Diclofenac is chemically 2-[(2,
6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt and was selected as model drug. Diclofenac sodium is
a white to off-white, hygroscopic, crystalline powder, sparingly soluble in
water; soluble in alcohol; practically insoluble in chloroform and in ether;
freely soluble in methyl alcohol. Diclofenac is an NSAID. It is used mainly as
the sodium salt for the relief of pain and inflammation in various conditions:
musculoskeletal and joint disorders such as rheumatoid arthritis,
osteoarthritis, and ankylosing spondylitis; peri-articular disorders such as
bursitis and tendinitis; soft-tissue disorders such as sprains and strains; and
other painful conditions such as renal colic, acute gout, dysmenorrhoea,
migraine, and following some surgical procedures. The most frequent adverse
effects reported are gastrointestinal in nature. Typical reactions include
epigastric pain, nausea, vomiting, and diarrhoea. In order to avoid these
adverse effects, diclofenac sodium is enteric coated to avoid its release in
stomach.
Modified-release
preparations can be administered orally in single or multiple-unit dosage
forms. Although, similar drug release profiles can be obtained with both the
dosage forms, multiple-unit dosage forms offer several advantages over
single-unit systems such as non-disintegrating tablets or capsules1.
When multiple-unit systems are taken orally, the subunits of multiple-unit
preparations distribute readily over a large surface area in the
gastrointestinal tract and these small particles (< 2 mm) behave like
liquids leaving the stomach within a short period of time. Their small size
also enables them to be well distributed along the gastrointestinal tract that
could improve the bioavailability, which potentially could result in a
reduction in local drug concentration, risk of toxicity, and side-effects2.
Inter- and intra-individual variations in bioavailability caused, for example
food effects, are reduced3, 4. Premature drug release from
enteric-coated dosage forms in the stomach, potentially resulting in
degradation of drug or irritation of gastric mucosa, can be reduced with coated
pellets because of more rapid transit time when compared to enteric-coated
tablets [3, 4]. In multiple-unit system, the total drug is divided into many
units. Failure of few units may not be as consequential as failure of a
single-unit system. This is apparent in sustained-release single-unit dosage
form, where a failure may lead to dose-dumping of the drug [3]. Other advantages of this divided dose include
easy adjustment of the strength of a dosage unit, administration of
incompatible drugs in a single dosage unit separating them in different
multiparticulates and combination of multiparticulates with different
drug-release rates to obtain desired overall release profile. In this
study, diclofenac sodium DR granules/ pellets contained
50 mg was prepared in a single step without DR polymer membrane coating and the
dissolution profile was compared with reference product, Voveran®,
diclofenac sodium DR tablets.
With regards to the
final dosage form, multiparticulates can be filled into hard gelatin capsules
or be compressed into tablets. Usually multiple-unit dosage forms are filled
into hard gelatin capsule. Unfortunately, the production costs for capsules are
high and their production rate is low compared with those of tablets. This is
due to the lower output of capsule filling machines and to the higher cost of
capsules themselves. Although it is recognized that oral administration of
multiple-unit dosage form is preferred over single-unit system, it is not
advisable to present a low-potency, highly dosed drug as a multiparticulate
drug delivery system, mainly because of poor patient compliance due to large
capsule size5. Moreover, capsules cannot be divided into subunits in
the same way as tablets. These disadvantages make compression of subunits into
rapidly disintegrating tablets an interesting issue. The advantages of
tabletting of multiparticulates include a reduced risk of tampering (e.g.
Tylenol® and Sudafed-12)6, and lower tendency of adhesion
of dosage form to oesophagus during swallowing7. Tablets from
pellets can be prepared at low cost when compared to pellet-filled capsules
because of the higher production rate of tablet process. The expensive control
of capsule integrity after filling is also eliminated. In addition, tablets
containing multiparticulates could be scored without losing modified-release
properties. Scored tablets allow a more flexible dosage regimen. Tabletting of
pellets as opposed to that of powder also result in reduction of dust8.
It may also provide an opportunity to understand the compaction process by
examining the change in size, shape and density of pellets after their
compaction and retrieval of individual pellets from disintegration tubes5
or from the highly lubricated compacts, which provides a reduction in the
coherence of the pellets9. The compaction of pellets is a
challenging area. Only a few multiple unit-containing tablet products are
available, such as Beloc® ZOK10 Antra® MUPS11
and Prevacid® SoluTabTM12. Beloc® ZOK is an
extended-release multiple-unit tablet formulation, containing the
antihypertensive drug metoprolol succinate, which releases the drug over a wide
range with zero-order kinetics (ZOK). Antra® MUPS is a multiple-unit
pellet system (MUPS) consisting of micropellets of the proton pump inhibitor,
omeprazole. Prevacid® SoluTabTM is a MUPS consisting of
delayed-release orally disintegrating microgranules of proton pump inhibitor,
lansoprazole. Compaction of multiparticulates into tablets could either result
in a disintegrating tablet providing a multiparticulate system during
gastrointestinal transit or intact tablets due to the fusion of the
multiparticulates in a larger compact. Ideally, the compacted pellets should
not fuse into a non-disintegrating matrix during compaction and should
disintegrate rapidly into individual pellets in gastrointestinal fluids to
attain more uniform concentration of active substances in the body.
Importantly, the drug release should not be affected by the compaction process.
The aim and objective
of this work was to obtain diclofenac sodium DR granules/ pellets in a single
step without a coating process and compaction of such DR multiple units into
tablets with tabletting excipients. To produce diclofenac sodium DR granules,
some common enteric polymers along with filler excipients were investigated.
The prepared delayed-release multiparticulates compressed with tabletting
excipients into MUPS tablets and compared with reference product, Voveran®,
diclofenac sodium DR tablets. The tablets were intended to disintegrate rapidly
into discrete, individual pellets upon contact with dissolution medium. The
influence of filler granules as well as pellet- to-filler ratio on the
properties of the compacts was also investigated.
2. MATERIALS AND METHODS:
2.1.
MATERIALS:
Diclofenac sodium
(Aarti drugs limited, India), methacrylic acid copolymer dispersion
(Eudragit® L 30 D 55, Evonik Industries, Germany), methacrylic acid
copolymer (Eudragit® L 100
55, Evonik Industries, Germany), hypromellose phthalate HP-55 (HPMCP (HP-55),
Shin-Etsu Chemical Co, Japan),
microcrystalline cellulose (PH101) (Vivapur (type 101), JRS Pharma,
Germany), mannitol (Pearlitol 25 C, Roquette Freres, France), crospovidone (XL)
(Polyplasdone XL, ISP Technologies, USA), and magnesium stearate (S Kant
Healthcare Limited, India). The reports of analysis of all raw materials used
in the present study showed the compliance with respective pharmacopoeial
specifications. Hence, they were used without any further analysis. Solvents,
chemicals and reagents used in the analytical methods were AR/GR grades. Water
used in the entire course of experimentation was deionised water.
2.2.
METHODS:
2.2.1.
PREPARATION OF DELAYED-RELEASE PELLETS:
Weighed
quantity of diclofenac sodium, microcrystalline cellulose (PH101) (MCC), and
hypromellose phthalate HP-55 (HPMCP) were sifted through sieve 425 micron
opening. The sifted drug and polymer mixture was blended in rapid mixer
granulator (RMG) (Bectochem,
India) for
15min. The blended mixture was wet granulated with required quantity of water.
The wet mass was milled through 0.5 mm sieve opening in the hammer mill (Bectochem, India).
