Multi Unit Pellet System (MUPS) Technology
The concept of multiple unit dosage form was initially introduced in the early 1950. These forms can be defined as oral dosage form consisting of a multiplicity of small discreat unit, each exhibiting some desired characteristics.
Compressed multiple unit pellet tablets/multiple unit particulate or pellet system commonly called MUPS. These are composed of polymer coated subunits namely pellets; which are embedded in an inert excipients matrix designed to overcome the difficulties in administering capsules and improved physico-chemical stability compared to suspensions. The functional coating like drug coating, barrier coating, enteric polymer coating is usually applied in a fluid bed coating processor provides each subunit with the characteristic desired drug release properties. The size, shape and surface morphology of the pellets to be coated are the prerequisites for coating of pellets. Design of MUPS involves formulating pellets by different techniques and further compression of these pellets into rapidly disintegrating tablets; disintegrate rapidly in the oral cavity for the delivery of coated pellets into the gastrointestinal tract or the site of release of the drug. In spite of the challenges like content uniformity of the compressed tablets, ability of the film to withstand compression force. MUPS occupy a prominent role in formulating drugs due to their greater patient compliance, process, formulation and therapeutic advantages. A design principle of increasing importance for sustained, controlled, delayed, site specific or pulsatile release preparations is the compaction of coated particles into disintegrating multiple unit tablets. One challenge in the production of disintegrating multiple unit tablets is maintaining the modified drug release after compaction, as the application of the compaction pressure can lead to deformation of film coating and, consequently, altered drug release, as reviewed by Bodmeier. To protect the coating from such changes, excipients with so-called cushioning or protective properties are usually incorporated in the tablet formulation in addition to fillers. The compression-induced changes in the structure of a film coating may depend on physical factors of pellets such as the size, shape, density, porosity and formulation factors such as type and amount of coating, the properties and structure of the substrate pellets and the incorporation of excipient particles. The demand for MUPS tablets has been increasing due to its greater advantage over other dosage forms. The present review focuses on compaction and characteristics of multiple unit pellets to tablets.
IDEAL CHARACTERISTICS OF MUPS
1. Should maintain all the tablet properties.
2. Pellets should not show any interaction during compression.
3. Coated pellets should not fuse into a non-disintegrating matrix.
4. Should not lose its coating integrity either by breaking or cracking
5. The pellets should not show any deviation in its release even after compression.
6. Like tablets, MUPS should have ease to packing, storage and transportation.
7. The dosage form must disintegrate rapidly into individual pellets in gastrointestinal fluids.

TYPES OF MUPS FORMULATIONS
MUPS formulations are broadly classified into two types A) MUPS with polymer coated pellets : using different pelletization techniques with all the desired characteristics for compression of pellets. B) MUPS with matrix pellets: used generally in controlled release formulations. These pellets are coated with swellable polymers.

PELLETIZATION
Pellets can be prepared by a special technique called Pelletization. This technique is referred to an agglomeration process that convert fine powder or granules of bulk drug or excipient in to small , free flowing , spherical or semi spherical pellet. This technique is needed to produce pellets of uniform size with high drug loading capacity and also prevent segregation and dust.

ADVANTAGES OF PELLETIZATION TECHNIQUE

1. When formulated as modified release dosage forms, pellets are less susceptible to dose dumping than reservoir type single unit formulations.
2. Pellets are recommended for patients with difficulty in swallowing and dysphasia like in case of children and aged people.
3. Pelletization reduces intra and inters subject variability of plasma profiles by reducing variations in gastric emptying rates and overall transit times.
4. Pelletization produces spheroids with high loading capacity of active ingredient without producing extensively large particles.
5. Pellets exhibit better roundness than the commercial nonpareil seeds and have excellent flow and packing properties.
6. Pellets composed of different drugs can be blended and formulated in single unit dosage form that facilitates delivery of two or more chemically compatible or incompatible drugs at the same or different site in GI tract.
7. Incompatible drugs processed separately and mixed later, or pellets with different release mechanisms can be mixed to give a new modified release profile.
8. Pellets reduce peak plasma fluctuations and minimize potential side effects without appreciably lowering the drug bioavailability.
9. Pellets disperse freely in the GI tract and hence greater absorption of the active drug occurs.
10. Particles less than 2-3 mm rapidly pass the pylorus regardless of the filling level of the stomach or the size and density of chyme. Also, GI irritations are limited spread as the particles spread in the intestine.

MECHANISM OF DRUG RELEASE FROM MULTI-PARTICULATES
The mechanism of drug release from multi particulates can be occurring in the following ways:
Diffusion
On contact with aqueous fluids in the gastrointestinal tract (GIT), water diffuses into the interior of the particle. Drug dissolution occurs and the drug solutions diffuse across the release coat to the exterior.
Erosion
Some coatings can be designed to erode gradually with time, thereby releasing the drug contained within the particle.
Osmosis
In allowing water to enter under the right circumstances, an osmotic pressure can be built up within the interior of the particle. The drug is forced out of the particle into the exterior through the coating.

DESIGN OF MULTIPARTICULATE DRUG DELIVERY SYSTEMS
The purpose of designing multi particulate dosage form is to develop a reliable formulation that has all the advantages of a single unit formulations and yet devoid of the danger of alteration in drug release profile and
Formulation behavior due to unit to unit variation, change in gastro –luminal pH and enzyme population. A generally accepted view is that multi particulate systems perform better in vivo than single unit system, as they spread out through the length of the intestine cause less irritation, enjoy a slower transit through the colon and give a more reproducible drug release. As in the case of single unit dosage forms, for the purpose of the designing multi particulate colon specific drug delivery system, the presence of specific bacterial populations in the colon and increasing pH gradient have been extensively explored as triggering mechanism in order to initiate colon specific drug release.

Multi particulate crystalline drug compositions
A multi particulate for controlled release of a drug comprises a crystalline drug, a glyceride having at least one alkylate substituent of not less than 16 carbon atoms, and a poloxamer, wherein at least 70 wt % of the drug in the multi particulate is crystalline. The multi particulate comprises crystalline drug particles embedded in the glyceride/ poloxamer mixture. The poloxamer 16 is substantially homogeneously distributed throughout the glyceride 14 and is present as a separate phase from the glyceride.
Multi particulates as NDDS
Incorporating an existing medicine into a novel drug delivery system (NDDS) can significantly improve its performance in terms of efficacy, safety and improved patient compliance. In the form of a NDDS, an existing drug molecule can get new life, thereby increasing its market value and competitiveness and even extending patent life
.
Intestinal Protective Drug Absorption System
Intestinal protective drug absorption system (IPDAS) is a multi particulate tablet technology that has been developed to enhance the gastric tolerability of potentially irritant or ulcerogenic drugs such as the NSAIDs. It consists of high density controlled release beads that are compressed into a tablet form. The beads may be manufactured by techniques such as extrusion spheronization and controlled release can be achieved with the use of different polymer systems to coat the resultant beads. Alternatively, the drug can also be coated into on an inert carrier such as non-pareil seeds to produce instant release multi particulates. Controlled release can be achieved by the formation of a polymeric membrane onto these instant release multi particulates. Once an IPDAS tablet is ingested, it rapidly disintegrates and disperses beads containing the drug in the stomach which subsequently pass into the duodenum and along the gastrointestinal tract in a controlled and gradual manner, independent of the feeding state. Release of active ingredient from the multi particulates occurs through a process of diffusion either through the polymeric membrane and /or the micro matrix of the polymer/active ingredient formed in the extruded/spheronized multi particulates. The intestinal protection of IPDAS is by virtue of the multiparticulate nature of the formulation which ensures wide dispersion of irritant drug throughout the gastrointestinal tract. Naprelan, which is marketed in the United States, employs IPDAS technology. This innovative formulation of naproxen sodium is a unique controlled release formulation indicated both for acute and chronic pain
.
Spheroidal oral drug absorption systems
Spheroidal Oral Drug Absorption System (SODAS) is a multi particulate technology that enables the production of customized dosage forms and responds directly to individual drug candidate needs. It can provide a number of tailored drugs release profiles including immediate release of drug followed by sustained release to give rise to a fast onset of action which is mainted for 24 hours. Alternatively, the opposite scenario can be achieved where drug release is delayed for a number of hours.

Programmable Oral Drug Absorption System
Programmable Oral Drug Absorption System (PRODAS) is presented as a number of mini tablets contained in hard gelatin capsule. It thus combines the benefits of tableting technology within a capsule. It is possible to incorporate many different minitablets, each one formulated individually and programmed to release drug at different sites within the GIT. These combinations may include immediate release, delayed release, and/or controlled release mini tablets. It is also possible to incorporate mini tablets of different sizes so that high drug loading is possible. Their size ranges usually from 1.5 – 4 mm in diameter .
Diffucaps
In this multi particulate system, drug profile are created by layering an active drug onto a neutral core such as sugar spheres, crystals or granules followed by the application of a rate-controlling, functional membrane (Figure 4). The coating materials can be water soluble, pH dependent or independent or water insoluble depending on the individual needs of compound. The resultant beads are small in size approximately 1mm or less in diameter. By incorporating beads of differing drug release profiles into hard gelatin capsules, combination release profiles can be achieved. It is possible to customize any combination of sustained release, pulsatile

release and immediate release profiles depending on the specific needs of the product. The drug layering process can be conducted either from aqueous or solvent based drug solutions. Eurand has also developed a formulation technology that combines the customized drug release offered by Diffuses with technologies that enhance the solubility of insoluble drugs in the gastrointestinal tract. Eurand is using this technology to provide a degree of delivery control that goes beyond that of single technology systems. Diffucaps beads are small in size, approximately 1mm in diameter, and are filled into a capsule to create the final dosage form. Beads of differing drug release profiles can be easily combined in a single capsule providing high levels of control over release profiles. Diffucaps beads of different drugs can be combined to make convenient single dose units for combination therapies.

Minitabs
The Eurand MINITABS technology is unique in that it offers the advantages of a tablet combined with those of a multi particulate drug form. Eurand MINITABS are tiny (2mm x 2mm) tablets containing gelforming excipients that control drug release rate. Additional membranes may be added to further control release rate.

