chapter v formulation development of...

80

CHAPTER V

FORMULATION DEVELOPMENT OF RITONAVIR TABLETS: EFFECT OF FORMULATION VARIABLES ON THE DISSOLUTION

RATE OF RITONAVIR FROM TABLETS

Ritonavir is practically insoluble in water and aqueous fluids. Its aqueous

solubility was reported as 2.56 mg/100 ml. As such its oral absorption is dissolution

rate limited. The very poor aqueous solubility of the drug gives rise to difficulties in

the formulation of solid dosage forms and leads to poor and variable dissolution rate

and oral bioavailability. In the case of poorly soluble drugs, the formulation

variables greatly influence their dissolution rate and bioavailability from tablets.

Though ritonavir tablets are available commercially, no work was reported on the

pharmaceutical formulation aspects of ritonavir. In the present work, the effect of

formulation variables such as binders, disintegrants and solubilizers and diluents on

the tablet qualities and dissolution rate of ritonavir from compressed tablets was

studied to optimize the formulation of ritonavir tablets.

5.1 EFFECT OF BINDERS ON THE DISSOLUTION RATE OF

RITONAVIR FROM TABLETS

Binder is a critical ingredient in tablets that influence tablet characters. The

effect of binding agents on the dissolution rate of poorly soluble drugs such as

hydrochlorthiazide, furosemide, nicotinic acid, aspirin, paracetamol, tolbutamide,

phenylbutazone and nimesulide was reported earlier.1, 2 In the present work the

effect of seven commonly used binders on the dissolution rate of ritonavir from

compressed tablets was studied.

81

Experimental

Materials

Ritonavir gift sample from (M/s Hetero Drugs Ltd., Hyderabad)

Polyvinyl pyrrolidone (Mfg: BASF, PVP K-30)

Hydroxy propyl methyl cellulose (having a viscosity of 50 cps in a 2%

weight aqueous solution at 20°C)

Potato starch (Loba Chemie)

Gelatin (oxoid)

Acacia (Loba Chemie)

Methyl cellulose (methoxyl content: 28-32%; viscosity: 65 cps)

Sucrose

Starch paste

Talc I.P

Magnesium stearate I.P

All other materials used were of Pharmacopoeial grade.

Preparation of Ritonavir Tablets

Compressed tablets each containing 100 mg of ritonavir were prepared by

conventional wet granulation method using various binders as per the formulae

given in Table 5.1.

82

Method

The required quantity of medicament and other ingredients (Table 5.1) were

taken in a mortar. Half the quantity of potato starch was added before granulation

and the remaining half was added after granulation.The aqueous binder solution

mucilage was added and mixed thoroughly to form dough mass. The mass was

passed through mesh No. 12 to obtain wet granules. The wet granules were dried at

60°C for 4 hr. The dried granules were passed through mesh No. 16 to break the

aggregates. Talc (2%) and magnesium stearate (2%) were passed through mesh No.

100 onto dry granules and blended in a polyethylene bag. The tablet granules were

then compressed into tablets on a rotary multi-station tablet punching machine (M/s.

Cadmach Machinery Co. Pvt. Ltd., Mumbai) to a hardness of 6-7 kg/sq.cm using 9

mm round and flat punches.

Evaluation of Tablets

All the tablets prepared are evaluated for

i) Content of active ingredient

ii) Hardness

iii) Friability

iv) Disintegration time

v) Dissolution rate

Content of Active Ingredient

Five tablets were accurately weighed and powdered. Tablet powder

equivalent to 100 mg of the medicament was taken into a boiling test tube and

extracted with 4 x 10 ml quantities of methanol. The methanolic extracts were

83

collected into 50 ml volumetric flask and the volume was made upto 50 ml with

methanol. The solution was subsequently diluted with 0.1 N hydrochloric acid and

assayed for the drug content by the UV spectrophotometric method described earlier

in Chapter IV.

Hardness

Hardness of the tablets was tested using a Monsanto hardness tester.

Friability

Friability of the tablets was determined in a Roche friabilator.

Disintegration Time

Disintegration times were determined in thermonic tablet disintegration test

machine using distilled water as fluid.

Dissolution Rate Study

The dissolution rate of ritonavir from the tablets was studied in 900 ml of

0.1 N hydrochoric acid using Disso 2000 (Labindia) 8-station dissolution test

apparatus with a paddle stirrer at 50 rpm. A temperature of 37°C ± 1°C was

maintained throughout the study. One tablet containing 100 mg of ritonavir was used

in each test. Samples of dissolution media (5 ml) were withdrawn through a filter

(0.45μ) at different intervals of time, suitably diluted and assayed for ritonavir at 210

nm. The sample of dissolution fluid withdrawn at each time was replaced with fresh

fluid and a suitable correction was applied for the amount of drug removed in the

sample of dissolution fluid at each time. The dissolution experiments were

conducted in triplicate (n=3).

84

Table 5.1

Formulae of Ritonavir Tablets Prepared with Various Binders

Formulation

Ingredient mg/tab.

TF1 TF2 TF3 TF4 TF5 TF6 TF7

Ritonavir 100 100 100 100 100 100 100

Acacia 5 - - - - - -

Sucrose - 5 - - - - -

PVP - - 5 - - - -

MC - - - 5 - - -

HPMC - - - - 5 - -

Starch paste - - - - - 5 -

Gelatin - - - - - - 5

Potato starch 40 40 40 40 40 40 40

Talc 4 4 4 4 4 4 4

Magnesium stearate

4 4 4 4 4 4 4

Lactose up to (mg) 200 200 200 200 200 200 200

85

Table 5.2

Drug Content, Hardness, Friability and Disintegration Time of Ritonavir

Tablets Formulated with Various Binders

Tablet Formulation

Ritonavir content

(mg/Tab)

Hardness

kg/sq. cm.

Friability

(%)

Disintegration Time (min.)

TF1 99.2 6.5 0.95 3.8

TF2 99.5 5.0 1.26 0.5

TF3 98.5 5.5 0.95 2.2

TF4 100.2 12.0 0.42 19.0

TF5 100.5 11.5 0.52 15.0

TF6 99.6 6.25 0.93 1.0

TF7 99.8

6.5 0.94

1.0

Binders used in formulations:

TF1 (Acacia), TF2 (Sucrose), TF3 (PVP), TF4 (MC), TF5 (HPMC), TF6 (Starch

paste), TF7 (Gelatin).

