A Seminar on Spherical techniques in pharmacy

Keyur Vasava..

Definition of sphere:
Solid figure with every point on its surface equidistant from its centre

Various spherical techniques

1. Microencapsulation 2. Pelletization 3. Spherical crystalization

Microencapsulation

Microencapsulation is a process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with a continuous film of polymeric material. The product obtained by this process is called as micro particles, microcapsules. Particles having diameter between 3 - 800m are known as micro particles or microcapsules or microspheres. Particles larger than 1000m are known as Macroparticles.

Microspheres and microcapsules

Micro-particles are the polymeric entities falling in the range of 1-1000m. Covering two types of the forms as follows: Microcapsules: micrometric reservoir systems Microspheres: micrometric matrix systems.

Polymer Coat Drug Core

Polymer = Drug

Microcapsules

Microspheres

Advantages:
To convert liquid to a solid ( clofibrate, codliver oil) To protect drug from environment ( aspirin, citric acid, l-dopa) To reduce volatility ( methyl salicylate, peppermint oil, flavors) To avoid incompatibilities in combinations e.g. aspirin and CPM To disguise unpleasant taste e.g.penicillin derivatives To mask bad odor ( castor oil, cod liver oil) To sustain / prolong / delay / control drug release To reduce gastric irritation (ferrous sulphate, KCl ) To reduce hygroscopicity e.g. sodium chloride To reduce hazards to operators (insecticides, pesticides) To improve flow properties e.g. Vitamins To produce NDDS (IUDs, Intra Nasal, Intra Ocular) To design targeted drug delivery systems Not adaptable to all core materials Products may be too bulky Coating may be incomplete or uneven Clumping of microcapsules is often reported Unsatisfactory or non reproducible core release may occur Accidental chewing or crushing of the formulation may create problems Difficulties in scale up and large scale manufacturing The process equipments are often costly Mechanical stress may damage the coat Regulatory constraints Need to establish safety, efficacy, BA/BE profile

Disadvantages

CHARACTERISTICS OF MICROCAPSULES
The core material used plays an important role in the production of microcapsules. It decides the process as well as the polymer that should be used as the coating material. The core-material should be insoluble and non-reactive with the coating material and the solvent used. The unique feature of microcapsules is the small sized coated particles and their use and adaptation to a wide variety of dosage forms. Due to the smallness of the particles, drugs can be widely distributed throughout the GI tract, hence improving the drug absorption. The quantity of polymer coating can vary from 1 to 70% of the weight of the microcapsule. In most of the cases, it is between 3 and 30% corresponding to a dry polymer coating film thickness of less than 0.1 to 50 nm. Biodegradable polymers are also used in microcapsule production.
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The coating can be made rigid, fragile or strong. Strength is controlled by the choice of the polymer, coating thickness and plasticizer. They are highly stable.

Formulation aspect
Microencapsulation Core material = solid or liquid Coating material = polymer, Waxes, resins, protein, Polysaccharides Vehicle =aqueous and Nonaqueous

Factor affecting the selection of coating materials 1.Purpose for which the microencapsulation is done like
Stability Taste masking Release modification Environmental condition Physical properties Chemical properties

2.Properties of core material like

Different types of methods used for manufacturing microcapsules are as follows:

TYPE A (CHEMICALPROCESSES) Coacervation phase separation Spray drying and congealing Polymer-polymer incompatibility Interfacial polymerization media in liquid Spray chilling Fluidized bed / air suspension technique Electrostatic deposition Solvent evaporation Centrifugal centrifugal extrusion / multi-orifice TYPE B (MECHANICAL PROCESSES) Pan coating

Polymerization at liquid-gas or solid-gas interface In situ polymerization In-liquid drying Thermal and ionic gelation in liquid media Desolvation in liquid media

Spinning disk or rotational suspension separation Pressure extrusion or spraying into solvent extraction bath.

A. COACERVATION-PHASE SEPARATION
This process may be used to microencapsulate a variety of liquids, solids, solutions and dispersions of solids in liquids. The polymers used the coat the materials should be soluble in water or any other solvent used. Water-soluble core materials are microencapsulated in organic solvents, whereas, water-insoluble materials are microencapsulated in water. Method: The process is batch-type carried put under continuous agitation. Formation of three immiscible phases, The liquid-vehicle phase, the core material and the liquid polymer coating. Deposition of the coating Solidification of the coating.