The small size of Eurand minitabs means that they can be filled into capsules as a final dosage form. As a result, combination products can be developed to allow for two or more release profiles within a single capsule. Eurand minitabs offer high drug loading, the ability to fine tune release rates for targeted delivery and content uniformity for more accurate dosing. Eurand Minitabs offer high drug loading, a wide range of release rate designs, and fine tuning of these release rates. The capsules can be opened and the contents used as a "sprinkle" formulation.
Stabilized Pellet Delivery System
Stabilized pellet delivery system technology uses functional polymers or a combination of functional polymers and specific additives, such as composite polymeric materials to deliver a drug to a site of optimal absorption along the intestinal tract. The active drug is incorporated in multi particulate dosage forms such as diffucaps or eurand minitabs, which are then subsequently coated with pH dependent/independent polymeric membranes that will deliver the drug to the desired site. These are then filled into hard gelatin capsules. This technology is designed specifically for unstable drugs and incorporates a pellet core of drug and protective polymer outer layer(s) .
Pelletized Delivery System
Pelletized Delivery System (PDS) is a sustained release system using pellets or beads manufactured using marumerization/ pheronization/pelletization techniques or by layering powders or solutions on nonpareil seeds. Release modulating polymers are sprayed on the beads using various coating techniques. The coated beads are filled in to hard gelatin capsules. Drug release occurs by diffusion associated with bioerosion or by osmosis via the surface membrane. The release mechanism can be pH-activated or pH-independent. The beads can be formulated to produce first order or zero order release.
Pelletised tablet
Pelletised tablet system utilizes polymer-coated drug pellets or drug crystals, which are compressed into tablets. In order to provide a controlled release, a water insoluble polymer is used to coat discrete drug pellets or crystals, which then can resist the action of fluids in the GIT. This technology incorporates a strong polymer coating enabling the coated pellets to be compressed into tablets without significant breakage.
Multi particle Drug Dispersing Shuttle
Multi particle drug dispersing shuttle consists of a tablet carrier for the delivery of controlled release beads or pellets through the GIT which preserves the integrity and release properties of the beads. The distribution of the beads is triggered by the disintegration of the tablet carrier in the Stomach. Drug release from the beads is triggered by super disintegration of the tablets. It can be pH-activated or pH-independent and can occur by disintegration or osmosis. The beads can be formulated to produce first or zero order release.
Macrocap
Macrocap consists of immediate release beads made by extrusion/ spheronization/ pelletization techniques or by layering powders or solutions on nonpareil seeds. Release modulating polymers are sprayed on the beads using various coating techniques. The coated beads are filled in hard gelatin capsules. Drug release occurs by diffusion associated with bioerosion or by osmosis via the surface membrane. The release mechanism can be pH-activated or pHindependent. The beads can be formulated to produce first or zero order release.
Orbexa
Orbexa technology is a multi particulate system that enables high drug loading and is suitable for products that require granulation. This technology produces beads that are of controlled size and density using granulation, extrusion and spheronization techniques. This process is unique in that it allows for higher drug loading than other systems, is flexible and is suitable for use with sensitive materials such as enzymes .
Flashtab
Flash tab technology is a fast dissolving/disintegrating oral tablet formulation. It is a combination of taste masked multi particulate active drug
Substances with specific excipients compressed into tablets. A disintegrating agent and a swelling agent are used in combination with coated drug particles in this formulation to produce a tablet that disintegrates in the mouth in less than one minute. These oro-dispersible tablets disperse rapidly before the patient swallow them.
Layering process for multi particulate dosage form
Layering processes involve loading solid inert cores with drugs and/or excipients. Inert cores, placed in a suitable vessel such as a coating pan or a fluid bed, may be layered according to different methods. Some methods consist of spraying onto the cores a solution/suspension containing both drug and binding agent. Others are based on layering the drug directly in powdery form where drug loading occurs by gravity and adhesion is ensured by a liquid binder sprayed onto the cores. The layering process is particularly suitable for production of small drug loaded units, multiples of which are placed into capsules for patient delivery. In the case of spherical inert cores such as non-pareils, the layering techniques from solution/suspensions produce homogeneous drug loaded particles, which retain an approximately spherical shape. They are therefore particularly suitable for successively film coating to build up the particle with the aim of providing a desired drug release profile.
Delayed release oral polypeptides
In one embodiment, the composition further includes an inert core. The inert core can be, e.g., a pellet, sphere or bead made up of sugar, starch, microcrystalline cellulose or any other pharmaceutically acceptable inert excipient. A preferred inert core is a carbohydrate, such as a monosaccharide, disaccharide, or polysaccharide, i.e., a polymer including three or more sugar molecules. An example of a suitable carbohydrate is sucrose. In some embodients, the sucrose is present in the composition at a concentration of 60-75%. When the bioactive polypeptide is IL-11, the
IL-11 layer is preferentially provided with a stabilizer such as methionine, glycine, polysorbate 80 and phosphate buffer, and/or a pharmaceutically acceptable binder, such as hydroxypropyl methylcellulose, povidone or hydroxypropyl ‘cellulose. The composition can additionally include one or more pharmaceutical excipients. Such pharmaceutical excipients include, e.g., binders, disintegrants, fillers, plasticizers, lubricants, glidants, coatings and suspending/ ispersing agents. In some embodiments, the composition is provided as a multiparticulate system that includes a plurality of enteric coated, IL-11 layered pellets in a capsule dosage form. The enteric coated IL-11 pellets include an inert core, such as a carbohydrate sphere, a layer of IL-11 and an enteric coat. The enteric coat can include, e.g., a pH dependent polymer, a plasticizer, and an antisticking agent/glidant. Preferred polymers include e.g., methacrylic acid copolymer, cellulose acetate phthalate, hydroxyl propyl methylcellulose phthalate, polyvinyl acetate phthalate, shellac, hydroxylpropyl methylcellulose acetate succinate and carboxymethylcellulose. Preferably, an inert seal coat is present in the composition as a barrier between the IL-11 layer and enteric coat. The inert seal coat can be e.g. hydroxyl propyl methyl cellulose, povidone, hydroxylpropyl cellulose or another pharmaceutically acceptable binder. Suitable sustained release polymers include, e.g., amino methacrylate copolymers (Eudragit RL, Eudragit RS), ethylcellulose or hydroxypropyl methylcellulose. In some embodiments, the methacrylic acid copolymer is a pH dependent anionic polymer solubilizing above pH 5.5. The methacrylic acid copolymer can be provided as a dispersion and be present in the composition at a concentration of 10-20% wt/wt. A preferred methacrylic acid copolymer Eudragit L30D-55 19.
Multi particulate mucoadhesive formulations
In a preferred embodiment, illustrated by way of example, there is provided a supply of gasdeveloping components as well as a number of film-like, stacked individual particles which consist of a mucoadhesive, active substancecontaining layer and of a backing layer controlling the direction of active substance release, these components being located within a polymer enclosure which is resistant to gastric juice but permeable to intestinal juice. Here, the active substance may be present embedded in the film-like component. The process for the production of a gastric juice-resistant device, consisting of at least one active substance in the form of a
Multi particulate preparation with mucoadhesive properties, and of a blowing agent which on contact with liquid produces gas individual particles being enclosed by a gastric juice-resistant, intestinal juice-soluble polymer enclosure, is as follows:
(a) Transfer of a polymer material in web form to a moulding board provided with bores, and applying a vacuum to form the compartments of the polymer enclosure. (b) Alternately filling-in the active substance-containing preparation and the blowing agent-containing preparation (c) Superposing a second polymer web, and closing the compartments by sealing with application of heat and pressure; and
(d) Separating the individual devices by punching or cutting.

PELLETIZATION TECHNIQUE * The preparation of spherical agglomerates can be approached by several techniques * which can be subdivided into the basic types of systems shown in figure.

* Pelletization * Compaction * Compression * Extrusion / * Spheronization * Layering * Powder * Fluid bed coating * Globulation * Spray * Drying * Spray * Congealin

Powder layering technique This technique involves the deposition of successive layer of drug powder of drug and excipient or both on preformed nuclei or core with the help of a binding liquid. During powder layering the binding solution and finely milled powder are added simultaneously to a bed of starter seeds at a pre-determined controlled rate .

In initial stages the drug particle are bound to the starter seeds of subsequently to the forming pellets with the help of a liquid bridges originated from sprayed binding liquid .These liquid bridges are replaced by solid bridges derived either from a binder in the liquid medium or from any material. Successive layering of a drug and the binder solution continuous until desired pellet size are reached. The first equipment used to manufacture pellets on commercial scale was the conventional coating pan but it has significant limitation that is the degree of mixing is very poor and the drying process is not efficient. Throughout the processes it is extremely important to deliver the powder accurately at a predetermine rate and in a manner that maintains equilibrium between the binder liquid application rate and powder delivery rate is not maintained ,over wetting or dust generation may occur and neither the quality nor the yield of the product can be maximized .More over the fines may be generated by inter particle and wall to particle friction and appear in the yield. The above problem can be overcome if the application medium is sprayed on the cascading pellets at the end to increase the moisture level at the pellets surface and facilitate layering of fines on to the pellets. For this purpose now it is equipment like tangential spray granulator and centrifugal bed granulator are used.

2. Suspension /Solution layering technique This technique involves the deposition of successive layer of solution and /or suspension of drug substances and binders on starter seeds which may be inert material or crystal of granules of the same drug. In this technique drug particles and others component are dissolved or suspended in the application medium .