The milled wet mass was spheronized in Marumerizer (Fuji-Paudal, Japan)
fitted with cross-hatched pattern plate with 1.00 mm pitch groves running at
right angle to one another at the speed of 1500 rpm for 3 min. The resulting
drug containing pellets were dried in a fluid bed dryer (Uni Glatt) at a bed
temperature of 50-60şC for 120 min to get loss on drying value less than 2.0 %
w/w at 105şC.
2.2.2.
COMPRESSION OF DICLOFENAC SODIUM DELAYED-RELEASE PELLETS:
The percentages of DR pellets in the tablet compression
blend were selected as 40%, 50% and 60%w/w respectively. The range, 40% to 60%,
under study was selected based on the preliminary compression trials (data are
not shown). The percentage of SR pellets below 30 % in the compression blend
caused slow disintegration (more than 15 min) and above 70% SR pellets in the
compression blend caused monolithic matrix system due to fusion of SR pellets
with each other. The different size fraction of filler excipients were prepared
as follows: mannitol (80%), MCC (10%), and crospovidone (10%) were sifted
together through mesh 40 ASTM (425 micron opening) and granulated with water
and extruded through 0.6 mm screen in the single screw extruder and spheronized
in the Marumerizer at the speed of 1000 rpm for 1 min. The wet spheronized mass
was dried in fluid bed equipment at the bed temperature of 60şC, to get loss on
drying value about 1.0%w/w at 105şC. The dried mass was sifted through 850 µm
(mesh 20 ASTM) and fractions of the granules between 850 µm (mesh 20 ASTM) and
150 µm (mesh 100 ASTM) were collected. The collected granules were sifted
through different sieves to get various size fraction of granules such as 425
µm to 850 µm, (mesh 20 to 40 ASTM), 250 µm to 600 µm, (mesh 30 to 60 ASTM) and
150 µm to 300 µm (mesh 50 to 100 ASTM). Apart from excipients size and amount,
the compression machine speed was also considered to account for its effect on
content uniformity of the tablet. Thus, the composition
of tabletting matrix was based on a 33 factorial design where each
of the above mentioned three factors were considered at three levels and a
total of 27 batches were prepared. The lubricated compression blend was
compressed in single rotary compression machine fitted with 10 mm circular,
flat, beveled punch operating at different speed such as 10, 20 and 30 rpm with
the aim of having tablets of sufficient mechanical strength (to provide less
than 1.0% w/w friability), and disintegration time less than 5 min in the
dissolution media, 0.1 N hydrochloric acid. The statistical experimental study
was carried out as per method described by Armstrong13. The chosen
dependent variables or responses were less than 5% variation in content
uniformity and cumulative percentage drug release after 45 min in phosphate
buffer pH 6.8. Analysis of the data obtained from this design generated a
mathematical model with quadratic terms describing non-linear responses. This
statistical design also allowed resolution of two and three-factor interactions
from the main effects of individual variables.
2.2.3. DISSOLUTION
TESTING:
The
dissolution tests were carried out on pellets or tablets containing 50 mg of
diclofenac sodium (n = 6) in dissolution testing equipment (Electrolab, India)
using USP apparatus II , at 50 rpm, in medium of 900 ml of 0.1 N hydrochloric
acid, at 37±0.5şC for 2 h. The samples were removed from the vessels by a
peristaltic pump (Electolab,
India), and
assayed at 276 nm by UV/Vis Spectrometer (Perkin Elmer, Germany). After
acid stage dissolution, the acid treated pellets or tablets were subjected to
buffer stage, using USP apparatus 2, at 50 rpm, in medium of 1000 ml of
phosphate buffer pH 6.8, at 37±0.5şC for 45 min. The samples were taken from
the vessels by a peristaltic pump (Electolab,
India), and
assayed at 276 nm by UV/Vis Spectrometer (Perkin Elmer, Germany). The
aim of the present study was to develop a delayed- release formulation for diclofenac
sodium meeting the USP Drug Release Test criteria given as follows: the range
of dissolved diclofenac sodium in 0.1 N hydrochloric acid as less than15% in 2
h, and in phosphate buffer pH 6.8 as more than 75% in 45 min and the
percentages of the labeled amount of diclofenac sodium dissolved were confirmed
according to the acceptance ranges given above14.
3. RESULTS AND
DISCUSSION:
3.1. DICLOFENAC SODIUM
DELAYED-RELEASE PELLETS:
In
the preliminary trials, the preparation of delayed-release
diclofenac sodium granules/ pellets in a single step without a coating process
using extrusion and spheronisation process required the use of a
thermoplastic matrix polymer with acidic groups (enteric coating polymers).
Polymers used in the enteric coating fall into two broad groups - cellulosic
and acrylic polymers. The acrylic polymers are marketed under the trade names
of Eudragit® or Kollicoat®. The major cellulosic polymer
used for delayed-release is hypromellose phthalate. Among these polymer
materials, the acrylic polymer, methacrylic acid copolymer USP-NF (Eudragit®
L 100- 55), and the cellulosic polymer, hypromellose phthalate USP-NF (HPMCP
(HP-55) were investigated as potential carrier materials. The compositions of
blends containing diclofenac sodium, microcrystalline cellulose PH101 (MCC),
and the mentioned enteric polymers are listed in Table 1.
Due
to the specific nature of extrusion and spheronization process, not every
moistened powder mixture can be successfully extruded and spheronized. Newton15
defined the specific requirements for a wetted mass suitable for extrusion and
spheronisation based on the pioneering papers from Reynolds16 and
Conine and Hadley8. To allow for extrusion, a cohesive plastic mass
must be formulated that remains homogeneous during extrusion. The mass must
possess inherent fluidity, permitting flow during extrusion and self
lubricating properties as it passes through the die. The resultant strands of
extrudates must not adhere to each other, and must exhibit plasticity such that
the shape imposed by the die is maintained. The requirements for spheronisation
of the cylindrical extrudates are as follows: (a) the extrudates must possess
sufficient mechanical strength when wet, yet it must be brittle enough to be
broken down to short lengths in the spheronizer, but not so fragile that it
disintegrates completely, (b) the extrudates must be sufficiently plastic to
enable the cylindrical rods to be rolled into spheres by the action of the
friction plate in the spheronizer, (c) the strands of the extrudates must not
adhere to each other in order that particles do not aggregate during
spheronisation15. In relation to the above-mentioned requirements of
the wetted mass, MCC is incorporated in most formulations processed via
extrusion–spheronisation, since it provides the proper rheological properties
to the wetted mass15 for successful extrusion and spheronisation17.
MCC is the golden standard as extrusion–spheronisation aid based on its good
binding properties that provide cohesiveness to a wetted mass containing MCC.
Furthermore, it is able to absorb and retain a large quantity of water due to
its large surface area and high internal porosity18, thus
facilitating extrusion, improving wetted mass plasticity and enhancing
spheronisation. Moreover, by controlling the movement of water through the
plastic mass, it prevents phase separation during extrusion or spheronisation19.
Due to these properties MCC-based pellets produced via extrusion–spheronisation
have good sphericity, low friability, high density and smooth surface
properties. Furthermore, from a processing viewpoint, relatively wide ranges of
water content and processing parameters can be employed to provide pellets with
acceptable quality, indicating the robustness of the formulations.
The
formulation containing Eudragit® L100-55 (DCST-01) and HPMCP HP-55
(DCST-02) provided about 2-4% drug release in 0.1 M hydrochloric acid after 2 h
whereas the former released about 75% and the latter released about 95% in
phosphate buffer 6.8 after 45 min (Fig. 1). The pH sensitive enteric films
consist of a long polymer chain with carboxyl groups that ionize as the pH is
increased. In the low pH environment of the gastric fluid, the acidic groups
are unionized and therefore the polymers are insoluble. At the higher pH values
of the small intestine, the acidic groups undergo ionization and the polymeric
film materials become water soluble. Ionization of the acid groups causes charge
repulsion within the polymer, leading to a stretching of the polymer chain.