TYPES OF COACERVATION-PHASE SEPARATION

I. SIMPLE COACERVATION
It includes a simple coacervation process in which microencapsulation is carried out by using water as the solvent phase and a water-soluble polymer as the coating material. Coacervation is induced by the addition of a soluble salt. Example: An oily material Vitamin A Palmitate in gelatin by adding a water-soluble salt.

II. COMPLEX COACERVATION

This method is based on the ability of cationic and anionic water-soluble polymers to interact in water to form a liquid, polymer-rich phase called a complex coacervate. Gelatin is normally the cationic polymer used. A variety of natural and synthetic anionic water-soluble polymers interact with gelatin to form complex coacervates suitable for encapsulation. If a water-insoluble core material is dispersed in the system and the complex coacervate wets this core material, each droplet or particle of dispersed core material is spontaneously coated with a thin film of coacervate. When this liquid film is solidified, microcapsules are formed. This technology usually produces single capsules of 20-800 m diameter that contain 80-90% by weight core material.

B. MICROENCAPSULATION BY NON-SOLVENT ADDITION

These processes are designed to produce microcapsules of solids that are insoluble in the solvent non-solvent pairs. Method: In this process, phase separation is induced by the addition of a non-solvent to a solution of a polymer. The ability of the non-solvent to cause the polymer to separate is measured by the solubility parameter. As the solubility parameter of the non-solvent and the polymer surpasses 1.1, liquid phase separation occurs. When a core material wettable by the polymer is present, microcapsules are formed.

C. TEMPERATURE CHANGE
This process involves a polymer soluble in a solvent at elevated temperature but insoluble in the same solvent at room temperature. When certain polymers are dispersed in a cold solvent with a core material present, heating the mixture with agitation to a selected temperature and slowly cooling the dispersion back to room temperature can result in microencapsulation. For example: Water-insoluble liquids can be microencapsulated in methylcellulose from water, and water-soluble solids can be microencapsulated in ethyl cellulose from cylcohexane.

D. POLYMER-POLYMER INCOMPATIBILITY
This is probably the most classical method to produce microcapsules. This technology utilizes a polymer phase-separation phenomenon. Method: The polymer-polymer incompatibility occurs because two chemically different polymers dissolved in a common solvent are incompatible and do not mix in solution.

They repel each other and form two distinct liquid phases. One phase is rich in
polymer designed to act as the capsule shell. The other one is rich in the incompatible polymer. The incompatible polymer is present in the system to cause formation of two phases.

E. INTERFACIAL POLYMERIZATION
The capsule shell is formed at or on the surface of a droplet or particle by polymerization of reactive monomers. A multifunctional monomer is dissolved in the liquid core material. The resulting solution is dispersed to a desired drop size in an aqueous phase that contains a dispersing agent. A co-reactant, usually a multifunctional amine, is then added to the aqueous phase. This produces a rapid polymerization reaction at the interface, which generates the capsule shell.

F. IN SITU POLYMERIZATION
Microcapsule shell formation occurs as a result of polymerization of monomers added to the encapsulation reactor. Polymerization occurs exclusively in the continuous phase and on the continuousphase side of the interface formed by the dispersed core material and continuous phase.

This technique produces small: 3 to 6 m diameter microcapsules. Larger

microcapsules loaded with mineral oil are used for cosmetic applications.

TYPE B: MECHANICAL ENCAPSULATION PROCESSES A. SPRAY DRYING

The core material is emulsified or dispersed in a concentrated (40-60% by wt solids) solution of shell material. The core material generally is water-immiscible oil such as a fragrance, flavour or vitamin. It is emulsified in a solution of shell material until 1 to 3 m oil droplets are obtained. The shell material normally is a water-soluble polymer like gum Arabic or a modified starch. Once a suitable dispersion of core material in a solution of shell material has been prepared, the resulting emulsion is fed as droplets into the heated chamber of a spray drier. They are rapidly dehydrated in a heated chamber, thereby producing dry capsules. The capsules fall to the bottom of the spray-drying chamber where they are harvested. Microcapsules produced in this manner typically are in the range of 10 to 300 m in diameter.
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They tend to have an irregular geometry and may be aggregates of a number of small particles.