The droplets impringe on the starter seeds or cores and spread evenly as the solution or suspension is sprayed on the cores. Followed by drying phase allows dissolved material to crystallize and form solid bridges between the cores and initial layer of the drug substances and among the successive layer of drug substances or polymer. Continue this process until the desired layer of drug or polymer formed.Consequently conventional coating press, fluidized bed centrifugal granulator of wurster coater have been used successfully to manufacture pellets. The most common configuration for bottom spray coating is known as the Wurster system. Inthis study solution/ layering of neutral pellets has been conducted applying novel fluidized bed technology from .This technology claims to improve the product movement in defined direction in all the equipment by the Disk jet gas distribution plate. Furthermore, a 3-component spray nozzle isused in order to improve the film formation on the pellets due to constant and reproducible drop size distribution. Accessibility of clogged nozzles without stopping and interrupting the process makes the equipment advantageous in respect to Wurster system. Hüettlin’s three component nozzle is an air nozzle with an additional channel through which a second gas or component can be introduced to create a special microclimate around the nozzle which prevents excessive spray drying or clogging of the nozzle. Such Journal of Current Pharmaceutical Research 2012 ;9 (1): 19-25 microclimates near nozzle apertures are very useful when a film former with a relatively high minimum film-forming temperature
(MFT) issued. The MFT of aqueous shellac suspensions, for example, lies between 35 and 55°C, depending on the plasticizer selected. 3. Extrusion and Spheronization Extrusion spheronization was developed in the early 1960s as a pelletization technique. The extrusion-spheronization process is commonly used in the pharmaceutical industry to make uniformly sized spheroids.It is especially useful for making dense granules with high drug loading for controlled-release oral solid dosage forms with a minimum amount of excipients. Extrusion spheronization is a multi-step compaction process comprising of following steps.
I. Dry mixing
Dry mixing of all ingredients is done to get homogeneous powder dispersion or mixer using different types of mixers like twin shell blender, high shear mixer, tumbler mixer and planetary mixer.

II. Wet Massing
This process of powder dispersion is done to produce a sufficient plastic mass for Extrusion. It is similar to the wet granulation method but the granulation and point is determined by the behaviour of the wetted mass during the extrusion operation
The most commonly used granulator is Planetory mixer or sigma blade mixer or high shear mixer and Horbat mixer.

Figure : Snap shot of spheronization process

III. Extrusion
This is a method of applying pressure to a mass until it flows through an opening and determine two dimension of an agglomeration of particles .This operation is the major contributing factor in the final particle size of the pellets. In this process the wetted mass is passed through the extruder to form rod shaped particles of uniform diameter. The extrudate must have enough plasticity to deform but not so much that the extrudate particles adheres to other particles when rolled during spheronization process. The granulation solvent serves as the binding agent to form the granules and as the lubricating during the extrusion operation.

IV. Spheronization
This process is used to round up these rod shaped particles in to spherical particle in to spherical particle with narrow size distribution. The instrument used is called Spheronizer where the extrudate is rotated at higher speed by friction plate that breaks the rod shaped particles in to smaller particles and rounded them to form spheres.

V. Drying
In order to get desired moisture content in pellets a drying stage is required the pellets are dried at room temperature or at a elevated temperature in a tray dryer or in a fluidized bed dryer,according to DI.Wilsom et. Al, 2006 freeze drying method retains the shape and size and the granules whereas the oven drying produce rough granules.
VI. Screening
It is necessary to achieve the desired size distribution and for this purpose sieves are used. Based on the type of feed mechanism and to transfer the mass towards the die, Variety of extruders is used in the above mentioned technique. These extruders are classified in to following classes
i. Screw fed extruders
The screw rotates along the horizontal axis and hence transports the material horizontally. They may be of two types:
a) Axial screw extruders- These have a die plate that is positioned axially, consist of a feeding zone, a compression zone, and an extrusion zone.
b) Radial screw extruders-The transport zone is short, and the material is extruded radially through screens mounted around the horizontal axis of the screws. ii. Gravity-fed extruders:
These are of two types, which differ primarily in the design of the two counter-rotating cylinders.
The Rotary Cylinder - One of the
a) two counter-rotating cylinders is hollow and perforated, whereas the other cylinder is solid and acts as a pressure roller.
b) Rotary-Gear Extruder: There are two hollow counter-rotating gear cylinders with counter bored holes iii. Ram Extruders:
This is probably the oldest type of extruders; a piston displaces and forces the material through a die at the end. These extruders are preferentially used in the development phase, because they can also measure the rheological properties of formulations. iv. Marumerizer:
It consists of a two parts:
a) Static cylinder or stator
b) Rotating friction plate.

A typical friction plate has a crosshatch pattern, where the grooves intersect at a 900 angle. The rotational speed of the friction plate is variable and ranges from 100 to 2000 rpm; depending on the diameter of the unit. Spheronizer friction plate with a crosshatch pattern.

4. Spherical Agglomeration
Spherical agglomeration, or balling, is a pelletization process in which powders, on addition of an appropriate quantity of liquid or when subjected to high temperatures, are converted to spherical particles by a continuous rolling or tumbling action. Spherical agglomeration can be divided into two categories— Liquid-induced and Melt-induced agglomerations.
Liquid-induced agglomeration: During liquid-induced agglomeration, liquid is added to the powder before or during the agitation step. As powders come in contact with a liquid phase, they form agglomerates or nuclei, which initially are bound together by liquid bridges. These are subsequently replaced by solid bridges, which are derived from the hardening binder or any other dissolved material within the liquid phase. The nuclei formed collide with other adjacent nuclei and coalesce to form larger nuclei or pellets. At this point, coalescence is replaced by layering,
Whereby small particles adhere on much larger particles and increase the size of the latter until pelletization is completed.
Melt-induced agglomeration: Melt-induced agglomeration processes are similar to liquid-induced processes except that the binding material is a melt. Therefore, the pellets are formed with the help of congealed material without having to go through the formation of solvent-based liquid bridges. If the surface moisture is not optimum, some particles may undergo nucleation and coalescence at different rates and form different sizes of nuclei admixed with the larger pellets. As a result, spherical agglomeration tends to produce pellets with a wide particle size distribution.
5. Spray Drying and Spray Congealing
Spray Drying and Spray Congealing, also known as globulation process, 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.
Spray Drying: The drug entities in solution or suspension are sprayed, with or without excipients, into a hot air stream to generate dry and highly spherical particles. As the atomized droplets come in contact with hot air, evaporation of the application medium is initiated. This drying process continues through a series of stages whereby the viscosity of the droplets constantly increases until finally almost the entire application medium is driven off and solid particles are formed. Generally, spray-dried pellets tend to be porous.
Spray Congealing: This process consists of suspending the particles in a molten coating material and pumping the resultant slurry into a spray dryer in which cold air is circulated. The slurry droplets congeal on contact with the air. The coating agents normally employed is low melting materials such as waxes. The congealing process require higher ratio of coating agents to active material than does the spray drying, because only the molten coating agent constitutes the liquid phase.
6. Melt Spheronization
Melt Spheronization is a process whereby a drug substance and excipients are converted into a molten or semi molten state and subsequently shaped using appropriate equipment to provide solid spheres or pellets. The drug substance is first blended with the appropriate pharmaceutical excipients, such as polymers and waxes, and extruded at a predetermined temperature. The extrusion temperature must be high enough to melt at least one or more of the formulation components. The extrudate is cut into uniform cylindrical segments with a cutter. The segments are spheronized in a jacketed Spheronizer to generate uniformly sized pellets.
7. Cryopelletization:
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 technology, which was initially developed for lyophilization of viscous bacterial suspensions, can be used to produce drug-loaded pellets in liquid nitrogen at -1600C. 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 amount of liquid nitrogen required for manufacturing a given quantity depends on the solids content and temperature of the solution or suspension being processed. The equipment consists of a container equipped with: Perforated Plates A Reservoir Conveyor belt with Transport baffles Storage Container 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 - 600C before drying.

FACTOR AFFECTING PELLETIZATION TECHNIQUE 1. Moisture Content:
It is one of the critical parameter for pellet growth in pelletization technique .Moisture in the wet mass bring cohesiveness to the powder so that the wet mass can be extracted and spheronize to give spherical shape. High moisture contents lead to agglomeration of pellets during the process of spheronization which is one of the technique of pelletization due to excess of water in the surface of pellets and low moisture content lead to generation of fines with large variation in size
2. Rheological characteristics:
The Rheological condition of the wet mass determines the flow ability in extruder optimum Rheological condition leads to good flow ability in order to extrude the wet mass variation in rheology make improper and non-uniform extrusion.
3. Solubility of excipients and Drug in granulating fluid :
A soluble drug get dissolve in a granulating liquid .Thus increasing the volume of liquid phase lead to over wetting of system of agglomeration of pellet sand increase in wetting liquid increases plasticity but induces sticky mass
4. Composition of Granulating Fluid :
Besides water, alcohol,water / alcohol mixture, Ethyl Ether, Dilute Acetic Acid, Isopropyl alcohol is also used as a granulating liquid. According to researcher likeMillili and Schwartz, a minimum of 5 % of granulation liquid have to be water in order to produce pellets be water in order to produce pellets containing Avicel pH (101) and theophylline (Millili, G.P.,1990).Some researchers used water and dilute acetic acid in different powder to liquid ratio and concluded that mass fraction can be increased up to 100% by using dilute acetic acid for granulation step in place of demineralized water . Aqueous polymer dispersion containing Eudragit, Hydroxy Propyl Methylcellulose (HPMC), Poly vinyl pyrrilodine (PVP) and Gelatin is used in the moistening liquid.
5. Physical Properties of Starting Material :
Formulation variable such as type and content of starting material, type of filler and particle size of constituent have the effect on the pelletization process. Quality of pellets depends not only composition but also on different grades of the same product. The swelling property of material used in pelletization technique decides the release rate of the drug in pellets.
6. Speed of the Spheronizer :
The speed of the spheronizer affects the size, hardness, sphericity and density of pellets, high speed gives high sphericity, lower friability,smooth surface and higher crushing strength
7. Drying technique and drying temperature :
It is important to get proper size, shape and flow of pellets and it must be reproducible and consistent in all the batches.Variation in pellet's size, shape and flow will lead to difference in physicochemical properties of final dosage form like weight variation, improper filling etc, which will further affect the therapeutic efficiency of the delivery system. Wider particle size distribution may lead to variation in the dose of drug delivery. Variation in shape may lead to variation in flow and compressibility.
8. Extrusion Screen :
The quality of the extrudate/ pellets is greatly influenced by the characteristics of the orifice of the screen. An increase in orifice dimension resulted in increased mean pellet size. The increase in orifice depth decreased with the presence of water at the extrudate surface, increasing the extrusion force, and then had a negative effect on granulometric distribution and on shape.

