ROLE OF ADDITIVES IN

FORMULATION DEVELOPMENT
& PROCESSING

By
ASHISH KUMAR PAL
Reg. No. 1702-10-885-010
Pharmaceutical Analysis and Quality Assurance

1
 Definition of Additives

Pharmaceutical additives are defined as secondary

ingredients present in both prescription and over-
the-counter drug formulations and contributing in
one or more of the following ways:
• improving consumption ease of the dosage form
• enabling or enhancing the delivery of the drug or medicine
• increasing the stability of active ingredients
• acting as a filler or diluents so that an adequate amount of
material is available to properly fill a dosage form
• acting as an antimicrobial or antioxidant to extend the
shelf life of the active ingredient

2
PREPARATION AND IN VITRO EVALUATION OF
GASTRIC FLOATING MICROCAPSULES OF
METFORMIN HCL
INTRODUCTION
• Despite tremendous advancement in the drug delivery system,
oral route remains the preferred route because of low cost
therapy and ease of administration leads to higher levels of patient
compliance
• An incomplete release of the drug and shorter residence time of
the dosage forms in the upper GIT, which is a prominent site for
the absorption of many drugs, leads to decreased bioavailability.
Metformin HCI, which is an antihyperglycaemic agent widely used
in the management of N IDDM.
• Stepensky et all concluded that absolute oral bioavailability of
Metformin HCl is 50-60%.It is safe drug and it has a half-life of 1.5-
3 hrs. It is not absorbed completely and gives low bioavailability
problem. Almost 80-100% of the drug is excreted unchanged. The
total daily requirement of Metformin HCI is 1.5-3g/day
• However, bioavailability of the drug has been found to be reduced
further with controlled release dosage forms, probably due to the
fact that
1. passage of the controlled release single unit dosage forms from
absorption region of the drug is faster than its release and
2. most of the drug released at the colon where metformin
hydrochloride is poorly absorbed 3
 APPROACHES
• Controlled release formulation suitable for metformin
hydrochloride, therefore, should be a gastro-retentive
dosage form, which releases the drug slowly in the
stomach for gradual absorption in the intestines.
• Among the different approaches that have been
developed, low density system holds promise. Floating
DDS systems are low density systems that have
sufficient buoyancy to float over gastric contents, and the
drug is released slowly at the desired rate, which results
in increased gastro-retention and reduces fluctuations in
plasma drug concentration

4
 OBJECTIVE
• To design a SR floating microspheres of Metformin
HCI using two polymers Cellulose Acetate Butyrate
and Eudragit RLI 00, in order to achieve an
extended retention in the upper GlT, which may
result in enhanced absorption and thereby improved
bioavailability.
• The prepared rnicrospheres were also studied for
drug release behavior in simulated gastric fluid at pH
1.2 and phosphate buffer at pH 6.8 respectively, and
optimize the drug release to match the target
release profile and possible release mechanism
proposed.

5
  
MATERIALS
• Metformin HCI
• Cellulose Acetate Butyrate (Mol.
Wt 16,000)
• Eudragit RLIOO (Mol. Wt 150,000)
• Acetone,
• liquid Paraffin (Light),
• Span 80 AR,
• Magnesium stearate

6
 Preparation of floating microspheres
• non- aqueous emulsion solvent evaporation method.
• Eudragit RLI 00 (10% w/w) and Cellulose acetate butyrate (10% w/w) were
used separately, and mixed together to form microspheres.
• In case of microsphere made of combination polymers, firstly weighed
quantity of eudragit RLlOO and CAB was completely dissolved in acetone at
the polymer ratio 1:1, 5% w/w of magnesium stearate (to the total polymer
conc. used) and weighed quantity of Metformin HCI (50%w/w) were
dispersed to the above slurry and stirred in a magnetic stirrer.
• The drug polymer dispersions were pressurized under CO2 gas, which upon
release of the pressure form cavities on the polymeric surface.
• The porous drug polymer dispersions were then slowly introduced into 70 ml
liquid paraffin previously emulsified with 1 % Span 80, while stirring at 1000
rpm.
• The whole system was stirred for 3 hour to allow the complete evaporation of
acetone. The oil layer was decanted and microspheres were washed several
times with petroleum ether (40-60°) The washed micro spheres were dried in
an oven at room temperature not exceeding 25°C. 7
 Detail composition of each
formulation
Drug Polymer Quantity of
Polymer concentration %w/w Stirring
Formulation magnesium
Code ratio 10%w/w Speed (rpm)
stearate