B. FLUIDIZED BED TECHNIQUE

They are limited to encapsulate solid particles or porous particles into which a liquid is absorbed. A bed or column of solid particles is suspended in a moving gas stream, usually air. A liquid coating formation is sprayed onto the individual particles and the freshly coated particles are cycled into a zone where the coating formulation is dried either by solvent evaporation or by cooling. This coating and drying sequence is repeated until a desired coating thickness has been applied. Enteric polymer solutions have been of particular interest, since they are used by the pharmaceutical industry to produce drug-dosage formulations that survive passage through the stomach.

Process variables:
Density, surface area, melting point, solubility, friability, volatility, crystalinity, flowability of coating material Coating material concentration Coating material application rate Volume of air required to support and fluidised the core material Amount of coating material required

Inlet and outlet operating temperature C. SOLVENT EVAPORATION AND SOLVENT EXTRACTION
Method: The polymeric supporting material is dissolved in a volatile organic solvent. The active medicinal principle to be encapsulated is then dispersed or dissolved in the organic solution to form a suspension, an emulsion or a solution. Then, the organic phase is emulsified under agitation in a dispersing phase consisting of a non-solvent of the polymer, which is immiscible with the organic solvent, which contains an appropriate surface-active additive. Once the emulsion is stabilized, agitation is maintained and the solvent evaporates after diffusing through the continuous phase. The result is the creation of solid microspheres. On the completion of the solvent evaporation process, the microspheres held in suspension in the continuous phase are recovered by filtration or centrifugal and are washed and dried.

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Process variables
Evaporation rate of solvent Temperature of system Agitation rate Concentration of solution Viscosity of solution

D. CENTRIFUGAL EXTRUSION
The core and shell material, which are two mutually immiscible liquids, are pumped through a spinning two-fluid nozzle. This produces a continuous two-fluid column or rod of liquid that spontaneously breaks up into a stream of spherical droplets immediately after it emerging from the nozzle. Each droplet contains a continuous core region surrounded by a liquid shell. How these droplets are converted into capsules is determined by the nature of the shell material. If the shell material is a relatively low-viscosity hot melt that crystallizes rapidly on cooling, the droplets are converted into solid particles as they fall away from the nozzle. Suitable core materials typically are polar liquids like water or aqueous solutions, since they are immiscible with a range of hot melt shell materials like waxes.

E. ROTATIONAL SUSPENSION SEPARATION

In this process, core material dispersed in a liquid shell formation is fed onto a rotating disk. Individual core particles coated with a film of shell formulation are flung off the edge of the rotating disk along with droplets of pure coating material. When the shell formulation is solidified e.g.: by cooling, discrete microcapsules are produced. The droplets of pure coating material also solidify, but they are said to collect in a discrete zone away from the microcapsules. In order to obtain optimal results, the core material must have a spherical geometry.

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F. MULTIORIFICE-CENTRIFUGAL PROCESS

Process variables
Flow rate of core application Concentration of coating solution Viscosity of coating solution Coating material application rate Rotational speed of rotating cylinder and counter rotating disc

APPLICATIONS OF MICROCAPSULE
APPLICATIONS Taste masking Enteric coating Sustained and controlled release Instability to environment (O2, H2O) and volatility Separation of incompatibles Isolation from tissues Administration in solid state and dry handling Encapsulation of cells Improvement of flow EXAMPLES Fish oils, sulfa drugs, alkaloids and salts Aspirin, pancrelipase, erythromycin Potassium chloride, ibuprofen, theophylline Vitamins, aspirin, volatile flavors Drugs, excipient or buffers Potassium chloride, aspirin Liquids, soft or sticky solids, oils, flavors, vitamin A Artificial cells, live cells & organs On conversion of powders to spherical shaped
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microspheres Detoxification Vaccines, Safe handling of toxic substances

