Effect of Sieve Size for wet and Dry Screening on the Physical Properties of Lactose Granules and Their Corresponding Tablets

Abstract

Various batches of lactose granules were prepared by wet granulation process using acacia, cassava starch and polyvinylpyrrolidone separately as binders by inter-changing sieves for wet and dry screening, The effects of wet and dry screen aperture sizes together with the effects of the binders used on the physical properties of such granules and the corresponding tablets were investigated. The bulk volume of granules was found to be increased as the aperture size of sieves for dry screening increased while keeping a particular sieve constant for wet screening. No significant difference was observed with regards to the effect of sieve size upon the flow rate.

It was also observed that keeping the sieve size for wet screening constant, the mean tablet weight increased while the tablet weight variation decreased as the sieve size for dry screening decreased. There found to be an observable relationship between the sieve sizes used for dry and wet screening, average granule size and hardness of tablets. When a particular sieve was kept constant for wet screening, an increase in the sieve aperture size for dry screening resulted in an increase in average granule size and a decrease in tablet hardness. This may be due to increase in void space, decrease in die fill and less bonding between the granules. The disintegration time of the tablets was found to be significantly influenced by the sieve size combination used for wet and dry screening. When sieves for wet screening were kept constant, an increase in the sieve size for dry screening generally produced tablets of lower disintegration time.     

Influence of Metronidazole Particle Properties on Granules Prepared in a High-Shear Mixer-Granulator

ABSTRACT

Metronidazole is a good example of high-dose drug substance with poor granulating and tableting properties. Tablets are generally produced by liquid granulation; however, the technological process failure is quite frequent. In order to verify how the metronidazole particle characteristics can influence granule properties, three metronidazole batches differing for crystal habit, mean particle size, BET surface area and wettability were selected, primarily designed according to their different elongation ratio: needle-shaped, stick-shaped, and isodimensional. In the presence of lactose monohydrate and pregelatinized maize starch, respectively as diluent and binder, they were included in a formula for wet granulation in a high-shear mixer-granulator. In order to render the process comparable as far as possible, all parameters and experimental conditions were maintained constant. Four granule batches were obtained: granules from placebo (G-placebo), granules from needle-shaped crystals (G-needle-shaped), granules from stick-shaped crystals (G-stick-shaped), and granules from isodimensional crystals (G-isodimensional). Different granule properties were considered, in particular concerning porosity, friability, loss on drying (LOD), and flowability. In order to study their tabletability and compressibility, the different granules obtained were then compressed in a rotary press. The best tabletability was obtained with the isodimensional batch, while the poorest was exhibited by the stick-shaped one. Differences in tabletability are in good accordance with compressibility results: to a better tabletability corresponds an important granule ability to undergo a volume reduction as a result of an applied pressure. In particular, it was proposed that the greatest compressibility of the G-isodimensional must be related to the greatest granule porosity percentage.     

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.     

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.     

An Evaluation of Process Variables in wet Granulation

Abstract

In wet granulation, determining the process variables which play an essential role in granule quality is crucial for optimizing the manufacturing process. An L16(2⁵) fractional factorial experimental design using the table of orthogonal arrays was employed in order to estimate the relative intensity of the influences of five process variables on granule quality in wet granulation using a high-speed mixer granulator. Total volume and formulation of binder solution, blade rotation speed, granulation time, and amount of powder supplied into the granulator were selected as decisive process variables in the formation of granules. Granule yield, geometrical mean granule size and uniformity of granule size were evaluated as representative properties of granule quality. Experimental results were analyzed according to the analysis of variance (ANOVA).

The results of significance test and contribution ratio in ANOVA indicated that, within the experimental region, only binder solution had a critical effect on the three physical properties of the obtained granules. The effects of other variables were found to be minimal. Further, the contribution of sampling error to total variance was quite small.     

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.     

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.     

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.     

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.     

Investigation of the effect of impeller speed on granules formed using a PMA-1 high shear granulator

Impeller speed was varied from 300 to 1500?rpm during the wet high shear granulation of a placebo formulation using a new vertical shaft PharmaMATRIX-1 granulator. The resulting granules were extensively analysed for differences caused by the varying impeller speed with emphasis on flowability. Microscopy showed that initial granules were formed primarily from microcrystalline cellulose at all tested impeller speeds. At low impeller speed of 300?rpm in the "bumpy" flow regime, forces from the impeller were insufficient to incorporate all the components of the formulation into the granules and to promote granule growth to a size that significantly improved flowability. The "roping" flow regime at higher impeller speeds promoted granule growth to a median particle size of at least 100 μm that improved the flowability of the mixture. Particle size distribution measurements and advanced indicators based on avalanching behavior, however, showed that an impeller speed of 700?rpm produced the largest fraction of optimal granules with the best flowability potential. This impeller speed allowed good development of "roping" flow for sufficient mixing, collision rates and kinetic energy for collisions while minimizing excessive centrifugal forces that promote buildup around the bowl perimeter.     

