Pharmaceutics

Granulation, Generally, all of the particles are distributed in irregular manner, when particles create bond between them then granules are formed. To create bond between the particles is not automatic process, mechanical forces are applied to the particles or various types of binding agents are used to create granules. Granulation is simply a particle collecting process where particles are particles create bond between them by compression or with the help of binding agent.

List of binding agent used in pharmaceutical company in granulation process of different material-Various types of binders use in pharmaceutical industry such as-

Natural Binders

• Alginic Acid
• Acacia
• Cellulose
• Gelatin
• Pregelatinized Starch
• Starch Paste
• Tragacanth

Synthetic/Semisynthetic Polymer

• Ethyl Cellulose
• Hydroxy Propyl Methyl Cellulose (HPMC)
• Hydroxy Propyl Cellulose
• Methyl Cellulose
• Microcrystalline Cellulose
• Polyvinyl Pyrrolidone (PVP)
• Polyvinylcaprolactam
• Polyethylene Glycol (PEG)
• Polyvinyl Alcohols
• Polymethacrylates
• Sodium Carboxy Methyl Cellulose

Top Binder Manufacturer

• BASF Company
• Colorcon
• Dow Chemicals
• FMC Corporation
• Natural Starch and Chemical Company
• Penwest Pharmaceutical
• Quest International Group
• Wolff-Cellulosics

Most of the granules size distribute from 0.2 to 4.0mm and this size may be change based on their mode of use. Granulation process refers to the activity where particles are adhere to form larger and this repeated procedure create multiple particle entities called granules. Granules are formed from series of primary particle, after completion of the process the identity of the primary particle is no longer available.

Objective of Granulation:

1. To produce quality product is the top most priority of the granulation process.

2. To avoid segregation of the ingredients in the powder mix.

-Different size of particle presents in particle mix, segregation mainly occur for the different size of particle with irregular ratio in power mix. Normally two types of particle present in a mix. Normally smaller and coarser particle tend to settle down in the bottom of the container and comparatively large particle store on the top of the container. If granulation process conducted standard way then no particle settle down on the container.

If segregation of the powder mix occur then, tablet compression leads to irregular pattern. Physical criteria didn’t match as per set parameter then directly affect the product quality. To avoid this problem, granulation process to be conduct by using suitable binding agent from appropriate source. Correct proportion of particle mix prevent settle down of the granules.

3. To increase the flow properties of the powder mix.

-Powder contains small size particle, irregular shape or surface characteristics denote poor flow property as the cohesive forces are not dominant here. Cohesive forces to be increase to get better flow property of powder. If cohesive forces is not dominant, particles are generally settle down to the bottom of the container.

4. To produce even mixtures.

5. To control powder density.

6. To produce dust free preparation.

7. To remove poor content uniformity.

8. To increase the compaction characteristics of the Mix.

9. To seizure and fuse small quantities of active material.

Mechanism of Granulation: How granules are formed

In pharmaceutical industry, granulation is the key step to prepare any type of tablets, pellets, powder for suspension and related powder products. So this is very important to know how to develop gangues from powder. How granules quantity may be develop and how we can overcome associate problem during granulation.

This is very important to form bond between powder particles as they adhere between them form particle-particle bond. The bond formation to be adequately strong so that they can overcome the breakdown tendency during subsequent handling.

Type of bonding mechanism: Five Types

• Solid bridges
• Mobile liquid films
• Immobile liquid films
• Mechanical interlocking
• Attractive forces between solid particles

Methods of Granulation

Wet Granulation

Dry Granulation

1. Adhesion and cohesion forces in immobile films

In the presence of sufficient liquid in powder mix to form thin and immobile layer then inter-particulate distance will be reparably decrease and subsequently contact area between the particles will be increase.

Due to more surface availability bond strength between the particles will be increase, as per Van Der Waals force of Attraction, the forces are proportion to the particle diameter and inversely proportional to the separation distance.

During Dry Granulation, the pressure will increase the contact surface between the layers and subsequently decrease inter-particulate distance in the result; this will contribute the granule strength.

In the presence of highly viscus solution of adhesive, the thin, immobile layer form which will strengthen the bond between the particles compare to mobile films.

2.Interfacial forces in mobile liquid films

In the time of wet granulation, sufficient liquid is added to the powder and this liquid distributed around and between the particles. Sufficient liquid help to exceed the immobile layer to convert into the mobile film. Several types of water distribution systems which has been demonstrate here-

Pendular Phase:

During this phase, lens shaped rings of liquid hold particles where as this phase generally occur low moisture condition in the powder mix. Surface tension forces in the liquid-air interface and the hydrostatic suction pressure in the liquid bridge cause adhesion.

