5.1 results and discussion of aripiprazole...

Chapter 5: Results and Discussion, Interpretations and Data Analysis

151

5.1 Results and discussion of Aripiprazole Immediate Release Tablets

5.1.1 Innovator Product Evaluation

Table No. 63: Drug release profile in different media of innovator

ABILIFY

(aripiprazole) tablets 10 mg 2B71310

Time

(min) 1.2 pH USP buffer 4.5 pH Acetate buffer 6.8+0.5% pH SLS

0 0 0 0

10 92 64 85

15 99 79 93

20 100 87 96

30 101 95 98

45 101 99 99

60 101 100 100

Figure No. 16: RLD dissolution profile in 900 ml of medium (pH as shown) using

USP apparatus 2 at 60 rpm

The drug release was conducted through dissolution and highest release in 1.2

phosphate buffer was observed.


152

Table No. 64: Solubility of Aripiprazole in various media with different pH

Media Solubility (mg/ml) Solubility (mg/250ml)

0.1 N HCl 0.069 17.25

Acetate buffer pH 4.5 0.054 13.50

6.8 pH phosphate buffer Insoluble


Water Insoluble

Aripiprazole is highly soluble in dichloromethane, sparingly soluble in toluene &

insoluble in methanol.

5.1.1.1 Stability Studies

Table No. 65: Aripiprazole stability under stress condition

Sr.

No.

Degradation DCPP

impurity

3-Chloro

impurity

Dehydro

aripiprazole

1 Oxidative 5ml of H2O2 solution

kept on water bath at

70oC for 30 minutes

ND 0.024 0.097

2 Acid 5ml of 5N HCl solution

heated on water bath at

70oC for 60 minutes

ND ND 0.110

3 Alkali 5ml of 5N NaOH

solution, heated on water

bath at 70oC for 60

minutes

ND ND 0.067

4 Thermal Exposed in oven at

1050C for about 24 hrs

ND ND 0.067

5 Humidity Exposed in humidity

chamber at 40oC±2

oC,

75%RH±5%RH for 24

hrs

ND ND 0.064

6 Photolytic


153

Degradation-

1

Exposed under UV

lamp at 254nm for 24

hrs

ND ND 0.065

Degradation-

2

Exposed to

photolytic treatment

for about 22

hrs(exposure ∼1.2

million lux hour)

ND ND 0.063

Sr.

No.

Degradation N-Oxide

aripipraz

ole

Dimer

impurity

Chlorobut

oxy

carbostyril

Aripipra-

zole

1 Oxidative 5ml of H2O2

solution kept

on water bath

at 70oC for

30 minutes

15.638 0.017 ND 0.134

2 Acid 5ml of 5N

HCl solution,

heated on

water bath at

70oC for 60

minutes

ND 0.016 ND 0.200

3 Alkali 5ml of 5N

NaOH

solution,

heated on

water bath at

70oC for 60

minutes

ND 0.018 ND 0.079

4 Thermal Exposed in

oven at

1050C for

ND 0.017 ND 0.188


154

about 24 hrs

5 Humidity Exposed in

humidity

chamber at

40oC±2

oC,

75%RH±5%

RH for 24 hrs

ND 0.019 ND 0.173

6 Photolytic

Degradati

on-1

Exposed

under UV

lamp at

254nm for 24

hrs

ND 0.019 ND 0.180

Degradati

on-2

Exposed to

photolytic

treatment for

about 22

hrs(exposure

∼1.2 million

lux hour)

ND 0.018 ND 0.196

Conclusion: Based on the forced degradation data it is found that the N oxide

impurity, Dimer impurity and Dehydro Aripiprazole impurities are increasing. Dimer

and dehydro Aripiprazole impurity are process impurities. We have analyzed our drug

product for these impurities. Based on the data we conclude that N oxide impurity is a

degradation product in our formulation.

5.1.1.2 Excipient Compatibility Study

Table No. 66: Excipient Compatibility (binary mixtures)

Sr.

no. Drug: Excipients RATIO Initial

Observations

40 oC/75 %RH

1W 2W 4W

- Aripiprazole (API) White to off white √ √ √


155

Sr.

no. Drug: Excipients RATIO Initial

Observations

40 oC/75 %RH

1W 2W 4W

powder

A API + Lactose

monohydrate

(Pharmatose 200M)

1:36 White to off white

powder √ √ √

B API + MCC (Avicel

PH101)

1:3.5 White to off white

powder √ √ √

C API + Corn starch

(Unipure FL)

1:5 White to off white

powder √ √ √

D API + L HPC LH-21 1:2.5 White to off white

powder √ √ √

E API + Lake blend

LB-510003 Green

1:0.06 faint green colored

powder without

lumps

√ √ √

F API + FD&C Blue

#2 Al 11%-14%

1:0.06 faint blue colored

powder without

lumps

√ √ √

G API + Red iron

oxide (Sicovit Red

30)

1:0.003 faint pink colored

powder without

lumps

√ √ √

H API + Yellow iron

oxide (Sicovit

Yellow 10)

1:0.014 faint Yellow

colored powder

without lumps

√ √ √

I API + MCC (Avicel

PH112)


powder √ √ √

J API + Magnesium

stearate (Hyqual)


powder √ √ √

K API: Pigment Blend

Green PB 1543

1: 0.06 faint green colored

powder without

lumps

√ √ √


156

Table No. 67: Excipient Compatibility (Interaction study)

Initial

Impurities API A B C D E F G H I J K

Related comp.A 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

Related comp.B 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

DCCP (Imp-C) 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

3-chloro 0.001 0.000 0.002 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

Related comp.G 0.095 0.095 0.095 0.095 0.095 0.095 0.095 0.095 0.072 0.096 0.071 0.064

N-oxide 0.001 0.002 0.001 0.004 0.001 0.002 0.001 0.001 0.003 0.003 0.002 0.004

Dimer imp. 0.032 0.029 0.032 0.028 0.031 0.031 0.031 0.031 0.037 0.031 0.037 0.030

Chlorobutoxy

carbostyril

0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.008 0.010 0.008 0.002

Highest unknown 0.004 0.004 0.004 0.004 0.004 0.004 0.004 0.004 0.006 0.006 0.004 0.006

Total unknown 0.023 0.019 0.028 0.023 0.025 0.026 0.026 0.025 0.027 0.027 0.025 0.013

Total imp. 0.162 0.155 0.168 0.161 0.163 0.165 0.164 0.163 0.169 0.164 0.166 0.111


157

1M, 250C/60%RH:


Related comp. A 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

Related comp. B 0.000 0.001 0.001 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.000

DCCP (Imp-C) 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

3-chloro 0.001 0.001 0.001 0.002 0.001 0.001 0.001 0.002 0.001 0.001 0.000 0.001

Related comp.G 0.094 0.095 0.095 0.095 0.095 0.095 0.095 0.096 0.071 0.095 0.071 0.064

N-oxide 0.001 0.002 0.001 0.003 0.001 0.001 0.002 0.003 0.001 0.001 0.001 0.003

Dimer imp. 0.031 0.031 0.031 0.031 0.030 0.031 0.031 0.031 0.037 0.031 0.036 0.030

Chlorobutoxy

carbostyril

0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.007 0.009 0.008 0.006

Highest unknown 0.005 0.004 0.004 0.004 0.005 0.005 0.005 0.006 0.004 0.004 0.004 0.006

Total unknown 0.034 0.029 0.025 0.023 0.031 0.031 0.028 0.031 0.028 0.028 0.028 0.014

Total imp. 0.170 0.169 0.163 0.166 0.170 0.170 0.169 0.175 0.167 0.167 0.165 0111


158

1M, 400C/75%RH:


Related comp.A 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

Related comp.B 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.001 0.000

DCCP (Imp-C) 0.000 0.002 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000

3-chloro 0.001 0.001 0.002 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

Related comp.G 0.095 0.096 0.096 0.095 0.095 0.095 0.095 0.096 0.071 0.095 0.071 0.062

N-oxide 0.001 0.007 0.007 0.004 0.001 0.001 0.001 0.001 0.001 0.001 0.004 0.003

Dimer imp. 0.031 0.030 0.031 0.031 0.031 0.031 0.031 0.031 0.036 0.031 0.037 0.035

Chlorobutoxy

carbostyril

0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.010 0.008 0.010 0.008 0.001

Highest unknown 0.004 0.008 0.004 0.004 0.004 0.005 0.005 0.006 0.006 0.006 0.006 0.005

Total unknown 0.030 0.034 0.025 0.027 0.029 0.030 0.034 0.032 0.029 0.029 0.033 0.011

Total imp. 0.169 0.182 0.173 0.170 0.168 0.169 0.173 0.173 0.168 0.175 0.173 0.111


159

Conclusions: There is no change in the description of the samples at room

temperature and at accelerated temperature. Based on the Related substances data can

be concluded that all the above given excipients are compatible with Aripiprazole.

5.1.2 Formulation and Development

5. 1.2.1 PROTOTYPE FORMULATION –I

Table No. 68: Tablet parameters: LOT NO.: MLR (100)-22-71

10 mg 30 mg

Weight 101-103 mg 300-303

Hardness 50-65 N 45-60 N

Thickness 2.67-2.70mm 4.10-4.15 mm

Disintegration Time 1 minute 50 sec

Friability 0.27% 0.29%

Observation: Compression parameters satisfactory for 30 mg strength. Based on the

earlier trials we fix the loss on drying for the nonlubricated granules as not more than

2.0% w/w

Tablet No. 69: Dissolution comparison of MLR (100)-22-71A with innovator

Time (min)

Innovator Wockhardt

ABILIFY 10 mg MLR (100)-22-71A

10 86 53

20 97 63

30 99 65

45 100 65

60 100 66


160

Figure No. 17: Abilify 10mg comparison with MLR (100) 22-71 A dissolution

profile in 900 ml of medium (pH as shown) using USP apparatus 2 at 60 rpm

Tablet No. 70: Dissolution comparison of MLR (100)-22-71B with innovator

Time (min)

Innovator Wockhardt

ABILIFY 30 mg MLR (100)-22-71B

10 96 51

20 100 61

30 100 62

45 102 62

60 102 63

Figure No. 18: Abilify 10mg comparison with MLR (100) 22-71 B dissolution



161

Observation: Dissolution was not complete and slower than innovator. A trial with

cornstarch with 15.0mg/ tab was planned.

