INTRODUCTION:

Multiparticulate system is oral dosage form consisting of small discrete units each having desirable characteristics and size¹. These multiparticulate systems for oral use are generally presented in the form of capsule or tablets. There are some disadvantages associated with capsule such as feasibility of tempering, difficulties in esophageal transport and higher production cost. But, developments of multiparticulate formulation in the form of tablets is more cost effective² and allow higher drug content compared to encapsulated form of pellets, Which are limited by packaging properties of the pellets and size of capsule³ as well as, reduced liability to tempering and less problems encountered during esophageal transport⁴.

Multiparticulate drug delivery systems have number of advantages on single unit system such as coated tablets. Pellets offer high degree of flexibility in the design and development of oral dosage forms.

They can divide into desirable dose strength without formulation or process changes and also can be blended to deliver incompatible bioactive agents simultaneously and/ or to provide different release profile at the same or different part of gastrointestinal tract. In addition pellets taken orally disperse freely in the GI tract, maximize the drug absorption, minimize local irritation of the mucosa by certain irritant drug, and reduce inter and intra-patient variability⁵. Due to enormous advantages of multiparticulate drug delivery system over single unit oral dosage form, extensive research has been focused recently on refining and optimizing existing pelletization technique as well as on the development of novel manufacturing approaches that use innovative formulations and processing equipment. The most commonly used and extensively investigated pelletization processes are extrusion spheronization, powder layering and solution / suspension layering.

Compaction of pellets is the challenging area, only few multiunit’s containing tablets are in the markets now available such as Beloc ® Zok, Antra MUPS®⁶. Compaction of pellets is the modern technological and challenging process because during compaction pellet may fuse into non-disintegrating matrix or result in rupturing of coated film of pellets, thus losing their integrity and advantages as multiparticulate system and lastly may not posses adequate hardness, friability and disintegration time. In order to protect the integrity of coated pellets various approaches have been attempted toward the problem associated with compression of coated pellets in to tablets. Present study aimed to focus a light on various problems associated with formulation of pellets like core composition, porosity, density, size and shape of the pellets also nature of polymer, thickness of film coat, amount of excipients and various strategies to solve the problem of failure of functionality of coated pellets into tablets include modulation of tableting excipients, addition of cushioning agents, enhancement of coating flexibility, preparation of microsphere or microcapsule, curing of film coat etc.

Formulation variables posing problems during compression of coated pellets-

1. Core composition –

Core material affects the drug release as well as compressibility⁷. Pellets core should have some degree of plastic deformation and accommodate change in shape during compression⁸. Various core material were tried such as lactose⁹, microcrystalline cellulose(MCC)¹⁰ MCC-Wax¹¹, pectin¹², kappa- carrageenan^13-15, xanthan gum¹⁶, Chitosan¹⁷alginate-chitosan¹⁸,¹⁹, lactose- PVP²⁰,lactose-corn starch-MCC²¹, Eudragit RS PO and RL PO²² and Polyethylene oxide (PEO)²³,to improve the functionality of the coated pellets into tablets during compression cycle. Currently compression behavior of Kappa-carrageenan is studied and observed that carrageenan is promising candidate for multiparticulate system²⁴.

2. Porosity of pellets –

Porosity of pellets was found to control the degree of deformation of the pellets during compression²⁵. Highly porous pellets results into proper compression²⁶. Porosity could be increased by increasing concentration of sodium alginate²⁷ or rate of drying²⁸.

3. Size of pellets –

Pellets are spherical beads that have mean diameter ranging from 0.5-2.0 mm²⁹. Their reproducible particle size is ideal for proper coating of the pellets. Small pellets are more fragile than larger pellets and less affected by compaction process³⁰ and vice versa³¹.

4. Shape of pellets –

Shapes of pellets have a main effect on compression behavior and tablets forming ability of granular material³². Irregular shape of the pellets result increased degree of deformation of pellets and rupture of lubricant film³³. Spherical shape of pellets is also ideal for uniform packaging. Different grade of MCC has effect on shape and shape distribution of pellets.³⁴

5. Density of pellets –

Segregation of pellets due to vibration of turrets during tableting lead to weight variation and content uniformity this problem is solved by using pellets of narrow size distribution and compressed with excipients of same size, shape and density.

6. Nature of polymer and polymer coating –

Polymer coat should have mechanical stability and should remain intact during compression³⁵. Solvent based coating are more flexible and have a higher degree of mechanical stability than the aqueous based ones and acrylic film was found more flexible and suitable for coating of pellets when compared with ethyl cellulose film³⁶. Utility of HPMC and HPMCP have been reported^37,38.

7. Thickness of polymer coating –

Thickness of coat has also important role in the protection of integrity of polymer coating during compression cycle. Kollicoat SR 30D as coating material using propylene glycol as plasticizer at different thickness was tried and it was found that pellets with film thickness 50 µm could prevent the deformation³⁹. Thicker coating offer resistance to frictional forces but thickness with optimum value have synergistic effect on elasticity and reduce film damage during compression⁴⁰.