Funicular Phase:

This is the intermediate stage between the pendular and capillary phase when air start to displace between the particles then the particles arrange funicular phase. After completion of the intermediate phase- Funicular Phase then capillary phase visible where air completely displace/remove between the particles.

Capillary Phase:

As all the air remove between the particles, the Capillary Phase arrive and the entire particle held by the help of capillary suction in liquid-air interface at the granule surface. Tensile strength increases almost three times in moist granule in capillary and pendular phase.

The total moisture content plays a vital role in the phase of the power bed where total moisture content is the key factor, if separation of the particle can be decrease capillary phase may be reached easily which is the most desirable phase in granulation.

Droplet Phase:

This is the most undesirable phase in granulation. This phase is important in granulation at spray drying of suspension.

Mechanism

During the wetting and mechanical handling of particulates, the Agglomeration, granulation and pelletizing processes is greatly involved. If we increase the wetting and mixing, then open and porous agglomerate structure changes into more close and grain like granule structure. The control of moisture is the main factor in particle engineering, energy input require achieving desired structure of the granules.

Generally wet bridges considered as temporary structure as the moist granule will be dried in the certain period of time. This phase is measured prerequisite for the creation of solid bridges which is created by adhesive present the liquid.

3. Formation of Solid Bridge after Evaporation:

Solid bridges:

First, solid bridges formed by the help of adhesives present in the liquid or dissolving materials present in the granulating liquid. This can be formed in several ways-

• Partial melting
• Hardening binders
• Crystallization of dissolved substances

Partial melting

Most of the low melting substances present in granulation process melt down by applying of pressure in the dry granulating process. Particles are readily bind with one after another and crystallization develop as the applying of pressure.

Hardening binders

By the help of adhesive which add to the granulating solvent, the liquid form liquid bridges, and upon drying the adhesive harden the phase and form solid bridges and bind the particles together. Common uses binders like PVP[ Polyvinylpyrrolidone], CMC[Carboxymethylcellulose], starch etc. plays the vital role.

Crystallization of dissolved substances

The powdered ingredients use in the solvent use in wet granulation may partially dissolve the powdered ingredients. At time of drying of granules, crystallization of powder material occur and act as hardening binder.

Drying rate of the granules are greatly hampered by the size of the crystals create in the bridges, larger the particle size will require more drying time and vice-versa.

4. Attractive forces between solid particles

There are two types of attractive forced which can operate between particle in pharmaceutical system beside the liquids and solid bridges formed by binding agents, demonstrate here-

•Van der Waals forces

•Electrostatic forces

This to me mention here that the Electrostatic forces don’t contribute to the final strength of the granules moreover this is important in the powder cohesion and initial formation of agglomerates e.g. during mixing. This force may be increase during when grain sizes decrease.

Van der Waals forces having four orders of magnitude which consider the greater compare to electrostatic and add great strength to the granules. When the distance between adjacent surfaces decreases then the magnitude of these forces increase. Dry graduation process is achieved by applying the forces to the particles.

5. Mechanical Interlocking:

mechanical interlocking phases that the adhesion occurs when adhesive properly penetrates into the holes, crevices and pores, and other loopholes of the adhered surface of a substrate and which locks mechanically of the substrate and must have the right rheological properties which will help to penetrate pores and other opening in due time.

Adhesion

Besides adsorption, there are Four other mechanisms of adhesion has been projected.  The first mechanism is mechanical interlocking, which occur when adhesive drifts into the pores in the adhered surface. The second mechanism is interdiffusion, result when liquid adhesives are subject to dissolve and diffuse in the adhered materials. Adsorption and surface reaction projected to third reaction.

Mechanisms of Granule Formation:

a)Nucleation

Particle with particle[Particle-particle] contact and adhesion for liquid bridges is the key factor in the Granulation process. Particles are joined together to form pendular phase. Application of agitation, desifies the pendular forms and form the capillary phase and this form act as nuclei for granule growth and the next phase.

b) Transition

Nuclei can grow in two ways e.g. Single particle can be added to the respective nuclei with the help of pendular bridges, another possible ways, where two or more nuclei combine and form big nuclei. After completion of the phase, upon application of agitation to the bed the combined nuclei reshape and this phase can defined as a condition where large number of small granule present in greater range of distribution.

c) Ball Growth

When agitation continued, granule coalescence continue produce unusable, over-massed system where this phase greatly depend on the liquid quantity and material properties.

Coalescence

In this stage, two or more granule join and form large granule.

Breakage

Granules subject to break into fragments and this fragments adhere/join with other granule form a layer to the persisting/living granule.

Layering

Addition  of the new powder mix with the existing granules, the powder mix adhere with the existing granules and form a layer over the existing granule and increase the granule size.

