Disintegration and Dissolution Parameters of Compressed Tablets Prepared by Direct Compression-Wet Granulation Process and Compression of Wet Granulation of Both Sections

Hardness, disintegration and dissolution of compressed tablets were assessed by compressing tablets from granulations prepared by dry and wet granulation process of two sections and by composite wet granulation process. Modified USP XVIII apparatus for disintegration, rotating basket apparatus USP XVIII and constant circulation apparatus were employed for measuring dissolution. The constant circulation apparatus was used in the studies as only it proved to be sensitive to reflect the differences in the dissolution rates and was a close analog of physiological situation. Four types of tablets containing acetylsalicylic acid, codeine phosphate and propoxyphene hydrochloride were prepared. Tablets prepared by partial dry and wet granulation process did not show significant differences in the rates of dissolution as compared to those prepared by complete wet granulation process.     

Moisture, Hardness, Disintegration and Dissolution Interrelationships in Compressed Tablets Prepared by the Wet Granulation Process

Interrelationships among moisture, hardness, disintegration and dissolution in compressed tablets were studied by compressing tablets from granulations prepared by the wet granulation process containing low moisture levels. Hardness, disintegration and dissolution of these tablets did not change on exposure to ambient room conditions. After equilibration under high humidities, a decrease in tablet hardness occurred which depended linearly on tablet hardnesses at the time of compression. After overnight exposure to ambient room conditions, the softened tablets increased in hardness and this increase greatly exceeded the initial hardnesses. The magnitude of hardness increase was independent of the hardnesses at the time of compression. Increased tablet hardnesses resulted in an increase in the disintegration time, although in vitro dissolution of the drug remained unaffected. The results suggest that moisture gain and subsequent loss on storage under varying humidity conditions could account for major increases in hardness of compressed tablets in storage.     

The Effect of the Wet Granulation Process on Drug Dissolution

Abstract

Wet granulation can be an important processing step for pharmaceutical solid dosage forms. In this investigation emphasis was directed towards the influence of a “simple” wet granulation process on drug release from granules and their resulting tablets. Direct compression blends of the same materials were used as controls. Binary mixtures containing a 5% level of either theophylline, hydrochlorothiazide or chlorpheniramine maleate in microcrystalline cellulose or lactose were granulated with water. Experimentally, the powders were dry blended in a planetary mixer, wet granulated, and subsequently wet milled and dried. No dry milling step was included. Granule characterization consisted of particle size, density, porosity, compression and dissolution testing. Dissolution results varied with the drug, as expected, and dissolution at 10 minutes ranged from 35 to 95 % release. In general, however, the results indicate that dissolution from granules and the corresponding direct compression blend are similar. Although differences in compressibility were observed in the systems studied, granulation was not found to be detrimental to drug release.     

Aging of Tablets Prepared by Direct Compression of Bases with Different Moisture Content

Abstract

Properties of aged tablets prepared by the wet granulation method were found to be affected by the moisture content of the granules. In this study, the storage-induced changes in hardness, disintegration and drug release were evaluated for tablets made by direct compression of three different bases with different initial moisture content. Tablets with high initial moisture content were found to increase in hardness upon storage. The magnititude of such increase is dependant upon the physical properties of the base and the absolute moisture content. The increase in hardness may increase the disintegration time and decrease drug release. Tablets with low initial moisture content were minimally affected by storage. The gain of moisture by some of these tablets led to enhancement in disintegration and drug release. Among the tablets studied lactose based tablets with different initial moisture content were found to be the most resistant to changes upon storage.     

Effect of Drug Solubility in Wet Granulation Fluids on the Dissolution Rates of the Resulting Tablets

One factor in wet granulation processes which affects dissolution rates of the final tablets is shown to be the solubility of the drug substance in the granulating liquid. The relationship is not a direct correlation and a feasible explanation is offered.     

Comparative Tablet and Rheological Properties of New Microcrystalline Cellulose: Direct Compression and Wet Granulation Methods

The overall objective of this study was to compare the rheological properties and tablet characteristics of two new varieties of celluloses (Vivacel 101 and 102), recently produced and commercialized, with the classical varieties of celluloses (Avicel and Elcema). The results showed no significant differences in the rheological properties of Vivacel and Avicel, while significant differences were found between the two celluloses and Elcema. Furthermore, there were no statistically significant differences in the disintegration times and T_d values of Vivacel and Avicel. In conclusion, it was found that these new celluloses offer all the known advantages of Avicel.     

