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.     

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.     

A Process to Produce Effervescent Tablets: Fluidized Bed Dryer Melt Granulation

The purpose of the present study was to apply melt granulation in a fluidized bed dryer (fluidized bed dryer melt granulation) to manufacture one-step effervescent granules composed of anhydrous citric acid and sodium bicarbonate to make tablets. This study permitted us to establish that such process parameters as concentrations of polyethylene glycol (PEG) 6000, residence times in the fluidized bed dryer, fineness of PEG6000, fineness of initial mixture effervescent systems, and efficiency of two lubricants markedly affect some granule and tablet characteristics. It is a dry process that is simple, rapid, effective, economical, reproducible, and particularly adapted to produce effervescent granules that are easily compressed into effervescent tablets.     

A process to produce effervescent tablets: fluidized bed dryer melt granulation

The purpose of the present study was to apply melt granulation in a fluidized bed dryer (fluidized bed dryer melt granulation) to manufacture one-step effervescent granules composed of anhydrous citric acid and sodium bicarbonate to make tablets. This study permitted us to establish that such process parameters as concentrations of polyethylene glycol (PEG) 6000, residence times in the fluidized bed dryer, fineness of PEG6000, fineness of initial mixture effervescent systems, and efficiency of two lubricants markedly affect some granule and tablet characteristics. It is a dry process that is simple, rapid, effective, economical, reproducible, and particularly adapted to produce effervescent granules that are easily compressed into effervescent tablets.     

The Production and Evaluation of Orally Administered Insulin Nanoparticles

Abstract

Wet granulation of a hydrophilic sustained release matrix tablet formulation has been studied. A fractional factorial experimental design was employed to identify principal influences and interacting factors from the following : granulation fluid volume, mixing time, mixer speed and inclusion of a wet screening step. Fluid volume and mixing time were primary factors affecting mean granule size. Fines in the granulation were reduced at higher fluid levels and by inclusion of a wet screening operation. There were several interacting factors influencing the particle size properties of the granulation. The factors studied had little influence on the bulk density of the granulation.

The influence of granule mean particle size on flow, compressibility and drug release from finished tablets was evaluated. Flow and compressibility were influenced by granule properties and the data generated suggested that should final tablet properties deteriorate on scale up it may be possible to ameliorate the effect by modification of granulation fluid volume or mixing time or both.

The factors studies had no influence on release of drug from finished tablets.     

Alternative Granulation Technique: Melt Granulation

Abstract

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Study of granule growth kinetics during in situ fluid bed melt granulation using in-line FBRM and SFT probes

Objective: The aim of this work was to study the granule growth kinetics during in situ fluid bed melt granulation process using real-time particle size measurement techniques. In addition, the usefulness of these techniques during scale-up of melt granulation was evaluated.

Materials and methods: Focused beam reflectance measurement (FBRM) and spatial filtering technique (SFT) probes were used within the process chamber of fluid bed granulator for real-time in-line granule size analysis.

Results: The results demonstrated that the use of in-line particle size probes in fluid bed granulator during the process offers an insightful view of granule growth and allows in-process monitoring of granule chord length changes. The effect of selected critical parameters (binder content, inlet air temperature and product endpoint temperature) on the granule growth was clearly presented by in-line measurements in a laboratory scale. A comparison of granule size measurements from both FBRM and SFT probes showed similar particle growth trends, which were in close correlation to the product temperature. Comparable trends in end granule particle size were observed when comparing different in-line, at-line and off-line particle size measurements.

Conclusion: The in-line FBRM and SFT probes were successfully employed in in situ fluid bed melt granulation process to study the influence of critical formulation/process parameters on the granule growth kinetics. The scale-up experiment confirmed the potential of these in-line granule size measurement techniques as a viable tool for process monitoring during the transfer of granulation to the larger scale or another manufacturing site/equipment.     

