Use of a Moist Granulation Technique (MGT) to Develop Controlled-Release Dosage Forms of Acetaminophen

The moist granulation technique (MGT), which involves agglomeration and moisture absorption, has only been applied to immediate-release dosage forms. Our results indicate that MGT appears to be applicable in developing a controlled-release formulation. A small amount of granulating fluid (water) was added to a powder blend to activate a dry binder (such as polyvinylpyrrolidone [PVP] at 2% and 3.6%) and to facilitate agglomeration. Then, a moisture-absorbing material (microcrystalline cellulose [MCC]) was added to absorb any excess moisture. By adding MCC in this way, a drying step was not necessary. Acetaminophen (APAP) was the model drug, with diluents lactose FastFlo® and dicalcium phosphate. Hydroxypropylcellulose (HPC) was used as the controlled-release agent. The MGT was compared to conventional wet granulation (WG) and direct compression (DC) processing methods. The results indicate that MGT appears to be applicable in developing a controlled-release formulation. Particle size distribution of MGT and WG batches containing 3.6% PVP is similar.     

Use of a Moist Granulation Technique (MGT) to Develop Controlled-Release Dosage Forms of Acetaminophen

The moist granulation technique (MGT), which involves agglomeration and moisture absorption, has only been applied to immediate-release dosage forms. Our results indicate that MGT appears to be applicable in developing a controlled-release formulation. A small amount of granulating fluid (water) was added to a powder blend to activate a dry binder (such as polyvinylpyrrolidone [PVP] at 2% and 3.6%) and to facilitate agglomeration. Then, a moisture-absorbing material (microcrystalline cellulose [MCC]) was added to absorb any excess moisture. By adding MCC in this way, a drying step was not necessary. Acetaminophen (APAP) was the model drug, with diluents lactose FastFlo® and dicalcium phosphate. Hydroxypropylcellulose (HPC) was used as the controlled-release agent. The MGT was compared to conventional wet granulation (WG) and direct compression (DC) processing methods. The results indicate that MGT appears to be applicable in developing a controlled-release formulation. Particle size distribution of MGT and WG batches containing 3.6% PVP is similar.     

The Effects of Formulation Factors on the Moist Granulation Technique for Controlled-Release Tablets

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.     

The Effects of Formulation Factors on the Moist Granulation Technique for Controlled-Release Tablets

Controlled-release tablets were prepared by the moist granulation technique (MGT), a granulating method that uses very limited amounts of liquid and requires microcrystalline cellulose (MCC) to absorb moisture. Acetaminophen (APAP) was the model drug, and the polymer hydroxypropylcellulose (HPC) served as the controlled-release agent. The effects of varying drug, binder (polyvinylpyrrolidone, PVP), polymer, and MCC levels on granule properties and tablet dissolution were studied. Dissolution testing was carried out in distilled water using the USP paddle method. In all cases, the granules flowed and compressed well. The granule properties were evaluated by calculating the mean particle size for all batches from sieve analysis data. The results indicate that MGT can be applied to control drug release, and at a polymer content of 44.6% or more, the process is robust enough to allow slight variations in formulation factors without affecting drug release.     

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.     

Melt Granulation in A Laboratory Scale High Shear Mixer

The applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.

It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.     

Optimal Massing Liquid Volume Determination by Energy Consumption Measurement: Study of the Influence of Some Physical Properties of Solvents and Products Used

This study tried to investigate, by the power comsumption technique, the influence of the powder's and solvent's properties on wet granulation.

It could be shown that the required amount of granulation liquid decreases when the particle size of the powder to be granulated increases. This relationship is however only true when the particle size distribution of the powder to be granulated is rather narrow.

Powders having the same solubility in different solvents require the same optimal liquid quantity for granulation, but the properties of resulting granules depend on surface tension and wetting properties of the solvent.

When the powder to be granulated contains crystallisation water, the temperature rising in the mixer can be sufficient to liberate this water, which must be taken into account in the optimal granulation liquid requirement.

The effect of a macromolecular binder (PVP, HPMC) has also been studied: the optimal liquid quantity required changes with the kind of binder used and the manufacturing process (binder used in solution or added as dry powder).

It was also shown that in the case of lactose, the optimal quantity of PVP or HPMC can be determined from the power consumption records and from the granules friability studies     

Foam granulation: new developments in pharmaceutical solid oral dosage forms using twin screw extrusion machinery

This paper investigates foam granulation in a twin screw extruder as a new continuous wet granulation technique for pharmaceutical powder drug formulations. Foamed aqueous binder has a reportedly lower soak-to-spread ratio than drop or spray liquid addition in batch granulation. This work demonstrates a twin screw extruder configuration for foam granulation and subsequently compares the new approach against liquid injection in the granulation of α-lactose monohydrate with a methylcellulose binder. Trials were conducted at high powder output rates (20-40 kg/h) and high screw speeds (220-320 RPM) with two screw configurations. Process stability improved with the new technique allowing granulation with less binder. The extruded mass maintained a low exit temperature, being insensitive to operating conditions unlike the liquid injection approach, where temperatures rose significantly as flow rate increased. The particle size distribution by foam granulation reflected a more uniformly wetted mass with larger granule growth noted even for conditions where dry powder exited by liquid injection. Other factors were found similar between the two binder delivery methods such as consumed mechanical energy, as well as fracture strength and compressibility of produced granules.     