Principle of operation of fluid bed coating * With fluid bed coating, particles are fluidized and the coating fluid sprayed on and dried.
Small droplets and a low viscosity of the spray medium ensure an even product coating 3 criteria of fluid bed coating are: a. Top Spray Coating
b. Bottom Spray Coating
c. Tangential Spray Coating (Rotor Pellet Coating)
Fluid Bed Coating
Spray coating can be used for all fluid bed systems, be it in batch or continuous operation or if the film is applied from a sprayed solution, suspension or hot melt. For this processing option the parameters have to be chosen to avoid agglomeration, i.e. liquid bridges between the air suspended particles. If spraying a solution or suspension the liquid only serves as a vehicle to deliver the coating material to the surface of the substrate. For hot melt coating the droplets must be small enough not to form solid bridges.
The quality of the coating extensively depends on the statistical residence time of the particles in the coating zone. For a classic fluid bed unit only top-spray coating is possible. Bottom-spray or tangential-spray coating inserts can also be hosted by means of the relevant technical provisions.

Top-Spray Coating
This processing option is frequently used by the food, feed and chemical industries as the function of the film mainly serves to improve the general handling or storage times, i.e. time limited protection against moisture, oxygen or light. A perfect film is generally not required for this function, but care must be taken that the droplets do not become too viscous before touching the substrate, in order to maintain a good spreadability. As however neither the particle motion, nor the travel distance of droplet from nozzle to substrate are uniform the film structure is generally rather porous, but nevertheless measuring up to the above described requirements.

Bottom-Spray Coating
This processing option uses the energies and controls of the fluid bed to create a pneumatic mass transport inside a special insert, which consists of a perforated bottom screen with defined free areas. Most of the process air is channeled through the center via a tube, as such producing a venturi effect, which sucks the product from outside the partition past the spray nozzle. Leaving the cylindrical partition and entering the conical expansion chamber the particle velocity is dramatically reduced, excess moisture is rapidly evaporated with the dry product returning again and again through the coating zone to receive more coating material. This uniform statistical residence time of all particles in the coating zone results in a very homogenous coating. Due to the high kinetic energy provided by the pneumatic mass flow moist particles are separated, as such allowing the individual coating of even very small particles. Due to the nozzle being positioned directly inside the product and concurrently spraying a premature viscosity change of the coating droplet is avoided. All this features result in the highest possible coating quality, which is imperatively required to produce defined and reproducible drug delivery profiles.

Tangential Spray Coating
This processing technique is with its physical principles quite similar to bottom-spray coating, only that the production motion is provided by a motor driven rotor disc. Otherwise, the quality producing parameters are the same: • | Uniform statistical residence time is warranted by defined rotor revolution speed | • | The coating material is sprayed concurrently inside the rotating product | • | The rolling motion of the particles provide an even higher separation force, as such preventing agglomeration. However, this high kinetic energy makes it somewhat difficult to coat very small particles and is generally destructive for larger and non-spherical products. The benefits of this processing option are mainly for the layering and subsequent filmcoating of pellets. |

Challenges Associated With Compression Of Coated Pellets:
Compression of a coated pellet is a challenging task as the polymeric coating may not withstand the compression force and the drug release may vary due to the unpredictable concentration of deposited polymer left after compaction process and altered surface area during in-vivo dissolution. The optimization of various process variables like compression force required, velocity of the punches, hardness, thickness and porosity of the tablets to be maintained is required.
The surface area of tablet containing pellets can be maintained by compressing material to form a tablet with cup shape. The parameters to be considered during compression of pellets are presented briefly here.
Nature of Polymer:
The polymer used in preparation of pellet plays an important role in drug release after compression. It must have sufficient elastic properties to prevent rupture of coating polymer and plastic properties to accommodate the changes in shape and deformation during tableting. Ethyl cellulose possesses weak mechanical properties and hence the pellets compacted with ethyl cellulose showed loss of sustained properties. Use of pseudo latexes plasticized ethyl cellulose showed minimal effect on mechanical properties of ethyl cellulose making it brittle with low values of puncture strength and elongation. Compression of ethyl cellulose coated diltiazem hydrochloride tablets showed faster drug release compared to non compressed pellets indicating the loss of release properties.5
The coatings prepared from organic solvents of ethyl cellulose were more resistant to compaction compared to that of aqueous solutions. The films formed by using organic solvents showed better mechanical properties. To reduce the damage to coating, compressed pellets can be kept in hot air oven above the glass transition temperature which resulted in covering of ruptures due to compression.3 Brittle character of ethyl cellulose can be overcome by using multilayered beads consisting of alternating layers of ethyl cellulose, drug or cushioning agent.
Crystals, granules or pellets coated with aqueous acrylic polymer dispersions (Eudragit NE 30D, Eudragit RS/RL 30D) were more flexible than ethyl cellulose films and they can be compressed with little damage to the coating.3

Thickness of Polymer Coating:-
In general, a thicker coating can prevent damage due to compression than the thinner coating. The deformation characteristics changed with the increased coating. Ability of pellets to undergo plastic deformation as well as elastic deformation increased with increasing coating level.3 However, an increased coating level caused decrease in tensile strength, yield pressure and increased elastic recovery on ejection. Increasing the punch velocity resulted in decrease in tensile strength of the compacts and increase in both yield pressure and elastic recovery values. The punch velocity dependence increased with increased coating levels.3 Irrespective of compaction pressure and coating level, the pellets lost their sustained release properties due to compaction.
Pellet Core:-
Not only the film but also the core of pellet should also have sufficient flexibility. It must possess some degree of elasticity, which can accommodate changes in shape and deformation during tableting. It should deform and recover after compression without damage to the coating. Harder pellets were able to withstand compression forces as they deformed to a lesser degree.6 Compactability of lactose rich pellets was better than that of micro crystalline cellulose pellets. The poor compactability of micro crystalline cellulose pellets is due to loss of plasticity during wet granulation process. Lactose/micro crystalline cellulose beads were more compressible and exhibited more fracture than micro crystalline cellulose beads.7 Dicalcium phosphate/microcrystalline cellulose beads underwent plastic flow more easily than the other two bead formulations, had a higher degree of fracture and were more compressible.
MCC pellets containing the plasticizers such as PEG 6000 in the powder mixture can modulate compression behavior of pellets without marked changes in the main dimensions and porosity of the pellets. MCC based bead formulations incorporating wax is more compressible than those made without wax. Presence of wax made the compact to undergo elastic recovery. Hence the desired compaction profile can be obtained by changing bead formulation.
Porosity:-
Increased pellet porosity increased the degree of deformation of pellets during compression and tensile strength of tablets because of formation of stronger inter-granular bonds. The effect of intragranular porosity on drug release is also high. Compacted pellets of high porosity were densely packed and deformed. So the drug release was unaffected. The drug release was markedly increased when low porosity pellets were compacted due to slight densification and deformation. So the use of highly porous pellets was advantageous, in terms of preserving the drug release profile after compaction, compared with pellets of low porosity.8
Porosity of pellets depends upon materials such as granulating fluid used in their formation. Increasing the amount of water in the mixture resulted in harder and less porous tablets and a slower drug release. Pellets prepared using 95% ethanol had excellent compressibility compared with that of water3.
The final porosity attained after compaction depends on pressure applied. Unlubricated pellets require higher pressures than lubricated.3
Size:-
The size of the pellets also affects compaction properties and drug release from the compacted pellets. At the same coating level, smaller pellets were more fragile than larger pellets. This is due to the reason that increased surface area resulted in reduced film thickness9 It was also found that increase in particle size resulted in more damage to the coating, as indicated by larger difference between the release profile of tablets and uncompressed pellets.
Shape:-
Shape of the pellets was found to affect the compression behavior and tablet forming ability of granular materials. More irregular shape induced more complex compression behavior of granules i.e., more attrition of the granules was induced and increased deformation was resulted4. Isometric shaped pellets offer less contact points and uniform drug release when compared with anisometric shaped particles.
Density:-
Density of pellet is required to achieve prolonged gastric residence. The critical density to achieve prolonged gastric residence may lie between 2.4 to 2.8g/cm3 4
Density and size of the pellets play an important role for achieving content and weight uniformity. Segregation may occur when pellets are compressed using excipients with smaller particle size and density.
Use of pellets with a narrow size distribution along with excipients of similar size, shape and density can prevent seggregation10.
Hardness Of Pellets:-
Harder pellets coated with Eudragit L30 D-55 were able to resist the compression forces better when compared with softer, more porous pellets, which deform easier and therefore resulted in a higher degree of film rupture.
Compression Force:-
It is one of the critical parameter that must be optimized. A compaction force of 15KN was required to obtain tablets with a smooth surface. Lower compression forces may result in tablets with granular appearance. The compaction induced pellet deformation was practically complete at 6KN and no change indissolution rate was observed upon increasing the compression force to 20KN for the pellets of theophylline prepared using Eudragit NE 30 –D. Compression force is decided by Hiestand indices.
Tableting Excipients:-
Several excipients have to be used to assist the compaction process and to prevent rupture and damage of the coated pellets during compression. When, reservoir pellets are compacted without including any excipients, disintegration of the tablet cannot be ensured and matrix tablets are often formed.
An ideal excipient should prevent the direct contact of pellets and act as cushion during compression. It should fill the void space to prevent adhesion and fusion of coated pellets during compression. The filler excipient can be either primary powder particles or in the form of secondary agglomerates such as granules or pellets. The use of agglomerates is preferred because of low risk of segregation owing to difference in particle size.
The physical integrity of tablet components can be maintained by using a polar organic solvent for the preparation of cushioning beads of micro crystalline cellulose (MCC). More compressibility can be achieved by the use of freeze dried MCC. Along with MCC beads, when a hydro carbon wax was incorporated with it, damage of the coat can be minimized. Inclusion of approximately 30% of excipients in the tablet formulation is most often needed to fill the void space between the coated pellets, and to prevent separation of the coatings, so that no significant changes observed in damaging to coatings or drug release.
With respect to excipient particle size, particles smaller than 20μm were found to protect the coating irrespective of excipient material used, while larger excipient particles increased the dissolution rate on compaction. It was found that small MCC particles increased dissolution rate.
Differences between the particle size and density of pellets and that of excipient particles lead to segregation of the pellets from the powder blend. The segregation may also result due to vibration and centrifugal force of rotary compression machine. This may result in weight variation and content uniformity problems.
One Step Dry-Coated Tablet Technology (OSDRC):
This technique involves three compression stages. In the first stage, a small amount is compressed which forms the outer layer. In the second stage, first outer layer/core layer complex is formed and in third stage, whole tablet containing upper outer and side outer layer is formed. The first and last layers contain diluents with good formability characteristics while the core layer contains pellets. So the segregation problem does not arise and therefore weight variation and content uniformity problems can be nullified.
Another different approach is to layer the cushioning agents as extra coating layers to the reservoir pellets. One such layer is poly ethylene oxide. It hydrates and forms a sealant for the cracks formed in the rupture polymer coating.
EVALUATION OF PELLETS
1. Size Distribution
The sizing of pellets is necessary because it has significant influence on the release kinetics Particle size distribution, mean ferret diameter, geometric mean diameter, mean particle width and length, are the parameters by which size of pellets can be determined. In most of the cases particle size determination is carried out by simplesieve analysis using sieve shaker.
2. Pellets Shape
Sphericity of the pellets is the most important characteristics and various methods have been used to determine it. The shape factor estimates the amount by which the projected image of particles deviate from a circle and it is calculated by means of the projected area of the pellets and its circumference .For acceptable quality of pellets the roundness index/shape factor should be between 1 and 1.2. For perfectly circular projected image, the shape factor should be 1 while a value of 0.6 describes a particle of good sphericity. Visual inspection of pellets by microscope and stereomicroscope is another method to determine shape of pellets. One plane critical stability, which an angle at which a plane has to be tilted before a particle begins to roll, is one of the important methods used for determining shape (Bornhoft M., 2005). The angle of repose is an indirect indication of the circularity of pellets and is calculated by the ratio of double the pile height and pile radius by fixed funnel method measured after a certain amount of pellets are allowed to fall from a given height through a specific orifice.
3. Surface Morphology
Scanning electron microscopy is used to examine the surface morphology and cross section of pellets.Soodet al. in 2004 reported the use of optical microscopy to examine the microstructure of pellet surface . Some researcheranalyzed surface roughness of pellets by applying a noncontractinglaserprofilometer.

