INTERNATIONAL JOURNAL OF PHARMACEUTICAL … 995.pdf · Preformulation study of paracetamol...

Research Article CODEN: IJPRNK ISSN: 2277-8713 Hemant Vyas, IJPRBS, 2015; Volume 4(3): 415-447 IJPRBS

Available Online at www.ijprbs.com 415

AN OPTIMIZATION OF FOAM GRANULATION PROCESS FOR PREPARATION OF PARACETEMOL TABLETS AS MODEL DRUG

HEMANT VYAS, B. P. NAGORI, R. ISHRANI, M. P. SINGH

Dept of Pharmaceutics, Lachoo Memorial College of Science & Technology, Pharmacy Wing, Jodhpur, Rajasthan.

Accepted Date: 23/06/2015; Published Date: 27/06/2015

Abstract: The aim of this study was to compare conventional wet granulation technique with novel foam granulation technique. In conventional wet granulation method the binder solution either sprayed or poured on the powder bed. This may cause of over wetting. The spraying of binder solution requires spray nozzles. Selection of spray nozzle, distance between nozzle and powder mix, binder solution spray rate are some critical factors which may cause of variations in granulation process. Recently an innovative technology for adding the binder to powder mix is under investigation. This novel technique involves addition of binder in the form of foam to the powder mix. The critical issue in the foam granulation is the quality of foam which is assessed based on- foam quality, foam stability, specific penetration time and nucleation ratio. In this dissertation work four semi synthetic cellulosic polymers (HPMC, HEC, HPC and sod. CMC) were used to generate the foam. The prepared foam batches were evaluated for foam quality, foam stability, specific penetration time and nucleation ratio. The preference was given to foam stability and foam quality for selection of foam batches. The 3% w/v HPMC, 4% w/v HEC, 3%w/v HPC and 1% sod. CMC batches were selected for preparation of granules and tablets. The prepared granules were evaluated for carr’s index, hausner’s ratio, angle of repose, moisture content, drying time and size distribution. The flow properties of granules of wet granulation batch, A, B, and C were excellent while the flow properties of batch D, E and F were good. The larger sized granules (1195 and >1680 µm) were prepared when wet granulation was used in comparison to foam granulation. This implies that more energy and time would be requiring reducing the size of larger granules. The foam granulation batches showed significantly less drying time and moisture content than the wet granulation batch. It means that the foam granulation method requires less processing time than wet granulation batch due to less drying time. The tablets were prepared using wet granulation and foam granulation methods. The optimized batch C was used for comparison. The tablets prepared using wet granulation and foam granulation were evaluated for weight variation, thickness, hardness, drug content, disintegration time and dissolution. The tablets prepared using both techniques showed acceptable characteristics. The tablets of both batches were subjected to accelerated stability testing. The tablets of both batches showed good stability.

Keywords: Foam Granulation, Paracetemol, Model Drug

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Hemant Vyas, IJPRBS, 2015; Volume 4(3): 415-447



INTRODUCTION

Granulation

Granulation is a vital unit operation in the production of pharmaceutical oral dosage forms.

Granulation is a particle design process that involves collecting of particles together by creating

bonds between them. Bonds are formed by compression or by using a binding agent1.

Granulation techniques

Several granulation techniques have been developed which include:

A. Conventional methods

i. Dry granulation

ii. Wet granulation

a. High-shear wet granulation

b. Low-shear wet granulation

B. Novel/advanced methods

i Moisture activated dry granulation

ii Thermal adhesion granulation

iii Pneumatic dry granulation

iv Melt/thermoplastic granulation

v Fluidized bed granulation

vi Extrusion - Spheronization granulation

vii Spray drying granulation

viii Freeze granulation

ix Steam granulation

x Foam binder granulation



MATERIALS

Detail of drug (paracetamol)

Drug Name Supp. /Mfg. By Batch No. Mfg. Date Exp. Date

Paracetamol Workhardt Research Centtre, Aurangabad

1000369 Nov 2011 Oct 2015

Chemicals / Reagents used

All the chemicals used were of IP/AR or equivalent grade.

S. No. Name Manufacturer/Supplier

1. Potassium di hydrogen phosphate

Loba Chemie Pvt. Ltd., Mumbai

2. Sodium hydroxide Loba Chemie Pvt. Ltd.,Mumbai

3 HPMC E15 plv Qualigens Fine Chemicals Pvt. Ltd., Mumbai

4. HEC S.D. Fine Chemical Ltd., Mumbai

5. Sod. CMC Ases Chemical Works, Jodhpur

6 HPC Workhardt Research Centtre, Aurangabad

7. Microcrystalline cellulose Qualigens Fine Chemicals Pvt. Ltd., Mumbai

8. Sodium lauryal sulphate S.D. Fine Chemical Ltd., Mumbai

9. Lactose S.D. Fine Chemical Ltd., Mumbai

10 Deionised water In house laboratory.

Preformulation study of paracetamol

Solubility determination

Solubility was determined by using shake flask method. In this paracetamol was added in

surplus to medium phosphate buffer pH 6.8 and shaken for 6 hrs. The saturation was confirmed

by observation of the presence of un-dissolved paracetamol. After filtration of the slurry a



sample for analysis was taken. Sample was analyzed by using U.V. spectrophotometer. The

solubility of paracetamol is shown in Table-3.

Table-3 Solubility of paracetamol

Medium/Solvent Solubility

(mg/ml)

Volume of the medium required to dissolve single dose (200mg)

of paracetamol

(ml)

Parts of solvent required for 1 part of paracetamol

Phosphate buffer PH 6.8

42.6 4.68 23.47

RESULTS AND DISCUSSION

Solubility is determined for selection of appropriate solvent for formulation development, for

selection of dissolution medium having acidic or alkaline pH or for extraction of drug for drug

content estimation. Solubility of paracetamol was determined in phosphate buffer pH 6.8 and it

was found that volume of phosphate buffer pH 6.8 required to dissolve the dose of

paracetamol in one tablet is 4.68ml. This implies that phosphate buffer pH 6.8 can very well be

used as dissolution medium and also for drug content determination. Further as per Indian

Pharmacopoeia, paracetamol was found to be- soluble i.e. 1 part of paracetamol dissolved in

10-100ml parts (23.47 parts) of solvent (Appendix Table-A1).

