INTRODUCTION:

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 Bodmeier¹. 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.

MUPS: Novel Technology for Preparation of Extended Release (ER) Tablet

Extended release (ER) dosage form is one of the drug products categorized under the term modified release dosage forms². It refers to products, which are formulated to make the drug available over an extended period after ingestion; thus, it allows a reduction in dosing frequency compared to a conventional type i.e. immediate release (IR) dosage form. Several advantages of ER products over IR ones have long been recognized³.

ER solid oral dosage forms can be classified into two broad groups:

I. Single unit dosage forms (e.g. tablets) and

II. Multiple unit dosage forms or multiparticulate pellet systems. The systems can be further subdivided into two concepts regarding to the design of dosage forms:

(i) Matrix systems and

(ii) Reservoir systems.

Multiparticulate pellet systems

Several advantages of multiparticulate systems over the single unit ones have been well known and documented¹.

It includes,

1) The multiparticulates spread uniformly throughout the gastrointestinal tract. High localised drug concentrations and the risk of toxicity due to locally restricted tablets can be avoided.

2) Premature drug release from enteric coated dosage forms in the stomach, potentially resulting in the degradation of the drug or irritation of the gastric mucosa, can be reduced with coated pellets because of a more rapid transit time when compared to enteric coated tablets.

3) The better distribution of multiparticulates along the GI-tract could improve the bioavailability, which potentially could result in a reduction in drug dose and side effects.

4) Inter and intra-individual variations in bioavailability-caused for example by food effects-are reduced.

5) In the multiple-unit system, the total drug is divided into many units. Failure of few units may not be as consequential as failure of a single-unit system. This is apparent in sustained-release single-unit dosage form, where a failure may lead to dose-dumping of the drug.

6) Various drug release profiles can be obtained by simply mixing pellets with different release characteristics; in addition, a more rapid onset of action can be achieved easier with pellets than with tablets.

7) Administration of incompatible drugs in a single dosage unit by separating them in different multiparticulates.

With respect to (w.r.t) the final dosage form, multiparticulates can be filled into hard gelatin capsules or be compressed into tablets of which the former is more common. Unfortunately, the production costs for capsules are high and their production rate is low compared with those of tablets. This is due to the lower output of capsule filling machines and to the higher cost of empty hard gelatine capsules themselves. Although it is recognized that oral administration of multiple-unit dosage form is preferred over single-unit system, it is not advisable to present a low potency, highly dosed drug as a multiparticulate drug delivery system, mainly because of poor patient compliance due to large capsule size. Moreover, capsules cannot be divided into subunits in the same way as tablets. These disadvantages make compression of subunits into rapidly disintegrating tablets an interesting issue.

The advantages of tableting of multiparticulates include

1) A reduced risk of tampering (e.g. Tylenol® and Sudafed-12)⁴, and lower tendency of adhesion of dosage form to oesophagus during swallowing⁵.

2) Tablets from pellets can be prepared at low cost when compared to pellet-filled into capsules because of the higher production rate of tablet process.

3) The expensive control of capsule integrity after filling is also eliminated.

4) In addition, tablets containing multiparticulates can be scored without losing modified-release properties thus allowing a more flexible dosage regimen.

5) Tableting of pellets as opposed to that of powder also results in reduction of dust during manufacturing and handling⁶.

6) It may also provide an opportunity to understand the compaction process by examining the change in size, shape and density of pellets after their compaction and retrieval of individual pellets from disintegration tubes or from the highly lubricated compacts, which provides a reduction in the coherence of the pellets⁷.

Figure 1 Schematic representation of types of MUPS — (a) MUPS comprising of coated pellets, and (b) MUPS prepared from uncoated/matrix pellet⁸

Fig. 1 illustrates two different types of MUPS: one comprising of coated pellets (reservoir systems), and the other prepared by compaction of matrix and/or uncoated drug pellets.

1. Matrix systems

The matrix type of multiparticulate systems can be prepared by several techniques such as extrusion/spheronisation, spherical crystal agglomeration and melt-solidification.

