chapter-5 zidovudine matrix tablets and...

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CHAPTER-5

ZIDOVUDINE MATRIX TABLETS AND MICROCAPSULES

110

5.1 Pre formulation Studies for Zidovudine

5.1.1 Determination of ZIDO Solubility

Solubility study of ZIDO in different media was determined by

the general procedure described in the section 3.3.4 of chapter 3.

5.1.2 Construction of standard calibration curves for ZIDO

Standard graph of ZIDO was determined by the general

procedure described in the section 3.3.5 of chapter 3.

5.1.3 Multimedia dissolution of marketed Zidovudine formulation

The drug release rate from Zidovudine tablets (Retrovir-300 mg,

Batch No-3ZP1962, manufacture by Glaxo Smithkline) was

characterized using USP type 2 at 50 rpm, 900 ml of dissolution

medium at 37 ±0.5 °C. The various dissolution media used in the

study were water, 0.1 N HCl, USP acetate buffer pH 4.5 and USP

phosphate buffer pH 6.8. A sample of 5 ml was withdrawn from the

dissolution medium and replaced with 5 ml of blank media. The

samples were withdrawn at 5, 10, 15, 30 and 45 minutes and

analyzed using UV visible spectrophotometer at 266 nm after suitable

dilution.

5.1.4 Fourier Transform Infrared spectroscopy (FT-IR)

The FT-IR spectrum was taken for pure ZIDO powder, initial

formulation and stability samples were determined by the method

described in the 3.3.6 of chapter 3.

111

5.1.5 DSC studies

Thermal properties of pure ZIDO powder, Initial formulation and

stability samples were evaluated by the method described in the 3.3.7

of chapter 3.

5.1.6 Analytical Methods

Ultraviolet Spectroscopy

The UV spectroscopic method for ZIDO was developed in the

four different pH media to study the solubility and dissolution and

drug content estimation in the prepared formulations by the method

described in the 3.3.5 of chapter 3. Finally, the quantity of ZIDO was

calculated from the regression equation of the calibration curve.

5.2 Formulation of Zidovudine matrix tablets

5.2.1 Preparation of granules

Matrix tablets of ZIDO were prepared using various proportions

of HPMC K100 M as the retarding polymer. The tablets were

manufactured by wet granulation method as described in the section

3.3.2 of chapter 3. The lubricated granules were characterized for

drug content. The lubricated granules were compressed on 16-station

tablet compression machine using 15 X 7.5 mm partial scored capsule

shaped punch embossed with „E‟ on upper punch and „38‟ on lower

punch. Three batches were prepared for each formulation and

compressed 500 tablets from each batch for the characterization

study.

112

5.2.2 Characterization of granules

Loss on drying (LOD)

For the detection of drying end point of the granulation process,

the weight loss of the samples on thermal drying was measured (using

Moisture Analyser MX-30 A&D Company) thermal balance at fixed

temperature of 105°C. In particular, 1 gram of each sample was

withdrawn from the dried samples and heated in the thermal balance

until a constant weight was achieved.

Particle size distribution (PSD)

The granule size distribution was evaluated by sieve analysis,

using Retesh Digital particle size analyzer at medium vibration level

for 15 minutes. Standard sieve sizes like #30, #40, #60, #80, #100,

#120 were used for the PSD. The fractions were calculated by

collecting for each sieve and percent retained and cumulated percent

retained were calculated.

Angle of repose

Angle of repose was calculated by the method described in the

USP115. The general measure for the angle of repose was as follows. A

funnel was fixed at certain height and then the granules were passed

through the funnel onto the fixed base. The height of the pile and the

radius of the particles distributed were measured with a scale. Then

the angle of repose was calculated using the following formula

Tan θ= h/r

Where θ is angle of repose, h is height of the pile and r is radius of the

circle.

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Bulk and Tapped density

The granules were weighed and poured in 100 ml graduated

cylinder. The bulk volume Vb and tapped volume Vt after 1250 taps on

a tap density apparatus (Electrolab ETD 1020) was used to calculate

the Vb and Vt. Three determinations of each batch were performed.

Then, the compressibility index (CI) and Hausner‟s ratio was

calculated to investigate the flow of the granules.

5.2.3 Characterization of the Designed Tablets

Drug content estimation

The drug content of the prepared matrix tablets was determined

by the general procedure described in the section 3.3.8 of chapter 3.

The sample was analyzed after making appropriate dilutions using the

developed analytical method.

Hardness, weight variation and friability determination

The weight variation, hardness and friability were determined by

the general procedure described in the section 3.3.8 of chapter 3.

5.2.4 In vitro drug release studies

The in vitro dissolution studies were performed up to 14 hours

using USP type II dissolution apparatus (LABINDIA, DISSO-2000,

Mumbai, India) at 75 rpm. The dissolution medium consisted of

phosphate buffer pH 6.8 (900 mL), maintained at 37 ±0.5 °C. An

aliquot (5 mL) was withdrawn at specific time intervals and filtered

through 0.45 µ (Millipore) filter. After appropriate dilution the samples

were analyzed and cumulative percentage of the drug released was

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calculated. 6 tablets from 3 different batches were used in data

analysis.

5.2.5 Accelerated stability studies on the prepared formations

Selected formulations from prepared matrix tablets were filled in

HDPE containers and stored at the following conditions like

40°C/75% RH for 3 months as per ICH guidelines. The samples were

characterized for % drug content, FTIR and DSC study.

115

5.3 Results and discussion

5.3.1 Construction of standard calibration curves for ZIDO

Zidovudine standard calibration curve was constructed by

scanning the 20 μg/ml solution of Zidovudine in different buffers

solution used in the solubility study. This was described later in this

chapter.

5.3.2 Determination of ZIDO solubility

Zidovudine showed highest solubility in both water and 0.1 N

HCl which was around 28 mg/ml. The solubility of zidovudine in 6.8

phosphate buffer was 20. 1 mg/ml where as in acetate buffer pH 4.5

the solubility was 21.36 mg/ml. (Table 5.1) indicating the high

solubility of the drug in the pH range of 1 to 7. The solubility is

graphically represented in the Fig 5.1 The dissolution of zidovudine in

all pH media showing similar release profile and showing good

correlation (Table 5.2). The overall dissolution rate in all the media

showing more than 86 % of drug release in 15 minutes from their

dosage forms is clearly indicating the availability of drug at the site of

absorption. Controlling the drug release from the highly soluble drug

thus is an important aspect in the formulation development. Fig 5.2

showed the cumulative percent drug released vs time of Zidovudine

conventional tablets in various pH media.

116

Table 5.1: Solubility of Zidovudine in various pH media

pH 6.8

Phosphate

buffer

pH 4.5 acetate

buffer

0.1 N HClwater

0

5

10

15

20

25

30

35

1 2 3 4

SO

LU

BIL

ITY

IN

MG

/ML

Fig. 5.1: Histogram representing solubility of Zidovudine in various pH

media

Media

Solubility (mg/ml)

Water

28.90

0.1 N HCl 27.36

pH 4.5 Acetate buffer 21.36

pH 6.8 phosphate buffer 20.1

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Table 5.2: In-vitro dissolution studies of Zidovudine tablets 300 mg, (Retrovir-300 mg, Batch No-3ZP1962, manufacture by Glaxo

Smithkline) in various pH media

Fig. 5.2 Cumulative percent of drug released vs time (min) plots of

zidovudine tablets 300 mg (Retrovir-300 mg, Batch No-3ZP1962, manufacture by Glaxo Smithkline) in various pH media

Time (min)

Water

0.1 N HCl

pH 4.5 Acetate

buffer

pH 6.8

phosphate buffer

5 76 ±2.15

53 ±2.36

55 ±2.56

62 ±3.15

10 88 ±2.45

88 ±2.56

73 ±3.87

76 ±2.56

15 92 ±2.66

93 ±2.35

86 ±3.15

88 ±1.56

30 96 ±2.56

95 ±2.31

91 ±3.16

91 ±2.15

45 99 ±1.25

99 ±1.01

97 ±1.82

96 ±1.23

118


The FT-IR spectrum was taken for ZIDO powder. The study of

the FTIR spectra of Zidovudine demonstrated that the characteristic

absorption peaks for the carbonyl group at 1685 cm -1 and azido

group117 stretching at 2082 -1. This further confirms the purity of

zidovudine. Fig 5.3 shows the spectrum peak points of zidovudine

during in FTIR study.

