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.

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 [5]. 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 [14].

Intragranular porosity also shows some correlation with power consumption.

Shop Handbook Of Pharmaceutical Granulation Technology

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 [16] or control of the endpoint by a rapid image processing system [17].


Powder flow patterns in wet granulation can be studied using positron emission particle tracking [18]. Emerging Technologies a Acoustic. Applicability of piezo-electric acoustic emission sensors to endpoint determination has been studied since the beginning of this century [19].

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 [20]. 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 [21]. 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 [22].

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.

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. Cambridge; Oxford: Cambridge University Press.

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The liver features you chose Messiah Interestingly in a Two-Day malware. Please Remember own e-mail wars. Social Outsiders in Nazi Germany. Princeton University Press. United States Holocaust Memorial Museum.

Statistisches Bundesamt Wiederschein, Harald 21 July An Engineering Perspective 6 Bryan J. Heng 4. Wendell 6. Supercritical Fluid Technology Martin A.


Wahl 7. Roller Compaction Technology Ronald W. Miller 9. Trivedi Parikh and David M. Jones Erkoboni Effervescent Granulation Guia Bertuzzi Granulation Characterization Cecil W. Propst Bioavailability and Granule Properties Sunil S.

Jambhekar Granulation Process Modeling Ian T. Cameron and Fu Y. Wang Liu, James D. Litster, and Defne Kayrak-Talay Macias and M. Wendell Regulatory Issues in Granulation: Simmons Index xiv Contents Brzeczko Acura Pharmaceuticals, Inc.

Ian T. David F. China David M.

China James D. Lian X. Ronald W. Sree Nadkarni FibroGen Inc. Cecil W. John E. Namrata R. Martin A. China xvi Contributors The practice of delivering medicinal powder by hand rolling into a pill by using honey or sugar has been used for centuries.

It is still the practice to deliver the botanical and herbal extracts in homeopathic and ayurvedic branches of medicine, which are still practiced in India along with allopathic medicine.

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To obtain these ends is the intention of pharmacy. This method was further modified to make granules with very little heat or moisture, which can be placed on the tongue and washed over with water, which was a modification of the method of granulating gunpowder.

The granulated material can be obtained by direct size enlargement of primary particles or size reduction from dry, compacted material. In modern times, granulation technology has been widely used by a wide range of industries, such as chemical, coal, mining, metallurgy, ceramic, and agrochemical. The development of pharmaceutical granulation was driven by the invention of the tablet press by W.

Brockedon in Subsequent improvements in the tablet machinery were patented in the United States by J. McFerran , T. Young , and J. Dunton The demands on the granulation properties were further enhanced in the s as high-speed tablet and capsule-filling machines with automated controls were introduced.

The high-speed compression and capsule-filling machines require a uniform flow of material to the dies or filling stations that produce pharmaceutical dosage form.

Direct Compression The processing of drug substance with the excipients can be achieved without employing the process of granulation. By simply mixing in a blender, a directly compressible formulation can be processed and compressed in tablets or filled in the hard gelatin capsules. In the s, microcrystalline cellulose, as a directly compressible vehicle, was introduced.

The compressible formulation containing microcrystalline cellulose is suitable for a number of products. This has several obvious advantages, such as lower equipment cost, faster process time, and efficient operation involving only two process steps.

Sometimes, excipient costs may have to be compared against the savings in the processing steps and equipment by using alternate methods. There are, however, a number of products that cannot be directly compressed because of low dosage, or flow properties of the drug and excipient mixture.

Blend uniformity and the content uniformity in the drug product are critical attributes with low dose drug formulation. Other than content uniformity of a low-dose drug substance, there are a number of reasons why direct compression may not be suitable for a wide array of products.

Current Granulation Techniques and Research The classical granulation process using either wet or dry methods is employed in the process industries. Pharmaceutical granulation process is used for tablet, capsule, and spherical granules for the modified-release indications or to prepare granules as sprinkles to be used by pediatric patients. The reasons for granulating a pharmaceutical compound are well documented in the literature. Many researchers studied the influence of material properties of the granulating powders and process conditions on the granulation process in a rather empirical way.

In the s, fundamental approach to research was started on various topics in the granulation process, looking into more detailed aspects of particle wetting, mechanism of granulation, material properties, and influence of mixing apparatus on the product. The overall hypothesis suggested that the granulation can be predicted from the raw material properties and the processing conditions of the granulation process. One of the major difficulties encountered in granulation technology is the incomplete description of the behavior of powders in general.