Table No. 71: Tablet parameters: LOT NO.: MLR (100)-21-67

10 mg 30 mg

Weight 101.1-101.9 298.3-300.9

Hardness 58-63 41-46

Thickness 2.60-2.64 4.14-4.15

Disintegration Time 1 minute 1 min 10 sec


Tablet No. 72: Dissolution comparison of MLR (100)-21-67A with innovator

Time (min)

Innovator Wockhardt

ABILIFY 10 mg MLR (100)-21-67A

10 86 79

20 97 86

30 99 87

45 100 88

60 100 90

Tablet No. 73: Dissolution comparison of MLR (100)-21-67B with innovator

Time (min)

Innovator Wockhardt

ABILIFY 30 mg MLR (100)-21-67B

10 96 68

20 100 78

30 100 78

45 102 85

60 102 87


162

Figure No. 19: Abilify 30mg comparison with MLR (100) 21-67 B dissolution


Observation: Dissolution slower than innovator. Trials with L-HPC LH 21 was

planned to evaluate the impact of the change in binder on the dissolution of the drug

product.

Table No. 74: Tablet parameters LOT NO.: MLR (100)-28-95

10 mg 30 mg

Weight 100-103 mg 300-304 mg


Thickness 2.72-2.74mm 3.90-4.30 mm

Disintegration Time 15 sec 20 sec


Table No. 75: Dissolution comparison of MLR (100)-21-67A with innovator

Time (min)

Innovator Wockhardt

ABILIFY 10 mg MLR (100)-28-095 A

10 86 79

20 97 87

30 99 90

45 100 92

60 100 92


163

Figure No. 20: Abilify 10mg comparison with MLR (100) 28-95A dissolution


Table No. 76: Dissolution comparison of MLR (100)-28-095 B with innovator

Time (min)

Innovator Wockhardt

ABILIFY

30 mg MLR (100)-28-095 B

10 96 81

20 100 87

30 100 90

45 102 92

60 102 92

Figure No. 21: Abilify 30mg comparison with MLR (100) 28-95B dissolution



164

Observation: Dissolution profile was significantly improved, Next trial was planned

with decreased concentration of corn starch and LHPC LH 21 increased by 3 mg/tab

and with micronised API to match dissolution profile with innovator.

Table No. 77: Tablet parameters: LOT NO.: PS(100)-35-120

10 mg Low Opt. High

Weight 100.7-102.8 mg 98.6-100.1 mg 100.3-102.0 mg

Hardness 37-45 N 61-70 N 76-86N

Thickness 2.78-2.84mm 2.66-2.68mm 2.63-2.65mm

Disintegration Time 8-10 sec 18-22 sec 36-44 sec

Friability 0.13% 0.13% 0.13%

30 mg Low Opt. High

Weight 296.9-303.8 mg 296.4-305.0 mg 292.0-301.1 mg

Hardness 46-76 N 73-95 N 102-125 N

Thickness 4.15-31 mm 4.15-4.21 mm 3.97-4.18 mm


Friability 0.21% 0.21% 0.21%

Observation: After compression of 100 tablets sticking was observed on lower punch. Based

on this observation next trial was planned with increased lubricant conc. to eliminate sticking.


10 mg Low Opt. High

Weight 99.4-101.3 mg 99.4-101.9 mg 100.6-101.9 mg

Hardness 33-43 N 51-57 N 56-66 N

Thickness 2.78-2.81mm 2.65-2.69mm 2.64-2.68mm


Friability 0.13% 0.13% 0.13%

30 mg Low Opt. High

Weight 299.7-305.5 mg 298.2-304.1 mg 300.2-304.6 mg

Hardness 58-64 N 89-105 N 102-122 N

Thickness 4.22-4.27 mm 4.05-4.07 mm 4.05-4.06 mm


Friability 0.21% 0.21% 0.21%


165

Table No. 79: Dissolution comparison of PS(100)-37-132A with innovator

Time (min) Innovator Wockhardt

ABILIFY 10 mg PS(100)-37-132A

10 92 94

15 99 98

20 100 99

30 101 99

45 101 98

60 101 99

Figure No. 22: Dissolution comparison of PS(100)-37-132A with innovator

Table No. 80: Dissolution comparison of PS(100)-37-132B with innovator

Time (min)

Innovator Wockhardt

ABILIFY 30 mg PS(100)-37-132B

10 95 91

15 100 97

20 101 97

30 102 97

45 102 97

60 102 97


166

Figure No. 23: Dissolution comparison of PS(100)-37-132B with innovator

Observation: All the physical parameters were found satisfactory. Both the 10 & 30 mg

strengths were packed 30T’s bottle with 3 g silica gel canister & Alu-Alu blister packs and

loaded on stability.

5. 1.2.2 PROTOTYPE FORMULATION –II


Parameters 10 mg 30 mg

Weight 99.5-101.9 mg 295.0-306.5 mg


Thickness 2.68-2.72mm 4.04-4.11 mm

Disintegration Time 24 sec 36 sec

Tablet No. 82: Dissolution comparison of PS(100)-49-177A with innovator

Time (min)

Innovator Wockhardt

Abilify 10 mg PS(100)-49-177A

10 92 95

15 99 98

20 100 98

30 101 98

45 101 98

60 101 98


167

Figure No. 24: Dissolution comparison of PS(100)-49-177A with innovator

Table No. 83: Dissolution comparison of PS(100)-49-177B with innovator

Time (min)

Innovator Wockhardt

Abilify 30 mg PS(100)-49-177B

10 95 95

15 100 100

20 101 99

30 102 98

45 102 99

60 102 99

Figure No. 25: Dissolution comparison of PS(100)-49-177B with innovator

Observation: Dissolution was found to be in line with innovator. Both the 10 & 30 mg

strengths were packed 30T’s bottle with 3 g silica gel canister & Alu-Alu blister packs and

loaded on stability.


168


Parameters 2 mg

Weight 99.5-101.6 mg

Hardness 41-49 N

Thickness 2.68-2.74 mm

Disintegration Time 14 sec

Table No. 85: Dissolution comparison of PS(100)-50-181with innovator

Time (min)

Innovator Wockhardt

Abilify 2 mg PS(100)-50-181

10 97 97

15 104 103

20 105 103

30 105 103

45 104 102

60 104 102

Figure No. 26: Dissolution comparison of PS(100)-50-181 with innovator

Observation: Dissolution was found to be similar to innovator. Tablets were packed 30T’s

bottle with 3 g silica canister & Alu-Alu blister packs and loaded on stability.

Table No. 86: Tablet parameters: LOT NO.: PS (100)-51-184

parameters 15 mg


Hardness 59-71 N


169

parameters 15 mg



Table No. 87: Dissolution comparison of PS(100)-51-184with innovator

Time (min)

Innovator Wockhardt

Abilify 15 mg PS(100)-51-184

10 91 82

15 97 90

20 100 91

30 101 93

45 101 94

60 101 94


Observation: Dissolution was found to be in line with innovator. Tablets were packed 30T’s

bottle with 3 g silica canister & Alu-Alu blister packs and loaded on stability.


Parameters 5 mg

Weight 100.3-102.5 mg

Hardness 43-48 N




170

Table No. 89: Dissolution comparison of PS (100)-52-187with innovator

Time (min)

Innovator Wockhardt

Abilify 5 mg PS(100)-52-187

10 97 99

15 99 103

20 100 103

30 100 103

45 100 103

60 100 102


Observation: Dissolution was found to be in line with innovator. Tablets were packed

30T’s bottle with 3 g silica canister & Alu-Alu blister packs and loaded on stability.


Parameters 20 mg

Weight 199.5-204.1 mg

Hardness 46-54 N




171

Table No. 91: Dissolution comparison of PS (100)-53-190 innovator

Time (min)

Innovator Wockhardt

Abilify 20 mg PS (100)-53-190

10 89 94

15 95 95

20 98 95

30 98 97

45 99 97

60 99 97


Observation: Dissolution was found to be in line with innovator and complete. Tablets were

packed 30T’s bottle & Alu-Alu blister packs and loaded on stability.

5. 1.2.3 PROTOTYPE FORMULATION –III


Parameters 10 mg


Hardness 50-60 N

Thickness 2.65-2.69mm



172

Table No. 93: Dissolution comparison of PS (100)-54-193 with innovator

Time (min)

Innovator Wockhardt

Abilify 10 mg PS(100)-54-193

10 92 25

15 99 31

20 100 33

30 101 36

45 101 40

60 101 44


Observation: Based on the dissolution profile it was observed that, the particle size effects

the dissolution rate significantly. So a particle size range of D(0.9) of NMT 30 Microns is

fixed in the API specifications.

