1.0 INTRODUCTION:
1.1 Fast dissolving tablets:
Drugs are rarely administered solely as
pure chemical substances but are almost given in formulated preparation. These
can vary from relatively simple solutions to complex drug delivery systems. The
oral route of drug delivery is typically considered the preferred and most
patient convenient means of drug administration. Amongst various dosage forms
available in the pharmaceutical market, tablets share almost 50 % of the total
market. Several novel technologies for oral delivery have recently become
available to address the physicochemical and pharmacokinetic characteristic of
drugs while improving patient compliance.
One such NDDS is Orodispersible Drug Delivery Systems (ODDDS).
Orodispersible tablets (ODT) when placed in mouth disintegrate in presence of
saliva3. Suspension thus formed is swallowed easily without the aid
of water. After the ingestion of the tablet, a pleasant taste/flavor remains in
the patient’s mouth. Such ODTs are also
known as mouth disperse/fast melts /fast dispersing /fast dissolve/quick
melt/quick dissolve/flash tabs/melt in mouth.
Advantages
of ODDDS include:
1. Administration to patients who
cannot swallow, such as the elderly stroke victims, healthcare facility and
bedridden patient; patients who should not swallow such as those affected by
renal failure and patients who refuse to swallow, such as pediatric, geriatric
and psychiatric patients.
2. Rapid drug therapy intervention.
3. Convenience and patient
compliance, such as disabled bedridden patients and for traveling and busy
people who do not have ready access to water.
4. More rapid drug absorption.
5. New business opportunities:
product differentiation, line extension, and life cycle management, exclusivity
of product promotion and patent life extension.
1.1.1 Desired characteristics and development challenges of fast
dissolving tablets: [14-17]
Because administration of ODTs
is different from conventional tablets, the ODTs should have several unique
properties to accommodate. Several properties essential to good ODTs are listed
below.
A. Fast disintegration
ODTs should disintegrate in the
mouth without taking water or with a very small amount (e.g., 1 or 2 ml) of
water. The disintegration fluid is provided by the saliva of the patient. The
disintegrated tablet should become a soft paste or liquid suspension which can
provide good mouth feel and smooth swallowing. The "fast
disintegration" usually means disintegration of tablets in less than a
minute, but it is preferred to have disintegration in less than 30 seconds.
B. Taste of the active ingredient
Because fast-dissolve dosage
forms dissolve or disintegrate in the patient's mouth, the drug will be
partially dissolved in close proximity to the taste buds. After swallowing,
there should be minimal or no residue in the mouth. A pleasant taste inside the
mouth becomes critical for patient acceptance. Unless the drug is tasteless or
does not have an undesirable taste, taste-masking techniques should be used. An
ideal taste masking technology should provide drugs without grittiness and with
good mouth feel. In the meantime, the amount of taste masking materials used in
the dosage forms should be kept low to avoid excessive increase in tablet size.
The taste masking technology should also be compatible to formulation of ODTs.
C. The drug property
For the ideal ODT technology,
the drug properties should not significantly affect the tablet property. Many
drug properties could potentially affect the performance of ODTs. For example,
the solubility, crystal morphology, particle size and bulk density of a drug
can affect the final tablet characteristics, such as tablet strength and
disintegration. The fast dissolving tablet technology should be versatile
enough to accommodate unique properties of each drug.
D. Tablet strength and porosity
Because the fast dissolving
dosage form was designed to have quick dissolution/disintegration time, tablet
porosity was usually maximized to ensure the water absorption into the tablets.
The soft-molded method or tablets compressed at very low compression forces are
used in some ODT technologies to maximize the porosity. However, this causes
mouth dissolving dosage forms to be soft, friable, and unsuitable for packaging
in conventional blisters or bottles. A strategy to increase tablet hardness
without sacrificing tablet porosity or requiring a special packaging to handle
fragile tablets should be provided.
E. Moisture sensitivity
ODTs should have low sensitivity
to humidity. This problem can be especially challenging because many highly
soluble excipients are used in formulation to enhance
fast dissolving properties as well as create good mouth feel. Those highly
soluble excipients are susceptible to moisture; some
will even deliquesce at high humidity. A good package design or other strategy
should be made to protect MDTs from various environmental conditions. Finally,
ODTs need to be manufactured at low cost11.
1.2 Limitations of orally disintegrating
tablets:
Despite
the different advantages of this drug delivery system, application of this
technology is limited by loading of the drug that can be incorporated in each
unit dose. For lyophilized dosage forms, drug dose must be lower than 400 mg
for insoluble drugs and less than 60 mg for soluble drugs12. Freeze dried wafer dosage
forms are fragile in nature; these products require special unit dose
packaging, which may add to the cost.
2.0 MATERIALS, EQUIPMENTS AND ANALYTICAL
METHODOLOGY:
2.1 Materials
The following drug, excipients and chemicals were used for the formulation and
evaluation studies of RDTs.
|
Table
2.1: List of chemicals and excipients
|
|
Sr. No.
|
Name
|
Company
|
|
1.
|
API
|
Debris, France
|
|
2.
|
Polacrilin potassium (Amberlite IRP 88)
|
Rohm
and Hass Pvt. Ltd.
|
|
3.
|
Citric acid anhydrous
|
Merk chemicals, Mumbai, India
|
|
4.
|
Mannitol (Pearlitol
SD-200)
|
Roquette, France
|
|
5.
|
Microcrystalline cellulose
|
FMC biopolymer, USA
|
|
6.
|
Sodium Starch Glycolate
|
DMV international, Europe
|
|
7.
|
Crospovidone
|
ISP Corp Ltd. NJ, USA.
|
|
8.
|
Croscarmellose Sodium
|
Signet chemicals, USA
|
|
9.
|
Aspartame
|
Nutrasweet,
South Korea.