Fig. 5.3 FTIR spectrum of pure zidovudine

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5.3.4 DSC Analysis

The DSC results presented in Fig. 5.4 demonstrated a sharp

endothermic peak for ZIDO at 122˚C, which corresponded to its

melting point. The melting point reported for ALP is 122˚C [Punna rao)

116 and 124°C (MK Das) 117. This indicated the crystalline nature of the

drug. Fig 5.4 shows the melting process of the zidovudine in DSC.

Fig. 5.4 Endothermic peak of ZIDO during melting process

120

5.3.5 Analytical methods

The UV spectra of Zidovudine showed similar absorption

maxima (Table 5.3) in different media and almost similar absorbance

in all the media. (Fig-5.5). Standard concentrations of Zidovudine in

different media were prepared and stored for 24 hours to see the

stability of the Zidovudine. Similar absorption spectra were observed

with similar max indicating the stable nature of the drug.

Table 5.3 max values of zidovudine in different pH media

Fig 5.5 Overlay spectra of zidovudine in different pH media at initial and 24 hours

Media Water 0.1NHCl

pH 4.5 acetate

buffer

pH 6.8 phosphate

buffer

max

Initial 266.00 266.40 266.00 266.00

24 Hours 266.16 266.27 266.10 266.13

121

The UV spectroscopic method was developed in 6.8 phosphate

buffer for the quantification of ZIDO (Table 5.4). This method is used

for the determination of solubility and the amount of drug released

from the matrix tablet into a dissolution medium during the

dissolution study. Linear correlation was observed over the

concentration range of 5 - 40 μg/ml for ZIDO. The linearity of the

standard curves (Fig- 5.6) was excellent with correlation coefficient in

the range of 0.9992 as shown in the graph. The precession of the UV

method was determined by measuring the absorbance of the same

working in replicates of five, which had an RSD of less than 1 %.

Table 5.4 Standard calibration values of zidovudine

in different pH media.

Media pH 6.8 phosphate buffer

Concentration

(μg/ml) Absorbance at 266nm

0 0

5 0.240

10 0.464

20 0.906

30 1.382

40 1.849

122

y = 0.047x - 0.0071

R2 = 0.9992

0

0.5

1

1.5

2

0 10 20 30 40

Concentration

Ab

so

rba

nc

e

Fig. 5.6 Standard calibration curves of Zidovudine

in pH 6.8 phosphate buffer.

123

5.3.6 Zidovudine matrix tablets prepared with HPMC K 100 M

Matrix tablets of zidovudine were prepared with HPMC K 100 M

at different proportions of polymer in the tablets. The polymer

concentration was used in the range of 15-25 % to the total weight of

the tablet (Table-5.5). Lactose monohydrate was used as diluent in the

tablet. The PVP was dissolved in the water and used as a binder

solution for the preparation of the granules. The tablets were

compressed with 15 X 7.5 partial scored capsule shaped punch

embossed with „E‟ on upper punch and „38‟ on lower punch. The

tablets were examined for various physical properties. The physical

and chemical characteristics were given in Table-5.5. No sticking was

observed during the compression process. It is clearly indicating the

uniform lubrication of the blend. The bulk density of the granules was

found in the range of 0.45- 0.52 g/ml. Good compressibility index

value of 20-22 was observed in all the formulations.

The prepared matrix tablets were examined for the hardness,

thickness, friability. The hardness was found between 9-10 kg/cm2.

Almost no friability was observed is clearly indicating the mechanical

strength of the tablets.

Drug content was estimated with the developed analytical

method. The drug content was found to be in the range of 99-101 %

with less than 1 % RSD indicating the uniform distribution of the drug

in the tablet. The formulation components and the physical–chemical

properties of the tablets are given in the table 5.5.

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Table 5.5 Formulation and physical characteristics of designed controlled release matrix tablets of Zidovudine with HPMCK100M

Formulation FZ-1 FZ-2 FZ-3

Components mg per tablet

Zidovudine 300 300 300

HPMC K 100 M 125 150 175

Lactose Monohydrate 150 125 100

Poly vinyl pyrollidine (PVP) 10 10 10

Purified water QS QS QS

Colloidal silicon dioxide 6 6 6

Talc 4 4 4

Magnesium stearate 5 5 5

Total weight 600 600 600

Physical/chemical Properties

Water quantity (%) 10% 10% 10%

Bulk density (g/ml) 0.447 0.446 0.521

Tapped density (g/ml) 0.562 0.572 0.656

Compressibility index 20.46 21.875 20.57

HR 1.257 1.208 1.259

Drug content (% ) 99.12 100.01 100.25

Hardness (kg/cm2) 9 (±0.5) 10 (±0.4) 10 (±0.4)

Thickness (mm) 5.9 5.86 5.9

Friability (%) < 0.1 < 0.1 < 0.1

In vitro dissolution studies

In vitro dissolution studies showed (Table-5.6) that the drug

release was around 50 % in formulation FZ-3. It was clearly observed

that as the polymer proportion increases in the formulation the

release rate decreased (FZ-1 to FZ-3). The formulation containing 20

% of polymer, releases around 94 % of drug in 12 hours. The polymer

proportion of 25 % releases around 67 % in 12 hours. Similarly the

polymer proportion of 30 % release only 50 % of drug in 12 hours.

Fig. 5.7 shows the gel layer formation from outer layer to core with

125

time during dissolution. Fig 5.8 shows the swelling behavior of

zidovudine matrix tablets during dissolution.

Table 5.6 In vitro dissolution of controlled release matrix tablets of

Zidovudine with HPMC K100 M

Time(Hrs.) FZ-1 FZ-2 FZ-3

1 14 ±2.36 10 ±2.36 9 ±2.56

2 19 ±2.15 15 ±3.55 12 ±2.36

3 24 ±2.22 21 ±2.12 18 ±1.56

4 30 ±1.56 24 ±2.36 20 ±1.21

5 34 ±3.15 29 ±3.56 25 ±3.56

6 40 ±2.56 34 ±3.23 31 ±3.71

7 51 ±3.21 39 ±3.56 33 ±2.35

8 63 ±2.15 47 ±3.46 37 ±1.75

10 75 ±2.36 53 ±2.36 41 ±1.36

11 86 ±2.56 61 ±2.45 45 ±2.56

12 94 ±2.23 67 ±2.36

50 ±1.56

Fig. 5.7 cross section of tablet showing formation of gelling layer with

HPMCK 100 M during dissolution

126

Fig. 5.8 Swelling of Zidovudine tablets during dissolution at different time intervals

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16Time (hrs)

Cu

mu

lativ

e pe

rcen

t re

lea

sed

FZ-1

FZ-2

FZ-3

Fig. 5.9 Cumulative percent release of Zidovudine from different formulation (HPMC K 100M)

127

0

20

40

60

80

100

1

1.4

1

1.7

3 2

2.2

4

2.4

5

2.6

5

2.8

3

3.1

6

3.3

2

3.4

6

Sq RT of Time (hrs)

Cu

mu

lative

pe

rce

nt re

lea

se

d

FZ-1FZ-2FZ-3

Fig. 5.10 Higuchi plots of Zidovudine matrix tablets (HPMC K 100M)

-0.1

0.4

0.9

1.4

1.9

2.4

0 2 4 6 8 10 12 14

Time (hr)

Lo

g p

erc

en

t re

ma

inin

g

FZ-1

FZ-2

FZ-3

Fig. 5.11 Log percent remaining vs time plot of Zidovudine matrix tablets (HPMC K 100M)

128

Table 5.7 In vitro release kinetic data of

Zidovudine matrix tablets with HPMC K 100M

The in vitro release kinetics showed good correlation and best fit

to the Higuchi model (Fig-5.10). This clearly indicates the drug release

was diffusion controlled. (Table- 5.7).