Table No. 94 Tablet parameters: Innovator

Parameters 10 mg

Weight 100.7-103.2 mg

Hardness 50-60 N

Thickness 2.69-2.73mm

Disintegration Time 1 min 10 sec


173

5. 1.2.4 Design of Experiments Study

Table No. 95: Experimental results of DOE to study Intragranular excipients

Factors: Formulation variables Responses

Batch No. % MCC in

MCC/Lactose

combination

(A)

L HPC

LH-21

quantity

(B)

Corn starch

quantity

(C)

Dissolution

at 30 min

CU

(%) mg/tab mg/tab (%) (% RSD)

PS(740)-62-13 15 7 12 95 0.87

PS(740)-63-16 15 3 8 99 0.86

PS(740)-64-19 8 7 8 94 0.67

PS(740)-65-22 8 3 12 93 1.34

A. Significant factors for tablet dissolution at 30 min:

Initially, % drug release was evaluated by using the FDA-recommended method. All

batches shows rapid and comparable %drug release (> 80% dissolved in 30 min) to

the RLD. The results of Analysis of Variance (ANOVA) are reproduced in Table.

Table No. 96: significant factors for tablet dissolution at 30min

Source DF Seq SS Adj SS Adj MS F P

Main effects 3 20.750 20.750 6.917 * *

% MCC in MCC/Lactose ratio 1 12.250 12.250 12.250 * *

Corn starch quantity 1 6.250 6.250 6.250 * *

L HPC LH-21 quantity 1 2.250 2.250 2.250 * *

Residual Error 0 * * *

Total 3 20.750


174

Effe c t

Percent

1050-5-10

99

95

90

80

70

60

50

40

30

20

10

5

1

F a cto r N am e

A % M C C in M C C /La cto se ra t io

B L H P C LH -2 1

C C o rn sta rch

E ffec t T y p e

N o t S ig n ific an t

S ig n ific an t

N orma l P robab i l i ty P lo t o f the E f fe c ts( re spo nse is Dis so lu tion a t 30 m in , A lpha = .0 5 )

Le n th 's PS E = 3 .75

Figure No 31: Normal Probability plot of the effect dissolution at 30min

Term

Ef f e c t

B

C

A

5 0403020100

4 7 .6 5F a c to r N a m e

A % M C C in M C C /La c to se ra t io

B L H P C LH -2 1

C C o rn s ta rch

P a r e to C ha r t o f the E f fe c ts( r e s po n s e is D is s o lu tio n a t 3 0 m in , A lp h a = .0 5 )

Le n th 's P S E = 3 .7 5

Figure No. 32: Pareto chart of the effects

From the above half-normal & Pareto charts it was observed that L HPC LH-21

doesn’t have any significant effect on tablet dissolution at 30 min. As it is observed

that L HPC LH 21 doesn’t have significant effect. Therefore DOE was run with two

factors to study the impact on dissolution at 30 min.

Table No. 97: DOE with two factors


Main effects 3 18.500 18.500 9.250 * *

2-Way interactions 1 2.250 2.250 2.250 * *


Total 3 20.750


175

Effe c t

Percent

1050-5-10

99

95

90

80

70

60

50

40

30

20

10

5

1

F a cto r N am e

A % M C C in M C C /La cto se ra tio

C C o rn sta rch

E ffec t T y p e


S ig n ific an t

N orma l P robabil i ty P lot o f the E ffe c ts(re sponse is Dis so lution a t 30 m in , A lpha = .05 )

Lenth 's PS E = 3.75

Figure No 33: Two factors effect

Term

Ef fe c t

A C

C

A

50403020100

47 .6 5F a c to r N am e

A % M C C in M C C /La c to se ra t io

C C o rn s ta rch

P a re to C ha r t o f the E f fe c ts( re sponse is Dis s o lu tio n a t 30 m in , A lp ha = .05 )

Le n th 's PS E = 3 .75

Figure No. 34: Pareto Chart of two factors

From the above half-normal & Pareto charts it was observed that Cornstarch doesn’t

have any significant effect on tablet dissolution at 30 min. As it is observed that L

HPC LH 21 & Corn starch doesn’t have significant effect. Therefore DOE was run

with single factor to study the impact on dissolution at 30 min.

Table No. 98: DOE with single factor

Source DF Seq SS Adj SS Adj MS F P Comments

Main effects 1 12.250 12.250 12.250 2.88 0.232 Non-Significant

Residual Error 2 8.500 8.500 4.250

Pure Error 2 8.500 8.500 4.250

Total 3 20.750


176

All the batches demonstrated acceptable dissolution at 30 mins are within

specification limits and none of the factors showed significant impact on tablet

dissolution.

B. Significant factors for tablet Content uniformity (% RSD):

Table No. 99: Significant factors for tablet Content uniformity (% RSD)


Main effects 3 0.24410 0.24410 0.08137 * *

% MCC in MCC/Lactose ratio 1 0.01960 0.01960 0.01960 * *

Corn starch quantity 1 0.11560 0.11560 0.11560 * *

L HPC LH-21 quantity 1 0.10890 0.10890 0.10890 * *


Total 3 0.24410

E f f e c t

Percent

1 . 00 . 50 . 0- 0 . 5- 1 . 0

9 9

9 5

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

5

1

F a c t o r N a m e

A % M C C in M C C /L a c t o s e r a t io

B L H P C L H -2 1

C C o r n s t a r c h

E f f e c t T y p e

N o t S ig n if ic a n t

S ig n if ic a n t

N o r m a l P r o b a b i l i t y P l o t o f t h e E f f e c t s( r e s p o n s e i s C o n te n t u n i f o r m i t y , A lp h a = . 0 5 )

L e n th ' s P S E = 0 . 4 9 5

Figure No 35: Significant factors for tablet Content uniformity

Term

E f f e c t

A

B

C

76543210

6 .2 9 0F a c t o r N a m e

A % M C C in M C C /La c t o s e ra t io

B L H P C LH -2 1

C C o rn s t a r c h

P a r e t o C h a r t o f t h e E f f e c t s( r e s p o n s e is C o n te n t u n i f o r m ity , A lp h a = . 0 5 )

L e n th ' s P S E = 0 . 4 9 5

Figure No 36: Pareto chart for tablet Content uniformity


177

From the above half-normal & Pareto charts it was observed that % MCC in

MCC/Lactose ratio doesn’t have any significant effect on tablet Content uniformity.

Table No. 100: DOE was run with two factors to study the impact on Content

uniformity


Main effects 2 0.22450 0.22450 0.11225 * *

2-Way

interactions

1 0.01960 0.01960 0.01960 * *


Total 3 0.24410

E f f e c t

Percent

1 .00 . 50 . 0- 0 . 5- 1 . 0

9 9

9 5

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

5

1

F a c t o r N a m e

B L H P C LH -2 1


E f fe c t T y p e


S ig n if ic a n t

N o r m a l P r o b a b i l i t y P l o t o f t h e E f f e c t s( r e s p o n s e is C o n te n t u n i fo r m ity , A lp h a = . 0 5 )

L e n th ' s P S E = 0 . 4 9 5

Figure No 37: Two factors effect on content uniformity

Term

E f f e c t

B C

B

C

76543210

6 . 2 9 0F a c t o r N a m e

B L H P C L H -2 1


P a r e t o C h a r t o f t h e E f f e c t s( r e s p o n s e i s C o n te n t u n i f o r m i ty , A lp h a = . 0 5 )

L e n th ' s P S E = 0 . 4 9 5

From the above half-normal & Pareto charts it was observed that L HPC LH-21

doesn’t have any significant effect on tablet Content uniformity. Based on the above

interactions it was clear that L HPC LH 21 & % MCC in MCC/Lactose ratio doesn’t


178

have significant effect. Therefore DOE was run with single factor to study the impact

on Content uniformity.

Table No. 101: single factor to study the impact on Content uniformity


Main effects 1 0.1156 0.1156 0.11560 1.80 0.312 Non-Significant

Residual Error 2 0.1285 0.1285 0.06425

Pure Error 2 0.1285 0.1285 0.06425

Total 3 0.2441

All the batches demonstrated acceptable Tablet content uniformity(%RSD) which was

well within specification limits and none of the factors showed significant impact on

Tablet content uniformity(%RSD)

Summary of Formulation Study: 1

The intragranular L HPC LH 21, % MCC in MCC/Lactose ratio and corn starch

showed a insignificant impact on tablet dissolution at 30 mins and content uniformity.

Because no curvature effects were observed for any of the responses studied, and the

main effects and interaction effects were identified using a half factorial DOE, further

studies to optimize the intragranular excipients were unnecessary. The DOE models

were used to establish acceptable ranges for formulation variables. At the conclusion

of Prototype Formulation IV, the levels of intragranular excipients were tentatively

finalized as shown in below.

Table No. 102: Tentative composition of Generic Aripiprazole Tablets

Ingredients Function Composition

Mg/tab (%w/w)

Aripiprazole Active 10.00 10.00

Intragranular Excipients

Lactose monohydrate (Pharmatose

200M)

Filler 62.18 62.18

Microcrystalline cellulose (Avicel PH

101)

Filler 7.05 7.05

Corn starch Diluent 10.00 10.00


179

Ingredients Function Composition

L HPC LH-21 Disintegrant 5.00 5.00

Red iron oxide Colorant 0.02 0.02

Purified water* Solvent q.s. q.s.

Extrgranular excipients

Microcrystalline cellulose

(Avicel PH 112)

Filler 5.00 5.00

Magnesium stearate Lubricant 0.75 0.75

*Levels to be studied in process development.

5. 1.2.5 Formulation Development conclusions

Based on the Formulation Development Studies #1, the formulation composition was

finalized. The MCC/Lactose ratio and the disintegrant level were finalized in this

study. The finalized formulation for Generic Aripiprazole Tablets, 2mg/5mg/ 10mg/

15 mg/ 20 mg/ 30 mg, is presented in Table below.