|
|
10.
|
Colloidal Silicon Dioxide (Aerosil 200)
|
Degussa, Germany.
|
|
11.
|
Ferric Oxide Red
|
BASF pharma
|
|
12.
|
Lactose
|
Meggle, Germany
|
|
13.
|
Magnesium Stearate
|
Ferro Corporation, USA
|
|
14.
|
Flavour (Tutti-frutti)
|
Firmenich, Chennai.
|
2.2 Equipments:
|
Table 2.2 List of equipments
|
|
Sr. No.
|
Instrument Name
|
Model No. and Manufacturer
Name
|
|
1
|
Digital Balance
|
AUX 120, Shimadzu, Japan
|
|
2
|
UV Spectrophotometer
|
1700, Shimadzu, Japan
|
|
3
|
Digital pH Meter
|
µ pH system 362, Systronics, India
|
|
4
|
Mechanical Stirrer
|
5MLH DX Remi, India
|
|
5
|
Rotary 10 station tablet
machine
|
Rimek minipress-1, Ahmedabad, India
|
|
6
|
Stability Chamber
|
CHM-10S Remi, India
|
|
7
|
FTIR
|
8400 S ,Shimadzu, Japan
|
|
8
|
Differential Scanning
Calorimeter
|
Mettler Toledo
|
|
9
|
Dissolution test apparatus II
|
USPXXIII,(TDT-08L) plus, Electrolab,
|
|
10.
|
X-ray Diffractometer
|
Brucker AXS D8 Advance
|
|
11.
|
Disintegration test apparatus
|
ED-2L Electrolab,
Mumbai, India
|
|
11.
|
Friability test apparatus
|
Electrolab, Mumbai, India
|
|
12.
|
Tensile tester
|
60001; Ubique
enterprises, Pune
|
|
13.
|
Tapped density tester
|
ETD 1020, Electrolab, Mumbai, India
|
2.3 Analytical
methodology
2.3.1 Preformulation study
Identification of drug
a)
The obtained sample was examined by DSC and an obtained spectrum
was compared with the reference standard spectrum of API.
b)
The obtained sample was examined by infrared absorption spectral
analysis and was compared with the reference standard IR spectrum of API.
2.3.2 Calibration
curves of API
Calibration curve
of API in pH 1.2 buffer
Procedure: 10 mg of API was dissolved in
100 ml of the pH 1.2 Buffer to obtain the working standard of 100 µg/ml.
Aliquots of 0.2 ml to 1.4 ml from the stock solution representing 2 to 14 µg/ml
of drug were transferred to 10 ml volumetric flask and the volume was adjusted
to 10 ml with pH 1.2 Buffer. The Absorbance’s of the above solutions were taken
at λmax 247 nm against the blank
solution prepared in the same manner without adding the drug. A graph of
absorbance Vs concentration was plotted and was found to be linear over a range
of 2 to 14 µg/ml indicating its compliance with Beer’s law.
Calibration curve
of API in pH 6.8
Procedure: 10 mg of API was dissolved in
100 ml of the pH 6.8 buffer to obtain the working standard of 100 µg/ml.
Aliquots of 0.2 ml to 1.4 ml from the stock solution representing 2 to 14 µg/ml
of drug were transferred to 10 ml volumetric flask and the volume was adjusted
to 10 ml with the pH 6.8 buffer. Absorbances of the above solutions were taken at λmax 273 nm against the blank solution
prepared in the same manner without adding the drug. A graph of absorbance Vs
concentration was plotted and was found to be linear over a range of 2 to 14
µg/ml indicating its compliance with Beer’s law.
Calibration curve
of API in pH 4.5
Procedure: 10 mg of API was dissolved in
100 ml of the pH 1.2 Buffer to obtain the working standard of 100 µg/ml.
Aliquots of 0.2 ml to 1.4 ml from the stock solution representing 2 to 14 µg/ml
of drug were transferred to 10 ml volumetric flask and the volume was adjusted
to 10 ml with pH 4.5 Buffer. The Absorbance’s of the above solutions were taken
at λmax 247 nm against the blank
solution prepared in the same manner without adding the drug. A graph of absorbance
Vs concentration was plotted and was found to be linear over a range of 2 to 14
µg/ml indicating its compliance with Beer’s law.
2.3.3 Drug and
polymer interaction study
A) IR Spectroscopy
The interaction between the drug and
polymer was studied by using the FTIR spectroscopy wherein infrared spectra of
API, Polacrilin potassium, physical mixture and DPC
were carried out using the KBr disk method (2 mg
sample in 200 mg KBr). The scanning range was 450 to
4000 cm -1 and the resolution was 1 cm -1.
Samples:
a) API
b) Polacrilin potassium
c) Physical mixture
B) Differential Scanning Calorimetry
The
possibility of any interaction between API and Polacrilin
potassium used in the formulation of rapidly disintegrating tablets was
assessed by carrying out the thermal analysis of
a) API
b) Polacrilin
potassium
c) Physical mixture.
The
thermal behavior of plain drug, Polacrilin potassium
and physical mixture were determined using differential scanning calorimeter at
heating rate of 50C /min. The measurements were performed at a
heating range of 40 to 4200C under nitrogen atmosphere.
2.4 Formulation and development
A) Preparation of drug –polymer complex
(DPC)
The drug: polymer was taken in
the ratio 1:1, 1:2, 1:3. The polymer (polacrilin
potassium) was dissolved in water (q.s) taken in
container-1 and stirred for an hour. In container-2 drug was dissolved in water
(q.s) and stirred for 5 min. Some quantity of citric
acid was dissolved in water (q.s) in container-3 and
it is poured in container-2. Stir for some time till clear solution is formed.
