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.     

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.     

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

Abstract

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.     

Physical Aspects of Wet Granulation IV - Effect of Kneadign time on Dissolution Rates and Tablet Properties

The phsical properties of sucrose-lactoes-strach granulations containing a water soluble drug are characterized, and the relationship between granulaion kneading time and each of the these properties is examined. In addition, the effect of granulation kneading time on the properties of tablets prepared from the granules is examined.     

Effect of Crospovidone on the Wet Granulation aspectc of Acetaminophen

Abstract

The effect of crospovidone on the characteristics of wet granulated acetaminophen was investigated. Power blends of acetaminophen and crospovidone were wet granulated using hydroxypropyl methlcellulose as the binder and water as the granulating liquid. The sieve analysis data showed that as the level of crospovidone in the powder blend increased, there was an increase in the ammount of fines in the particle distribution of the dried granulations. The bulk densities of fromulae containing a higher level of crospovidone were generally lower although no clear trend was seen for the tap denstiy values. Interferences in the hydratin of hydroxypropyl methylecellulose, and increase in the total surface ara were considered as two possible mechanisms for the effect foc crospolvidone. The results of this study indicate that an interaction of both mechanisms may be responsible for the effect of crospovidone on the chracteristics of wet granulated acetaminophen.     

Effect of Crospovidone on the Wet Granulation aspectc of Acetaminophen

The effect of crospovidone on the characteristics of wet granulated acetaminophen was investigated. Power blends of acetaminophen and crospovidone were wet granulated using hydroxypropyl methlcellulose as the binder and water as the granulating liquid. The sieve analysis data showed that as the level of crospovidone in the powder blend increased, there was an increase in the ammount of fines in the particle distribution of the dried granulations. The bulk densities of fromulae containing a higher level of crospovidone were generally lower although no clear trend was seen for the tap denstiy values. Interferences in the hydratin of hydroxypropyl methylecellulose, and increase in the total surface ara were considered as two possible mechanisms for the effect foc crospolvidone. The results of this study indicate that an interaction of both mechanisms may be responsible for the effect of crospovidone on the chracteristics of wet granulated acetaminophen.     

The Evolution of Microstructure in Three-Component Granulation and Its Effect on Dissolution

The relationship between microstructure and dissolution rate of three-component granules was investigated. Granules were prepared by fluid bed granulation from sucrose spheres as model excipient, sodium chloride as model active ingredient, and polyethylene glycol (PEG) as in situ melt binder. A novel method for controlling the distribution of active ingredient within the granule was developed, based on suspending its particles in the binder prior to granulation. Granule microstructure was varied by systematically changing the NaCl particle size and the active/excipient ratio in granules. The dissolution rate of granules in water was measured by conductometry. A minimum was found in the functional dependence of dissolution time on NaCl fraction in the granule, in line with earlier computer simulations. The primary particle size was found to influence dissolution time in a nonlinear way depending on the fraction of available particle surface immersed in the binder. The intrinsic binder dissolution can therefore be rate-controlling if primary particles of the active ingredient are totally coated by binder. This was confirmed by comparing the dissolution times of granules prepared with PEGs of different molecular weight.     

The Evolution of Microstructure in Three-Component Granulation and Its Effect on Dissolution

The relationship between microstructure and dissolution rate of three-component granules was investigated. Granules were prepared by fluid bed granulation from sucrose spheres as model excipient, sodium chloride as model active ingredient, and polyethylene glycol (PEG) as in situ melt binder. A novel method for controlling the distribution of active ingredient within the granule was developed, based on suspending its particles in the binder prior to granulation. Granule microstructure was varied by systematically changing the NaCl particle size and the active/excipient ratio in granules. The dissolution rate of granules in water was measured by conductometry. A minimum was found in the functional dependence of dissolution time on NaCl fraction in the granule, in line with earlier computer simulations. The primary particle size was found to influence dissolution time in a nonlinear way depending on the fraction of available particle surface immersed in the binder. The intrinsic binder dissolution can therefore be rate-controlling if primary particles of the active ingredient are totally coated by binder. This was confirmed by comparing the dissolution times of granules prepared with PEGs of different molecular weight.     

The Effect of Recompression on the Dissolution of Wet Massed Tablets Containing 'Super' Disintegrants

The effect of recompression on the disintegration, and dissolution of tablets employing 'super' disintegrants within a wet-massed Avicel matrix is reported. Differences were found in the disintegration times of tablets containing intra-granular or extra-granular disintegrants (Polyplasdone XL, Explotab and Ac-di-sol), both between disintegrant type and within the same disintegrant system following rework.