At lower polymer proportion the release kinetics best fitted to

the first order (FZ-1) release (Fig-5.11) i.e., the drug release was

depended on the drug concentration in the matrix system. As the

polymer concentration in the matrix increased, the release kinetics

shifted to the zero order release (Fig-5.9) (FZ-2). The same zero order

release was observed in the formulation FZ-3 which contains 30% of

the polymer in the matrix system.

It was clearly observed that, as the polymer proportion increases

the release rate constant decreases from 7.497 to 3.856 in zero order

release rate constant. This clearly indicates that the drug release was

mainly depends on the polymer proportion. Similarly in the Higuchi

Kinetics FZ-1 FZ-2 FZ-3

Zero order

r2 0.9806 0.9934 0.9873

K 3.856 5.236 7.497

t1/2 12.97 9.55 6.67

First order

r2 0.992 0.9715 0.8411

K 2.285 2.237 1.937

t1/2 0.30 0.31 0.36

Higuchi

r2 0.9835 0.9631 0.9274

K 16.825 23.15 33.45

t1/2 8.825 4.660 2.230

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model also the release rate constant decreases with the increase in

polymer proportion. Increase in half life (t½) with increase in polymer

proportion clearly indicates the drug‟s prolonged release.

5.3.7 Study of type of polymer and granulation fluid on the

Physico chemical properties and drug release from the zidovudine

matrix tablets

It has been known that particulate properties can profoundly

influence the bulk properties of the powders 118-123. In early days

pharmaceutical manufacturing batch to batch variability of bulk

excipients and active pharmaceutical ingredients could be great

because critical particulate properties were generally not controlled.

Variations in raw materials frequently resulted in processing difficulty

and even failed in commercial batches.

Reliable and consistent flow out of hopper and feeders without

excessive spillage and dust generation is important to pharmaceutical

industry 124,125. Poor powder flow properties may reduce productivity

leading to financial losses. These flow properties of the particles are

very much important and is minimum requirement in the tablet

weight uniformity. One approach to improve flow property is particle

size enlargement. The particle size enlargement may be achieved by

the process of granulation.

In this section we have attempted Zidovudine granulation with

different polymers and different granulation fluids.

To study the affect of the of polymer type on the drug release,

the basic formulation FZ-1 was selected because it releases around 94

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% of the drug in 12 hours. Different polymers such as Poly ethylene

oxide (PEO WSR 303), Carbopol (971P) and Eudragit (L 100) were

incorporated in the place of HPMC K 100 M.

To study the affect of granulation fluid on the physical and

chemical properties of the drug, each formulation was granulated with

both water and isopropyl alcohol. Similarly directly compressible

blends also prepared with the same polymer. The granules were

prepared by the same method adopted for the preparation of

formulation FZ-1 i.e., the matrix tablets prepared with HPMC K 100M.

5.3.8 Matrix tablets prepared with Poly ethylene Oxide (PEO WSR

303)

Polyethylene oxide is a widely used pharmaceutical sustained

release polymer. In this formulation PEO was incorporated as rate

controlling polymer. In the formulation three types of granules were

prepared. First directly compressible (DC) blends were prepared,

second wet granulation with water and third wet granulation with

isopropyl alcohol were prepared as described in the formulation table

5.8. Various granulation and compression parameters were studied

and compared with in the process. Finally in vitro dissolution studies

on the prepared matrix tablets were done and compared with each

other.

131

Table 5.8 Formulations designed controlled release matrix tablets of

Zidovudine with PEO WSR 303


Granulation fluid DC Water IPA



PEO WSR 303 125 125 125


Poly vinyl pyrollidine 10 10 10

Granulation fluid QS QS QS


Talc 4 4 4



Direct compression of PEO matrix tablets (FZ-4)

Intra granular drug and excipients were directly mixed and

sifted through # 30 mesh and mixed properly. Then the above blend

was pre lubricated with talc and aerosil and further lubricated with

magnesium stearate. Loss on drying of the above blend was calculated

using Mettler IR moisture analyzer. LOD of the directly compressible

blend was found to be 0.6 %. Final lubricated blend was subjected for

the bulk and tapped density. Bulk density of the granules was found

to be 0.5176. The compressibility index was found to be 30.769. Poor

Hausner‟s ratio was observed for the directly compressible blend of

the zidovudine with PEO. Angle of repose of the blend was found to be

31.84°. This indicates the good flow of the granules as per USP

specification. Even though there was a poor compressibility Index,

tablets were compressed to observe the drug release profile from the

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directly compressible blends of zidovudine. The hardness of the

tablets was found to be 10 kg/cm2 with a thickness of 5.7 mm. Table

5.9 describes the physical characteristics of the prepared matrix

tablets with PEO by direct compression.

Granulation of PEO matrix tablets with water (FZ-5)

All the intra granular ingredients were properly mixed and

then sifted through # 30 mesh. The thoroughly mixed blend was

granulated with purified water. Water quantity used in the

granulation was around 20% of the dry mix blend. The granules

formed were very large. The granules were dried at 60° C until a

desired LOD was obtained. The LOD obtained in the dry mix blend

was 0.6%. It was clearly observed that the LOD of the dried granules

was not decreasing below 1.37 %. This is because of the moisture

accumulation inside the granules. However the LOD has not shown

any effect on the assay and compression parameters. Dried granules

were sifted through # 30 mesh and prelubricated with talc and aerosil.

Finally the prelubricated granules were lubricated with magnesium

stearate. Lubricated granules were subjected for bulk density and

tapped density. Bulk density of the granules was found to be 0.477

with a compressibility index of 16.67. The angle of repose of the

granules was found to be 36.73° and the Hausner‟s ratio of 1.2 was

observed which indicates the fair flow properties. Tablets were

compressed with same tooling used in the formulation FZ-1. Hardness

of the tablets was found to be 10 kg/cm2 with a thickness of 5.5 mm.

No friability was observed in the tablets. Table 5.9 describes the

133

physical characteristics of the prepared matrix tablets with PEO by

wet granulation with water.

Granulation of PEO matrix tablets with IPA (FZ-6)

The granules were prepared by the same method that was

adopted in the wet granulation process. The dry mix was granulated

using IPA (33%v/v) in the granulation preparation. Wet granules were

dried at 60°C until the desired LOD was obtained. Final LOD of the

granules was found around 1 %. The LOD was found to be less when

compared to those prepared using water as granulating liquid. This

low LOD is because of the complete evaporation of the IPA from the

granules during drying process. However LOD was not reached to the

LOD obtained in the dry mix blend. This may be due to the water

present in the IPA could have accumulated inside the granules. The

granules were finally sifted through # 30 mesh and pre-lubricated

with aerosil and talc. Pre-lubricated granules were finally lubricated

with magnesium stearate. The prepared granules were subjected for

bulk density and tapped density. The BD and TD were found to be

0.537 and 0.761 respectively. Hausner‟s ratio was found to be around

1.417. Compressibility index of the granules was found to be around

29.4. Angle of repose of the granules was found to be 31.71°, which

further confirms the good flow properties of the granules. Finally the

granules were compressed in to tablets. Hardness of the tablets was

found around 9.5 kg/cm2 with a thickness of 5.7 mm. Table 5.9

describes the physical characteristics of the prepared matrix tablets

with PEO by wet granulation with IPA.

134

Similar results were obtained with the directly compressible blends

with respect to the physical properties. The results suggested that the

granulation with IPA alone was not sufficient for the preparation of

Zidovudine matrix tablets prepared with PEO. It may also be

suggested that addition of some other binder in IPA may improve the

bulk properties of the granules.