Stretching of the polymer chains allows water to penetrate into the core of the
dosage form, resulting in disintegration of the latter.
Being a poly-acid,
Eudragit® L 100-55 is not charged in 0.1 N hydrochloric acid, but
negatively charged in phosphate buffer pH 6.8. The electrostatic repulsion of
the negative charges at high pH leads to increased distances between the macro
molecules and, thus, to facilitated water imbibition. In phosphate buffer pH
6.8, the water content of the polymeric material increases much more rapidly
and to a higher extent than in 0.1 N hydrochloric acid. This may lead to the
leaching of the enteric polymer Eudragit® L 100-55 at high pH into
the bulk fluid, being replaced by imbibing water and lead to a higher degree of
swelling of still entrapped Eudragit® L 100 55 (due to the repulsion
of negatively charged COO−-ions) which hinders drug release in phosphate
buffer pH 6.8 [20]. This behavior correlates very well with the observed drug
release kinetics i.e. drug release relatively decreased (due to diffusion of
drug through swollen Eudragit® polymer) in phosphate buffer pH 6.8
and significantly decreased in 0.1 N hydrochloric acid (due to the unionized
acidic groups and therefore the polymer are not hydrophilic).
Hydroxypropyl
methylcellulose phthalate (HPMCP) is prepared from Hydroxypropyl
methylcellulose by esterification with phthalic anhydride resulting in a basic
repeating structure where hydroxyl groups of the glucose units are substituted
by methoxyl, hydroxypropyl, and carboxybenzyl (phthalyl) groups. The degree of
methoxyl and phthalyl substitution determines the properties of the polymer and
in particular pH at which it dissolves in aqueous media. HPMCP HP-50 grade
contains 20-24% methoxyl, 6-10% hydroxypropyl, and 21-27% phthalyl groups.
HPMCP HP-55 grade contains 18-22% methoxyl, 5-9% hydroxypropyl, and 27-35%
phthalyl groups. HPMCP is insoluble in gastric fluid (pH ~1.5), and thus
provides protection against dissolution of the drug contained within it. It is
not until the dosage form present within the upper small intestine where there
is a shift to pH ~5.0, that HPMCP (HP-50 grade, where as shift to pH~5.5, HPMCP
HP-55) undergoes rapid dissolution, thus releasing the active pharmaceutical
ingredient. The pH-responsive polymers consist of ionizable pendants that can
accept and donate protons in response to the environmental changes in pH. As
the environmental pH changes, the degree of ionization in polymer bearing
weakly ionizable groups are dramatically altered. This rapid change in net
charge of pendant groups causes an alteration of the hydrodynamic volume of the
polymer chains. The transition from collapsed state to expanded state is
explained by osmotic pressure exerted by mobile counterions neutralizing the
network charges21. HPMCP is hydrophobically modified pH responsive
polymer which has both the hydrophobic groups and ionizable groups. In HPMCP,
phthalyl groups act as ionizable groups and methoxyl groups act as hydrophobic
groups. In the aqueous medium, there is a pH sensitive balance between the
repulsion force of charged polymer chains and hydrophobic interactions of
polymer chains21. In 0.1 M hydrochloric acid, when ionizable groups
are protonated and electrostatic repulsion forces disappear within the polymer
network, hydrophobic properties dominate, introducing hydrophobic effects that
cause aggregation of the polymer chains from the aqueous environment. In this
situation, HPMCP is insoluble in 0.1 M hydrochloric acid and formed a
protective shell on the surface of pellets to prevent drug release22.
In phosphate buffer pH 6.8, when carboxyl groups of HPMCP are ionized and
electrostatic repulsion forces enhanced within the polymer network, hydrophobic
properties aid deaggregation of the polymer chains into the aqueous environment23.
The electrostatic repulsion of the negative charges at high pH leads to
increased distances between the macro molecules and, thus, facilitates water
imbibition. This may lead to the leaching of the enteric polymer HPMCP at high
pH into the bulk fluid which could be explained by osmotic pressure exerted by
mobile counterions neutralizing the network charges23. Being
replaced by imbibing water, which may effect a higher degree of swelling of
still entrapped HPMCP (due to the repulsion of negatively charged
COO−-ions), the collapsed state could be phase transformed into expanded
state by deaggregation of the polymer chains into bulk fluid due to the
interaction of hydrophobic groups with water23 which renders drug
release in phosphate buffer pH 6.8. As expected, the increase in water content
uniformly increased with increasing HPMCP content and leads to a higher degree
of swelling of HPMCP that collapsed by the interaction of hydrophobic groups.
This behavior correlates very well with the observed drug release kinetics i.e.
drug release was not changed (due to collapsing of swollen HPMCP polymer by the
interaction of hydrophobic groups) in phosphate buffer pH 6.8 and significantly
decreased in 0.1 M hydrochloric acid (due to the unionized acidic groups and
therefore the polymer did not dissolve).
The
above mentioned behaviour of two different polymers in phosphate buffer
pH 6.8 correlates very well with the observed drug release kinetics i.e. drug
release was faster for HPMCP containing formulation since collapsing of swollen
HPMCP polymer by the interaction of hydrophobic groups whereas drug release was
slower for Eudragit® L 100-55 containing formulation since
dissolution of Eudragit® L polymeric film caused higher degree of swelling of still entrapped
Eudragit® L 100-55 which hinders drug release in phosphate buffer pH
6.8.
The
problem during formulation of both the trials was that the formed extrudates
were wet, sticky, smooth surfaced and were not broken into small pieces during
spheronization. The dried, milled, and sifted (through mesh 30 ASTM (600 micron
sieve opening)) extrudates were subjected for dissolution testing. The amount
of MCC was increased (DCST-03) in the formulation containing HPMCP since it
provided faster release than Eudragit® L 100-55 containing
formulation in phosphate buffer pH 6.8, to provide proper rheological
properties to the wetted mass for successful extrusion and spheronization
(Table 1). However, the problem was not resolved and the drug release decreased
to 65% in phosphate buffer pH 6.8 after 45 min (Fig. 1).
Fig. 1
Dissolution of diclofenac sodium DR matrix pellets (
DCST-01,
DCST-02,
DCST-03)
prepared from enteric polymers (Table 1) using paddle apparatus at a rotation
speed 50 rpm, in 900 ml 0.1 N hydrochloric acid for 2 h (acid stage) followed
by pH change to 1000 ml pH 6.8 (buffer stage) by adding 250 ml of tribasic
sodium phosphate solution to 750 ml of acid stage 0.1 N hydrochloric acid. Each
result shows the mean of 6 values.
MCC
is described as purified, partially depolymerized cellulose prepared by
treating α-cellulose, obtained as a pulp from fibrous plant material with
mineral acids24. The cellulose fibres in the starting material are
composed of millions of microfibres. In the microfibres, two different regions
can be distinguished: a paracrystalline region, which is an amorphous and
flexible mass of cellulose chains, and a crystalline region, which is composed
of tight bundles of cellulose chains in a rigid linear arrangement24.
As an effect of controlled hydrolysis, the amorphous fraction has largely been
removed, yielding aggregates of the more crystalline portions of cellulose
fibres. After purification by filtration and spray drying, dry porous
agglomerated microcrystals are obtained. Two models have been proposed to
explain the behaviour of MCC during extrusion–spheronisation process: In the
first model, MCC is described as a ‘molecular sponge’25, 26. The MCC
particles are able to retain water in a manner similar to a sponge. Each
particle of MCC would behave as a porous sponge and each particle would be able
to absorb a large quantity of water. Part of the water in MCC is absorbed in
the pores inside the cellulose fibres and amorphous regions, and part is
located between the fibres with obstruction and hydration interactions with the
fibres27. All pores are supposed to be completely filled with water.