86

Table 5.3

Dissolution Profiles of Ritonavir Tablets Formulated Employing

Various Binders

Time Percent Ritonavir Dissolved ( x ± s.d.) (n=3)

(min) TF1 TF2 TF3 TF4 TF5 TF6 TF7

5 28.71 45 31.57 5.91 15.84 30.69 23.98

±1.3 ±1.2 ±1.4 ±1.5 ±1.1 ±1.6 ±1 .7

10 47.41 49.4 37.84 10.67 26.95 43.34 31.9

±1.1 ±1.6 ±1.2 ± 1.3 ± 1.4 ± 1.5 ±1.3

20 60.5 56.59 48.84 26.88 43.01 59.18 44.33

±1.6 ±1.3 ±1.1 ± 1.4 ±1.2 ± 1.7 ±1.5

30 70.07 61.93 54.78 38.83 49.94 69.85 54.45

±1.2 ±1.4 ±1.3 ±1.6 ±1.5 ± 1.1 ±1.7

40 78.2 66.82 60.26 41.25 54.2 77.5 61.05

±1.4 ±1.25 ±0.95 ±1.25 ±1.6 ±1.9 ±1.8

50 85.56 71.45 65.8 44.8 60.3 84.65 65.25

±1.6 ±2.2 ±1.85 ±1.2 ±1.9 ±2.1 ±2.1

60 91.25 78.25 71.95 49.5 64.65 90.85 70.86

±0.95 ±2.15 ±2.1 ±1.8 ±2.1 ±1.8 ±2.6

Binders used in formulations: TF1 (Acacia), TF2 (Sucrose), TF3 (PVP), TF4 (MC), TF5 (HPMC), TF6 (Starch Paste), TF7 (Gelatin).

87

Fig. 5.1: Dissolution Profiles of Ritonavir Tablets Prepared using

Various Binders

Fig. 5.2: First order Plots of Dissolution Profiles of Ritonavir

Tablets Prepared with Various Binders

0

0.5

1

1.5

2

2.5

0 10 20 30 40 50 60 70

Log Percent Undissolved

Time (min)

TF1 TF2 TF3 TF4 TF5 TF6 TF7

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70

Percent of Ritonavir Dissolved

Time (min)

TF1

TF2

TF3

TF4

TF5

TF6

TF7

88

Table 5.4

Correlation Coefficient (r) Values in the Analysis of Dissolution Data, as per Zero order and First order Models

Formulation Correlation coefficient value Zero order model First order model

TF1 0.9193 0.9753

TF2 0.9905 0.9976

TF3 0.9768 0.9887

TF4 0.9941 0.9939

TF5 0.9535 0.9748

TF6 0.9743 0.9974

TF7 0.9930 0.9997

Table 5.5

Dissolution Parameters of Ritonavir Tablets Formulated with Various Binders

Formulation Binder

Used K1

(min-1) DE30 (%)

Percent Drug Dissolved in 10

min TF1 Acacia 0.0400 49.37 47.41± 1.1 TF2 Sucrose 0.0322 47.03 49.40± 1.6 TF3 PVP 0.0264 40.14 37.84±1.2 TF4 MC 0.0163 19.08 10.67±1.3 TF5 HPMC 0.0231 32.03 26.95±1.4 TF6 Starch paste 0.0398 49.31 43.34±1.5 TF7 Gelatin 0.0262 35.82 31.90±1.3

Binders used in formulations:

TF1 (Acacia), TF2 (Sucrose), TF3 (PVP), TF4 (MC), TF5 (HPMC),TF6 (Starch

paste), TF7 (Gelatin).

89

RESULTS AND DISCUSSION

Ritonavir tablets could be prepared by wet granulation method employing the

commonly used binders. Ritonavir content, hardness, friability and disintegration

time of various tablets are given in Table 5.2. All the tablets were found to contain

the ritonavir within 100±2% of the label claim. Hardness of the tablets was in the

range 5-6.5 kg / sq.cm in all the batches of tablets except those prepared using

methyl cellulose and HPMC as binders. The tablets prepared using these binders

were found to be relatively harder with hardness in the range 11-12 kg/sq.cm. The

percentage weight loss in the friability test was less than 1.2 with all the batches of

tablets. Tablets formulated employing methyl cellulose and HPMC as binders did

not fulfilled the official (IP) disintegration test of uncoated tablets. Though the

tablets formulated with all other binders disintegrated within 4 min., variations were

observed in their disintegration time in the range 0.5 - 4.0 min.

Dissolution characteristics of various tablets prepared are shown in

Table 5.3 and Fig. 5.1. The dissolution data were analysed as per zero order and first

order kinetic models. The kinetic model that fits the dissolution data was evaluated

by comparing the correlation coefficient (r) values obtained in zero order and first

order models. The model that gave higher (r) value is considered as the best fit

model. The correlation coefficient (r) values in the analysis of data as per zero and

first order models are given in Table 5.4. The (r) values were found to be higher in

the first order model than those in zero order models indicating that the dissolution

of ritonavir from all the tablets prepared followed first order kinetics. The

correlation coefficient (r) value between log percent undissolved and time (Fig. 5.2)

90

was in the range 0.974 -0.999 with various tablet formulations. Dissolution

efficiency (DE30) values were calculated as suggested by Khan4.

Another parameter suitable for the evaluation of in vitro dissolution data has

been suggested by Khan4 who introduced the parameter dissolution efficiency (DE).

DE is defined as the area under dissolution curve upto a certain time T expressed as

a percentage of the area of the rectangle described by 100% dissolution in the same

time.

Dissolution Efficiency 0( ) 1 0 0

1 0 0 .

t y d tD E

y t

The dissolution efficiency can have a range of values depending on the time

intervals chosen. In any case, constant time intervals should be chosen for

comparison. For example the index DE30 would relate to the dissolution of drug

from a particular formulation after 30 min and could only be compared with DE3o of

other formulations. Summation of the large dissolution data into a single figure DE

enables ready comparison to be made between a large numbers of formulations.