8. Nature of excipients –

Ideal excipients in the tableting of multiparticulate system should act as the cushioning agent during compression. Protective effect of particle depends upon particle size and characteristic of material⁴¹. Generally material with plasticity gives better protective effect.

9. Amount of excipients –

Amount of excipients is the crucial challenging factor in the controlling of integrity of coated pellets during compression. It was found that approximately 30 % of excipients in the tablets fill the void space between the coated pellets, so that tablets disintegrated rapidly and separate coating with insignificant damage to the coating film⁴². Theoretical void space of powder in uniform sphere in closest packaging is about 26 %⁴³ the filler material must fill this void space to avoid adhesion and fusion of coated pellets during compression. It was also observed that tablets containing 40% of coated pellets had acceptable release profile⁴⁴ which indicate that no damage to coating film of pellets.

Solutions to overcome failure of functionality of coated pellets into tablets –

1) Curing of film coating –

When polymeric films are cured at temperature above their glass transition temperature the polymer chain become more flexible and rearrange themselves so that greater ordering of chain and densification of film occur⁴⁵ with homogeneous distribution of plasticizer with in polymer coating. It was found that curing of Eudragit RS PO and RL PO film at 60⁰ C in oven for 24 h, result in plastic deformation without fracture of coating of the pellets⁴⁶, also it was observed that solventless photocurable film coating may be the green solution of film curing in future, it was reported that curing by UV light was photostable and withstand normal stress^47,48.

2) Use of plasticizer –

Polymer coat should not get ruptured during compression it should have sufficient mechanical stability and should remain intact during compression in order to control drug release. So, it is important to increase degree of plasticization of polymer film, add plasticizer which result decrease the glass transition temperature of polymeric film and thus increase in mobility of macromolecules and make the film coat more flexible and elastic¹³. Effect of four plasticizer propylene glycol, PEG 400, tributyl acetate and triethy citrate on metaprolol tartarate granules coated with Eudragit 30D film results in improvement of the film coat with increasing concentration of plasticizer was studied⁴⁹. Plasticizer free Kollicoat SR coating is very brittle and during compression ruptures. However, addition of 10 % plasticizer triethyl citrate improves the flexibility of film and allows compaction of coated pellets without rupture⁶.

3) Use of cushioning agents –

Cushioning is the extra layering to protect the coated pellets. Concerning the tableting of coated particle, it has been pointed out that the coated membrane is to some extent ruptured during compression, resulting in reduction of membrane effectiveness. This problem is addressed in the studies conducted on developed technologies to minimize the changes in the characteristics of coated particle after compression and many pharmaceutical additive were tested for their cushioning effect, such the MCC, polyethylene glycol 3350, crospovidone, lactose and dicalcium phosphate⁵⁰. MCC ceolus KG 801 as novel tableting excipients was reported⁵¹ this granulated MCC is capable of cushioning controlled release particle from compression force used in tableting. The role of PEO as cushioning agent was investigated⁵². It was postulated that PEO hydrated and formed gel and act as sealant for crack formed in the ruptured polymer coat. Biologically inactive cushioning beads comprise at least one compressible component consisting essentially of microcrystalline hydrocarbon wax or natural wax and said wax being at least 30% by weight of biologically inactive cushioning beads. Such beads are useful for making solid shaped articles containing biologically inactive ingredients by compression⁵³. It was investigated that particle size of cushioning beads also play major role and demonstrate that smaller additive particle size result in superior protection of the membrane from compression damage and found that 20 µ seemed to be critical particle size for every additive to get good protective effect⁵⁴.

4) Use of microcapsule or microsphere –

Microcapsule or microsphere preparation make easy to prepare tablets by direct compression method. The tablets containing microcapsule or microsphere have minimal destruction rate of coating wall, show same dissolution pattern as pellets and provide mechanical strength. It was observed that when aerosil 200 (2%), MCC (18%) microcapsule of active drug (60%) were compressed at pressure of about 800-1000 kg /cm. sq found minimal destruction of coating during compression⁵⁵ also it was observed that compression of PLA microspheres of naltrexone prepared by solvent evaporation method shows desired release profile without burst effect⁵⁶.

CONCLUSION:–

Compression of coated pellets is the challenging task which needs optimization of several key variables such as pellets core composition, polymer coat and tableting excipients otherwise leads to different problem like weight variation, content uniformity, leakage of film coat result in failure of release profile and segregation etc which affect performance of dosage form. So, there is need to give more focus on these key variables. MCC has been known as the best core material and found beneficial when used with cured Eudragit RS PO and RL PO. Polymer coating must be enough thick and flexible to avoid the rupture during compression and should retain its nature even after compression. Pellet: excipients ratio must be optimized. Solution based on use of cushioning material or beads and curing of film coat are more desirable to protect the functionality of coated pellets.

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Received on 06.06.2010 Modified on 27.06.2010

Research J. Pharm. and Tech. 4 (1): January 2011; Page 43-46