Melt Granulation in A Laboratory Scale High Shear Mixer

Abstract

The applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.

It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.     

Optimal Massing Liquid Volume Determination by Energy Consumption Measurement: Study of the Influence of Some Physical Properties of Solvents and Products Used

Abstract

This study tried to investigate, by the power comsumption technique, the influence of the powder's and solvent's properties on wet granulation.

It could be shown that the required amount of granulation liquid decreases when the particle size of the powder to be granulated increases. This relationship is however only true when the particle size distribution of the powder to be granulated is rather narrow.

Powders having the same solubility in different solvents require the same optimal liquid quantity for granulation, but the properties of resulting granules depend on surface tension and wetting properties of the solvent.

When the powder to be granulated contains crystallisation water, the temperature rising in the mixer can be sufficient to liberate this water, which must be taken into account in the optimal granulation liquid requirement.

The effect of a macromolecular binder (PVP, HPMC) has also been studied: the optimal liquid quantity required changes with the kind of binder used and the manufacturing process (binder used in solution or added as dry powder).

It was also shown that in the case of lactose, the optimal quantity of PVP or HPMC can be determined from the power consumption records and from the granules friability studies     

Factors Affecting Rate of Dissolution of Prednisone from Tablets

Abstract

A study was carried out to evaluate some parameters which may have an effect on the dissolution rate of prednisone from tablets. The parameters examined involving formulation were: diluent proportion (Lactose-starch), dissintegrant type (starch, explotab (sodium starch glycolate) type of binder (starch paste, gelatine water solution and PVP alcoholic solution), lubricant, and dye concentration. The Manufacturing variables studied were: method of manufacture (wet granulation, direct compression and double compression), granule size in wet granulation and tablet hardness. dissolution profiles of tablets storaged 2 months at 45°C were compared with those of fresh samples. Tablets prepared with prednisone five years old, tablets with fresh active ingredient and tablets with two different prednisone concentrations (5 and 50 mg per tablet) were used for other evaluations.

In all cases micronized prednisone was used and all batches were physically and chemically evaluated before studying their dissolution following the USP basket method.

The parameters studied that affected significatively dissolution rate of prednisone were: type of binder, lubricant concentration, method of manufacture, active ingredient, age and prednisone concentration.     

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.     

Factors Affecting Rate of Dissolution of Prednisone from Tablets

A study was carried out to evaluate some parameters which may have an effect on the dissolution rate of prednisone from tablets. The parameters examined involving formulation were: diluent proportion (Lactose-starch), dissintegrant type (starch, explotab (sodium starch glycolate) type of binder (starch paste, gelatine water solution and PVP alcoholic solution), lubricant, and dye concentration. The Manufacturing variables studied were: method of manufacture (wet granulation, direct compression and double compression), granule size in wet granulation and tablet hardness. dissolution profiles of tablets storaged 2 months at 45°C were compared with those of fresh samples. Tablets prepared with prednisone five years old, tablets with fresh active ingredient and tablets with two different prednisone concentrations (5 and 50 mg per tablet) were used for other evaluations.

In all cases micronized prednisone was used and all batches were physically and chemically evaluated before studying their dissolution following the USP basket method.

The parameters studied that affected significatively dissolution rate of prednisone were: type of binder, lubricant concentration, method of manufacture, active ingredient, age and prednisone concentration.     

Optimizing a wet granulation process to obtain high-dose sustained-release tablets with Compritol 888 ATO

Context: Niacin (vitamin B3) is a micronized active pharmaceutical ingredient (API) with poor flow properties making the production of high-dose sustained-release tablets by direct compression a challenge.

Objective: We evaluated various wet granulation processes as a simple and efficient approach to obtain high-dose (500 and 1000?mg) niacin sustained-release lipid matrix tablets.

Materials and methods: A high melting-point lipid (Compritol® 888 ATO) was used as the sustained-release agent. Tablets were prepared by various wet granulation techniques, with different process parameters and binder concentrations to identify the optimal process conditions.

Results: A binder (PVP) was needed to increase particle bonding and tablet strength. Process parameters, such as spray rate and quantity of liquid, had only a slight impact on the properties of the granules and resultant tablets, in the presence of low binder concentrations. Increasing binder concentration improved granule wetting, resulting in significant granule growth and improved flow properties. Sustained-release over 12?h was observed for all the compacted granules, irrespective of the drug dose. The sustained-release kinetics for 1000?mg niacin matrix tablets with Compritol 888 produced with the identified optimal parameters were similar to those for the market reference product, Niaspan® FCT 1000?mg. The tablets were stable for up to six months when stored at 25 and 40?°C.

Conclusions: Wet granulation with Compritol 888 presents an effective approach to improve material flow and compressibility. High-dose lipid matrix tablets with sustained release profiles can be successfully produced.     