Although, the production of multiparticulate matrix systems is considered to be easier than that of the reservoir systems, their extent of retardation is limited because of pellet geometry.

Pelletization techniques^9,10:

Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small, free flowing, spherical or semi spherical units, referred to as pellets. Pellets range in size, typically, between 0.5 – 1.5 mm, though other sizes could be prepared. Pellets can be prepared by many methods, the compaction and drug-layering techniques being the most widely used as on today. Regardless of which manufacturing process is used, pellets have to meet the following requirements.

1. They should be near spherical and have a smooth surface; both considered optimum characteristics for subsequent film coating.

2. The particle size range should be as narrow as possible. The optimum size of pellets for pharmaceutical use is considered to be between 600 and 1000μm.

3. The pellets should contain as much as possible of the active ingredient to keep the size of the final dosage form within pre-defined limits.

Different Pelletization techniques are summarized in the figure 2.

Figure 2 Techniques of Pelletization

Extrusion / Spheronization:

Extrusion-spheronization is a multiple step process capable of making uniformly sized spherical particles. Although the process is more efficient than other techniques for producing spheres, it is more labor and time-intensive than the more common granulation techniques. Therefore, it should be considered as a granulating technique when the desired particle properties are essential and cannot be produced using more conventional techniques¹¹.

It involves the following steps;

(a) Dry Mixing: Dry mixing of ingredients is done to achieve homogeneous powder dispersion using twin shell blender, planetary mixer, high speed mixer and tumbler mixer.

(b) Wet Massing: Wet massing is done to produce a sufficient plastic mass for extrusion, by employing normal equipment and processes as employed in wet granulation for compaction. The most commonly used granulator is planetary mixer or Hobart mixer or sigma blade mixer and high shear mixer. Evaporation of the fluid phase is a major problem with high shear mixers as they introduce a high amount of energy into the wet mass which is partly transformed into heat and induces evaporation of the granulation liquid thus changing the extrusion behavior of the wet mass. Cooling of the granulation bowl may avoid this problem.

Figure 3 Principle of the Extruded product spheronizing process

(c) Extrusion: This is the third step in the process, which produces rod shaped particles of uniform diameter from the wet mass. The wet mass is forced through dies and shaped into small cylindrical particles with uniform diameter. Such shaping of the wet mass into long rods, commonly termed ‘extrudate.’ The extrudate particles break at similar length under their own weight. Thus, the extrudate must have enough plasticity to deform but not so much that the extrudate particles adhere to other particles when rolled during spheronization process. (fig. 3)

Extruders are classified into three categories namely, Screw feed extruder (axial or end plate, dome and radial), the screw extruder consists of one or two (twin -screw) feeding the wet mass to an axial or radial extrusion screen. In the axial type, (fig. 4a) the screen is placed at the end of the screw, while in radial type the screen is placed around the screw (fig. 4c), discharging the extrudate perpendicularly to the axis of the screw.

(a)

(b)

(c)

Figure 4 (a) Axial Screw Feed Extruder,

(b) Dome Screw Feed Extruder,

(c) Radial Screw Feed Extruder

Gravity feed extruder (cylinder roll or gear roll) and Gravity feed extruders include rotary cylinder and rotary gear extruders, which differ mainly in the design of the two counter rotating cylinders. In the rotary cylinder extruder, one of the two counter rotating cylinders is hollow and perforated, whereas the other cylinder is solid and acts as a pressure roller. In the rotary gear extruders there are two hollow counter rotating gear cylinders with counter board holes. (fig. 5a,b)

Piston feed extruders (ram) which are probably the oldest type of extruders (fig 6a,b); a piston displaces and forces the material through a die at the end. Ram extruders are preferentially used in the development phase, because they can also be used to measure the rheological properties of the formulations.