Under pressure the water would be partly squeezed out and lubricate a particle
rearrangement. During extrusion these sponges are compressed, and water that is
squeezed from the internal structures acts as a lubricant. After extrusion, the
volume of the sponges expands and they appear dry and brittle, which
facilitates the breaking of the extrudates during the initial phase of
spheronization. During the spheronization phase, the sponges are densified due
to collisions between particles and the spheronizer plate and wall, and water
facilitates spheronization of pellets. Kleinebudde proposed the crystallite-gel
model in which a gel is formed during extrusion / spheronisation with MCC28.
The concept of the crystallite-gel model could also be valid for the
pelletization process. It has been shown29 that powder particles of
MCC are broken down into smaller sub-units due to the presence of water and
shear (for example during granulation and extrusion). Single crystallites with
a size of a few microns can be obtained. These single particles are able to
form a crystallite-gel and immobilize the water. The crystallites or their
agglomerates can form a network by cross-linking with hydrogen bonds at the
amorphous ends. The viscosity of the gel depends on the water content and the
degree of cross-linking (e.g. the size of the resulting structural components).
At increasing liquid content, the fraction of gelling agent in the gel decreases
and the deformability increases. The gel is not sticky, because the gelling
agent is not soluble in water. The formation of hydrogen bonds in the amorphous
ends of the crystallites during drying can be described as an autohesion effect
resulting in a stable matrix (autohesion is defined as the mutual
inter-diffusion of free polymer chain ends across the particle-particle
interface of high molecular weight polymers resulting in a stable link30.
These phenomena would contribute to the hindered release of diclofenac sodium,
by forming a more effective retardant matrix and by providing a greater surface
area of cellulosic material for drug binding. Therefore, increased amount of
MCC decreased the release rate along with increasing the diffusional path length.
From
the above studies it can be concluded that the formation of wet, sticky, smooth
surfaced long extrudates was not due to MCC (as mentioned in the
crystallite-gel model, the formed gel at high liquid content is not sticky
since gelling agent is not soluble in water) and may be due to the inherent
property (sticky and elastic in nature when in contact with water) of enteric
polymer. The amount of water and extruder speed were varied to get suitable
extrudates to form spheroids (data are not shown). But the trials led to forced
heat generated flow with low water content irrespective of extruder speed and
smooth steady state flow with high water content irrespective of extruder speed
and the forced flow caused powdery extrudates and steady state flow caused long
smooth unbreakable extrudates which could not be made into spheroids.
Alternative approach used to prepare spheroids was high-shear pelletization
process.
The
pelletization process in a high-shear mixer can be divided into several stages:
premixing of the solids; liquid addition stage; wet massing stage; and drying
stage. High-shear mixer is equipped with a mixing bowl; an impeller, rotating
at the bottom of the bowl; a chopper, rotating near the wall of the bowl; and a
nozzle to supply the binder liquid. The mixing bowl can be jacketed for heating
or cooling the contents in the bowl, by circulating hot or cool liquid or steam
through the jacket. An impeller is employed to mix the dry powder and spread
the granulating fluid. The impeller of the high-shear mixer granulator normally
rotates at a speed ranging from 100 to 500 rpm. The function of the chopper is
to break down the wet mass to produce granules. The rotation speed of the
chopper ranges from 1000 to 3000 rpm. In the equipment used in this study
(bottom driven vertical high-shear granulator with horizontal chopper shaft,
rapid mixer granulator (RMG)), the first three stages take place inside
high-shear mixer. The drying stage occurs in fluid bed drying.
Process
variables play a critical role in the granulation process since they influence
how the binder liquid is distributed in the powder bed and the degree of
densification for the powder mixture. The degree of powder densification
affects the level of liquid saturation of the moist agglomerates. Therefore,
process variables could influence properties such as particle size distribution
of the obtained granules. The required particle size distribution ranged from
250 to 600 micron (mesh 30 to 60 ASTM) with low friable granules (less than
0.1%w/w at 500 rpm in abrasion drum). The process variables affecting the
granulation process and the physical properties of the obtained granules
studied were: impeller speed; granulating solution addition method; granulating
solution addition rate; chopper speed; and wet-massing (kneading) time.
The
high-shear wet-granulation process can be divided into five stages namely
mixing, adding binder solution, wetting and nucleation, consolidation and
growth, and granule attrition and breakage.
During
the first step, powders are dry mixed to achieve a uniform blend prior to wet
granulation. The dry mixing step is typically taken for granted because wet
massing follows. Weighed quantity of diclofenac sodium, MCC and HPMCP were
sifted through sieve 425 micron opening (DCS-04) (Table 1). The sifted drug and
polymer mixture was blended in RMG (Bectochem,
India) for 10
min at 100 rpm.
The
binder solution or the granulating liquid was distributed through the powder
bed by mechanical agitation created by the impellers. At this stage, the powder
mixture becomes wetted and initiates agglomeration via nucleation. Nucleation
of particles occurs by the formation of liquid bridges between primary
particles, which adhere together to form agglomerates. At this stage, the
concentration of liquid phase in the powder mixture is relatively low, but high
enough to establish liquid bridges. The impeller speed (100 and 500 rpm), the
binder addition method (pouring and spraying) and binder addition rate (5g and
25 g/min) were studied. The results indicated that wide particle size
distribution was obtained at slow impeller speed irrespective of mode of binder
addition and binder addition rate. This may be due to the poor binder
distribution at this slow speed. These granules could include large, overwetted
particles, as well as small dry particles. The mode of addition of the liquid
binder affected the characteristics of the granules. When water, used as a
binder liquid, was added to the powder mixture by atomization, granules with a
slightly narrower particle size distribution were obtained when compared to
controlled pouring method at 500 rpm impeller speed. This may be attributed to
the formation of sticky wet agglomerates when HPMCP contacted with water and
controlled pouring method may have caused local wetting and spraying method may
have caused uniform wet powder mass at impeller speed 500 rpm. The lower binder
addition rate produced narrower particle size distribution and the higher
addition rate caused the large overwetted particles. During binder addition,
the optimized impeller speed, the addition method, and addition rate were 500
rpm and spaying of binder solution at the rate of 5g/min respectively to
provide narrow sized wet granules.
Granule
growth is dominated by one of the two mechanisms: coalescence or layering31.
Coalescence is agglomeration which occurs by collision and consolidation of
deformable nuclei/granules, provided the agglomerates could withstand the shear
forces applied by the impellers. Layering,
also called snowballing, is the mechanism in which many primary particles (e.g.
the non-granulated starting material) stick on the surface of a larger granule,
due to the formation of capillary bridges. There is no distinct difference
between the mechanisms coalescence and layering. In fact, only the size of the
initial particles differs. Coalescence assigns all successful collisions
between two granules, while layering is the mechanism in which primary
particles stick on to a larger granule. Granule attrition and breakage reduce
the granule size. Granule breakage is determined by the dynamic granule
strength and the shear forces within the granulator. If the impact forces are
larger than the granule strength, continuous breakage and immediate coalescence
of the granules takes place32. However, when the granule strength
exceeds the impact forces, granules will not break. In that case, granule
growth is more static, i.e., the exchange of primary particles between the
granules is minimal. Thus, there is a balance between agglomerate growth and
degradation of the granules. Breakage
of granules has been divided in literature into several mechanisms33.