The ongoing fundamental research on mixing, segregation mechanisms of powder, surface chemistry, and material science is necessary to develop the theoretical framework of granulation technology. An excellent review of the wet granulation process was presented by Iveson et al. The authors have advanced the understanding of the granulation process by stating that there are three fundamental sets of rate processes, which are important in determining wet granulation behavior.

These are wetting and nucleation, consolidation and growth; and breakage and attrition. Once these processes are sufficiently understood, then it will be possible to predict the effect of formulation properties, equipment type, and operating conditions of granulation behavior, provided these can be adequately characterized according to the reviewers. Five primary methods exist to form an agglomerated granule.

They are formation of solid bridges, sintering, chemical reaction, crystallization, and deposition of colloidal particles. Binding can also be achieved through adhesion and cohesion forces in highly viscous binders. Successful processing for the agglomeration of primary particles depends on proper control of the adhesional forces between particles, which encourage agglomerate formation and growth and provide adequate mechanical strength in the product.

Furthermore, the rheology of the particulate system can be critical to the rearrangement of particles necessary to permit densification of the agglomerate and the development of an agglomerate structure appropriate for the end-use requirements.

If the particles are close enough, then the surface forces such as van der Waals forces short range and electrostatic forces can interact to bond particles. Decreasing particle size increases surface-mass ratio and favors the bonding.

The cohesive forces that operate during the moist agglomerates are mainly due to the liquid bridges that develop between the solid particles. Electrostatic forces keep particles in contact long enough for another mechanism to govern the agglomeration process.

Dry compaction technique like roller compaction is experiencing renewed interest in the industry. There are a number of drug substances that are moisture sensitive and cannot be directly compressed. The roller compaction provides suitable alternative technology for processing these products. There are a number of products currently manufactured using these low-shear 2 Parikh The process control and efficiency have increased over the years; however, the industry has embraced high-shear granulators for wet granulation because of its efficient process reproducibility and modern process control capabilities.

Fluid-bed processors have been used in the pharmaceutical industry for the last 40 years, initially only as a dryer and now as a multiprocessor to granulate, dry, pelletize, and coat particles. The most preferred method of granulation is to use the high-shear mixer to granulate and use the fluid bed as a dryer in an integrated equipment setup. This provides the best of both technologies: Here again, the choice of this approach will be dependent on the product being processed and its desired properties at the end of the granulation process.

Handbook of Pharmaceutical Granulation Technology

These pellets can be produced as matrix pellets with the appropriate polymer or are coated in fluid-bed unit to produce modified-release dosage forms. Other techniques have been used by researchers such as steam granulation, using foam binder in place of liquid binders or moisture-activated dry granulation MADG where a small amount of moisture is added to the blend containing certain binders under constant mixing in high-shear mixer.

This process eliminates the need for processing of the granulation however, essentially suffers from the same shortcomings as would be encountered with direct compression blend. Table 1 lists the most common techniques to granulate a pharmaceutical compound in the industry. Granulation and Particle Design Granulation is an example of particle design. The desired attributes of the granule are controlled by a combination of the formulation and the process.

Spray drying technique is now routinely used to prepare particles for inhalation dosage forms or to create solid dispersions of poorly soluble drugs. Recent interest in nanotechnology research has opened up a number of avenues for creating newer drugs. Various development groups are working to enhance traditional oral delivery systems with nano-engineered improvements. There are some areas where nano-enhanced drugs could make a big difference in increasing oral bioavailability and reducing undesirable side effects.

By increasing bioavailability, nanoparticles can increase the yield in drug development and, more importantly, may help treat previously untreatable conditions. Another approach in the s was to use supercritical fluid technology to produce uniform particles to replace crystallization.

Even though supercritical fluids were discovered over years ago and the commercial plant was built over 20 years ago in the United States, it is only now that the technology is used for a number of pharmaceutical applications 4—7 so as to produce aspirin, caffeine, ibuprofen, acetaminophen, etc. When the supercritical fluid and drug solution make contact, a volume expansion occurs, leading to a reduction in solvent capacity, increase in solute saturation, and then supersaturation with associated nucleation and particle formation.

A number of advantages are claimed by using this platform technology such as particle formation from nanometers to tens of micrometers, low residual solvent levels in products, preparation of polymorphic forms of drug, etc. Attempts to make solid dosage forms of large molecules are under way even though there are numerous challenges. Current Industry Status and Challenges Efficient and cost-effective manufacturing of pharmaceutical products is being evaluated by the scientists, engineers, and operational managers of pharmaceutical companies worldwide.