Table No. 103: Biowaiver strategy for the generic Aripiprazole tablets

2 mg 5 mg 10 mg 15 mg 20 mg 30 mg

INGREDIENTS mg/tab

Aripiprazole 2.00 5.00 10.00 15.00 20.00 30.00

Lactose Monohydrate (Pharmatose 200M) 70.10 67.10 62.18 57.00 124.40186.54

Microcrystalline Cellulose (Avicel PH 101) 7.05 7.05 7.05 7.05 14.10 21.15

Corn Starch (Unipure FL) 10.00 10.00 10.00 10.00 20.00 30.00

Hydroxypropyl Cellulose (L –HPC LH 21) 5.00 5.00 5.00 5.00 10.00 15.00

Pigment Blend Green PB 1543 0.10 - - -

FD&C Blue N0.2 AL 11%-14% - 0.10 - -

Iron Oxide Red (Sicovit red 30) - - 0.02 - 0.06

Iron Oxide Yellow (Sicovit Yellow 10) - - - 0.20 - -

MCC (Avicel PH 112) 5.00 5.00 5.00 5.00 10.00 15.00

Magnesium Stearate (Hyqual) 0.75 0.75 0.75 0.75 1.50 2.25

Tablet Wt (mg) 100.00100.00 100.00 100.00200.00300.00


180

Table No. 104: The blend uniformity results for 10 mg strength are presented in

table below

Location

Assay (% w/w)

10 mg 2 mg

After 3

minutes

After 5

minutes

After 7

minutes

After 3

minutes

After 5

minutes

After 7

minutes

U1 79.5 99.7 102.2 106.0 99.0 100.5

U2 98.9 98.9 99.1 100.0 99.5 99.0

U3 99.4 98.4 99.3 101.0 101.0 100.5

M1 100.2 98.4 104.9 100.5 100.5 98.5

M2 100.5 99.9 100.5 101.5 100.5 106.0

M3 101.6 98.6 99.9 100.0 100.0 100.5

L1 106.5 99.4 110.2 100.5 99.5 99.0

L2 104.3 97.6 98.3 101.0 99.5 99.0

L3 102.1 100.2 101.8 100.0 101.0 97.5

Minimum 79.5 97.6 98.3 100.0 99.0 97.5

Maximum 106.5 100.2 110.2 106.0 101.0 106.0

Mean 99.2 99.0 101.8 101.2 100.1 100.1

SD 7.8 0.8 3.7 1.9 0.7 2.5

%RSD 7.86 0.81 3.63 1.88 0.7 2.50

Summary of dry mixing on Process Development

Based on the results of the dry mixing studies, the time needed to achieve blend

uniformity was fixed to 5 mins.

Table No. 105: Design of the 23

full factorial DOE to study granulation

parameters

Factors: ProcessVariables Levels

-1 0 +1

A Qty of water 15 25 35

B Water addition time 0 2 4

C Kneading time 1 3 6

Responses Goal Acceptable ranges


181

Factors: ProcessVariables Levels

-1 0 +1

Y1 Dissolution at 30 mins Maximize ≥ 80%

Y2 Angle of repose 30-40 degrees 30-45 degrees

Y2 Hardness Maximize NLT 80N

5.2: Table No. 106: DOE trials planned for granulation parameters optimization

Exp. No. Qty of water Water addition time Kneading time

PS(740)-69-33A 35 0 1

PS(740)-69-33B 35 4 1

PS(740)-69-33C 15 0 6

PS(740)-69-33D 35 4 6

PS(740)-69-33E 35 0 6

PS(740)-69-33F 15 4 1

PS(740)-69-33G 15 0 1

PS(740)-69-33H 15 4 6

Table No. 107: Experimental results of DOE to study granulation parameters

Factors: Formulation variables Responses

Batch No. Qty of

water

Water

addition

time

Kneading

time

Dissolution

at 30 min

Angle

of

Repose

Hardness

(%) mg/tab mg/tab (%) N

PS(740)-69-33A 35 0 1 96 37.56 104

PS(740)-69-33B 35 4 1 97 39.22 100

PS(740)-69-33C 15 0 6 85 40.99 95

PS(740)-69-33D 35 4 6 97 35.52 115

PS(740)-69-33E 35 0 6 96 37.57 90

PS(740)-69-33F 15 4 1 85 42.28 97

PS(740)-69-33G 15 0 1 87 40.39 84

PS(740)-69-33H 15 4 6 86 43.59 85


182

Table No. 108: Significant factors for tablet dissolution at 30 min


Main effects 3 231.375 231.375 77.125 * *

Qty of water 1 231.375 231.375 231.125 * *

Water addition time 1 0.125 0.125 0.125 * *

Kneading time 1 0.125 0.125 0.125 * *

2-Way Interactions 3 2.375 2.375 0.792 * *

% Qty. of Water*Water addition time 1 1.125 1.125 1.125 * *

% Qty. of Water*Kneading time 1 0.125 0.125 0.125 * *

Water addition time*Kneading time 1 1.125 1.125 1.125 * *


% Qty. of Water*Water addition

time*Kneading time

1 1.125 1.125 1.125 * *


Total 7 234.875

Ef fe c t

Percent

1 29630

99

95

90

80

70

60

50

40

30

20

10

5

1

F a c to r N a m e

A Q ty . o f w a te r

B W a te r a d d it io n t im e

C k n e a d in g t im e

E f fe c t T y p e


S ig n if ic a n t

A

N o rm a l P r o b a b i l i ty P l o t o f th e E f f e c ts( r e s p o n s e is D is s o a t 3 0 m in s , A lp h a = .0 5 )

Le n th 's P S E = 0 .7 5

Term

Ef fe c t

C

AC

B

AB

BC

A BC

A

121086420

2 .82F a cto r N am e


B W a te r a dd it io n tim e

C k ne a d ing tim e

P are to Cha r t o f the E f fec ts(re sponse is Dis so a t 30 m ins , A lpha = .05 )

Le nth 's PS E = 0 .75


183

From the above interactions results it was found that qty of water has a significant

impact on tablet dissolution at 30 mins, whereas the water addition time and kneading

time does not have significant impact on the tablet dissolution. Therefore DOE was

run with two factors.

Table No. 109: DOE with two factors


Main effects 2 231.250 231.250 115.625 185.00 0.00

2-Way Interactions 1 1.125 1.125 1.125 1.80 0.251

Residual Error 4 2.500 2.500 0.625

Pure error 4 2.500 2.500 0.625

Total 7 234.875

S t a n d a r d iz e d E f f e c t

Percent

2 01 51 050

9 9

9 5

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

5

1

F a c t o r N a m e

A Q t y . o f w a t e r

B W a t e r a d d i t i o n t im e

E f f e c t T y p e

N o t S ig n i f ic a n t

S ig n i f ic a n t

A

N o r m a l P r o b a b i l i t y P l o t o f t h e S t a n d a r d i z e d E f f e c t s( r e s p o n s e i s D i s s o a t 3 0 m in s , A l p h a = . 0 5 )

Term


B

A B

A

2 01 51 050

2 .7 8F a c to r N a m e



P a r e to C h a r t o f th e S ta n d a r d i z e d E f f e c t s( r e s p o n s e is D is s o a t 3 0 m in s , A lp h a = . 0 5 )

Figure No. 38: Significant factors for tablet dissolution at 30 min

From the above ANOVA results and half- normal plots of the adjusted model, the

significant factors affecting dissolution was found to be % quantity of water. Contour


184

Plots for effect of % quantity of water and water addition time on dissolution at 30

mins.

Q t y . o f w a t e r

Water addition time

3 53 02 52 01 5

4

3

2

1

0

D is so a t

8 8 - 9 0

9 0 - 9 2

9 2

3 0 m in s

- 9 4

9 4 - 9 6

> 9 6

< 8 6

8 6 - 8 8

C o n to u r P l o t o f D i s s o a t 3 0 m i n s v s W a te r a d d i t i o n t im e , Q t y . o f w a te r

Figure No. 39: counter plot of dissolution at 30min vs water addition time

Table No. 110: Significant factors for Angle of Repose:


Main effects 3 19.6714 19.6714 6.5571 * *




Total 7 50.7192

Effect

Percent

86420-2-4-6-8

99

95

90

80

70

60

50

40

30

20

10

5

1

F a cto r N am e


B Wa te r add ition tim e

C k ne ad ing tim e

E ffec t Ty p e


S ig n ific an t

Normal P robability P lot of the Effects(response is Ang le of repose , A lpha = .05)

Lenth's PS E = 2.985

Figure No 40: Angle of repose probability chart


185

Term

Effe c t

A BC

A

A B

B

BC

C

A C

121086420

11 .24F a cto r N am e


B W a te r a d d itio n t im e

C k n e a d ing tim e

P a re to C ha r t o f the E f fe c ts(r e s ponse is A ng le o f re po s e , A lpha = .05 )

Le n th 's PS E = 2 .985

Figure No. 41: Pareto chart for angle of repose

From the above interactions results it was found that % qty of water doesn’t have a

significant impact on angle of repose. Therefore DOE was run with two factors to

study the impact on angle of repose.

Table No. 111: DOE was run with two factors to study the impact on angle of

repose

Source DF Seq SS Adj SS Adj

MS

F P Comments

Main effects 2 17.2514 17.2514 8.626 1.38 0.351 Non significant

2-Way Interactions 1 8.4050 8.4050 8.405 1.34 0.311 Non significant

Residual Error 4 25.0628 25.0628 6.266

Pure error 4 25.0628 25.0628 6.266

Total 7 50.7192


186

S t a n d a r d iz e d E f fe c t

Percent

3210- 1- 2- 3

9 9

9 5

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

5

1

F a c to r N a m e



E ffe c t T y p e


S ig n if ic a n t

N o r m a l P r o b a b i l i t y P l o t o f t h e S ta n d a r d i z e d E f f e c t s( r e s p o n s e is A n g le o f r e p o s e , A lp h a = .0 5 )

Figure No 42: DOE was run with two factors to study the impact on angle of

repose

Term


B

B C

C

3 . 02 . 52 . 01 . 51 . 00 . 50 . 0

2 . 7 7 6F a c t o r N a m e



P a r e t o C h a r t o f t h e S t a n d a r d i z e d E f f e c t s( r e s p o n s e i s A n g l e o f r e p o s e , A l p h a = . 0 5 )

All the batches demonstrated acceptable angle of repose (i.e., flow properties) and

none of the factors showed significant impact on angle of repose.

