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NATIONAL UNIVERSITY OF SAN MARCOS

Professional School of Pharmacy and Biochemistry
Academic Department of Pharmacotechnics and Pharmaceutical Administration

COMPARISON OF STAGES IN THE GRANULATION PROCESS

WET AND GRANULATION BY FLUID BED

By ALEX JUNIOR ALBERCO MICHUE

By DARA EDITH CURIOSO MELO
By CRISTINA HUERTA SANCHEZ
By RAYMI CELESTE OBISPO HUAMANÍ
By KEVIN ANGEL SUAREZ SANTA CRUZ
Seminar presented to the Pharmacotechnics I course
Teacher: ALFREDO CASTILLO CALLE
April 12, 2019
Lima Peru
Research Article

Impact of different dry and wet granulation techniques on granule and tablet properties: a comparative study

Oscar Rupert Amndt 1 . Roberto Baggio 2 . Anna Kira Adam 1 . Julia Harting 1 .
Erica Franceses inis a . Peter Kleinebudde 1 , *
11rssituco lie Fastiadia f Bidfaritiacia, Heinrich Heine University, Univessitbesst. 1, 40225 Düsseldorf, Germany
i Department of Cendbs Faritiscéutcas f fartttscdlógicds, Univ ere id of Padua, Via Msrzalo 5, 35131 Psdus, helie

Item information summar

y
Four granulation techniques were evaluated to demonstrate their impact on the properties of the GRANULES . Tablet. A common formulation was chosen to be processed using two wet or dry granulation techniques: Corn pear or dry

granulation, shear wing granulation, double loin granulation, f

Florida Granulation Tuldlzado-bed. The produced granules were characterized in terms of granule size distribution, X-ray particle fraction, scanning electron microscopy, porosity, and strength. The granules will be
H rerin ill mrleuiz: compressed, and the compacts will be evaluated in terms of tensile strength and mass variation. A particular focus was given to granular intensity measurements. The type of granules was shown to be strongly affected by
Enet des 30 en Jul= du z.01 B4rmd aud= en
the granulation technique used. On the other hand, a non-linear reverse reaction is identical between the granule strength and tensile strength of the tablet, high shear granulation producing the densest and strongest
Ip Mnan =• X 015 Hl 1 D of du
granules, which it presents. plus resistance = the traction of the tablet. The granules manufactured by the compaction/dry granulation roller showed no loss of compressibility with the formula used, even for the most
up: » — :■■■ : ■ X 015
compacted and thickest granules. The tablets produced by the Florida fluidized-bed granulackon showed the best properties in terms of tensile strength and mass variation, comparable results However, double-hill

granulation presented for the speci 11 formulation c evaluated in the study, which reveals great potential of this technique.

plizer eixem:
tablei Twist granule
Introduction
Four granulation techniques were compared in evaluating their impact on granule
properties and tableting strength.
Introduction
• Granulation is one of the most important processes in the manufacture of solid oral
dosage pharmaceutical forms.
• Granulation is performed to improve the characteristics of the starting materials, such
as flow properties, tablet capacity and bulk density.
• It ensures uniformity of particle formulations and prevents active pharmaceutical
ingredient (API) segregation and dust formation, thus improving operator safety.
• Granules produced are used as a pharmaceutical dosage form but more often used as
an intermediate for the production of tablets.
SUMMARY
High shear granulation (HSG): produced the densest and strongest granules, which had the
lowest tensile strength of the tablet.

Granules manufactured by roller compaction/dry granulation (RSDG) did not show any loss in
tableting ability with the formulation used.

Tablets produced by fluidized bed granulation (FBG) showed the best properties in terms of
tensile strength and mass variation. and the recently introduced twin screw granulation
(TSG).

GOALS

• Improve the compaction characteristics of the mixture

• Improve the slip properties of the mixture
In granular fractions of 355-500 mm. Figure 2 shows for each
granulation method a representative SEM image.

Figure 2. SEM images of granules: RCDG 3 (a). HSG 1 (b), TSG 1 (c) t and FBG 3 (d).
 Importance of granulation
Avoid segregation of constituents. Improve compression properties of the
mixture.
Improve the flow properties of the sample.
Avoid cake formation (hygroscopic substances).
Improve powder compaction. Improve product appearance.

Reduce the risk of poisoning due to dust that Improve storage and/or shipping (granules have
may arise from toxic materials. less volume per unit of weight.

