IMPACT OF AGGLOMERATIVE PHASE OF COMMINUTION (APOC) … · Dry granulation 4. APOC Wet granulation In wet granulation, granules are formed by the addition of a granulation liquid

www.wjpr.net Vol 3, Issue 3, 2014.

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Manoj Patil. et al. World Journal of Pharmaceutical Research

IMPACT OF AGGLOMERATIVE PHASE OF COMMINUTION (APOC)

ON PERFORMANCE CHARACTERISTICS OF UNCOATED TABLET

RajveerBhaskar, Monika Ola, ManojPatil*

Department of Pharmaceutics and Quality Assurance,

R. C. Patel Institute of Pharmaceutical Educational and Research, Shirpur. Dist. Dhule,

Maharashtra India.

ABSTRACT

Agglomerative phase of comminution is a relatively newer granulation

cum particle size reduction technique in which agglomeration of the

fine coherent particle take place into loose granular structure.

Agglomeration of the fine cohesive particles produced during grinding

particularly with rotating or oscillating ball mills. Reduction of particle

size during prolonged grinding by a ball mill has been used as a novel

means of producing a pharmaceutical granulation. When compared

with conventional granulation methods, this method produced

mechanically stronger tablets with a higher dissolution rate than those

compacted from granules made by a conventional wet granulation

method. A possible mechanism for the increased dissolution rate is the

increased internal surface area of the particles produced by the

prolonged grinding method. Increased homogeneity and bioavailability characteristics can be

obtained both by help of this granulation technique.

Keywords: Agglomeration, granulation, particle size, bioavailability, dissolution, ball mill.

INTRODUCTION

In pharmaceutical industry, Granulation defines the process as “any process whereby small

particles are gathered into larger, permanent,masses in which the original particles can still be

identified”. Granulation refers to the act or process in which primary powder particles are

made to adhere to form larger, multiparticles entities called granules. Bonds are formed by

compression or by using a binding agent. Granulation is extensively used in the

manufacturing of tablets and pellets or (spheroids). The granulation process combines one or

World Journal of Pharmaceutical ReseaRch

Volume 3, Issue 3, 4287-4304. Research Article ISSN 2277 – 7105

Article Received on 02 March 2014, Revised on 25 March 2014, Accepted on 18 April 2014

*Correspondence for Author

ManojPatil

Department of Pharmaceutics

and Quality Assurance

R. C. Patel Institute of

Pharmaceutical Educational

and Research, Shirpur. Dist.

Dhule, Maharashtra India.


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more powder particles form a granule that will allow tableting or spheronization process to be

required limits.

Tablets are solid dosage form usually prepared with the aid of suitable pharmaceutical

excipients. They may vary in size, shape, weight, hardness, thickness, disintegration and

dissolution characteristics and in other aspects, depending on their intended use and method

of manufacture. Most tablets are used in the oral administration of drugs. Many of these are

prepared with colorants and coating of various types. Other tablets such as those administered

sublingually bucally or vaginally are prepared to have features most applicable to their

particular routes of administration.

Tablet formulation contains several excipients along with the active ingredient is the most

important among them. The remaining excipients are necessary because a suitable tablet

cannot be composed of active ingredients alone. The tablet may require variations such as

additional bulk, improved flow, better compressibility, flavoring, improved disintegration

characteristics and enhanced appearance. The active ingredient in a formulation represents

only a very small portion of the overall tablet, and then the challenge is to ensure that each

tablet has the same amount of active ingredients. Sometimes, blending the ingredients is not

enough. The active ingredients may segregate from the other ingredients in the blending

process. The ingredients may be incompatible because of particle size, particle density, flow

characteristics, compressibility, and moisture content. Granulating the active ingredients by

itself and blending it with the rest of the ingredients is one solution to the segregation

problem. The best course to ensure that each tablet contains the correct amount of active

ingredients especially if the active is only a small percentage of the tablet ingredients, is to

mix the active ingredients thoroughly with some or most of the other ingredients and then

granulate the blend. Each granule would contain a little of each of the ingredients, and the

active ingredients would be distributed evenly tables (no content uniformity), or all the

powder won’t fit into the die cavity (the place where powders are filled on the tablet press).