The dissolution parameters of various tablets prepared are summarized in

Table 5.5. Much variation was observed in the dissolution characteristics of tablets

prepared with various binders. The order of performance of binders based on

increasing dissolution rate was found to be acacia > starch paste > sucrose > PVP>

gelatin> HPMC> MC. The same order of performance was observed based on the

dissolution efficiency. Tablets formulated with acacia, starch paste and sucrose

exhibited higher dissolution rates and dissolution efficiency values among all and

these tablets also fulfilled all official (IP) and GMP requirements of compressed

tablets. Overall acacia, starch paste and sucrose were found to be suitable binders for

ritonavir tablets.

91

CONCLUSIONS

1. The binder used has significant influence on the tablet qualities and

dissolution rate of ritonavir from the tablets.

2. The order of performance of binders based on increasing dissolution rate and

dissolution efficiency was acacia > starch paste > sucrose > PVP >gelatin >

HPMC > MC.

3. Tablets formulated with acacia, starch paste, and sucrose exhibited higher

dissolution rates and dissolution efficiency values fulfilling all other official

(IP) and GMP requirements of compressed tablets.

92

5.2 EFFECT OF SUPERDISINTEGRANTS ON THE DISSOLUTION

RATE OF RITONAVIR FROM TABLETS

Disintegrant is a critical ingredient in tablets that influences the dissolution

rate and bioavailability of the drug from tablets. The effect of disintegrants on the

dissolution rate of poorly soluble drugs such as itraconazole and sparfloxacin from

tablets was reported earlier5,6. In the present work, the effect of five

superdisintegrants on the tablets qualities and dissolution rate of ritonavir from

compressed tablets was studied to optimize the formulation of ritonavir tablets.

Experimental

Materials


Primogel gift sample from (M/s Natco Pharma. Ltd., Hyderabad)

Croscarmellose sodium gift sample from (M/s Natco Pharma. Ltd., Hyderabad)

Crospovidone gift sample from (M/s Natco Pharma Ltd., Hyderabad)

Prosolve gift sample from (M/s Orchid Health Care Ltd., Chennai)

Modified Starch gift sample from (M/s Natco Pharma Ltd., Hyderabad)



Talc I.P


93

METHODS



conventional wet granulation method using various superdisintegrants as per the

formulae given in Table 5.6. All superdisintegrants except Prosolve were used at 4%

concentration and Prosolve was used at 10% concentration. Acacia (2.5%) was used

as binder in the form of aqueous mucilage in all the formulations.

Method

The required quantity of medicament and other ingradients (Table 5.6) was

taken in a mortar. The aqueous mucilage of binder was added and mixed thoroughly

to form dough mass. The mass was passed through mesh No. 12 to obtain wet

granules. The wet granules were dried at 60°C for 4 hr. The dried granules were

passed through mesh No. 16 to break the aggregates. The superdisintegrant, talc

(2%) and magnesium stearate (2%) were passed through mesh No. 100 onto dry

granules and blended in a polyethylene bag. The tablet granules were then

compressed into tablets on a rotary multi-station tablet punching machine (M/s.

Cadmach Machinery Co. Pvt. Ltd., Mumbai) to a hardness of 6-7 kg/sq.cm using 9

mm round and flat punches.




ii) Hardness

94

iii) Friability


v) Dissolution rate








in Chapter IV.

Hardness


Friability


Disintegration Time





95

0.1 N hydrochloric acid using Disso 2000 (Labindia) 8-station dissolution test




(0.45µ) at different intervals of time, suitably diluted and assayed for ritonavir at 210


fluid. The dissolution experiments were conducted in triplicate (n=3).

Table 5.6 Formulae of Ritonavir Tablets Prepared with Various Superdisintegrants

Ingredient

(mg/tab) Formulation

TF8 TF9 TF10 TF11 TF12

Ritonavir 100 100 100 100 100

Acacia 5 5 5 5 5

Modified Starch 8 - - - -

Primogel - 8 - - -

Crospovidone - - 8 - -

Croscarmellose

Sodium

- - - 8 -

Prosolve - - - - 20

Talc 4 4 4 4 4

Magnesium stearate 4 4 4 4 4

Lactose up to (mg) 200 200 200 200 200

96

Table 5.7

Drug Content, Hardness, Friability and Disintegration Time of Ritonavir Tablets Formulated with Various Superdisintegrants

Tablet

Formulation

Drug content

(mg/Tab)

Hardness

(kg/sq. cm)

Friability

(%)

Disintegration

(min)

TF8 98.7 6.5 0.95 5.5

TF9 99.1 6.5 0.9 8.0

TF10 100.3 5.5 0.91 6.0

TF11 98.5 6.0 0.9 6.5

TF12 99.2 5.5 1.03 5.0

Superdisintegrants used in formulations:

TF8 (Modified Starch), TF9 (Primogel), TF10 (Crospovidone), TF11 (Cros

carmellose sodium), TF12 (Prosolve)

97

Table 5.8 Dissolution Profiles of Ritonavir Tablets Formulated Employing

Various Superdisintegrants Time

(min) Percent Drug Dissolved (x ± s.d.) (n=3)


5

08.70

± 1.51

10.53

± 1.32

15.73

± 1.24

16.84

±1.11

12.56

± 1.44

10 13.97

± 1.32

16.35

± 1.25

20.03

±1.14

25.54

± 1.42

31.05

± 1.22

20 27.62

±1.67

27.90

± 1.52

25.61

± 1.53

32.72

± 1.35

46.04

± 1.55

30 38.23

± 1.15

31.84

± 1.43

30.65

± 1.72

40.15

±1.24

56.08

± 1.23

40 46.25

±1.5

36.08

±1.09

36.12

±1.25

47.34

±0.86

64.65

±0.95

50 51.60

±1.40

40.25

±1.26

41.25

±1.6

53.90

±1.8

70.25

±1.65

60 58.45

±1.68

44.90

±1.75

46.95

±1.4

60.55

±1.25

77.40

±2.10


TF8 (Modified Starch), TF9 (Primogel), TF10 (Crospovidone), TF11

(Croscarmellose sodium), TF12 (Prosolve)