4. Specific Surface Area
Surface area of pellets is directly related with size andshape of the pellets. of the surface area is desirable especially if film coating is considered. Knowledge about the surface area is important even in case of uncoated pellets, since drug release isinfluenced bythesurface area. Specific surface area of pellets is determined by gas adsorption technique.
5. Friability
The mechanical properties of pellets are important for processing. Pellets flake off during handling and coating process resulting in formation of dust. In the case of subsequent coating it is desirable to have pellets with low friability. Friability of pellets are determined by using Erkewa type tablet friabiliator or turbula mixer for a fixed period of time combined with glass beads of certain diameter in order to generate abrasion. Friability can also be determined using fluidized bed with Wurster insert by using stream of air application.
1. Taste masking
Micropellets are ideal for products where perfect abatement of taste is required. Although various technique have been utilized to mask the bitter taste of a drug such as the addition of sweetners and flavours, filling in capsules, coating with water insoluble polymers or pH dependent soluble polymers, complexing with ion-exchange resins, microencapsulation with various polymers, compelxing with cyclodextrins and chemical modifications such as the use of insoluble prodrugs, few reports have described the masking of unpleasant taste without lowering of bioavailability especially for oral products. The micropelletization technique solves difficult taste masking problems while maintaining a high degree of bioavailability due to their high surface area, especially for oral products. Furthermore, because of the special design of the manufacturing process, dust fractions that representing an uncoated fragments which could cause taste problems are absent in micropellets. Many products, such as antibiotics (clarithromycin, roxithromycin and cephelexin) and anti-inflammatory drugs with a prohibitively bitter taste, can now be formulated in products with high patient compliance, thus markedly increasing the sales potential of the product.
2. Immediate release
Administering drugs in pellet form leads to an increased surface area as compared to traditional compressed tablets and capsules. This would considerably reduce the time required for disintegration and have the potential for use in rapidly dispersible tablets. 3. Sustained release
The pellet form provides a smoother absorption profile from the gastrointestinal tract as the beads pass gradually through the stomach in to the small intestine at a steady rate. Pellets are being increasingly used in the manufacture of sustained release dosage form of drugs. The advantages of the dosage form is well known and some examples are given below
Extend day time and night time activity of the drugs.
Potential for reduced incidence of side effects,
Reduced dosage frequency of dosage forms,
Increased patient compliance, patients who are required to take 2 or more doses of formulation a day are thought to be less likely to forget a dose then if they are required to take 3 or 4 times a day,
Potential lower daily cost to patient due to fewer dosage units,
In contrast the whole tablet is released at once in to the small intestine as the stomach empties itself, and
Different type of polymers e.g. carboxymethylcellulose, ethylcellulose, Eudragit etc., are utilized for coating of different drugs to enable the sustained release/controlled release rate of drugs. Pellets ensure improved flow properties and flexibility in formulation development and manufacture. If the pellet surface is smoother it allows thin or thick coat of the polymer on the surface of the pellets. The thickness of the coat determines the rate at which the drug is released from the coated pellets. The coating material may be colored with a dye materials so that the beads of different coating thickness will be darker in colour and distinguishable from those having fewer coating. It is widely used for frequently administered drugs having a half-life of 0.5-2 hr. The excellent reproducibility and homogeneity of the particle size and the round shape and smooth surface of the particles makes micropellets with sizes smaller than 200mm a perfect match for powder injections. In addition, the very high drug substance load level of the micropellets promotes lower injection volumes, thus increasing patient acceptance. Many drug substances, e.g. neuroleptics, peptides, hormones, therapeutic proteins; vaccines etc. in need of slow release formulations are product candidates for this technology. Micropellets have thus opened a new dimension in parenteral depot technologies. Drug substance particles can either be coated with biodegradable polymers or embedded in a polymer matrix. Using these approaches, release profiles ranging from days to months and even pulsed release can be obtained at wish. The release rate of drugs from the polymer coat can be modified using various concentration of plasticizer and influence of pH. Even they are useful as drugs, the necessity of frequent injection makes them inconvenient and often causes pain and trouble to patients.
4. Chemically incompatible products
At times such ingredients are required to be delivered in a single dose. In the compressed tablet dosage form separate tablets would have to be administered, but the pellets can be administered in a single capsule.
5. Varying dosage without reformulation
Pellets have excellent flow properties, due to this, they can be conveniently used for filling capsules and the manufacturer can vary the dosage by varying the capsule size without reformulating the product.

Disintegration and Dissolution Behavior of MUPS:
Since MUPS are often designed to possess particulates having modified release characteristics, they are expected to disintegrate in one of the following ways –
1. Rapid disintegration in the oral cavity, if the MUPS contains taste-masked coated particles or modifiede release coated particles but designed as a compact in an or dispersible base (orally disintegrating tablets) e.g. Prevacid SoluTab.
2. Rapid disintegration in the gastrointestinal tract after oral administration or swallowing, e.g. Losec MUPS.
3. Slow and gradual erosion of MUPS in the GIT to release polymer-coated particles slowly, e.g. Toprol XL. The dissolution behavior of individual coated
Multi particulates that separate out as a result of disintegration of MUPS, follow the one that is expected of such particles and is often dictated by the type of coating or matrix design of such pellets.
Formulation Approaches to Prevent Destruction of Drug Release Characteristics and other Attributes of Compacted MUPS:
Several approaches have been employed to prevent damage to the pellet coating membrane during compaction of MUPS and can be categorized into following means –
1. Modulation of fillers or cushioning excipients
2. Modulation of pellet coating
3. Modulation of pellet core
Cushioning fillers/excipients:
Cushioning excipients are those that take up the pressures of compaction by re-arranging themselves within the tablet structure or by preferentially getting deformed and/or fractured. Thereby preventing damage to the coating on drug pellets. They can be categorized further into two classes:-
a. Conventional powder excipients:-These include excipients such as microcrystalline cellulose, lactose, etc. and their blends. Disintegrates are also used as part of such excipients. A proper blend of deformable materials, e.g. microcrystalline cellulose and material that fractures e.g. lactose is often required to provide optimum cushion.
b. Cushioning pellets:- These are normally more porous and soft compared to coated drug pellets and normally made of excipients which are used as cushioning excipients. The drug pellets-to-cushioning excipient(s) ratio is very critical in preventing coating film damage – a ratio of 1:3 or 1:4 is considered most suitable.18 Ideally speaking, the amount of cushioning excipients used should be sufficient to – Facilitate good cohesion of tablet ingredients, and produce mechanically strong tablets at low compression forces that can withstand subsequent stresses of further processing, transportation and handling,· Yield tablets having elegant surface topography, and when exposed to aqueous environment, aid rapid disintegration of tablets (preferably less than 15 minutes) that result in separation of discrete pellets free from fusion with other pellets. Hard, less porous and noncompressible materials such as inorganic salts are unsuitable for use as cushioning excipients. Homogeneous mixtures of pellets and filler-binders are crucial to obtain tablets of uniform weight and drug content, and thus to ensure a high reproducibility in production.

