for hard gelatin capsules cross-linked with 1500 ppm formaldehyde. On the contrary, the use of enzyme in the dissolution medium did not increase the dissolution of CBZ from highly stressed hard gelatin capsules. Surprisingly, the addition of SLS in the medium did not allow the release of the CBZ both in SGF and in SIF. The results of this study demonstrate that the use of enzyme in the dissolution medium is justified for moderately cross-linked hard gelatin capsules. However, the action of a surfactant added in the medium containing enzyme remains unclear.     

On the release of drug from hard gelatin capsules

The effect of particle size and packing on the in vitro release of a water-insoluble hydrophobic drug from hard gelatin capsules has been related to the liquid permeability of powder beds of similar porosities. Drug release and permeability decrease with a decrease in particle size and porosity of the powder bed. A simple moist granulation process transforms a non-permeable powder bed, which allows low drug release, into one with high permeability and high drug release.     

Further studies on the effect of additives on the release of drug from hard gelatin capsules

An experiment based on a 3³ design has been undertaken to establish the effect on drug release from capsules produced by adding lactose (0, 10 and 50%), magnesium stearate (0, 1 and 5%), and sodium lauryl sulphate (0, 1 and 10%) to a 76–105μm particle size fraction of ethinamate filled into capsules at a high and low packing density. Statistical analysis of the results indicated the presence of 2nd order interaction at all time intervals and for both sets of capsule fill weights. This signifies that the effect produced by each additive is dependent on the presence and the level of the other two additives. The interaction limits the conclusions that can be drawn about the main factors of diluent, lubricant and wetting agent, but the indications are that (a) 10% diluent reduces drug release, whereas 50% produces enhanced release; (b) the presence of 1% sodium lauryl sulphate is sufficient to enhance drug release; (c) the additive effects are independent of the capsule packing density.     

The influence of polymorphism on the manufacturability and in vitro dissolution of sulindac-containing hard gelatin capsules

Abstract

Context: Drug polymorphism could affect drug product dissolution, manufacturability, stability and bioavailability/bioequivalence. The impact of polymorphism on the manufacturability and in vitro dissolution profiles of sulindac capsules has not been studied yet.

Objective: To evaluate the impact of polymorphism on the manufacturability and in vitro dissolution of sulindac hard gelatin capsules.

Materials and methods: Sulindac crystal forms I and II (SLDI and SLDII, respectively) were prepared and characterized. Powder formulations containing one of the polymorphs, lactose and magnesium stearate (at three different levels) were prepared and their flow properties determined. Hard gelatin capsules were filled with the formulations and tested for fill-weight variations. Drug dissolution for SLDI- and SLDII-containing hard gelatin capsules was determined.

Results: Differences in flow properties for each polymorph were observed, as well as for their formulations, which in turn affected capsule weight homogeneity. Statistically significant differences in the rate and extent of drug release were observed between SLDI- and SLDII-containing capsules.

Discussion: Formulations containing SLDI showed a better manufacturability and a better dissolution profile than those with SLDII.

Conclusion: Sulindac crystalline form I was the best candidate for hard gelatin capsule formulation because of its technological and in vitro dissolution properties.     

A study of enteric-coated liquid-filled hard gelatin capsules with biphasic release characteristics

Studies were carried out using enteric-coated, liquid-filled hard gelatin capsules with biphasic rapid and sustained release characteristics, containing 80 mg of propranolol in a novel HALO^™ drug delivery formulation designed to avoid hepatic first-pass metabolism. The disintegration at pH 1.0 of HALO^™-propranolol capsules, coated with different levels (3–12 mg/cm²) of enteric polymer (methacrylic acid copolymer, type A USP/NF) was visually assessed using the disintegration test for enteric-coated capsules described in the BP 1988. Quantification of propranolol release, at pH 1.0, from enteric-coated capsules was carried out using a dissolution procedure based on the USP XXII method. The results of the study showed that significant release of propranolol (> 10%) could take place at low coating levels (3 mg/cm²) without visible breakdown of the enteric coat. In a further study, enteric-coated HALO^™-propranolol capsules coated with 4 mg/cm² of enteric polymer were stored under a variety of conditions for up to 18 months. Dissolution and disintegration studies showed that under conditions of low temperature storage (4°C) HALO^™-propranolol capsules released significant amounts ( > 10%) of propranolol at pH 1.0 without visible breakdown of the enteric coat. Dissolution studies carried out at pH 6.8 following acid challenge demonstrated that inadequate enteric protection greatly affected the subsequent sustained-release dissolution profile of HALO^™-propranolol capsules. The present investigation demonstrates the importance of ensuring a sufficient enteric-coating level for oral dosage vehicles to maintain post gastric dissolution characteristics and illustrates the need for a reliable means of assessing enteric coat performance in vitro.     

The influence of pH of dissolution fluid and particle size of drug on the in-vitro release of drug from hard gelatin capsules

The influence of pH of the dissolution fluid on the in-vitro release of acetylsalicylic acid from hard gelatin capsules has been studied for a series of particle size fractions of the drug. Generally, the time required for 50% of the drug content of the capsule to appear in solution during a dissolution test, T50, increased as the pH increased from 1.2 to 2.0; thereafter the value of T50 decreased as the pH increased from 3 to 7. These changes were found to be related to the apparent solubility of the drug. The extent of the changes was found to be further dependent on the particle size of the drug. For capsules filled with particle size fractions of 2.5 and 5.5 microns median diameter, the changes were small. Larger changes were observed with particles of median diameters of 45, 100, 220 and 330 microns while the largest changes (greater than two-fold) were obtained with particles of median diameter 130 and 430 microns. The type of kinetics that could be used to express the release rates was found to be particle size-dependent. For particles of 45 microns and larger, the release rate followed an apparent zero order process while an apparent first order process represented the release for the two smallest particle size fractions.     

