1. INTRODUCTION:

In 1950, Multiparticulate drug delivery/ multi-unit dosage form was introduced⁽¹⁾. It helps in designing the dosage form, as it possesses special properties and more flexible for production. Solid dosage form has 2 types namely, Single (Matrix tablet, coated, uncoated tablets) and multi-unit dosage form (Pellets/microencapsulated drug placed in capsules). This plays an important role in the design of solid dosage form because of their special properties and their flexibility identified in the manufacture and this solid dosage form or oral dosage form⁽⁴⁾. It consists of many small discrete particles and each has some peculiar characteristics with the characteristic unit, which helps in the controlled release of the drug⁽²⁾. Multi-unit dosage form is discrete, small, repetitive units of drug particle which can be or cannot be one similar drug release pattern. Multiparticulate also exists as microcapsules, beads, pellets or microparticles, mini-tablets.⁽³⁾.

Multiparticulates, reduces the risk of dose dumping, systemic toxicity, irritation and huge variation in bioavailability because they are less dependent on GI transit time. In recent trends, it is used as Controlled Release/Delayed Release with low risk of dose dumping⁽⁴⁾. A mass process that converts fine powders or granules of bulk drugs and excipients into small, free flowing, spherical or semi-spherical units, referred to as pellet is called pelletization. Fine powders mixed with binder solution produces pellets/Spherical granules. Size of the pellet generally ranges from 0.5 -1.5mm (upto 3mm). This contains several particles with size range [0.05-2.0mm diameter]⁽⁵⁾. These particles are compressed into tablet, which is encapsulated for administration. Formulating multiparticulate drug delivery system is simple, providing numerous advantages and avoids many drawbacks associated with single unit dosage form. In this review, an overall view about multi-particulate drug delivery system is given, including its advantages and disadvantages, mechanism of drug release, types of multi-particulate drug delivery system.

2. ADVANTAGES AND DISADVANTAGES:

2.1 Advantages:

1. Dose dumping avoided.

2. Faster gastric emptying.

3. Less local irritant and Distribution is better.

4. Better stability.

5. Desired drug release

6. Flexibility in design.

7. Increased in Bioavailability.

8. Reduced Adverse effects/.

9. Reduced risk of local irritation.

10. Expected gastric emptying.⁽⁴⁾

2.2 Disadvantages:

1. Drug loading is low.

2. Higher need of excipients.

3. Huge number of process variables.

4. Many formulations steps.

5. Huge cost of production.

6. Advance technology is needed.

7. Trained and skilled person needed.⁽⁷⁾

3. MECHANISM OF DRUG RELEASE FROM MULTIPARTICULATES:

3.1 Diffusion:

Water diffuses into the particle, when drug comes in contact with GI and dissolution of drug occurs.

There are two different methods by which diffusion controlled release can be obtained that includes, reservoir device and monolithic device in monolithic device drug product tend to distribute in a matrix and diffusion may take place through polymer matrix or by crossing between polymer chain and a molecular level. In difference to above said devices, reservoir device is the example in which drug is available as encapsulated or core within polymer film.

3.2 Osmosis:

With the help of osmotic pressure developed within the particle, drug is expelled out into the extrinsic through coating.

Osmotically controlled DDS (CDDS) based devices are supposed to be the most compatible CDDS especially for drug delivery through oral route. To check a drug release in a controlled manner by osmotic pressure can be used by special such as driving force. These systems generally consist of osmotic agents such as excipients. Semipermeable membrane, and drug.

3.3 Erosion:

In some of the cases, wherever coatings are particularly designed to wear away gradually with time, and hence these type of drugs which are contained within the particle can be delivered by erosion^(2,4,8).

4. TYPES OF MULTIPARTICULATE DRUG DELIVERY SYSTEM:

1. Pellets

2. Minitablets

3. Spheroids

4. Granulation

4.1 Pellets:

Pellets are small, free flowing, systemically produced, in spherical or semispherical shape and its size range from 0.2mm to 2.0mm, obtained from fine powders or granules exploit various pelletization.

Orally administered pellets in hard gelatin capsules/ disintegrating tablet release the drug in stomach and distributed over GIT without loss of any given effect 2,3. The subunit act as a self-contained store.