(Verma,
Ideal Granule Characteristics

spherical shape Fluency

Narrow distribution of improvement
particle size Uniformity of content
volumetric.
Humidity and hardness
Avoid breakage and
suitable dust formation.
and dispensing

(Verma,
 DRY GRANULATION
Compression of the mixture by the action of high pressures, without heat or
solvents.
Dry granulation stages
Slug screening Mixture with lubricant
and disintegration agent

tablet
compression

Ground powder
mix

Grinding of drugs and

excipients
 Formation of large, hard
tablets (slugs)

(Verma, 2017)
 WET GRANULATION
Granules are formed by adding a binder solution to the mixture.
dust. Wet sizing and drying should be considered.
Sifting of the wet mass
(appropriate sieve depending
on the desired product)
Formation of wet
dough (powder
mixture + binder
solution)
Preparation of binder solution

Mixture of drugs
and excipients

(Verma, 2017)
 Advanta
ges

Improves
Produces cohesion. Reduce
less dust and entrapment
pollution of air
crusade
Improving powder flow
Allows the properties by
increasing size
mechanical handling of
powders without loss of
quality of the mixture.
Increases and of particle and
Hydrophobic improves the sphericity.
surfaces uniformity of
become powder
hydrophilic. density.

(Verma,
2017)
 Limitations

Elderl
y
difficulty
High
cost
process,
validation
Not suitable for and
thermolabile and/or control
Increased
humidity sensitive incompatibility
drugs
Loss of between
material components
during the
process

(Verma, 2017)
Advantages Limitations

Use less
equipment
and
space.

Advantageous for
moisture,
thermolabile
No binding
substances and for
solution or
drying
disintegration.
required
(time and
cost).

(Verma, 2017)
 DRY GRANULATION
THISmethod is based: It is applied when the
The primary dust •
Mix components of the mixture
particles are •
Compaction: press are sensitive to moisture,
added under or with rollers cannot
high pressure . Chopping or withstand
fragmentation
Granulation
(with sieving)

Pre-compression or double
compression A large fragment is elevated drying temperatures or
produced in a high-pressure do not have sufficient intrinsic
compression machine bonding or adhesion.
Two types of
dry granulation are distinguished :
Compaction with rollers. (Abraham, 2014)
A sheet of material is produced
General dry granulation method

Compaction granulation involves

the compaction of the The initial mixing of the
components of a formulation by powders is forced into the
means of a tablet press or molds of a large capacity press
specially designed machinery and compacted, the resulting
followed by milling and sieving. compact masses are called
ingots, and the process is
referred to as slugging.

When a simple slugging The ingots are sieved or

process is insufficient to give broken up to produce a
the desired granular granular material, which
properties to the material, the now flows more uniformly
ingots are subjected to than the original mixture.
sieving, slugging and sieving
once more.

(Abraham, 2014)
Fig. x General method showing
the classic dry granulation
process.
(Abraham, 2014)
Limitations of dry granulation (Abraham, 2014)

A large amount of fine powders are produced that must be recycled.

High compaction pressures can prolong dissolution time.

The difference in densities and particle sizes between the active substance and the excipients
can produce stratification of the mixture and in turn produce content uniformity problems.

Active substances that are dosed in large quantities and do not have compressibility are
difficult to handle by this method.

Because the process is carried out dry, a large amount of dust is produced, which can
generate electrostatic charges and a non-uniform distribution of the active substance in the
mixture and in the final tablet.
BY DOUBLE COMPRESSION -bishop

BURDEN

Dry powders are compressed using a conventional tablet press.

To fragment these compact materials, the hammer mill is suitable.stationary

plate

rotating
disc

Hammers

Retaining grille nC 10

PRODUCT
Aulton,200
ROLLER COMPACTORS-bishop.
a method
milder alternative in
where the powder mixture
is extruded between two
rollers to form a
compressed sheet (weak
and brittle) and is
fragments into flakes

granule sieve

Aulton,200
Development of a secnidazole 500 mg coated tablet
formulation

Development of a formulation of coated secnidazole tablets 500

mg

Iverlis Diaz Polanco 1 ; Saúl Padron Yaquis 11 ; Bertha López 111 ; Loreta Delgado-;
Miriam Moya Jure-; Juana Tillan Capo 11
I
Associate Researcher. Research and Development Center
Medicines. Havana Cuba.
II
Assistant Researcher. CIDEM. Havana Cuba.
III
Technique in Chemical Control . CIDEM. Havana Cuba.
IV Technology Specialist A. CIDEM. Havana Cuba.
Secnidazole 500 mg (TR) formulation

A mp was used of secnidazole (Trifarma

SPA) that meets the quality
Different trials were designed containing specifications established by the
500 mg/tablet of secnidazole and auxiliary manufacturer.
substances for the preparation of oral solids.