1:2 RLI00 5 1000

A1
1:2 CAB 5 1000
Bl a
1:2 RLlOO,CAB 5 1000
AlBIa
(1:1) _
1:2 CAB 5 1500
B1
1:2 RLlOO,CAB 5 1800
A1B1
(1:1)

8
OTHER PARAMETERS
The following studies were carriedout
• Viscosity of the Polymer Organic Phase
• Yield of Microspheres
• Particle size analysis
• Scanning electron microscopy
• Fourier Transform Infrared Spectroscopy
(FT-IR):
• Drug entrapment efficiency

9
 In vitro Drug Release Study

• In vitro drug release studies were carried out for all

products in USP type II fitted with six rotating basket
dissolution test apparatus. The microspheres were
evaluated for drug release using 900 ml of simulated
gastric fluid (pH 1.2) and simulated intestinal fluid (pH
6.8) for 10 hour maintained at 37 ± 0.1 °C and stirred at
100 rpm.
• sink conditions were maintained
• Withdrawn samples were analysed
spectrophotometrically at 233nm using a UV-Visible
double beam Spectro- photometer.

10
 RESULTS AND DISCUSSION
 
• The present study was aimed at not only to improve the buoyancy of
Microspheres, but also to release the drug in the acidic pH in
controlled fashion. Also, to make a formulation having density lower
than the gastric contents, using mixture of two polymers of different
permeability characteristics. 
• The two polymers are selected in such a way that one will give initial
burst release, which is essential from therapeutic point of view, while
the other will control the drug release by maintaining the buoyancy 
• Eudragit RL 100 contain higher amount of quaternary ammonium
groups, which renders it more permeable. It was evident that
addition of eudragit RL100 increased the permeability of the
microspheres to the surrounding dissolution medium due to the
swelling nature of the polymer.
• In addition to this, the porous nature of the microsphere produces an
upward motion of the dosage form to float on the gastric contents
11
 * All values are expressed as mean ± SD, n=3

In vitro drug release profile data

Cumulative % drug released of coded formulations
in 0.1 M HCI at pH 1.2 in Phosphate buffer at pH 6.8
Time Al Bl AlBl MKT Al Bl AIBI MK
(hr)
1 43.59 24.11 37.31 21.3 46.51 25.16 38.1 23.17
± 1.03 ±1.98 ±2.23 ±1.l7 ±1.05 ±1.12 ±1.01 ±1.l5
2 47.08 27.21 41.03 33.15 49.25 29.07 42.3 37.11
±1.02 ±1.15 ±2.15 ±2.18 ±1.63 ±1.l8 ±1.49 ±1.43
3 56.11 31.03 49.25 39.59 57.69 33.51 47.41 41.39
±1.15 ±1.93 ±2.13 ±2.57 ±1.46 ±2.13 ±1.63 ±1.23
4 69.15 39.17 58.31 48.91 71.85 41.25 61.05 53.22
±1.23 ±1.23 ± 2.35 ±1.8 ±1.23 ±2.23 ±1.87 ±1.47
5 74.21 47.51 64.17 57.07 73.49 49.69 66.31 59.71
±1.93 ±1.03 ±1.97 ±2.23 ±1.89 ±2.43 ±1.98 ±1.56
6 77.16 53.79 67.52 68.33 79.71 56.22 69.43 67.33
±1.54 ±1.l2 ±2.96 ±1.54 ±1.57 ±2.47 ±2.13 ±1.41
7 79.51 57.88 71.69 79.24 84.22 59.31 73.34 76.15
±1.29 ±1.99 ±2.57 ±1.47 ±1.63 ±2.51 ±2.23 ±1.l4
8 81.75 59.18 73.41 83.03 86.39 67.75 77.15 87.21
±1.27 ±1.05 ±1.97 ±1.97 ±1.17 ±2.41 ±2.54 ±1.23
9 82.07 64.61 75.16 87.41 87.15 69.19 79.03 89.08
±1.23 ±1.97 ±2.13 ±2.13 ±1.87 ±2.17 ±1.67 ±1.18
10 83.13 67.22 77.21 91.57 89.61 71.81 81.35± 1. 94.55
±1.98 ±1.07 ±1.98 ±2.57 ±1.56 ±1.98 17 12 ±1.12
* All values are expressed as mean ± SD, n=3
 RESULTS AND DISCUSSION
• In vitro dissolution studies of all batches of micro pheres ,micro pheres made of
eudragit RL I 00 showed good flow properties, maximum floating tendency, but faster
in vitro drug release rate in both simulated gastric media (pH 1.2) and phosphate
buffer (pH 6.8). The prepared microspheres made of eudragit RL I 00 showed
maximum drug release of 81-83% within 8-10 hours in 0.1 M HCI. However, the same
micro pheres showed higher amount of drug release, 85-89% in phosphate buffer (pH
6.8) as compared to the release in 0.1 M HCI
• Likewise, microspheres made of CAB showed good flow properties, minimum floating
behaviour but slower rate of invitro drug release initiated by lag time in both the
dissolution media, as compared to the eudragit RLIOO microspheres. It is observed
from the release profile that around 59-67% drug released in 0.1M HCI and 67-71%
drug released in phosphate buffer (pH 6.8) within 8-10 hours.
• It was also evident that combination of eudragit RL I 00 and CAB imparts a synergi tic
increase in the relative viscosity compared to the single polymers. The addition of
eudragit RL I 00 to CAB polymer increases the permeability of the microspheres to
dissolution medium due to the swelling nature of eudragit RLIOO. Moreover, eudragit
RL 100 contain higher amount of quaternary ammonium groups, which renders it
more permeable. This would increase the porosity of CAB membrane and minimizes
the lag time initiated by CAB microspheres
13
 CONCLUSION