Abrasion Transfer

If agitation applied to the granules bed, then agitated granule leave abraded materials, which further add to the other granules and accelerate the granules growth.

Factors Affecting Granulation Methods

Liquid Requirement

In high shear mixers, the liquid requirement margin is narrow to granule growth and produce over wetted mas. For the intensive wet mass and densification of the granule less liquid requirement assume compare to low share mixers. Impeller rotation speed is another factor for liquid requirements and resulting evaporation of the solvent specially water in the binder solution. In high-shear mixers, intense agitation results temperature rise and subsequently loss of solvent for evaporation.

Theory of granule formation in general

At the early stage of studies near at 1950’s, it was stated that the granules growth by coalescence and limiting moisture content and further mechanical agitation modifies granule shape.

The modern science has divided the process in four major class for granulation process such as-

• Powder wetting and nucleation
• Granule coalescence or growth
• Granule consolidation
• Granule attrition or breakage
• Granulation is a complex combination of these subsequent processes.

Pharmaceutical Granulation Technology

The word “granulated” derived from Latin Word ‘‘granulatum,’’ denote “grained”. Granulated materials come from two way, by “size enlargement” of primary particles and “size reduction” of dry compacted materials. Now a day’s granulation technology has been widely applicate at mining, agrochemical and coal industry.

In these industries, agglomeration techniques mainly used to reduce dust and this technique provide easy handling and boost the material’s decisive effectiveness.

In the year of 1843, W. rockedon invent the tablet press and subsequent modification and patent was done by J. A. McFerran[1874], T. J. Young (1874), and J. Dunton (1876)  in USA which tremendously hit the granulation technology in pharmaceutical technology. The granulation technology was further reshuffle at 1970 when high speed tablet and capsule filling machine with PLC was invented.

The regulatory bindings such as content uniformity/blend uniformity facilitate to produce desired granule characteristics for pharmaceutical company. On the other hand, continuous uniform materials/granule flow must be ensure for high-speed compression and capsule filling machines. Granulation is the best example of particle design. The attributes of the granules controlled by formulation and the process respectively.

Granulation method can be divided into two major group as Wet granulation where liquid use to bind primary particles and Dry Granulation where no liquid is used.

The reasons for granulating a pharmaceutical compound are demonstrated as follows:

• To decrease dust.
• To densify the materials.
• To increase the appearance of the product.
• To simplify metering or volumetric dispensing.
• To improve the flow rates and rate of uniformity.
• To escalation the uniformity of drug dissemination in the product.

Processing steps of drug substance can be easily achieved avoiding granulation steps. By using a direct compressible excipients like MCC[Microcrystalline Cellulose] which was introduce in 1970s in a blender then compress tablets or filled hard gelatin capsule. This is very efficient method for cost effective method, faster process time and simple process steps.

In this technique, low dose of drug substance show reverse criteria, uniformity of drug substance is not possible/ accurate result may not found. The sample need to collect from the blender and time require performing the test to get satisfactory result. A newly introduce PAT[Process Analytical Technology], online measurement of ingredients made possible. FDA also release latest guideline about PAT.

Beside content uniformity, there are numerous cause to avoid direct compression technique for wide range of products where drugs substance need to densified to reduce size and physical criteria such as disintegration, hardness, friability need to meet.

Another approach like traditional spray-drying process become popular in day to day to produce drum to hopper granulation avoiding conventional granulation process.  This is very suitable for OTC drug which generally produce large amounts.

In pharmaceutical company, some of the products/drug substances are moisture sensitive which can’t subject to direct compression, then roller compaction is the best method to compress this product.

Before introduce of high shear-mixer, low-shear mixer was the first priority, shear-mixer generally use in in wet granulation their efficient, reproducible and modern process control capability. High-shear mixers enhanced with new technologies as one-pot processing and subsequent drying using gas stripping/vacuum or microwave.

The most versatile featured Fluid-bed processors has been using in the pharmaceutical industry over the last 35 years though initially it was introduce with single dryer, now enhanced with multiprocessor to coat particles, pelletize, granulate and drying. Now combination of high-shear mixer for granulate and fluid bed as dryer is the most popular method in granulation technology.

Theory of Granulation

Wet granulation technology is especially considered in size enlargement where small particles are compacted; agglomerated or else brought together to form larger particle comparatively permanent structure though the original particle can be distinguished. Size-enlargement and Granulation technology has the wide range of application in various industries like pharmaceutical, fertilizer and detergent production factory.

Particle Bonding Mechanism: 

The particles which form bond between themselves help to build up granules. So particle bond is essential to form effective granules which prevent breaking of granules during transportation. Particles are primarily form bond between themselves then number of particle form granules. There are several ways to form bond between the particles.