Simply blending powders does not form a granule. Many processes are unnecessarily

implemented because the objective and reason for choosing a process path were incorrect. [1]


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Figure1. Proportion of various dosage forms available in market. [2]

GRANULATION TECHNIQUE

A tablet with good characteristics is not made on a tablet press; it is made in the granulation

process. Joining particles within a given granulation process will improve flow and

compression. Characteristics, reduce segregation, improve content uniformity, and eliminate

excessive amounts of fine particles. The results will be improved yields, reduced tablet

defects, increase productivity, and reduced down time. The objective of the process is to

combine ingredients to produce a quality tablet. [1]

Different existing granulation techniques use for the preparing form such as tablets, capsule,

and pellets are following-

1. Wet granulation 3. Direct granulation

2. Dry granulation 4. APOC

Wet granulation

In wet granulation, granules are formed by the addition of a granulation liquid into a powder

bed which is under influence of an impeller (in a High shear granulator, screws (in a twin

screw granulator) or (in a fluidized bed granulator). The agitation resulting in the system

along with the wetting of the components within the formulation results in the aggregation of

the primary powder particles to produce wet granules. The granulation liquid contains a

solvent which must be volatile so that it can be removed by drying and be non-toxic.

Granulation liquid solution can be either aqueous based or solvent based. Aqueous solutions

have the advantages of being to deal with than solvents.

The process can be very simple or very complex depending on the characteristics of the

powders, the final objective of tablet making, and the equipment that is available. In the


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traditional wet granulation method the wet mass is forced through a sieve to produce wet

granules which are subsequently dried. [1]

Figure2. Process of Wet granulation

Figure3. Step in Wet granulation process

Figure3.1 Flow chart of Wet granulation

Dry granulation:Different existing granulation techniques use for the preparing form such as

tablets, capsule, and pellets are following-

1. Wet granulation 3. Direct granulation

2. Dry granulation 4. APOC


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The dry granulation process is used to form granules without using a liquid solution because

the product to be granulated may be sensitive to moisture and heat. Forming granules without

moisture requires compacting and densifying the powders. In this process the primary powder

particles are aggregated under high pressure. Sweying granulator or high shear mixer-

granulator can be used for the dry granulation.

Dry granulation can be conducted under two processes; either a larger (slug) is produced in a

heavy duty tableting press or the powder is squeezed between two rollers to produce a sheet

of materials (roller compactor, commonly referred to as a chilsonator).

Figure4. High shear mixing granulator Figure5.Chilsonator

Direct Compression

Direct Compression is one of the easiest means of producing tablets, because it only involves

the powder blending, lubrication and compaction. Because there is no granulation step to

improve flow and compaction it is usually necessary to use excipients specially designed for

direct compression, and engineered to provide necessary flow and compaction properties.

Such materials are sometimes known as “filler-binder”. The examples of fillers and binder

are lactose, sucrose, magnesium stearate, glucose, plant cellulose, calcium carbonate,

microcrystalline cellulose, malitol, sorbitol, xylitol etc. Despite the availability of these

materials, the utility of direct compression may be limited by the dose of drug to be tableted.

Other direct compression excipients, such as superdisintegrants are the same as those used for

wet or dry granulation.


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Figure6. Flow chart of Direct Compression

Agglomerative phase of comminution (APOC)-

A newer technology called as agglomerative phase of comminution (APOC) was found to

produce mechanically stronger tablets with higher dissolution rates than those of made by wet

granulation. A possible mechanism is increased internal surface area of particles produced by

APOC method.A successful processing for the agglomeration of primary particles depends on

proper control of the adhesional forces between particles, which encourage agglomerate

formation and growth and provide adequate mechanical strength in the product.

Agglomeration refers to a phenomenon where small particles dispersed to form relatively

permanent larger particles. Usually the sizes and shape of the original particles can still be

distinguished. Agglomeration is a common phenomenon within a wide variety of industries

that deal with solid particles. These industries include fields like minerals processing

pharmaceutical, agriculture, chemicals and fertilizers, food, biological materials and

ceramics. In industries production agglomeration can be either or desired. As points out, size

classification, comminution and conveying are examples of unit operations where

agglomeration undesired. Furthermore, agglomerates may entrap mother liquor and

impurities, thus preventing efficient washing of the product. The properties of single particles

usually improve when the particle size becomes smaller. These include properties like

homogeneity, strength and bioavailability. However, as the particle size gets reduced, the

Pre-mix

Media mill

Spray Dry

Screen /Sieve

Blend

Compress


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tendency of the particles to form agglomerate during operation further increases [16]. Also,

processing fine powders in general is problematic. A powder takes a lot of space, create dust

and it can be improve handling properties of both the products and the intermediates.