4.1.1 Ideal characteristics of pellets:

Coated and uncoated pellets has spherical shape with smooth surface which improves flow property. pellets has a good hardness and low friability which is foremost property of coating it has a high physical strength and integrity and it has a particle size between 500µm to 1000µm which required for efficient coating, prevents segregation during capsule filling and compression. High bulk density of pellets is very important role in achieving of weight uniformity.

4.1.2 Different pelletization technique:

Figure. no.1 - Different Pelletization Technique.

4.1.2.1 Balling:

In Balling, required amount of liquid is added before or during the agitation state. The obtained finely divided particle with consistent rolling or tumbling motion results in spherical particles.

Some of the Equipment used are discs, pans, mixers or drums.

4.1.2.2 Compaction:

1. Compression:

Pellitization is a process which active ingredients and excipients are blends or mixed and kept under prerssure to obtain pellets and definite shapes are 15,16

This pellets are small sized distribution and can be filed into the capsules.

2. Extrusion Spheronization:

Extrusion Sphernoization as introduced in the year 1960 as pellitization techniques(6).The foremost benefit of this is to mould drug loaded sphere high drug content upto 90%.This involves mixing active component and excipients in dry state to acheive same powder. Dry mixture, on addition of granulating fluid produces wet mass, which is extruded to formspaghetti- like extrudates. Extrudates are transferred to spheronizer resulting in spheroids, which is dried and screened to get uniform particle size. It is also called as cold-mass extrusion- spheronization.

4.1.2.3 Layering:

In layering, in which drug is layered onto coarse material in powder ,solution or suspension aid of a binder that assists many types of a pellets which consists of a inner core region and outer shelf region of a different composition 19,20.Thenonpareilseeds should have spherical shape,uniform particle size distribution,smooth surface.

Layering are classified into 3 categories

1. Direct pellitizing

2. Powder layering

3. Solution / Suspension Layering

4.1.2.4 Globulation:

1. Spray Drying:

To obtain dry spherical particles, solution/suspension o drug entities sprayed (either with/without excipients) into hot air stream, which improves the rate of dissolution and bioavailability of poorly soluble drugs.

2. Spray Congealing:

Drug is melted , dispersed / dissolved in hot melts of gum, fatty acid, waxes etc.., Once the temperature attains the melting point below the formulation components , this mixture is sprayed into air chamber, to obtain spherical congealed pellets.

4.1.3 Methods of pellets preparation:

Based on the application and choice of producer, pellets are classified as,

1. spray drying

2. spray congealing

3. Fluidized bed technology

4. Rotary process

5. ExtrusionandSpheronization

In the above one extrusion and spheroinzation are most used method of pellets preparation and used in the study

4.1.3.1 Extrusion and Spheronization:

It is one of the most widely used technique to prepare pellets, as it provides numerous pellets by avoiding drawbacks associated with other dosage forms. With the hhelp of extrusion- Spheronization, high quality pellets can be obtained.⁽¹³⁾.

Advantage of Extrusion and Spheronization

· Operating is easy

· High usage and less wastage

· Less friable

· Used in film coating

· Used in controlled and more sustained release of drugs⁽¹²⁾.

Process and equipment

In terms the extrusion and spheronization process involves in four steps:

· Granulation-wet mass preparation

· Extrusion-wet mass shaped into cylinder

· Spheronization-Extrudates breaks and forms sphers by rounding off particles.

· Drying- Formed pellets are dried⁽⁶⁾

Figure.no.2 - Pelletization Process

4.1.4 Theories of pellet formulation and growth:

Granule formation and its growth is important to select and optimize any pelletization process.With trace techniques, results obtained are acceptable.In ordinary classic pellitization which involves rotatory drum,a pan or disc which has three regions regionsnamely nucleation,transition,and ball growth⁽¹³⁾.

It is essential to understand the mechanism of pellet formation. Many theories explains the mechanism of pellet formation. Some theories are obtained from experimental results, while others from visual observation. In these theories , following steps are invoilved in the mechanism of pellet formation⁽¹⁴⁾.

1. Nucleation

2. Transition

3. Ball growth

Mechanism of pellet formation also involves following steps based on the experiment carried out on mechanism of pellet formation.