Now the clear solution is poured in container-1 under continuous stirring and
the remaining solution of citric acid was added to adjust pH 6. Stirring was
continued for another 2 hours. After 2 hours the complex in dispersion form was
formed. This dispersion was used as binder for Granulation.
B) Characterization of DPC
The
DPC solution was filtered through 0.4mm filter paper and filtrate was dried to
obtain complex in powder form for characterization.
1. Drug content76
Drug
content was determined by dissolving 30 mg of DPC in 100 mL
of simulated gastric fluid (SGF) of pH 1.2 buffer and analyzing appropriately
diluted sample by UV-Vis Spectrophotometer at λmax
254 nm using pH 1.2 buffer (SGF) as a blank.
2. In vitro taste evaluation
Taste
of DPC was studied in vitro by determining drug release in simulated salivary
fluid (SSF) (pH 6.8) to predict release in the human saliva. DPC, equivalent to
10 mg of API was placed in 10 mL of SSF and shaken
for 60 seconds. The amount of drug released was analyzed using UV
spectrophotometer at λmax 254 nm. The
ratio in which minimum amount of drug release takes place was taken as
optimized ratio for further study.
3. In vivo taste evaluation76
Taste evaluation was done in six healthy
human volunteers by holding DPC equivalent 10 mg of API sample in mouth for 5
to 10 sec, then were asked to spat out;
followed by rinsing the mouth by distilled water and the bitterness
level was then recorded. A numerical scale was used with the following values:
0 = tasteless, 0.5 =
very slight, 1.0=
slight, 1.5 =
slight to moderate, 2.0 =
moderate, 2.5 = moderate to strong, 3 =
strong, and 3+ =
very strong.
4. Molecular
Properties
Molecular
properties on complexation were studied by X- ray
powder diffraction (XRPD)76, DSC and infrared spectroscopy (IR). The
X-ray powder diffractograms of the API, Polacrilin potassium, physical mixture of API and Polacrilin potassium (1:3) and DPC were recorded using
X-ray diffractometer. Infrared (IR) spectra of these
samples were obtained by KBr disc method (Perkin
Elmer) in the range of 4000 to 400 cm-1 with resolution 1 cm-1.
2.4.1 Selection of Superdisintegrant
Before
formulation of tablets, the best superdisintegrant
among crosspovidone, Vivasol,
and sodium starch glycolate was screened out. Various
batches of tablets were prepared containing a blend of microcrystalline
cellulose (MCC) PH 105 and mannitol (1:1) as a diluent and superdisintegrant in
various concentrations (Table 7.8). The superdisintegrant
which gives least disintegration time was used for the final formulation of
tablets.
2.4.2 Formulation of Rapidly Disintegrating
Tablets (RDTs)
Rapidly disintegrating tablets
of API: Polacrilin potassium (1:3) complex were
prepared using Wet Granulation method incorporating cross-povidone
as superdisintegrant. The DPC solution was used for
granulation.
Intragranular part
Step: 1 Microcystalline cellulose (MCC PH 105),
Crosspovidone XL and Colloidal Silicon Dioxide (Aerosil 200) was passed through 30 mesh and blended in a
zip-lock polybag for 10 min.
Step: 2 Then Ferric oxide red colour was passed
through 100 mesh and was mixed geometrically with the previously passed
ingredients.
Step: 3 The mixed ingredients were loaded in RMG and dry mixed for 10 min.
Then it was granulated with DPC solution at slow impeller speed in 2 mins. If required some water quantity has been added till
end point of granulation is reached. Chopper was run for 30 sec at slow speed.
Step: 4 The granulated ingredients were passed through 30 mesh and loaded
in FBD. It was dried at 60-65°C inlet temperature till required LOD was
reached. The dried granules were passed through 30 mesh.
Extragranular part
Step: 5 Xylisorb, Crosspovidone
XL, Lactose fast flow 316, Mannitol SD-200 and Flavour (Tutti-frutti) were passed through 40 mesh.
Step: 6 The extragranular part was blended with intragranular
part for 10 min in Conta Blender. Then Magnesium Stearate was passed through 60 mesh and added in Conta Blender and blending was continued for another 5 min.
Step: 7 The lubricated blend was compressed in 8 station “B” compression
machine using 8mm round, FFBE punches.
2.4.3 Pre-compression
evaluation:
A) For un-lubricated
blend :
Sieve analysis :
Particle size, and especially particle size distribution are important to the compression
characteristics of a granulation. A granulation with too large a particle size and insufficient
fines is unable to fill the die cavities uniformly during compression and
the weight of the tablets fluctuates considerably. For colored granulations, the coarser
the granulation, the more mottled the final apparence
will be. On other hand if too many fines are present, tablet weight variation occurs because of flow problems. Therefore the first step is to determine
particle size distribution of the granulation using a series of stacked sieves of decreasing mesh openings.
B) For lubricated blend
Flow properties (Angle of repose)16
The frictional force between granules can
be measured by angle of repose. It is the maximum angle possible between the
surface of pile of granule and the horizontal plane. The angle of repose was
determined by the fixed funnel method. The accurately weighed granules were
taken in a funnel. The height of the funnel was adjusted in such a way that the
tip of the funnel just touched the apex of the heap of the granule. The
granules were allowed to flow through the funnel freely onto the surface. The
diameter of the granule cone was measured.
|
Table 2.4 Standard values of angle of repose (θ)
|
|
Flow Property
|
Angle of repose
|
|
Excellent
|
<25
|
|
Good
|
25-30
|
|
Passable*
|
30-40
|
|
Poor
|
37-45
|
|
Very poor
|
>45
|
* suggesting addition of glidants
for improving flow
The
angle of repose was calculated using the following equation.