Outsourcing allows these companies to pursue potential new revenue streams outside of their core focus areas and to benefit from improved productivity, emerging technologies, in-licensing opportunities, and increased growth. Consumers and local govern- ments in the United States are pressuring the FDA authorities and politicians to allow importation of the drugs from other countries where costs are generally lower than in the United States. Demands for price control also extend to Europe; government-backed pharmaceutical payment plans in Germany and Italy, for example, have cut back reimburse- ments.

Other European countries have controls on the drug prices. As a result of these pricing pressures and to enhance the drugs in the pipeline, mergers and acquisitions have accelerated.

Acquisitions remain the preferred route to quickly enhance a product portfolio. This trend of merging of equals or takeover of the significant biotechnological and technological companies will continue.

Major pharmaceutical companies are witnessing the end of traditional research and development. This has created emergence of small niche technology companies as well. Drug delivery companies are becoming potential targets for mergers or strategic alliances.

Because biologics are less susceptible to generic competition, big pharmaceutical companies are acquiring biotech companies as well. Table 2 lists the 12 biggest mergers that have taken place in — alone which shows how the industry is accelerating the acquisition approach. During all of the upheaval that the industry is going through, it is becoming obvious that the cost of development, production, and goods must be controlled.

The efficiencies in the research, development, and manufacturing, which were not necessarily sought after, are becoming the first priority of the pharmaceutical companies however small they may be in comparison to the final cost of the product to the consumer. The manufacturing of solid dosage product is no exception. The significant advances that have taken place in the pharmaceutical granulation technology are presented in this book to provide the readers with choices that are available.

The various techniques presented in this book will further help the scientists in their understanding and selection of the granulation process most appropriate for the drug substance. There is no substitute for good science. The characterization of the drug substance 4 Parikh Each drug substance poses a unique challenge that must be taken into consideration at the process selection stage by the scientists.

The optimization techniques due to availability of state of the art computers, process control, and mathematical techniques to model the granulation process will advance the traditional granulation technology. For production engineering, validation, and quality professionals in the industry, this book is intended to provide the fundamental understanding of the technique of granulation and the rationale behind the selection of each particular technique.

This will further enhance the ability to design the production plant, carry out the technology transfer, scale up, troubleshoot, and maintain the pharmaceutical granulation operation in accordance with regulatory compliance. Skinner T. The Granulation of medicines. Br Med J ; 1 Particle enlargement. Perry RH, Greens D, eds. New York: McGraw Hill, Nucleation, growth, and breakage phenomenon in agitated wet granulation process: Powder Technol ; Micronization by RESS to enhance the dissolution rates of poorly water soluble pharmaceuticals.

Rapid expansion of supercritical fluid solutions: Ind Eng Chem Res ; Precipitation of pure and mixed caffeine and anthracene by rapid expansion of supercritical solutions. Particle engineering for pharmaceutical applications—a process scale up. Fluid dynamics, mass transfer and particle formation in super critical fluids. Marcel Dekker, ; 91— Report identifies increasing outsourcing by pharma. September 29, Available at: Pharma Top 10 Deals of From Refs.

Introduction 5 An Engineering Perspective Bryan J. Granulation technology and size enlargement processes have been used by a wide range of industries, ranging from the pharmaceutical industry to fertilizer or detergent production to the mineral processing industries. Size enlargement generally encompasses a variety of unit operations or processing techniques dedicated to particle agglomeration.

These processes can be loosely broken down into agitation and compression methods. Although terminology is industry specific, agglomeration by agitation will be referred to as granulation. A particulate feed is introduced to a process vessel and is agglomerated, either batch-wise and continuously, to form a granulated product. Agitative processes include fluid bed, pan or disk , drum, and mixer granulators.

Such processes are also used as coating operations for controlled release, taste masking, and cases where solid cores may act as a carrier for a drug coating. The feed typically consists of a mixture of solid ingredients, referred to as a formulation, which includes an active or key ingredient, binders, diluents, flow aids, surfactants, wetting agents, lubricants, fillers, or end-use aids e.

A closely related process of spray drying is also included here, but discussed in detail elsewhere See Ref. Product forms generally include agglomerated or layered granules, coated carrier cores, or spray dried product consisting of agglomerated solidified drops.