1. Nucleation

2. Coalescence

3. Layering

4. Abrasion transfer

Nucleation occurs when the powder is wetted with solvent system, which is the first step involved. Once after wetting, it forms 3 phases (air-water-liquid nuclei), by drawing primitiveparticles together. Transitition occurs after nucleation in which growth mechanism is affected by coalesence layering.

Coalescence is formed by random collision of well- formed nuclei, which leads to the formation of large particles, which requires slight moisture. As the moisture increases , number of nuclei decreases, whereas the total mass of the system remains constant

In layering, mechanism of growth is slow in which the number of particles does not change. Mass of the system increasesdue to increase in particle size. The particle size reduction the fragments can be obtained⁽¹⁶⁾.

Abrasion transfer is the transfer of materials from oe granule to another in no specific direction. Total mass of the particle remains constant. Only the size undergoes change until transfer of material exists.

4.1.5 Pellet Formulation:

APIs is potential for delivery in multi unit dosage form technology. Drugs with immediate and sustained release can be developed using pellets.Depending on the size, pellet formulation can be given through intramuscular/ Subcutaneous route. It is mainly used in the delivery of drugs to GIT, as it provides targeted and controlled release of drugs.

1. Binders

2. Granulating fluid

3. Spheronising enhancer

4. Filler

5. Platsicizer

6. Lubricant

7. Separating agent

4.1.5.1 Binder:

Binder are also called as agglomerating bridging agent or inducers.Adhesive materials helps in powder binding and to develop integrity in pellet formation. Binders can exists as solution, which is more suitable than dry form. With the help of organic/ aqueous solvent, binders are dissolved /dispersed, when it is applied as solution. Binder in the form of solution is commonly preferred. Binders are used in the conc from 2-10%⁽¹⁵⁾.

4.1.5.2 Granulating fluid:

Granulating fluid plays a major role in pellet formation, which provides plasticity and cohesiveness to the wet mass, When the wet mass is extruded and spheronized, it produces perfect spherical shape pellets. Required quuantity of moisture is needed for good quality pellets ⁽¹⁷⁾.

4.1.5.3 Spheronising enhancer:

Spheronization enhacer is used to develop spherical pellets. Spheronising enhancer not only possesses binding properties but also impart plasticity onto the formulation, which is needed for integrity and pellet strength.

4.1.5.4 Filler:

Filler ingredients is used here to bulk the material Excipients is formed by 70-80% fillers. Basically MCC is used ⁽¹⁸⁾.

4.1.5.5 Plasticizer:

Plasticizer which improves the polymers flexibility by reducing its material by glass transition temperature. In somecases excipients and drugs are employed as plasticizer.

4.1.5.6 Lubricant:

Lubricant are rarely used in this pellitization process. Lubricant palys a crucial role in compression and Extrusion-spheronization for the sucessuful for their production of pellets. It decreases the friction between material mix and die wall during the ejection phase and compression process.It helps in the smooth removal of pellets ⁽¹⁹⁾.

4.1.5.7 Separating agents:

It helps in the separation of pellets into individual units during formulation/ processing.It prevents pellet attraction that occurs due to surface charge.

4.2 Mini-Tablets:

Mini-tablets size ranges between 1.0-3.0 mm. Shape of the mini-tablets are flat or slightly curved tablets, which is filled in capsule or compressed into a large tablets or placed in sachet.⁽¹⁰⁾. Minitablets are attractive and alternative to the products of pellets the mini matrices and tableting techniques is used⁽²²⁾.

4.2.1 Constituent of Mini-Tablets:

Various mini-tablets can be individually formulated and designed, which is filled into capsules Minitablets can also be used for immediate release, delayed release, and/or controlled release formulations. Minitablets can improve therapeutic effectiveness of drug and more preferred than pellets.

4.2.2 Advantages:

· Compared pellets minitablets has high reproducibility, especially regarding their equal dimension their weight and smooth regular surface, high strength and low porosity.

· Minitablets the dependent on gastric emptying are less and gastrointestinal transit time is less in inter-intra subject variation^(23,24).

· Easy manufacture.

· Good flexibility during formulation.

· Good size uniformity, smooth surface, regular shape these acts as a good excellent coating substrate.

· Accumulation of drug is avoided.

· Reduced intra and inter-subject variability

· Great alternate for granules and pellets because they are simply easy to manufacture and it is equal dimensional of dosage form and weight⁽¹⁰⁾.