Melt granulation in fluidized bed: a comparative study of spray-on versus in situ procedure

Objective: The aim of this study was to investigate the influence of process parameters, binder content and binder addition method on characteristics of the granules obtained by melt granulation (MG) in fluidized bed.

Methods: Spray-on experiments were performed according to 2³ full factorial design. The effect of binder content, molten binder feed rate, and spray air pressure on granule size and size distribution, granule shape, ?owability and drug release rate was investigated. In the in situ experiments, the influence of binder particle size and binder content was evaluated. Solid-state characterization was performed by means of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy.

Results: Size of the granules obtained by spray-on procedure was significantly influenced by binder content and spray air pressure, while the width of particle size distribution was mainly affected by binder feed rate. Spray air pressure showed the most significant influence on granule shape. It was shown that smooth and spherical particles with good flow properties may be obtained by both procedures, spray-on and in situ MG. The results obtained indicated the influence of agglomeration mechanism on granule sphericity, with higher degree of granule sphericity observed when immersion and layering was the dominant mechanism. Paracetamol release from granulates was very rapid, but after compression of the granules into tablets, drug release was considerably slower. Solid-state analysis confirmed that the physical form of the granulate components remained unaffected after the MG process.

Conclusion: The results presented indicate that MG in fluidized bed could be a good alternative to conventional granulation techniques.     

Aluminium-Magnesium Hydroxide Tablets: Effect of Processing and Composition of Granulating Solution on the Granule Properties and In Vitro Antacid Performance

Abstract

Wet granulation experiments on aluminium-; magnesium hydroxide; mannitol blends were carried out, in order to produce chewable antacid tablets.

The influence of binder solvent, of type and concentration of polyvinylpyrrolidone as a binder and of granulating and drying equipment on the granule and tablet characteristics was investigated.

Water as a binder solvent offered several advantages over the use of alcohol. The use of high molecular weight polyvinylpyrrolidone reduced the antacid capacity and caused some manufacturing problems.

The granulating equipment (high shear granulator or planetary mixer) and the drying technique (oven or fluidized bed) had no major influence on the granule and tablet characteristics.     

Influence of Technological Factors on the Optimal Granulation Liquid Requirement Measured by Power Consumption

Abstract

The optimal liquid requirement for wet granulation can be investigated by recording the power consumption of the mixer during liquid addition. In this work it was tried to use this technique on a small laboratory scale (one kg or less) for lactose wet granulation with water. The validity of the power consumption method could be confirmed by granule size analysis. Different factors were studied: kind of mixer, powder quantity, mixer speed, liquid addition speed, granulator screen size, mixing time.     

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.     

Granulation in a Fluidized Bed II Effect of Binder Amount on the Final Granules

Abstract

There are many parameters affecting the properties of the final granules prepared in a fluidized bed. In this study one of the product parameters, quantity of the binder, has been studied for its effect on the final granule size, size distribution and friability

Determination of granule size change as a function of binder quantity leaded us to study the growth mechanisms during fluidized bed granulation. Two mechanisms are suggested;

1) Snowballing of primary granules (nuclei)

2) Agglomeration of primary granules

It has been shown that there is a critical amount of binder at which the formation of the primary granules comes to an end if more binder is added to the system. Then granule growth occurs by agglomeration of the primary granules. The physical properties of the granules formed before and after this critical binder concentration varies significantly     

Characteristics of piroxicam granules prepared by fluidized bed hot melt granulation

The aim of this study was to investigate the granulation of piroxicam by fluidized bed hot melt method using polyethylene glycol 4000 as the hydrophilic carrier and spray dried lactose as the fluidizing substrate. The effects of the spray nozzle air flow rate, axial position of the spray nozzle and load of fluidizing substrate on granules properties were investigated using a Box Behnken factorial design. The dependent variables evaluated were the mean particle size distribution, drug content and flow properties of the granules. The granule sizes ranged from 453.5?µm to 894.7?µm and piroxicam content was above 83.2%. However, the response surface ANOVA showed that sizes and piroxicam content were not affected by the granulation conditions and microscopy evidenced the presence of piroxicam crystals on granules surface. On the other hand, ANOVA showed that the granules flow properties were affected at the significance level of 5%. Thermal and infrared analysis showed that there was no interaction of piroxicam with carriers during the process. The dissolution profile of piroxicam was remarkably improved. Therefore, the results confirm the high potential of the fluidized bed hot melt granulation technique to obtain granules with enhanced drug solubility and release rates.     