Relative bioavailability of danazol in dogs from liquid-filled hard gelatin capsules

Danazol was dissolved in non-aqueous mixtures containing either polyethylene glycol 400 or polysorbate 80, and filled into hard gelatin capsules at 50 mg concentrations. The bioavailability of these formulations was compared with commercial danazol capsules in a two-way crossover study using young female beagle dogs. Both formulations showed greater oral bioavailability when compared with either the 100 or 200 mg commercial brand of danazol. The bioavailability of the polyethylene glycol 400 and polysorbate 80 formulations was enhanced 3.7 and 15.8 times, respectively, when compared at the 100 mg dose level.Copyright     

The effect of capsule-filling machine vibrations on average fill weight

The aim of this paper is to study the effect of the speed of capsule filling and the inherent machine vibrations on fill weight for a dosator-nozzle machine. The results show that increasing speed of capsule filling amplifies the vibration intensity (as measured by Laser Doppler vibrometer) of the machine frame, which leads to powder densification. The mass of the powder (fill weight) collected via the nozzle is significantly larger at a higher capsule filling speed. Therefore, there is a correlation between powder densification under more intense vibrations and larger fill weights. Quality-by Design of powder based products should evaluate the effect of environmental vibrations on material attributes, which in turn may affect product quality.     

The influence of agitation intensity, particle size and pH of dissolution fluid on the in-vitro release of drug from hard gelatin capsules

The influence of agitation intensity on the in-vitro release of controlled particle size fractions of acetylsalicylic acid from hard gelatin capsules into buffered dissolution fluids has been investigated employing a dissolution technique. The value of T50 decreased as the stirring rate increased from 120 to 320 rev min-1 for all particle size fractions and pH values. A further increase in the stirring rate had a limited effect on the value of T50 and the changes were particle size dependent. The influence of the drug solubility, induced by changing the pH of the dissolution fluid, was decreased by increased agitation. When the capsules were filled at bulk densities above the maximum tapped bulk density, the value of T50 was increased, the extent of increase being greater the smaller the particle size of the drug. The kinetics of the solution process were influenced by agitation intensity and particle packing.     

The influence of additives on the in vitro release of drugs from hard gelatin capsules

A factorially designed experiment has been used to assess the total percentage of drug released from hard gelatin capsules in vitro as a function of (a) the drug—the drugs being nitrofurantoin, nitrofurazone, oxytetracycline dihydrate and tetracycline hydrochloride; (b) the diluent—the diluents being lactose, Primojel and Dry-Flow starch; (c) the quantity of diluent, either 20 or 80%; (d) the presence (at a 1 % level) and absence of magnesium stearate and (e) the presence (at a 1 % level) and absence of sodium lauryl sulphate. Treatment of the results by analysis of variance, in 5,4, 3 and 2 factor combinations, indicates that the influence of a given factor is often dependent on the other factors. These interdependencies take the form of either a variation in the extent of an effect or the reversal of an effect. The influence of drug and level of diluent show interdependencies of the former kind. Hence, whilst the overall average for drug release indicates that the drugs can be ranked in the ascending order: nitrofurantoin < nitrofurazone < oxytetracycline < tetracycline, the interactions predict that the quantitative ratios of 1:1·8:2·7:5·1 for the drugs above will vary when an additive is present and according to the additive. The rank order will, however, remain unchanged. Similarly, the higher level of diluent will usually increase drug release but not by a constant ratio between drugs. A reversal of an effect is shown by the addition of magnesium stearate, which in some instances increases rather than decreases drug release (its more usual effect). The addition of 1 % sodium lauryl sulphate does not provide a major enhancement of drug release, and in certain cases can be detrimental. There is no consistent order of effectiveness of the three diluents, and thus a universal capsule diluent, which will always improve drug release, does not appear to be a possibility.     

Use of texture analysis to study hydrophilic solvent effects on the mechanical properties of hard gelatin capsules

The aim of this work was to explore texture analysis for quantitative evaluation of the effect of hydrophilic solvent systems used as capsule fills on the mechanical properties of hard gelatin capsules. For this purpose, a texture analyzer (Stable Micro Systems, model TA.XT Plus) equipped with a capsule separating rod fixture was used. The tests were conducted in a tension mode. Elastic stiffness, tensile force and elongation at break were determined from the experimental stress-strain curve in order to quantitatively describe both brittleness and softening of capsules. In this paper, it has been demonstrated that the effect of various hydrophilic solvent (i.e. propylene glycol (PG), polyethylene glycol 400 (PEG 400), ethanol) mixtures on the mechanical properties of hard gelatin capsules can be easily monitored using texture analysis. Significant counteractive effects between PG and PEG 400 or ethanol on the integrity of capsule shells were discovered in this study. Texture analysis is found to be a convenient tool for studying formulation compatibility. It can be invaluable in early screening studies of liquid filled hard gelatin capsules.