4.2.3 Theories of mini-tablets:

In order EC and HPMC are used as a matrix agent which helps to delay the drug release corresponding to the prolonged release component of dual release system this drug are from the minitablets. For release mechanism of drug the characteristics of the matrix plays a important role. For controlled release drug delivery, one of the most commonly used carrier is HPMC. Which act as a protective barrier when gel becomes a viscous layer to both the influx of efflux and water of the drug in solution^(25,26).

When liquid comes in contact with hydrophilic polymers, gel layer is formed, which is required for the controlled and sustain release of drugs. More than 40 years in pharmaceutical industry hydrogels are used in the controlled drug delivery from water swellable matrix system. HPMC, a hydrophilic carrier material is used in oral controlled release dosage form, since 1960⁽²⁷⁾.

The systems are complex because of their underlying mechanism of drug release, and the diffusion, swelling and erosion these are involved in three moving boundaries. HPMC matrix is shown to radial water uptake when drug load swellable high viscosity⁽²⁸⁾.

4.2.4 Formulation of minitablets:

APIs is potential for delivery in multi unit dosage form technology.There are possible for many different minitablets, different one formulated in different individual and which assessed to release the drug in different sites in GI track, into one capsule .This combination include delayed release, immediate release or controlled release minitablets.

1. Diluents

2. Binder

3. Glidant

4.2.4.1 Diluents:

Diluents are fillers which can be in a solution form water or alcohol and this which designed to make up the needed bulk of the tablet.But for some drugs they are sufficient high no need of filler is required.the selected diluent should be non-toxic, physically stable and chemically stable,physiologically inert by themselves and combination with drug and other components. Lactose is mostly used diluents in tablet formulation. Whether hydrous or anhydrous form the excipients that has no reaction with most of the drug. For direct compression spray dried lactose is one of the diluents⁽²⁹⁾.

4.2.4.2 Binders:

A binder sometime called as adhesives and this added to drug filler mixture which gain mechanical strength to the tablets and granules.In different ways binder can be added to powder.

· Before a compaction with other ingredients dry powder is mixed (dry binder).

· Prior wet agglomeration with other ingredients, dry powder is mixed.

· A soultion (agglomeration liquid) during wet granulation

4.2.4.3 Glidant:

It helps in the improvement of flow property of powder. Befor tabletting a glidant is also added often.As a glidant talc is used in tablet formulation 1-2% concentration of by weight. Silica is a collidal glidant which used most commonly used in the conc 0.2% by weight because all silica particles are very small.

4.3 Spheroids:

In the recent invention water-insoluble drugs relates to a controlled release pharmaceutical composition for administered to human or animal. The sphecial term "spheroid” means aspherical granule having a diameter between 0.5mm and 2.5mm, especially between 0.8mm. MCC, a non-water soluble pharmaceutical excipient is used for the formation of spheroids by spheronisation. Greater amount of MCC, helps to form spheroids in a easier way. In contrast, microcrystalline cellulose possess less control over drug release, so it cannot show controlled release characteristics.

This drawback can be overcome by,

1. Coating the spheroids with controlled release polymer.

2. Amount of MCC is either decreased to 50%w/w or less than the excipients weight and an excipient is added, which does not influence the drug release at a conc of 10% or more than the excipient weight. Disadvantages is associated in both the instances. In the first instance, a step is included, which is uneconomic, whereas in the second instance, less amount of MCC leads to the difficulty in the spheroid production⁽²¹⁾.

4.4 Granulation:

It is the process of conversion of powder to small particles ranging from 0.2-0.4mm in size. Granulation helps to modify the flow properties, compression characteristics, packing arrangement, dissolution-disintegration parameters of powder drug. Depending on the methods granulation could be classified as dry granulation and wet granulation. In wet granulation compact mass of powder drug is prepared with the help of addition of liquid or water and then it is sieved to required size granules. In dry granulation, granules are formed without addition of liquid substances. Effectiveness of granules affected by, type and volume of binder used, less or more time required for preparation of wet mass, amount of force applied and rate of drying of granules. The most popular novel granulation techniques are;

1. Pneumatic dry granulation

2. Freeze granulation

3. Foamed binder technology

4. Steam Granulation

5. Moisture activated dry granulation

6. Melt granulation technology

7. Thermal adhesion granulation process⁽¹¹⁾.

4.4.1 Granulation methods:

4.4.1.1 Wet granulation:

The general method which widely used for tablet preparation is wet granulation method. Granulation which meet all the physical requirement for compression of good tablet due to its greater probability. Its main disadvantage is number of steps involved as to carry out the procedure labour necessary and the time, especially on a large scale.