• The combination polymer at polymer to polymer

ratio 1:1 helps to leach out the drug from its
matrices and exhibits an initial rapid drug release
for the first 2 to 3
hours and then slower drug release.
14
 TASTE MASKING AND FORMULATION OF OFLOXACIN RAPID
DISINTEGRATING TABLETS AND ORAL SUSPENSION
 
INTRODUCTION

• With the advancement in technology and experience, pharmaceuticals are

prepared and administered to patients in more compliant and efficient
manner. Rapid disintegrating tablets are the new improved dosage forms
developed especially for the young and the elderly patients who find inability
to swallow tablets and capsules due to under developed muscular,nervous
system and dysphagia.
• When this type of tablet is placed into the mouth, the saliva serves to rapidly
dissolve the tablet usually in about 30 seconds.The critical formulation
problem is the masking of bitter taste associated with most of the drugs and
this can be overcome by taste masking techniques such as:

1.polymer coating,
2.complex formation,
3. granulation,
4.microencapsulation and
5.use of ion exchange resins). 15
 INTRODUCTION
• Ofloxacin is widely used antibacterial drug
recommended in the treatment of chronic
bronchitis, respiratory/ENT infections,
nonspecific urethritis, gonorrhoea, atypical
pneumonia, leprosy, cervicitis.
• One of the major drawbacks of this drug is
its bitter taste which may give rise to
patient noncompliance when formulated as
conventional dosage forms.

16
 OBJECTIVE

• In the present study taste masking of bitter

drug ofloxacin was achieved by preparing
taste masked granules using a pH sensitive
polymer, Eudragit E- 100. These granules
were then formulated into rapidly
disintegrating tablets using the technique of
super- disintegrant addition. Also a
suspension dosage form was prepared
using taste- masked granules of ofloxacin.

17
 Materials

• Ofloxacin
• Eudragit E-I 00
• Microcrystalline cellulose
• Sodium starch glycolate