Table No. 112: Significant factors for Tablet Hardness


Main effects 3 360.000 360.000 120.000 * *

Qty of water 1 288.000 288.000 288.000 * *

Water addition time 1 72.000 72.000 72.000 * *

Kneading time 1 0.000 0.000 0.000 * *


% Qty. of Water*Water

addition time

1 40.500 40.500 40.500 * *

% Qty. of Water*Kneading

time

1 0.500 0.500 0.500 * *


187

Water addition time*Kneading

time

1 4.500 4.500 4.500 * *


% Qty. of Water*Water

addition time*Kneading time

1 338.000 338.000 338.000 * *


Total 7 743.500

Effect

Percent

20100-10-20

99

95

90

80

70

60

50

40

30

20

10

5

1

F acto r N am e

A Q ty . o f w a ter

B Wa te r addition tim e

C k nead ing tim e

E ffec t Ty p e

N o t S ig n ifican t

S ig n ifican t

Normal Probability P lot of the Effects(response is Max harndess, A lpha = .05)

Lenth's PS E = 6.75

Term

E f f e c t

C

A C

B C

A B

B

A

A B C

2 52 01 51 050

2 5 . 4 1F a c t o r N a m e




P a r e t o C h a r t o f t h e E f f e c t s( r e s p o n s e i s M a x h a r n d e s s , A l p h a = . 0 5 )

L e n t h ' s P S E = 6 . 7 5

From the above interactions results it was found that kneading time does not have

significant impact on the bulk density of the blend. Therefore DOE was run with two

factors.


188

Table No. 113: DOE with two factors of bulk density


Main effects 2 360.00 360.00 180.00 2.10 0.238 Non significant

2-Way Interactions 1 40.50 40.50 40.50 0.47 0.530 Non significant

Residual Error 4 343.00 343.00 85.75

Pure error 4 343.00 343.00 85.75

Total 7 743.50


Percent

3210- 1- 2- 3

9 9

9 5

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

5

1

F a c t o r N a m e



E f f e c t T y p e

N o t S i g n i f ic a n t

S ig n i f i c a n t

N o r m a l P r o b a b i l i t y P l o t o f t h e S t a n d a r d i z e d E f f e c t s( r e s p o n s e i s M a x h a r n d e s s , A l p h a = . 0 5 )

Figure No. 43: Significant factors for Tablet Hardness

Term


A B

B

A

3 . 02 . 52 . 01 . 51 .00 .50 .0

2 .7 7 6F a c to r N a m e

A Q ty . o f w a t e r


P a r e t o C h a r t o f t h e S t a n d a r d i z e d E f f e c t s( r e s p o n s e is M a x h a r n d e s s , A lp h a = .0 5 )

Figure No. 44: Pareto charts of significant factors for Tablet Hardness

All the batches demonstrated acceptable Hardness which is well within specification

limits and none of the factors showed significant impact on Hardness.

Summary of Wet granulation Process Development

The % Quantity of water in granulation showed a significant impact on tablet

dissolution at 30 mins. Based on the results it is observed that % quantity of water

does not have any adverse effect on the formulation. This may be due to the drug


189

property, as the drug substance belongs to BCS class IV wetting of drug substance is

required for complete dissolution. So as per the results of DOE for % quantity of

water is significant factor for dissolution. Because no curvature effects were observed

for any other responses studied, and the main effects and interaction effects were

identified using a full factorial DOE, further studies to optimize the process

parameters were unnecessary. The DOE models were used to establish acceptable

ranges for process variables. At the conclusion, the levels of process variable were

tentatively finalized as shown in below.

Table No. 114: Proposed levels for the process variables

Factors: Process Variables Optimum level as optimized by DOE

A % Qty of water 30

B Water addition time 3

C Kneading time 2

Table No. 115: The blend uniformity results for 10 mg strength

Location

Assay (% w/w)

10 mg 2 mg

After 2

minutes

After 3

minutes

After 4

minutes

After 2

minutes

After 3

minutes

After 4

minutes

U1 99.8 97.2 100.9 96.0 97.5 94.0

U2 101.2 95.3 100.2 97.5 94.0 93.5

U3 101.9 99.4 100.4 94.0 100.5 92.0

M1 99.5 94.9 99.1 101.0 95.5 95.5

M2 99.1 99.9 101.6 94.5 95.5 94.0

M3 100.5 98.3 99.0 94.0 94.5 94.0

L1 109.8 101.8 99.3 94.0 96.0 93.5

L2 100.7 99.2 96.8 91.0 95.0 94.5

L3 100.1 92.9 99.5 96.5 93.5 93.5

Minimum 99.1 92.9 96.8 91.0 93.5 92.0

Maximum 109.8 101.8 101.6 101.0 100.5 96.5

Mean 101.4 97.7 99.6 97.5 95.6 94.1

SD 3.3 2.8 1.4 1.3 2.1 1.2

%RSD 3.25 2.87 1.41 1.33 2.20 1.28


190

Table No. 116: Effect of blending time of Lubrication on blend uniformity.

Location

Assay (% w/w)

10 mg 2 mg

After 2

mins

After 3

mins

After 4

mins

After 2

mins

After 3

mins

After 4

mins

U1 98.2 97.6 99.4 98.5 97.5 95.0

U2 82.4 99.1 99.5 97.5 97.0 94.0

U3 97.3 101.0 100.7 98.0 96.5 95.0

M1 98.0 99.0 99.5 99.0 96.5 97.0

M2 98.4 99.8 99.2 97.5 98.5 93.5

M3 104.4 99.2 98.9 97.5 97.5 96.5

L1 97.5 98.6 99.8 97.0 95.5 95.0

L2 101.0 101.4 101.2 98.5 99.0 95.5

L3 98.0 97.5 99.0 98.5 98.5 96.5

Minimum 82.4 97.5 98.9 97.0 95.5 93.5

Maximum 104.4 101.4 101.2 99.0 99.0 97.0

Mean 97.2 99.2 99.7 98.0 97.4 95.3

SD 6.0 1.3 0.8 0.7 1.1 1.2

%RSD 6.17 1.31 0.8 0.71 1.13 1.26

Summary for blending time of Pre lubrication and Lubrication on Process

development:

Based on the results of the Blending time of Pre lubrication and Lubrication studies.

The time needed to achieve blend uniformity was fixed to 3 mins for pre lubrication

and 3 mins for lubrication.

The results are as follows:

2 mg strength

a) Description: Light green to green colored, modified rectangular, standard concave

beveled edged tablets embossed with ‘705’ on one side and ‘W’ on the other side.

b) Dimensions: 8.1 X 4.6 + 0.2 mm

Table No. 117: Compression Parameters

i) Speed Challenge: -


191

No. Parameters

Observations

Low Speed

(20 rpm)

Optimum speed

(30 rpm)

High speed

(40 rpm)

1 Average weight

of Tablets (mg) 99.9 mg 101.2 mg 100.7 mg

2 Weight variation

(mg)

97 – 102 mg

(-3.0% to +2.0%)

98 - 103 mg

(-2.0% to +3.0%)

95 - 106 mg

(-5.0% to +6.0%)

3 Thickness (mm) 2.56 – 2.62 mm 2.53 – 2.61 mm 2.59 – 2.66 mm

4 Hardness (N) 45.3 – 61.5 N 50.4 – 63.2 N 46 – 59 N

5 Friability (%) 0.03 % 0.04 % 0.06 %

6 Disintegration

time 47 sec 38 sec 38 sec

ii) Hardness Challenge: -

No. Parameters

Observations

Low

Hardness

Optimum

Hardness

High

Hardness

1 Average weight of

Tablets (mg) 101.3 mg 101.2 mg 102.1 mg

2 Weight variation

(mg)

98 – 103 mg

(-2.0% to +3.0%)

98 - 103 mg

(-2.0% to +3.0%)

95 – 105 mg

(-5.0% to +5.0%)

3 Thickness (mm) 2.69 – 2.84 mm 2.53 – 2.61 mm 2.34 – 2.53 mm

4 Hardness (N) 21.3 – 36.1 N 50.4 – 63.2 N 82.3 – 106.7 N

5 Friability (%) 0.20 % 0.04 % 0.01 %

6 Disintegration time 29 sec 38 sec 2 min 13 sec


192

Table No. 118: Content uniformity

Stage: Performed during Low/High Speed (Speed Challenge) and Optimum

speed

Location

Assay (% of claim)

Low Speed

(20 RPM)

High speed

(40 RPM)

Optimum

speed

(30 RPM)

CU-1 98.3 99.7 96.5

CU-2 97.6 100.4 96.4

CU-3 97.7 98.2 97.6

CU-4 98.1 98.5 96.4

CU-5 98.1 97.4 101.2

CU-6 101.9 98.2 97.4

CU-7 99.5 99.2 98.1

CU-8 99.2 102.1 97.3

CU-9 99.9 97.7 98.0

CU-10 99.3 102.8 97.6

Minimum 97.6 97.4 96.4

Maximum 101.9 102.8 101.2

Mean 99 99.4 97.7

SD 1.3 1.8 1.4

%RSD 1.31 1.81 1.43

Acceptance value

(L1) 3.1 4.3 4.2

Table No. 119: Dissolution profile results

Time

in min

Low hardness

Optimum hardness

High Hardness

10 91 91 92

15 97 98 94

20 96 98 94

30 97 100 94


193

Time

in min

Low hardness

Optimum hardness

High Hardness

45 97 99 94

60 97 99 94

f) Assay of Tablets: - 96.8%

10 mg strength

a) Description: Pink colored, modified rectangular beveled edged tablets embossed

with W on one side and 707 on the other side.

