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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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