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.     

Investigation of the effect of impeller speed on granules formed using a PMA-1 high shear granulator

Impeller speed was varied from 300 to 1500?rpm during the wet high shear granulation of a placebo formulation using a new vertical shaft PharmaMATRIX-1 granulator. The resulting granules were extensively analysed for differences caused by the varying impeller speed with emphasis on flowability. Microscopy showed that initial granules were formed primarily from microcrystalline cellulose at all tested impeller speeds. At low impeller speed of 300?rpm in the “bumpy” flow regime, forces from the impeller were insufficient to incorporate all the components of the formulation into the granules and to promote granule growth to a size that significantly improved flowability. The “roping” flow regime at higher impeller speeds promoted granule growth to a median particle size of at least 100 µm that improved the flowability of the mixture. Particle size distribution measurements and advanced indicators based on avalanching behavior, however, showed that an impeller speed of 700?rpm produced the largest fraction of optimal granules with the best flowability potential. This impeller speed allowed good development of “roping” flow for sufficient mixing, collision rates and kinetic energy for collisions while minimizing excessive centrifugal forces that promote buildup around the bowl perimeter.     

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

Abstract

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.     

Influence of metronidazole particle properties on granules prepared in a high-shear mixer-granulator

Metronidazole is a good example of high-dose drug substance with poor granulating and tableting properties. Tablets are generally produced by liquid granulation; however, the technological process failure is quite frequent. In order to verify how the metronidazole particle characteristics can influence granule properties, three metronidazole batches differing for crystal habit, mean particle size, BET surface area and wettability were selected, primarily designed according to their different elongation ratio: needle-shaped, stick-shaped, and isodimensional. In the presence of lactose monohydrate and pregelatinized maize starch, respectively as diluent and binder, they were included in a formula for wet granulation in a high-shear mixer-granulator. In order to render the process comparable as far as possible, all parameters and experimental conditions were maintained constant. Four granule batches were obtained: granules from placebo (G-placebo), granules from needle-shaped crystals (G-needle-shaped), granules from stick-shaped crystals (G-stick-shaped), and granules from isodimensional crystals (G-isodimensional). Different granule properties were considered, in particular concerning porosity, friability, loss on drying (LOD), and flowability. In order to study their tabletability and compressibility, the different granules obtained were then compressed in a rotary press. The best tabletability was obtained with the isodimensional batch, while the poorest was exhibited by the stick-shaped one. Differences in tabletability are in good accordance with compressibility results: to a better tabletability corresponds an important granule ability to undergo a volume reduction as a result of an applied pressure. In particular, it was proposed that the greatest compressibility of the G-isodimensional must be related to the greatest granule porosity percentage.     

Effect of Sieve Size for wet and Dry Screening on the Physical Properties of Lactose Granules and Their Corresponding Tablets

Various batches of lactose granules were prepared by wet granulation process using acacia, cassava starch and polyvinylpyrrolidone separately as binders by inter-changing sieves for wet and dry screening, The effects of wet and dry screen aperture sizes together with the effects of the binders used on the physical properties of such granules and the corresponding tablets were investigated. The bulk volume of granules was found to be increased as the aperture size of sieves for dry screening increased while keeping a particular sieve constant for wet screening. No significant difference was observed with regards to the effect of sieve size upon the flow rate.

It was also observed that keeping the sieve size for wet screening constant, the mean tablet weight increased while the tablet weight variation decreased as the sieve size for dry screening decreased. There found to be an observable relationship between the sieve sizes used for dry and wet screening, average granule size and hardness of tablets. When a particular sieve was kept constant for wet screening, an increase in the sieve aperture size for dry screening resulted in an increase in average granule size and a decrease in tablet hardness. This may be due to increase in void space, decrease in die fill and less bonding between the granules. The disintegration time of the tablets was found to be significantly influenced by the sieve size combination used for wet and dry screening. When sieves for wet screening were kept constant, an increase in the sieve size for dry screening generally produced tablets of lower disintegration time.     

Preparation of Essential Oils Loaded Granule by Melt Granulation

Abstract

A comparative study on three granulation methods; melt granulation, fluidized bed granulation and wet granulation was performed to fabricate an essential oils loaded granule. The granule properties such as particle size distribution and the loading efficiency of anethole from fennel and cinnamaldehyde from cinnamon showed that the melt granulation in a high shear mixer was the most feasible method among the three methods.