Agglomeration of the fine cohesive particles produced during grinding, particularly with

rotating oscillating ball mills, has long been recognized as an end point of the comminution

operation. There is considerable literature on the use of grinding aids to prevent or delay the

onset of agglomeration during the comminution of a wide variety of materials, [13],[14].

A typical grinding operation leading to subsequent agglomeration to exist in three separate

stages, [15]. The first (Rittinger’s stage) is the first stage which is normal comminution

operation carried out, where the energy input (or grinding time) is directly proportional to the

size reduction produced. During the second or coating stage, particles adhere to the milling

and grinding media due to the presence of unsaturated bonds caused by crystal lattice

distortion produced during prolonged milling. This phase can be delayed or eliminated by

adding surface- active grinding aids to neutralize the free bonds forces. The final or

agglomeration stage follows on prolonged milling and is largely unaffected by the presence

of grinding aids [16] and [17] have discussed the mechanisms and forces necessary to

produce granulation. These include molecular (London or Van der Waal’s forces),

electrostatic forces, melting, chemical interaction, recrystallization or mechanical

interlocking. Many or all these forcesmay be employed in the agglomerative phase of

comminution. Despite the extensive literature on the agglomeration of a wide variety of

materials produced by prolonged grinding operation, few reports are available on the

applicability of this technique as a granulation operation. Such a granulation technique could

offer advantages in that during preparative stage, fine particles are employed. Thus increased

homogeneity and bioavailability characteristics may result from the use of this granulation

technique.

Figure7. Theoretical diagram of grinding process, (L. Opoczky, 1977), [15]

aggregation

agglomeration

coating

Rittinger’s stage

Degree of Dispersity


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Figure8. Relationship between different particle group, [18]

(A) (B) C)

Figure9. (A) represents primary particle, (B) represents aggregates and (C) represents

agglomerates, Size nature of dry particles, [18]

The most feature determining the bulk properties of a powder are the characteristics of the

single particles it is composed of most powders are made up of three types of particles

assemblies: Primary particles, aggregates of primary particles and larger loose agglomerates

of primary particles. Agglomeration depends on the size of the individual particles are more

cohesive than coarse particles, which are mainly influenced by gravitational forces. The

property to form agglomerates is very important during the dissolution of a poorly water

soluble drug becomes when particles form coherent masses in the dissolution medium. The

surface are available for dissolution is reduced. [44]

G. Santhosh Kumar and V. SubbaRao had conducted an experiment on Batch by ball mill

grinding of dolomite using Box- Behnken design and concluded a result that as grinding time

increases, specific surface increases, power consumption increases. [51]


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The influence of milling on the dissolution performance of simvastatin had shown the result

that a central composite face centered design was successfully applied to determine optimum

milling parameters for simvastatin in a dry ball milling process with regard to particle size.

This study also shows the importance of dissolution testing at an early stage of drug

development in order to ensure the performance of the final formulation. [55]

Figure10. Diagrammatic represents of material behavior after prolonged milling. After

grinding for 0.5 h, substance decreases to a minimum size. On further grinding,

agglomeration commences maximum size reached at 16h as evidences of large pore size

of the structure. Further grinding may cause recomminution or compaction or both. [3]

3. Recent Advances in Granulation technique

Steam Granulation: Modification of wet granulation; steam is used as a binder instead

of water; granules are more spherical and exhibit higher rate of dissolution.

Melt Granulation: Thermoplastic Granulation: Granulation is achieved by the addition

of meltable binder i.e. binder is in solid state at room temperature but melts in the

temperature range of 500-800C [e.g. PEG (water soluble), stearic acid, cetyl or stearyl

alcohol (water insoluble) - drying phase unnecessary since dried granules is obtained by

cooling them to room temperature.

Moisture Activated Dry Granulation (MADG): Involves distribution of moisture to

induce agglomeration – drying time is reduced. In MADG, moisture is used to activate

granule formation, without the need to apply heat to dry granules.

Agglomeration Moisture Distribution/Absorption

Moist activated dry granulation:


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Dry is blend with diluents and Powder.

A small amount of water (1-4%) is

sprayed.

Agglomeration formation (size 150-

500um)

Moisture absorbent like

microcrystalline cellulose silicon

dioxide are added while mixing.