First of all crushing, in which smaller granules are crushed and subsequently
distributed over the surface of the remaining granule by layering. Crushing can
occur by shattering, fragmentation, or abrasion. The other breakage
mechanism referred to in literature is abrasion
transfer. In this mechanism material is transferred between two
colliding granules, leaving both intact. This mechanism has been identified
experimentally34, but is thought to have a negligible effect on the
final granule size distribution. The variables studied were impeller speed (100
and 500 rpm), chopper speed (1000 and 3000 rpm) and wet-massing time (5 and 15
min) on the consolidation and growth, and granule attrition and breakage of
formed granules in the aspect of particle size distribution and friability of
dried (in fluid bed processor) granules. The results indicated that granules
with finer particles and a wider particle size distribution were obtained at a
slow impeller speed (100 rpm) irrespective of chopper speed and kneading time.
However, at higher impeller speeds, granules with less fine particles and a
narrower size distribution were observed. Increasing the wet-massing time
increased the mean granule size of the formulations at impeller speed 500rpm.
The speed of the chopper did not affect granule size distribution for the
formulations tested. Free liquid on the surface of agglomerates, which renders
the necessary bonding strength and plasticity to the agglomerate, is required
for coalescence or layering. The free liquid on the surface of the agglomerates
could be formed from the expulsion of liquid inside the agglomerates due to the
consolidation of the agglomerates at higher impeller speed and high wet-massing
time and caused the coalescence or layering of granules and may have led to
increased mean granule size of the formulations. Granule attrition and breakage
reduce the granule size. Granule breakage is determined by the dynamic granule
strength and the shear forces within the granulator. Increasing the impeller
speed (500 rpm) and wet-massing time (15min) decreased fragmentation propensity
that led to the decreased friability of the dried granules. These findings
suggested that the long-chain structures in MCC were disrupted, resulting in
smaller units with shorter chain lengths due to the strong shear force of the
impeller. These smaller units then formed a network within the granules. Thus,
MCC granules were strengthened with longer granulation time resulting in a more
intricate network. In this case, granule growth was more static, i.e., the
exchange of primary particles between the granules was minimal. From these
studies, it was observed that the fast impeller speed with more wet-massing
time required for the formation of narrow size distributed less friable
granules. The particle size distribution of less friable (0.02% w/w) granules
was between 250 and 850 µm (mesh 20 to 60ASTM). The required particle size of
granules was below 600 µm (mesh 30 ASTM). Therefore, the mesh 30 oversized
granules were sifted through mesh 30 ASTM. However, the granules were very
difficult to sift through the same since the formed granules were less porous,
hard granules. Alternative approach used was milling the wet mass, prepared in
RMG at fast impeller and chopper with more wet-massing time, through hammer
mill fitted with 0.5 mm screen and followed by spheronisation to provide to
spheroids of required size.
The
hammer mill is one of the most versatile and widely used mills in the
pharmaceutical industry. The principle of size reduction in the hammer mill is
one of high-velocity impact between the rapidly moving hammers mounted on a
rotor and the powder particles. The force imparted by the hammers and the
screen opening size and shape control the degree of particle size reduction.
The operating variables in a hammer mill that can influence size reduction
studied were: rotor shaft configuration; material feed rate; blade type; rotor
speed; and screen size and type.
The
hammers may be mounted on a vertical or horizontal shaft. The vertical shaft
mills have feed inlets at the top and material is fed perpendicular to the
swing of the hammers. In the case of horizontal shaft mills, the material is
fed tangentially to the hammer swing. Rotor configuration can influence the
particle size distribution of granules. In the vertical configuration, the
screen is placed 360ş around the hammers and this provides more screen open area
and less time for the granules to stay in the milling chamber when compared
with the horizontal shaft mills. In the present study vertical shaft mill was
used. The feed rate controls the amount of the feed material that enters the
comminutor and prevents overfeeding (slugging) or underfeeding (starving) in
the milling chamber. If the rate of feed is relatively slow, the product gets
discharged readily, and the amount of undersize material, or fines, is
minimized. On the other hand, overfed material stayed in the milling chamber
for a longer time, because its discharge was impeded by the mass of material.
This led to a greater reduction of particle size, and overloads the motor. The
rule of thumb followed was to keep the feed rate equal to the rate of discharge.
Comminution is effected by the impact of the material with the fast moving
blades and attrition with the screen. Generally, the blades of a hammer mill
have a blunt or flat edge on one side and a sharp or knife-edge on the other
side. The desired particle size range determines which blades to use. The hammer mill used in this study, have a rotor that may be turned 180ş, so that
the blunt edges can be used for fine grinding or the knife-edge can be used for
cutting or granulating. In the present study, the knife-edge was used since the
sharper edge caused cutting of the oversized granules into generated the
required size of granules. The size of the product is markedly affected by the
speed of the hammers. As a general rule, the faster the rotor’s speed, the
finer the grind if all other variables are kept constant. The available speed
settings were: slow (1000 rpm), medium (2500 rpm), and fast (4000 rpm). Rotor
speeds of 2500–4000 rpm resulted in finer granules whereas speeds of 1000–2500
rpm resulted in coarse granules. At or below 1000 rpm, more spheroidal granules
were obtained since the material experienced attrition, rather than impact
action. The screen is usually an integral part of the hammer mill and does not
act as a sieve. The particle size of the product depends on the openings in the
screen. The particle size of the output granules will be much smaller than the
size of the screen used, because particles exit at an angle, with high
velocity. In the present study, 0.5 mm screen was used to get below 600 micron
granules. To convert irregular shaped wet granules into spherical shaped
granules, spheronizer was used.
Spheronization
is carried out in a relatively simple piece of equipment. The working parts
consist of a bowl having fixed sidewalls with a rapidly rotating bottom plate
or disk. The rounding of the milled granules into spheres or pellets is
dependent on frictional forces. The forces are generated by particle–particle
and particle–equipment interactions. For this reason, the disk is generally
machined to have a grooved surface that increases the forces generated as
particles move across its surface. During the spheronization step, wet milled
granules transform irregular shaped particles into spherical particles. This
transition occurs in various stages. Once charged into the spheronizer, the wet
milled granules are drawn to the walls of the spheronizer due to centrifugal
forces. Within a short period of time, the length of each piece was
approximately equal to the diameter the attrition and the rapid movement of the
bottom plate or disk. The differential in particle velocity as the pieces move
outward to the walls, begin to climb the walls, and fall back onto the rotating
bed—along with the angular motion of the disk—results in a ropelike formation.
During the spheronization process, the relatively long and fluffy granules may
be broken up into shorter lengths. They may also coalesce to form granules
which then agglomerate and densify. Moisture is forced out from the interior to
the outer surfaces as they spin on the rotating plate. This available moisture
plasticizes the surfaces and aids the formation of spheroids. For fixed load of
250 g of milled wet granules, the influence of the plate speed and residence
time on the particle size were studied. When the granules were spun at a
relatively low speed (at 500 rpm), the forces set up in the spheronizer were
insufficient to round them off. At this
speed, it was apparent that there was no rounding and only increase in width
marginally. The speed 750 rpm reduced the irregularity of granules, even by 1
min, and after 2 min there was considerable densification. Rounding took a
little longer but in 5 min the particles were well rounded. Generally,
spheroids were more spherical after 5 min at speeds of 750 rpm and above. At
higher speeds, the stronger centrifugal and rotational forces contribute to the
rounding off of granules to form spheroids. Spheroid size increased
progressively with higher spheronization speeds and residence times. This was
observed up to 1000 rpm and 10 min, respectively. The growth in size was
attributed to agglomeration. Further increase in spheronization speed (1500
rpm) and residence time (5 min) resulted in a size decrease. The spinning
motion of the friction plate generated forces which caused collisions between
the particles. Cohesive forces responsible for the formation of spheroids must
withstand the destructive forces in order to promote growth. At the extreme
high end of the speed range studied, the forces acting may be far too great to
be conductive to agglomeration. Instead, the high speeds encouraged the
formation of smaller spheroids. The amount of fines produced during a run may
be represented by the percentage weight of 250 µm (mesh 60 ASTM) undersize
fraction. During spheronization, the amount of fines decreased with longer
residence times. This observation could be attributed to a longer opportunity
for agglomeration. With shorter residence times, spheronization at very high
speeds produced less fines than at lower speeds. The above findings showed that
for the formulation studied; speeds ranging 1200 to 1500 rpm and residence
times of 2-5 min may be used to form spherical granules with a modal class in
the size range of 250 to 600 µm (mesh 30 to 60 ASTM).