5.1.2. Melting point

Melting point of paracetamol was carried out by capillary method using the melting point

apparatus. The observed and reported melting point of paracetamol are given below in Table-4

Table-4 Melting point of paracetamol

Drug Name Reported melting point

(ºC)

Observed melting point (ºC)

Paracetamol 170 C 168C




Melting point determination is used to assess purity of drug sample. As the observed melting

point of paracetamol is found to be 2oC less than the reported melting point, so it can be

concluded that drug sample contains some impurities.

5.1.3. Preparation of standard curve of paracetamol

a. Determination of wavelength of maximum absorbance for paracetamol

The stock solution (100ppm) of paracetamol was prepared in phosphate buffer pH 6.8. The

10ml of this stock solution was taken in a 100ml volumetric flask and diluted up to 100ml with

phosphate buffer. This 10ppm solution was scanned in range 400-200nm by using UV-Visible

spectrophotometer. Spectrum of paracetamol is shown in Figure-10.


The maximum absorbance was found to be 0.657 at 242.4nm. So the λmax was found to

be242.4nm.

Standard curve

100mg of paracetamol was dissolved in 100ml of phosphate buffer pH 6.8 to prepare 1000ppm

stock solution. 10ml of this solution was diluted up to 100ml to prepare 100ppm stock solution.

Further 20ml of this stock solution was diluted up to 100ml to prepare 20ppm solution. From

this, aliquots 1ml, 2ml, 3ml……..9ml were taken in 9 different 10ml volumetric flasks and

diluted up to 10ml to prepare dilutions of 2,4,6…18ppm. The prepared dilutions were analyzed

by using UV-Visible spectrophotometer at 242.4nm. The absorbances are shown in Table-5 and

the standard curve in Fig. 11

Abs.

Figure-10 UV spectrum of paracetamol in phosphate buffer pH 6.8 (10ppm)

242.4 nm



Table-5 Data for standard curve of paracetamol in phosphate buffer pH 6.8

S. no. Concentration (µg/ml)

Absorbance

A1 A2 A3 Absorbance

1. 2 0.138 0.1378 0.1378 0.1379

2. 4 0.2491 0.2492 0.2493 0.2492

3. 6 0.3876 0.3877 0.3875 0.3876

4. 8 0.5073 0.5071 0.5071 0.5072

5. 10 0.634 0.6343 0.6342 0.6342

6. 12 0.7527 0.753 0.7532 0.753

7. 14 0.8776 0.8767 0.8764 0.8769

8. 16 0.9983 0.9982 0.9981 0.9982

9. 18 1.1283 1.1285 1.1277 1.1282

Figure-11 Standard curve of paracetamol in phosphate buffer pH 6.8

RESULT AND DISCUSSION

The calibration curve of drug showed linearity in concentration range of 2-18µg/ml, since the

regression co-efficient (r2) was 0.999 and the equation in terms of, y= mx + c

Absorbance = slope * concentration + intercept

Was, y = 0.062x + 0.008

0

0.2

0.4

0.6

0.8

1

1.2

0 5 10 15 20

Concentration of Paracetamol (µg/ml)

Ab

s.



∴ Concentration = (Absorbance) – 0.008 / 0.062

(At λmax = 242.4 nm)

5.2 Generation of foam and its optimization

5.2.1 Foam generation process

Foam was prepared by using Silverson mixer. 100ml of distilled water was taken in a 250ml of

beaker, and 1gm of sodium lauryl sulphate was added. The mixer was operated at medium

speeds for five minutes after that the stabilizer (HPMC/ HEC/ HPC/ sod. CMC), in different

amount was (1%/2%/3%/4%) added. The mixer was further operated for 25 minutes. The

prepared foam batches with different polymers are shown in Table-6.

Table-6 Foam batches prepared with different polymers

P o l y m e r s (% w/w)

Batches

A B C D A 1 A 2 A 3 A 4 B 1 B 2 B 3 B 4 C 1 C 2 C 3 C 4 D 1 D 2 D 3 D 4

HEC 1 2 3 4 _ _ _ _ _ _ _ _ _ _ _ _ HPMC _ _ _ _ 1 2 3 4 _ _ _ _ _ _ _ _ HPC _ _ _ _ _ _ _ _ 1 2 3 4 _ _ _ _ Sod. CMC _ _ _ _ _ _ _ _ _ _ _ _ 1 2 3 4 Sodium lauryl sulphate

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Water(qs) 100 ml for each batch

5.2.2. Evaluation of foam batches

i. Foam stability

The foam stability was studied by filling the foam in a 10ml measuring cylinder. The water

drained at different time periods was determined. The stability profile of foam is shown in

Table-7. The water drained at different time intervals for 3% HPMC batch is depicted in Figure-

12.



Table-7 Stability profile of foam batches

Batches Volume of drained water at different time intervals (ml)

5 min. 15min. 25min. 35min. 45min.

HPMC 1% 0.4 0.5 0.5 0.6 0.6

2% 0.1 0.3 0.5 0.5 0.5 3% 0.0 0.3 0.5 0.7 0.8 4% 0.0 0.1 0.2 0.4 0.5

HEC 1% 0.1 0.1 0.1 0.1 0.1 2% 0.2 0.5 0.5 0.5 0.6 3% 0.2 0.5 0.5 0.6 0.6 4% 0.2 0.8 1.1 1.2 1.3

HPC 1% 0.3 0.4 0.5 0.5 0.5 2% 0.3 0.3 0.4 0.4 0.4 3% 0.8 0.9 0.9 0.9 0.9 4% 0.5 0.7 0.8 0.8 0.8

Sod. CMC 1% 0.3 0.8 1.1 1.2 1.2 2% 0.0 0.1 0.2 0.3 0.4 3% 0.0 0.2 0.4 0.7 1.0 4% 0.0 0.0 0.0 0.0 0.1

Initial (0.0 ml) After 1 hr (8 ml) After 1:30 hr (10 ml)

Figure-12 Photograph depicting stability of foam (HPMC 3%w/v)




The stability of foam is important during the transfer of foam from foam generator though a

pipe to the high shear granulator so the foam of good stability should be selected for this

purpose.