98

Fig. 5.3: Dissolution Profiles of Ritonavir Tablets Prepared with Various Superdisintegrants

Fig. 5.4: First order Plots of Dissolution Profiles of Ritonavir Tablets

Prepared with Various Superdisintegrants

0

10

20

30

40

50

60

70

80

90

0 10 20 30 40 50 60 70


Time (min)


99

Table 5.9 Correlation Coefficient (r) Values in the Analysis of

Dissolution Data as per Zero order and First order Models

Formulation Correlation coefficient value

Zero order model First order model

TF 8 0.9970 0.9977

TF 9 0.9529 0.9620

TF 10 0.9899 0.9944

TF 11 0.9657 0.9798

TF12 0.9318 0.9727

Table 5.10 Dissolution Parameters of Ritonavir Tablets Formulated with Various Superdisintegrants

Formulation T50 (min) K1 (min-1) DE30 (%) Percent Drug

Dissolved in 10 min

TF8 48 0.0159 20.52 13.97± 1.32

TF9 >60 0.0112 20.44 16.35± 1.25

TF10 >60 0.0076 21.27 20.03± 1.14

TF11 45 0.0125 26.79 25.54± 1.42

TF12 22 0.0265 34.54 31.05± 1.22


TF8 (Modified Starch), TF9 (Primogel), TF10 (Crospovidone), TF11 (Croscarmellose Sodium), TF12 (Prosolve)

100


Ritonavir tablets could be prepared by wet granulation method employing

various superdisintegrants. Superdisintegrants were added after drying the wet

granules and before compression. Ritonavir content, hardness, friability and

disintegration time of various tablets are given in Table 5.7. All the tablets were

found to contain the ritonavir within 100 ± 2% of the label claim. Hardness of the

tablets was in the range 5.5 - 6.5 kg/sq.cm in all the batches of tablets. The

percentage weight loss in the friability test was less than 1.1% with all the batches of

tablets. All the tablets formulated were disintegrated in 5-8 min. All tablets prepared

were of good quality fulfilling the official (I.P) and GMP requirements of tablets.

Dissolution characteristics of various tablets prepared were shown in Table

5.8 and in Fig. 5.3. Dissolution of ritonavir from all the tablets prepared followed

first order kinetics. The correlation coefficient (r) between log percent undissolved

and time was in the range 0.962 - 0.997 with various tablet formulations (Table 5.9).

Dissolution efficiency (DE30) values were calculated as suggested by Khan4. Much

variation was observed in the dissolution characteristics of tablets prepared with

various superdisintegrants (Table 5.10).

The order of performance of superdisintegrants based on increasing

dissolution rate was found to be Prosolve > modified starch > croscarmellose

sodium > Primogel > crospovidone. Based on the dissolution efficiency the order of

performance of superdisintegrants was Prosolve > croscarmellose sodium >

crospovidone > modified starch >Primogel. Tablets formulated with Prosolve,

modified starch and croscarmellose sodium exhibited higher dissolution rates and

101

dissolution efficiency among all and these tablets also fulfilled all official (I.P) and

GMP requirements of compressed tablets. Prosolve is a commercial directly

compressible vehicle consisting of microcrystalline cellulose (98%) and colloidal

silicon dioxide (2%). Croscarmellose sodium is a cross-linked polymer of

carboxymethyl cellulose sodium. Thus, Prosolve, modified starch and

croscarmellose sodium were found to be better superdisintegrants for ritonavir

tablets.

102

CONCLUSIONS

1. The superdisintegrant used has significant influence on the tablet qualities

and dissolution rate of ritonavir from the tablets.

2. The order of performance of the superdisintegrants based on increasing

dissolution rate was Prosolve > modified starch > croscarmellose sodium >

Primogel > crospovidone.

3. Tablets formulated with Prosolve, modified starch and croscarmellose

sodium exhibited higher dissolution rates and dissolution efficiency values

fulfilling all other official (I.P) and GMP requirements of compressed tablets.

4. Prosolve, modified starch and croscarmellose sodium were found to be better

superdisintegrants for ritonavir tablets.

103

5.3 EFFECT OF SOLUBILIZERS ON THE SOLUBILITY AND

DISSOLUTION RATE OF RITONAVIR FROM TABLETS

Formulation strategies of poorly soluble drugs include the use of surfactants

and polyethylene glycols as solubilizers to enhance the absorption of poorly soluble

drugs by enhancing drug dissolution8-10. In the present study sodium lauryl sulphate

(SLS), Tween 80 and polyethylene glycol 600 (PEG 600) were tried as solubilizers

to enhance the solubility and dissolution rate of ritonavir from tablets. The effect of

the solubilizers on the solubility of ritonavir was studied at different concentrations

of each solubilizer. Ritonavir tablets were formulated employing the solubilizers and

the tablets were evaluated in comparison to plain tablets without solubilizers to

assess the effect of solubilizers on the dissolution rate of ritonavir from tablet

formulations.

Experimental

Materials

Ritonavir (M/s Hetero drugs Ltd., Hyderabad)

Polyvinyl pyrrolidone (Mfg. BASF, PVP K-30) (Sigma)


Sodium Lauryl Sulphate (Qualigens)

Tween 80 (Sigma)

PEG 600 (SD Fine Chemicals)

Prosolve (gift sample from M/s Orchid Health Care Ltd., Chennai)

Croscarmellose sodium (M/s Natco Pharma. Ltd., Hyderabad)

104

Talc IP



Methods

Solubility Determination

Solubility of ritonavir in water and water containing different concentrations

(0.5, 1, 2 and 5%) of the three solubilizers (SLS, Tween 80 and PEG 600) was

determined as follows.

Excess drug (25 mg) was added to 15 ml of each fluid taken in a 50 ml

stoppered conical flask and the mixtures were shaken for 72 h at room temperature

(28° C) on a rotary flask shaker. After 72 h of shaking to achieve equilibrium, 2 ml

aliquots were withdrawn from each flask at 1 hr interval and filtered immediately

using 0.45 µ nylon disc filter. The filtered samples were diluted suitably with 0.1N

hydrochloric acid and assayed for ritonavir at 210 nm against the corresponding

fluid as blank. Shaking was continued until three consecutive estimations were the

same. The solubility experiments were conducted in triplicate. The results were

given in Table 5.11 and shown in Fig. 5.5.



conventional wet granulation method using three solubilizers as per formulae given

in Table 5.12. All the solubilizers were used at 5% concentration.