0
The physical-chemical
\© /n )
0
N" BCH3 characteristics of the active
ingredient were that it has poor
\s) ""/om H,C fluidity and compressibility
SECNIDAZOLE
(S)-1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol properties, and it also has a
small particle size (23.4 µm).
Fig 15. Chemical structure of the active ingredient. (López,
2013)
Secnidazole 500 mg TR formulation
5 tests were carried out of the
which were both used
granulation routes for
secnidazole formulation
500 mg TR
A DIOSNA mixer-granulator was used, and a
(López, 2013)
It started with the method The formation of heavy
dry granulation or through weight tablets, for which a
” double compression, for MANESTY 16-station
make granules and eccentric die-cutter was used.
tablets (A,B,C).
then v
It was evaluated for
method of
_ this granulation
VIANI fluidized bed, for drying. (C moist.
and D)
Results of the dry or double compression route
Essay A Essay B Essay C

Granule fluidity Low Inadequate No improvements

Fails Fails Compliant

• Height • Time of • Times of
• Hardness disintegration disintegration
Limits set for • Friability
parameters • Time of Fails
disintegration • Hardness (+)
• Friability

Table 1. Results of tests A, B, C carried out by dry method d

 Table X: Physical-mechanical and technological properties of the cores

Property TO b c d AND

Mass ± SD (mg) 726,30 ± 7,48 725,90 ± 6,22 725,70 ± 3,41 700,10 ± 0,89 701,20 ± 5,57

Height ±OD (mm) 6,80 ± 3,25 6,60 ± 2,89 6,50 ± 1,78 6,30 ± 0,22 6,40 ± 1,45

Hardness ± SD (kg/f) 7,00 ± 4,15 7,50 ± 3,33 8,20 ± 2,76 9,70 ± 0,43 7,80 ± 2,45

Friability ± SD (%) 1,39 ± 2,50 1,25 ± 1,80 0,81 ± 1,50 0,14 ± 0,20 0,65 ± 1,22

Durability ± SD (%) 25,00 20,10 10,21 3,15 5,25

Limits: mass: 721.0 ± 72.10 mg (tests AC), 700.0 ± 70.0 mg (tests D,E); height:
6.40±0.15mm; hardness: 9.0 ± 1.0 kgf; friability: ≤ 1.00%;
disintegration: ≤ 15 min in water at 37 ± 2 °C
 CONCLUSIONS
• An improvement was observed in the compaction characteristics of the mixture since some
powders are difficult to compact even if adhesives are included, in some it depends on the
method to produce the granule and the good distribution of the adhesive within the granule.

• since the granules produced from a cohesive system will be larger and with a more

homogeneous diameter, an improvement in the sliding properties of the mixture is observed.

BIBLIOGRAPHIC REFERENCES
1. Verma, B., S. Pandey, and P. Arya. (2017) “TABLET GRANULATION: CURRENT SCENARIO AND
 RECENT ADVANCES”. Universal Journal of Pharmaceutical Research , Vol. 2, no. 5. Available at:
https://www.ujpr.org/index.php/journal/article/view/90/68
2. Aulton. (2004). pharmacy the science of the design of pharmaceutical forms (2nd ed., pp. 372-373). elsevier.
3. Abraham Resendiz Carlos Eduardo, Casillas Salazar Diego Alexis. Preparation of a video for the granulation unit
operation. Faculty of Higher Studies Zaragoza. Mexico DF; 2014
4. Díaz Polanco Iverlis, Padrón Yaquis Saúl, Bertha López, Delgado Loreta, Moya Jure Miriam, Tillán Capo Juana.
Development of a formulation of secnidazole 500 mg coated tablets. Rev Cubana Farm [Internet]. 2008 Apr [cited
2019 Apr 18] ; 42(1). Available at: http://scielo.sld.cu/scielo.php ? script=sci_arttext&pid=S0034-
75152008000100004&lng=es.