Drying is the final
step in the process. This can be accomplished in tray dryers, and column-type
fluid beds. The results indicated that the release of diclofenac sodium in
phosphate buffer pH 6.8 was more for pellets dried in the fluid bed processor
than those dried in hot air oven (data are not shown). There was shrinkage of
pellets observed for oven dried pellets while fluid bed processor provided
smooth surface pellets. Based on the different rate of moisture removal, means
of heat and mass transfer, and static or dynamic nature of the bed, the
different drying techniques produced pellets of different structural and
mechanical properties. The most crucial of these was the porosity as a result
of different extent of shrinkage of the pellets. The rapid evaporation of water
as a result of turbulent motion of the fluidized pellets (fluid-bed) may have
suppressed the shrinkage of pellets during drying to produce pellets of higher
porosity with smooth surface characteristics. This high porosity may have led
to greater release for fluid bed dried pellets. On the other hand, the
evaporation of the fluid occurs slowly when oven drying is done. This could be
reason for the greater shrinkage and lower porosity of the pellets in the
latter technique. Low porosity may also have led to reduced drug release for
oven dried pellets as compared to fluid bed dried pellets. Because tray drying
is a slow process in a static bed, it can offer the greatest opportunity for a
drug to migrate toward the surface and to recrystallize. Rapid rate of drying
in a fluid bed will minimize the effects of migration. This phenomenon could
have an effect on a number of particle properties. The increased active
concentration at the surface of the particle can influence the rate of
dissolution.
It can be concluded
from the above studies that during the wet granulation process in RMG, better
distribution of binder solution can be achieved with spraying of binder
solution at the rate of 5 g/min with the impeller and chopper at fast speed and
narrow sized wet granules were formed by wet massing carried out for 15 min
with impeller and chopper at fast speed. Thus, formed wet granules were milled
with knife at the speed of 1000 rpm in hammer mill fitted with 0.5 mm screen to
form spherical granules. The good spherical shaped, narrow sized pellets were
obtained at the disc speed of 1500 rpm with dwell time of 2-5 min in the
spheronizer. The spheronized wet mass was dried in fluid bed processor with
50-60şC bed temperature for 120 min to get loss on drying value less than 2.0 %
w/w at 105şC.
The
formulation, DCST-04, prepared as mentioned, provided about 5% drug release in
0.1 M hydrochloric acid after 2 h followed by 65% release in phosphate buffer
6.8 after 45 min (Fig. 2). To increase the drug release in phosphate buffer pH
6.8, the amount of MCC was decreased as given in DCST-05 (Table 1) and the
delayed-release pellets were prepared as per the optimized method described
above. The release was similar to that obtained in DCST-02 i.e. about 4% drug
release in 0.1 N hydrochloric acid after 2 h followed by95% release in
phosphate buffer pH 6.8, after 45 min (Fig. 2). The increased drug release by
decreasing MCC content was attributed to matrix forming effect of MCC, as
discussed above.
Fig. 2
Dissolution of diclofenac sodium DR matrix pellets (DCST-04,
DCST-05,
DCST-06
and 
DCST-07) prepared from various ratio of HPMCP
and MCC (Table 1) using paddle apparatus at a rotation speed 50 rpm, in 900 ml
0.1 N hydrochloric acid for 2 h (acid stage) followed by pH change to 1000 ml
pH 6.8 (buffer stage) by adding 250 ml of tribasic sodium phosphate solution to
750 ml of acid stage 0.1 N hydrochloric acid. Each result shows the mean of 6
values.
Furthermore,
the incorporation of high drug loads into microparticulate pellets is
challenging since a large fraction of the drug is located near the particle
surface that could result in burst release during the acidic stage dissolution.
Young et al reported that beads based on Eudragit® L100-55 that were
extruded through a 1.2 mm die and contained 20% theophylline as the model drug
released more than 25% drug in 2 h at pH 1.235. There was a
recommendation from the patent application WO 2008/101743 that use of a water-
insoluble carrier (Eudragit® RL, RS or NE) in combination with an
anionic polymer reduces the permeability of the enteric matrix pellets during
the acidic stage [36]. However, in the present study, no such a burst release
of diclofenac sodium in 0.1 N hydrochloric acid dissolution media was observed
and there was no requirement of inclusion of any water-insoluble,
sustained-release matrix forming agent since the selected model drug,
diclofenac sodium, is insoluble in 0.1 N hydrochloric acid dissolution media.
The studied delayed-release formula (DCST-05) contained 50mg of diclofenac
sodium, 25 mg of HPMCP and 50 mg of MCC; wet granulated in RMG, milled in
hammer mill and finally spheronized was taken to study the compression of such
delayed-release granules since it was comparable to the reference product,
Voveran®, diclofenac sodium DR tablets (Fig. 3). The reduced amount
of HPMCP (Table 1) from 25 mg to 18 (DCST-06) and 10 mg (DCST-07) caused about
70 to 75% drug release in phosphate buffer pH 6.8 after 45 min previously subjected in 0.1 N
hydrochloric acid for 2 h (Fig. 2). The decreased drug release rate by
decreasing the amount of HPMCP may be due to the disintegrating effect of HPMCP
since it swells in phosphate buffer pH 6.8 and may disintegrate the MCC matrix
pellets.
Fig. 3
Dissolution of diclofenac sodium DR matrix pellets prepared from 20% HPMCP and
40%MCC (
DCST-05)
and comparison of the same with the reference product (
Voveran),
Voveran® using paddle
apparatus at a rotation speed 50 rpm, in 900 ml 0.1 N hydrochloric acid for 2 h
(acid stage) followed by pH change to 1000 ml pH 6.8 (buffer stage) by adding
250 ml of tribasic sodium phosphate solution to 750 ml of acid stage 0.1 N
hydrochloric acid. Each result shows the mean of 6 values.
3.2.
COMPRESSION OF DICLOFENAC SODIUM DELAYED-RELEASE PELLETS:
Various tabletting
excipients have to be added to assist the compaction of uncoated pellets since
the compaction of uncoated pellets without addition of tabletting excipients
lead to fusion of pellets to each other and does not result in MUPS and remain
as monolithic system. The excipients are used to fill the void space between
the pellets to be compressed and act as cushioning agent to absorb compression
forces. The filler materials are used for separation of individual pellets to
prevent direct contact of pellets by forming a layer around the pellets. These
inert excipients should also provide protection to the drug containing pellets
from rupture and damage during compression. The excipients should result in
hard and rapidly disintegrating tablets at low compression forces and should
not affect the drug release. Besides their compaction properties, the
excipients have to result in a uniform blend with the coated pellets, avoiding
segregation and therefore weight variation and poor content uniformly of the resulting
tablets.