Effect of Granulating Method on Content Uniformity and Other Physical Properties of Granules and their Corresponding Tablets. II

Various properties of dexamethasone and sulfadiazine granules and tablets prepared by microgranulation, slugging, wet granulation and direct compression were compared.

The dexamethasone tablets showed comparable disintegration rates by all methods. The sulfadiazine tablets prepared by slugging did not meet the USP XIX limit, whereas those by microgranulating were satisfactory.

It was found that granule-homogeneity was not only dependent on the particle size and distribution, but also dependent on the granulating method. For either drug, the microgranulating procedure gave the best weight and content uniformity.     

The changes in the Mechanic Properties of a direct tableting agent Microcrystalline Cellulose by Precompression

In the manufacturing of tablets, direct tableting agents are not only used in direct compression, but are also used in wet granulation and slugging methods. These agents are effective only if their particle size and form is appropriate. However, the precompression, milling and grinding which are applied in the slugging method changes the particular properties of these agents.

In this study, microcrystalline cellulose tablets were prepared both by direct compression and slugging. The consolidation, compressibility and flow properties of the two mixed powders were compared. Finally, it was observed that the compressibility of the mixed powder was influenced negatively by the slugging method.     

The changes in the Mechanic Properties of a direct tableting agent Microcrystalline Cellulose by Precompression

Abstract

In the manufacturing of tablets, direct tableting agents are not only used in direct compression, but are also used in wet granulation and slugging methods. These agents are effective only if their particle size and form is appropriate. However, the precompression, milling and grinding which are applied in the slugging method changes the particular properties of these agents.

In this study, microcrystalline cellulose tablets were prepared both by direct compression and slugging. The consolidation, compressibility and flow properties of the two mixed powders were compared. Finally, it was observed that the compressibility of the mixed powder was influenced negatively by the slugging method.     

Effect of Binder Concentration and Method of Addition on Granule Growth in a High Intensity Mixer

A model system consisting of microcrystalline cellulose and povidone was used to study the effect of binder concentration and method of addition on granule growth in a high intensity mixer. The methods of binder addition include blending the dry binder with the excipient prior to granulating with water and granulation of the excipient with an aqueous solution of the binder. When the binder was dry-mixed with excipient prior to wetting, a good correlation was obtained between granule size and binder level. The growth of granules prepared by this method also appears to be related to the mechanical “resistance” encountered by the mixing blade during wet massing. In general, granules prepared by the addition of aqueous binder solutions are smaller than granules prepared with corresponding concentrations of dry binder and demonstrate a lesser degree of granule growth with respect to increasing binder level. For the wet addition method, the mechanical resistance was found to be essentially constant with respect to binder level.     

Drug release kinetics from tablet matrices based upon ethylcellulose ether-derivatives: a comparison between different formulations

The present study involved the preparation of ibuprofen-containing controlled release tablets formulated from either the established granular product, Ethocel®Standard Premium, or the novel finely-milled product, Ethocel®Standard FP Premium. The tablets were prepared by either direct compression or wet granulation. The aim was to explore the influence of different parameters on the kinetics and mechanisms of ibuprofen release from the tablets. These parameters were; polymer particle size, polymer molecular weight, drug : polymer ratio, preparation methodology and partial replacement of lactose with the coexcipient—hydroxypropyl methylcellulose (HPMC). The derived drug release data were analyzed with reference to various established mathematical models while the f₂-metric technique was used in order to determine profile equivalency. It was found that drug release was mostly modulated by several interactive factors apparently exhibiting crosstalk. Nevertheless, it was possible to identify some simple rules. Incorporation of Ethocel® FP polymers and application of the wet granulation technique facilitated greater efficiency in controlling ibuprofen release behavior from the matrices. Furthermore, drug release profiles could be modulated by partial substitution of the primary excipient with HPMC. Polymer concentrations and particle sizes, rather than viscosity grade, were found to be decisive factors in controlling drug release rates.     

Investigations at an industrial scale on granule and tablet attributes in high shear rapid mixer granulator

Particle agglomeration by granulation was a very ubiquitous operation that finds applications in various industries such as pharmaceutical, food, chemical, fertilizer, etc. Among many granulators, the high shear rapid mixer granulator (RMG) was a very commonly used wet granulator in pharmaceutical industry. The wet granulation process was sensitive to the process parameters and the input product variables. The flow pattern, fill ratio, cohesive forces, velocities, and the kinetic energy of the particles have impact on the granular and the tablet properties. In this work, solid dosage formulation integrated with the RMG process has been studied at an industrial scale. The total formulation of the tablet was kept constant and the impact of various critical operating and process parameters of RMG viz., impeller design, impeller speed, batch size, binder concentration, and binder type on granule and tablet attributes has been studied and analyzed. The optimal set of process parameters to achieve the desired granular and tablet attributes viz., bulk density, compressibility (Carr index) flow properties (Hausner ratio), particle size distribution, texture, tablet hardness, dissolution, and disintegration times were found in the study.