Modulation of Pellet Coating:
After compaction into MUPS, maintenance of integrity of functional coating present on the surface of drug pellet is vital for preservation of desired product characteristics, which could be taste masking, sustained-release, delayed release or drug stability. Approaches adopted to retain the characteristics of applied membrane coating include:-
a. Use of more elastic coating composition: - Coating films have been made more elastic to withstand pressures of compaction by use of more elastic materials such as acrylic polymers instead of cellulosic polymers, use of more quantity of plasticizers or a more efficient plasticizer, etc. However, there should not be tendency of coated pellets to fuse with each other. Fusion tendency of pellets during compaction can be reduced by incorporation of lubricants and pigments such as talc in the coating composition but such materials are known to reduce elasticity of coating.
b. Increased thickness of coating:- Thicker but elastic polymeric coat can better withstand the deformation and rupturing forces of compression in comparison to thinner coatings.
c. Elastic/thermoplastic layer on the outer surface of drug pellets:- Presence of an outer coating comprising of thermoplastic material such as carbowaxes on the surface of drug pellets, on which is applied the functional polymer coating, is known to absorb the stresses that may otherwise tear or fissure the outermost surface coating.
d. Powder layer over the surface of polymer coated pellets:- Application of an integral but porous powder layer on the outside of polymer coated pellets results in preferential damage to the powder shell resulting in its breakage thus preventing/reducing transmission of compaction force to polymer coated core drug pellet present beneath.
Modulation of Core Pellet:
Besides the role of polymer coating on the pellets, the nature of core drug pellet can dramatically influence the damage to its own structure and the coating on its surface. Following pellet-related factors influence compaction
Characteristics:-
a. Composition:- Besides the inherent nature of drug, the other excipients that comprise core pellets can influence compaction characteristics. Presence of hard and brittle materials produce rigid pellet core that resists bulk deformation while elastic/plastic materials such as microcrystalline cellulose get easily deformed.

b. Pellet porosity:- If the pellets being compacted are coated, during compaction, pellet deformation (change in shape of pellets) and densification (reduction in pellet porosity) occurs to a larger extent while fragmentation is seen to a lesser extent. Porous pellets get more deformed during compaction, due to the higher freedom degree of rearrangement of the powder particles within them. On the other hand, more compact pellets are more intensively buffered during compaction by powder particles, because they cannot widely rearrange.
c. Pellet size:- Larger pellets deform more easily than smaller pellets.
d. Pellet elasticity:- Findings of various researchers on elasticity of core pellets are discordant. Bodmeier et al. claimed that the bead core should possess some degree of elasticity, in order to accommodate changes in shape and deformation during tabletting. To sum up, pellets that are smaller in size, stronger mechanically, less porous and more uniform in size distribution are more suited for compaction without deformation than pellets with wide size distribution, greater porosity, larger size and mechanically soft. Further, the polymer coating on such core drug pellets should be thick and elastic21. Often a combination of above approaches can be employed to result in a MUPS that retains the desired drug release and product characteristics. Even if compaction of coated particles do not result in destruction of coating, there still exist two possible outcome of compaction on drug release profile of coated pellets:-
a. Faster drug release:-The deformation of the substrate pellet may stretch out the coating, making it thinner or more permeable, which has a negative effect on the control of the drug release. This often explains that the release rate increases with increased irregularity of the compacted reservoir pellets.
b. Prolonged drug release:- The densification of the substrate pellet may compress the coating, making it thicker or less permeable, and consequently prolong the drug release.
Matrix pellets:- Pellets which inherently contain excipients that retard drug release by being contained within the matrix of pellet structure, for example matrix pellets of swellable polymers or waxes, retain their controlled release characteristics to a larger extent even on compression since the release of drug from such pellets depend upon swelling or erosion of matrix rather than by diffusion through the membrane.23,24 However, an important point that needs consideration in the design of MUPS of such matrix pellets is fusion of pellets with each other during compaction which may not be obvious during compression of coated pellets. Fusion of matrix pellets as a result of compaction can be avoided by application of film coating on such pellets or excessive blending with a hydrophobic agent separately prior to mixing them other extra granular materials before compression into tablets.

Figure: Illustrates the MUPS comprising of reservoir and matrix pellets, figure 2 represents the approaches adopted for preparation of MUPS without damaging the membrane coating while figure 3 portrays the impact of compaction on pellet deformation and drug release.

Significance The rationale in formulating MUPS is to design: a. controlled release, b. sustained release, c. delayed release and d. colon targeted drug delivery system. oral disintegrating taste-masked dosage form, combining drugs with different release characteristics in the same dosage form.
The drug dose administered in modified release form can be increased as compared with other dosage form and enhance the stability of dosage form.
MUPS drugs disintegrate rapidly in water

Controlled release,
Controlled drug delivery systems can include the maintenance of drug levels within a desired range, the need for fewer administrations, optimal use of the drug in question, and increased patient compliance. While these advantages can be significant, the potential disadvantages cannot be ignored like the possible toxicity or non-biocompatibility of the materials used, undesirable by-products of degradation, any surgery required to implant or remove the system, the chance of patient discomfort from the delivery device, and the higher cost of controlled-release systems compared with traditional pharmaceutical formulations. The ideal drug delivery system should be inert, biocompatible, mechanically strong, comfortable for the patient, capable of achieving high drug loading, safe from accidental release, simple to administer and remove, and easy to fabricate and sterilize. The goal of many of the original controlled-release systems was to achieve a delivery profile that would yield a high blood level of the drug over a long period of time. With traditional drug delivery systems, the drug level in the blood follows the in which the level rises after each administration of the drug and then decreases until the next administration. The key point with traditional drug administration is that the blood level of the agent should remain between a maximum value, which may represent a toxic level, and a minimum value, below which the drug is no longer effective.
POLYMER USED IN CONTROL DRUG DELIVERY SYSTEM
Polymers are becoming increasingly important in the field of drug delivery. The pharmaceutical applications of polymers range from their use as binders in tablets to viscosity and flow controlling agents in liquids, suspensions and emulsions. Polymers can be used as film coatings to disguise the unpleasant taste of a drug, to enhance drug stability and to modify drug release characteristics. The review focuses on the significance of pharmaceutical polymer for controlled drug delivery applications. Sixty million patients benefit from advanced drug delivery systems today, receiving safer and more effective doses of the medicines they need to fight a variety of human ailments, including cancer. Controlled Drug Delivery (CDD) occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released from the material in a predesigned manner. The release of the active agent may be constant over a long period, it may be cyclic over a long period, or it may be triggered by the environment or other external events. In any case, the purpose behind controlling the drug delivery is to achieve more effective therapies while eliminating the potential for both under and overdosing.
CONTROL RELEASE DOSAGE FORM
The United States Pharmacopoeia (USP) defines1 the modified-release (MR) dosage form as “the one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms”. One class of MR dosage form is an extended-release (ER) dosage form and is defined as the one that allows at least a 2-fold reduction in dosing frequency or significant increase in patient compliance or therapeutic performance when compared with that presented as a conventional dosage form (a solution or a prompt drug-releasing dosage form). The terms “controlled release (CR)”, “prolonged release”, “sustained or slow release (SR)” and “long-acting (LA)” have been used synonymously with “extended release”. Nearly all of the currently marketed monolithic oral ER dosage forms fall into one of the following two technologies:
1. Hydrophilic, hydrophobic or inert matrix systems: These consist of a rate controlling polymer matrix through which the drug is dissolved or dispersed.
2. Reservoir (coated) systems where drug containing core is enclosed within a polymer coating. Depending on the polymer used, two types of reservoir systems are considered.
(a) Simple diffusion/erosion systems where a drug-containing core is enclosed within hydrophilic and/or water-insoluble polymer coatings. Drug release is achieved by diffusion of the drug through the coating or after the erosion of the polymer coating.
(b) Osmotic systems where the drug core is contained within a semi-permeable polymer membrane with a mechanical/laser drilled hole for drug delivery. Drug release is achieved by osmotic pressure generated within the tablet core.

Advantages and Limitations of Control Release Dosage Forms
Clinical Advantages2, 6
 Reduction in frequency of drug administration
 Improved patient compliance
 Reduction in drug level fluctuation in blood
 Reduction in total drug usage when compared with conventional therapy
 Reduction in drug accumulation with chronic therapy
 Reduction in drug toxicity (local/systemic)
 Stabilization of medical condition (because of more uniform drug levels) Improvement in bioavailability of some drugs because of spatial control
 Economical to the health care providers and the patient Commercial / Industrial Advantages
 Illustration of innovative/technological leadership
 Product life-cycle extension
 Product differentiation
 Market expansion
 Patent extension
Potential Limitations
 Delay in onset of drug action
 Possibility of dose dumping in the case of a poor formulation strategy
 Increased potential for first pass metabolism
 Greater dependence on GI residence time of dosage form
 Possibility of less accurate dose adjustment in some cases
 Cost per unit dose is higher when compared with conventional doses
 Not all drugs are suitable for formulating into ER dosage form Selection of drug for formulation into extended release dosage form is the key step. Following candidates are generally not suitable for ER dosage forms

Characteristics That May Make a Drug Unsuitable for Control release Dosage Form
 Short elimination half-life.
 Long elimination half-life
 Narrow therapeutic index
 Poor absorption
 Active absorption
 Low or slow absorption
 Extensive first pass effect
Control release dosage form Release Formulation Designs 1. Dissolution controlled release  Encapsulation Dissolution control
 Seed or granule coated
 Micro encapsulation
 Matrix Dissolution control
2. Diffusion controlled release7
 Reservoir type devices
 Matrix type devices
3. Diffusion and Dissolution controlled systems
4. Ion exchange resins
5. Osmotically controlled release sustained release, release drug the design of oral sustain drug delivery system (DDS) should be primarily aimed to achieve the more predictability and reproducibility to control the drug release, drug concentration in the target tissue and optimization of the therapeutic effect of a drug by controlling its release in the body with lower and less frequent dose. Conventional drug therapy typically involves the periodic dosing of a therapeutic agent that has been formulated in a manner to ensure its stability, activity and bioavailability. For most of the drugs, conventional methods of formulation are quite effective. However some drugs are unstable and toxic and have a narrow therapeutic range, exhibit extreme solubility problems, require localization to a particular site in the body or require strict compliance or long-term use. In such cases a method of continuous administration of drug is desirable to maintain fixed plasma drug.