18
Preparation of taste-masked granules

• Ofloxacin was thoroughly mixed with varying

amounts of powdered Eudragit E-I00. Then 10%
ethanol was added to this mixture in a glass
beaker and a gel was prepared.
• The prepared gel was manually pressed out
using a syringe. After extrusion of the gel,
ethanol was removed by evaporation overnight
at room temperature.
• Subsequently the solidified gel was crushed into
granules using a pestle and mortar.
• The drug: polymer ratio which produced taste
masked granules was used for further studies.
19
 Formulation of rapidly disintegrating
tablets (RDTs)
• The prepared Eudragit E-I00 granules of ofloxacin were
compressed into (RDTs) by using microcrystalline cellulose (MCC)
as directly compressible binder and sodium starch glycolate (SSG)
as the super- disintegrant.
• Flavoring was done with menthol to give the tablets more palatable
feel. Magnesium stearate was added as the lubricant while mannitol
was added as the diluent.
• Similarly control tablets were prepared using pure drug instead of
taste masked granules. Different ratios of the super-disintegrant,
SSG and the binder, MCC were investigated for the formulation of
ofloxacin ROTs and the ratio that gave the minimum disintegrating
time along with acceptable hardness was chosen for the formulation
of the final batch of tablets.

20
Effect of sodium starch glycolate (SSG) and microcrystalline cellulose (MCC)
ratio on the
disintegration time of ofloxacin RDTs
Tablet
Formulation SSG: MCC Disintegration strength
code time (s) (hardness in
kg/cm')

OF-1 1:0.5 7.00 ± 0.94 0.5

OF-2 1:1.0 15.00 ± 1.36 1.0
OF-3 1:2.0 52.00 ± 1.11 1.5
OF-4 1:3.0 58.00 ± 1.31 2.5
OF-5 1:4.0 63.00 ± 0.97 3.0
OF-6 1:5.0 84.00 ± 1.54 3.5
OF-7 1:6.0 86.00 ± 2.01 4.0
OF-8 1:8.0 98,00± 1.73 4.5
OF-9 1:10 119.00 ± 0.63 5.5

21
  
Evaluation of RDTs
• The force required to break the tablet (tensile strength) was measured
using Monsanto hardness tester.
• For the measurement of in vitro disintegration time a modified dissolution
apparatus (paddle type) was used. 900 ml of water maintained at 37°C
and stirred with a paddle at 100 rpm was used as the disintegration fluid.
• In vitro dissolution studies were carried out using USP XXIII Dissolution
apparatus II (paddle type). A tablet was placed in a basket and rotated at
50 rpm. The
release profile was studied both in phosphate buffer at pH 6.8 and
hydrochloric acid buffer pH 1.2.
• The taste evaluation was done using spectrophotometric method and by
panel testing. For panel testing, 20 healthy human volunteers, of either
sex, in the age group of 20-30 years were selected out of 31 volunteers

22
 RESULTS AND CONCLUSIONS
• Sensory evaluation for taste by the panel confirmed the tasteless
characteristics of the granules as none of the subjects felt bitter
taste even after keeping in mouth for 20-30 s. Hence, this technique
of taste- masking using a pH-sensitive polymer was found to be
effective in masking the bitter taste of the drug.
 
• The taste masked granules were compressed into rapidly
disintegrating tablets. Different ratios of the super-disintegrant, SSG
and the directly compressible binder, Ratios of SSG: MCC below
ratio 1: 1 gave very less disintegration times (less than 19 s) but the
tablet hardness was very low.

• All the ratios above 1:3 (i.e., Formulations OF-5 to OF-9) gave high
disintegration times and therefore, were rejected. Formulation OF-
4 gave acceptable hardness as well as rapid disintegration.
Therefore, it was selected for the preparation of final batch of RDTs.
23
 CONCLUSION

• To conclude, efficient taste masking was achieved for the bitter drug
ofloxacin using the technique of granulation. Patient compliant dosage
forms i.e. oral liquid suspension and rapidly disintegrating tablets that had
good taste were successfully formulated. These studies suggest that these
patient friendly taste masked dosage forms may be useful for children and
elderly patients.

24
 DESIGN AND EVALUATION OF BUCCAL
PATCHES OF GRANISETRON HYDROCHLORIDE
INTRODUCTION

• Granisetron hydrochloride (5 HT) receptor antagonist)

is a drug used in the management of nausea and
vomiting induced by cytotoxic chemotherapy and for
prevention and treatment of post-operative nausea
and vomiting.
• The drug is well absorbed from the gastrointestinal
tract, but its oral bioavailability is low (60%) due to
extensive first-pass metabolism. Since buccal route
bypasses first- pass effect.

25
 APPROACHES
• The physico-chemical properties of
GRN, its suitable biological half-life (3-
4 h) and low molecular weight (348.9)
make it suitable candidate for
administration by buccal route, There
are several reported studies on
administration of drugs via buccal
route, as patches or discs.

