Twin-screw granulation: Mechanistic understanding of the effect of material properties on key granule quality attributes through the analysis of mixing dynamics and granulation rate mechanisms

This study focuses on understanding the effect of material properties on granule quality attributes through the analysis of mixing dynamics and granulation rate mechanisms. Powder wettability, binder viscosity, and liquid-to-solid (L/S) ratio were the factors that were investigated in this study. The mixing occurring inside the twin-screw granulator (TSG) was quantitatively assessed by obtaining the axial dispersion coefficient from the experimentally measured residence time distribution (RTD) curves. It was observed that the quality of the nuclei fed to the kneading zone significantly affected the mixing dynamics. The quality of nuclei was governed by nucleation kinetics, which in turn was principally affected by the liquid saturation of the nuclei and the ratio of drop penetration time and encounter time, which in turn were affected by the L/S ratio and binder viscosity respectively. The hydrophobicity of the blend mainly affected the extent of nucleation. The type of nuclei entering the kneading zone and mixing dynamics in the TSG also determined whether the granulation growth mechanism was “layering-dominant” or “viscous-dominant”. It was also shown that the resultant granule quality attributes were a reflection of the growth mechanisms. Ultimately, a mechanistic link between material properties, mixing dynamics, granulation rate mechanisms, and granule quality attributes was established.     

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.     

Celecoxib-cyclodextrin systems: characterization and evaluation of in vitro and in vivo advantage

Solid dispersions of Celecoxib were prepared with hydroxypropyl β cyclodextrin by various methods such as physical mixture, cogrinding, kneading, and coevaporation. The dispersions were characterized by differential scanning calorimetry (DSC), X-ray diffraction patterns, infrared spectroscopy, and nuclear magnetic resonance studies. The DSC thermograms of the dispersions indicated potential of heat-induced interaction between Celecoxib and cyclodextrin that could influence in vitro drug dissolution. The dispersions exhibited faster rates of dissolution compared to that of Celecoxib. The kneaded dispersion with the fastest in vitro dissolution rate when compressed into tablets showed a better release profile compared to the tablets of pure Celecoxib. In vivo studies revealed that the kneaded dispersion provided for quicker response and was more effective in inhibiting rat paw edema as compared to Celecoxib alone, thus confirming the advantage of improved pharmacological activity of Celecoxib when administered as a solid dispersion with cyclodextrin.     

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.     

Factors influencing capping and cracking of mefenamic acid tablets

The tendency of capping and longitudinal cracks of mefenamic acid tablets was evaluated in relation to the amount of the binder, the influence of the granulation technique, and the relative humidity of the granules. Tablets made from fluidized bed granules using methylcellulose in the granulating liquid showed significantly lower capping and longitudinal cracks than tablets from conventional granules prepared by wet granulation using methylcellulose as a dry binder.     

Factors Influencing Capping and Cracking of Mefenamic Acid Tablets

The tendency of capping and longitudinal cracks of mefenamic acid tablets was evaluated in relation to the amount of the binder, the influence of the granulation technique, and the relative humidity of the granules. Tablets made from fluidized bed granules using methylcellulose in the granulating liquid showed significantly lower capping and longitudinal cracks than tablets from conventional granules prepared by wet granulation using methylcellulose as a dry binder.     

Physical aspects of wet granulation III. effect of wet granulation on granule porosity

The porosity of granules produced by wet granulation has been studied using mercury porosimetry. Granule pore size distribution appears to be bimodal, with a population of micropores and macropores. Pore surface area varies with kneading time, going through a maxima at a point where physical properties such as flow and bulk density also exhibit a maxima. True granule density displays a direct relationship to rate of flow. The information in general supports the postulate that equilibrium microporous granules are formed first in the wet granulation process, followed by consolidation with subsequent formation of microporous twins and agglomerates.     

Physical aspects of wet granulation III. effect of wet granulation on granule porosity

Abstract

The porosity of granules produced by wet granulation has been studied using mercury porosimetry. Granule pore size distribution appears to be bimodal, with a population of micropores and macropores. Pore surface area varies with kneading time, going through a maxima at a point where physical properties such as flow and bulk density also exhibit a maxima. True granule density displays a direct relationship to rate of flow. The information in general supports the postulate that equilibrium microporous granules are formed first in the wet granulation process, followed by consolidation with subsequent formation of microporous twins and agglomerates.     

Evaluation of A High-Speed Pelletization Process and Equipment

A single step high-speed centrifugal pelletization procedure is described. Pellets of three model drugs of varying solubilities were prepared and characterized. Scanning electron microscopy showed that the external layer which is composed of binder and drug is very porous relative to the nonpareil seed core material. Bulk density measurements also confirmed the loose structural makeup of the drug layer. Preparation of pellets from small non-pareil seeds provided particles that have high drug content and are amenable to high dose formulations. Common wet granulation binders such as polyvinylpyrrolidone, sodium carboxymethylcellulose and gelatin exhibited good binding capacities and generated excellent pellets.     

Evaluation of A High-Speed Pelletization Process and Equipment

Abstract

A single step high-speed centrifugal pelletization procedure is described. Pellets of three model drugs of varying solubilities were prepared and characterized. Scanning electron microscopy showed that the external layer which is composed of binder and drug is very porous relative to the nonpareil seed core material. Bulk density measurements also confirmed the loose structural makeup of the drug layer. Preparation of pellets from small non-pareil seeds provided particles that have high drug content and are amenable to high dose formulations. Common wet granulation binders such as polyvinylpyrrolidone, sodium carboxymethylcellulose and gelatin exhibited good binding capacities and generated excellent pellets.     