HPMC batches: Foam prepared using 4% HPMC showed the maximum stability while foam

prepared using 1% HPMC showed minimum stability.

HEC batches: Foam prepared using 1% HEC formed dry foam. Foam prepared using 2% HEC

formed the most stable foam while foam prepared using 4% HEC formed the least stable foams.

These foam released very high volume of liquid so can be used for granulation easily.

HPC batches: Foam prepared using 2% HPC formed the most stable foam while foam prepared

using 3% HPC formed the foam of least stability.

Sodium CMC batches: Foam prepared using 4% Sod. CMC formed the most stable foam while

foam prepared using 1% Sodium CMC formed the least stable foam.

ii. . Foam quality

The foam quality was determined by using modified Tan and Hapgood method. The 10ml of

foam was filled in a 50ml measuring cylinder. After 10 minutes the volume of drained water

was noted and the foam quality was determined by using following formula-

Vg

FQ =

Vg + VL

Where-

FQ = foam quality

Vg = volume of air

VL = volume of liquid drained



The foams of different quality are shown in Figure-13.

Foam of 88% quality Foam of 93% quality Foam of 95% quality

Figure-13 Photograph depicting foams of different quality

iii. Nucleation ratio

1gm foam was weighed in a Petridish; 1gm of lactose was weighed in a 100ml beaker. The foam

was added in small increments to the lactose powder until a wet mass was formed. The

Petridish was weighed again; the difference in initial and final weight was taken to determine

the used amount of foam.

Nucleation ratio= 1000mg of lactose/amount of foam used in mg

The nucleation of lactose is depicted in Figure-14

Figure-14 Nucleation during foam granulation

iii. Specific penetration time

Lactose was filled in a 10ml measuring cylinder up to 2ml by tapping the measuring cylinder

until there was no further change in volume. 1ml foam was filled in the same measuring

cylinder. The time required for the foam to penetrate the lactose bed up to 0.6ml was noted.

The foam quality, nucleation ratio, and specific penetration time are shown in Table-8



Table 8: Foam quality, nucleation ratio and specific penetration time of different foam

batches

*Data indicates mean± SD of triplicate data


All the evaluation parameters (Table-8) were considered for selection of foam of optimum

performance. The priority was given to the stability data followed by % quality, nucleation ratio

and the specific penetration time. The foam stability was studied up to a period of 1 hr 30 min.

and the volume of binder solution drained at 45min.was taken as prime criteria for the

selection of the foam batch. The higher the volume drained by foam of appropriate quality

Parameters Batches

Foam Quality* (%)

Nucleation ratio*

Specific penetration time* (sec.)

Volume drained at 45 min. (ml)

HPMC 1% 96.0±0.20 4.098±0.01 300±5.00 0.6 2% 90.0±0.78 3.55±0.08 600±4.00 0.5 3% 95.7±0.71 2.46±0.05 72±8.00 0.8 4% 99.0±0.45 3.086±0.03 1500±12.00 0.5

HEC 1% 93.0±0.39 3.703±0.07 300±7.00 0.1 2% 95.0±0.37 4.184±0.11 516±11.00 0.6

3% 88.0±0.85 4.273±0.15 630±10.00 0.6 4% 88.0±0.54 4.854±0.12 506±4.00 1.3

Parameters Batches

Foam Quality* (%)

Nucleation ratio*

Specific penetration time* (sec.)

Volume drained at 45 min. (ml)

HPC 1% 92.0±0.65 3.184±0.09 68±4.00 0.5 2% 88.0±0.51 4.166±0.11 45±2.00 0.4 3% 93.0±0.29 3.412±0.13 50±3.00 0.9 4% 87.0±0.73 3.759±0.02 65±2.00 0.8

Sod. CMC 1% 86.0±0.24 4.580±0.04 55±5.00 1.2 2% 99.0±0.56 5.290±0.02 675±14.00 0.4 3% The 3% and 4% concentration did not form the foam.

4%



better is foam performance. Based on these four parameters the four foam batches were

optimized.

HPMC batches: Foam prepared using 3% HPMC resulted in maximum drained volume at 45min.

and the % quality of 95.7%.

HEC batches: Foam prepared using 4% HEC had 88% foam quality and 1.3ml drained volume at

45min.

HPC batches: Foam prepared using 3% HPC had 93% foam quality and 0.9ml drained volume at

45min.

Sod. CMC batches: Foam prepared using 1% Sod. CMC had 86% foam quality and 1.2ml drained

volume at 45min.

5.3. Preparation of paracetamol granules using foam granulation and wet granulation

techniques

The formulation composition used for preparation of paracetamol granules is presented in

Table-9

Table-9 Formulation composition of paracetamol tablets using wet and foam granulation

methods

Batch

Material

Wet A B C D E F

Paracetamol 80% 80% 80% 80% 80% 80% 80%

MCC 17% 17% 17% 17% 17% 17% 17%

HPMC (powder form)

3% 2% 2% - - - -

Lactose - 1% 1% 3% 3% 3% 3%

Water 6ml* - 5.4ml* - - - -

1% HPMC foam - 18ml* 1%w/w - - - -

3% HPMC foam - - - 15ml* - - -

4% HEC foam - - - - 14ml* - -



3% HPC foam - - - - - 21ml* -

1% Sod. CMC foam

- - - - - - 13ml*

* The volume of water/ foam used for granulation

5.3.1. Wet granulation process

All the ingredients were weighed accurately and transferred to the mortar. All the ingredients

were mixed by triturating. The water was added in small amounts to make the powder blend

wet. The wet mass was then passed through 10 mesh sieve to make granules. These granules

were dried at 600C. The dried granules were size reduced and passed through 22 mesh sieve to

achieve uniform size distribution.