Wet method steps are weighing, mixing. granulation, screening, drying, dry screening, lubricant and compression. Depends on the quantity or size of the batch the equipment involved.

4.4.1.2 Fluid bed granulation:

The new method for granulating developed from the fluid bed drying technology. The concept of this to spray a granulating solution on to the suspending air. The main benefit of this system is drying of a batch and rapid granulation. The two main things developed this technology are Glatt and Aromatic (now NIRO). Fluidized bed system consists of

· Product Container and Air Distributor

· Control System

· Air-Handling Unit (AHU)

· Solution Delivery System

· Spray Nozzle

· Disengagement Area and Process Filters

· Exhaust Blower or Fan

4.4.1.3 Dry granulation:

Dry granulation which involves in sensitive moisture by granule formation product or heat without using any liquid solution In this process to obtain flakes compression into slugs or by roller compression be brought together mechanically by dry process⁽²⁰⁾.

5. CHARACTERIZATION OF MDDS:

5.1. Particle size and size distribution:

Intent by sieving technique which is simple and economical. The characteristic which affect the drug release and coating. And there is another method to identify the size which is estimation of fret diameter which looks in four angles.

5.2. Shape:

which influence the flow during coating which fills into capsules and dies. Ring gap analyser is the most common method for analysis. For qualitative and quantitative analysis is by scanning electron microscopy (SEM). Using microscope and stereomicroscope, visually pellets shape can also be determined.

5.3. Surface area:

To ensure the production of consistent surface area, shape is analyzed by air permeability method, particle size distribution, gas adsorption (BET method- Brunauer, Emmett and Teller). Analyzeda surface roughness by microscopy with image analysis and SEM. This property influences flow and packing.

5.4. Porosity:

influences rate of drug release by affecting dissolved drug capillary action, which is analysed qualitatively (SEM)and quantitatively (mercury porosimetry). The sample is brought into the chamber, degassed, and covered with mercury. After applying the pressure, volume of mercury that penetrates into the pores is recorded. Washburn equation tells about the pore radius.

5.5. Bulk Density and tap density:

Final product get influence, batch to batch variation produces segregation during mixing and leads. The ratio of weight was calculated by bulk density occupied volume and is measured by pycnometer.

5.6. True density:

Extent of compactness and densification. Air- comparison helium pycnometer, pycnometer or solvent different methods are displacement method of analysis.

5.7. Friability and hardness:

Helps to withstand subsequent coating and high attrition during coating. Roche friabilator, Erweka friabilator, Pharma Test friabilator are different equipment used. The % friability of pellets should be not more than 0.08%. Kaul pellet hardness tester is used to determine the hardness.

5.8. Tensile strength:

5kg load cell is determined by using tensile apparatus. The radius is recorded and these were strained continuously till failure occurs. Further load is noted. By applying the value of failure load (F) and radius (R). tensile strength is calculated by formula σ f (s) = 0.4F/ πR2.

5.9. Flowability:

If Ө<30°- the angle of repose is excellent, Ө>40°- which is poor flow ability.

5.10. In-vitro Dissolution Testing:

USP I (basket), USP II (paddle)are commonly used to study the drug release pattern (3).

6. CONCLUSION:

The modern market for MDDS has impressive rate of growth. Recent technologies for drug delivery can be developed by assimilating drug into various drug delivery system, which is a booming area in the pharmaceutical industry. In MDDS production, reproducibility and efficacy is achieved to a greater extent than other dosage form. MDDS can also serves to release the drug in a controlled and sustained manner. So, MDDS can serve as a potential alternative to single-unit dosage form.

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Received on 18.09.2019 Modified on 24.11.2019

Research J. Pharm. and Tech. 2020; 13(7): 3501-3507.

DOI: 10.5958/0974-360X.2020.00620.4