In melt granulation, the granule particle size was well controlled by polyethylene glycol 6000 (PEG) content of which the optimum value was found to De 20%. Impeller speed and massing time in high shear mixer had small contribution to the particle growth when PEG content was optimized, while PEG particle size had some effect. Finer PEG powder improved the uniformity of granule size. Moreover, the cooling method of the hot mass affected the final granule properties significantly. The cooling with a fluid bed dryer was the best method.

Both of the retention rates of anethole and cinnamaldehyde in the final granule were more than 95% of initial doses irrespective of cooling method. Further, the adoption of a fluid bed dryer enabled very rapid cooling of hot granule with negligible loss of essential oils.     

Effect of Granulating Method on Particle Size Distribution of Granules and Disintegrated Tablets. I

Abstract

The average particle size and distribution of granules were found to be dependent on the granulating method. The slugging method produced the widest particle size distribution and the largest average particle size, while the microgranulating method produced the narrowest distribution and the smallest average particle size. The average particle size of dexamethasone granules produced by wet granulating, microgranulating and slugging methods, were reduced on compaction by fragmentation. Of the three, the granules prepared by the slugging method, exhibited maximal average size reduction on compaction. On the other hand, the average particle size of sulfadiazine microgranulates and sulfadiazine slugs were enlarged by consolidation during compaction.     

Formulation and Evaluation of Insulin Dry Powder for Inhalation

Abstract

Purpose. Dry powder formulation of insulin for pulmonary administration was prepared to obtain increased drug deposition in the alveolar absorptive region. The deposition was studied by investigating the dispersion and deaggregation of insulin from the carrier lactose using an Andersen cascade impactor and twin stage impinger. The subsequent absorption following the deposition was studied by in vivo method. Methods. Insulin in solution with absorption promoters was lyophilized. The powder was incorporated with lactose of different grades and their combinations as carriers to deliver using an inhaler device. Solid-state characteristics of the carrier as well as the drug powder were assessed by particle size and distribution measurement. The flow properties such as moisture content, powder density, angle of repose, and carr's compressibility index of the powder mixture were determined. The aerosol behavior of the powder was studied by dispersion using rotahaler^© connected to a twin-stage impinger (TSI) and an eight-stage Andersen cascade impactor (ACI) operating at different flow rates of 30–90 l/min. The in vivo performance was studied by deliverance to the respiratory tract of guinea pigs. The intratracheal bioavailability with respective to intravenous route was calculated by measuring the blood glucose reduction. Results. The coarser particles of lactose in fractions of carrier containing a wide particle size distribution impacted in the preseperator of cascade impactor, and only the particle less than 10 µm size entered stage 0–stage 7. Formulation containing 1:1 mixture of Respitose ML006 (62%<50 µm) and Respitose ML003 (37.8%<50 µm) as carrier imparts well deaggregation of insulin, and higher deposition leads to 52.3% of fine particle fraction at 60 Lit/min and in vivo bioavailability of 82%. Conclusions. Insulin formulations containing 1:1 mixture of Respitose ML006 and Respitose ML003 as carrier can impart deeper deposition of drug particles and cause higher bioavailability. This suggests that carrier used in the formulation influenced the amount of insulin deposition in the alveolar region of the lung. Hence, it was concluded that the availability of insulin for systemic absorption depends on the particle size of the drug as well as the carrier lactose.     

Evaluation of Microwave Drying for Pharmaceutical Granulations

Abstract

The experiments were designed to compare the granule characteristics following the microwave drying and conventional tray drying. The formulations were designed to study the effect of microwave radiation under different conditions. This later criterion was studied by using granules prepared with different granulating fluids. The granules were prepared by using sulfathiazole as a model drug, lactose as a diluent, and starch as a disintegrating agent. The granulating fluids were 5% solution of PVP in 100% water, 50% water 50% ethanol, and 100% ethanol, respectively. The granules were dried in a microwave oven and in a conventional tray oven at 40±2° C. The loose and bulk densities were measured in a 100 ml glass cylinder. The granule morphology was examined using a scanning electron microscope. Dissolution rates of the granules were monitored using a rotating paddle dissolution apparatus. The loose and tapped bulk densities, the percentage compressibility, hardness, and the time required for 100% dissolution of the granules dried in the microwave oven and in the conventional tray oven were not significantly different (p>0.05). The scanning electron micrographs of the granules also showed no evidence of morphological changes or thermal damage to the granule surface or interior. In conclusion, the microwave radiation has no significant effect on the granules' characteristics.     

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.