5.3.2. Foam granulation process

Six foam granulation batches were prepared. Step batch method was used for the addition of

foam to the powder blend. In this method the foam in small amounts was added and the

granulation end point was observed visually for proper wetness. In the batch “A”, 2% HPMC

was added in dry form and then the foam of 1% HPMC was used to granulate the powder

blend. In batch “B”, 2% HPMC was added as dry form and then 1% HPMC foam was added and

then the water was used to granulate the blend. In batch “C”, 3% HPMC foam was used to

granulate the powder blend. In batch “D”, 4% HEC foam was used to granulate the powder

blend. In batch “E”, 3% HPC foam was used to granulate the powder blend. In batch “F”, 1%

Sod. CMC was used to granulate the powder blend.

5.4. Characterization of prepared paracetamol granules

5.4.1. Moisture content and drying time

The granules were weighed before drying, and then kept for drying in the hot air oven at 600C

for 30 minutes. After that the granules were weighed again. The difference between the initial

and final weights was taken to determine the moisture content. The drying time was also

determined. The moisture content and drying time are shown in Table-10



Table-10 Drying time and moisture content of prepared paracetamol granules

Batch Moisture content (%) Drying time (sec.)

Wet granulation 23.79 540 A 23.28 480 B 23.27 450 C 21.46 450 D 18.99 491 E 27.49 563 F 22.95 443


Moisture content: Batch “A” had 2.14% less moisture content than the wet granulation batch.

Batch “B”, “C”, “D”, and “F” had 2.18%, 9.79%, 20.17% and 3.53% less moisture content than

wet granulation batch respectively. Batch “E” had 15.55% more moisture content than the wet

granulation batch. The data for moisture content of granules prepared using wet granulation

and foam granulation (batch C) was analyzed using student’s-t-test. The granules prepared

using foam granulation were found to have significantly less (p≤0.05; df= 2; tstat = 82.37; tcrit

=2.92) moisture content than the granules prepared using wet granulation method (Fig. 15)

* Significantly (p≤0.05) less moisture content

Fig.-15 Comparative effect of method of granulation on moisture content

Drying time: Batch “A”, “B”, “C”, “D” and “F” required 11.11%, 16.66%, 16.66%, 9.07%, and

17.96% less drying time than the wet granulation batch. Batch “E” required 4.26% more drying

time than the wet granulation batch. The data for drying time of granules prepared using wet

granulation and foam granulation method was analyzed using student-t-test and there was a

significant (p≤0.05; tstat=63.64; tcrit=2.92) decrease in drying time for granules prepared using

foam granulation method (Fig. 16).

20

21

22

23

24

Wet Foam

Mois

ture

conte

nt

(%)

Method of granulation

*



* Significantly (p≤0.05) less drying time

Fig.-16 Comparative effect of method of granulation on drying time

5.4.2. Granule size distribution

The granules were passed through 10, 22, 30, 44, 60, 80 and 100 mesh sieves before sizing. The

granules retained on each sieve were weighed. A graph was plotted between the %w/w and

size in µm. The particle size distribution before and after sizing for the different batches is given

in Table-11 and 12 respectively and depicted graphically in Fig. 17 and 18 respectively.

Table-11 Granule size distribution before sizing

Mean mesh size(µm)

%w/w retained on each size range

wet A B C D E F 137.50 0.0 0.0 0.0 0.0 0.0 0.0 0.0 166 0.21 1.23 2.23 3.32 3.74 4.34 5.92 215.5 0.68 2.17 4.18 6.28 1.52 2.73 0.31 302.5 0.79 5.46 9.19 9.80 4.83 5.19 5.09 427 5.34 8.89 14.27 13.45 7.57 8.35 5.61 605 7.24 9.47 11.87 11.78 7.33 14.38 7.78 1195 70.75 66.80 56.08 52.69 68.15 60.19 65.96 1840 14.99 5.98 2.18 2.68 6.82 4.77 9.30 2000 0.0 0.0 0.0 0.0 0.0 0.0 0.0

Figure-17 Granule weight size distribution (before sizing)

400

450

500

550

Wet Foam

Dry

ing

tim

e (

sec.)

*


-50

0

50

100

0 500 1000 1500 2000 2500

wet

A

B

C

Granule size (µm)

Dis

trib

uti

on(%

w/w

)



Table-12 Granule size distribution after sizing

Mean mesh size(µm)

%w/w retained on each size range

wet A B C D E F 137.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 166 3.46 4.33 5.33 6.70 6.85 5.96 6.63

215.5 6.29 7.03 8.89 10.77 8.84 6.91 1.27 302.5 10.43 15.88 15.72 17.02 14.22 15.18 12.20 427 22.28 23.40 25.68 26.46 31.85 30.50 17.34 605 34.64 38.95 34.86 25.85 29.40 38.13 30.70

1195 22.90 10.41 9.52 13.20 8.82 3.30 12.26 1840 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2000 0.0 0.0 0.0 0.0 0.0 0.0 0.0

Figure-18 Granule weight size distribution (after sizing)

Result and discussion

It is seen that particle size is skewed to right side using either of the granulation method.

However it is seen from Fig. 17 that larger sized granules (1195 and >1680 µm) are prepared

when wet granulation is used in comparison to foam granulation. This implies that more energy

and time would be required to reduce the size of larger granules to achieve the desired size

range of granules (Appendix Table A2).

5.4.3. Flow properties

(i) Angle of repose

The granules after sizing were filled in a funnel which was placed on a tripod stand. The

granules were allowed to flow under the influence of gravity. The height and diameter of the

pile formed beneath the funnel was noted down. The angle of repose was calculated as follows-

tan θ = h/r

-10

0

10

20

30

40

50

0 1000 2000 3000

wetA

Dis

trib

ution(

%w

/w)

Granule size (µm)



θ = tan-1 h/r

Where-

h = height of pile in cm.

r = radius of the base of pile

(ii) Carr’s index (compressibility)

The granules of each batch were weighed and filled in a 50ml measuring cylinder. The volume

was noted down to determine bulk density.

The measuring cylinder was tapped 100 times by using tapped density apparatus. After 100

tapings the volume was again noted down to determine the tapped density. The

compressibility can be determined by using following formula-

Tapped density – Bulk density

Carr’s index = x 100

Tapped density

(iii) Hausner’s ratio

The Hausner’s ratioo was determined by using following formula-

Hausner’s ratio = Tapped density / Bulk density

The flow property parameters are shown in Table-13.