Moisture redistribution within the

mixture.

Entire mixture becomes relatively dry

Moist Granulation Technique (MGT): A small of granulating fluid is added to activate

dry binder and to facilitate agglomeration. Then a moisture absorbing material like

Microcrystalline Cellulose (MCC) is added to absorb any moisture making drying step

unnecessary. Mainly employed for controlled release formulations.

Thermal Adhesion Granulation Process (TAGP): Granules are prepared by

moisturizing excipient mixture with very little solvent in a closed system (Tumble

mixing) with low heating- mainly employed for preparing direct compression

formulations.

Foam Granulation: Binders are added as aqueous foam.

4. Table 1. Advantages and Disadvantages of APOC

Sr. no Advantages Disadvantages 1 The APOC technique produced

mechanically stronger tablets with a higher dissolution rate.

Adhere to the mill lining and grinding media.

2. Reduction of disintegration time and increases bioavailabilitycharacteristics of drug.

3. It is also a solubility enhancement granulation technique.

4. Installation, operation, and labour cost are low.

5. Significance of APOC regarding BCS Class II/ IV drugs. (B. B. Kumar Reddy and A.

Karunakar), (2011)

The large number of drug candidates with poor dissolution characteristics seen in the past

decade, If a poorly soluble drug (BCS class 2 drug) can be transferred into a solubilized

state, one can achieve an absorption profile close to that of a soluble drug (BCS class 1 drug).

Thus, formulation development typically endeavors to achieve the most robust solubility

enhancement.


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Table2. The Bio pharmaceutics Classification System:

Class I

High solubility

High Permeability

Class II

Low solubility

High permeability

Class III

High solubility

Low permeability

Class IV

Low solubility

Low permeability

The drugs of this class have a high absorption number but a low dissolution number. In vivo

drug dissolution is then a rate- limiting step for absorption except at a very high dose number.

The absorption for Class II drug is usually slower than for Class I and occurs over a longer

period of time. In vitro- vivo correlation (IVIVC) is usually accepted for Class I and Class II

drugs. The bioavailability of these products islimited by their solvation rates. Hence,a

correlation between the in vivo bioavailability and the in vitro solvation can be found.

APOC granulation technique is used to increase the solubility of the low soluble drug (BCS

class II) by prolonged grinding with the help of ball mill. A possible mechanism for the

increased dissolution rate is the increased internal surface area of the granules produced by

the prolonged grinding method, increased homogeneity and bioavailability characteristics

may result from the use of this granulation technique.

Table3. Problems related towards the granulation by the granulators

Sr. no Why do it Which are the equipment’s What are the problems

1. Provides homogeneity of drug distribution in blend.

Dry Granulator ( roller compactor, Tableting machine)

Loss of material during various stages of processing.

2. Improves flow, compressibility and hardness of tablets.

Wet High-shear Granulator (horizontal, vertical)

Multiple processing steps-validation and control difficult.

3.

The formulation of an active compound and other excipients need to be mixed homogenously

Wet Low- Shear Granulator (planetary, kneading, screw)

Incompatibility between formulation components is aggravated.

4.

To achieve good granulation and particles must be uniformly mixed.

Fluid Bed Granulator, Spray Dry Granulator, RMG

Excessively coarse granules, Final moisture inconsistency, low yield, final product non uniformity.


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7. EQUIPMENT’S USED FOR APOC GRANULATION TECHNIQUE-

Ball Mill

Ball mill works on the principle of combination of impact and attrition. In a ball mill the ball

rotating at slow speed the ball roll and cascade over one another provides an attrition

function. As speed is increased the ball are carried up and fall freely and impact action is

provided. These are responsible for the size reduction.

Figure11. Working principle of ball mill Figure12. Industrial ball mill

Vibratory ball mill: [19]

Vibratory ball mill are used extensively in the pharmaceutical industry as a simple,

economical and rapid means of particle size reduction. However, prolonged comminution in

this type of high energy mill results in a practical grind limit, or Hiittig grinding equilibrium,

[20] due to agglomeration of ground particles [21] described the three phases of milling. The

initial grinding or Rittinger’s stage is followed by a reversible aggregation phase and finally,

on prolonged grinding, irreversible agglomeration occurs. The forces involved in

agglomeration have been extensively described by [22] and [23]. [24] considered that

agglomeration was due to the oversupply of some 80% of energy in ball mill. [25] was able to

show that the lattice defects occurring during comminution of lactose monohydrateled to

‘mechano-activation’, which may be manifested as agglomeration [26]. There is considerable

literature on the use of grinding aids to delay the onset of agglomeration; the effect these

agents exert is attributed to their ability to reduce surface energy [27-30]. This mechanism is

supported by [31], who showed an increase in surface energy, while specific surface area

decreased, during the comminution of sucrose in a vibratory ball mill.