Table 5.9 Physical characteristics of designed controlled release

matrix tablets of Zidovudine with PEO WSR 303



% of granulation fluid -- 20 % 33 %

Physical observation Fine blend

Large granules

Excellent granules

Loss on drying (LOD) 0.6 1.37 1.02

Bulk density (g/ml) 0.5176 0.477 0.537



HR 1.444 1.20 1.417

Angle of Repose in (°) 31.84° 36.73° 31.71°

Tablets

Drug content (% ) 98.3 99.7 99.2

Weight variation 600

(±0.5%) 600

(±0.5%) 600

(±0.5%)

Hardness (kg/cm2) 10 (±0.5) 10 (±0.5) 9.5 (±0.5)


Friability (%) Nil Nil Nil

5.3.9 Matrix tablets prepared with Carbopol 971

Carbopols are a widely used pharmaceutical sustained release

polymers. In the formulation three types of granules were prepared

with the use of Carbopol as release rate retardants. First directly

compressible (DC) blends were prepared, second wet granulation with

135

water and third wet granulation with isopropyl alcohol were prepared

as described in the formulation table 5.10. Various granulation and

compression parameters were studied and compared with in the

process. Finally in vitro dissolution studies on the prepared matrix

tablets were done and compared with each other.

Table 5.10 Formulations of designed controlled release matrix tablets of Zidovudine Carbopol 971





Carbopol 971 125 125 125


Poly vinyl pyrollidine 10 10 10



Talc 4 4 4



Direct compression of Zidovudine matrix tables with Carbopol

(FZ-7)

All the excipients were directly mixed and sifted through mesh #

30 sieve. Dry mix blend then pre lubricated with aerosil and talc. The

pre-lubricated blend was then lubricated with magnesium stearate.

Loss on drying was checked and LOD of the directly compressible

granules was found to be around 0.55. The blend was then subjected

for Bulk density and Tapped density. Very poor bulk density of 0.337

was obtained. Poor angle of repose 56.3° was observed for the directly

136

compressible blend Very poor compressibility index of 46.156 with

Hausner‟s ratio of 1.857 was observed. By observing these poor flow

and bulk properties, the final blend was not compressed into tablets

and it was discarded. Table 5.11 describes the physical characteristics

of the prepared matrix tablets with Carbopol by direct compression.

Granulation of Carbopol matrix tablets with Water (FZ-8)

Intra granular ingredients were sifted and mixed thoroughly.

Required quantity of purified water was added to the above dry mix

blend for granulation. Immediately after addition of water, Carbopol

was wetted and localized lump formation occurred as shown in the Fig

5.12. Only 13 % of purified water was added to the above dry mix. So

it was found impossible to prepare granulation using Zido-Carbopol

971 and water in the preparation of Zidovudine matrix tablets.

Granulation of Carbopol matrix tablets with IPA (FZ-9)

All intra granular ingredients were sifted through # 30 size

mesh and mixed thoroughly. The above dry mix blend was granulated

with Isopropyl alcohol. 40 % of IPA was used for the granulation

process. The wet granules were dried at 60°C to get the desired LOD

(ie 0.55%). It was observed that LOD of the granules was not

decreasing below1.01 %. So, final LOD of the granules was 1.01 %.

The dried granules were sifted through # 30 mesh and pre lubricated

with aerosil and talc. The prelubricated granules were then lubricated

with magnesium stearate. Bulk density and tapped density was

checked for the lubricated granules. Bulk density of the granules was

found to be around 0.473. Good compressibility index was observed

137

around 24.24 with Hausner‟s ration 1.32 and good angle of repose

28.53° was observed for the granules. It was clearly observed that

increase in bulk density and decrease in compressibility index and

Hausner‟s ration indicates the good flow property of the granules. It is

suggested that wet granulation with IPA gives very good compression

results for the Zidovudine matrix tablets prepared with Carbopol 971.

Table 5.11 describes the physical characteristics of the prepared

matrix tablets with PEO by wet granulation with IPA.

Fig. 5.12 Photograph showing the lump formation during granulation

of Zidovudine Carbopol with water.

138

Table 5.11 Physical characteristics of designed controlled release matrix tablets of Zidovudine with Carbopol 971




Properties of granules


Lump

formation

Excellent granules

Loss on drying (LOD) 0.55 1.01

Bulk density (g/ml) 0.337 0.473

Tapped density (g/ml) 0.626 0.624

Compressibility index 46.156 24.24

HR 1.857 1.320

Angle of Repose in (°) 56.30° 28.53°

Properties of Tablets

Drug content (% )

Impossible to

compress

98.2 (±3.16)

Weight variation

600

(±23.6%)

Hardness (kg/cm2) 9.6 (±0.5)

Thickness (mm) 5.6

Friability (%) Nil

5.3.10 Matrix tablets prepared with Eudragit L 100

Eudragit L 100 is also a widely used pharmaceutical sustained

release polymer. Similar type of directly compressible (DC) blends, wet

granulation with water and isopropyl alcohol were prepared as

described in the formulation table 5.12. Various granulation and

compression parameters were studied and compared with in the

process. Finally in vitro dissolution studies on the prepared matrix

tablets were done and compared with each other.

139

Table 5.12 Formulations of designed controlled release matrix tablets of Zidovudine with Eudragit L 100





Eudragit L 100 125 125 125


Poly vinyl pyrrolidone 10 10 10



Talc 4 4 4



Direct compression of Zidovudine matrix tablets with Eudragit

L100 (FZ-10)

All the excipients were directly mixed and sifted through # 30

size mesh. The dry mix blend was pre lubricated with talc and aerosil

and lubricated with magnesium stearate. The blend was checked for

LOD, BD and TD. LOD of the blend was found to be 1.4 %. Bulk

density was observed as 0.496. Angle of repose of the directly

compressible blend was found to be 25.90°, which indicates good flow

but poor compressibility of 34.21 with Hausner‟s ratio of 1.52 was

observed. However the blend was compressed into tablets for the

observation of dissolution pattern in the directly compressible blends

of Zidovudine prepared with Eudragit L100. Hardness of the tablets

was found around 9.5 kg/cm2 with a thickness of 5.9 mm. Table 5.13

describes the physical characteristics of the prepared matrix tablets

with Eudragit L100 by direct compression.

140

Granulation of Eudragit L100 matrix tablets with Water (FZ-11)

All intra granular excipients were sifted and mixed thoroughly.

The dry mix blend was granulated with required quantity of purified

water. Wet granules were dried at 60° C until to get the desired LOD.

The LOD of the dried granules was found around 1.82 which was

almost similar to the LOD obtained in the directly compressible blend.

Dried granules were sifted through # 30 size mesh and pre lubricated

with talc and aerosil. Pre lubricated granules then lubricated with

magnesium stearate. The lubricated granules were subjected for bulk

density and tapped density. BD of the granules was found around

0.496. Angle of repose of the granules found to be 26.56°, this clearly

indicates good flow properties of the granules. Compressibility index

was found to be 28.125. Finally the granules were compressed into

tablets. The tablets having hardness of 9.5 kg/cm2 and thickness was

found around 5.87 mm. Table 5.13 describes the physical

characteristics of the prepared matrix tablets with Eudragit L100 by

wet granulation with water.

Granulation of Eudragit L100 matrix tablets with IPA (FZ-11)

All ingredients were sifted through # 30 mesh and mixed

thoroughly. Dry mix was granulated using Isopropyl alcohol (30 %

v/v). The granules were dried at 60° C until a desired LOD was

obtained. The LOD of the final dried granules was found around 1.67.

The dried granules were pre lubricated with talc and aerosil and

lubricated with magnesium stearate. Bulk density of the granules was

found to be 0.5146. Angle of repose of the granules was found to be

141

24.19° which indicates excellent flow properties. Good compressibility

index of 25.01 and Hausner‟s ratio of 1.333 was observed. The

compressibility index was less when compared with the granulation

prepared with water. Finally the prepared granules were compressed

into tablets. The tablets showed hardness of 9.5 kg/cm2 and

thickness of 5.9 mm. Table 5.13 describes the physical characteristics

of the prepared matrix tablets with Eudragit L100 by wet granulation

with IPA.

Except direct compression, both water and IPA granulation was

feasible for the Zidovudine matrix tablets prepared with Eudragit

L100.