Table-13 Flow properties of prepared paracetamol granules

Factors Batch

Angle of repose* (%)

Carr’s index* (%) Hausner’s ratio

Wet 11.12±0.32 5.87±0.21 1.06±0.03 A 18.97±0.32 9.52±0.27 1.11±0.02 B 17.08±0.33 6.65±0.39 1.07±0.04 C 17.83±0.24 9.37±0.11 1.10±0.04 D 19.27±0.14 17.38±0.21 1.21±0.01 E 23.78±0.23 10.72±0.13 1.12±0.02 F 23.02±0.29 22.23±0.19 1.28±0.03

* Data indicates mean ± SD of triplicate determination

Results and discussion

The angle of repose varied from 11.120 to 23.780, the Carr’s index varied from 5.87 to 22.23 and

the Hausner’s ratio varied from 1.06 to 1.28. It was found that the flow properties of prepared



granules of Wet granulation batch, and batch “A”, “B”, “C”, were excellent while the flow

properties of batch “D”, “E”, and “F” were good (Appendix Table-A3-A5).

5.5. Preparation of paracetamol tablets and their evaluation

Preparation of paracetamol tablet batches

Seven tablet batches were prepared designated as wet granulation, A, B, C, D, E, and F. The

prepared granules using wet granulation and foam granulation methods were compressed

using tablet press. The prepared tablet batches were evaluated against the following

parameters.

5.5.1. Weight variation

Twenty tablets from each batch were selected and weighed individually. The average weight

was determined, and checked for criteria that no tablet deviates by more than 5% of average

tablet weight. The evaluation of weight variation test is shown in Table-14.

Table 14: Weight variation of prepared paracetamol tablets

Batch Avg. wt.*(gm)

Wet 249.1±4.5 A 248.2±3.7 B 249.4±4.1 C 247.6±3.2 D 248.8±5.2 E 246.3±4.8 F 249.8±5.2

* Data indicates mean ± SD of twenty tablets


The tablets weighing ≥250mg have the limit of ± 5% variation according to IP 2010. The tablets

evaluated showed the weight variation within limit, and had RSD of less than of 6% and thus

passed the test (Appendix table A6).

5.5.2. Drug content

20 tablets were weighed and powdered. The powder equivalent to 200mg of paracetamol was

taken in a 250ml volumetric flask. 50ml of 0.1M NaOH was added. 100ml of distilled water was

added in this and shaken for 15 min. The above solution was diluted up to 200ml. 10ml of this

stock solution was taken in a 100ml volumetric flask and diluted with distilled water up to

100ml. 10ml from this solution was taken in a 100ml volumetric flask. In this the 10ml of 0.1M

NaOH was added, and then diluted up to 100ml with distilled water.



The absorbance of this final solution was taken by using UV-Visible spectrophotometer at

257nm. The absorptivity (ε) was used 715. The drug content is presented in Table-15

Table 15: Drug Content of prepared paracetamol tablets

Batch Drug content*(%)

Wet granulation 102±0.76 A 99.61±0.71 B 101.48±0.62 C 97.81±0.42 D 96.24±0.57 E 98.67±0.86 F 99.78±0.92

* Data indicates mean ± SD of triplicate determination


The drug content of the all the selected formulations were found to be within the limits (±15%)

i.e 85-115% as per IP 2010.

5.5.3. Disintegration

The disintegration time of tablets (n = 6) was determined using disintegration test

apparatus in distilled water maintained at 37 ± 0.5 ºC. The All tablets were checked for criteria

that not any tablet should disintegrate within 15 min. The disintegration time of different

batches is shown in Table-16.

Table 16: Disintegration time of prepared paracetamol tablets

Batch Disintegration Time (min.)*

Wet granulation 27.0±1.29 A 28.0±1.98 B 28.0±2.36 C 28.0±1.16 D 26.0±1.25 E 29.0±2.49 F 27.0±1.47

*Data represent mean ± SD, n=6


The disintegration time was studied by using disintegration apparatus (VEEGO-VDT-DV), the

disintegration time varied from 26 to 29 min. so none of the batches comply with the limit

specified in IP 2010.



5.5.4. Hardness and friability:

Friability of tablets (n =6) was determined by using a Roche friabilator. Hardness tester was

used to determine the hardness of tablet. The friability and hardness data are shown in Table-

17 and 18 respectively.

Table 17: Hardness of prepared paracetamol tablets

Batch Hardness (kg/cm2)*

Wet 4.6±0.4 A 4.5±0.4 B 4.5±0.2 C 4.5±0.6 D 4.5±0.8 E 4.4±0.4 F 4.6±0.4



The Hardness varied from 4.5 to 4.6 Kg/cm2. The hardness of all the tablet batches was found to

be within the specified limit (≤5Kg/cm2).

Table 18: Friability of prepared paracetamol tablets

Batch % Friability

Wet granulation 0.60 A 0.54 B 0.73 C 0.73 D 0.82 E 0.78 F 0.69


The %friability varied from 0.54 to 0.82. The %friability for all tablet batches was found to be

within the specified limit (≤1%).

5.5.5. Thickness

The thickness was measured by using the vernier calipers. The thickness was measured by

taking 6 readings of each tablet and then the average value was taken. The thickness data are

shown in Table-19.



Table 19: Thickness of prepared paracetamol tablets

Batch Thickness (cm.)*

Wet 0.35±0.1 A 0.35±0.2 B 0.36±0.1 C 0.36±0.2 D O.35±0.2 E 0.34±0.1 F 0.36±0.1



The thickness varied from 0.35 to 0.36 cm.

5.5.6. Dissolution

The dissolution study was performed by using USP type II dissolution apparatus. The

temperature was maintained at 37±20C. The speed of the paddles was kept at 50 rpm. The

dissolution was carried out in phosphate buffer PH 6.8. Samples (5ml) were collected

periodically and replaced with a fresh dissolution medium. After filtration through Whatmann

filter paper 41, concentration of Paracetemol in samples was determined

spectrophotometrically at 242.4 nm. The dissolution profile of all batches is shown in Table-20.