Types of Particle Bonding Mechanism

In the context of granulation, particle bonding mechanism refers to the processes by which individual particles adhere to each other to form larger agglomerates or granules. Granulation is a process widely used in various industries such as pharmaceuticals, food processing, and fertilizer production to create granular materials with improved properties such as flowability, compressibility, and dissolution characteristics.

• Several mechanisms contribute to particle bonding in granulation
• Mechanical interlocking
• Van der Waals forces
• Capillary forces
• Chemical bonding
• Sintering
• Electrostatic attraction

 

Mechanical interlocking:

 This process involves the physical entanglement of particles due to their irregular shape or surface properties. When particles come into contact, the irregularities mesh together and bonds form between adjacent particles.

Mechanical entanglement is an interesting phenomenon in which the irregular shape or surface properties of particles lead to physical entanglement. Imagine a scenario where you have a pile of Lego blocks. Each brick has a unique shape and surface texture, including projections, ridges, and edges. If you stack these bricks on top of each other, you will notice that they are not just stacked on top of each other. Rather, they are intertwined. Cracks in one brick lie over cracks in the other brick, forming a strong bond between the two bricks. This is a perfect example of a mechanical lock in action.

Also consider the structure of the Velcro. Velcro fasteners consist of two strips. One has a small ring (called the “male” side) and the other has a small ring (called the “female” side). When these strips are tied together, the loops on one side form a strong connection with the loops on the other side. This connection is purely mechanical and uses interlocking hooks and rings to hold the strips together.

Another example of mechanical interlocking in construction is the use of interlocking bricks or blocks. These bricks have a unique shape that allows them to fit together like puzzle pieces, creating a stable structure without the need for mortar or glue. The irregularities and projections on the surface of each brick mesh with adjacent bricks, preventing them from easily moving or separating.

Simply put, mechanical locks play an important role in many aspects of our daily lives, from simple activities like playing with LEGO bricks to more complex applications in design and manufacturing. This highlights the importance of understanding how the physical properties of materials can affect their behavior and interactions.

 

Van der Waals forces:

Van der Waals forces are weak attractions that exist due to temporary dipoles between molecules or particles. These forces can attract nearby particles to each other and contribute to particle bonding.

Van der Waals forces, named after Dutch scientist Johannes Diederick van der Waals, describe the weak but significant attractive forces that occur between molecules or particles. These forces arise from temporary fluctuations in the distribution of electrons within the molecule, resulting in temporary dipoles. Although van der Waals forces are weaker than ionic or covalent bonds, they play an important role in various phenomena such as the cohesion of liquids, the formation of molecular aggregates, and the adhesion of materials.

Let’s take the example of geckos, fascinating creatures known for their incredible ability to climb vertical surfaces and even walk upside down on rooftops. This extraordinary result is made possible by the complex interplay of van der Waals forces. Tiny hair-like structures called setae cover the gecko’s legs, and each bristle is divided into hundreds of smaller structures called spades. These spatulas create a large surface area, maximizing the potential for van der Waals interaction with the surface. When a gecko presses its paws against a surface, the weak van der Waals forces between the spatula and the surface combine to create an adhesive force that allows the gecko to cling tightly.

In everyday life, van der Waals forces also play a role in phenomena such as the condensation of a gas into a liquid, where molecules are held together by this weak attraction. For example, water vapor condenses in a glass of cold water, forming droplets due to van der Waals forces between water molecules. Similarly, coordination between molecules in liquid water is facilitated by surface tension and van der Waals forces, which contribute to the droplet forming ability.

Additionally, van der Waals forces are largely involved in interactions between molecules in biological systems. For example, the structure of DNA, the genetic blueprint of living organisms, is based, among other things, on the stacking of base pairs governed by van der Waals forces. Moreover, the folding of proteins into functional three-dimensional conformations is influenced by van der Waals interactions between amino acid side chains.

In summary, van der Waals forces may individually be weak, but their cumulative effects can be profound, shaping the behavior of molecules in a variety of situations, from the motion of a gecko to the structure and function of biological macromolecules.

 

Capillary forces:

Capillary forces arise due to the presence of liquid bridges between particles. When a liquid binder is added to the granulation process, it fills the voids between particles and creates liquid bridges. These bridges can solidify through processes such as evaporation or cooling, forming bonds between particles.

Capillary forces result from the formation of liquid bridges between particles, a phenomenon commonly observed in a variety of natural and industrial situations. For example, consider the granular process of pharmaceutical manufacturing. When a liquid binder, such as a solution of water and a polymer, is introduced into the dry powder mixture, it enters the spaces between the particles, effectively filling the voids and forming liquid crosslinks.