The content uniformity and weight variation mainly depend
on ratio of tabletting excipients, particle size of excipients, along with
compression machine speed. The tabletting excipients are granulated and
extruded and spheronized. Along with particle size of granulated mass, ratio of
granules with pellets to be compressed has to be considered since the
granulated mass densifies during spheronization and may not separate the drug
containing pellets to avoid fusion during compression. Apart from excipients
particle size and amount, the compression machine speed also has to be
considered since at all compression machine speeds; the content uniformity
should be obtained. The percentages of drug containing pellets in the tablets
were selected as 40%, 50% and 60%w/w respectively. The various size fractions
of filler (mannitol) granules were 425 µm to 850 µm, (mesh 20 to 40 ASTM), 250
µm to 600 µm, (mesh 30 to 60 ASTM) and 150 µm to 300 µm (mesh 50 to 100 ASTM).
The compression blend was compressed in single rotary compression machine
fitted with 10 mm circular, flat, beveled, punches and operated at different
speeds such as 10, 20 and 30 rpm with the aim of having tablets with sufficient
strength to withstand the friability test and disintegrate in dissolution media
within 5 min. The composition of tabletting matrix was based
on a 33 factorial design where each of the three factors was
considered at three levels and a total of 27 batches were executed with the aim
to achieve the required physical properties such as better content uniformity,
acceptable hardness, low friability and disintegration within 5 min in 0.1N
hydrochloric acid dissolution media along with required release pattern in
phosphate buffer pH 6.8 after 45 min.
The study indicated that an increase in the amount of DR
pellets (from 40% to 60%w/w) in the compression blend decreased the content
variation in the tablet irrespective of the particle size of tabletting
excipients used. This was also confirmed from factorial data analysis where one
of the significant factor affecting the content uniformity was the percentage
of DR pellets at P=0.05 (Table 2). A
decrease in particle size of the excipients significantly (at P=0.05) increased the variation in
content uniformity irrespective of amount of percentage of pellets and
compression speed. The variation in content uniformity may be due to
segregation and may be attributed to differences in bulk density between DR
pellets (about 0.80 g/ml) and tabletting excipients (about 0.60 g/ml). This was
also confirmed from factorial data analysis where the one of significant
factors affecting the content uniformity was compression speed at P=0.05. But all these factors produced
independent effects on content uniformity rather than mixed effects, except
mixed effect of amount of DR pellets and particle size of the excipient, which
was confirmed from the factorial analysis that showed there was no significant
effect for three-factor interactions at P=0.05
and even at P=0.10 (Table 2).
Table
2
Three-factor, three-level factorial design to investigate the percentage of
delayed-release pellets in the compression blend (factor X1), particle size of tabletting excipients (factor X2),
and compression machine speed (factor X3) on the content
uniformity (denoted by % variation from mean value) of diclofenac sodium
delayed-release disintegrating tablets. For the data under consideration and
with a significance level of P= 0.05,
the tabulated value of F values at 2,
4, and 8 DF are 9.55, 9.12, and 8.85 respectively.
|
Source
|
Sum of Squares
|
Degrees of freedom
|
Mean Squares
|
F
|
|
X1
|
108.99
|
2
|
54.50
|
180.41
|
|
X2
|
53.54
|
2
|
26.77
|
88.62
|
|
X3
|
16.14
|
2
|
8.07
|
26.71
|
|
X1X2
|
22.78
|
4
|
5.70
|
18.85
|
|
X1X3
|
1.40
|
4
|
0.35
|
1.16
|
|
X2X3
|
1.68
|
4
|
0.42
|
1.39
|
|
X1X2 X3
|
1.10
|
8
|
0.14
|
0.45
|
There was undesirable damage observed for DR matrix
pellets which may be due to insufficient protection by tabletting excipients.
Decreasing the percentage of DR pellets (60% to 40%w/w) in the compression
blend decreased the damage to the DR pellets irrespective of particle size of
tabletting excipients and decreasing compression speed. This was confirmed from
the drug in phosphate buffer pH 6.8 after 45 min previously treated in acid
stage for 2h (Table 3). The decreased drug release may be due to insufficient
protection to DR matrix pellets and may have resulted in fusion of adjacent DR
matrix pellets while increasing the amount of pellets in the compression blend.
The decreasing compression speed decreased the drug release that may be due to
the greater dwell time in die for less compression speed. This was also
confirmed from factorial data analysis where the significant (at P = 0.05) factors affecting the buffer
stage release were percentage of DR pellets in the compression blend and
compression speed. But these factors produced independent effects on buffer
stage release rather than mixed effects which was confirmed from the factorial
analysis that showed there was no significant effect for two-factor and
three-factor interactions at P = 0.05
(Table 3).
Table
3
Three-factor, three-level factorial design to investigate the percentage of
delayed-release pellets in the compression blend (factor X1), particle size of tabletting excipients (factor X2),
and compression machine speed (factor X3) on the buffer stage
release of diclofenac sodium delayed-release disintegrating tablets. For the
data under consideration and with a significance level of P= 0.05, the tabulated value of F
values at 2, 4, and 8 DF are 19.00, 19.25, and 19.37 respectively.
|
Source
|
Sum of Squares
|
Degrees of freedom
|
Mean Squares
|
F
|
|
X1
|
2780.03
|
2
|
1390.01
|
1713.10
|
|
X2
|
24.83
|
2
|
12.41
|
15.30
|
|
X3
|
31.67
|
2
|
15.84
|
19.52
|
|
X1X2
|
62.06
|
4
|
15.52
|
19.12
|
|
X1X3
|
62.28
|
4
|
15.57
|
19.19
|
|
X2X3
|
3.51
|
4
|
0.88
|
1.08
|
|
X1X2 X3
|
5.97
|
8
|
0.75
|
0.92
|
To avoid segregation
within the pellet-excipient mixture, some researchers prefer filler-binders
that are almost equal in size to the pellets37-40, while others
report of reduced segregation tendency especially when using a smaller size to
the pellets41, 42. As far as the size of excipient particles is
concerned, some studies have recommended use of small particles, while others
have recommended larger ones. Wagner et
al43 studied the compaction of modified-release pellets using
MCC as the excipient, either as a powder or in the form of granules. They found
the drug release to be less affected when using granules than powder, but
recommended the use of powder for less flexible polymers. In a study by Yao et al44, excipient particles
smaller than 20µm were found to protect theophylline drug containing particles
irrespective of the excipient material used, while larger excipient particles
increased the dissolution rate after compaction. Haslam et al45, on the other hand, concluded that large
excipient particles reduced the compression-effects on beads. In this study particle size of excipients
played a significant role in the variation of content uniformity (at P = 0.05) and in release of drug in
phosphate buffer pH 6.8 significantly (P =
0.10) irrespective of percentage of DR pellets and compression machine speed
(Table 2 and 3). This may be attributed to large excipient particles that
apparently resulted in an increased excipient-excipient interaction and thereby
produced an environment in which the compression forces impacted the beads less
directly whereas small excipient particles resulted in more surface area and
thereby produced better protection from compression induced changes. However,
variation in content uniformity was significantly observed when decreasing the
size of tabletting excipients was reduced which may be due to the fact that
small excipient particles result in more surface area and thereby cause content
uniformity variation.