Table-20 Dissolution profile of prepared paracetamol tablets

Batch Amount dissolved (% cumulative)* at different time intervals

5 min. 10 min. 20 min. 30 min. 40 min. 50 min. 60 min. WET 11.46

±0.89 24.29 ±1.43

39.38 ±2.15

59.08 ±1.49

65.56 ±1.69

79.45 ±1.89

90.61 ±1.97

A 12.40 ±0.99

23.73 ±2.44

40.13 ±1.89

58.24 ±2.32

66.47 ±1.85

79.98 ±3.31

91.38 ±1.81

B 13.14 ±0.87

24.76 ±2.49

40.78 ±1.49

59.77 ±2.19

67.43 ±2.01

81.41 ±1.98

92.17 ±2.42

C 13.72 ±1.46

28.39 ±1.10

43.19 ±1.73

60.74 ±1.98

70.94 ±2.62

82.81 ±4.59

93.81 ±0.99

D 11.76 ±1.25

26.79 ±2.11

44.49 ±0.89

61.47 ±1.67

71.83 ±2.44

83.29 ±1.62

93.28 ±0.67

E 12.58 ±2.31

25.96 ±1.68

43.56 ±2.31

62.58 ±0.57

72.46 ±2.32

82.85 ±1.76

92.59 ±0.92

F 11.49 ±1.43

23.67 ±2.23

41.26 ±1.53

59.12 ±0.76

66.38 ±2.19

80.49 ±1.49

91.49 ±2.76

* Data represent mean ± SD, n=6



Figure-19 Dissolution profile of all batches


The % release was found to be 90.16% in case of wet granulation batch. The % release was

found to be 91.38%, 92.17%, 93.81%, 93.28%, 92.59% and 91.49% for “A”, “B”, “C”, “D”, “E”

and “F” (foam) batches respectively. The t-test was performed on % dissolved at 30 min. for

wet granulation batch and foam granulation batch “C”. It was found that there was no

significant (P≤0.05; df=2; tstat=0.6; tcrit=2.92) difference between both batches.

5.6 Stability study of selected optimized paracetamol tablets as per ICH Q1 stability testing

guideline

It is the responsibility of the manufacturers to see that the medicine reaches the consumer in

an active form. So the stability of pharmaceuticals is an important criterion. Stability of

medicinal products may be defined as the capability of a particular formulation in a specific

container to remain within its physical, chemical, microbial, therapeutic and toxicological

specification, i.e. stability of drug is its ability to resist detoriation. 90% of labeled potency is

generally recognized as the minimum acceptable potency level. Detoriation of drug may take

several forms arising from changes in physical, chemical and microbiological properties. The

changes may affect the therapeutic value of preparation or increase its toxicity.

Accelerated Stability Testing:

Since the period of stability testing can be as long as two years, it is time consuming and

expensive. Therefore, it is essential to devise a method that will help rapid prediction of long

term stability of drug. The accelerated stability testing is defined as the validated method by

which the product stability may be predicted by storage of the product under the conditions

that accelerate the change in defined and predictable manner. The stability study of prepared

paracetamol tablet batches (wet granulation and batch C) were carried out at

40/75(°C/RH) for one month. The effects of temperature, humidity and time on the physical

characteristics of the prepared tablet batches were evaluated for assessing the stability of the

prepared formulation. Protocol for accelerated stability testing is shown in Table 21.

0

20

40

60

80

100

0 20 40 60 80

WET

A

B

C

D

E

F

Time (min.)

%

Dis

solv

ed



Table 21: Protocol for accelerated stability testing of the developed paracetamol tablets

based on ICH Q1 Stability testing guideline

Procedure Among the formulations, formulation “C” showed minimum moisture content and

drying time and maximum release at t = 60 min. The formulation C was packed in amber

colored screw capped glass bottle and stored at 40±2°C and 75±5% RH for 4 weeks in stability

chamber. Samples were withdrawn at 7 day time interval and evaluated for hardness, friability,

disintegration time, drug content, and drug release. Physical stability data of the prepared

tablet batches of paracetamol is shown in Table 22 and 23 and in vitro release profile of

paracetamol from the prepared tablet batches during stability is shown in Table 24 and 25 and

Figure 20 and 21.

Table 22: Physical accelerated stability data of paracetamol tablets prepared using wet

granulation method

1 Objective To ensure whether the developed paracetamol tablet batches have adequate stability.

To predict shelf life of the developed paracetamol tablets.

2 Selection of batches Wet granulation batch and batch C (prepared using foam granulation) Number of batches-3 for each

3 Container-closure Glass bottle with screw cap 4 Specifications Parameter Acceptance

Criteria Test method

Hardness 4-5 Kg/cm2 Mosanto hardness tester

Friability ≤1% Roche friabilitor

Disintegration time 30 min. Disintegration time apparatus

In vitro drug release at 60 min.

>90% USP II apparatus

Weight uniformity ±5% Analytical balance

Drug content 100±15% U.V.spectrophotometer at 242.4 nm.

5 Testing frequency 5 samples at 0,1,2,3 and 4 week 6 Storage condition 40±2 °C and 75±5% RH

Quality attribute

Sampling interval

0 day 1st week 2nd week 3rd week 4th week Hardness (kg) 4.3±0.4 4.4±0.6 4.5±0.7 4.7±0.5 4.8±0.7 Friability (%) 0.65±0.16 0.65±0.22 0.62±0.18 0.62±0.13 0.61±0.14



Table 23: Physical accelerated stability data of paracetamol tablets prepared using foam

granulation method

Table 24: In vitro release of paracetamol from tablets prepared using wet granulation

subjected to accelerated stability storage conditions

Time (Min.)