142

Table 5.13 Physical characteristics of designed controlled release matrix tablets of Zidovudine with Eudragit L 100





Good granules

Good granules

Loss on drying (LOD) 1.4 1.82 1.67

Bulk density (g/ml) 0.469 0.496 0.5146



HR 1.520 1.391 1.333

Angle of Repose in (°) 25.96° 26.56° 24.19°

Tablets

Drug content (% ) 98.3 98.91 99.7

Weight variation

600

(±0.5%)

600

(±0.5%)

600

(±0.5%)

Hardness (kg/cm2) 9.5 (±0.5) 9.5 (±0.3) 9.5 (±0.3)


Friability (%) Nil Nil Nil

5.3.11 Particle size distribution (PSD)

Particle size distribution of Zidovudine granules prepared with

different polymers and different granulation fluid were calculated.

Granules prepared with PEO WSR 303

Zidovudine/PEO granules prepared with water gives 43.8 %

retains on #60 mesh sieve where as the granules prepared with IPA

resulted 36.8% of retains on # 60 mesh sieve. Excess fine percentage

was observed in both the granulation process with PEO.

143

Granules prepared with Eudragit L 100

Zidovuidne/Eudragit L100 granules prepared with both IPA and

water resulted 59% retains on # 60 mesh sieve. Excess fine percentage

was observed in the granules prepared with water than IPA.

Granules prepared with Carbopol

Zidovudine/Carbapol granules prepared with IPA resulted 62.5

% retains on # 60 mesh. Table 5.14 and 5.15 describes the percent of

granules retained and cumulative percent retained on different sieves.

Figs 5.13 to 5.17 show graphical representation of particle size

distribution of zidovudine granules with different polymers and

granulation fluids.

Table 5.14 Percent of granules retained during particle size

distribution of Zidovudine with different polymers and granulation fluids

SEIVE

NO PEO/Water PEO/IPA EUD/Water EUD/IPA CBP/IPA

30 6.3±1.12 0 3.2±0.21 0 2.5±0.21

40 12.5±0.81 10.5±0.23 19.7±0.89 28.5±0.21 41.25±0.89

60 25±0.96 26.3±0.87 35.9±0.56 30±0.55 18.75±0.21

80 6.3±0.56 15.8±0.96 11.8±0.23 12.5±0.87 6.25±0.85

100 3.1±1.21 10.5±1.21 0 6.25±1.21 6.25±0.65

120 9.4±0.96 10.5±0.56 11.8±0.15 12.5±1.56 12.5±0.21

Pan 37.5±1.22 26.3±1.36 17.6±0.56 10±.89 12.5±0.87

Table 5.15 Cumulative percent retained of granules during particle size distribution of Zidovudine with

different polymers and granulation fluids

SEIVE NO PEO/Water PEO/IPA EUD/Water EUD/IPA CBP/IPA

30 6.3 0.0 3.2 0 2.5

40 18.8 10.5 22.9 28.8 43.8

60 43.8 36.8 58.8 58.8 62.5

80 50.0 52.6 70.6 71.3 68.8

100 53.1 63.2 70.6 77.5 75.0

120 62.5 73.7 82.3 90.0 87.5

Pan 100.0 100.0 100.0 100.0 100.0

144

Fig. 5.13 Histogram showing particle size distribution of

Zidovudine with PEO and water granulation

Fig. 5.14 Histogram showing particle size distribution of Zidovudine with PEO and IPA granulation

145

Fig. 5.15 Histogram showing particle size distribution of

Zidovudine with Eudragit L100 and water granulation

Fig. 5.16 Histogram showing particle size distribution of Zidovudine with Eudragit L100 and IPA granulation

146

Fig. 5.17 Histogram showing particle size distribution of Zidovudine with Carbopol and IPA granulation

5.3.12 Microscopic study of Zidovudine granules

Microscopic study was done on the prepared zidovudine matrix

tablets prepared with different polymers and with different granulation

fluids. Different photomicrographs were taken at 10X and 40X optical

zoom to study the morphological characteristics of the prepared

granules. The microscope used to study the morphological

characteristics was QUASMO ANISO 9001-2000 microscope equipped

with Digital camera DCE2.

The matrix tablets of Zidovudine-PEO prepared with water

granulation yielded rough surface, straight, elongated, needle shaped

granules with different sizes (Fig 5.18 and 5.19).

147

Fig. 5.18 Photomicrograph showing granule of Zidovudine with PEO and water granulation (40 X resolution)

Fig. 5.19 Photomicrograph showing granule of

Zidovudine with PEO and water granulation (10 X resolution)

148

The matrix tablets of Zidovudine-PEO prepared with IPA

granulation yielded large, straight, elongated, sharp edged, needle

shaped granules with different sizes (Fig 5.20 and 5.21).


Zidovudine with PEO and IPA granulation (40 X resolution)


Zidovudine with PEO and IPA granulation (10 X resolution)

149

The matrix tablets of Zidovudine-Eudragit L100 prepared with

water granulation yielded irregular shaped, rough surface lumpy mass

shaped granules with different sizes (Fig 5.22 and 5.23).

Fig. 5.22 Photomicrograph showing granule of Zidovudine with Eudragit L100 and Water granulation (40 X

resolution)


Zidovudine with Eudragit L100 and Water granulation (10 X resolution)

150

The matrix tablets of Zidovudine-Eudragit L100 prepared with

IPA granulation yielded smooth shaped, lumpy mass granules with

different sizes (Fig 5.24 and 5.25).


Zidovudine with Eudragit L100 and IPA granulation (40 X resolution)

Fig. 5.25 Photomicrograph showing granule of Zidovudine with Eudragit L100 and IPA granulation (10 X resolution)

151

The matrix tablets of Zidovudine-Carbopol prepared with IPA

granulation yielded crystal like, uniform granules with different

shapes (Fig 6.26 and 6.27).

Fig. 5.26 Photomicrograph showing granule of Zidovudine with Carbopol and IPA granulation (40 X resolution)

Fig. 5.27 Photomicrograph showing granule of Zidovudine with Carbopol and IPA granulation (10 X resolution)

152

5.3.13 In vitro dissolution studies of prepared tablets

Matrix tablets prepared with PEO

In vitro dissolution studies were conducted on Zidovudine

matrix tablets prepared with PEO. Release from the directly

compressed tablets (FZ-4) showed initial fast release in the first hours.

Initial slow release around 15 % (FZ-5) was observed in the matrix

tablets prepared with water granulation process. Initial 18 % (FZ-6)

drug was release in the first hour for the matrix tablets prepared with

IPA granulation process. The drug release slowed down after 6 hours

in the matrix tablets prepared with IPA granulation process. Table

5.16 shows in vitro dissolution of controlled release matrix tablets of

Zidovudine – PEO prepared using different granulation fluids.

In vitro drug release kinetics showed first order indicating that

the drug release from the tablets was directly proportional to the

concentration of the drug in the matrix system. The release kinetics

was best fitted to the Higuchi model clearly indicating that the drug

release mechanism was diffusion controlled. Low elimination rate

constants such as 8.37, 6.99 and 6.09, high elimination half life

values such as 5.97, 7.15 and 8.25 hours for the matrix tablets

prepared by direct compression, wet granulation with water and wet

granulation with IPA clearly indicates that the drug is released slowly.

Table 5.17 shows the release kinetics of controlled release matrix

tablets of Zidovudine-PEO prepared with different granulation fluids.

Fig 5.28 shows the plots of release kinetics of the Zidovudine-PEO

matrix tablets prepared with different granulation fluids.

153

Table 5.16 In vitro dissolution of controlled release matrix tablets of

Zidovudine – PEO prepared with different granulation fluids

Time (Hrs.)

FZ-4 FZ-5 FZ-6

1 19 ±2.15 15 ±1.21 18 ±1.56

2 32 ±3.56 31 ±2.36 33 ±1.74

3 45 ±3.56 44 ±3.12 49 ±2.71

4 53 ±3.55 51 ±2.12 55 ±2.85

5 65 ±2.45 66 ±2.36 61 ±2.56

6 70 ±3.45 69 ±2.58 66 ±2.31

7 76 ±2.12 74 ±4.15 69 ±3.12

8 81 ±2.36 79 ±3.12 74 ±3.54

9 89 ±3.12 85 ±4.12 79 ±2.16

10 94 ±4.56 89 ±3.12 84 ±1.56

11 97 ±1.21 93 ±3.58 89 ±1.01

12 -- 98 ±1.21 93 ±1.02

Table 5.17 Release kinetics of controlled release matrix tablets of

Zidovudine- PEO prepared with different granulation fluids.