(a)

(b)

Figure 5 (a) Cylinder Roll Type, (b) Gear Roll Type

(a)

(b)

Figure 6 (a) Axial Piston Extruder,

(b) Radial Piston Extruder

(d) Spheronization: The spheronization technology was first introduced by Nakahara in 1964. A spheronizer also known as merumerizer consists of a static cylinder and a rotating friction plate where the extrudate is broken up into smaller cylinders with a length equal to their diameter and these plastic cylinders are rounded due to frictional forces. During spheronization process different stages can be distinguished depending upon the shape. The friction plate, a rotating disk with a characteristically grooved surface to increase the frictional forces, is the most important component of the equipment. Two geometric patterns are generally used¹².

It includes a cross-hatched pattern with grooves running at right angle to one another, a radial pattern with grooves running radially from the centre of the disc. The rotational speed of the friction plate varies from 100- 2000 rpm. Spheronization process involves transition from rods to spheres that might occur in various stages which usually take 5 to 30 minutes provided mass should not be too dry wherein no more spheres are formed and the rods will transform as far as dumbbells only.

(e) Drying: A drying stage is required in order to achieve the desired moisture content. Drying rate also important an increase drying rate gave more porous pellets due to decrease pellet densification during that drying process. The pellets can be dried at room temperature or at elevated temperature in a tray drier/ oven or in a fluidized bed drier.

(f) Screening: Screening may be necessary to achieve the desired size distribution, and for this purpose sieves are used. In case of pellets prepared by extrusion-spheronization, screening is essentially required after manufacture, in order to avoid pellets having high size polydispersity index.

2. Reservoir systems

Coated pellets as a mean to control drug delivery are widely used in the pharmaceutical industry, although the development and optimisation of the systems are rather complex.

Functional Coating:

A reservoir coated system consists of a drug layered core surrounded by a polymer. The major advantages of this system rely on the fact that very high drug loadings can be used and variable drug release profiles can be obtained, by just varying the type of polymeric membrane.

Aqueous coating and organic coating

Pellets can be coated with an aqueous polymeric dispersion or an organic solution in order to achieve controlled drug release. Organic coatings present many disadvantages as the dependence of viscosity on molecular weight and the concentration of polymer used. In contrast, aqueous polymer dispersions are characterized by low viscosity even at high solid contents, leading to a decrease in coating process time. Organic solvents present additional disadvantages like the presence of residual solvents in the coating that can create changes in film properties, environmental pollution, adverse effects (carcinogenic) and explosion hazards. As a result, the use of aqueous polymeric dispersions is preferred for pharmaceutical coatings. With organic polymer solutions, polymer macromolecules are dissolved and this can create a high viscosity solution. During solvent evaporation, an intermediate gel-like phase is formed. After complete solvent evaporation, a polymeric film is obtained (Figure 7).

Figure 7 Schematic presentation of the film forming mechanism from organic polymer solution¹³.

In contrast, film formation from aqueous dispersions is a more complex process¹⁴. During drying of aqueous dispersions, polymer particles come into contact with each other in a closed packed order (Figure 8). Usually the coating process is performed at sufficient high temperatures to guarantee softness of the discrete polymer particles. The softening is related to the glass transition temperature (Tg) of the polymer. A curing step (post coating thermal treatment) is carried out after coating process to assure complete film formation and to avoid further gradual coalescence¹⁵.

Figure 8 Schematic presentation of the film forming mechanism from aqueous polymer dispersions¹³.

Formulation parameters¹⁶

1. Polymer

Ethylcellulose

Ethylcellulose is a hydrophobic coating material used for controlled drug release, moisture protection and taste masking. Ethylcellulose is insoluble in gastro-intestinal tract and assures pH independent drug release profiles due to its neutral side chains. It is widely used in oral drug delivery as film former, since it is non-toxic, non-allergenic and non-irritant. Ethylcellulose can be applied either using organic solvent or from aqueous dispersions.

Aquacoat^® ECD and Surelease^® are aqueous dispersions of ethylcellulose available on the market.