b) Dimensions: 8.1 X 4.6 + 0.2 mm

c) Compression Parameters:

Table 120: i) Speed Challenge: -

No. Parameters

Observations

Low Speed

(20 rpm)

Optimum speed

(30 rpm)

High speed

(40 rpm)

1 Average weight of Tablets

(mg) 100.4 101.1 98.8

2

Weight variation (mg) 98 – 104

(-2.0% to

+4.0%)

96 – 103

(-4.0% to

+3.0%)

95 – 106

(-5.0% to

+6.0%)

3 Thickness (mm) 2.53 – 2.60 2.54 – 2.62 2.56 – 2.64

4 Hardness (N) 38.9 – 61.1 44.6 – 62.9 45.1 – 56.0

5 Friability (%) 0.05 Nil 0.12

6 Disintegration time 1 min 40 sec 1 min 30 sec 1 min 22 sec

ii) Hardness Challenge: -

No. Parameters

Observations

Low

Hardness

Optimum

Hardness

High

Hardness

1 Average weight of Tablets

(mg) 101.4 101.1 99.1

2

Weight variation (mg) 98 – 103

(-2.0% to +3.0%)

96 – 103

(-4.0% to

+3.0%)

97 – 105

(-3.0% to

+5.0%)


194

No. Parameters

Observations

Low

Hardness

Optimum

Hardness

High

Hardness

3 Thickness (mm) 2.68 – 2.86 2.54 – 2.62 2.39 – 2.51

4 Hardness (N) 21.6 – 36.7 44.6 – 62.9 62.9 – 88.7

5 Friability (%) 0.24 Nil 0.01

6 Disintegration time 24 sec 1 min 30 sec 2 min 40 sec

d) Content uniformity:

Table No. 121: Stage: Performed during Low/High Speed (Speed Challenge) and

Optimum Hardness

Location Assay (% of claim)

Low RPM (20RPM) High RPM (40 RPM) Optimum RPM (30 RPM)

CU-1 104.5 112.7 101.6

CU-2 100.4 99.9 102.6

CU-3 98.6 100.0 103.0

CU-4 99.9 105.0 101.9

CU-5 101.9 112.1 102.8

CU-6 100.9 100.9 103.1

CU-7 100.3 101.7 102.7

CU-8 100.7 101.3 102.0

CU-9 100.7 99.2 104.0

CU-10 99.9 99.3 103.8

Minimum 98.6 99.2 101.6

Maximum 104.5 112.7 104.0

Mean 100.8 103.2 102.8

SD 1.6 5.1 0.8

%RSD 1.59 4.94 0.78

Acceptance

Value (L1) 3.8 13.9 3.2


195

Table No. 122: e) Dissolution profile results

Time in min Low hardness Optimum Hardness High Hardness

10 93 92 95

15 95 94 97

20 96 95 97

30 96 95 97

45 96 95 98

60 96 95 97

Assay of Tablets: - 99.3%

30 mg strength

a) Description: Pink colored round, beveled edged tablets debossed with W on one

side and 710 on the other side.

b) Diameter: 9.1 + 0.2 mm

c) Compression Parameters:

i) Speed Challenge: -

Table No. 123: Compression Parameters of 30mg

No. Parameters

Observations

Low Speed

(20 rpm)

Optimum speed

(30 rpm)

High speed

(40 rpm)

1 Average weight of

Tablets (mg) 300.7 298.6 301.3

2 Individual weight

variation (mg)

296 – 308

(-1.3% to +2.6%)

294 – 307

(-2.0% to +2.3%)

292 – 309

(-2.6% to +3.0%)

3 Thickness (mm) 3.84 – 3.92 3.82 – 3.95 3.76 – 4.09

4 Hardness (N) 64.5 – 80.1 65.1 – 79.0 53.9 – 72.9

5 Friability (%) 0.14 0.08 0.18

6 Disintegration Time 32 sec 30 sec 33ec


196

Table No. 124: Hardness Challenge (30mg)

No. Parameters

Observations

Low

Hardness

Optimum

Hardness

High

Hardness

1 Average weight of Tab (mg) 300.7 298.6 297.8

2 Weight variation (mg) 292- 309

(-2.6% to +3.0%)

294 – 307

(-2.0% to +2.3%)

291 – 307

(-3.0% to +2.3%)

3 Thickness (mm) 4.01 – 4.18 3.82 – 3.95 3.69 – 3.79

4 Hardness (N) 41.3 – 56.7 65.1 – 79.0 80.1 – 98.8

5 Friability (%) 0.28 0.08 0.10

6 Disintegration time 24 sec 30 sec 3min 42 sec

Table No. 125: Content uniformity (30mg)

Stage: Performed during Low/High Speed (Speed Challenge) and Optimum

Hardness

Location Assay (% of claim)

Low Speed (20 RPM) High Speed (40 RPM) Optimum Speed (30RPM)

CU-1 97.8 96.9 99.4

CU-2 97.0 98.2 100.4

CU-3 103.1 97.9 98.5

CU-4 103.2 97.0 100.0

CU-5 96.3 98.1 101.8

CU-6 103.2 98.8 99.6

CU-7 98.1 98.3 99.9

CU-8 97.0 99.2 101.0

CU-9 96.6 98.8 98.5

CU-10 97.0 98.6 100.3

Minimum 96.3 96.9 98.5

Maximum 103.2 99.2 101.8

Mean 98.9 98.2 99.9

SD 3.0 0.8 1.0


197

%RSD 3.03 0.81 1.00

Acceptance

value (L1) 7.2 2.2 2.4

Table No. 126: Dissolution profile results (30mg)

Time

in min Low hardness Optimum Hardness High Hardness

10 94 97 97

15 100 102 101

20 98 102 102

30 99 103 100

45 101 103 102

60 101 103 102

Assay of Tablets: - 97.7%

Table No. 127: Proposed in-process controls for the compression step

Test Frequency Limits

2 mg 5 mg 10 mg 15 mg 20 mg 30 mg

Average

weight (mg)

Every 30

min 100.0 ± 5%

150 ±

5%

200±

5%

300 ±

3%

Weight

Variation

Every 30

min ± 7.5% of target weight

Thickness

(mm)