Modified release delivery systems may be divided conveniently in to four categories.
A) Delayed release
B) Sustained release
i) Controlled release ii) Extended release
C) Site specific targeting
D) Receptor targeting
A) Delayed Release:
These systems are those that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form. Examples of delayed release systems include repeat action tablets and capsules and enteric-coated tablets where timed release is achieved by a barrier coating.
B) Sustained release:
During the last two decades there has been remarkable increase in interest in sustained release drug delivery system. This has been due to various factor viz. the prohibitive cost of developing new drug entities, expiration of existing international patents, discovery of new polymeric materials suitable for prolonging the drug release, and the improvement in therapeutic efficiency and safety achieved by these delivery systems. Now-a-days the technology of sustained release is also being applied to veterinary products. These systems also provide a slow release of drug over an extended period of time and also can provide some control, whether this be of a temporal or spatial nature, or both, of drug release in the body, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells.
1) Controlled Release:
These systems include any drug delivery system that achieves slow release of drug over an extended period of time.
2) Extended Release:
Pharmaceutical dosage forms that release the drug slower than normal manner at predetermined rate & necessarily reduce the dosage frequency by two folds.
C) Site specific targeting:
These systems refer to targeting of a drug directly to a certain biological location. In this case the target is adjacent to or in the diseased organ or tissue.
D) Receptor targeting:
These systems refer to targeting of a drug directly to a certain biological location. In this case the target is the particular receptor for a drug within an organ or tissue. Site specific targeting and receptor targeting systems satisfy the spatial aspect of drug delivery and are also considered to be sustained drug delivery systems.
Potential advantages and disadvantages of sustained release dosage forms
Advantages: 2,3,4,5 i] Patient Compliance:
Lack of compliance is generally observed with long term treatment of chronic disease, as success of drug therapy depends upon the ability of patient to comply with the regimen. Patient compliance is affected by a combination of several factors, like awareness of disease process, patient faith in therapy, his understanding of the need to adhere to a strict treatment schedule. Also the complexity of therapeutic regimens, the cost of therapy and magnitude of local and or systemic side effect of the dosage form. The problem of lack of patient compliance can be resolved to some extent by administering sustained release drug delivery system. ii] Reduced 'see- saw' fluctuation:
Administration of a drug in a conventional dosage form [except via intravenous infusion at a constant rate] often results in 'see – saw' pattern of drug concentration in the systemic circulation and tissue compartments. The magnitudes of these fluctuations depend on drug kinetics such as the rate of absorption, distribution, elimination and dosing intervals. The 'see-saw' or 'peak and valley' pattern is more striking in case of drugs with biological half lives of less than four hours, since prescribed dosing intervals are rarely less than four hours. A well-designed sustained release drug delivery system can significantly reduce the frequency of drug dosing and also maintain a more steady drug concentration in blood circulation and target tissue cells. iii] Reduced total dose:
Sustained release drug delivery systems have repeatedly been shown to use less amount of total drug to treat a diseased condition. By reducing the total amount of drug, decrease in systemic or local side effects are observed. This would also lead to greater economy. iv] Improved efficiency in treatment:
Optimal therapy of a disease requires an efficient delivery of active drugs to the tissues, organs that need treatment. Very often doses far in excess to those required in the cells have to be administered in order to achieve the necessary therapeutically effective concentration. This unfortunately may lead to undesirable, toxicological and immunological effects in non-target tissue. A sustained release dosage forms leads to better management of the acute or chronic disease condition.
Other advantages are:
Sustained drug delivery:
As mentioned earlier, drug absorption from oral controlled release (CR) dosage forms is often limited by the short GRT available for absorption.
However, HBS type dosage forms can retain in the stomach for several hours and therefore, significantly prolong the GRT of numerous drugs. These special dosage forms are light, relatively large in size, and do not easily pass through pylorus, which has an opening of approx. 0.1– 1.9 cms. Site specific drug delivery
A floating dosage form is a feasible approach especially for drugs which have limited absorption sites in upper small intestine. The controlled, slow delivery of drug to the stomach provides sufficient local therapeutic levels and limits the systemic exposure to the drug. This reduces side effects that are caused by the drug in the blood circulation. In addition the prolonged gastric availability from a site directed delivery system may also reduce the dosing frequency. The eradication of Helicobacter pylori requires the administration of various medicaments several times a day, which often results in poor patient compliance. More reliable therapy can be achieved by using GRDDS. Floating alginate beads have been used for the sustained release of Amoxycillin trihydrate. Thus, it can be expected that the topical delivery of antibiotic through a FDDS may result in complete removal of the organisms in the fundal area due to bactericidal drug levels being reached in this area, and might lead to better treatment of peptic ulcer.
Pharmacokinetic advantages
As sustained release systems, floating dosage forms offer various potential advantages. Drugs that have poor bioavailability because their absorption is limited to upper GI tract can be delivered efficiently thereby maximizing their absorption and improving their absolute bioavailability. Floating dosage forms with SR characteristics can also be expected to reduce the variability in transit performance. In addition, it might provide a beneficial strategy for gastric and duodenal cancer treatment. The concept of FDDS has also been utilized in the development of various anti- reflux formulations. Floating systems are particularly useful for acid soluble drugs, drugs poorly soluble or unstable in intestinal fluids, and those which may undergo abrupt changes in their pH dependent solubility due to food, age and disease states.
LIMITATIONS
1. The major disadvantage of floating system is requirement of a sufficient high level of fluids in the stomach for the drug delivery to float. However this limitation can be overcome by coating the dosage form with the help of Bioadhesive polymers that easily adhere to the mucosal lining of the stomach.
2. Floating system is not feasible for those drugs that have solubility or stability problem in gastric fluids.
3. The dosage form should be administered with a minimum of glass full of water (200-250 ml).
4. The drugs, which are absorbed throughout gastro-intestinal tract, which undergo first pass metabolism (nifedipine, propranolol etc.), are not desirable candidate.
5. Some drugs present in the floating system causes irritation to gastric mucosa.
Criteria to be met by drug proposed to be formulated in sustained release dosage forms.
3,4.
a) Desirable half-life.
b) High therapeutic index
c) Small dose
d) Desirable absorption and solubility characteristics.
e) Desirable absorption window.
f) First past clearance.
a) Desirable half-life:
The half-life of a drug is an index of its residence time in the body. If the drug has a short half life (less than 2 hours), the dosage form may contain a prohibitively large quantity of the drug. On the other hand, drug with elimination half-life of eight hours or more are sufficiently sustained in the body, when administered in conventional dosage from, and sustained release drug delivery system is generally not necessary in such cases.
Ideally, the drug should have half-life of three to four hours.
b) High therapeutic index:
Drugs with low therapeutic index are unsuitable for incorporation in sustained release formulations. If the system fails in the body, dose dumping may occur, leading to fatalities eg. Digitoxin.
c) Small dose:
If the dose of a drug in the conventional dosage form is high, its suitability as a candidate for sustained release is seriously undetermined. This is chiefly because the size of a unit dose sustained release formulation would become too big, to administer without difficulty.
d) Desirable absorption and solubility characteristics:
Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into sustained release formulations is therefore unrealistic and may reduce overall absorption efficiency.
e) Desirable absorption window:
Certain drugs when administered orally are absorbed only from a specific part of gastrointestinal tract. This part is referred to as the ‘absorption window’. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as sustained release dosage form are unsuitable.
f) First pass clearance:
As discussed earlier in disadvantages of sustained delivery system, delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism, when administered in sustained release forms.
DESIGN AND FORMULATION OF ORAL SUSTAINED RELEASE DRUG DELIVERY SYSTEM AND THE FACTORS AFFECTING
THERE OF: 5,6,7,8
The oral route of administration is the most preferred route due to flexibility in dosage form, design and patient compliance. But here one has to take into consideration, the various pH that the dosage form would encounter during its transit, the gastrointestinal motility, the enzyme system and its influence on the drug and the dosage form. The majority of oral sustained release systems rely on dissolution, diffusion or a combination of both mechanisms, to generate slow release of drug to the gastrointestinal milieu.
Theoretically and desirably a sustained release delivery device, should release the drug by a zero-order process which would result in a blood-level time profile similar to that after intravenous constant rate infusion.
Plasma drug concentration-profiles for conventional tablet or capsule formulation, a sustained release formulation. Sustained (zero-order) drug release has been attempted to be achieved, by following classes of sustained drug delivery system.
A) Diffusion sustained system.
i) Reservoir type. ii) Matrix type
B) Dissolution sustained system.
i) Reservoir type. ii) Matrix type
C) Methods using Ion-exchange.
D) Methods using osmotic pressure.
E) pH independent formulations.
F) Altered density formulations.
A] Diffusion sustained system: 6,7,8
Basically diffusion process shows the movement of drug molecules from a region of a higher concentration to one of lower concentration. The flux of the drug J (in amount / area -time), across a membrane in the direction of decreasing concentration is given by Fick’s law.
J= - D dc/dx.
D = diffusion coefficient in area/ time dc/dx = change of concentration 'c' with distance 'x'
In common form, when a water insoluble membrane encloses a core of drug, it must diffuse through the membrane, the drug release rate dm/ dt is given by, dm/ dt= ADK C/L
Where A = area
K = Partition coefficient of drug between the membrane and drug core
L= diffusion path length [i.e. thickness of coat]
c= concentration difference across the membrane. 1] Reservoir type:

Figure No-1

Schematic representation of diffusion sustained drug release: reservoir system. In the system, a water insoluble polymeric material encases a core of drug. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the polymer, diffuse to the periphery and exchange with the surrounding media.
Characterization
Description:
Drug core surrounded by polymer membrane which controls release rate.
Advantages:
Zero order delivery is possible, release rates variable with polymer type.
Disadvantages:
System must be physically removed from implant sites. Difficult to deliver high molecular weight compound, generally increased cost per dosage unit, potential toxicity if system fails. ii] Matrix type:
A solid drug is dispersed in an insoluble matrix and the rate of release of drug is dependent on the rate of drug diffusion and not on the rate of solid dissolution. Higuchi has derived the appropriate equation for drug release for this system,
Q = D/ T [2 A –Cs] Cst ½
Where;
Q = weight in gms of drug released per unit area of surface at time t
D = Diffusion coefficient of drug in the release medium
 = porosity of the matrix
Cs = solubility of drug in release medium
T= Tortuosity of the matrix
A = concentration of drug in the tablet, as gm/ ml
Characterization
Description: Homogenous dispersion of solid drug in a polymer mixture.
Advantages: Easier to produce than reservoir or encapsulated devices, can deliver high molecular weight compounds.
Disadvantages: Cannot provide zero order release, removal of remaining matrix is necessary for implanted system.