Assists dispersion of water-insoluble substances in aqueous media. Sustainedrelease, controlled release and targeted medications: A controlledrelease microsphere product provides subdivision of a large dose, resulting in improved safety. Also, a microsphere controlled release formulation allows dispersion in the gastrointestinal tract, reducing the possibility of local concentrations that could result in irritation or toxic effects and permitting more reproducible absorption. In comparison, a controlled release tablets often do not disintegrate which can lead to local irritation and erratic absorption. Several batches of microspheres can be prepared with different coating thickness and mixed to achieve specific controlled-release patterns. Biocompatibility can be improved by the encapsulation of artificial cells and biomolecules such as peptides, proteins and hormones that can prevent unwanted immunological reactions that would lead to inactivation or rejection. Microspheres can be used for isolating materials until their activity is required. For Example: Aspirin is encapsulated to prevent gastric bleeding and other side effects associated with it. Sulfa drugs have been encapsulation to mask their bitter taste. Potassium chloride (KCl) when encapsulated in microspheres prevents gastrointestinal complications. The dispersibility of the microcapsules and the controlled release of the ions minimize the possibility of local high salt concentrations, which could result in ulceration, hemorrhage or perforation. Microspheres have also found potential applications as injection or inhalation products. Targeting: To a particular group of cells within the body such as Kupffer cells and even to intracellular structures like lysosomes or the cell nucleus. For this purpose, magnetically responsive drug carrier systems have been used to localize the carrier and the entrapped agent at specific in vivo target sites. For example: An improved anti-tumor effect was obtained with magnetic microspheres loaded with Adriamycin that were magnetically guided to the tumor site.

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Pelletization
Definition
Pellets are defined as small, spherical particulates produced by the agglomeration of fine powders or granules of drug substances and excipients using appropriate equipments. They are usually free flowing. The size of pellets vary from formulation to formulation but usually lies between 1 and 2mm.

Advantages:
They can be dispensed as such, filled into a capsule as well as can be compressed into a tablet. They can be also used to dispense incompatible bioactive agents together into a single formulation. They can be divided into desired dose strengths without formulation or process changes. Different release profiles in a single formulation can be met. Release of drugs at different sites in the GIT. Upon oral administration, they maximize absorption as they freely disperse in GIT.

Pelletization processes:
1. 2. 3. 4. Direct palletizing Palletizing by Layering Extrusion-Spheronization Sugar spheres

1. Direct Palletizing
Manufacture of pellets directly from powder. Round pellets, defined surface Ideal flow behaviour and dosability Narrow particle size distribution Low abrasion

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Pellets can be automatically dosed and filled into capsules or compressed to form tablets using a suitable formulation. The even shape and surface provide ideal conditions for application of a precise film, in order to achieve controlled release.

Process principle

Powder is mixed and moistened and the powder bed set into centrifugal motion (fluid bed pelletizing in the rotor).The impact and acceleration forces that occur in this process result in the formation of agglomerates, which become rounded out into uniform and dense pellets and are then dried. Another alternative for direct pelletizing is spray granulation.

2. Pelletizing by Layering
Layer-by-layer pellet build-up - around a given starting core.

Layered pellet Round pellets Ideal dosability Low hygroscopicity Dense, even surface Narrow grain size distribution Low wear Layer-by-layer build-up of different active ingredients possible

Active ingredients can be applied in powder or solution form on a layer-by-layer basis onto a carrier, and so unite wide-ranging different functions in a single pellet.

Principle of the powder layering process

Powder layering involves the deposition of successive layers of dry powder of drug or excipients or both on preformed nuclei or cores with the help of a binding liquid.
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Because powder layering involves the simultaneous application of the binding liquid and dry powder, it generally requires specialized equipment. The primary requirement in a powder-layering process is that the product container should have solid walls with no perforations to avoid powder loss beneath the product chamber before the powder is picked up by the wet mass of pellets that is being layered on. Conventional coating pans were the first equipments to be used for this method.

Limitations of powder layering process:

1. The degree of mixing is very poor, and the drying process is not efficient. 2. If the powder delivery rate is not maintained at pre-determined equilibrium levels, over-wetting or dust generation may occur. Toward the end of the layering process, it is likely that fines may be generated owing to potential inter-particle and wall-to-particle friction and appear in the final product, thereby lowering the yield.

Principle of the suspension and solution layering process

The equipments used for this process are 1. Conventional coating pans. 2. Fluid-bed Centrifugal granulators. 3. Wurster coaters.