…….(1)
Where ‘h’ and ‘r’ are the height and radius
respectively of the granule cone
Density
The
loose bulk density (LBD) and tapped bulk density (TBD) of drug, polymers and excipients were determined. Two grams of granules were
introduced into a 10 ml calibrated measuring cylinder. After noting down the
initial volume, the cylinder was allowed to fall under its own weight onto a
hard surface from the height of 2.5 cm at 2 seconds intervals. The tapping was
continued until no further change in volume was noted. LBD and TBD were
calculated using following equations.
LBD=
Weight of powder/ volume of the packing ……..(2)
TBD=
Weight of powder/ Tapped volume of the packing ……..(3)
Compressibility16
The compressibility index of all
ingredients was determined by following equations
Carr’s index =
[(TBD-LBD)]X100/TBD]……………..(4)
|
Table 2.5 Standard
values of Carr’s index
|
|
Carr’s Index
|
Type of flow
|
|
5-15
|
Excellent
|
|
12-16
|
Good
|
|
18-21
|
Fair to passable
|
|
23-35
|
Poor*
|
|
33-38
|
Very poor*
|
|
>40
|
Extremely poor*
|
* May
be improved by addition of glidants
Blend uniformity test:
When, lubricated granules were
ready for compression, different samples were taken and send for BUT
2.4.4 Post compression evaluation:
A) Hardness
Tablet
hardness (tablet crushing strength) is defined as the force required for
breaking a tablet in a diametric compression test. Tablets required a certain
amount of hardness or strength and resistance to the friability to withstand
mechanical shocks of manufacturing, packaging, and shipping. Hardness of the 6 tablets
from each batch was measured using hardness tester.
B) Friability
Friability test
was performed to assess the effect of friction and shocks, which may often
cause tablet to chip, cap or break. Roche friabilator
was used for the purpose. This device subjects a number of tablets to the
combined effect of abrasion and shock by utilizing a plastic chamber that
revolves at 25 rpm dropping the tablets at a distance of six inches with each
revolution. Pre-weighed 20 tablets were placed in the friabilator,
which was then operated for 100 revolutions. Tablets were dusted and reweighed.
Compressed tablets should not more than 1% of their weight.
C) Grittiness
As ODT tablet
disintegrates in the mouth, so grittiness is one of the important criteria to
be considered. The tablet should give a pleasant feel till it is in the mouth.
Tablets of all batches were tested for grittiness physically.
D) Weight variation16
USP weight
variation test is done by weighing 20 tablets individually; calculating the
average weight and comparing the individual tablet weight to the average weight
variation tolerance (Table 2.6).
|
Table 2.6 Weight variation tolerance
|
|
Average weight
of tablet (mg)
|
Maximum %
deviation allowed
|
|
130mg or less
|
10%
|
|
130mg to 324mg
|
7.5%
|
|
More than 324mg
|
5%
|
E) Content uniformity
The Assay was
performed by HPLC with UV detector.
Transfer 1 tablet into 100 ml volumetric flask. Add 75ml of diluents and
sonicate for 20 min until tablet disintegrates
completely. Make volume up to the mark with diluents and mix, filter solution
through 0.45 micron Millipore PVDF filter, collect the filtrate by discarding
few drops of filtrate. Inject blank and record the chromatogram. Perform five
injection of standard and record the chromatogram. Calculate the percentage
assay using appropriate formula.
F) Wetting Time and Water absorption ratio18
Wetting
time of tablet using disintegrants was determined
using the method reported by Bi et al. (1996) with slight modification. A piece
of tissue paper folded twice was kept in a culture dish (internal diameter 9
cm) containing ~10 mL of purified water. A tablet
having a small amount of amaranth powder on the upper surface was placed on the
tissue paper. The time required to develop a red color on the upper surface of
the tablet was recorded as the wetting time. The same procedure without
amaranth was followed for determining the water absorption ratio. The wetted
tablet was weighed and the water absorption ratio, R, was determined according
to the following equation,
……(6)
Where,
Wa
and Wb
are the weights before and after water absorption, respectively.
G) In vitro disintegration study
In
vitro disintegration time was measured using USP disintegration test
apparatus. Randomly six tablets were selected from each batch for
disintegration test. Disintegration test was performed without disc in
simulated gastric fluid, 900ml at 37±0.5 °C. The mean± standard deviation (SD)
of six tablets was calculated.
H) Dissolution
test
Apparatus : USP-II (Paddle)
RPM : 75
Temperature:
37°C ± 0.5°C
Time
: 45 min
2.4.5 Factors affecting disintegration time
(DT)
A) Effect of diluent
on disintegration time
Different
diluents were used in different proportion keeping lactose concentration fixed
in each batch to know the effect of diluents on the disintegration time.
Various diluents were used in the fixed concentration. The diluents used in
study were microcrystalline cellulose (Avicel PH101
and PH105), mannitol and lactose monohydrate.
B) Effect of superdisintegrant
The superdisintegrants SSG, CCS and CRP were used in the
concentration selected from above study which showed less DT. Different batches
F02, F03, F04 and F05 were planned using different types and different
concentration of this superdisintegrants in intra and
extra granular part of the formulation. The effect of it was checked on the
disintegration time of the tablets.
C) Effect of lubricants
The
lubricant Mg-stearate and Sodium stearyl
fumarate were used in the different concentration, to
check the effect of lubricant and its concentration on the disintegration time
of the tablets.
D) Effect of sweetener
The
batches F05, F06 and F07 were planned using sodium saccharin and aspartame as a
sweetener and evaluated for mouthfeel and taste.
E) Effect of colour
The
ferric oxide red colour was geometrically mixed with
the formulation and the batch F03 and F04 were evaluated for the effect of colour.
2.4.6 Compression challenge test
Ř Start, middle and end samples
during compression
Ř High speed, 40 rpm
Ř Low speed, 15 rpm
Ř High hardness, 7-10 kps
Ř Low hardness, 1-3 kps
Tablets were
evaluated with above parameters for weight variation, disintegration time and
dissolution.