Amount dissolved (% cumulative)* at different sampling intervals

0 1st week 2nd week 3rd week 4th week

5 11.29±0.23 11.27±0.52 11.14±0.18 12.61±0.26 10.54±0.22 10 24.34±0.45 24.33±0.19 23.89±0.27 23.66±0.55 22.76±0.26 20 39.35±0.16 39.43±0.63 38.49±0.36 38.12±0.52 38.76±0.54 30 59.12±0.32 59.16±0.26 58.76±0.29 57.94±0.78 57.73±0.52 40 65.59±0.25 65.46±0.53 64.21±0.56 64.26±0.49 63.71±0.86 50 78.54±0.45 78.47±0.43 77.29±0.25 76.54±0.26 76.89±0.73 60 91.28±0.27 91.39±0.67 91.11±0.27 90.16±0.19 90.36±0.93

* Data indicate mean±SD of triplicate determinations

Figure 20: In vitro release of paracetamol from the developed wet granulation batch stored

under accelerated stability conditions

0

20

40

60

80

100

0 20 40 60 80

0 week

4 week

Time (min.)

%

Dru

gre

leas

ed

Disintegration time (min.)

27±1.29 27±1.33 29±1.26 29±1.11 31±1.22

Quality attribute

Sampling interval

0 day 1st week 2nd week 3rd week 4th week Hardness (kg) 4.2±0.3 4.2±0.4 4.4±0.8 4.7±0.4 4.8±0.5 Friability (%) 0.75±0.18 0.75±0.21 0.73±0.12 0.70±0.17 0.68±0.14 Disintegration time (min.)

28±1.36 28±1.21 29±1.08 30±1.34 31±0.89



Table 25: In vitro release of paracetamol from tablets prepared using foam granulation

subjected to accelerated stability storage conditions

Time (Min.)

Amount dissolved (% cumulative)* at different sampling intervals

0 1st week 2nd week 3rd week 4th week 5 13.78±0.76 13.54±0.17 13.31±0.12 12.13±0.23 12.16±0.87 10 26.39±0.22 27.69±0.22 26.67±0.34 25.24±0.33 24.36±0.47 20 42.76±0.56 43.19±0.59 41.56±0.73 42.26±0.29 41.94±0.73 30 63.58±0.59 63.44±0.28 62.34±0.32 62.76±0.76 61.11±0.48 40 69.24±0.18 68.36±0.26 67.76±0.59 66.34±0.32 66.74±0.49 50 81.96±0.29 82.14±0.58 80.94±0.43 81.24±0.39 80.79±0.63 60 92.54±0.86 92.19±0.87 90.13±0.41 90.26±0.24 90.51±0.73

Figure 21: In vitro release profile of paracetamol from the developed foam granulation batch

C stored under accelerated stability conditions

As per ICH Q1 Stability Testing guideline, prediction of shelf life involves

analyzing data of a quantitative attribute that is expected to change with time (drug content)

and determination of the time at which the 95% one sided confidence limit for the mean curve

intersects the acceptance criterion (90% drug remaining). If analysis shows that the batch to

batch variability is small, it is advantageous to combine the data into one overall estimate. This

can be done by first applying appropriate statistical tests (e.g., p values for level of significance

of rejection of more than 0.25) to the slopes of the regression lines and zero time

intercepts for the individual batches. If it is inappropriate to combine data from several

batches, the overall shelf life should be based on the minimum time a batch can be expected to

remain within acceptance criteria. The nature of the degradation relationship will determine

whether the data should be transformed for linear regression analysis. Usually the relationship

can be represented by a linear function on logarithmic scale. Degradation of paracetamol in wet

granulation batch and batch C at 40±2°C and 75±5% RH is presented in Table 26 and 27 and

Figure 22 and 23.

0

20

40

60

80

100

0 20 40 60 80

0 Week

4 week

Time (min.)

% D

rug

rele

ase



Table 26: Chemical accelerated stability data of the paracetamol tablets prepared using wet

granulation method

Time (Weak) % drug remaining (Mean± S.D.)

Log % drug remaining (Mean± S.D.)

95%

UCI LCI 0 99.79±0.03 1.9991±0.000131 1.9994 1.9806 1 99.40±0.232881 1.9974±0.001017 1.9999 1.9779 2 98.72±0.133167 1.9944±0.000586 1.9958 1.9778 3 97.36±0.03 1.9883±0.000134 1.9887 1.9748 4 96.76±0.157162 1.9856±0.000705 1.9874 1.9755 Slope -0.115 -0.0005 -0.0005 -0.0005 Intercept 100 2.0 2.0 1.9999 r 0.963 0.963 0.892 0.985

Figure 22: First order degradation of paracetamol in tablets prepared using wet granulation

method at accelerated storage conditions

Table 27: Chemical accelerated stability data of paracetamol tablets prepared by foam

granulation method

Time (Weak) % drug remaining (Mean± S.D.)

Log % drug remaining (Mean± S.D.)

95%

UCI LCI 0 98.64±0.0305 1.9941±0.000134 1.9944 1.9937 1 98.38±0.0556 1.9929±0.00024 1.9935 1.9923 2 97.77±0.0611 1.9904±0.000271 1.9911 1.9897 3 96.69±0.02 1.9853±0.000089 1.9855 1.9851 4 95.87±0.0513 1.9817±0.000232 1.9823 1.9811 Slope -0.103 -0.0005 -0.0005 -0.0005 Intercept 98.92 1.99 1.9958 1.9949 r 0.952 0.952 0.939 0.961

1.93

1.94

1.95

1.96

1.97

1.98

1.99

2

2.01

0 10 20 30 40 50 60 70 80 90 100

Mean drug remaining

Time (days)

Log %

dru

g

rem

ain

ing



Figure 23: First order degradation of paracetamol in tablets of foam granulation batch C

stored under accelerated storage conditions

Bracket Method: Activation energy is usually estimated based on Arrhenius equation by

subjecting the product to stress conditions. However, when the activation energy is known, the

degradation rate at storage temperature may be predicted from data collected at only one

elevated/accelerated temperature. This practice is sometimes preferred in industry since it

reduces the size and time of accelerated stability tests. Experience indicates that some

pharmaceutical analytes have activation energy in the range of 10 - 20 kcal/mol, but it is

unlikely to have precise information about the activation energy of a certain product.