Kinetics FZ-4 FZ-5 FZ-6

Zero order

r2 0.9326 0.9356 0.9165

K 8.37 6.99 6.06

t1/2 5.97 7.15 8.25

First order

r2 0.9475 0.9884 0.986

K 0.302 0.9884 0.9884

t1/2 2.3 0.9884 0.9884

Higuchi

r2 0.966 0.9425 0.9389

K 34.37 33.08 28.71

t1/2 2.11 2.28 3.03

154

B

-0.1

0.4

0.9

1.4

1.9

2.4

0 2 4 6 8 10 12

Time (hr)

Lo

g p

erc

en

t re

ma

inin

g

PEO-DC PEO-Water PEO-IPA

C

0

20

40

60

80

100

1

1.73

21

2.23

61

2.64

58 3

3.31

66

Sq Rt of Time (hrs)

Cu

mu

lative

pe

rce

nt re

lea

se

d

PEO-DC PEO-Water PEO-IPA

Fig. 5.28 (A) Cumulative percent drug release vs time (B) Log percent

remaining vs time (C) Cumulative percent release vs square root of time (HIGUCHI) plots of Zidovudine-PEO matrix tablets prepared with

different granulation fluids.

Matrix tablets prepared with Carbopol

In vitro dissolution studies of Carbopol Zidovudine matrix

tablets (FZ-9), shows about 68 % of the drug released in 24 hours.

This clearly indicated that polymer proportion in the matrix system

was more. Therefore, in the further batch it was decided to decrease

A

0

20

40

60

80

100

0 2 4 6 8 10 12

Time (hrs)

Cu

mu

lative

perc

en

t re

lea

se

d

PEO-DC

PEO-Water

PEO-IPA

155

the concentration of the Carbopol to 10% (60 mg to the target tablet

weight) and again dissolution studies were performed on the freshly

prepared matrix tablets with IPA granulation. Results showed that 98

% drug was released in 12 hours. (Table 5.18).

The drug release kinetics followed zeroorder and the best

fitted to the Higuchi model indicating that the drug release is diffusion

controlled. Half life was found to be around 17.24 and 13.15 hours for

both formulation FZ-9 and FZ9-A respectively, which clearly indicates

the prolonged release of the drug (Table 5.19). Figs 5.29 to 5.31 show

the plots of release kinetics.

Table 5.18 Cumulative Percent of drug released from Zidovudine-Carbopol matrix tablets

Time(Hrs.) FZ-9 FZ-9-A

1 2±2.67 9±1.11

2 2±2.21 18±2.35

3 3±2.26 22±2.19

4 7±2.35 26±2.25

5 9±1.11 30±2.55

6 11±2.67 34±2.19

7 17±3.11 37±2.31

8 19±1.23 42±3.25

9 23±2.11 44±3.11

10 26±2.22 47±4.01

11 29±1.89 51±3.11

12 33±2.11 56±2.91

14 39±2.16 62±1.92

16 45±2.32 70±1.97

18 48±1.76 77±1.56

20 55±3.16 85±1.66

22 61±1.11 91±1.56

24 68±2.16 98±1.45

156

Table 5.19 Release kinetics of Zidovudine–Carbopol with IPA granulation

Kinetics FZ-9 FZ-9-A

Zero order

r2 0.9941 0.9906

K 2.87 3.82

t1/2 17.24 13.15

First order

r2 0.9775 0.8206

K 0.0526 0.123

t1/2 13.10 5.77

Higuchi

r2 0.9713 0.9765

K 17.90 22.56

t1/2 7.8 4.89

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hrs)

Cu

mu

lative

per

cent r

ele

ase

d

FZ-9 FZ-9-A

Fig. 5.29 Cumulative percent released vs time plot of

Zidovudine with Carbopol

157

Fig. 5.30 Log percent remaining vs time plot of

Zidovudine with Carbopol

Fig. 5.31 Cumulative percent released vs square root of time plot of

Zidovudine with Carbopol (HIGUCHI)

158

Matrix tablets prepared with Eudragit L100

In vitro dissolution of Zidovudine matrix tablets prepared with

direct compression showed 100 % drug release in 7 hours (FZ-10).

Dissolution of matrix tablets prepared with IPA (FZ-12) granulation

showed 99 % drug release for around 12 hours while 99 % of drug

release in 11 hours was observed for the matrix tablets prepared with

water granulation (FZ-11) (Table 5.20 and Fig-5.32).

In vitro release kinetics have shown zero order release and best

fitted to the Higuchi correlation indicating that the drug release

mechanism was diffusion controlled (Fig-5.34).

Elimination half life of 5.8 hours indicated that the prolongation

of drug release from the matrix tablets prepared with IPA granulation

process. The release rate constant of 8.62 hours -1 was observed for

the matrix tablets prepared with IPA granulation process.

Table 5.20 Percent drug release of Zidovudine- Eudragit L100 matrix tablets with different granulation fluids

Time(Hrs.) FZ-10 FZ-11 FZ-12

1 10 ±1.56 7 ±1.25 5 ±2.36

2 31 ±3.56 17 ±2.56 15 ±2.15

3 42 ±2.45 26 ±1.85 24 ±3.12

4 57 ±2.89 37 ±2.89 36 ±2.15

5 71 ±1.56 49 ±3.15 43 ±2.45

6 84 ±2.45 59 ±3.78 57 ±2.87

7 99 ±1.02 67 ±2.13 64 ±1.23

8 77±2.45 71 ±2.89

9 87 ±2.87 77 ±1.56

10 94 ±2.71 85 ±1.89

11 99 ±1.17 94 ±1.91

12 99 ±1.21

159

Table 5.21 Release kinetics of Zidovudine- Eudragit L100 matrix tablets with different granulation fluids

Kinetics FZ-10

DC

FZ-11

Water

FZ-12

IPA

Zero

order

r2 0.9971 0.9959 0.9933

K 14.26 9.5 8.62

t1/2 3.51 5.26 5.80

First

order

r2 0.7869 0.8992 0.956

K 0.322 0.276 0.230

t1/2 2.15 2.51 3.01

Higuchi

r2 0.9959 0.9948 0.9915

K 52.870 42.250 39.820

t1/2 0.894 1.399 1.577

0

20

40

60

80

100

0 2 4 6 8 10 12Time (hrs)

Cu

mu

lativ

e pe

rcen

t re

lea

sed

EUDRAGIT-DC

EUDRAGIT-WaterEUDRAGIT-IPA

Fig. 5.32 Cumulative percent released vs time plots of

Zidovudine prepared with Eudragit L100

160

-0.1

0.4

0.9

1.4

1.9

2.4

0 2 4 6 8 10 12 14

Time (hr)

Lo

g p

erc

en

t re

ma

inin

g

EUDRAGIT-DC EUDRAGIT-WaterEUDRAGIT-IPA

Fig. 5.33 Log percent remaining vs time plots of

Zidovudine prepared with Eudragit L100

0

20

40

60

80

100

1

1.73

21

2.23

61

2.64

58 3

3.31

66

Sq Rt of Time (hrs)

Cu

mu

lative

pe

rce

nt re

lea

se

d

EUDRAGIT-DCEUDRAGIT-WaterEUDRAGIT-IPA

Fig. 5.34 Cumulative percent released vs square root of time plots of

Zidovudine prepared with Eudragit L100 (HIGUCHI)

161

5.3.14 DSC Studies

DSC studies were conducted for Zidovudine matrix tablets

prepared with HPMC K 100 M at initial time, 40°/75 % RH- 1 months

and 40°/75% RH-3 months. Pure Zidovudine showed sharp

endothermic peak at 123.8 °C (Fig-5.35 A). Matrix tablets tested soon

after compression show a sharp endothermic peak at 122.87°C (Fig-

5.35 B). Matrix tablets at 40°/75% RH- 1 months and 40°/75% RH-3

months show sharp endothermic peaks at 122.86°C and 123.20°C

respectively. This confirms the stable nature of the drug. (Fig-5.35 C

and 5.36 D ).