2.4.7 Comparison with marketed ODT tablet
The optimized
batch was compared with marketed ODT tablet for hardness, thickness, weight of
tablet, DT and dissolution.
2.4.8 Stability studies of
optimized tablets
The
ICH Guidelines have established that long term stability testing should be done
at 25°C±2°C / 60%±5% RH; stress testing should be done at 40°C±2°C / 75%±5% RH
for 6 months. If significant change occurs at these stress conditions, then
the formulation should be tested at an
intermediate condition at 30°C±2°C /75%±5% RH. Table No shows different
temperatures and period of stability testing.
|
Table 2.7 ICH
guidelines for stability study
|
|
Study
|
Storage
condition
|
Minimum time
period covered by data at submission
|
|
Long term
|
25°C±2°C / 60%±5% RH
|
12 months
|
|
Intermediate
|
30°C±2°C / 65%±5% RH
|
6 months
|
|
Accelerated
|
40°C±2°C / 75%±5% RH
|
6 months
|
The
stability studies of the optimized tablets were carried out at 40○C
temperature and 75 % relative humidity (accelerated stability) in stability
chamber for three months. Tablets were withdrawn at 1, 2, 3 months intervals
and evaluated for disintegration time, hardness, drug content and in vitro
release.
3.0 RESULT AND DISCUSSION:
3.1 Preformulation study
3.1.1
Identification of drug
Identification of drug was carried out by
DSC and IR spectroscopy.
3.1.1.1
Differential Scanning Calorimetry
The thermogram of
API exhibited sharp endothermic peak at 1570C indicated melting
point which is reported in literature.
Figure 3.1: DSC
curve of API
3.1.1.2 IR Spectroscopy
An
infrared (IR) spectrum of API was taken by using the KBr
disk method (2 mg sample in 200 mg KBr). The scanning
range was 450 to 4000 cm -1 and the resolution was 1 cm -1
Figure
3.2: IR Spectra of API
|
Table 3.1: Peak and chemical group present in
IR spectrum of API
|
|
Peak(cm-1)
|
Chemical group
|
|
3345
|
N-H stretching vibrations of secondary amine
|
|
3053.59
|
Aromatic C-H stretch of pyridine ring
|
|
2941.30, 2918.65
|
C-H stretch of aliphatic amine
|
|
1287.06, 1328.98
|
C-N stretch of secondary aromatic amine
|
|
1634.34
|
N-H bending of aliphatic amine
|
|
1087.44
|
C-N stretch of aliphatic amine
|
|
1434.82,1478.47, 1585.03
|
C=C, C=N ring stretching of pyridine.
|
|
704.42
|
C-H bending of pyridine ring.
|
|
778.95, 795.55
|
Aliphatic C-Cl stretching
vibration.
|
3.2 Standard
calibration curves of API:
|
Table 3.2:
Standard calibration curve of API in pH 1.2 buffer
|
|
Sr.
No.
|
Concentration
(μg/ml)
|
Absorbance
|
|
1
|
2
|
0.074
|
|
2
|
4
|
0.151
|
|
3
|
6
|
0.218
|
|
4
|
8
|
0.330
|
|
5
|
10
|
0.365
|
|
6
|
12
|
0.443
|
|
7
|
14
|
0.519
|
Figure 3.3: Calibration curve of API in
pH 1.2 buffer
|
Table 3.3: Standard
calibration curve of API in pH 4.5 buffer
|
|
Sr. No.
|
Concentration (μg/ml)
|
Absorbance
|
|
1
|
2
|
0.082
|
|
2
|
4
|
0.165
|
|
3
|
6
|
0.229
|
|
4
|
8
|
0.303
|
|
5
|
10
|
0.376
|
|
6
|
12
|
0.452
|
|
7
|
14
|
0.53
|
Figure 3.4: Calibration curve of API in pH 4.5 buffer.
|
Table 3.4: Standard
calibration curve of API in pH 6.8 buffer
|
|
Sr. No.
|
Concentration (μg/ml)
|
Absorbance
|
|
1
|
2
|
0.082
|
|
2
|
4
|
0.165
|
|
3
|
6
|
0.229
|
|
4
|
8
|
0.303
|
|
5
|
10
|
0.376
|
|
6
|
12
|
0.452
|
|
7
|
14
|
0.53
|
Figure 3.5: Calibration curve of API in pH 6.8 buffer.
6.3 Drug and
polymer interaction study
A) IR Spectroscopy
IR spectras were recorded for API, physical mixture and DPC
(“see Figure 6-9”). Pure API spectra
showed sharp characteristic peaks at 3345, 2941.3, 1287.06, 1634.34, 1087.44,
1434.82, 1478.47, 1585.03, 704.42 cm-1. All the above characteristic
peaks of drug appears in the spectra of physical mixture at the same wave
number indicating no modification or interaction between drug and the polymer.
Figure 3.6: IR
spectra of API
Figure 3.7: IR
spectra of Polacrilin potassium
Figure 3.8: IR
spectra of physical mixture.
B) Differential
Scanning Calorimetry
The
DSC thermograms of plain drug, polymer and drug
polymer physical mixture are shown in figure 10-13. The thermogram of
API exhibited sharp endothermic peak at 1570C indicated melting
point which is reported in literature. Characteristic peak of API was well
recognized in the drug polymer physical mixture. Thus, there observed no interaction between
API and polacrilin potassium. While in case of the
DPC there observed shift in the peak 2180C, that indicates there is
complex was formed between the drug and polymer.