Figure No-2
Schematic representation of diffusion sustained drug release: matrix system.
A third possible diffusional mechanism is the system where a partially soluble membrane encloses a drug core. Dissolution of part of membrane allows for diffusion of the constrained drug through pores in the polymer coat. The release rate can be given by following equation:-
Release rate = AD / L = [ C1- C2 ]
Where,
A = Area
D = diffusion coefficient
C1 = Drug concentration in the core
C2 = Drug concentration in the surrounding medium
L = diffusional path length
Thus diffusion sustained products are based on two approaches the first approach entails placement of the drug in an insoluble matrix of some sort. The eluting medium penetrates the matrix and drug diffuses out of the matrix to the surrounding pool for ultimate absorption. The second approach involves enclosing the drug particle with a polymer coat. In this case the portion of the drug which has dissolved in the polymer coat diffuses through an unstirred film of liquid into the surrounding fluid.
B] Dissolution sustained systems:7,8
A drug with a slow dissolution rate is inherently sustained and for those drugs with high water solubility, one can decrease dissolution through appropriate salt or derivative formation. These systems are most commonly employed in the production of enteric coated dosage forms. To protect the stomach from the effects of drugs such as Aspirin, a coating that dissolves in natural or alkaline media is used. This inhibits release of drug from the device until it reaches the higher pH of the intestine. In most cases, enteric coated dosage forms are not truly sustaining in nature, but serve as a useful function in directing release of the drug to a special site. The same approach can be employed for compounds that are degraded by the harsh conditions found in the gastric region.
i) Reservoir type:
Drug is coated with a given thickness coating, which is slowly dissolved in the contents of gastrointestinal tract. By alternating layers of drug with the rate controlling coats as shown in figure, a pulsed delivery can be achieved. If the outer layer is quickly releasing bolus dose of the drug, initial levels of the drug in the body can be quickly established with pulsed intervals. Although this is not a true sustained release system, the biological effects can be similar. An alternative method is to administer the drug as group of beads that have coating of different thickness. This is shown in figure. Since the beads have different coating thickness, their release occurs in a progressive manner. Those with the thinnest layers will provide the initial dose. The maintenance of drug levels at late times will be achieved from those with thicker coating. This is the principle of the spansule capsule. Cellulose nitrate phthalate was synthesized and used as an enteric coating agent for acetyl salicylic acid tablets. ii) Matrix type:
The more common type of dissolution sustained dosage form as shown in figure. It can be either a drug impregnated sphere or a drug impregnated tablet, which will be subjected to slow erosion.
Two types of dissolution- sustained pulsed delivery systems: a] Single bead– type device with alternating drug and rate-controlling layer. b] Beads containing drug with differing thickness of dissolving coats.
C] Methods using lon Exchange:6,7
It is based on the formation of drug resin complex formed when a ionic solution is kept in contact with ionic resins. The drug from these complex gets exchanged in gastrointestinal tract and released with excess of Na+ and Cl- present in gastrointestinal tract
Resin + - Drug - + Cl- goes to resin + Cl- +
Drug-
Where x- is cl- conversely
Resin - - drug+ + Na +goes resin – Na+ +
Drug.These systems generally utilize resin compounds of water insoluble cross – linked polymer. They contain salt – forming functional group in repeating positions on the polymer chain. The rate of drug diffusion out of the resin is sustained by the area of diffusion, diffusional path length and rigidity of the resin which is function of the amount of cross linking agent used to prepare resins .The release rate can be further sustained by coating the drug resin complex by microencapsulation process.15 The resins used include Amberlite, Indion, polysterol resins and others.
D] Methods using osmotic pressure:7
A semi permeable membrane is placed around a tablet, particle or drug solution that allows transport of water into the tablet with eventual pumping of drug solution out of the tablet through a small delivery aperture in tablet coating. Two types of osmotically sustained systems are:-
Type A contains an osmotic core with drug
Type B contains the drug in flexible bag with

EVALUATION OF SUSTAINED RELEASE
TABLETS:10,11
Before marketing a sustained release product, it is must to assure the strength, safety, stability and reliability of a product by forming in-vitro and invivo analysis and correlation between the two. Various authors have discussed the evaluating parameters and procedures for sustained release formulations.
1. In – Vitro Methods
These are:-
a. Beaker method
b. Rotating disc method
c. Rotating Bottle method
d. Rotating Basket method
e. Stationary Basket Method
f. Oscillating tube method
g. Dialysis method
h. USP dissolution method.
2. In–Vivo Methods
Once the satisfactory in-vitro profile is achieved, it becomes necessary to conduct in-vivo evaluation and establish in-vitro in-vivo correlation. The various in-vivo evaluation methods are:-
a. Clinical response
b. Blood level data
c. Urinary excretion studies
d. Nutritional studies.
e. Toxicity studies
f. Radioactive tracer techniques
3. Stability Studies :
Adequate stability data of the drug and its dosage form is essential to ensure the strength, safety, identity, quality, purity and in-vitro in-vivo release rates, that they claim to have at the time of use. A sustained release product should release a predetermined amount of the drug at specified time intervals, which should not change on storage. Any considerable deviation from the appropriate release would render the sustained release product useless. The in-vitro and in-vivo release rates of sustained release product may be altered by atmospheric or accelerated conditions such as temperature & humidity. The stability programmes of a sustained release product include storage at both nominal and accelerated conditions such as temperature & humidity to ensure that the product will withstand these conditions.
In vitro- In vivo Correlations:4,10
The requirement of establishing good in-vitro invivo correlation in the development of sustained release delivery systems is self-evident. To make a meaningful in-vitro in-vivo correlation one has to consider not only the pharmaceutical aspect of sustained release drug delivery system but also the biopharmaceutics and pharmacokinetics of the therapeutic agent in the body after its release from the drug delivery system and also the pharmacodynamics of therapeutic agent at the site of drug action. A simple in vitro-in vitro relationship can be established by conducting in-vitro and in-vivo evaluations of a potential drug delivery system simultaneously to study and compare the mechanism and rate profiles of sustained drug release. When the in-vivo drug release mechanism is proven to be in good agreement with that observed in the in-vitro drug release studies, then in-vitro in-vivo correlation factor is derived. For capsule type drug delivery system the factor can be represented as:
(Q/t) in-vivo
Q=
(Q/t) in-vitro
Where Q/t = Rate of release ‘Q’ values are dependent profiles of drug delivery systems. upon the sites of administration and environmental conditions to which the animals are exposed during treatment (study).
The above relationship can be used for optimization of sustained release Levy has classified in-vivo – in-vitro correlation in to: a] Pharmacological correlations based on clinical observations; b] Semi-quantitative correlations based on blood levels or urinary excretion data; c] Quantitative correlation arising from absorption kinetics. While most of the published correlations are of semi-quantitative nature, the most valuable are those based on absorption kinetics.
Bioavailability Testing:
Bioavailability is generally defined as the rate and extent of absorption of unchanged drug from its site of application to the general circulation. Bioavailability is defined in terms of a specific drug moiety, usually active therapeutic entity, which may be the unchanged drug or as with prodrug, for instance, a metabolite. In contrast, the term "absorption" often refers to net transport of drug related mass from its site of application into the body. Hence, a compound may be completely absorbed but only partially bioavailable as would occur, when low bioavailability is caused by incomplete absorption. Pharmaceutical optimization of the dosage form may be warranted to improve absorption characteristics of the drug and thereby also its bioavailability. Bioavailability studies are ordinarily single dose comparisons of tested drug product in normal adults in a fasting state. A crossover design, in which all subjects receive both, the product and reference material on different days is preferred. Guidelines for clinical testing have been published for multiple dose studies. Correlation of pharmacological activity or clinical evidence of therapeutic effectiveness with bioavailability may be necessary to validate the single significance of sustained release claims. While single dose studies are usually sufficient to establish the validity of sustained release dosage form design; multiple dose studies are required to establish optimum dosing regimen. They are also required when difference may exist in the rate but not the extent of absorption. When there is excessive subject-tosubject variation or when the observed blood levels after a single dose are too low to be measured accurately. A sufficient number of doses must be administered to attain steady stateblood levels. According to an extensive study of sustaine release Theophylline products; for example, encapsulated forms showed less peaking during multiple dosing and therefore better control of blood level within the desired limits,

Instruments used in MUPS

View of the spheronizer disc

Direct Pilletizing/ Powder layering

Laboratory pelletizer

Pelletizing cascade

Mini fluidized bed

Rotary tablet press machine

Single Punch Tablet Press

In process technique of compress machine

Advantages of Compaction of MUPS
i. Rapid but uniform transit of micropellets contained in MUPS from the stomach into small intestine owing to their small size, localized irritation, better and more uniform drug absorption and greater bioavailability. ii. Uniform emptying of micropellets from stomach into small intestine facilitates rapid dissolution of enteric coating and drug release resulting in early tmax and Cmax in case of delayed-release formulations. 3.Mouth disintegrating MUPS dosage form having a palatable taste is suitable for paediatric and geriatric patients who cannot swallow tablet or capsule.
4.The orodispersible MUPS medication can be taken without water.
5. Smaller volume/size of tablet leads to better patient compliance than capsules.
6. Greater physicochemical and microbiological stability of pellets owing to their embedment in inert matrix.
7. Lower cost of processing owing to higher
Processing speed, elimination of capsule cost, etc
8. Unlike conventional tablets, there is reduction in
Dust problems during compression.
9. Being tablets, quite unlike a capsule formulation, MUPS can be also designed into a divisible dosage form

Application
MUPS drugs are applicable in various purpose such as a) Multiple Unit Pellet Systems (MUPS) tablets are widely used in solid dosage form design. b) MUPS is considered to provide pharmacokinetic advantages compared to monolithic dosage forms.

MARKETED PRODUCTS OF MUPS
Losec MUPS, consisting of microencapsulated drug granules tabletted with excipients is the second highest selling pharmaceutical drug product.
Different marketed products are tabulated in the Table. Product | Company | Drug | Therapeutic Category | Formulation type | Losec MUPS | Astra Zeneca | Omeprazole magnesium | Antiulcer | Antiulcer | Esomeprazole | Astra Zeneca | Esomeprazole magnesium | Antiulcer | Antiulcer | Theodur | Key | Theophylline | Antiasthamatic | Extended release | Prevaci SoluTab | Takeda | Lansoprazole | Antiulcer | Delayed release |