The agglomeration of a wide range of materials including cement, [24, 32] sand, [33] sugar,

[31, 34] sodium chloride [35] and pharmaceuticals during comminution process has been


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reported. However, few reports exist on the application of this technique to granulation

operations. Ho and Hersey [3] investigated granulation in a rotary ball mill; it is thought that

increased homogeneity and bioavailability characteristics may result from this use of this

granulation technique [26].

Figure13. Vibratory ball mill

Other ball mill variant- [37]

Ball mills are applicable to wide variety of materials, large ones being used for grinding ores

prior to manufacture of pharmaceutical chemicals and small versions for the final grinding of

drugs or for grinding suspensions. Variants of the simple ball mill include,

1) Hardinge Mill

Hardinge mill in which the cylinder has a conical endtowards a discharge point. In this mill,

the balls become segregated, the largest collecting in the cylindrical portion, and those of

decreasing size towards the apex of the cone. As a result, the coarse grinding is carried out by

the larger balls, the particle size decreasing as the material works its way towards the smaller

balls. The product is finer and more uniform than produced by a simple cylindrical model.

Raw feed Regrind Dust exhaust

Screen

Grind discharge Isolation springs

Reactor springs

Grinding media


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2) Tube Mill

The Tube mill as implies, has a long narrow cylinder and grind to a finer product than the

convectional ball mill.

3) Rod Mill

The Rod mill has rods, which extend the length of the mill, instead of balls and is useful with

sticky materials, since the rods unlike balls,do not adhere to form aggregates.

A recent variation on the ball mill is to use a vibratory movement instead of rotational, know,

therefore, as vibration milling. The casing is on a spring mounting and connected to an off-

balanced flywheel, which sets up vibration, the mill moves through a circular path, with an

amplitude of vibration up to about 20nm and a rotational frequency of 15 to 50 s.

4) Pebble Mill

The cylinder may be of metal, porcelain or of rubber abrasion. The balls may be of metal,

porcelain or, occasionally, pebbles are used, when the mill may be described as a pebble mill.

The amount of the materials in the mill is of considerable importance, too much exerting a

cushioning effect and too little leading of efficiency and to abrasion.

5) Planetary Ball Mill

In Planetary ball mill, the comminution of the materials to be ground takes place primarily

through the high- energy impact of grinding balls in rotating grinding bowls, The FRITSCH

Planetary Mill premium line enables revolutionary rotational speeds up to 1100 rpm. Its

advantage: short grinding times, finest grinding results down into Nano range.

7.4 Advantages Compared with Conventional Ball milling

(a) Grinding is faster and has been claimed that only tenth of the time or even less is needed.

(b) For most materials, a closer size range is produced.

(c) The power requirements are lower.

(d) Although the rotating mill is unlikely to be replaced in large equipment’s, for example the

crushing of ores, vibration milling shows considerable advantages for medium and small-

scale applications.

8. APPLICATIONS

The application of this granulation technique APOC it may increase the dissolution rate

and reduce the disintegration time.


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The Granulation in a rotary ball mill increased the bioavailability characteristics of drug

may result from the use of this grinding techniques.

The ball mills be sterilized and sealed for sterile milling in the production of ophthalmic

and parenteral products.

9. CONCLUSION

Various innovative approaches have been explored to simplify and control the granulation

process and improved quality of produced granules. One of the novel approaches included of

granulation technique is Agglomerative phase of comminution (APOC). The particles size

changed during the grinding of drug and excipients. As the comminution proceeds,

agglomeration commences and eventually a wide size range of particles is produced

consisting essentially of very coarse and very fine particles. Future advancement in the

granulation technique could further improve the granulation process, thus increased the

bioavailability and homogeneity of the drug.

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IMPACT OF AGGLOMERATIVE PHASE OF COMMINUTION (APOC) … · Dry granulation 4. APOC Wet granulation In wet granulation, granules are formed by the addition of a granulation liquid