Prospective Validation of High-Shear Wet Granulation Process by Wet Granule Sieving Method. I. Selection and Characterization of Sieving Parameters for Wet Granules

To characterize the progression of high-shear wet granulation for various drugs and formulations based on the particle size distribution of wet granules during granulation, a general sieving method for wet granules was investigated. Wet granulation was conducted in a 25-liter high-shear mixer using four model drugs with different solubilities and particle sizes (ethenzamide, unmilled and milled acetaminophen, and antipyrine). Because of its small size and efficient sifting mechanism, a sonic sifter was used to determine the wet granulation particle size distribution. From the good correlation of particle size distribution between wet granules and dry-sized granules, an intensity of 80% of full-scale amplitude and a sieving time of 3 min were selected as wet granule sieving parameters. 7% general sieving method showed good measurement precision as long as the determination was completed within 20 min after sampling, Further, the method was independent of sampling position within the mixer chamber.     

Effect of Re-Conpression on the Properties of Tablets Prepared by Dry Granulation

The effect of re-compression on the tableting properties of some direct compression excipients (directly compressible starch, dicalcium phosphate dihydrate and microcrystalline cellulose) and their formulations was examined. Re-compression generally reduced the tablet strength and this reduction was more significant when the initial compaction was carried out at a higher pressure. The reason for the reduction of tensile strength upon re-working is attributed to work hardening and the production of robust granules, which have increased resistance to deformation compared to unworked granules.

This paper is based on a presentation made to the 31st National meeting of the Academy of Pharmaceutical Sciences, American Pharmaceutical Association, held at Orlando, Florida, U.S.A. on November 15-19th, 1981.     

Effect of Re-Compression on the Properties of Tablets Prepared by Moist Granulation

The effect of re-compression on the properties of tablets prepared by moist granulation using various binding agents was examined. The results show that re-working by dry granulation and re-compression (i.e. a slugging process) caused a reduction in tablet strength, which was related to the initial compaction pressure. This loss of compressibility was attributed to work hardening of granules during the compaction process. However, when compacts were milled, re-wetted and then re-compressed, the tablets produced were of similar strength to those obtained on initial compaction. Re-wetting reversed the effect of work hardening by reactivating the binder to produce granules more porous than those obtained by dry granulation.

This paper is based on a presentation made to the 31st National meeting of the Academy of Pharmaceutical Sciences, American Pharmaceutical Association, held at Orlando, Florida, U.S.A. on November 15-19th, 1981.     

Effect of Pressure on Disintegration of Tablets and Dissolution of Ephedrine Sulfate

The influence of applied pressure on the disintegration of model ephedrine sulfate tablets and the release of ephedrine sulfate is reported. Six frequently used disintegrating agents were employed with a water-soluble diluent (lactose) and with a water-insoluble diluent (dibasic calcium phosphate). Although disintegration time may be independent of pressure (dibasic calcium phosphate) or may be lengthened by increased pressures (lactose), changes in applied pressures did not significantly alter the dissolution of the water-soluble medicinal compound.     

Effect of Pressure on Disintegration of Tablets and Dissolution of Ephedrine Sulfate

Abstract

The influence of applied pressure on the disintegration of model ephedrine sulfate tablets and the release of ephedrine sulfate is reported. Six frequently used disintegrating agents were employed with a water-soluble diluent (lactose) and with a water-insoluble diluent (dibasic calcium phosphate). Although disintegration time may be independent of pressure (dibasic calcium phosphate) or may be lengthened by increased pressures (lactose), changes in applied pressures did not significantly alter the dissolution of the water-soluble medicinal compound.     

The Effect of Recompression on Disintegrant Efficiency in Tablets Prepared by wet Granulation

Abstract

The efficiency of three modern disintegrants, Explotab, Ac-Di-Sol and Polyplasdone XL, has been investigated following rework of a wet massed, slowly eroding, tablet formulation. When the disintegrants were placed extra-granularly it was found that only Explotab retained good efficiency following rework. All disintegrants placed intra-granularly had rework efficiencies that were essentially the same as the control (no disintegrant). However, the addition of 2% extra-granular disintegrant prior to the second compression restored tablet disintegration behaviour for Polyplasdone XL and partially for Ac-Di-Sol.

Two of the factors potentially affecting the reworkability of disintegrants (comminution and regranulation) were also investigated. Regranulation caused Ac-Di-Sol and Explotab to significantly lose disintegrant efficiency. However milling alone caused no reduction in efficiency of any disintegrant.     

The Effect of Recompression on Disintegrant Efficiency in Tablets Prepared by wet Granulation

The efficiency of three modern disintegrants, Explotab, Ac-Di-Sol and Polyplasdone XL, has been investigated following rework of a wet massed, slowly eroding, tablet formulation. When the disintegrants were placed extra-granularly it was found that only Explotab retained good efficiency following rework. All disintegrants placed intra-granularly had rework efficiencies that were essentially the same as the control (no disintegrant). However, the addition of 2% extra-granular disintegrant prior to the second compression restored tablet disintegration behaviour for Polyplasdone XL and partially for Ac-Di-Sol.