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     

Influence of process variables on physical properties of the pellets using extruder and spheronizer

Placebo pellets containing lactose and microcrystalline cellulose (Avicel PH101®) ratio 60:40 were prepared by the extrusion-spheronization process. The influence of processing variables, including the spheronizer speed, the spheronization time, the binder type, and the concentration and amount of water content on physical properties of the pellets, were studied. The sphericity of pellets was increased with increasing spheronizer speed during wet mass process. When spheronization time was increased, sphericity, smooth surface, and particle size of pellets were increased. Increasing binder concentration will increase particle size. Pellets using HPC-M® as a binder at high spheronizer speeds showed spherical shape, narrow size distribution, and good flow properties when compared with Methocel E-15LV®, HPC-L®, and Methocel A4M®. In addition, increasing HPC-M concentration had no effect on shape and particle size of pellets. The amount of water content was found to affect shape, flow rate, and density. In summary, suitable conditions consisted of 2% w/w of HPC-M, 40% w/w of water, and 15 min of spheronization time at 951 rpm of spheronizer speed.     

Extrusion granulation and high shear granulation of different grades of lactose and highly dosed drugs: a comparative study

Formulations containing different lactose grades, paracetamol, and cimetidine were granulated by extrusion granulation and high shear granulation. Granules were evaluated for yield, friability, and compressibility. Tablets were prepared from those granules and evaluated for tensile strength, friability, disintegration time, and dissolution. The different lactose grades had an important effect on the extrusion granulation process. Particle size and morphology affected powder feeding and power consumption, but had only a minor influence on the granule and tablet properties obtained by extrusion granulation. In contrast, the lactose grades had a major influence on the granule properties obtained by high shear granulation. Addition of polyvinylpyrrolidone (PVP) was required to process pure paracetamol and cimetidine by high shear granulation, whereas it was feasible to granulate these drugs without PVP by extrusion granulation. Granules prepared by extrusion granulation exhibited a higher yield and a lower friability than those produced by high shear granulation. Paracetamol and cimetidine tablets compressed from granules prepared by extrusion granulation showed a higher tensile strength, lower friability, and lower disintegration time than those prepared from granules produced by high shear granulation. Paracetamol tablets obtained via extrusion granulation exhibited faster dissolution than those obtained via high shear granulation. For all lactose grades studied, extrusion granulation resulted in superior granule and tablet properties in comparison with those obtained by high shear granulation. These results indicate that extrusion granulation is more efficient than high shear 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     

Evaluation and comparison of a moist granulation technique to conventional methods

In the moist granulation technique (MGT), a minimum amount of liquid is used to activate a binder in a planetary mixer. Then, any excess moisture is absorbed by the addition of a moisture-absorbing substance. In the experiments described below, acetaminophen (APAP) was the model drug; polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC) served as the binder and moisture-absorbing material, respectively. Water was used as the granulating fluid. Comparison of the MGT with direct compression (DC) and wet granulation (WG) methods was accomplished by sieve analysis (particle size) and density measurements. Moist granulation yielded an increase in particle size compared to direct compression; these results are comparable to those from the traditional wet granulation after drying and screening. Based only on the particle size, moist granulation appears comparable to conventional wet granulation for this formula. The moist granulation technique appears to have potential for the development of controlled-release formulations.     

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.     

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.     

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.     

The Preparation of Ascorbic Acid Pellets Using the Wet Pelletization Process in Liquid Media

The pellets of ascorbic acid were prepared from wet granulation using modifided spherical agglomeration technique, named as wet pelletization, in liquid media. The wet granules made by conventional method were placed into the baffled cylinderical vessel which was previously filled with water saturated ethylether. The wet granules were composed of ascorbic acid, microcrystalline cellulose and 3% of aqueous PVP K-30 solution as binding agent. To prepare highly spherical pellets with narrow size distribution, the system, at first, was agitated strongly about 1,500 rpm for 10 min with screw type agitator. Then the medium was changed to an anhydrous ethylether and agitated slowly about 900 rpm until pellets are shaped and densified. The shape and size distribution of pellets depend largely on the amounts of binding solution and the proportion of microcrystalline cellulose at fixed agitation speed. This wet pelletization technique was simple, reproducible and might have application for the spheronization of other hydrophilic drugs.     

Preparation and characterization of quercetin and rutin cyclodextrin inclusion complexes

The objective of the present study is to prepare and characterize cyclodextrin inclusion complexes of quercetin and rutin to improve their aqueous solubility and dissolution properties. Inclusion complexes of quercetin and rutin with beta-cyclodextrin (beta-CD) and hydroxyl propyl-beta-cyclodextrin (HP-beta-CD) were prepared by kneading and coevaporation methods. Characterization of inclusion complexes was done by phase solubility analysis and was supported by X-ray powder diffractometry (XRD), differential scanning calorimetry (DSC), and Fourier-transform infra red spectroscopy (FT-IR) analysis. Inclusion complexes exhibited higher rates of dissolution than the corresponding physical mixtures and pure drug. Higher dissolution rates were observed with HP-beta-CD kneaded complexes in comparison to the products with beta-CD.