Fig. 5.35 DSC thermograms of (A) Pure Zidovudine (B) Zidovudine HPMC K 100 M matrix tablets- Initial time

162

Fig.5.36 DSC thermograms of (C) Zidovudine HPMC K 100 M matrix tablets- 40°C/75% RH - 1 Month (D) Zidovudine HPMC K 100M

matrix tablets- 40°C/75% RH - 3 Months

163

5.3.15 FTIR Studies

FTIR studies were conducted on the matrix tablets prepared

with HMPC K 100 M at initial time, 1 Month 40°C/75% RH and 3

months 40°C/75% RH. These studies were also conducted for matrix

tablets prepared with Eudragit L100, Carbopol and PEO with different

granulation fluids.

FTIR studies for matrix tablets prepared with HPMC K 100M

The FTIR spectra of pure Zidovudine demonstrated

characteristic absorption peaks for carbonyl group at 1685.42 cm-1

and for azido group at 2082.56cm-1. Similar absorption peaks were

observed in matrix tablets at initial for carbonyl group at 1685.74 and

for azido group at 2082.92 cm-1. Similar absorption peaks at 1682.42

and 2083.15 cm-1 for carbonyl and azido groups respectively (1 Month

40°C/75% RH) and 1685 and 2083.11 for carbonyl and azido groups

respectively (3 Month 40°C/75% RH), clearly further confirms the

stable nature of the drug. (Fig-5.37).

FTIR studies for matrix tablets prepared with PEO

FTIR absorption peaks for water granulation were found at

1685.92 and 2082.81 cm-1 for carbonyl and azido groups and FTIR

absorption for IPA granulation were found at 1685.63 and 2082.96

cm-1 for carbonyl and azido groups. This confirms the stable nature of

the drug.

FTIR studies for the matrix tablets prepared with Eudragit L100

FTIR absorption peaks for water granulation were found at

1686.47 and 2083.11 cm-1 for carbonyl and azido groups and FTIR

164

absorption for IPA granulation were found at 1685.46 and 2083 cm-1

for carbonyl and azido groups. Similar peaks were with pure

Zidovudine at similar wave number clearly indicates the stable nature

of the drug in the polymer matrix system.

FTIR studies for the matrix tablets prepared with Carbopol

FTIR corresponding peaks with IPA granulation of Zidovudine

matrix tablets were found at 1685.78 and 2083.08 cm -1 for carbonyl

and azido groups. Similar absorption peaks were observed in pure

Zidovudine confirms the stable nature of the Zidovudine - Carbopol.

Fig 5.38 shows the spectrum peak points of Zidovudine with different

polymers and different granulation fluids.

Fig. 5.37 FTIR spectrum peak points of Zidovudine HPMC matrix tablets- Initial, Zidovudine matrix tablets 40°C/75% RH- 1 Month ,

Zidovudine HPMC K 100 M matrix tablets- 40°C/75% RH - 3months

165

Fig. 5.38 FTIR spectrum peak points of Zidovudine-PEO matrix tablets

with water granulation, Zidovudine-PEO matrix tablets with IPA granulation, Zidovudine-Carbopol matrix tablets with IPA granulation,

Zidovudine-Eudragit L100 matrix tablets with water granulation,

Zidovudine-Eudragit L100 matrix tablets with IPA granulation.

166

ZIDOVUDINE MICROCAPSULES

167

5.4 Preparation of Zidovudine microcapsules

Zidovudine microcapsules were prepared with Eudragit RL 100

and Eudragit RS 100 by using solvent evaporation method described

in the section 3.3.3 of chapter 3.

5.5 Characterization of microcapsules

5.5.1 Encapsulation efficiency (EE)

Encapsulation efficiency of the drug loaded microcapsules was

determined by the general assay method described in the section

3.3.14 of chapter 3.

5.5.2 Particle size distribution

Particle size analysis of the microcapsules was done by the

method described in the section 3.3.15 of chapter 3.


The FT-IR spectrum microcapsules at initial and stability

samples were determined by the method described in the 3.3.6 of

chapter 3.

5.5.4 Differential scanning calorimetry (DSC) study

Thermal properties of microcapsules at initial and stability

samples were evaluated by the method described in the 3.3.7 of

chapter 3.

5.5.5 Morphological study of microcapsules

Morphological characterization of the microcapsules was done

by using microscope.

168

5.5.6 In Vitro Drug Release Studies

The in vitro dissolution studies were performed using USP type I

dissolution apparatus (LABINDIA, DISSO-2000, Mumbai, India) at 100

rpm. The microcapsules were weighed and filled in the empty hard

gelatin capsule shells size “2” and placed in the basket. The

dissolution medium consisted of 900 ml of phosphate buffer pH 6.8

maintained at 37 ±0.5 °C. An aliquot (5 mL) was withdrawn at specific

time intervals and drug content was determined by UV visible

spectrophotometer (Schimadzu, UV-1700 E 23) at 266 nm. The

dissolution study was conducted in triplicate.

169

5.6 Results and discussion

5.6.1 Preparation of microcapsules

Zidovudine microcapsules were prepared by using solvent

evaporation method and found to be discrete and free flowing.

5.6.2 Encapsulation efficiency (EE)

Encapsulation efficiency was increased with increase in the

polymer proportion in the formulation. Encapsulation efficiency of

69-76 % was observed in the microcapsules prepared with Eudragit

RL 100 and that of 72-76 % was observed in the microcapsules

prepared with Eudragit RS 100 (Table 5.22).

5.6.3 Particle size distribution

Particle size analysis12 of the microcapsules was done by sieving

method using Indian Standard Sieves #10, #20, #30, #40, #60 and

#80. Highest particle size was observed in the range of 445 μ

(Table 5.22) in both the microcapsules prepared with Eudragit RL 100

and RS 100. The percent of microcapsules obtained varies with the

polymer proportion in the formulation. 70-80 % of the particles were

obtained in the range of 445 μ. However the particle size may change

with the polymer proportion and stirring rpm because of the droplet

formation in the emulsification process. Figs-5.39 and 5.40 show the

particle size distribution of the microcapsules.

170

0

20

40

60

80

100

0 500 1000 1500

Particle size in microns

Pe

rce

nt

reta

ine

d

FR D:L100-1(1:1)

FR D:L100-1(1:2)

FR D:L100-1(1:3)

Fig. 5.39 Particle size distributions of Zidovudine microcapsules prepared with Eudragit RL 100

0

20

40

60

80

100

0 500 1000 1500

Particle size in microns

Pe

rce

nt

reta

ine

d

FR D:S100-1(1:1)FR D:S100-1(1:2)FR D:S100-1(1:3)

Fig. 5.40 Particle size distributions of Zidovudine

microcapsules prepared with Eudragit RS 100

171

Table 5.22 Sieve analysis, Drug content and entrapment efficiency of

Zidovudine microcapsules

DRUG :RL 100 DRUG :RS 100

Size 1:1 1:2 1:3 1:1 1:2 1:3

10/20 (1242 µ) 5 ±0.15 7 ±0.15 12 ±0.85 1 ±0.87 7 ±0.56 12 ±0.56

20/30 (666.5 µ) 15 ±1.01 10 ±0.26 10 ±1.21 9 ±0.78 10 ±0.74 10 ±0.21

30/40 (445 µ) 70 ±0.56 78 ±0.69 69 ±0.88 82 ±0.56 76 ±0.87 70 ±0.32

60/80 (225 µ) 10 ±0.87 5 ± 0.99 9 ±0.78 8 ±0.56 7 ±0.47 8 ±0.87

Drug content (%)

Theoretical (%) 50 33.3 25 50 33.3 25

Estimated (%) 34.56

± 2.16

25.33

±3.12

19.16

±1.65

36.11

±1.89

24.32

±1.23

19.17

±3.61

Entrapment

efficiency (%)

69.12 76.06 76.64 72.22 73.03 76.68

172


FTIR studies were conducted on the prepared microcapsules.