Solution/suspension layering technique is usually used when the desired drug loading of the pellets is low. Micronized drug particles tend to provide pellets that are smooth in appearance, a property that is extremely desirable during subsequent film coating, particulary for controlled-release applications.

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A starting grain or a pellet can be presented as the starting material. The pellet is built up to the required size and active ingredient content on a layer-by-layer basis by spray application of the layering substance. Powder and binders, suspensions or solutions make suitable layering substances. The layers are densely and quickly applied during powder layering in the rotor (fluid bed pelletizing), whereby different types of layers can be formed.

3. Pelletizing by Spheronizing A round pellet for moist granulates and extruded products. Round, even shape Ideal flow behaviour and dosability Compact structure Low hygroscopicity High bulk density Dense surface Narrow grain size distribution Low abrasion Round pellets are characterized by optimum dosability. The other shape is optional for even coating.

Principle of the granulate spheronizing process

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Principle of the extruded product spheronizing process

Irregular particles can be spheronized with the help of a Pelletizer/Spheronizer. The most granulates or extruded products are fed onto the rotating pelletizing plate. The surface is smoothed due to the intensive rolling movement and spherical pellets are produced. (Spheronizing in the pelletizer). It is a multi-step process involving dry mixing, wet granulation, extrusion, spheronization, drying and screening.

The extruders used for this process are: 1. Screw-Fed Extruder 2. Gravity-Fed Extruder 3. Ram Extruder

Applications of extrusion spheronization technique:

1. High drug loading is possible. 2. Extended release pellets can be produced.

4. Sugar Spheres Sugar spheres are produced, preferably using layered sugar-coating structure. The result is sugar spheres with sufficient mechanical stability for further processing. The
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ideally rounded spheres classed in closely graduated particle sizes are then coated with the active substance and sustained release additives. The core of finished pellet contains no active substance itself so that this solution is used for low-dose substances or substances with a high effect/dose relation. But the use of small sugar spheres and corresponding procedures also makes it possible to use this method to produce pellets containing more than 75 % active substance. Sugar spheres characteristically consist of sucrose and corn starch, which are pharmacologically indifferent, digestible excipients frequently occurring in the normal diet. Mechanical stability Sugar spheres must have adequate mechanical stability to withstand the loads during subsequent coating, including contact with solvents. Interesting parameters here are friability and crushing strength.

Newer Techniques:
1. 2. 3. 4. Melt Spheronization Spray Drying and Spray Congealing. Cryopelletization Freeze-Pelletization:

1. Melt Spheronization
Drug substance and excipients are converted into a molten or semisolid state and shaped using appropriate equipment to provide solid spheres or pellets. Equipments used are: blenders, extruders, cutters (known as pelletizers in the plastic industry) and spheronizers. The spheronization temperature needs to be high to partially soften the extrudate and facilitate deformation eventual spheronization. Depending on the characteristics of the formulation ingredients, pellets that exhibit immediate- or sustained-release characteristics can be manufactured in a single step. The pellets produced are unique in that they are mono-size, a property unmatched by any other pelletization technique.

2. Spray Drying And Spray Congealing

Spray drying and spray congealing, involve atomization of hot melts, solutions, or suspensions to generate spherical particles or pellets. The droplet size in both processes is kept small to maximize the rate of evaporation or congealing, and consequently the particle size of the pellets produced is usually very small. During spray drying, drug entities in solution or suspension are sprayed, with or without excipients, into a hot air stream to generate dry and highly spherical particles. Generally, spray-dried pellets tend to be porous.
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During spray congealing, a drug substance is allowed to melt, disperse, or dissolve in hot melts of waxes, fatty acids, etc., and sprayed into an air chamber, where the temperature is below the melting temperatures of the formulation components, to provide spherical congealed pellets under appropriate processing conditions. A critical requirement in a spray-congealing process is that the formulation components have well-defined, sharp melting points or narrow melting zones.

3. Cryopelletization Technique: Cryopelletization is a process whereby droplets of a liquid formulation are converted into solid spherical particles or pellets by using liquid nitrogen as the fixing medium. The procedure permits instantaneous and uniform freezing of the processed material owing to the rapid heat transfer that occurs between the droplets and liquid nitrogen. The pellets are dried in conventional freeze dryers.

