Pharmaceutical Statistics: Practical and Clinical Applications,. Third Edition, Sanford Bolton. Handbook of Pharmaceutical Granulation Technology, edited by. Handbook of Pharmaceutical Granulation Technology DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and. Handbook of Pharmaceutical Granulation Technology DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs Executive.
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Handbook of Pharmaceutical. Granulation Technology. Second Edition edited by. Dilip M. Parikh. Synthon Pharmaceuticals Inc. Research Triangle Park, North. Handbook of Pharmaceutical Granulation Technology DownloadPDF MB Read online. The Third Edition presents all pharmaceutical. In addition, all chapters in the Handbook of Pharmaceutical Granulation Technology explore the fundamentals of powder characterization, granulation, and.
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Ensuring Better Control of Granulation
Statistisches Bundesamt Wiederschein, Harald 21 July Further agitation densifies the pendular bodies to form the capillary state, and these bodies act as nuclei for further granule growth .
Nuclei can grow in two possible ways: either single particles can be added to the nuclei by pendular bridges, or two or more nuclei may combine. The combined nuclei will be reshaped by the agitation of the bed.
This stage is characterized by the presence of a large number of small granules with a fairly wide size distribution. If agitation is continued, granule coalescence will continue and produce an unusable, over-massed system, although this is dependent upon the amount of liquid added and the properties of the material being granulated . There are four possible mechanisms of ball growth, which are illustrated in Figure 1 : Coalescence.
Two or more granules join to form a larger granule.
Granules break into fragments which adhere to other granules, forming a layer of material over the surviving granule. When a second batch of powder mix is added to a bed of granules, the powder will adhere to the granules, forming a layer over the surface and increasing the granule size. Abrasion Transfer. Agitation of the granule bed leads to the attrition of material from granules. This abraded material adheres to other granules.
This requires two pieces of equipment, a machine for compressing the dry powders into compacts or flakes, and a mill for breaking up these intermediate products into granules. The dry method may be used for drugs that do not compress well after wet granulation, or those which are sensitive to moisture. Wet Granulation. In this method, the wet mass is forced through a sieve to produce wet granules which are then dried.
A subsequent screening stage breaks agglomerates of granules. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required. Because direct compressing is not the best technology for many active substances, wet granulation is still a preferred method.
Even if the active substance is sensitive to hydrolysis, modern equipment e. High-shear mixers may exhibit a narrow margin between the liquid required to obtain granule growth and the amount that results in an over-wetted mass. Because of the intensive wet massing and densification of the granules, less liquid is normally required with high- than with low-shear mixers .
In addition, impeller rotation speed influences the liquid requirements, as does evaporation of the solvent, usually water, in the binder solution. Especially with high-shear mixers, intense agitation results in a temperature rise and loss of solvent by evaporation.
Effects of Raw Material Properties. The following properties influence granule formation and growth: Contact angle of the binder liquid to the solids Solubility of the particles in the binder liquid Mean particle size and size distribution of the solids Particle shape and surface morphology Packing properties of the solids Raw materials must have good wetting properties if there is to be uniform liquid distribution and, hence, controlled granule growth.
The smaller the particle size of the raw material, the more binder liquid required. Binder Properties Binder Concentration. The binder forms an internal matrix; consequently, the granule strength and tablet strength increase as binder concentration increases.
Mechanical Properties of Binder.
The mechanical properties of the binder determine binder strength and deformation behavior of the binder matrix. Properties of Drug and Other Excipients in the Formulation Wet granulation depends upon wetting of powder by the binder solution, surface tension of lenticular bridge films formed and solution viscosity. Binder Distribution.
The processing method used to distribute the binder influences binder efficiency. Endpoint Determination Endpoint can be defined as a target particle size mean or distribution. Traditional Methods a Power Consumption. Power consumption of the mixer motor for end-point determination and scale-up is widely used because the measurement is economical, does not require extensive mixer modifications and is well correlated with granule growth .
Intragranular porosity also shows some correlation with power consumption.
Normalized work of granulation power profile integrated over time can accurately determine endpoints and is correlated well with properties of granulates. Direct torque measurement requires installation of strain gauges on the impeller shaft or on the coupling between the motor and impeller shaft. Since the shaft is rotating, a device called a slip ring is used to transmit the signal to the stationary data acquisition system.
A torque rheometer provides an off-line measurement of torque required to rotate the blades of the device and can be used to assess rheological properties of the granulation. It has been extensively used for endpoint determination.
As the impeller shaft rotates, the motor tries to rotate in the opposite direction, but does not because it is bolted in place. The tensions in the stationary motor base can be measured by a reaction torque transducer. When agglomeration is progressing very rapidly, neither power consumption nor torque on the impeller may be sensitive enough to adequately reflect material changes. Some investigators feel that other measurements, such as torque or force on the impeller blades, may be better suited to monitor such events.
There are other ideas floating around—for example, use of neural networks to describe and predict the behavior of the wet granulation  or control of the endpoint by a rapid image processing system . Powder flow patterns in wet granulation can be studied using positron emission particle tracking .
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Emerging Technologies a Acoustic. Applicability of piezo-electric acoustic emission sensors to endpoint determination has been studied since the beginning of this century . The technique is very promising, especially since it is non-invasive, sensitive and relatively inexpensive.
Granulation process signatures obtained with an acoustic transducer can be used to monitor changes in particle size, flow and compression properties. Use of a refractive NIR moisture sensor for endpoint determination of wet granulation has been described by several authors . There are technological challenges associated with this approach, as the sensor can only measure the amount of water at the powder surface.
Focused beam reflectance measurement FBRM is a particle-size determination technique based on a laser beam focusing in the vicinity of a sapphire window of a probe . When it intersects with the edge of a particle passing by the window surface, an optical collector records a backscatter signal.
The time interval of the signal multiplied by the beam speed represents a chord length between two points on the edge of a particle. The chord length distribution CLD can be recalculated to represent either a number or volume-weighted particle size distribution. In many cases, CLD measurements are adequate to monitor dynamic changes in process parameters related to particle size and shape, concentration and rheology of fluid suspensions.
Processing-Induced Transformations in Wet Granulation The physicochemical properties of pharmaceuticals, including solubility and dissolution rate, can be influenced by the degree of crystallinity, solvation state and crystal form . Problems related with wet granulation include: Hydrate Formation. Tablets prepared using the metastable form dissolve at a slower rate than those containing the stable polymorph.
Thus, processing-induced phase transformations significantly influence the dissolution behavior of theophylline tablets. For online monitoring of the transformation from one form to another, Raman spectroscopy is most widely used.
Granulation techniques and technologies: recent progresses
Polymorphic Transformation. NIR is used to monitor the blending of the starting materials. Raman spectroscopy, NIR, and x-ray powder diffraction have been used in the characterization of polymorphic changes during the process. References Henning, G, Torben, S. Granulation, In: Encyclopedia of Pharmaceutical Technology.
Marcel Dekker. New York.
Augsburger, L. Handbook of Pharmaceutical Granulation Technology. New York, 81 Summers, M.
Das, S, Jarowski, C. Effect of granulating method on particle size distribution of granules and disintegrated tablets.CRC Press, https: Investigations on the influence of the type of extruder for pelletization by extrusion—spheronization I.
The second important area of contribution involves the work of Rumpf and colleagues 20—22 , who studied the impact of interparticle force H, and in detail for capillary forces, on granule static tensile strength, or: Social Outsiders in Nazi Germany. John E. Handbook of Pharmaceutical Granulation Technology. An Engineering Perspective 25 Pages pages. Andrews, G. However, common to most processes is a specific granule size distribution and granule voidage.