Tabletting of pellets
requires a homogenous distribution of pellets within each tablet. Variation in
machine speed and filler-binders lead to different pellet-distributions in the
tablet and therefore has to be considered for each formulation. In this study,
content uniformity variation was more pronounced in the tabletting matrix that
contains 40%w/w DR matrix pellets at 10, 20 and 30 rpm than 50% and 60%w/w DR
matrix pellets where good uniformity of content was obtained at all range of
machine speed which may be due to the formation of percolating cluster of the
pellets according to percolation theory. In the compression of tabletting
matrix that contains 40%w/w DR matrix pellets at 10, 20 and 30 rpm, there was
difference in content uniformity. A high pellet density was found on the lower
surface of the tablet at 10 rpm while a high pellet density were found at the
upper surface of the tablet at high machine speeds (20 and 30rpm). This
indicated that there was an almost complete vertical segregation of the pellets
at higher machine speeds as compared to low speed. In the compression of
tabletting matrix that contains 50% and 60%w/w DR pellets at 10, 20 and 30 rpm,
there was no significant difference in content uniformity. This could be
explained by the formation of a percolating cluster of pellets, which prevented
segregation at entire range of compression machine speed. This study also
confirmed by Beckert et al 46.
Enteric-coated bisacodyl pellets of 1mm diameter were compressed into 10mm
tablets using granules and powders as filler-binders of different particle size
and cohesiveness46. The mixtures contained between 10 and 70% w/w
pellets with a particle size in the range 0.8-1.25mm. Egermann’s equations were
used to calculate the coefficient of random variation of content. Tablets
containing 10% w/w pellets showed pronounced variation in mass and content.
Mixtures with 30% w/w pellets showed good uniformity of mass and content. With
50-70% w/w pellets in a tablet, good content uniformity was found with all
filler-binders used. This could be explained by the formation of a percolating
cluster of the pellets, which prevented segregation. With 50% w/w corresponding
to 30% v/v, the coefficient of variation of content agreed well with the values
calculated according to Egermann’s equation. They also recommended that if less
than 30% v/v was compressed; suitable granules have to be added until 30% v/v
was reached to form a percolating cluster.
In the present study, the true volume of the pellets present in the
mixtures that contain 50% and 60%w/w DR pellets was about 27%v/v to 32%v/v
respectively.
From the above studies
it was concluded that the content uniformity was significantly affected by all
the three factors under study and the buffer stage release was significantly
affected by amount of DR pellets in the compression blend and compression speed
at the significant level of P = 0.05.
If the results are carefully analyzed, the content uniformity varied between
40% and 60%w/w and not between 50% and 60%w/w pellets in the compression blend
which was also conformed from the formation of percolating cluster in the later
pair. This was also true for amount of drug released in phosphate buffer pH
6.8. The compression blends that contained 50%w/w DR pellets were further
selected since 40%w/w DR pellets blend caused variation in content uniformity
and 60%w/w DR pellets blend caused slower release in phosphate buffer pH 6.8.
In the case of 50%w/w DR pellets blend, less content uniformity was observed as
compared to 40% w/w DR pellets blend and less affected by compression induced
changes when compared to 60%w/w DR pellets blend. However, literature study
showed that the amount of pellets corresponding to 30% v/v in the tabletting
matrix enable the production of disintegrating tablets having an approximately
homogenous pellet distribution within large range of machine speeds. The
percentage of DR pellets was slightly adjusted about 50%w/w, along with
collection of filler granules from 150 to 850 µm (mesh 20 to 100 ASTM) since
the particle size of the tabletting excipients did not play a role (at 50%w/w
DR pellets containing blends), to provide 30% v/v of SR pellets in the
tabletting matrix. The adjustment resulted in 31% v/v of DR pellets in the
tabletting matrix which contains 50%w/w DR matrix pellets and filler granules
ranging from 150 to 850 µm (mesh 20 to 100 ASTM); enable the production of disintegrating
tablets having an approximately homogenous pellet distribution within large
range of machine speeds.
From these studies,
good content uniformity (99.85 ± 2.10%) and less than 5% deviation in drug
release when compared to the uncompacted DR matrix pellets in phosphate buffer
pH 6.8, was achieved by blending DR matrix pellets and 150 to 850 µm (mesh 20
to 100 ASTM) fraction of filler granules along with required lubricating agents
(Fig 4).
Fig. 4
Dissolution of diclofenac sodium DR matrix pellets prepared (DCST-05) from 20% HPMCP and 40%MCC (
DR pellets) and compression of the same with suitable tabletting excipients (
DR
pellets in tablets) and comparison of the same with the reference product (
Voveran),
Voveran® using paddle
apparatus at a rotation speed 50 rpm, in 900 ml 0.1 N hydrochloric acid for 2 h
(acid stage) followed by pH change to 1000 ml pH 6.8 (buffer stage) by adding
250 ml of tribasic sodium phosphate solution to 750 ml of acid stage 0.1 N
hydrochloric acid. Each result shows the mean of 6 values.
4.
CONCLUSION:
Diclofenac sodium DR
granules in a single step without a coating process were prepared by high-shear
pelletization process. The process variables involving the different
stages of high-shear pelletization process such as premixing of the solids;
liquid addition stage; wet massing stage; and drying stage and spheronization
process along with formulation variables including different types and amount
of enteric polymers were investigated. During the wet granulation process in
RMG, better distribution of binder solution can be achieved with spraying of
binder solution at the rate of 5 g/min with the impeller and chopper at fast
speed and narrow size wet granules were formed by wet massing carried out for
15 min with impeller and chopper at fast speed. Thus formed wet granules when
milled with knife at the speed of 1000 rpm in hammer mill fitted with 0.5 mm
screen formed spherical granules. The good spherical shape, narrow size pellets
were obtained at the disc speed of 1500 rpm with dwell time of 2-5 min in the
spheronizer. The spheronized wet mass was dried in fluid bed processor with
50-60şC bed temperature for 120 min to get loss on drying value less than 2.0 %
w/w at 105şC. The drug release was faster for HPMCP containing formulation
since collapsing of swollen HPMCP polymer by the interaction of hydrophobic
groups whereas drug release was slower for Eudragit® L 100-55
containing formulation since dissolution of Eudragit® L polymeric
film caused higher degree of swelling of
still entrapped Eudragit® L 100-55 which hinders drug release in
phosphate buffer pH 6.8. The optimised DR multiparticulates were compressed
with tabletting excipients into multiple unit pellet system (MUPS) tablets. The
percentage of DR pellets in the tablet compression blend, the different size
fraction of filler excipients, the compression machine speed were considered to
have less variation in content uniformity in tablets by using a 33
factorial design. Decreasing the percentage of DR pellets (60% to 40%w/w) in
the compression blend decreased the damage to the DR pellets irrespective of
particle size of tabletting excipients and decreasing compression speed. The
decreased drug release may be due to insufficient protection to DR matrix
pellets and may have resulted in fusion of adjacent DR matrix pellets while
increasing the amount of pellets in the compression blend. A decrease in
compression speed decreased the drug release that may be due to greater dwell
time in die for less compression speed. In this study particle size of
excipients played a significant role in the variation of content uniformity (at
P = 0.05) and in release of drug in
phosphate buffer pH 6.8 significantly (P =
0.10) irrespective of percentage of DR pellets and compression machine speed
(Table 2 and 3). This may be attributed to large excipient particles that
apparently resulted in an increased excipient-excipient interaction and thereby
produced an environment in which the compression forces impacted the beads less
directly whereas small excipient particles resulted in more surface area and
thereby produced better protection from compression induced changes. However,
variation in content uniformity was significantly observed when the size of
tabletting excipients was reduced which may be due to more particle surface
area. By including an optimum amount of DR pellets in the compression blend and
with tabletting excipients with required particle size distribution can provide
the tablets with less variation in content uniformity and unaffected drug
release profile at all compression speeds. The release profile of the prepared
DR disintegrating tablets was found to be comparable with
reference product, Voveran®, diclofenac sodium
DR tablets.
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