Acrylate

Eudragit NE 30 D and Eudragit NM 30 D are ethylacrylatemethylmethacrylate (2:1) copolymer. The main difference between both dispersions remains in the content and nature of emulsifier. Eudragit NE 30 D containsα-(4-nonylphenyl)ω-hydroxypoly-(oxy-1,2-ethanediyl), namely nonoxynol 100 (1.5%) and Eudragit NM 30 D contains polyethylene glycol stearyl ether (0.7%). Both aqueous dispersions have a solid content of 30% and a low MFT (5°C). Eudragit NE 30 D and Eudragit NM 30 D films are highly flexible and do not need addition of a plasticizer. These films are insoluble in gastro-intestinal tract, show very low permeability and a pH independent swelling.

Polyvinylacetate

Kollicoat SR 30 D has a solid content of 30% and contains of polyvinyl acetate (27%), polyvinyl pyrrolidone (2.7%) and sodium lauryl sulfate (0.3%).

2. Additional additives

Plasticizers

When formulating a coating dispersion, the selection of plasticizer is of utmost importance. Plasticizers should remain in the films, exhibiting little or no tendency for migration or volatilization and must be compatible with the polymer. Plasticizers for film coating are excipients with high boiling point.

They should be homogenously distributed and give flexibility and mechanical resistance to the polymeric film. Plasticizers facilitate the process of polymer particle coalescence by increasing the mobility of the polymer chains and by weakening the intra and intermolecular attraction forces between the chains.

Plasticizers can be divided into 2 types: water soluble and water insoluble. Water soluble plasticizers dissolve in the aqueous medium when they are added to polymer dispersions. Upon exposure to medium, they leach out from the film and may increase drug release rate¹⁷. In contrast, water insoluble plasticizers partition into the polymer.

In summary, the addition of plasticizers is required to reduce MFT of aqueous polymeric dispersions below the coating temperature and to enhance coalescence process.

Pore formers

Drug release from aqueous polymeric coatings may be very low and require the addition of hydrophilic polymers to act as pore formers. The amount and type of hydrophilic polymer used is related with the desired release profiles. A variety of pore formers can be applied and hydroxyl propyl methylcellulose (HPMC) is widely used. Furthermore, drug release profiles were unchanged upon storage, if a curing step was performed before storage¹⁸.

Anti-tacking agents

Anti-tacking agents are necessary to reduce the tackiness of coatings. Often talc and glyceryl monostearate are used to prevent sticking of the coated pellets to each other and to the wall of the coating chamber and to improve coating performance. In order to reduce tackiness, much higher amount of talc is needed in comparison with glyceryl monostearate, due to higher effectiveness of glyceryl monostearate as anti-tacking agent.

Coating equipment and process conditions:¹⁹

There are different coating technologies to coat pellets.Fluidized bed equipment is available for coating small cores or pellets.

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 a uniform product coating. Glatt (fig. 11) offers Batch Fluid Bed Systems in different batch sizes with: (fig. 9 a,b,c)

a) Top Spray Coating

b) Bottom Spray Coating (Wruster Coating)

c) Tangential Spray Coating (Rotor Pellet Coating)

(a)

(b)

(c)

Figure 9 (a) Principle of Top spray batch fluid coating, (b) Principle of Bottom sprays batch fluid coating, (c) Principle of Tangential spray batch fluid coating

a) Top Spray Coating:

This process is used for general coatings right up to enteric coating. With top spray coating in the fluid bed (batch and continuous), particles are fluidized in the flow of heated air, which is introduced into the product container via a base plate. The coating liquid is sprayed into the fluid bed from above against the air flow (counter-current) by means of a spray nozzle. Drying takes place as the particles continue to move upwards in the airflow. Small droplets and a low viscosity of the spray medium ensure that the distribution is uniform.

b) Bottom spray coating (Wrustercoating):

This process is particularly suitable for a controlled release of active ingredients. In the Wruster process, a complete sealing of the surface can be achieved with a low usage of coating substance. The spray nozzle is fitted in the base plate resulting in a spray pattern that is concurrent with the air feed. By using a Wruster cylinder and a base plate with different sized perforations, the particles to be coated are accelerated inside the Wruster tube and fed through the spray cone concurrently. As the particles continue traveling upwards, they dry and fall outside the Wruster tube back towards the base plate. They are guided from the outside back to the inside of the tube where they are once again accelerated by the spray. This produces an extremely even film. Particles of different sizes are evenly coated.