The bracket method is a straight forward application of the Arrhenius equation that can be

used if the value of the activation energy is known. Stability at recommended storage

temperature is calculated with a modified version of Arrhenius equation as:

Where,

Ea Energy of Activation 20 Kcal/mol

Ts Temperature at which shelf life is to be predicted 298K (273+250C) Te Temperature at which stability study was performed 313K (273+400C) te shelf life at Te (t90% drug remaining) 88 days for both

batches ts shelf life at Ts To be predicted

On substituting the values into the equation:

1.93

1.94

1.95

1.96

1.97

1.98

1.99

2

0 10 20 30 40 50 60 70 80 90 100

Mean drug remaining

Time (days)

Log %

dru

g

rem

ain

ing

ts = exp [Ea/0.00199 (1/Ts-1/Te)] te

ts = exp [20/0.00199 (1/298 - 1/313)] 88



= 443 days as 14 months for both batches

Q-Rule: The Q-Rule states that the degradation rate decreases by a constant factor when

temperature is lowered by certain degrees. The value of Q is typically set at 2, 3, or 4. This

factor is proportional to the temperature change as Qn, where n equals the temperature

change in °C divided by 10°C. Since 10°C is the baseline temperature, the Q-Rule is sometimes

referred to as Q10.

Where, t90 (T2) is the estimated shelf life at temperature T2, t90 (T1) is the given shelf life at given

temperature T1, and Δ T is the difference in the temperature (T2 –T1).

Note: the estimate of t90 (T2) is independent of the reaction order.

Setting on an intermediate value of Q = 3 and substituting the value in the equation:

t90(T2) = 88

3(25-40)/10

= 457 days as 15 months

This approach is more conservative when lower values of Q are used. Both Q-Rule and the

bracket methods are rough approximations of stability. They can be effectively used to plan

elevated temperature levels as well as the duration of testing in the accelerated stability testing

protocol.

Limitation of accelerated stability studies

Accelerated stability studies are valid only when the breakdown depends on temperature.

Accelerated stability studies are valid only the energy of activation is about 10 to 30 kcal /

mol.

The result obtained for one set of conditions for a preparation cannot be applied to other

preparation of same drug.

Stability prediction at elevated temperature is of little use when degradation is due to

diffusion, microbial contamination, and photo-chemical reaction.

t90 (T1)

t90 (T2) =

Q10(ΔT/10)



Stability studies are meaningless when the product loses its physical integrity at higher

temperature like coagulation of suspending agent, denaturation of proteins.

RESULT AND DISCUSSION:

Both selected formulations showed good physical stability, as there was no discoloration or any

significant physical changes after storage. Paracetamol degradation, result obtained showed log

linear profile, from which the degradation rate constant (k) was calculated from the slope. This

was found to be 1.15×10-3 (month-1) at 40°c for both batches. The shelf life at 250C was

determined by using Bracket Method and Q-Rule shown in Table 28.

Table 28: Conformance period and shelf life at 25°C of the developed paracetamol tablets by

wet granulation and foam granulation methods

t90% at 40°c t90%at 25°c

88 days Method Conformance period Shelf life Bracket Method 443 days =14.76 months 14 Months

Q-Rule 457 days = 15.23 months 15 months

Conformance period is the time period during which an active pharmaceutical ingredient (API)

or a finished pharmaceutical product (FPP) is expected to remain within approved shelf life

specification, provided that it is stored under the conditions defined on the container label.

The proposed shelf life, as estimated from the accelerated stability study, has to be backed up

by real time/long term stability testing as per ICH Q1 Stability Testing guidelines depending

upon World Climatic Zones (Appendix Table A7) under which a country is classified in which the

product is to be marketed.

CONCLUSION

The aim of this dissertation work was to study the effect of type of granulation (wet and foam

granulation) on the parameters of granules and the parameters of tablets. In this dissertation

work the different polymers (HPMC, HPC, Sod.CMC, and HEC) were used to generate the foams.

These generated foams were evaluated for foam quality, nucleation ratio, specific penetration

time, and foam stability. On the basis of these parameters the optimum foam batches were

selected. The preference was given to the foam stability and foam quality for selection of foam

batches. The effect of foam quality on the nucleation ratio and specific penetration time was

studied. The results of evaluation of foam of optimized batch prepared using 3% HPMC are

shown in Table-29.



Table-29 Evaluation parameters of optimized foam batch (3%w/v HPMC)

Foam quality (%)

Foam stability (ml.) Nucleation ratio Specific penetration time (sec.)

95.7 0.8 2.46 720

The optimized foam batch was used to prepare paracetamol granules. The granule parameters

were studied with respect to type of granulation.

Table-30 Comparative effect of method of granulation on the granule parameters


Parameter

Angle of repose

Hausner’s ratio

Carr’s index (%) Moisture content

Drying time (sec.)

Wet granulation

11.12 1.06 5.87 23.79 540

Foam granulation

17.83 1.10 9.37 21.46* 450*

* = Significant difference (p≤0.05)

The moisture content and drying time were decreased significantly, so the foam granulation

process is able to decrease the processing time. Seven tablet batches were prepared. The tablet

batches were evaluated and the effect of method of granulation and polymer used to generate

foam was studied. On the evaluation of prepared paracetamol tablets, it was observed that

tablets prepared using either granulation method complied with all the quality control

parameters.

In foam granulation batches “C”, “D”, “E”, and “F” the effect of foam quality and nucleation

ratio on different parameters were studied. It was found that as the foam quality increases and

the nucleation ratio decreases the moisture content and drying time decreases.

Table-31 Comparison of different foam parameters between different foam granulation

batches

Parameters Batch

C D E F Foam quality 95.70 88.0 93 86

Nucleation ratio 2.46 4.854 3.412 4.580 Moisture content 21.46 18.99 27.49 22.95

Drying time 450 491 563 443



% of optimum sized particles

23.25 12.4 13.54 10.7

Thus it can be concluded that foam granulation can be used to prepare tablets complying with

pharmacopoeial specifications with decreased processing time in comparison to wet

granulation method.

Further the foam granulation method can be explored for development of low dose drugs such

as- propranolol, aceclofenac, and for moisture sensitive drugs such as- aspirin.

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