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

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

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 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.     

The Granulation of Lactose and Starch in a Recording High-Speed Mixer,Diosna P25

Abstract

Lactose 100 mesh was granulated faster than the 350 mesh quality.

Corn starch required large volumes of granulating solution. When agglomerating pure corn starch, its loss on drying influenced the process.

Suitable limits for the end-point determination when granulating a mixture of 2/3 of lactose 100 mesh and 1/3 of corn starch, with povidone as binder, were determined for the liquid addition under controlled conditions.

In a 1/2 ? 2₆ factorial experiment, the influence of the process variables on the response variables was studied. The former are the main impeller and chopper speed; the method of fluid addition; the way of adding the binder; the volume of granulating liquid added, and the wet massing time. The response variables concerned are the fraction <0.150 or >2.00 mm; the granule median diameter; the change in the rotation rate of the impeller shaft; and heat production in the mass. The impeller and chopper speed, the way of adding the binder, and the volume of granulating solution that was added, influenced all the response variables significantly. However, the dominating variables were the volume of solution and the impeller rate. Besides, the granule median diameter was influenced by the method of fluid addition. Also, the heat production during granulation was influenced by the method of fluid addition as well as by the wet massing time.     

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.     

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

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.     

Use of in-line near-infrared spectroscopy in combination with chemometrics for improved understanding of pharmaceutical processes

High shear granulation is a complex unit operation with several interacting process parameters. No generally accepted real-time in-line tools are available to gain insight into this process, and in practice, a highly experienced process formulator and operator are needed to develop a wet granulated solid dosage form. In this study, the use of in-line near-infrared (NIR) spectroscopy as a process analytical tool for high shear granulation was investigated. In combination with principal component-based methods, process analysis of three separate phases of high shear wet granulation (mixing, spraying, and wet massing) was facilitated. Critical information, both chemical and physical, was collected during processing. Chemical information included the homogeneity of the formulation and the amount of water in wet mass. In addition, physical information related to the particle size of granules was extracted. Principal component loadings were fully interpreted to validate the conclusions drawn from scores and predictions. Thus NIR spectroscopy could be used to determine the end points of the three subphases of high shear wet granulation and, as such, provide a fast in-line quality control tool.     

New gentle-wing high-shear granulator: impact of processing variables on granules and tablets characteristics of high-drug loading formulation using design of experiment approach

The aim of this work was to study the application of design of experiment (DoE) approach in defining design space for granulation and tableting processes using a novel gentle-wing high-shear granulator. According to quality-by-design (QbD) prospective, critical attributes of granules, and tablets should be ensured by manufacturing process design. A face-centered central composite design has been employed in order to investigate the effect of water amount (X₁), impeller speed (X₂), wet massing time (X₃), and water addition rate (X₄) as independent process variables on granules and tablets characteristics. Acetaminophen was used as a model drug and granulation experiments were carried out using dry addition of povidone k30. The dried granules have been analyzed for their size distribution, density, and flow pattern. Additionally, the produced tablets have been investigated for; weight uniformity, breaking force, friability and percent capping, disintegration time, and drug dissolution. Results of regression analysis showed that water amount, impeller speed and wet massing time have significant (p?相似文献   

Effect of Primary Particle Size on Granule Growth and Endpoint Determination in High Shear Granulators

ABSTRACT

Three different grades of lactose monohydrate having widely differing mean particle sizes, yet similar tap densities, were granulated using a 25L instrumented Fielder mixer. The size distribution, porosity, and pore saturation of the wet granules were determined using a combination of “frozen granule” sieve analysis, mercury pycnometry, and oven drying. The granulating system was found to operate at quasi-steady-state, as granule growth ceased afler liquid addition was terminated. The resultant granule size distributions were strongly dependent on lactose grade. with coarser grades yielding larger granules for identical process conditions. In contrast. the magnitude of the power curves decreased with increasing primary particle size. Both of these observations are consistent with the fact that both the capillary and viscous interparticle fluid forces, which are believed to provide the main interparticle bonding forces in the wet mass, are inversely proportional to particle size.     

Agglomeration process of dry ice particles produced by expanding liquid carbon dioxide

Formation of dry ice particles and their agglomeration process have been studied experimentally. The dry ice particles were produced by expanding liquid carbon dioxide at room temperature and pressure, and then introduced into an additional tube acting as an agglomeration chamber. In the experiments, the temperatures of the jet flow and the tube wall were measured by thermocouples, and dry ice particles in the jet flow were observed by a high speed camera with a zoom lens. It was found that two stages of temperature reduction occurred in the jet flow, corresponding to the agglomeration process. It was also found that the particle size of the agglomerates increased and the particle velocity decreased with increasing tube diameter. The agglomeration process of dry ice particles can be explained by the particle deposition and reentrainment, i.e. dry ice particles of several micrometers are deposited on the tube wall and form a deposition layer; then, agglomerates are reentrained from the layer into the jet flow.     

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.     