Figure
3.9: DSC curve of API
Figure 3.10: DSC
curve of Polacrilin potassium
Figure 3.11: DSC
curve of drug-polymer physical mixture
3.4
Characterization of DPC
3.4.1 Drug content
Percentage drug loading in DPCs was found
from 98.0 to 99.40. The results are shown in table 6.5.
|
Table 6.5:
Percentage drug content in DPC
|
|
Sr.no
|
Drug-polymer
ratio
|
% Drug content*
|
|
1
|
1: 1
|
98.89±0.56
|
|
2
|
1: 2
|
98.96±0.18
|
|
3
|
1: 3
|
99.12±0.34
|
|
* Results are the mean of three observations ± SD
|
3.4.2 In Vitro
Taste Evaluation
Drug release was observed in SSF from
complexes with the drug-polymer ratios of 1:1, 1:2 and 1:3 were found to be
1.34±0.32, 0.89±0.12 and 0.43±0.42 respectively. Thus 1:3 ratios, which showed
lesser amount of % drug release, was considered the optimal concentration of
DPC with significant masking of bitter taste.
|
Table 3.6: Drug
release of DPC in pH 6.8 buffer (SSF)
|
|
Sr. no.
|
Drug-polymer
ratio
|
% drug release
in pH 6.8 buffer
|
|
1
|
1: 1
|
1.34±0.32
|
|
2
|
1: 2
|
0.89±0.12
|
|
3
|
1: 3
|
0.43±0.42
|
3.4.3 In Vivo
taste evaluation
Taste
evaluation of DPC (1:3) by human volunteers revealed considerable taste masking
with the degree of bitterness below threshold value (0.5) within 10 seconds,
whereas, API was rated intensely bitter with a score of +3 for 10 seconds. A
numerical scale was used with the following values: 0 =
tasteless, 0.5 = very slight, 1.0=
slight, 1.5 =
slight to moderate, 2.0 =
moderate, 2.5 = moderate to strong, 3 =
strong, and 3+ =
very strong.
|
Table 3.7: Bitterness
evaluation of DPC by taste panel
|
|
Volunteer
|
1
|
2
|
3
|
4
|
5
|
6
|
|
Pure drug
|
3+
|
3+
|
3+
|
3+
|
3+
|
3+
|
|
DPC
1:1
1:2
1:3
|
2
1
0.5
|
2
1
0
|
3
1
0
|
2
1
0.5
|
2
1
0
|
2
1
0.5
|
3.4.4 Molecular properties:
a) The IR spectrum of DPC was found to
exhibit some significant difference in the characteristic peaks of API,
revealing modification of the drug environment. The dimuniation
of some peaks of API in DPC i.e. aliphatic secondary amine N-H stretching and
bending indicates that there is an interaction.
Figure 3.12: IR
spectra of DPC (Drug-polymer complex).
Figure 3.13: IR
Spectra Overlay
b) In case of the DSC of DPC there observed
shift in the peak 2180C, that indicates there is complex was formed
between the drug and polymer.
Figure 3.14: DSC
curve of drug-polymer complex
Figure 3.15: DSC Curve Overlay
c) The X-ray diffractogram
of API confirms its crystalline nature, as evidenced from the number of sharp
and intense peaks (Figure 7.16). However, the diffraction pattern of DPC
represents disappearance of crystalline peaks of drug. These findings suggest
the formation of a new solid phase with a lower degree of crystallinity
due to complexation.
Figure 3.16: X-ray
powder diffractogram of API
Figure 3.17: X-ray
powder diffractogram of Drug-polymer complex
3.5 Selection of Superdisintegrant
Initially
tablets containing superdisintegrants in the
concentrations 5, 8, 10, and 12% w/w were tested for disintegration time. From
table 7.8, it was concluded that the disintegration time increases with
increase in concentration of sodium starch glycolate
in the tablets. It indicates that increase in the concentration of sodium
starch glycolate had a negative effect on the
disintegration of tablets. It was observed that at higher concentration,
formation of viscous gel layer by sodium starch glycolate
might have formed the thick barrier to the further penetration of the disintegration
medium and hindered the disintegration of tablets. In case of tablets
containing crospovidone, increasing concentration of crospovidone, the disintegration time of tablets decreases.
It was same observed that the disintegration time of tablets decreased with
increase in the concentration of the crosscarmellose
sodium. Based on the disintegration results (Table 7.8), the investigated superdisintegrants can be ranked according to their ability
to swell in water as crospovidone > croscarmellose sodium >sodium starch glycolate.
On the basis of the results obtained in the preliminary screening studies, the
batch containing crospovidone showed fastest
disintegration. Hence, crosspovidone was selected for
the formulation of ODTs.
|
Table 3.8: Disintegration time
of different superdisintegrants
|
|
Batch
|
Disintegrant
|
Disintegrant
% w/w
|
% Diluent
w/w *
|
Disintegration time(sec)
|
|
FD1
|
SSG
|
5
|
75
|
34±0.44
|
|
FD2
|
SSG
|
8
|
72
|
28±0.12
|
|
FD3
|
SSG
|
10
|
70
|
31±0.15
|
|
FD4
|
SSG
|
12
|
68
|
33±0.32
|
|
FD5
|
CCS
|
5
|
75
|
30±0.25
|
|
FD6
|
CCS
|
8
|
72
|
25±0.17
|
|
FD7
|
CCS
|
10
|
70
|
23±0.20
|
|
FD8
|
CCS
|
12
|
68
|
20±0.15
|
|
FD9
|
CRP
|
5
|
75
|
26±0.65
|
|
FD10
|
CRP
|
8
|
72
|
20±0.23
|
|
FD11
|
CRP
|
10
|
70
|
18±0.13
|
|
FD12
|
CRP
|
12
|
68
|
15±0.15
|
SSG indicates (Sodium starch glycolate);
CCS, vivasol (Croscarmellose
sodium); CRP (Crosspovidone) and 1:1 mixture of
microcrystalline cellulose and mannitol.