26
 Materials

• Granisetron hydrochloride (GRN)

• chitosan (65 cps)
• hydroxypropyl methylcellulose
(HPMC 15 cps),
• ethyl cellulose (Ee),
• polyvinyl pyrrolidone (PVP K-30) and
propylene glycol
27
  
Method of preparation of buccal patches

• PVP (16.7% by weight of polymers) was used as mucoadhesive polymer and

propylene glycol (30-50% of the polymer weight) as plasticizer.
• The weighed quantity of HPMC was properly dispersed in aqueous acetic acid
solution (1% vlv, 25 ml). Then weighed quantity of chitosan was taken and
mixed with the above solution.
• PVP was accurately weighed and dissolved in the filtered solution. The
required quantity of plasticizer propylene glycol and aspartame (2% by weight
of polymers) were added.
Then the drug was dispersed uniformly in the viscous solution with continuous
stirring.
• The resultant mixture was poured into specially fabricated glass moulds (5x5
cm) lined with aluminum foil. Drying was carried out at room temperature for 24
h.
• Small patches of (l x 1 cm in size) containing 1.12 mg of granisetron
hydrochloride (equivalent to 1 mg granisetron) were cut with the help of
sharp pen knife.

28
Formulatio
Chitosan- Chitosan- HPMC Propylene
n
Code HPMC (mg) (mg) glycol
Ratio (mg)
CH1 1:2 250 500 225
CH2 1: 1 375 375 225
CH3 2:1 500 250 225
CH4 1:2 250 500 300
CH5 1:1 375 375 300
CH6 2:1 500 250 300
CH7 1:2 250 500 375
CH8 1:1 375 375 375
CH9 2:1 500 250 375
29
 Evaluation of buccal patches
• Thickness of the films was determined using a micrometer
screw gauge.
• Bioadhesive strength of all the formulations was tested;
i.e., weight required to pull off the formulation from mucus
tissue is recorded as mucoadhesion bioadhesion strength.
This parameter for the film was measured on a modified
physical balance. A self designed and locally fabricated
apparatus was used for determination of tensile strength
and percent elongation at break, which measure the
mechanical strength of the film.
• In vitro drug release study was carried out using the
beaker method as described by Ilango R et al.