An alternative approach to size enlargement is by agglomeration by compression, or compaction, where the mixture of particulate matter is fed to a compression device, which promotes agglomeration due to pressure. Either continuous sheets of solid material are produced or some solid form such as a briquette or tablet. Compaction processes range from confined compression devices, such as tabletting, to continuous devices, such as roll presses chap.

Some processes operate in a semicontinuous fashion such as ram extrusion. Capsule filling operations would be considered a low-pressure compaction process. At the level of a manufacturing plant, the size enlargement process involves several peripheral, unit operations such as milling, blending, drying or cooling, and classification, referred to generically as an agglomeration circuit Fig. In addition, more than one agglomeration step may be present.

In the case of pharmaceutical granulation, granulated material is almost exclusively an intermediate product form, which is then followed by tabletting.

In the context of granulation, therefore, it is important to understand compaction processes to establish desirable granule properties for tabletting performance. Numerous benefits result from size enlargement processes as summarized in Table 1.

A wide variety of size enlargement methods are available; a classification of available equipment and initial criteria of process selection is given in Tables 2 and 3.

A primary purpose of wet granulation, in the case of pharmaceutical processing, is to create free flowing, nonsegregating blends of ingredients of controlled strength, which may be reproducibly metered in subsequent tabletting or for vial or capsule filling operations.

The wet granulation process must generally achieve desired granule properties within some prescribed range. These However, common to most processes is a specific granule size distribution and granule voidage. Size distribution affects flow and segregation properties, as well as compaction behavior. Granule voidage controls strength, and impacts capsule and tablet dissolution behavior, as well as compaction behavior and tablet hardness.

Control of granule size and voidage will be discussed in detail throughout this chapter.

Handbook of Pharmaceutical Granulation Technology, Third Edition

The approach taken here relies heavily on attempting to understand interactions at a particle level, and scaling to bulk effects. Developing an understanding of these microlevel processes of agglomeration allows a rational approach to the design, scale-up, and control of agglomeration processes Figs.

Although the approach is difficult, qualitative trends are uncovered along the way, which aid in formulation development and process optimization, and which emphasize powder characterization as an integral part of product development and process design work.

Figure 1 A typical agglomeration circuit utilized in the processing of pharmaceuticals involving both granulation and compression techniques.

Table 1 Objectives of Size Enlargement Production of useful structural form Provision of a defined quantity for dispensing, with improved flow properties for metering and tabletting Improved product appearance Reduced propensity to caking Increased bulk density for storage and tabletting feeds.

Creation of nonsegregating blends with ideally uniform distribution of key ingredients. Control of solubility, and dissolution profiles. Control of porosity, hardness and surface to volume ratio and particle size Source: An Engineering Perspective 7 Able toprocessbrittle,abrasive,elastic,mostplasticmaterials. An Engineering Perspective 9 Granulation Mechanisms Four key mechanisms or rate processes contribute to granulation, as originally outlined by Ennis 4,5 , and later developed further by Litster and Ennis 6.

These include wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage Fig. Initial wetting of the feed powder and existing granules by the binding fluid is strongly influenced by spray rate or fluid distribution, as well as feed formulation properties, in comparison with Figure 2 The mechanisms or micro- level processes of compressive agglomeration or compaction.

These processes combined control compact strength, hardness, and porosity. From Ref. Figure 3 The mechanisms or rate processes of agitative agglomeration, or granulation, which include powder wetting, granule growth, granule consolidation, and granule attrition. These processes combine to control granule size and porosity, and they may be influenced by formulation or process design changes.

Wetting promotes nucleation of fine powders, or coating in the case of feed particle size in excess of drop size.

In the coalescence or growth stage, partially wetted primary particles and larger nuclei coalesce to form granules composed of several particles. The term nucleation is typically applied to the initial coalescence of primary particles in the immediate vicinity of the larger wetting drop, whereas the more general term of coalescence refers to the successful collision of two granules to form a new larger granule.Maibach Direct Compression The processing of drug substance with the excipients can be achieved without employing the process of granulation.

United States Holocaust Memorial Museum. These include wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage Fig. Formulation Vs. Brzeczko Acura Pharmaceuticals, Inc. At the other extreme, if drop penetration is slow and spray flux is large, drop coalescence and pooling of binder Figure 15 Influence of capillary penetration on drum granule size.

Material variables are specified by the choice of ingredients, or product formulation.