105

Method

The required quantity of medicament, PVP and solubilizer were mixed

thoroughly in a mortar. To this the binder solution was added and mixed thoroughly

to form dough mass. The mass was passed through mesh No. 12 to obtain wet

granules. The wet granules were dried at 60°C at 4 hr. The dried granules were

passed through mesh No. 16 to break the aggregates. The superdisintegrant

croscarmellose sodium (4%), the lubricants talc (2%) and magnesium stearate (2%)

were passed through mesh No. 100 on to dry granules and blended in a closed

polyethylene bag. The tablet granules were compressed into tablets on a rotary

multi-station tablet punching machine (M/s Cadmach Machinery Co. Pvt. Ltd.,

Mumbai) to a hardness of 5-6 kg / sq.cm using a 9 mm round and flat punches.


All the tablets prepared were evaluated for;

I. Content of active ingredient

II. Hardness

III. Friability

IV. Disintegration time

V. Dissolution rate





106


methanol. The solution was subsequently diluted with 0.1N hydrochloric acids and


in Chapter IV.

Hardness


Friability


Disintegration Time





0.1 N hydrochloric acid using Disso 2000 (Labindia) 8-station dissolution test




(0.45µ) at different intervals of time, suitably diluted and assayed for ritonavir at 210


fluid. The dissolution experiments were conducted in triplicate (n=3).

107

Table 5.11

Effect of Solubilizers (Tween 80, PEG- 600 and SLS) on the Solubility of Ritonavir

Fluid

Solubility of drug (mg/ml)

Solubilizer concentration (%)

0 0.5 1.0 2.0 5.0

Distilled Water 0.025 - - - -

Distilled Water + Tween 80

0.025 6.13 6.72 6.93 7.83

Distilled Water + PEG - 600

0.025 2.25 2.96 3.62 4.92

Distilled Water + SLS

0.025 1.42 1.39 2.10 2.90

Fig. 5.5: Effect of Solubilizers (Tween80, PEG-600, SLS) on the Solubility of Ritonavir

0

1

2

3

4

5

6

7

8

9

0 1 2 3 4 5 6

Sol

ub

ilit

y of

Dru

g (m

g/m

l)

Solubilizer Concentration(%)

DW+Tween 80 DW+PEG 600 DW+SLS

108

Table 5.12

Formulae of Ritonavir Tablets Formulated Employing Various Solubilizers

Ingredient (mg/Tab)

TF13 TF14 TF15 TF16 TF17 TF18 TF19 TF20

Ritonavir 100 100 100 100 100 100 100 100

PVP 5 5 5 5

Acacia 5 5 5 5

Tween 80 -- 5 - - - 5

PEG - 600 -- -- 5 5

SLS -- - 5 5

Cross carmellose sodium

8 8 8 8 8 8 8 8

Talc 4 4 4 4 4 4 4 4

Magnesium stearate

4 4 4 4 4 4 4 4

Lactose up to (mg)

200 200 200 200 200 200 200 200

TF 13 (Control) - PVP as binder TF 17 (Control) - Acacia as binder

TF 14 (Tween 80) - PVP as binder TF 18 (Tween 80) - Acacia as binder

TF15 (PEG-600)-PVP as binder TF 19 (PEG 600) - Acacia as binder

TF16 (SLS)-PVP as binder TF 20 (SLS) - Acacia as binder

109

Table 5.13


Tablets Formulated with Various Solubilizers

Tablet Formulation

Ritonavir Content

(mg/Tab)

Hardness (kg/sq.cm)

Friability

(%)

Disintegration time (min.)

TFl3 99.9 6.0 0.53 3.5

TF14 99.1 4.5 0.60 3.0

TF15 99.7 5.0 0.65 4.0

TF16 99.3 5.5 0.58 4.6

TF17 99.5 4.7 0.70 4.9

TF18 98.9 4.9 0.68 2.9

TF19 98.2 5.0 0.60 3.5

TF20 99.1 5.5 0.55 4.5

110

Table 5.14

Dissolution Profiles of Ritonavir Tablets Prepared by Using Solubilizers

Tween 80, PEG-600 and SLS

Time (min)

Percent Ritonavir Dissolved (x ± s.d.) (n=3)


5 25.48

±1.37

31.06

±1.03

29.44

±1.65

15.96

±1.56

24.87

±1.23

38.98

±1.02

33.28

±1.45

28.14

± 1.45

10 29.70

± 1.65

43.18

±1.08

38.11

±1.70

26.59

±1.23

32.48

±1.24

48.38

±1.81

42.44

±1.74

41.82

±1.78

20 34.52

± 1.41

52.34

±1.23

49.50

±1.05

40.09

±1.07

41.70

±1.08

57.42

±1.47

51.35

±1.23

47.82

± 1.45

30

38.35

±1.07

60.01

±1.09

57.04

±1.82

49.36

±1.42

46.97

±1.05

63.61

±1.08

57.17

±1.23

53.20

± 1.74

40 42.85

±1.65

68.46

±2.1

63.96

±1.9

54.85

±2.1

52.60

±1.6

70.25

±2.1

63.80

±1.9

59.25

±1.2

50 46.25

±1.80

76.10

±2.4

71.25

±1.8

61.30

±1.8

59.28

±1.8

78.80

±1.8

71.62

±1.8

65.25

±1.1

60 50.65

±1.05

85.65

±1.9

79.45

±2.4

68.25

±2.2

64.75

±2.2

86.25

±2.1

79.25

±2.2

71.85

±1.6

TF 13 (Control) - PVP as binder TF 17 (Control) - Acacia as binder

TF 14 (Tween 80) - PVP as binder TF 18 (Tween 80) - Acacia as binder

TF15(PEG-600)-PVP as binder TF 19 (PEG 600) - Acacia as binder

TF16(SLS)-PVP as binder TF 20 (SLS) - Acacia as binder

111

Fig. 5.6: Dissolution Profile of Ritonavir Tablets Prepared by Using Various Solubilizers