3.6 Pre-compression evaluation
A) For un-lubricated blend :
Sieve analysis
|
Table 3.9: Sieve analysis of
un-lubricated blend
|
|
Test
|
Mesh
|
F01
|
F02
|
F03
|
F06
|
F08
|
|
Particle size distribution
(Sieve analysis)
|
|
0.0
|
0.0
|
0.0
|
0.0
|
0.0
|
|
30 #
|
3.0
|
3.2
|
2.8
|
2.6
|
4.2
|
|
60 #
|
7.0
|
6.5
|
5.2
|
5.4
|
7.6
|
|
80 #
|
5.2
|
4.8
|
3.4
|
3.4
|
10.1
|
|
|
8.1
|
8.5
|
7.0
|
7.1
|
12.0
|
|
Fines
|
76.7
|
77.0
|
81.6
|
81.5
|
66.1
|
|
Table 3.21: Dissolution data of batch F11 in pH 1.2 buffer
|
|
3 min
|
6 min
|
10 min
|
15 min
|
|
89.6±1.7
|
95.2±1.6
|
99.1±2.3
|
101.2±1.9
|
As pre-compression and post-compression
parameters of batch F11 were found within acceptable limits, compression
challenge tests were planned.
3.11 Compression
challenge test:
3.11.1 Compression time challenge test:
|
Table 3.22: Compression time challenge
test for batch F11
|
Test
|
Sampling
time
|
|
Start
|
Middle
|
End
|
|
Thickness
|
3.1±0.2
|
3.1±0.4
|
3.2±0.1
|
|
Weight of 10 tablets
|
171.22
|
172.32
|
170.36
|
|
Hardness
|
4.5
|
4.8
|
4.2
|
|
%Friability
|
0.42
|
0.36
|
0.53
|
|
DT
|
15.56
|
13.22
|
14.6
|
|
CU
|
100.4
|
100.5
|
101.0
|
|
Assay
|
98.4
|
98.2
|
98.5
|
|
Dissolution
|
10 min
15 min
|
98.8
101.3
|
99.5
101.2
|
99.3
100.4
|
|
|
|
|
|
3.11.2 Compression
speed challenge test:
|
Table 3.23: Compression speed challenge
test for batch F11
|
Test
|
Compression
machine speed
|
|
Low
Speed:
15
RPM
|
Normal
Speed: 30RPM
|
High
Speed:
45
RPM
|
|
Thickness
|
3.2
|
3.1
|
3.2
|
|
Wt
of tablets
|
171.3
|
170.8
|
172.2
|
|
Hardness
|
.4.6
|
4.3
|
4.7
|
|
DT
|
17.4
|
14.5
|
16.1
|
|
CU
|
100.4
|
101.4
|
101.4
|
3.11.3 Hardness challenge test:
|
Table 3.24:
Hardness challenge test for batch F11
|
Test
|
Hardness
|
|
Low
hardness:
1-3
kps
|
Normal
hardness:
3-5
kps
|
High
hardness:
7-10
kps
|
|
Thickness
|
3.1
|
3.2
|
3.2
|
|
Weight
of 10 tablets
|
172.3
|
172.1
|
170.8
|
|
DT
|
11.8
|
14.5
|
19.7
|
|
Friability
|
0.83
|
0.45
|
0.32
|
|
Dissolution
|
3 min
6 min
10
min
15
min
|
95.5±1.0
101.2±1.1
100.3±1.1
101.2±0.6
|
89.6±1.7
96.2±1.6
99.1±2.3
100.2±1.9
|
85.5±0.8
90.8±1.0
96.7±1.1
99.8±1.5
|
|
|
|
|
|
As above results, compression
challenge tests were found to be satisfactory and within the acceptable limits,
so batch F11 was considered as an optimized batch.
3.12 Dissolution of optimized batch F11 in other media
As per EP, dissolution data of
optimized batch in three different media are required. On the basis of
solubility of API, 4.5 pH acetate buffer and 6.8 pH phosphate buffer were used
as other two dissolution media.
|
Table 3.25: Dissolution data of batch F11
|
|
Dissolution media
|
Sampling time
|
|
3 min
|
6 min
|
10 min
|
15 min
|
|
4.5 pH acetate buffer
|
41.4±7.6
|
79.2±6.8
|
95.1±4.5
|
100.4±4.2
|
|
6.8 pH phosphate buffer
|
19.6±1.4
|
29.2±1.5
|
38.0±1.3
|
43.6±1.7
|
3.13 Comparison
of optimized formulated tablet with marketed tablet
From the results of the tests,
tablets of batch F11 were considered to posses the best physical properties
accompanied with quick disintegration and, therefore, tested and compared with
the marketed ODT tablet for dissolution. The dissolution study of the optimized
tablet revealed rapid release of drug (t90 of 180 sec.) in SGF
compared with marketed formulation, which had a t90 of 360 sec.
(Figure 7.21). From in vitro dissolution data it was concluded that there may
be rapid absorption of the drug from F11 formulation as compared with the
marketed ODT tablet.