The equipment consists of a container equipped with perforated plates at the bottom. Immediately below the plates at a predetermined distance is a reservoir of liquid nitrogen. In which a conveyor belt with transport baffles is immersed. The conveyor belt has a variable speed and can be adjusted to provide the residence time required for freezing the pellets. The perforated plates generate droplets that fall and freeze instantaneously as they come in contact with the liquid nitrogen below. The frozen pellets are transported out of the nitrogen bath into a storage container at 60C before drying.

Disadvantages of cryopelletization process:

It requires liquid nitrogen, which has a temperature of -196 C. Moreover, the impact of liquid or semi-solid droplets on the surface of the liquid nitrogen creates surface irregularities in the pellets. In addition, pellets produced by freeze-drying are highly porous and may be spherical.

5. Freeze-Pelletization:
Freeze pelletization is simple technique for producing spherical pellets for pharmaceutical use. In this method, molten-solid carrier containing (drug + excipients) as droplets is added into a liquid, into which the molten solids are immiscible.
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Depending upon the differences in density, the solidified droplets may move downwards or upwards. If the density of molten droplets is higher than that of liquid, then the droplets are passed from upwards, and thus they solidify when they reach the bottom of the liquid filled vessel. If the density of molten droplets is lower than that of liquid, then the droplets are passed from downwards, and thus they solidify when they reach the top of the liquid filled vessel.

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Disadvantages:
If the pellets are volume filled, for example in capsules, it may lead to the problems of content uniformity and differences in dosing. If the pellets are coated, then upon compression into a tablet, there are chances that the coat of pellets may rupture.Pronounced surface roughness of pellets may hinder the filling process. If the pellets are coated with an ethyl cellulose film, the batches could not be filled to an acceptable standard because electro-static charges develop that lead to blocking during the filling process.

Spherical Crystallization Technique

Kawashima (1986) defined spherical crystallization as An agglomeration process that transforms crystals directly into compact spherical forms during the crystallization process.

Advantages of Spherical Crystallization:

1. Spherical crystallization technique has been successfully utilized for improvement of flowability and compressibility of crystalline drug. 2. This technique could enable subsequent processes such as separation, filtration, drying etc to be carried out more efficiently. 3. By using this technology, physicochemical properties of pharmaceutical crystals are dramatically improved for pharmaceutical process i.e. milling, mixing and tabletting because of their excellent flowability and Packability 4. This technique may enable crystalline form of a drug to be converted into different polymorphic form and thus attain better bioavailability. 5. For masking of the bitter taste of drug 6. Preparation of microsponges, microspheres and nanaospheres, microbaloons, nanoparticles and micro pellets as novel particulate drug delivery system.

Formulation aspect Solvents for spherical crystallization:

1. First is substance dissolution medium (Good solvent). 2. Second is partially dissolution medium for the substance (Bridging liquid). 3. Third one is immiscible with the substance. (poor solvent)

Role of bridging liquid in the spherical crystallization technique:

The spherical crystallization technique involved the selective formation of agglomerated crystals held together by liquid bridges.
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The agglomerates were formed by agitating the crystals in the liquid suspension in the presence of the bridging liquid. The bridging liquid should be immiscible in the suspending medium but capable of cementing the particle to be agglomerated. The finally divided solid crystals in the liquid suspension initially separated from each other but by adding small amount of bridging liquid which preferentially wets the surface of solids, form the bridges between the solid crystals and finally agglomerate into spherical form. Thus the nature of bridging liquid and surface properties of crystals play important role in agglomeration process.

METHODS OF SPHERICAL CRYSTALLIZATION

Following are the methods used to prepare the spherical crystals. 1. Spherical Agglomeration method (SA) 2. Quasi-Emulsion Solvent Diffusion method (QESD) 3. Ammonia diffusion system (ADS) 4. Neutralization Technique (NT). 5. Traditional crystallization process.