Fig. 5.7: First Order Plots of Dissolution Profile of Ritonavir Tablets Prepared by Using Various Solubilizers

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80


Time (min)TF13 TF14 TF15 TF16

TF17 TF18 TF19 TF20

0

0.5

1

1.5

2

2.5

0 10 20 30 40 50 60 70

Log percent drug undissolved

Time(min)


112

Table 5.15 Correlation Coefficient (r) Values in the Analysis of Dissolution Data,

as per Zero order and First order Models

Formulation Correlation coefficient value


TF 13 0.9770 0.9843

TF 14 0.9410 0.9723

TF15 0.9753 0.9918

TF 16 0.9754 0.9922

TF 17 0.9604 0.9764

TF 18 0.9529 0.9789

TF 19 0.9505 0.9740

TF 20 0.8604 0.9005

Table 5.16 Dissolution Parameters of Ritonavir Tablets

Formulated with Various Solubilizers


Dissolved in 10 min

TF13 60 0.0073 29.57 29.70± 1.65

TF 14 18 0.0207 43.42 43.18± 1.08

TF 15 21 0.0196 40.44 38.11± 1.70

TF16 31 0.0200 30.89 26.59± 1.23

TF17 33 0.0137 33.99 32.48± 1.24

TF18 17 0.0201 48.32 48.38± 1.81

TF19 19 0.0172 42.80 42.44± 1.74

TF20 22 0.0156 39.95 41.82± 1.78

113


The solubility of ritonavir in water and water containing different

concentrations of the solubilizers (SLS, Tween 80 and PEG– 600) was determined to

evaluate the efficiency of solubilizers on the solubility of ritonavir. The results were

given in Table 5.11 and shown in Fig. 5.5.

The solubility of ritonavir in water was found to be 0.025 mg/ml. The

aqueous solubility of ritonavir markedly enhanced in the presence of the solubilizers.

In each case the solubility was increased as the concentration of solubilizer was

increased (Fig.5.5). Among the three solubilizers Tween 80 gave highest

enhancement (14.77 fold) in the solubility of ritonavir. The order of increasing

solubility observed with various solubilizers was Tween 80 (14.77 fold) > PEG –

600 (9.28 fold) > SLS (5.47 fold.) Thus, the solubility of ritonavir was markedly

enhanced by the solubilizers tested. The feasibility of using the solubilizers in tablet

formulations for enhancing the dissolution rate of ritonavir from tablets were further

investigated.

Tablets each containing 100 mg of ritonavir could be prepared by

conventional wet granulation method employing SLS, Tween 80 and PEG – 600 as

solubilizers. Tween 80, PEG 600 and SLS were used at concentration of 5 % in the

formulae. (Table 5.12) Ritonavir content, hardness, friability and disintegration time

of the tablets prepared are given in Table 5.13. All the tablets were found to contain

ritonavir within 98.2- 99.9 of the labeled claim. Hardness of the tablets was in the

range 4.5 - 6.0 kg/sq.cm. The percentage weight loss in the friability test was less

than 0.70 with all the tablets prepared. (Table 5.13) All the tablets disintegrated

114

within 5 min (Table 5.13). As such ritonavir tablets prepared employing the three

solubilizers were of good quality fulfilling the official (I.P) and GMP requirements

of uncoated tablets.

Dissolution characteristics of various tablets prepared are shown in Table

5.14 and Fig. 5.6. Analysis of dissolution data as per zero order and first order

kinetics indicated that the dissolution of ritonavir from all the tablets followed first

order kinetics. The correlation coefficient (r) values were higher in first order kinetic

model (Table 5.15 and Fig. 5.7,). Dissolution efficiency values were calculated as

suggested by Khan4. The dissolution parameters of various tablets are summarized in

Table 5.16.

All the dissolution parameters (K1, DE30, T50 and % dissolved in 10 min)

indicated rapid and higher dissolution of ritonavir from tablets containing

solubilizers when compared to control tablets without solubilizers. Formulations

TF13, TF14, TF15 and TF16 were prepared employing PVP (2.5%) as binder.

Formulations TF 13 is a control formulation without solubilizer. Formulations TF14,

TF15 and TF16 contained Tween 80, PEG 600 and SLS respectively as solubilizers.

Dissolution rate (K1 min-1) was found to be 0.0073, 0.0207, 0.0196 and 0.0200

respectively with formulations TF13, TF14, TF15 and TF16. The dissolution

efficiency DE30 was also increased from 29.57% for formulation TF13 to 43.42%

with formulation TF14 and to 40.44% with formulation TF15 and to 30.89% with

formulation TF 16. The order of increasing dissolution rate (K1 min-1) and

dissolution efficiency (DE30) with various formulations was TF14 (Tween 80) >

TF16 (SLS) > TF15 (PEG-600) > TF13 (control).

115

Formulations TF17, TF18, TF19 and TF20 were formulated employing

acacia (2.5%) as binder. Formulations TF17 are a control formulation without

solubilizer. Formulations TF18, TF19 and TF20 contain Tween 80, PEG-600 and

SLS respectively as solubilizers. With binder acacia also, the dissolution rate (K1

min-1) and dissolution efficiency (DE30) were higher in the case of formulations

containing solubilizers (TF18, TF19 and TF20) when compared to TF17 (control)

(Table 5.16). The order of increasing K1 and DE30 observed with various

formulations was TF18 (Tween 80) > TF19 (PEG -600) > TF20 (SLS) > TF17

(control).

Thus with both the binders (PVP and acacia) the tablets formulated with

solubilizers gave rapid and higher dissolution of ritonavir when compared to control

formulations without solubilizers. With all the three solubilizers, formulations made

with acacia as binder gave higher dissolution rate and dissolution efficiency of

ritonavir when compared to those formulated with PVP as binder. Thus, the results

of the study indicated that the dissolution rate and efficiency of ritonavir from tablets

could be enhanced by incorporating solubilizers in the tablets.

116

CONCLUSIONS

1. The aqueous solubility of ritonavir was markedly enhanced by the

solubilizers.