This process is similar to the way water flows through a sponge, sticking to the surface of the material and creating bonds between the fibers. In the granulation process, these liquid cross-links play an important role in shaping the properties of the final product. When the liquid binder penetrates the particle composite, it wets the surface, reduces interfacial tension, and promotes particle reorganization. This allows the powder mixture to dissolve into a cohesive aggregate.

Subsequent solidification of these liquid cross-links further solidifies the granular structure. This solidification can occur through a variety of processes depending on the type of liquid binder and environmental conditions. For example, if water acts as a binder, evaporation from heat or air flow will gradually remove the moisture, causing the liquid bridge to solidify and bond between adjacent particles. Similarly, in cooling processes such as freeze granulation, a drop in temperature causes the liquid binder to phase change from a liquid state to a solid state, causing the particles to stick together.

In essence, capillary forces and the addition of liquid binders ensure the coagulation of the granular material, allowing it to form a cohesive structure with appropriate properties. This phenomenon applies not only to the pharmaceutical industry but also to many other fields, from food processing and construction to ceramics and metallurgy. Manipulating particle interactions through liquid bridges is critical to achieving desired material properties and product performance.

 

Chemical bonding:

In some cases, chemical reactions may occur between particles or between particles and the binder. These reactions can form chemical bonds that provide strong adhesion between particles.

Chemical reactions can occur under a variety of conditions, particularly between particles or between particles and binders. These reactions are very important because they favor the formation of chemical bonds, creating strong adhesion between particles.

Consider the concrete curing process as a real-life example. When water is added to cement, a chemical reaction occurs between the water and cement particles to form hydrated calcium silicate gel (C-S-H). This gel acts as a binder and forms strong chemical bonds with the aggregate particles present in the mixture. As a result, concrete hardens and gains strength over time due to the chemical bonds formed between the components. This demonstrates how chemical reactions contribute to the cohesion and stability of materials, improving their structural integrity and performance in real-world applications.

 

Sintering:

An important process in materials science and manufacturing, sintering involves partial melting that occurs at the surface of particles when they are exposed to high temperatures. This heat treatment triggers a transformation step in which adjacent particles are exposed to heat and undergo surface liquefaction upon exposure, resulting in the formation of molecular bonds that bind them together.

To illustrate this concept, let us consider ceramic tile production. In the sintering stage of ceramic production, fine particles obtained from raw materials such as clay, silica and other additives are compressed into the desired shape. When these compressed particles are fired in a high-temperature furnace, typically in the range of 1,000 to 1,500°C, sintering is initiated by heat. At these high temperatures, the particle surfaces begin to soften and slightly melt, allowing intermolecular compounds to fuse and form. As a result, the separated particles gradually fuse to form a hard and dense ceramic structure. This process not only increases the strength and durability of ceramic tiles, but also helps develop desirable properties such as smoothness and uniformity of surface texture. Sintering therefore constitutes a fundamental technology for achieving the structural integrity and functional properties required for a wide range of industrial applications, from ceramics to metallurgy and beyond.

 

Electrostatic attraction:

Electrostatic forces can play an important role in particle bonding, especially in processes where particles become charged. Conversely, charged particles can attract one another and form bonds. Understanding and controlling these bonding processes is important to optimize the granulation process and achieve desired granulation characteristics such as size, shape, strength, and dissolution rate.

Electrostatic forces have a significant impact on particle bonding, especially in charged particle situations. When particles carry opposite charges, they exert a mutual attraction force, promoting bonding between particles. This phenomenon has wide application in various practical situations, such as granulation processes in pharmaceutical manufacturing.

Take tablet production as an example, where granulation is a critical step. In this process, powdered ingredients are combined and mixed with a binder to form granules. These particles must have specific characteristics such as size, shape, strength and dissolution rate to ensure the quality and effectiveness of the final product. During the granulation process, electrostatic forces are exerted when charged particles interact with each other. Conversely, charged particles are attracted to each other, promoting bonding and cohesion between particles.

Granulation Method Advancements

Understanding the complexity of electrostatic interactions and their impact on particle bonding is important for optimizing granulation processes. By controlling these bonding mechanisms, manufacturers can tailor particle properties to their desired specifications. This level of control allows the production of tablets with uniform active ingredient content, consistent dissolution profile, and improved bioavailability.

The same principles also apply to industries other than pharmaceuticals, such as ceramics or pesticide production. By using electrostatic forces to bind particles together, manufacturers can improve the quality, functionality, and performance of their products, ultimately meeting the diverse needs of consumers and industry.

Powder and Granules: here is the brief description of Powder and Granules, You will get the short description of Powder and Granules in this area-

Definition of Powder

Powders, which are finely divided solids, offer versatility in industry and everyday life through easy integration with solvents such as water, facilitating a variety of applications such as pharmaceutical formulations and industrial processes, while being tailored to specific needs and requirements. can be adjusted. This improves human health, comfort and productivity.

