Influence of Granulating Method on Physical and Mechanical Properties,Compression Behavior,and Compactibility of Lactose and Microcrystalline Cellulose Granules

The physical and mechanical properties of lactose (LC) and microcrystalline cellulose (MCC) granules prepared by various granulating methods were determined, and their effects on the compression and strength of the tablets were examined. From the force-displacement curve obtained in a crushing test on a single granule, all LC granules appeared brittle, and MCC granules were somewhat plastically deformable. Intergranular porosity ε_inter clearly decreased with greater spherical granule shape for both materials. Decrease in intragranular porosity ε_intra enhanced the crushing force of a single granule F_g. Agitating granulation brought about the most compactness and hardness of granules. In granule compression tests, the initial slope of Heckel plots K₁ appeared closely related to ease of filling voids in a granule bed by the slippage or rolling of granules. The reciprocal of the slope in the succeeding step 1/K₂ in compression of MCC granules indicated positive correlation to F_g, while in LC granules, no such obvious relation was evident. 1/K₂ differed only slightly among granulating methods. Tensile strength of tablets T_t obtained by compression of various LC granules was low as a whole and was little influenced by granulating method. For MCC granules, which are plastically deformable, tablet strength greatly depended on granulation. Granules prepared by extruding or dry granulation gave strong tablets. Tablets prepared from granules made by the agitating method showed particularly low T_t. From stereomicroscopic observation, the contact area between granule particles in a tablet appeared smaller; this would explain the decrease in intergranular bond formation.     

Dextrose monohydrate as a non-animal sourced alternative diluent in high shear wet granulation tablet formulations

The feasibility of dextrose monohydrate as a non-animal sourced diluent in high shear wet granulation (HSWG) tablet formulations was determined. Impacts of granulation solution amount and addition time, wet massing time, impeller speed, powder and solution binder, and dry milling speed and screen opening size on granule size, friability and density, and tablet solid fraction (SF) and tensile strength (TS) were evaluated. The stability of theophylline tablets TS, disintegration time (DT) and in vitro dissolution were also studied. Following post-granulation drying at 60?°C, dextrose monohydrate lost 9% water and converted into the anhydrate form. Higher granulation solution amounts and faster addition, faster impeller speeds, and solution binder produced larger, denser and stronger (less friable) granules. All granules were compressed into tablets with acceptable TS. Contrary to what is normally observed, denser and larger granules (at ≥21% water level) produced tablets with a higher TS. The TS of the weakest tablets increased the most after storage at both 25?°C/60% RH and 40?°C/75% RH. Tablet DT was higher for stronger granules and after storage. Tablet dissolution profiles for 21% or less water were comparable and did not change on stability. However, the dissolution profile for tablets prepared with 24% water was slower initially and continued to decrease on stability. The results indicate a granulation water amount of not more than 21% is required to achieve acceptable tablet properties. This study clearly demonstrated the utility of dextrose monohydrate as a non-animal sourced diluent in a HSWG tablet formulation.     

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.     

Influence of granulating method on physical and mechanical properties, compression behavior, and compactibility of lactose and microcrystalline cellulose granules

The physical and mechanical properties of lactose (LC) and microcrystalline cellulose (MCC) granules prepared by various granulating methods were determined, and their effects on the compression and strength of the tablets were examined. From the force-displacement curve obtained in a crushing test on a single granule, all LC granules appeared brittle, and MCC granules were somewhat plastically deformable. Intergranular porosity ε_inter clearly decreased with greater spherical granule shape for both materials. Decrease in intragranular porosity ε_intra enhanced the crushing force of a single granule F_g. Agitating granulation brought about the most compactness and hardness of granules. In granule compression tests, the initial slope of Heckel plots K₁ appeared closely related to ease of filling voids in a granule bed by the slippage or rolling of granules. The reciprocal of the slope in the succeeding step 1/K₂ in compression of MCC granules indicated positive correlation to F_g, while in LC granules, no such obvious relation was evident. 1/K₂ differed only slightly among granulating methods. Tensile strength of tablets T_t obtained by compression of various LC granules was low as a whole and was little influenced by granulating method. For MCC granules, which are plastically deformable, tablet strength greatly depended on granulation. Granules prepared by extruding or dry granulation gave strong tablets. Tablets prepared from granules made by the agitating method showed particularly low T_t. From stereomicroscopic observation, the contact area between granule particles in a tablet appeared smaller; this would explain the decrease in intergranular bond formation.     