C. Tangential spray coating (Rotor pellet coating):

Tangential spray is ideal for coatings with high solid content. The product is set into a spiral motion by means of a rotating base plate, which has air fed into the powder bed at its edge. The spray nozzle is arranged tangentially to the rotor disc and also sprays concurrently into the powder bed. Very thick film layers can be applied by means of the rotor method.

Figure 10 Mechanism of coating on the surface of the powder particle

All above processes have in common essential coating steps (fig. 10): (i) the formation of suitable droplets from the coating formulation, (ii) contact and adhesion of the droplets onto the particles’ surface and subsequently (iii) spreading and coalescence¹³.

Figure 11Glatt GPCG Equipment

Process parameters

The coating process includes several phases occurring at the same time, like atomization of the spray liquid and droplet formation, contact and spreading over the surface of the substrate, evaporation of liquid and coalescence of particles and film formation. The critical process parameters for application of coating dispersions include:

1) Fluidization air volume, affecting the movement of the pellets;

2) Fluidization air temperature, important for the evaporation of the solvent and the softening of the latex particles;

3) Solid content of the dispersion, too high solid contents may cause strong variations on batch reproducibility;

4) Spray rate, important parameter since a low spray rate leads to porous films due to partial drying on surface of pellets and film formation is comparable to spray drying. Too high spray rates lead to problems such as sticking and agglomeration of pellets;

5) Atomization air pressure influences the droplet size and spraying pattern²⁰.

The product temperature should be 10°C to 20°C²¹ above MFT of the polymer dispersion in order to achieve sufficient solvent evaporation and complete film formation. The product temperature can be adjusted by varying the inlet air temperature.

Figure 12 Flow chart representing factors influencing compaction of reservoir pellets.⁸

Compaction of pellets

Compaction of pellets is a challenging area. Compaction of multiparticulates into tablets could either result in a disintegrating tablet providing a multiparticulate system that disintegrates during gastrointestinal transit or intact tablets due to the fusion of the multiparticulates in a larger compact. Ideally, the compacted pellets should not fuse into a non-disintegrating matrix during compaction and should disintegrate rapidly into individual pellets in gastrointestinal fluids to attain more uniform concentration of active substances in the body. Importantly, the drug release should not be affected by the compaction process. With reservoir-type coated-pellet dosage forms, the polymeric coating must be able to withstand the compaction force.

It may deform but should not rupture, since, for example, the existence of crack in the coating may have undesirable effects on the drug release properties of that subunit. The type and amount of coating agent, the size of subunits, selection of external additives, and the rate and magnitude of pressure applied during compression must be considered carefully to maintain the desired drug release properties of that subunit⁴. Fig. 12 is a flow chart representing factors influencing design of MUPS tablets.

Tableting excipients

Various tableting excipients have to be added to assist the compaction of coated pellets. The excipients are used to fill the void space between the pellets to be compressed and act as cushioning agent to absorb compression forces. The filler materials are used for separation of individual pellets to prevent direct contact of pellets (e.g. polymer-coated pellets that tend to fuse with each other during compression) by forming a layer around the pellets. These inert excipients should also provide protection to the coated particles from rupture and damage during compression. The excipients should result in hard and rapidly disintegrating tablets at low compression forces and should not affect the drug release. Besides their compaction properties, the excipients have to result in a uniform blend with the coated pellets, avoiding segregation and therefore weight variation and poor content uniformly of the resulting tablets.

Evaluation of Pellets:²²

Size distribution: The sizing of pellets is necessary because it has significant influence on the release kinetics. In most of the cases particle size determination is carried out by simple sieve analysis using sieve shaker.

Pellets shape: Achieving spherical shape of the pellets is the most important characteristics and various methods have been used to determine it. The pellets were mounted on a light microscope fitted to a Camera Lucida and the images of the pellets were drawn manually on a graph paper. 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 spherical size.

Visual inspection of pellets by microscope and stereomicroscope are another method to determine shape of pellets. An angle at which a plane has to be tilted before a particle begins to roll is called to be one plane critical stability, is one of the important methods used for determining shape. 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 flow through a specific orifice from a given height.