Powder, often understood as a finely divided solid substance, has many uses in industry and everyday life. Its versatility lies in the fact that it is easily mixed with suitable solvents such as water or liquids, making it easy to apply in a variety of forms and functions. For example, imagine a powdered drug, a common scenario in the pharmaceutical industry. This powdered drug can be dissolved in a suitable solvent, such as water, to form an orally administrable solution. Alternatively, the powder can be applied topically and used as a powder to treat skin conditions or wounds.

Additionally, the composition of the powder can be made individually depending on each need. Diluents are often added to pharmaceuticals to adjust the density and properties of the powder. For example, liquids contain small amounts of methyl paraben and propyl paraben, typically in a 2 to 3:1 ratio, which is about 0.05% to 0.10% of the total mixture. This combination is classified by the FDA as “generally recognized as safe” (GRAS) for food preservation, ensuring both effectiveness and safety of the final product.

The classification of powders goes beyond their composition to include a variety of uses. For example, powders can be classified according to their use, such as pharmaceutical powders for medical use, cosmetic powders for beauty products, and industrial powders for manufacturing processes. Each classification may have specific requirements and regulations that apply to production and use.

In essence, the definition of Powder goes beyond a simple physical state and embodies a realm of possibility where careful composition and application can lead to innovations that improve human health, comfort, and productivity.

 

Classification of Powder on the basis of use.

• Internal Use Bulk Powder
• External Use Bulk Powder
• Unit dose or Divided Dose Powder

Internal Use Bulk Powder

The finely divided chemicals or drugs in dry form can be used in internal purpose [Oral Power]

Classifications:

• Dry powder inhalers
• Effervescent powders
• Oral powder
• Powder spray

External Use Bulk Powder

The finely divided chemicals or drugs in dry form can be used in External purpose [Dusting Powder] and available in multiple doses[Dusting Powder]

Classification:

• Dentifrices
• Dusting powders
• Insufflations

Unit dose or Divided Dose Powder

The finely divided chemicals or drugs in dry form can be used in internal purpose [Oral Power] but the individual doses are separately wrapped.

Classification

• Powder for injection
• Effervescent powders
• Douche powders

Classification of Powders based on size

Powder can be divided into several categories based on its size.

• Macroscopic Powder
• Microscopic Powder
• Submicron Powder
• Nano Powder
• Ultrafine Powder

Macroscopic Powder:

These powders have particle sizes ranging from 10 μm (micrometers) to 1000 μm. They are usually visible to the naked eye and are often used in applications where physical properties are important, such as tablet or granule production.

Microscopic Powder:

The particle size of this powder varies from 0.1μm to 10μm. They are invisible to the naked eye and are widely used in pharmaceutical, cosmetics and other industries where fine particles are needed for specific properties.

Submicron Powder:

The particle size of this powder is 0.01μm to 0.1μm. They are very fine and are used in advanced materials, nanotechnology and some medical applications where precise control of particle size is essential.

Nano powder:

This powder has a particle size of less than 100 nanometers (0.1 μm). They exhibit unique properties due to their small size and high surface-to-volume ratio and have applications in fields such as electronics, catalysis, and drug delivery.

Ultrafine Powder:

These powders have particle sizes ranging from 1μm to 100μm, which are finer than macroscopic powders but larger than fine and submicron powders. They are used in a variety of industries including paint, varnish and additive industries.

Classifying powders based on size is important because it affects the properties, behavior, and uses of the powder. Different particle sizes can lead to changes in fluidity, compressibility, surface area and reactivity, among other things. Therefore, understanding and controlling particle size distribution is important in many industries to achieve desired performance and effectiveness.

Mixing of Powders

The use of double tapping technology is essential for accurate mixing of powder ingredients, especially in pharmaceutical manufacturing where precise dosing is important. Known in the pharmaceutical industry for the efficiency of geometric dilution, this technique ensures uniform distribution of ingredients in the mixture.

The process begins with carefully measuring the smallest powdered substances and placing them in a mortar. Then more powder is added to the mortar in equal amounts. After mixing the two ingredients, rub the mixture vigorously until you have a uniform mixture. This rigorous mixing process ensures that each particle of the small ingredient is distributed evenly into the larger mass, preventing potential concentration gradients or uneven dosing.

One of the key principles of geometric dilution is the concept of incremental addition. As the mixing process progresses, each time you add more powder, you actually double the amount of material in the mortar. This incremental concentration ensures consistency and uniformity of the final product by ensuring small ingredients are fully incorporated into the overall mixture.

A practical example of the application of this technology is the development of effective drugs, especially those containing hormonal components. These preparations require precise doses of the active ingredient, which is usually present in small quantities. By using geometric liquids via double tapping technology, pharmaceutical manufacturers can ensure that these powerful compounds are evenly distributed throughout the formulation, reducing the risk of dosage variation and ensuring the safety and efficacy of the final product.