1. Spherical Agglomeration method (SA):The process involves the formation of fine crystals and their agglomeration. Crystallization is generally achieved by the change of solvent system or salting out. The solution of material in good solvent is poured in a poor solvent, so as to favour formation of fine crystals. Agitating the crystals in a liquid suspension and adding the bridging liquid, which preferentially wets the surface crystals to cause binding, form the agglomerates. The agglomerates may be spherical if the amount of bridging liquid and the rate of agitation are controlled. 2. Quasi-Emulsion Solvent Diffusion Method (QESD ) By this method, spherical crystallization can be carried out using a mixed system of two or three partially miscible solvents, i.e. bridging liquid-poor solvent system or good solvent bridging liquid-poor solvent system. When bridging liquid (or plus good solvent) solution of drug is poured in to poor solvent (dispersion medium) under agitation, quasi emulsion droplets of bridging liquid or good solvent forms the emulsion droplet in to the dispersing medium and induce the crystallization of drug followed by agglomeration.
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3. Ammonia Diffusion System Method (ADS)

In this method, the mixture of three partially immiscible solvent i.e. acetone, ammonia water, dichloromethane was used as a crystallization system. In this system ammonia water acted as bridging liquid as well as good solvent, Acetone was the water miscible but a poor solvent, thus Drug precipitated by solvent change without forming ammonium salt. Water immiscible solvent such as hydrocarbons or halogenated hydrocarbons e.g. dichloromethane induced liberation of ammonia water. Mechanism of the ammonia diffusion system method: It involves the three steps 1. Invasion of acetone into ammonia water droplets. 2. Diffusion of ammonia in the agglomerates to the outer solvent. 3. Agglomeration ending.

4. Neutralization Method (NT):

This process involves the formation of fine crystals and their agglomeration. The spherical crystallization of antidiabetic drug tolbutamide was reported by this technique. The drug was dissolved in sodium hydroxide solution. Aqueous solution of Hydroxypropyl methylcellulose and hydrochloric acid was added to neutralize sodium hydroxide solution of tolbutamide, which was then, crystallized out

5. Traditional crystallization process:

These methods also can be used to produce spherically crystallized agglomerates, which are carried out by controlling the physical and chemical properties and can be called as the non-typical spherical crystallization process. These are a) Salting out precipitation. b) Cooling crystallization. c) Crystallization from the melting.

Improvement of physicochemical properties of drug substances by spherical crystallization technique:

Particle size and shape (Crystal habit) Density Amorphous Form Stability Flowability Packability Compaction Behavior of Agglomerated Crystals Wettability
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Mechanical strength of resultant tablets Solubility

Dissolution Rate and Bioavailability Following are the other examples of drugs improving its physicochemical properties by spherical crystallization techniques. METHOD SA SA SA ADS SA SA SA SA SA /QESDS ADS SA /QESDS QESDS NT SA SA QESDS SA QESDS DRUG Aminophylline Naproxen Aspirin Ampicillin trihydrate Salicylic acid Aspartic acid Ibuprofen Acetyl salicylic acid Ascorbic acid Enoxacin Bucillamine Ibuprofen Tolbutamide Dibasic calcium phosphate Tranilast Acebutalol Hcl Naproxen Propyphenazone

SA = Spherical Agglomeration method ESDS = Quesi-Emulsion Solvent Diffusion System ADS = Ammonia Diffusion System NT = Neutralization Technique

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References
1. Simon B, Microencapsulation methods and industrial application, Publications ,second edition, volume-158,p.99-123.
2.

Marcel Dekker

The theory and practice of industrial pharmacy- by Leon Lachman

3. www.pharmtech.com 4. James S, Encyclopedia of Pharmaceutical technology, Third edition, Informa healthcare, volume 4, p.2651-2663. 5. Influence of process variables on physical properties of pellets using extruder spheronizer. Drug development industrial pharmacy, 25 (!) , 45-61 (1999). 6. Morshima K, Kawashima Y, Takeuchi H., Niwa, T,b Hino T, Tabletting properties of Bucillamine agglomerates prepared by the spherical crystallization technique, Int.Jr.Pharm, 105, 1994, 11-18. 7. Deshpande MC, Mahadik KR, Pawar AP, Paradkar, AR, Evaluation of spherical crystallization as particle size enlargement technique for Aspirin, Ind.Jr.Pharm.Sci.59 (1), 1997, 32-34. 8. Jbilou M, Ettabia A, Guyot-Hermann AM, Guyot JS, Ibuprofen agglomeration prepared by phase separation. Drug. Dev. Ind. Pharm, 25(3), 1990, 297-305.

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