In the case oE extra-granular disintegrant, reworked compacts dissolved faster than the first compression tablets, irrespective of disintegrant type. Thus, milling and dispersion of the drug during rework appear to dominate over the effects of impaired disintegration when 'super' disintegrants are present. The control compacts (no disintegrant), however, dissolved less quickly following rework, indicating that dissolution was controlled by disintegration.

Tablets with intra-granular Polyplasdone XL and Ac-di-sol dissolved less quickly following rework. Both disintegrants have poor intra-granular rework efficiencies. However, for Explotab, which has better rework intra-granular efficiency, reworked tablets dissolved faster than first compression compacts.     

Use of Mixer-Torque Measurements as an Aid to Optimizing Wet Granulation Process

Instrumentation designed for monitoring the wet granulation process is described. A Hobart mixer was instrumented with a slip ring torque sensor using a voltage of 5 volts D.C. to excite a strain gauge bridge. An amplifier was used to magnify the low signal levels produced by the strain gauge bridge and the gain was set at 179.6 so that 2 volts equals 200 inch ounce. The output was recorded using a Bascom-Turner recorder. The relative dynamic torque, was measured in millivolts as a function of granulating fluid added and time to optimize the granulation process using the planetary mixer. The instrumentation described in this paper has considerable potential for optimization and validation studies for wet granulation procedures.     

Use of Mixer-Torque Measurements as an Aid to Optimizing Wet Granulation Process

Abstract

Instrumentation designed for monitoring the wet granulation process is described. A Hobart mixer was instrumented with a slip ring torque sensor using a voltage of 5 volts D.C. to excite a strain gauge bridge. An amplifier was used to magnify the low signal levels produced by the strain gauge bridge and the gain was set at 179.6 so that 2 volts equals 200 inch ounce. The output was recorded using a Bascom-Turner recorder. The relative dynamic torque, was measured in millivolts as a function of granulating fluid added and time to optimize the granulation process using the planetary mixer. The instrumentation described in this paper has considerable potential for optimization and validation studies for wet granulation procedures.     

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.     

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.     

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.     

The effect of Mill Variables on a Granulation Milling Process

An instrumented mill was used to evaluate the milling of a pharmaceutical granulation. The effects of changing mill speed, screen hole size, impeller type, and impeller-screen clearance on milling time and work, as well as particle size reduction were investigated. Screen hole size had the largest effect on milling time and work as well as particle size reduction, while impeller type had the largest effect on overall milling performance. A new impeller design was tested and found to enhance milling efficiency by improving both particle size reduction and mill output rate.     

The effect of Mill Variables on a Granulation Milling Process

Abstract

An instrumented mill was used to evaluate the milling of a pharmaceutical granulation. The effects of changing mill speed, screen hole size, impeller type, and impeller-screen clearance on milling time and work, as well as particle size reduction were investigated. Screen hole size had the largest effect on milling time and work as well as particle size reduction, while impeller type had the largest effect on overall milling performance. A new impeller design was tested and found to enhance milling efficiency by improving both particle size reduction and mill output rate.     

The Control of Drug Release from Conventional Melt Granulation Matrices

Sustained release potassium chloride tablets were prepared using a melt granulation formulation in a Baker Perkins Granulator. Parts of the validation for this manufacturing process are highlighted in this paper including granulation end point temperature, incorporation of extragranular excipients, amount of wax in the formulation, granule cooling rate and scale of the operation. A number of other factors have been studied which are not Included here although they are no less important. The release of potassium chloride from tablets was found to be dependent on the wax level and the amount of extragranular excipients (“wicklng agent”). Within the controlled production process, any variation in granulation end point temperature and granule cooling rate should not have any significant effect.     

The Control of Drug Release from Conventional Melt Granulation Matrices

Abstract

Sustained release potassium chloride tablets were prepared using a melt granulation formulation in a Baker Perkins Granulator. Parts of the validation for this manufacturing process are highlighted in this paper including granulation end point temperature, incorporation of extragranular excipients, amount of wax in the formulation, granule cooling rate and scale of the operation. A number of other factors have been studied which are not Included here although they are no less important. The release of potassium chloride from tablets was found to be dependent on the wax level and the amount of extragranular excipients (“wicklng agent”). Within the controlled production process, any variation in granulation end point temperature and granule cooling rate should not have any significant effect.     

粉石英细磨过程中的团聚现象

以粉石英为例，揭示了超细粉碎过程中特有的团聚现象．以大量实验数据和理论分析为基础，描述和论证了团聚现象的种种表现．具有普遍的意义。为在超细粉碎中合理选择工艺条件．有效控制粉碎极限和延缓粉碎平衡，推迟“逆粉碎”的出现提供了一定的参考依据，对推进粉体技术的发展具有一定的理论意义和实用价值。