 

Process Steps

To facilitate homogenization and to prevent stratification the particle size has to be reduced. The process steps is depicted here-

• Sieving
• Weighing of each ingredient
• Mixing
• Packaging

General method for preparation of bulk Powders: Geometric dilution

• Firstly weigh the Smallest Volume[Powder X] and place into a mortar
• Secondly weigh the Large Volume[Powder Y] and place into a separate labeled container
• Add the same amount of Powder Y as of same amount of Powder X into the mortar
• Use pestle to mix well
• Now add the same amount of “Powder Y” as the same amount of Powder as of Mortar then mix with Pestle, continue this process. Every time the powder quantity will be double compare to previous quantity in mortar.

General method for preparation of Divided Powders

• Weigh the Active ingredients and diluent accurately.
• Arrange trituration of two powers separately before mixing.
• The mix the two ingredients with spatulation method.
• Place the powders in a surface ensure they are in proper quantity using block and divide method.
• Arrange dividing the quantity as per requirement.
• Wrap them into individual paper.
• Place them into individual container and
• Finally label the container.

To dilute the active ingredients of the powder, generally lactose is used to produce the required quantity due to Lactose is colorless, odorless, soluble and also harmless can easily maintain the flow property. The patient who are susceptible to Lactose then Light Kaolin may be used.

Powder calculations

If you are dealing with Powder calculation, you have to calculate at least 1% extra powder to compensate loss during compounding.Always try to take minimum quantity of active ingredients compare to dilution, then minimum weighable quantity is diluted several times.

Advantages of Powders

• Powder is more stable compare to liquid dosage form
• Very much useful for multiple dosage of single product
• Helpful for children and senior citizen
• Ensure first rate of bioavailability due to small particle size

Disadvantages of Powders

• Unstable in atmospheric conditions
• Uniformity dosage failure occur frequently
• Not suitable for carry out from here and there.

Shelf life and storage of Internal Powders

• Internal powders shelf life is 14 to 30 days
• Due to protective packaging proprietary power have longer shelf life
• Powder should be store in moisture proof and airtight area.

Shelf life and storage of External Powders

• External powders shelf life is 30 days.
• If ensure proper packaging then dry power remain stable in longer period of time.
• Must be store in a cool and dry place.

Containers for Internal Powders

• If powders are prepare extemporaneously then then wrapped powders are often dispensed in paperboard box.
• An air tight container is preferable to store internal powder to protect from moisture.
• Almost all bulk powders are packed in airtight container.

Containers for External Powders

Glass, metal or plastic containers can be used for storage of external powders. For packaging of propellant and lubricants, pressurized containers are commercially available to ensure proper safety and security.

Labels and advice for Internal Powders

Mix with suitable solvent or supplied solvent if comes with powder container itself otherwise mix indicated amount of water slowly in a divided portion and shake upon addition of divided amount. Don’t add all indicated amount of solvent at a time. Add it gradually in several portion. Bulk powder must be dilute and measure carefully. Bulk powder use for babies can be placed into mouth with a drink

Labels and advice for External Powders

• For external use only.
• Store in cool and dry place.
• Protect from direct sunlight

Uses of Powders

• The powder is uses for the following cases-
• Used as counter-irritant e.g camphor starch dusting powder.
• Used as antimicrobial e.g. Chlorhexidine dusting powder.
• Used as antipyretic e.g. ipecacuanha and opium[Dover’s Powder]
• Treatment of antacid and anti-flatulent e.g. Magnesium trisilicate
• Used as antiseptics i. g. 5% of Povidone-Iodine Powder[Betadine Powder]
• Treatment of juvenile arthritis i.e. Ibuprofen powder
• Aluminium free baking powder e.g. Rumford
• Widely use in Cosmetics and Face Powders
• To relief skin burn e.g. prickly heat powders
• Protect skin and nappy rashes e.g. Baby powders
• Used in dyspepsia e.g. Rhubarb powder

 

Granules:

Granules are produced by the agglomeration of minute particle produce large free flowing particles. The particle range vary between 4 and 10 mesh size. Most of them are irregular shape but need to produce spherical shape. Granules are the intermediate form of Tablets and Capsules.

What’s the advantage of Granules over Powder?

• To avoid powder separation.
• To increase the flow of powder.
• To increase higher porosity.
• To increase the compressibility of powder.
• The materials having lightly hygroscopic tendency may adhere and form cake if store in powder form.