Surface morphology: Scanning electron microscopy is used to examine the surface morphology and cross section of pellets. The sampling pellets are mounted onto the aluminum stub, sputter-coated with a thin layer of Platinum using sputter coater (Polaron, UK) under Argon atmosphere, and then examined using SEM. While the SEM pictures collected to observe the influence of different fillers and concluded that MCC and corn- starch gives best quality pellets with smooth surface.

Specific surface area: Surface area of pellets is directly related with size and shape of the pellets. Knowledge 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 is influenced by the surface area. Specific surface area of pellets is determined by gas adsorption technique.

True density measurements can also be used to determine the specific surface area.

Hardness and Friability: The mechanical properties of pellets are important for processing. Pellets flake off during handling, shipping, storage coating process and other unit operations thereby resulting in formation of dust. Variations in the formulation and/or process of pellets, as well as variability in the raw materials, can potentially result in significant variations with hardness and/or friability of pellets. Hardness of pellets can be determined using Kahl pellet-hardness tester but might not be accurate. Friability of pellets are determined by using Erkewa type tablet friabilator or turbula mixer for a fixed period of time combined with glass beads of certain diameter in order to generate abrasion and to generate friability index. Friability can also be determined using fluidized bed with Wurster insert by using stream of air.

Density: Density of pellets (bulk and tapped) can be affected by change in the formulation or process which may affect other process or factors such as filling and packaging characteristic during capsule manufacture and tablet compression, and is determined simply by USP density apparatus. The bulk density of pellets can be measured by using an automated tapper, while the true density of pellets can be determined by an air-comparison pycnometer or by solvent displacement method. Bulk density is indicates the packing properties of pellets or spherical seeds which provide higher bulk densities due to small intra-particle porosities. True density indicates the extent of densification or compactness of pellets.

Disintegration time: Disintegration of pellets is one of the main characteristics for immediate release pellets.

In vitro dissolution studies: In vitro dissolution studies are predominantly recognized as an important element both in drug development and quality assessment over the past four decades. These tests were performed for studying the release behaviour of different formulations in different dissolution media and to establish a co-relation between in vitro release and in vivo absorption for the modified-release pellets. Release of drug from solid dosage form often constitute a determining step in the in vivo absorption process and used in conjunction with in vivo/in vitro correlation to establish quality control parameter. Release of the drug from pellet mainly depends on the composition, hardness and size of pellets and it is determined by using USP Apparatus I or by USP Apparatus II. The drug release profiles from pellets also depends on the Polymer and binder used, aqueous solubility of the drug, physical state of the drug in the pellet, drug loaded into the pellet and the presence of additives such as surfactants. In case of wax based freeze dried pellets, the drug release decreased as the hydrophobicity of wax increases and the drug release increased as the aqueous drug solubility increased.

CONCLUSION:

Formulation of different drugs to MUPS tablets has a prominent role because dissolution profiles can be tailor-made to obtain desired therapeutic concentration and to reduce fluctuation in plasma concentration of drug. Present scenario of MUPS find a greater advantage which is the compaction of pellets coated with drug and polymer due to its flexible design in variable release properties, stability, patient compliance and cost effectiveness compared to other dosage forms. For the pharmaceutical industry, not only the innovation of new products and techniques, creation of line extension, expansion of patent protection, achieving globalized product and thereby overcoming competition are also key strategies with respect to profit perspective and sustainability. MUPS meets all these with medical, health care, and business benefits.

REFERENCES:

1. Bodmeier R. Tableting of coated pellets. European Journal of Pharmaceutics and Biopharmaceutics. 1997;43(1): 1-8.

2. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), 1997. Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Forms. [Accessed on 13/02/2013]

3. Das NG and Das SK, 2003. Controlled-Release of Oral Dosage Forms. Formulation, Fill & Finish, 10-16[Online]. Available from: http://pharmtech.findpharma.com/pharmtech/data/articlestandard//pharmtech/23200 3/59302/article.pdf [Accessed on 07/11/2013].