Every 1

hour 2.60 ± 0.30

3.40 ±

0.30

3.60±

0.30

3.90±

0.30

Hardness (N) 60 ± 30 70± 30

Friability Every 2

hours

NMT 1.0%w/w

Disintegration

Time NMT 10 min


198

Table No. 128: Stability data 2mg Batch No. PS(100)-50-181

Table No. 129: Stability data 5mg Batch No: PS(100)52-187

40 cc TW HDPE Bottle+ One 3g Sil.Canister 5 mg Batch.No: PS(100)-52-187

Condition Initial 40/75 40/75 40/75 25/60

Stage 1M 2M 3M 3M

Related Substances

Aripiprazole Quinoline(Related compound A) 0.000 0.003 0.004 0.004 0.001

Aripiprazole related compound B 0.000 0.001 0.001 0.000 0.001

DCCP(Related compound C) 0.000 0.001 0.002 0.000 0.000

40 cc TW HDPE Bottle+ One 3g Sil.Canister 2mg Batch No. PS(100)-50-181


Stage 1M 2M 3M 3M

Related Substances




3-chloro Aripiprazole 0.001 0.001 0.001 0.002 0.001

Dehydro Aripiprazole(Related compound G) 0.097 0.095 0.094 0.098 0.095

Aripiprazole N-Oxide(Related compound F) 0.012 0.017 0.015 0.006 0.010

Dimer impurity(Related compound D) 0.028 0.029 0.028 0.028 0.028

Chlorobutoxy carbostyril(Related compound E) 0.009 0.010 0.010 0.009 0.009

Highest unknown 0.024 0.020 0.021 0.019 0.019

Total unknown 0.086 0.082 0.086 0.070 0.063

Total related substances 0.235 0.255 0.256 0.234 0.215

Assay (NLT 90.0% & NMT110.0% of the

labeled amount) 99.0 100.5 100.0 98.5 98.1

Water content (Not more than 8.0 % w/w) 5.89 5.50 5.30 5.20 4.98

Dissolution NLT 80 %(Q) of the labeled

amount of Aripiprazole is dissolved in 30

minutes 103 93 102 106 105


199






Highest unknown 0.097 0.100 0.099 0.061 0.040

Total unknown 0.136 0.137 0.137 0.102 0.070


Assay (NLT 90.0%& NMT110.0% of the

labeled amount) 100.8 99.0 99.6 100.3 98.8




minutes 103 95 97 103 102

Table No. 130: stability conditions of 10mg Batch No: PS(100) 49-177A

40 cc TW HDPE Bottle+ One 3g Sil.Canister 10mg Batch No: PS(100) 49-177A


Stage 1M 2M 3M 3M

Related Substances

Aripiprazole Quinoline (Related compound A) 0.001 0.004 0.004 0.005 0.001


DCCP (Related compound C) 0.000 0.003 0.003 0.002 0.002


Dehydro Aripiprazole (Related compound G) 0.096 0.096 0.098 0.100 0.098

Aripiprazole N-Oxide (Related compound F) 0.008 0.019 0.017 0.007 0.007

Dimer impurity (Related compound D) 0.028 0.030 0.029 0.027 0.027

Chlorobutoxy carbostyril (Related compound

E) 0.009 0.009 0.011 0.007 0.006

Highest unknown 0.004 0.005 0.005 0.005 0.004


200

Table No. 131: stability conditions 15mg Batch No: PS(100) 51-184

40 cc TW HDPE Bottle+ One 3g Sil.Canister 15mg Batch No: PS(100) 51-184


Stage 1M 2M 3M 3M

Related Substances









Highest unknown 0.005 0.004 0.006 0.005 0.005

Total unknown 0.020 0.032 0.037 0.021 0.018



labeled amount) 99.5 98.5 98.3 96.5 96.5



amount of Aripiprazole is dissolved in 30 min 93 96 96 98 98

Total unknown 0.026 0.047 0.042 0.027 0.022



labeled amount) 100.9 99.2 98.1 96.6 98.6




minutes 98 96 96 100 102


201

Table No. 132: stability conditions of 20mg Batch No: PS(100) 53-190

40 cc TW HDPE Bottle+ One 3g Sil.Canister 20mg Batch No: PS(100) 53-190


Stage 1M 2M 3M 3M

Related Substances









Highest unknown 0.004 0.004 0.009 0.009 0.005

Total unknown 0.021 0.033 0.045 0.040 0.019



labeled amount) 100.7 99.2 99.2 97.5 97.9




Table No. 133: stability conditions 30mg Batch No: PS(100) 49-177B

40 cc TW HDPE Bottle+ One 3g

Sil.Canister

30mg Batch No: PS(100) 49-177B


Stage 1M 2M 3M 3M

Related Substances




202






Chlorobutoxy carbostyril(Related compound

E) 0.009 0.010 0.010 0.007 0.008

Highest unknown 0.004 0.008 0.005 0.005 0.004

Total unknown 0.022 0.042 0.039 0.023 0.018



labeled amount) 100.5 99.8 97.5 97.5 97.4




minutes 98 103 100 108 103


Alu-Alu Blister 2mg Batch No: PS(100) 50-181


Stage 1M 2M 3M 3M

Related Substances










203


Alu-Alu Blister 5mg Batch No: PS(100) 52-187


Stage 1M 2M 3M 3M

Related Substances









Highest unknown 0.097 0.050 0.040 0.053 0.044

Total unknown 0.136 0.078 0.066 0.071 0.058



labeled amount) 100.8 99.1 97.0 99.6 97.6



Amount of Aripiprazole is dissolved in 30 min 103 98 98 94 103

Highest unknown 0.024 0.016 0.017 0.019 0.016

Total unknown 0.086 0.064 0.046 0.036 0.035



labeled amount) 99.0 98.4 100.2 98.4 99.5





204

Table No. 136: Alu-Alu Blister with 10mg Batch No. PS(100)-49-177A

Table No. 137: Stability of 15mg with Alu –Alu blister

Alu-Alu Blister 15 mg Batch. No: PS(100)-51-184


Stage 1M 2M 3M 3M

Related Substances




Alu-Alu Blister 10mg Batch No. PS(100)-49-177A


Stage 1M 2M 3M 3M

Related Substances









Highest unknown 0.004 0.004 0.005 0.003 0.005

Total unknown 0.026 0.023 0.033 0.013 0.018



labeled amount) 100.9 97.3 98.5 98.8 98.7



Amount of Aripiprazole is dissolved in 30 min 98 97 100 92 91


205






Highest unknown 0.005 0.005 0.005 0.006 0.005

Total unknown 0.020 0.019 0.024 0.021 0.018



labeled amount) 99.5 97.9 96.2 98.9 98.9




Table No. 138: Stability studies of 20mg with Alu –Alu blister

Alu-Alu Blister 20 mg Batch. No: PS(100)-53-190


Stage 1M 2M 3M 3M

Related Substances









Highest unknown 0.004 0.005 0.004 0.004 0.006

Total unknown 0.021 0.023 0.017 0.013 0.016



206


labeled amount) 100.7 98.1 101.1 99.9 98.8




Table No. 139: Stability studies of 30mg with Alu –Alu blister

Alu-Alu Blister 30 mg Batch. No: PS(100)-49-177B


Stage 1M 2M 3M 3M

Related Substances









Highest unknown 0.004 0.005 0.005 0.004 0.005

Total unknown 0.022 0.019 0.022 0.023 0.011



labeled amount) 100.5 99.6 100.0 100.9 104.8

Water content (Not more than 8.08.0 % w/w) 5.47 5.03 5.18 4.59 4.67

Dissolution NLT 80 % of the labeled


Conclusion:

For Related substances- All the impurities Aripiprazole Quinoline (Related compound A),

Aripiprazole related compound B, DCCP (Related compound C), 3-chloro Aripiprazole,

Dehydro Aripiprazole (Related compound G), Dimer impurity (Related compound D),


207

Chlorobutoxy carbostyril (Related compound E) are process impurity. N-oxide is

degradant impurity is monitored during stability. Product was found to be stable in HDPE

bottle pack with 3g Sil.Canister and Alu Alu blister pack.

5. 1.4 Dissolution Method Development and pilot bioequivalence study

5.1.4.1 Dissolution Method Development

Aripiprazole is a BCS Class IV compound displaying poor aqueous solubility across

the physiological pH range. As such, development of a dissolution method that can

act as the best available predictor of equivalent pharmacokinetics to the RLD was

pursued to allow assessment of Aripiprazole tablets manufactured during

development.

The target is an immediate release product, here the dissolution medium used having

pH low because the drug absorption was at upper intestine. Dissolution was carried

out with recommended dissolution procedure the FDA: 900 mL of pH1.2 USP buffer

(Hydrochloric acid) using USP apparatus 2 at 60 rpm. Further pH 4.5 and pH 6.8

buffers were evaluated using USP apparatus 2 at 60 rpm. Because of poor solubility &

dissolution profile of test product in pH 6.8 buffer, 0.5% SLS was added to the media.

Then it was found to be similar to the RLD tablets.

Table No. 140: Aripiprazole solubility in different media

Media Solubility (mg/ml) Solubility (mg/250ml)

0.1 N HCl 0.069 17.25

Acetate buffer pH 4.5 0.054 13.50



Water Insoluble

The dissolution method selected for development of product uses 900 mL of pH1.2

USP buffer (Hydrochloric acid) in a dissolution apparatus equipped with paddles

(speed 60 rpm) and maintained at a temperature of 37°C, followed by HPLC

determination. Additionally, this method is capable of detecting dissolution changes

in the drug product caused by deliberately varying the drug substance (DS) particle

size distribution (PSD). If dissolution is done in the absence of sodium lauryl sulfate

the release was found to be only 3 %.


208

5.1.4.2 Pilot Bioequivalence Study

Particle size Effect of Aripiprazole on dissolution

The formulation development studies identified drug substance particle size

distribution as the most significant factor that impacts drug product dissolution. In

order to understand the potential clinical relevance of drug substance PSD on in-vivo

performance three prototype formulations were studied with aripiprazole lots with a

different particle sizes.

Table No. 141: Particle size effect of Aripiprazole on Dissolution

API B.no. AII/A-401/177 APZ/001/2012-2013 PP110301

PSD D(0.9) 94.82 µ D(0.9) 17 µ D(0.9) 23.76 µ

Time

(min)

ABILIFY 10

mg 2B71310 PS(100)-54-193 PS(100)-49-177A PS(100)-37-132A

10 92 25 95 94

15 99 31 98 98

20 100 33 98 99

30 101 36 98 99

45 101 40 98 98

60 101 44 98 99

Figure No 45: RLD vs. Test sample dissolution profile in 900 ml of pH 1.2 USP

buffer medium using USP apparatus 2 at 60 rpm

Invitro dissolution and in vivo performance was carried out to know relation and the

dissolution test was performed on the three prototypes and the RLD using FDA-

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Time (min)

Dru

g R

ele

ase

Abilify 10 mg 2B71310PS(100)-54-193PS(100)-49-177APS(100)-37-132A


209

recommended dissolution method. The data indicated that particle size is the major

parameter for the in vitro dissolution performance. A dissolution rate of not less than

(NLT) 80% in 30 min in pH 1.2 USP buffer (Hydrochloric acid) was set as target for

pharmaceutical development studies based on dissolution rate as observed for the

innovator. The prototype formulation PS (100)-37-132 A & 2B71310 were used for

the pilot bioequivalence study.

1. Type of study: Fasting

Design: Single dose, two treatments, two period crossover in-vivo

Dose and tablet strength: 10mg

Subjects: Normal healthy males and females, general population

2. Type of study: Fed

Design: Single dose, two treatments, two period crossover in-vivo

Dose and tablet strength: 10mg

Subjects: Normal healthy males and females, general population

Analytes to measure: Aripiprazole in plasma

Bioequivalence based on 90% CI: Aripiprazole

Table No. 142: BE study of Aripiprazole Tablet 10 mg under Fed Condition

Ratios and 90% Confidence Intervals Based on Log Transformed PK Parameters [N=14]

PK

Parameters

Ratio %

(T/R)

90% C.I. P-Value

Power

(%) MSE

Intra-CV

(%) Lower Limit Upper Limit

Cmax 102.34 89.74 116.71 0.0066 88.23% 0.034587 18.76%

AUCt 99.11 92.85 105.79 0.0000 99.94% 0.008525 9.25%

AUCinf 93.91 82.14 107.36 0.0259 87.23% 0.035878 19.11%


210

Fig 46: untransformed mean plasma Fig 47: logtransformed mean

plasma

Concentration time curve (feed) Concentration time curve

Figure No 46: untransformed mean plasma Figure No 47: log transformed

mean Concentration time curve (fasting) Concentration time curve

Table No. 143: BE study of Aripiprazole Tablet 10 mg under Fasting Condition

Ratios and 90% Confidence Intervals Based on Log Transformed PK Parameters [N=14]

PK

Parameters

Ratio %

(T/R)

90% C.I. P-Value

Power

(%) MSE

Intra-CV

(%) Lower Limit Upper Limit

Cmax 118.44 103.14 136.02 0.2479 85.41% 0.034953 18.86%

AUCt 111.63 103.93 119.89 0.0083 99.84% 0.009317 9.67%

AUCinf 131.95 116.85 149.00 0.7808 92.00% 0.026962 16.53%

Figure No 48: untransformed mean plasma Figure No 49: log transformed

mean Concentration time curve (fasting) Concentration time curve

The results of the PK study indicated that a drug substance particle size distribution

with a D(0.9) of 23.76µ (NMT 30µ) or less showed similar performance based on test

to reference ratio calculations for AUC and Cmax.