Alternative Granulation Technique: Melt Granulation

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Influence of chopper and mixer speeds and microwave power level during the high-shear granulation process on the final granule characteristics

Although microwave drying technology has been used extensively, detailed studies in the pharmaceutical field are necessary to model the different operational parameters involved in microwave drying in combination with the high-shear granulation processes. The implications of the chopper and the mixer speeds during the granulation step and the microwave power level during the drying step on the final granule characteristics were investigated. alpha-Lactose monohydrate and microcrystalline cellulose were granulated at three different mixer and chopper speeds in a laboratory-scale high-shear mixer (Mi-Mi-Pro) and dried at three microwave power levels. The dried granules were characterized by friability tests, particle size analysis, bulk and tapped density studies, and porosimetry. Neither the mixer speed nor the chopper speed had a significant influence on the granule friability, which was low for all batches produced. The selected materials and experimental conditions induced a very robust granulation process, but the granule size distribution was influenced by the microwave power level. The reciprocal relationship between the dust formation and the microwave power level was analyzed using a central composite factorial design. The amount of dust remained low in all batches, but it influenced some of the inherent density properties and the volume reduction behavior of the granulation mass. In almost all cases, the Carr index decreased slightly with increasing microwave power. The major granule characteristics were not changed when different mixer or chopper speeds were changed, although the mixer speed did alter the intragranular pore size distribution.     

A Comparison Between Binders in the Wet Phase of Granulation in a High Shear Mixer

The effects of binder solutions on granule size, intragranular porosity and liquid saturation in a high shear mixer are examined during the liquid addition phase of the granulation process. The power consumption profiles of impeller motor are recorded. Five different binders (PVP, PVP-PVA-copolymer, hydrolysed gelatine and two HPMC'S) are investigated.

The PVP and hydrolysed gelatine produce granules with a higher mean granule size. This is shown to be due to the higher densification caused by these binders.

The power consumption profiles for PVP are significantly higher than for the other binder solutions. It is suggested that the high power consumption profiles are a result of the strength of mobile liquid bondings caused by the high surface tension of PVP solutions.     

Evaluation of Binder Activities on the Physical Properties and Compression Characteristics of Granules Prepared by Two Different Modes

Abstract

The effects of various binders and binder concentrations in production of granules by two different granulation modes were first investigated on the basis of the granule size distribution. Increasing the amount of binder produced larger and less friable granules associated with a decrease in flow rate and an increase in angle of repose. The strength of granules prepared by either the wet conventional or the fluidized bed was a function of its mean particle diameter and of binder-content with the later factor being more predominant. The inclusion of paracetamol into the placebo formula decreased the granule crushing strength. The effect was more pronounced with smaller granules and decreased with increasing granule size.

The rank order of the paracetamol-PVP granules crushing strength was reversed for the tensile strength of their corresponding tablets, viz., the paracetamol-PVP tablets prepared from fluidized granulation exhibited a higher tensile strength than that compressed from wet granules. A new parameter index “ø_b index” which combines tablet characteristics is presented. The index proposed allowed an overall simpler quantitative evaluation of a binder activity. Incorporated into this index are four tablet parameters, viz., tensile strength, percent porosity, median dissolution time, and percent friability. A higher “ø_b, index” infers better physical properties of tablets. Binders used in this study are then classified according to this index: PVP > gelatin > PEG 6000.     

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.     

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.