2. A 14.77, 9.28 and 5.47 fold increase in the solubility of ritonavir was

obtained with Tween 80, PEG - 600 and SLS respectively at 5%

concentration. The order of increasing enhancement in the solubility of

ritonavir with various solubilizers was Tween 80 > PEG – 600 > SLS.

3. Ritonavir tablets of good quality, fulfilling the official (I.P) and GMP

requirements could be formulated employing the three solubilizers, Tween

80, PEG - 600 and SLS.

4. The dissolution rate and dissolution efficiency of ritonavir tablets could be

significantly enhanced by incorporating the solubilizers (Tween 80, PEG -

600 and SLS) in the tablets.

5. The order of increasing dissolution rate observed with various solubilizers

was Tween 80 > PEG - 600> SLS.

Hence these solubilizers could be incorporated in the tablets to enhance the

dissolution rate of ritonavir tablets.

117

5.4 EVALUATION OF PROSOLVE AS DILUENT IN RITONAVIR

TABLETS

Prosolve also known as silicified microcrystalline cellulose, is a commercial

directly compressible vehicle consisting of microcrystalline cellulose (98%) and

colloidal silicon dioxide (2%). Silicified microcrystalline cellulose is used as filler in

the formulation of capsules and tablets. It has improved compaction properties in

both wet granulation and direct compression compared to conventional

microcrystalline cellulose. Silicified microcrystalline cellulose was specifically

developed to address the loss of compaction that occurs with microcrystalline

cellulose after wet granulation.

In the present study prosolve was evaluated as a diluent in ritonavir tablets.

Ritonavir tablets were formulated employing prosolve in different concentrations

(10, 20, and 30%) and the tablets were evaluated.

Experimental

Materials


Prosolve gift sample from ( M/s Orchid Health Care Ltd., Chennai)

Croscarmellose sodium a gift sample from (M/s Natco Pharma. Ltd., Hyderabad)

Polyvinyl pyrrolidone (Mfg.: BASF, PVP K-30) (Sigma)

Acacia (Loba Chemie.)

118

Talc IP

Magnesium stearate I.P.


METHODS

Preparation of Tablets


conventional wet granulation method using Prosolve as diluent in various

concentrations as per formulae given in Table 5.17.

Method

The required quantity of medicament, the total amount of prosolve and other

ingredients (Table 5.17) were mixed thoroughly in a mortar by following geometric

dilution technique. The binder was added and mixed thoroughly to form dough

mass. The mass was passed through mesh No. 12 to obtain wet granules. The wet

granules were dried at 60°C for 4 hr. The dried granules were passed through mesh

No. 16 to break the aggregates. The superdisintegrant croscarmellose sodium (4%),

the lubricants, talc (2%) and magnesium stearate (2%) were passed through mesh

No. 100 on to dry granules and blended in a closed polyethylene bag. The tablet

granules were compressed into tablets on a rotary multi-station tablet punching

machine (M/s Cadmach Machinery Co. Pvt. Ltd., Mumbai) to a hardness of 5-6 kg /

sq.cm using a 9 mm round and flat punches.

119




ii) Hardness

iii) Friability


v) Dissolution rate








in Chapter IV.

Hardness


Friability


120

Disintegration Time




The dissolution rate of ritonavir from the tablets was studied in 900 ml of 0.1

N hydrochloric acid using Disso 2000 (Labindia) 8-station dissolution test apparatus

with a paddle stirrer at 50 rpm. A temperature of 37°C±1°C was maintained

throughout the study. One tablet containing 100 mg of ritonavir was used in each

test. Samples of dissolution media (5 ml) were withdrawn through a filter (0.45µ) at

different intervals of time, suitably diluted and assayed for ritonavir at 210 nm. The

sample of dissolution fluid withdrawn at each time was replaced with fresh fluid.

The dissolution experiments were conducted in triplicate (n-=3).

121

Table 5.17

Formulae of Ritonavir Tablets Formulated Employing

Prosolve in Various Concentrations

Ingredient mg/Tab

Formulation


Ritonavir 100 100 100 100 100 100 100 100

Prosolve - 20 40 60 - 20 40 60

Croscarmellose

sodium 8 8 8 8 8 8 8 8

PVP 5 5 5 5 - - - -

Acacia - - - - 5 5 5 5

Talc 4 4 4 4 4 4 4 4

Magnesium stearate 4 4 4 4 4 4 4 4

Lactose up to (mg) 200 200 200 200 200 200 200 200

122

Table 5.18


Tablets Formulated with Prosolve as Diluent in Various Concentrations

(PVP and Acacia as Binders)

Tablet Formulation

Drug Content (mg/Tab)

Hardness (kg/sq.cm)

Friability

(%)

Disintegration time (min.)

TF2l 99.50 5.5 0.56 4.0

TF22 99.69 6.5 0.60 3.7

TF23 99.55 5.5 0.67 3.5

TF24 99.15 6.0 0.61 3.0

TF25 99.65 5.2 0.59 4.0

TF26 99.20 5.0 0.65 3.8

TF27 99.31 4.9 0.75 3.6

TF28 99.75 5.1 0.63 3.1

123

Table 5.19 Dissolution Profiles of Ritonavir Tablets Formulated Employing

Prosolve in Various Concentrations

Time (min)

Percent Ritonavir Dissolved (x ± s.d.) (n=3)

TF21 TF22 TF23 TF24 TF25 TF26 TF27 TF28 5 13.98

± 1.07 16.26 ± 1.02

20.17 ± 1.23

36.37 ± 1.25

19.04 ± 1.47

23.77 ± 1.50

27.17 ± 1.74

36.79 ± 1.74

10 19.55 ± 1.41

23.38 ± 1.11

32.72 ± 1.74

49.31 ± 1.70

27.01 ± 1.04

31.38 ± 1.13

41.41 ± 1.17

46.53 ± 1.40

20 29.45 ± 1.74

34.03 ± 1.89

46.77 ± 1.11

61.12 ± 1.74

31.50 ± 1.07

40.13 ± 1.19

46.72 ± 1.24

56.26 ± 1.73

30 36.75 ± 1.98

41.88 ± 1.09

52.09 ± 1.97

69.36 ± 1.45

37.96 ± 1.42

45.78 ± 1.85

52.37 ± 1.13

62.50 ± 1.02

40 42.82 ±1.2

47.50 ±1.45

58.95 ±1.2

77.64 ±1.8

43.65 ±1.6

50.25 ±1.85

58.35 ±1.6

68.86 ±1.65

50 48.25 ±1.8

53.65 ±1.26

65.61 ±2.2

85.20 ±2.1

49.25 ±1.4

56.36 ±2.15

64.25 ±1.4

72.46 ±2.15

60 54.25 ±1.65

59.76 ±2.1

72.85 ±1.95

92.75 ±2.25

54.96 ±1.9

62.26 ±2.65

71.36 ±2.1

79.20 ±2.25

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70

Percent of ritonavir dissolved

Time (min)