4. Celik M. Compaction of multiparticulate oral dosage form, in: I. Ghebre-Sellassie, ed. Multiparticulate Oral Drug Delivery, Marcel Dekker, New York; 1994, p. 181–215.

5. Marvola M, Rajamiemi M, Marttila E, Vahervno K, Sothmann A. Effect of dosage form and formulation factors on the adherence of drugs to esophagus, J. Pharm. Sci. 1983; 72: 1034–1037.

6. Conine JW, Hadley HR. Preparation of small, solid pharmaceutical spheres. Drug. Cosmet. Ind. 1970; 106: 38-41.

7. Aulton ME, Dyer AM, Khan KA. The strength and compaction of millispheres. The design of controlled-release drug delivery system for ibuprofen in a form of a tablet comprising compacted polymer-coated millispheres, Drug Dev. Ind. Pharm. 1954; 20: 3069–3104.

8. Abdul S, Chandewar AV, Jaiswal SB. A flexible technology for modified-release drugs: Multiple-unit pellet system (MUPS), Journal of Controlled Release. 2010; 147: 2–16.

9. Ghebre-sellassie I: Pharmaceutical Pelletization Technology, Marcledekkerinc.; NewYork, USA; 1989, p. 1-13.

10. Nakahara N. Method and apparatus for making spherical granules; US Patent 3277520; 1964.

11. Reynolds. A.D.: A new technique for the production of spherical particles; Manuf. Chem. Aerosol. News. 1970; 41: 40-6.

12. Hellen L., Ritala. M., Yliruusi. J., Palmroos. P, Kristof-fersson. E: Process variables of the radial screen extruder. Part II. Size and distribution of pellets; Pharm. Tech. Int. Biophys; 1992; 4: 50-7.

13. Muschert S. Polymeric coatings for solid dosage forms: characterization and optimization. Ph.D. Dissertation. Universite de Lille II, Lille; 2008. [Accessed on 13/04/2013]

14. Fukumori Y. Coating of Multiparticulates Using Polymeric dispersions. In: Ghebre-Sellassie I, ed. Multiparticulate Oral Drug Delivery. Marcel Dekker, New York; 1994, p. 79-111.

15. Harris MR, Ghebre-Sellassie I. Aqueous polymeric coating for modified release oral dosage forms. In: McGinity JW, ed. Aqueous polymeric film coatings for pharmaceutical dosage forms. Marcel Dekker, New York; 1997, p. 81-100.

16. Dashevsky, A., Ahmed, A.R., Mota, J., Irfan, M., Kolter, K., Bodmeier, R., Effect of water-soluble polymers on the physical stability of aqueous polymeric dispersions and their implications on the drug release from coated pellets. Drug Development and Industrial Pharmacy. 2010; 36: 152-160.

17. Bodmeier R, Paeratakul O. Leaching of water-soluble plasticizers from polymeric films prepared from aqueous colloidal polymer dispersions. Drug Development and Industrial Pharmacy. 1992; 18: 1865 - 1882.

18. Siepmann F, Hoffmann A, Leclercq B, Carlin B, Siepmann J. How to adjust desired drug release patterns from ethylcellulose-coated dosage forms. Journal of Controlled Release. 2007; 119: 182-189.

19. Glatt. Fluid Bed Coating Coating [online]. available from: http://www.glatt.com/cm/en/process-technologies/coating/fluid-bed-coating.html [Accessed on 11/04/2013]

20. Wagner K. Aqueous polymer dispersions for extended release dosage forms. Ph.D. Dissertation. FreieUniversitaet Berlin: Berlin; 2002.

21. Raymond RM, Ray KS. Acrylic latex film formation in the critical temperature range. Journal of Applied Polymer Science. 1964; 8: 755-764.

22. Lavanya K, Senthil V, Rathi V. Pelletization technology: a quick review, IJPSR. 2011; 2(6): 1337-1355.

Received on 31.05.2013 Modified on 07.06.2013

Research J. Pharm. and Tech. 6(8): August 2013; Page 856-864