Absorption peaks of carbonyl group at 1685.72 and azido group at

2083.03 for Zidovudine microcapsules prepared with Eudragit RL 100

and carbonyl group at 1685.06 and azido group at 2082.77 for

Zidovudine microcapsules prepared with Eudragit RS 100 clearly

indicated the stable nature of microcapsules prepared with these

polymers. Fig-5.41 shows the spectrum peaks points of zidovudine

microcapsules during FTIR.

Fig. 5.41 FTIR spectrum peak points of Zidovudine microcapsules with Eudragit RL 100 and Eudragit RS 100

173

5.6.5 Differential scanning calorimetry (DSC) study

Differential scanning calorimetric (DSC) study of drug loaded

microcapsules was performed using a Diamond DSC (Mettler Star SW

8.10) to determine the drug excipients compatibility. DSC

thermograms show sharp endothermic peaks at 121°C and 122°C

which corresponds to the Zidovudine microcapsules prepared with

Eudragit RL 100 and RS 100 clearly indicated the stable nature of the

drug. Fig-5.42 shows the endothermic peaks of zidovudine

microcapsules during melting process.

Fig. 5.42 DSC thermograms showing melting process of

Zidovudine microcapsules with Eudragit RL 100 and Eudragit RS 100.

174

5.6.6 Morphological study of Zidovudine microcapsules

Morphological characterization of the microcapsules was done

by using microscope. The microcapsules prepared with both the

Eudragit RL 100 and RS 100 are free flowing. Spherical microcapsules

were formed with Eudragit RL 100 (Fig 5.43) where as variety of

shapes, i.e., spherical, oval, rectangular, straight and elongated, were

formed with Eudragit RS 100 (Fig-5.44).

Fig. 5.43 Microscopic photograph showing

Zidovudine microcapsules with Eudragit RL 100

Fig. 5.44 Microscopic photograph showing Zidovudine microcapsules with Eudragit RS 100

175

5.6.7 In Vitro Drug Release Studies

Microcapsules prepared with Eudragit RL 100

Cumulative percent drug released varies with the polymer

proportion. As the polymer proportion increased the drug release rate

was decreased. Drug release of around 96 % was found in 1:3 drug to

polymer ratio in 12 hr in the microcapsules prepared with Eudragit RL

100 (Table 5.23) and the drug release has followed zero order kinetics

(Fig-5.45). Higuchi correlation indicated that the drug release

mechanism was diffusion controlled (Fig-5.49).

Elimination half life was found to be 6.23 hr for the

microcapsules of 1:3 drug to polymer ratio. Increase in the elimination

half life with increase in polymer proportion and decrease in release

rate constant clearly indicated the prolonged release of the drug.

Microcapsules prepared with Eudragit RS 100

A 97 % of the drug release in 10 hr, 96 % in 12 hr and 87 % in

12 hr was observed in 1:1, 1:2 and 1:3 drugs to polymer ratio

respectively. However the release was depended on the polymer

proportion and type of polymer and the drug release of Eudragit RS

100 was slower than Eudragit RL 100 (Table 5.23).

Drug release has followed Zero order kinetics (Fig-5.46). Higuchi

correlation indicated that the drug release mechanism was diffusion

controlled (Fig-5.46). Elimination half life found to be around 6.89 hr

for microcapsules of 1:3 drug to polymer ratio. Increase in the

elimination half life with increase in polymer proportion and decrease

176

in release rate constant clearly indicated the prolonged release of the

drug.

Table 5.23 Percent drug released of Zidovudine microcapsules with

Eudragit RL 100 and Eudragit RS 100

Table 5.24 Release kinetics of Zidovudine microcapsules with

Eudragit RL 100 and Eudragit RS 100

Kinetics Zero order First order Higuchi

1:1 1:2 1:3 1:1 1:2 1:3 1:1 1:2 1:3

Microcapsules with Eudragit RL 100

r2 0.986 0.985 0.9964 0.752 0.828 0.8843 0.991 0.9896 0.984

K 10.36 8.83 8.03 0.336 0.269 0.233 44.5 40.89 37.44

t1/2 4.83 5.66 6.23 2.06 2.87 2.98 1.25 1.49 1.8

Microcapsules with Eudragit RS 100

r2 0.994 0.998 0.998 0.934 0.842 0.919 0.982 0.9792 0.974

K 9.1 7.85 7.26 0.216 0.18 0.154 40.27 36.04 32.96

t1/2 5.49 6.37 6.89 3.2 3.56 4.49 1.53 2.75 2

Formu lation

DRUG :RL 100 DRUG :RS 100

Time (hr)

1:01 1:02 1:03 1:01 1:02 1:03

0 0 0 0 0 0 0

1 21 ±2.12 19 ±1.56 13 ±2.56 16 ±2.65 11 ±1.23 6 ±1.56

2 33 ±3.56 30 ±1.59 20 ±2.87 27 ±2.45 18 ±2.15 14 ±1.59

3 40 ±3.21 36 ±2.35 27 ±2.45 33 ±2.78 27 ±2.78 22 ±2.48

4 49 ±3.45 42 ±3.65 35 ±3.15 42 ±2.48 36 ±3.45 29 ±2.87

5 62 ±2.56 53 ±3.01 43 ±2.45 50 ±3.15 43 ±2.56 36 ±2.89

6 70 ±2.11 64 ±3.48 52 ±2.69 57 ±3.49 48 ±2.45 39 ±2.45

7 84 ±2.13 73 ±2.15 61 ±2.45 69 ±2.97 57 ±1.23 50 ±3.15

8 90 ±3.12 82 ±2.59 70 ±2.47 77 ±2.81 64 ±1.21 58 ±3.56

9 97 ±1.02 90 ±2.89 78 ±2.48 86 ±2.12 71 ±2.35 64 ±1.24

10 95 ±2.78 84 ±2.45 97 ±1.21 82 ±3.45 72 ±2.12

11 99 ±1.23 91 ±2.89 90 ±2.16 80 ±1.21

12 96 ±2.78 96 ±1.56 87 ±1.01

177

0

20

40

60

80

100

0 2 4 6 8 10 12

Time (hrs)

Cu

mu

lati

ve p

erc

en

t re

leased

FZ:RL100-(1:3)FZ:RL100-(1:2)FZ:RL100-(1:1)

Fig. 5.45 Cumulative Percent released vs time plots of Zidovudine microcapsules prepared with Eudragit RL 100

0

20

40

60

80

100

0 2 4 6 8 10 12

Time (hrs)

Cu

mu

lati

ve p

erc

en

t re

leased

FZ:RS100-(1:3)FZ:RS100-(1:2)FZ:RS100-(1:1)

Fig. 5.46 Cumulative Percent released vs time plots of Zidovudine microcapsules prepared with Eudragit RS 100

178

-0.1

0.4

0.9

1.4

1.9

2.4

0 2 4 6 8 10 12 14

Time (hr)

Lo

g p

erc

en

t re

main

ing

FZ:RS100-(1:3)

FZ:RS100-(1:2)

FZ:RS100-(1:1)

Fig. 5.47 Log percent remaining vs time plots of Zidovudine microcapsules prepared with Eudragit RS 100

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10 12

Time (hr)

Lo

g p

erc

en

t re

ma

inin

g

FZ:RL100-(1:3)

FZ:RL100-(1:2)

FZ:RL100-(1:1)

Fig. 5.48 Log percent remaining vs time plots of Zidovudine microcapsules prepared with Eudragit RL 100

179

0

20

40

60

80

100

0 2

Sq RT of Time (hrs)

Cu

mu

lative

pe

rce

nt re

lea

se

d

FZ:RL100-(1:3)

FZ:RL100-(1:2)

FZ:RL100-(1:1)

Fig. 5.49 Cumulative Percent released vs square root of time plots (HIGUCHI) of Zidovudine microcapsules prepared with Eudragit RL

100

0

20

40

60

80

100

0 2

Sq RT of Time (hrs)

Cu

mu

lati

ve p

erc

en

t

rele

ased

FZ:RS100-(1:3)

FZ:RS100-(1:2)

FZ:RS100-(1:1)

Fig. 5.50 Cumulative Percent released vs square root of time plots (HIGUCHI) of Zidovudine microcapsules prepared with Eudragit RS

100

chapter-5 zidovudine matrix tablets and...

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