Classification of Granules

Granules are classified into following Categories

• Coated granules
• Effervescent granules
• Gastro-resistant granules
• Modified release granules

Coated Granules

The granules are undergone single or multilayer coating process with the help of various types of excipient form coated granules use in multi dose preparations. The materials which are used to coat the granules are firstly made solutions or suspensions with suitable solvent may be Organic[Isopropyl Alcohol/Methanol/Metethelene Chloride or Inorganic[Water]. Solvents are generally evaporate during coating process.

Effervescent Granules

The uncoated granules, generally contains acid substances and hydrogen carbonate or carbonate which react instantly with water upon addition with it and release carbon-dioxide. The granules must be dispersed or dissolved with water before administration.

Gastro resistant Granules

The granules that are intended to resist the gastric fluid and release the active ingredients in intestinal fluid well known as delayed release granules. The gastro resistant properties are just attain by coating of suitable materials[Polymer Like-Hydroxypropyl methylcellulose phthalate/vinyl acetate phthalate/Cellulose acetate trimellitate/esters of aleurtic acid/Cellulose acetate phthalate etc.]

Modified release Granules

The granules contains special type of excipients or that is prepared with special procedure are both involved, and designed to altered the rate, the place or time at which the active ingredient release. The modified release granules are two types as Delayed release granules and Prolonged release granules.

Granules preparation Methods

All of the granules are made of mainly in two method

• Dry Granulation Method
• Wet Granulation Method

Dry Granulation Method

Dry Granulation methods are performed in two ways-

• Roller Compactor
• Slugging

Roller Compactor:

The dry powder passed through roller compactor then a granulating machine. A Roller compactor is also familiar as roll press, roll compactor use to process fine powder to dense sheet form by forcefully passing through two heavy rotating metal roll running counter to each other.

To attain different forms and textures the surface of the compacting rolls may contain corrugations or pocket indentation and surface of roller compactor may be smooth to do the same. The compacted powder further granulated in a mechanical granulator to get uniform particle.

Slugging

During slugging process the pressure may be difference between 8,000 to 12,000 lb to form large tablets based on the physical characteristics of powder form. The produced slug may be in flat faced in 1 inch diameter.

The resulted slugs are granulated to produce desired particle size used to produce tablets and capsule. During dry granulation, some fine particles are produced that is not agglomerated, the fines particle are collected, separated finally reprocessed.

 

 Wet Granulation Method

In the wet granulation method the, paste prepared by moisten the powder or powder mixture then the paste passed through the specific screen of mesh size and produced desired size of granules. Granules are then placed on tray for drying and dried it by heat or air. The granules are periodically moves on the drying tray to avoid adhesion to outsized mass.

The other type of wet granulation method is known as fluid bed granulation processing (also known as agglomeration) where particles are placed on conical shape of equipment and liquid excipient spray on the particle in  vigorously dispersed and suspended conditions then the product dried to form pellets of defined granules size.

How to prepare Effervescent Granules?

Here two methods followed-

• Fusion method
• Wet Granulation method

Fusion Method

The method, where equivalent molecule of Water and Citric Acid present[One Molecule of water in each molecule of Citric Acid] act as binding agent for Powder. First of all the Citric Acid Crystals are made powder then this powder mixed with other powder. Same sieve size to be ensure to get uniform powder mixture. The mixing equipment’s and the sieves are made of stainless steel to avoid effect of the acid

To avoid premature chemical reaction and absorption of moisture the mixing of powder performed rapidly in a low humidity area. Then the powder mixer transfer a suitable dish in an oven which temperature between 34°C to 40°C. Use heat resistant spatula to turn the powder. During this process, the heat release water of crystallization from Citric Acid which dissolve a portion of this power mixture and initiate chemical reaction produce Carbon Dioxide cause the soften of powder mass. Then the powder become to extend spongy and this spongy powder then rubbed through a sieve to produce desired size granules.

Difference between Powder and Granules

Various size of sieves are available in the market produce different size of granules e.g. No. 4 sieves use to produce large granules, No. 8 sieves use to produce medium size granules and No. 10 sieves use to produce small granules. To get best result during storage the granules are dried below 54°C and rapidly placed in container just after drying and tightly sealed.

Wet Granulation Method:

The wet granulation method is different  from that of the fusion granulation method as water didn’t come from crystal stage of materials and additionally water to be added moisten the granules. Here all materials remains anhydrous until addition of water. After addition of water the prepared mass are then dried to prepare desired granules.

Shelf life and storage:

The Shelf life of the granules is 2-3 weeks. Granules should be stored in double layer polybag in airtight containers, add silica gel pouch outside the container to get proper result. Must be stored in cool and dry place and protect from direct sunlight.

In this way Powder and Granules are very essential to our day to day life. Powder and granules are consider the important part of pharmaceutical preparations. Special precaution may requires during manufacturing of powder and granules. This is all about the short brief description about Powder and Granules.