Two of the factors potentially affecting the reworkability of disintegrants (comminution and regranulation) were also investigated. Regranulation caused Ac-Di-Sol and Explotab to significantly lose disintegrant efficiency. However milling alone caused no reduction in efficiency of any disintegrant.     

Controlled Release from Glycerol Palmito-Stearate Matrices Prepared by Dry-Heat Granulation and Compression at Elevated Temperature

Diprophylline release from glycerol palmito-stearate “precirol” matrices containing different direct compression (DC) excipients, with variable dissolving/disintegrating ability, is investigated. The matrices are formed by employing dry-heat granulation and compression at elevated temperature.

Greater drug release prolongation is achieved with the dissolving DC excipients than with the swelling ones. The release is described on the basis of two biexponential first order models and the Weibull function as well.

The effect of compression conditions (temperature and pressure) on the drug release is found to be related to the compaction behaviour of the DC excipients, i.e. plastic deformation or fragmentation.     

Experimentally Designed Optimization of Direct Compression Tablets

Abstract

The work reported here describes the improvement of an industrial production of tablets formed by direct compression. This formulation contained 50% active substance of plant origin as a nonhygroscopic powder. The first step was to evaluate a number of direct compression excipients in preformulation tests and then make up a basic formulation providing tablets with correct characteristics. The second step was the optimization of the initial formulation using a two-level factorial experimental design. This enabled the best formulations to be selected objectively.     

Controlled Release from Glycerol Palmito-Stearate Matrices Prepared by Dry-Heat Granulation and Compression at Elevated Temperature

Abstract

Diprophylline release from glycerol palmito-stearate “precirol” matrices containing different direct compression (DC) excipients, with variable dissolving/disintegrating ability, is investigated. The matrices are formed by employing dry-heat granulation and compression at elevated temperature.

Greater drug release prolongation is achieved with the dissolving DC excipients than with the swelling ones. The release is described on the basis of two biexponential first order models and the Weibull function as well.

The effect of compression conditions (temperature and pressure) on the drug release is found to be related to the compaction behaviour of the DC excipients, i.e. plastic deformation or fragmentation.     

Multiphase versus Single Pot Granulation Process: Influence of Process and Granulation Parameters on Granules Properties

ABSTRACT

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes.

The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.     

Effect of Granulating Method on Dissolution Rate of Compressed Tablets. III

The dissolution rates of dexamethasone granules prepared by all the methods were slower than the dissolution rates of the corresponding tablets. This was shown to be the result of a reduction of the average particle size on compaction. The dissolution rates of sulfadiazine tablets prepared by microgranulating and slugging were slower than the corresponding granules. This was demonstrated to be the result of enlargement of the granules on compaction. For both drugs the microgranulating procedure gave the most rapid dissolution of tablets and granules. In case of the dexamethasone formulation, direct compression exhibited the slowest dissolution rate. The dissolution rates of sulfadiazine granules and tablets prepared by the wet granulating method were also unsatisfactory.     

Prospective Validation of High-Shear Wet Granulation Process by Wet Granule Sieving Method. II. Utility of Wet Granule Sieving Method

The general utility of a method for determination of high-shear wet granulation end point by monitoring the wet granule particle size distribution was evaluated. Wet granulation was conducted in a 25-liter high-shear mixer using four model drugs with different solubilities and particle sizes (ethenzamide, unmilled and milled acetaminophen, and antipyrine). For each drug formulation, its wet granule particle size fraction and target range for granulation end point determination were selected based on the tablet characteristics that are known to be influenced by the wet granulation process. Granules manufactured under different conditions (i.e., different main and chopper blade speeds and binder supplying rate) but manufactured to the same granulation end point determined by the selected fraction and range showed very similar granule characteristics and subsequently very similar tabler characteristics. From the fact that there was a good correlation between the wet and dry-sized granule particle size distributions even if the drying method was changed from fluid-bed drying to vacuum drying, the general application of the end point determining method was verified. Further, the method was shown to be sensitive to the critical granulation parameters for granulation progression and to be very capable of determining the granulation extent. Thus, it was suggested that the method is applicable to various drugs and formulations for determination of wet granulation end point.     

The Dissolution of Verapamil from Tablets Prepared with two Sodium Polyphosphates

Abstract

The ratio of the two polyphosphates, soluble sodium polyphosphate (SPP) and insoluble Maddrell's Phosphate (MPI), will influence the release rate of verapamil from tablets and compressed discs. Dose forms which contain only MPI release the drug constantly for about 8 hours and the inclusion of SPP tends to increase the release rate. Although the tablets containing verapamil and the polyphosphate mixture are harder than similar tablets without the drug, the hardness of the tablets is not influenced by the ratio of the polyphosphates employed and does not cause the variation in release rate observed.