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.     

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.     

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.     

High-shear granulation of high-molecular weight hypromellose: effects of scale-up and process parameters on flow and compaction properties

Context: Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation.

Objective: The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer.

Methods: The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the ‘out-of-die’ Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High-shear granulation was performed at different scales: 4?L, 300?L, and 600?L.

Results and conclusion: The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction.     

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.     

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.     

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.     

High shear wet granulation: Improved understanding of the effects of process variables on granule and tablet properties of a high-dose,high-hydrophobicity API based on quality by design and multivariate analysis approaches

High shear wet granulation (HSWG), as a widely used granulation technology, has been studied extensively. However, for the HSWG of formulations containing hydrophobic components, the influence of process variables on the properties of granules and tablets has not been reported. In the present study, based on a combination of quality by design and multivariate analysis (MVA) approaches, quercetin with high-dose and high-hydrophobicity was used to study the relationship between process variables, granule properties, and tablet properties in HSWG systematically. Control and response variables were determined using risk assessment. The optimal fitting empirical models established by Box-Behnken design showed that the liquid to solid ratio and impeller speed were the most important factors, which affected all product properties except Carr’s index and yield pressure. Instead, the influence of wet massing time was relatively small (only the effects on yield, granule size, granule hardness, and compression ratio were significant). Then, the process design space was obtained by limiting the related critical quality attributes, which was verified effectively. Scanning electron microscope images showed that smooth granules were produced using higher process parameters, whereas rough and porous granules resulted at lower process parameters. Furthermore, the MVA results demonstrated that increasing the granule hardness led to an increase in the compression ratio and a decrease in tensile strength of the tablets. Tablet fragility and disintegration time were mainly affected by granule density and bulk density, respectively, and both were negatively correlated. The established research paradigm is not only conducive to the successful development of quercetin products, but also provides valuable guidance for improving HSWG–based product development with such formulation characteristics.     

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     

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.     

Physical Properties of Granules Containing Polysorbate 80

Abstract

The friability and crushing load of granules containing polysorbate 80 were determined. It was found that while polysorbate 80 decreased granule hardness, as indicated by the load required to crush it, friability values increased to a maximum then decreasing at higher polysorbate 80 concentration. Thus the use of granule friability to measure granule strength may be erroneous unless good correlation between granule friability and direct crushing weight was obtained.

Direct measurement of granule strength tends to vary with granule shape and size giving a rather wide scatter of results. For overcoming this difficulty, tablet triturates could be prepared and the crushing strength determined. The crushing strength of the tablet triturates was found to be similar to that of granules but with a smaller scatter and more easily handled.

Studies of other physical properties of the granules containing polysorbate 80 were also made. Small amounts of the nonionic surfactant (0.002 - 0.2%) generally improved granule fluidity as characterised by the orifice flow velocity and the angle of repose of the granules.     

The Effect of Lubricants on the Properties of Chloroquine Phosphate Tablets

Abstract

The properties of tablets prepared from different size fractions of chloroquine phosphate granules using different lubricants were evaluated. Lubricants used were magnesium stearate, stearic acid and talc, tablet properties studied include weight variation, crushing strength, friability and disintegration time

The effects obtained were largely dependent on the type and concentration of lubricant. Generally, as granule size increased, tablets were found to show increased weight variation, decreased hardness and increased friability. With tablets containing talc as lubricant, disintegration time was shown to decrease with increase in granule size.

There appears to be an optimum lubricant concentration for the compression of different granule size fractions.     

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.     

Effect of fill level in continuous twin-screw granulator: A combined experimental and simulation study

Twin-screw granulators for continuous wet granulation have attracted interest in the pharmaceutical industry. The physical properties of granules and tablets prepared through the twin granulation process depend on several factors, such as screw and barrel geometries, operating conditions, and formulations of raw materials. The fill level has been reported to be one of the most important factors in determining granule properties. However, the mechanism of the fill level effect on granule properties has not yet been fully clarified. In this study, the effects of the fill level in the twin-screw granulator on granule and tablet properties were investigated through a combination of experimental and simulation studies. In the experiment, temporal changes in the fill level were directly measured. It was found that a high fill level increased granule strength, resulting in large tablet hardness. The discrete element method simulations demonstrated that the compressive force on the particles in the granulator strongly depends on the fill level. In addition, by combining the experimental and simulation results, it was quantitatively revealed that a high fill level increased the interparticle adhesion, leading to the high hardness of tablets prepared with the granules.