|
Table 3.26: Comparison of Optimized tablet (F11) with marketed
ODT tablet
|
Test
|
Optimized batch F11
|
Marketed tablet
|
|
Thickness
|
3.2
|
2.9
|
|
Weight of tablet
|
170
|
170
|
|
DT (sec)
|
14.5
|
16.6
|
|
Hardness
|
4.3
|
Nil
|
|
Table 3.27: Comparison of dissolution of F11 with marketed ODT
tablet
|
|
|
Sampling time
|
1.2 pH 0.1N HCl buffer
|
4.5 pH acetate buffer
|
6.8 pH phosphate buffer
|
|
Marketed tablet
|
3 min
6 min
10 min
15 min
|
83.3±4.2
90.2±3.8
96.1±3.9
99.3±4.4
|
41.4±7.6
79.2±6.8
95.1±4.5
100.4±4.2
|
16.2±0.7
59.0±3.4
68.5±3.3
79.2±2.6
|
|
Optimized tablet
|
3 min
6 min
10 min
15 min
|
89.6±1.7
95.2±1.6
99.1±2.3
101.2±1.9
|
41.4±2.9
72.2±3.7
86.1±1.9
94.0±2.3
|
19.6±1.4
29.4±1.5
38.0±1.3
43.6±1.7
|
Figure 3.21: Dissolution profiles of F11 and marketed tablet in pH 1.2 buffer
Figure 3.22: Dissolution profiles of F11 and marketed tablet in pH 4.5 buffer
Figure 3.23: Dissolution profiles of F11 and marketed tablet in pH 6.8 buffer
The dissolution data of
optimized tablet matches with the marketed tablet for 1.2 pH 0.1N HCl buffer and 4.5 pH acetate buffer while for 6.8 pH
phosphate buffer it does not matches. So, the optimized batch was send for
further bio-study. The F11 batch was charged for accelerated stability.
3.14 Stability of the tablets
A)
Formulation showing minimum disintegration time was selected for stability
studies. According to ICH guidelines, selected formulation (F11) was stored at
40○C temperature and 75 % relative humidity (RH) for a period
of 3 months. Formulation was evaluated at periodical intervals of one month for
drug content; hardness, in vitro disintegration time and physical appearance
(“see Table 7.28”). Evaluation parameters do not show any major difference and
all are in acceptable limits.
|
Table 3.28: Evaluation parameters of
stability batch after 3 months
|
|
Formulation Code
|
Parameters
|
Storage time
|
|
0 month
|
1 month
|
2 month
|
3 month
|
|
F11
|
Hardness,
kps
|
4.34
±0.12
|
4.04
±0.21
|
3.60
±0.18
|
3.52
±0.13
|
|
Drug
content, %
|
101.34
±0.16
|
101.34
±0.21
|
101.32
±0.18
|
101.30
±0.33
|
|
In
vitro disintegration time, sec.
|
14.00
± 32
|
14.12
±0.12
|
12.10
±0.17
|
11.00
±0.22
|
|
Physical
appearance
|
No discolor- ation
|
No discolor-ation
|
No discolor-ation
|
No discolor- ation
|
B) Comparison of dissolution of
optimized tablet (F11) before and after the tablets was charged to the
stability study.
|
Table 3.29:
Comparison of dissolution of optimized tablet (F11) of initial and after 3
months
|
|
Time(min)
|
Initial
|
After 3 months
|
|
3
|
89.6±1.7
|
83.3±1.2
|
|
6
|
95.2±1.6
|
90.2±1.4
|
|
10
|
99.1±2.3
|
94.0±1.3
|
|
15
|
101.2±1.9
|
96.0±2.1
|
Figure 3.24: Comparison of dissolution profile before and after 3
month stability of optimized batch F11.
4.0 SUMMARY:
4.1 Summary
In this investigation, Polacrilin
potassium (Amberlite IRP-88) was used to mask the
bitter taste of drug. It is a cation exchange resin
[2-Methyl-2-propenoic acid polymer with divinylbenzene,
potassium salt]. Bitter drugs can get adsorbed onto ion exchange resin to form
complexes which is non-bitter. The complex of drug and resin does not break at
pH 6.7 of saliva with cation concentration of 40 meq/l. But at high concentration of cation
of stomach and at pH 1-3 free drug is immediately released. In this study, weak
cation exchange resin, Amberlite,
IRP-88 was used to mask the taste of bitter API.
Present study was aimed to mask the bitter
taste of the API by complexing the drug with Amberlite IRP-88. API and Amberlite
IRP-88 complexes were prepared using the ion-exchange method. The different
drugs to polymer ratios (1:1 to 1:3) were used. The prepared DPC were evaluated
for drug content, in vitro and in vivo taste evaluation, and physical
properties. On the basis of this evaluation drug to polymer ratio of 1:3 was
optimized. Further it was evaluated for molecular properties by IR
Spectroscopy, Differential Scanning Calorimetry and
X-ray powder diffractogram. From the result of above
three evaluation it was concluded that the complex was successfully formed
between drug and the polymer. The optimized DPC ratio then incorporated into
the orally disintegrating tablets.
Moreover here API contains amine group so
it has tendency to undergo Maillard reaction with
lactose. As lactose is most widely used as filler, formulator is restricted in
choosing the excipients. So by complexation
of API with cation exchange resin we had not exposed
of amine group of API with other excipients used and
the Maillard reaction was avoiding, thus offering flexibility to the formulator to use a wide range of excipients. These tablets were evaluated for physical
properties, drug content, in-vitro DT and dissolution study.
From the results of above evaluation
studies, formulation F11 was optimized and kept for stability studies carried
out at 40°C ± 5°C and 75 % RH ± 5 % RH for 90 days in order to know the
influence of temperature and relative humidity on hardness, physical
appearance, in-vitro disintegration time and dissolution. These studies showed that it is stable
formulation.
5.0 CONCLUSION:
The
study conclusively demonstrated significant taste masking of API and rapid
disintegration and dissolution of ODT. Taste masked ODTs of API are more
palatable form without need of water during administration, helpful to the
patients with gastroparesis, having symptoms of
vomiting and fullness of GIT. Thus, the patient-friendly dosage form of
intensely bitter API which is useful one especially for pediatric, geriatric,
bedridden, noncooperative and gastroparesis
patients can be successfully formulated using this technology. After stability
study no browning or discoloration with API was observed. Optimized batches
have been also compared with marketed product, which give satisfactory results.
Hence, the formula is optimized.
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