Assessment of granulation technologies for an API with poor physical properties

Granulation technologies are widely used in solid oral dosage forms to improve the physical properties during manufacture. Wet, dry, and melt granulation techniques were assessed for Compound A, a BCS class II compound. Characterization techniques were used to quantify physical property limitations inherent for Compound A including hygroscopicity, low solubility and bulk density, and poor powder flowability. High shear aqueous wet granulation induced an undesirable water mediated phase transition of the solid form. A formulation and process for dry granulation by roller compaction was developed and scaled to 10 kg batch size. Roll force, and roll gap parameters were assessed. Porosity of compacted ribbons was analyzed by mercury intrusion porosimetry, and particle size distributions of milled ribbons by sieve analysis. A roll force of 15 kN/cm produced granules with higher density and improved flow properties compared to the pre-blend. Fines content (<75 µm) decreased from approximately 90% pre-granulation to 26% post-granulation. Cohesive properties of Compound A limited drug loading (API:excipient ratio) in roller compaction to 0.6:1 or less. Hot melt granulation by extrusion assessed with four polymers. A vast improvement in drug loading of 4:1 was achieved via melt processes using low molecular weight thermo-binders (glyceryl behenate and Polyethylene glycol 4000). Granules produced by melt processing contained less fines compared to wet and dry granulation. Both roller compaction and melt extrusion are viable granulation process alternatives for scale up to overcome the physical property limitations of Compound A.     

Compressibility Characteristics of Matrices Prepared with Ethylcellulose Aqueous Dispersion

Granules of acetaminophen (APAP) and Lactose Fast Flo were prepared by wet granulation method using Surelease aqueous dispersion as a granulating liquid. Acetaminophen granules containing different total solids (from Surelease) were compacted into tablets using instrumented tablet press to investigate the effect of the levels of Surelease (total solids) on the compressional properties of various formulations. Measurements were made of their compressibility, force displacement, works and forces analysis during compaction. All formulations containing Surelease utilized the compaction energy better than formulations of the same composition prepared without Surelease. As the level of total solids from Surelease was increased in the formula, the compressibility characteristic was enhanced. Granules with Surelease exhibited better deformation and densification behaviors and gave tablets of better mechanical strength compared to control tablets.     

Fluidized Bed Granulation with Pvp K90 and Pvp K120

The characteristics and growth mechanisms of fluidized bed granules are dependent both on process variables and the grades of PVP binders used. Generally, an increase in the concentration, spraying rate and volume of binder solution caused an increase in granule size and a decrease in size distribution. These two factors will in turn affect the poured and tapped densities of granules. Granules prepared with PVP K90 solution appeared to grow by primary and secondary agglomeration to give an aggregate structure. Granules prepared with PVP K120 solution were formed through snowballing as the primary agglomeration process. This occurred at low binder solution concentration with secondary agglomeration taking place when the concentration of PVP K120 solution was increased.     

Compressibility Characteristics of Matrices Prepared with Ethylcellulose Aqueous Dispersion

Abstract

Granules of acetaminophen (APAP) and Lactose Fast Flo were prepared by wet granulation method using Surelease aqueous dispersion as a granulating liquid. Acetaminophen granules containing different total solids (from Surelease) were compacted into tablets using instrumented tablet press to investigate the effect of the levels of Surelease (total solids) on the compressional properties of various formulations. Measurements were made of their compressibility, force displacement, works and forces analysis during compaction. All formulations containing Surelease utilized the compaction energy better than formulations of the same composition prepared without Surelease. As the level of total solids from Surelease was increased in the formula, the compressibility characteristic was enhanced. Granules with Surelease exhibited better deformation and densification behaviors and gave tablets of better mechanical strength compared to control tablets.     

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.     

Granulation of Lactose in a Domestic-Type Mixer

When process variables controlling the droplet size and the distribution of the granulating liquid in the powder, i.e. the liquid flow rate, the way of adding the liquid and the wet massing time, are controlled during the granulation of lactose 350 mesh with water in a recording laboratory mixer, the amount of water added determines the torque of the mixing bowl. The torque value can be used as an indication of the granule size.     

Continuous high-shear granulation: Mechanistic understanding of the influence of process parameters on critical quality attributes via elucidating the internal physical and chemical microstructure

Over the past decade, continuous wet granulation has been emerging as a promising technology in drug product development. In this paper, the continuous high-shear mixer granulator, Lӧdige CoriMix® CM5, was investigated using a low-dose formulation with acetaminophen as the model drug. Design of experiments was deployed in conjunction with multivariate data analysis to explore the granulator design space and comprehensively understand the interrelation between process parameters and critical attributes of granules and tablets. Moreover, several complementary imaging techniques were implemented to unveil the underlying mechanisms of physical and chemical microstructure in affecting the tablet performance. The results indicated that L/S ratio and impeller speed outweighed materials feeding rate in modifying the granule and tablet properties. Increasing the degree of liquid saturation and mechanical shear input in the granulation system principally produced granules of larger size, smaller porosity, improved flowability and enhanced sphericity, which after compression generated tablets with slower disintegration process and drug release kinetics due to highly consolidated physical microstructure. Besides, in comparison to batch mixing, continuous mixing integrated with a conical mill enabled better powder de-agglomeration effect, thus accelerating the drug dissolution with increased surface area.     

Effect of Raw Materlals and Processing on the Quality of Granules Prepared from Microcrystalline Cellulose-Lactose Mixtures

Wet granulation, using lactose as an excipient, is widely used in the pharmceutical industry. The use of micro-crystalline cellulose, as part of the excipient, may offer several advantages. The purpose of this work is to investigate the effect of ingredients and processing variables on granule quality. For these studies, only two-component system granulated with water in a planetary mixer were considered. The variables studied included the volume of granulating solution, type of lactose, dissolved material (other than binder) in the granulating solution, massing time, mesh size for wet screening and drying technique (oven and fluidized bed drying).