30
 RESULTS AND DISCUSSION
In the present work attempt has been made to prepare buccal films of granisetron
hydrochloride, an anti-emetic drug (5-HT3 antagonist). A total of nine mucoadhesive
patches of GRN were prepared and evaluated for biological, physical and mechanical
parameters.
According to work plan, the films were evaluated for their
• appearance,
• surface texture,
• thickness,
• weight variation,
• folding endurance,
• swelling index,
• tensile strength,
• elongation at break,
• in situ bioadhesion strength,
• drug content uniformity,
• in vitro drug release,
• short-term stability and
• drug-excipient interaction.
31
Film Mean Mean Folding Swelling Tensile Elongation In vitro Mean
Code Thickness Weight" endurance Index Strength' At break' Biadhesion Drug
(mm) (mg) (dynes/ (%) Strength' Content
cm'xltl') (gm) %
CHI 0.20 9.77 92.66 45.60 1.79 5.01 3.93 97.96
(0.01) (0.36) (4.50) (0.36) (0.03) (0.078) (0.15) (2.28)
CH, 0.30 10.29 74.00 38.10 1.62 4.30 3.80 96.36
(0.02) (0.36) (4.72) (0.36) (0.08) (0.051 ) (0.20) (1.64)
CH3 0.22 10.26 52.66 36.90 1.86 5.75 4A3 96AO
(0.01) (0.35) (4.72) (0.35) (0.09) (0.070) (0.21) (0.76)
CH. 0.23 9.81 117.66 49AO 1.52 3.17 3.25 98.16
(0.01) (0.28) (2.51) (0.28) (0.06) (0.075) (0.13) (IA2)
CH, 0.29 11.70 83.33 40.60 1.92 5.04 3.90 96.24
(0.03) (0.38) (3.51 ) (0.38) (0.03) (OAI ) (0.23) (0.52)
CH. 0.23 10.68 60.00 38.25 2.08 6.57 4.33 96.33
(0.02) (OAO) (4.58) (OAO) (0.10) (0.231) (0.15) (0.72)
CH7 0.22 9.91 135.66 47.15 1.78 6.09 3.96 96.90
(0.02) (0.33) (4.50) (OAO) (0.02) (0.133) (0.16) (1.89)
CH. 0.34 11.75 99.38 43.60 2.06 7.18 4.16 99.21
(0.03) (OAO) (5.13) (0.33) (0.04) (0.032) (0.09) (0.55)
CH9, 0.20 9.86 79.33 33.80 2.13 7.31 5.56 96.78
(0.02) (0.22) (6.50) (0.22) (0.07) (0.096) (0.16) (0.51)
32
 RESULTS AND DISCUSSION
• The results revealed that the release of drug is dependent on polymer ratio
as well as on plasticizer (PG) concentration.
• The films were quite flexible as shown by measurement of folding
endurance . The folding endurance of films goes on increasing as we
increase the concentration of HPMC or propylene glycol. The maximum
folding endurance as shown by formulation CH7 is approximately 135.
• There was significant correlation between tensile strength and polymer
composition. The tensile strength of film increases as we increase the
concentration of chitosan and plasticizer concentration does not have much
effect.
• The mucoadhesivity (in vitro bioadhesion strength) of all the films of varying
ratios of polymers was tested and was found to increase as the proportion
of chitosan in the film increases . This may be due to the fact that positive
charges on the surface of chitosan could give rise to strong electrostatic
interaction with mucus or negatively charged mucous membrane.
• Drug release from the films was found to be largely dependent on polymer
ratio and plasticizer concentration and increases with an increase in the
concentration of HPMC and plasticizer.
33
 RESULTS AND DISCUSSION
• Formulation CH8containing chitosan and HPMC in I: I ratio with a plasticizer
concentration of 50% by weight of polymer has shown promising results and
displayed t50 and t70 values of 1.75 and 2.75 h respectively and released
more than 90% of drug in 5 h and it has got reasonably good tensile
strength and mucoadbesive properties
SI. No. Formulation code t50 (b) t.70 (b) Cumulative %
Drug release in
5b·±SD
1 CHI 2.25 3.30 86.50±1.28 2
2 CH2 2.25 3.60 78.18±1,283
3 CH3 2.26 4.50 71.07±1.764
4 CH. 1.75 3.00 88.46±1.00 5
5 CHs 2.24 3.50 87.85±1.326
6 CH6 2.21 4.25 79.27±0.50 7
7 CH7 1.52 2.80 91.25±1.738
8 CH8 1.75 2.75 90.37±1.73 9
9 CH9 2.15 3.75 80.49±1.62 34
 CONCLUSION

• The results of the present study indicated that buccal patches of the drug
GRN can be successfully prepared using a combination of chitosan and
HPMC (15cps). The formulation CH8(containing the above polymers in a
ratio of 1: 1 and plasticizer concentration of 50% by weight of polymer) has
emerged as the promising buccal drug delivery system of GRN and
displayed t50 and t70 values of 1.75 and 2.75 h respectively and released
more than 90% of the drug in 5 h, with reasonably good tensile
strength and mucoadhesive properties.
35
 REFERENCES
• Indian Journel For Pharmaceutical Education And Research(ILPER),
Volume-43(2),April-June 2009, Preparation and In vitro Evaluation of
Gastric Floating Microcapsules of Metformin HCl, Bipulath*, L.K. ath',
B.Mazumdarl, .K.Sharma, M.K.Sarkar ,p.177-184.
 
• Indian Journel For Pharmaceutical Education And Research(ILPER),
Volume-43(2),April-June 2009, Taste Masking and Formulation of
Ofloxacin Rapid Disintegrating Tablets and Oral Suspension,
Shishu*, Varun Rishi Kapoor and Kamalpreet, p.150-155.
 
• Indian Journel For Pharmaceutical Education And Research(ILPER),
Volume-44(1),April-January-March 2010, Design and Evaluation of
Buccal Patches of Granisetron Hydrochloride, Swamy P.V.*,
Amitkumar T., Shirsand S.B., Patil A. N. and Laeeq Farhana, p.95-
102

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FEED BACKS & DOUBTS

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