124

Fig. 5.8: Dissolution Profile of Ritonavir Tablets Formulated Employing Prosolve in Various Concentrations

Fig. 5.9: First Order Plots of Dissolution Profile of Ritonavir Tablets Prepared by Using Prosolve in Various Concentrations

Table 5.20

Correlation Coefficient (r) Values in the Analysis of Dissolution Data, as per Zero order and First order Models

0

0.5

1

1.5

2

2.5

0 10 20 30 40 50 60 70

Log percent drug undissolved

Time (min)


Formulations Correlation coefficient ( r )values


TF 21 0.9925 0.9927

TF22 0.9873 0.9959

TF23 0.9245 0.9528

TF24 0.9488 0.9844

TF25 0.9449 0.9589

TF26 0.9646 0.9799

TF27 0.8477 0.8886

TF28 0.9518 0.9782

125

Table 5.21

Dissolution Parameters of Ritonavir Tablets Formulated with Prosolve as Diluent at Different Concentrations PVP and Acacia as Binder


Dissolved in 10 min

TF21 54 0.0123 23.15 19.55± 1.41

TF 22 45 0.0145 26.87 23.38± 1.11

TF 23 22 0.0202 35.94 32.72± 1.74

TF 24 11 0.0284 50.32 49.31± 1.70

TF 25 51 0.0098 26.75 27.01± 1.04

TF26 40 0.0133 32.81 31.38± 1.13

TF27 28 0.0153 39.18 41.41± 1.17

TF28 15 0.0203 46.93 46.53± 1.40

0

0.005

0.01

0.015

0.02

0.025

0.03

0 5 10 15 20 25 30 35

K1(m

in‐1)

Concentration of prosolve(%)

PVP Acacia

126

Fig. 5.10: Relationship between Percent Prosolve in the Tablet and

Dissolution Rate of Ritonavir


Ritonavir tablets could be prepared employing Prosolve by wet granulation

method using PVP (2.5%) and acacia (2.5%) as binders. Ritonavir content, hardness,

friability and disintegration time of the tablets prepared are given in Table 5.18. All

the tablets were found to contain ritonavir within 99.15-99.75% of the labeled claim.

Hardness of the tablets was in the range 4.9 - 6.5 kg / sq.cm. The percentage weight

loss in the friability test was less than 0.75 with all the tablets prepared. All the

tablets disintegrated within 4 min. (Table 5.18). As such ritonavir tablets prepared

employing Prosolve were of good quality, fulfilling the official (I.P) and GMP

requirement of uncoated tablets.

Dissolution characteristics of various tablets prepared are shown in Table

5.19 and Fig. 5.9. Analysis of dissolution data as per zero order and first order

kinetics indicated that the dissolution of ritonavir from all the tablets followed first

order kinetics, the correlation coefficient (r) values were higher in first order kinetic

model (Table 5.20 and Fig. 5.10). The dissolution parameters of various tablets are

summarized in Table 5.21.

Formulations TF 21, TF 22, TF 23, TF 24 were prepared using PVP as the

binder. Formulation TF 21 is a control formulation without prosolve.

Formulations TF 22, TF 23 and TF 24 contain prosolve at 10, 20 and 30%

concentration respectively. Formulations TF 25, TF 26, TF 27 and TF 28 were

127

prepared using acacia as the binder. Formulation TF 25 is a control formulation

without prosolve. Formulations TF 26, TF 27 and TF 28 contain prosolve at 10, 20

and 30% concentration respectively. All the dissolution parameters (K1, DE30, T50

and percent dissolved after 10 min) indicated rapid and higher dissolution of

ritonavir from tablets formulated with Prosolve when compared to control

formulation without Prosolve with both the binders. The dissolution rate (K1 min-1)

has increased as the concentration of Prosolve in the tablets was increased in both

the series prepared with PVP and acacia as binders (Fig. 5.12).

128

CONCLUSIONS

1. Ritonavir tablets of good quality, fulfilling the official I.P. and other

requirements, could be prepared employing Prosolve as diluent by wet

granulation method using PVP and acacia as binders.

2. The dissolution of ritonavir was rapid and higher from tablets formulated

with Prosolve when compared to control formulations without Prosolve.

3. Prosolve could be added as a diluent to ritonavir tablets to enhance its

dissolution rate from tablets.

129

REFERENCES

1. Chowdary KPR and Aparajitha N. The Eastern Pharmacist., 1989; 32:121.

2. Chowdary KPR and Manjula T. Indian J. Pharm. Sci., 2000; 62: 224.

3. Lachman L, Liberman MA and Kanig JL, Eds., in: The Theory and Practice

of Industrial Pharmacy, 2nd Edn. Lea and Febiger, Philadelphia, 1978; 328.

4. Khan KA. J. Pharm. Pharmacol., 1975; 27: 48.

5. Chowdary KPR and Srinivasa Rao SK. Int. J, Pharma. Excip., 1999; 123.

6. Chowdary KPR, Radhika I and Rajyalakshmi Y, Int. J. Pharma. Excip.,

2000;181.

7. Luner PE and Vader, KD. J. Pharm. Sci., 2001; 90:359.

8. Poelma fG, Breas R, Tukker JJ and Crommelin DJ. J. Pharm. Pharmacol.,

1991; 43:317.

9. Mohamed Hassan G, Dehghana and Mohammad Jafarb. Iranian Journal of

Pharmaceutical Research.2006; 4: 231-238.

10. Aleem MA, Dehghan MH and Rajesh Babu V. Int.j.Pharma. Sci. Res.

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chapter v formulation development of...

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