211

In the fasting study 2 individuals were outlyers. After removing these two individuals

the BE acceptance criteria were achieved. As per the package insert there is no effect

of food on the bioequivalency of the product.

Figure No 50: Aripiprazole tablets


212

5.2. Results and discussion of Venlafaxine Extended Release Tablets

5.2.1 Innovator product evaluation

The innovator was characterised and evaluated for all the analytical parameters.

Table no144: Innovator product evaluation

Test Specification Result

64305005 64306012

Description White to off white polymer White powder White powder

Solubility The drug is freely soluble in water and

in methanol, soluble in anhydrous

ethanol and practically insoluble in

acetone.

Complies Complies

Identification

IR absorption The infrared absorption spectrum of a

Potassium Bromide dispersion of it

exhibits maxima at the same

wavelengths as that of a similar

preparation of Venlafaxine

Hydrochloride polymorph-C working

standard.

Complies Complies

By HPLC The retention time of the major peak

in the chromatogram of the Assay

preparation should correspond to that

in the chromatogram of the Standard

preparation, as obtained in the Assay.

Complies Complies

Test for

Chloride

A curdy white precipitate is formed

which is insoluble in nitric acid but

soluble in slight excess of l0 M

Ammonium hydroxide solution.

Complies

Complies

Specific optical

rotation (on

dried basis)

Between l0 to + 1.0 +0.070 -0.03°

pH (2% Between 5.0 and 7.0. 6.01 6.23


213


64305005 64306012

solution in

water)

Loss on drying

(At 105°C for 3

hours

Not more than 0.50% w/w. 0.43 0.24

Residue on

ignition

Not more than 0.l0% w/w. 0.03%w/w 0.05%w/w

Heavy metals Not more than 20 ppm Complies Complies

Hydrochloride

content (On

dried basis)

Between 11.0% and 12.2% w/w. 11.51 -

Related compounds(By HPLC)

Impurity A Not more than 0.10 % wlw ND ND

Impurity C Not more than 0.l0 % w/w ND ND

Impurity D Not more than 0.10 % wlw BDL ND

Impurity E Not more than 0.10 % wlw ND ND

Impurity F Not more than 0.10 % wlw ND ND

Impurity G Not more than 0.10 % wlw ND 0.09

Impurity H Not more than 0.10 % wlw ND ND

Hydroxy nitrile Not more than 0.10 % wlw ND ND

Any unknown

impurity

Not more than 0.10 % wlw ND 0.05

Total

impurities

Not more than 0.20% w/w Nil 0.14

Assay (By

HPLC) (On

dried basis)

Not less than 98.0% and not more

than 102.0%.

98.49% 100.2%

Residual solvents (by GC)

Methanol Not more than 500 ppm 19 14

Ethyl acetate Not more than 1500 ppm ND ND

Isopropyl Not more than 3000 ppm 1272 655


214


64305005 64306012

alcohol

Toluene Not more than 890 ppm 65 ND

Cyclohexanone Not more than 700 ppm 57 80

XRD X-Ray diffraction pattern of test

sample concordant with Venlafaxine

hydrochloride polymorph-C working

hydrochloride polymorph-C working.

Complies Complies

Particle size (By Malvern)

d (0.9) Not more than 175 microns 159 81

d (0.5) Not more than 50 microns 28 17

Discussion: The innovator evaluation was found to be matching with the analytical

data in the literature.

5.2.2 Excipients used and its compatibility:

Table no145: List of excipients used

S.

No.

Excipients used in

Proposed generic drug

product

Intended

Function

Justification

1 Microcrystalline cellulose

(Avicel PH 101)

Filler Most commonly used excipient and

recommended for use intragranularly

and grade also recommended for met

granulation process

2 Povidone (K 30) Binder Used intragranularly as binding agent

and does not retard release profile. Gives

good granulation characteristics

3 Ethyl cellulose (N 50) Rate

Controlling

Polymer

Grade recommended for rate controlling

film forming agent. Its form a

hydrophobic coating membrane and

functions in a pH independent manner.

Also used in the reference product.

4 Triethyl citrate Plasticizer Used as plasticizer during coating and


215

S.

No.

Excipients used in

Proposed generic drug

product

Intended

Function

Justification

complies as per pharmacopeial

requirements. It ensures coalescence of

the membrane as a continuous film

during coating, free from cracks.

5 Acryl-EZE MP 93018508

white

Rate

Controlling

Polymer

Methacrylic acid copolymer based

coating system recommended by

supplier for modified release coating

system. Already used in CDER

approved ANDA (ANDA No.: 77~296)

6 Talc Lubricant Commonly used as lubricant for coated

pellets

Discussions: The excipients used were GRAS listed and were found to be in IIG

limits. These were comparable to the excipients found in innovator.

5.2.3 Drug-Excipient Incompatability

Table no 146: Observation after four weeks at 40°C± 2 °C and 75 % ± 5% RH

and 25°C± 2°C and 60% ± 5% RH

S.

No.

Physical

admixture

Ratio Initial 25°C/60%RH 40°C/75%RH

Week

1st 2

nd 4

th 6

th 1

st 2

nd 4

th 6

th

1 Venlafaxine HCI As such White

powder

√ √ √ √ √ √ √ √

2 Venlafaxine HCI

+ Avicel PH 101

0.5:0.37 White

powder

√ √ √ √ √ √ √ √

3 Venlafaxine HCI

+ HPMC 6cps

0.5:0.11 White to

off white

powder

√ √ √ √ √ √ √ √

4 Venlafaxine HCI

+ Ethyl cellulose

0.5:0.11 White to

off white

√ √ √ √ √ √ √ √


216

S.

No.

Physical

admixture

Ratio Initial 25°C/60%RH 40°C/75%RH

Week

1st 2

nd 4

th 6

th 1

st 2

nd 4

th 6

th

powder

5 Venlafi1xine

HCI + Acry! EZ8

MP 93018508

While

1:0.1 White to

off white

powder

√ √ √ √ √ √ √ √

6 Venlafaxine HCI

+ Triethyl citrate

1:0.1 White

lumps

√ √ √ √ √ √ √ √

7 Venlafaxine HCI

+ PVP K30

1:0.1 White to

off white

powder

√ √ √ √ √ √ √ √

Discussions: Based on the initial observations it was inferred that no incompatibility

were observed between the drug and excipients. Thus all the excipients can be used in

the formulation along with the API.

5.2.4 Formulation Development:

The prototype formulation development followed the strategy on the lines of the

innovator. The innovator contains spheroids thus the spheroids formation and

evaluation technique was used. The batch number of that batch was taken was

B05403.

Table no147: Drug Release profiles of Effexor XL Capsules, 150 mg (Batch

number: B05403)

Volume of

Media:

900 mL, USP type: l, 100 rpm, Mean % .Drug Release

Apparatus:

Time in Hours (0.1 N) HCl (pH 4.5) acetate

buffer

(pH 6.8 ) Buffer

Phosphate

0 0 0 0

1 4 4 4


217

Volume of

Media:

900 mL, USP type: l, 100 rpm, Mean % .Drug Release

Apparatus:

Time in Hours (0.1 N) HCl (pH 4.5) acetate

buffer

(pH 6.8 ) Buffer

Phosphate

2 15 14 15

4 35 35 39

6 51 52 55

8 61 62 66

12 73 75 78

16 81 81 84

20 85 86 88

24 88 88 91

Figure No 51: Effexor dissolution profile

Discussion: Based on the results in table no. 147 and Figure No 51 the strategy to be

followed for the formulation was decided. The strategy was to include rate controlling

polymer and plasticizer.

5.2.5 Formulation using coating approach.

The optimization of percentage coating was carried out and dissolution profile of the

same was studied.


218

Table no 148: Comparison of Drug release profile of development batches vs.

Effexor XR®

Volume of Media 6.8 pH phosphate buffer, 900 mL, USP type-I,

100 rpm Apparatus

Mean % Drug Released

Time in

Hours

Effexor XR,

150 mg

Batch Number: VERC-39B/05

(Coating Weight Gain)

8%w/w 9%w/w 10% w/w

0 0 0 0 0

1 4 9 7 7

2 15 23 20 18

4 39 41 37 36

8 61 58 55 53

12 73 69 64 64

16 81 77 72 71

20 85 82 77 77

24 88 88 82 81

Figure No. 52: Comparison of 8%, 9%, 10% w/w coating

Discussion: The coating of 8, 9 and 10% w/w did not show any difference in the drug

release profile. Thus further optimization with 7.5% and 8.5% was done.


219

Table no 149: Comparison of Coating with Effexor XR, 150mg

Volume of Media 6.8 pH phosphate buffer, 900 mL,

USP type-I, 100 rpm Apparatus


Time in Hours Effexor XR, 150 mg Batch Number: VERC-39A/05

(Coating Weight Gain)

7.5% w/w 8.5% w/w

0 0 0 0

1 4 12 8

2 15 31 25

4 39 48 42

8 61 66 60

12 73 76 72

16 81 83 78

20 85 87 84

24 88 91 88

Figure No 53: Comparison of 7.5% w/w and 8.5% w/w

Discussions:

Dissolution profile of VERC 39A/05 was desirable and hence formulation with 10%

w/w coating and 8.5% w/w coating were selected for further development.


220

5.2.5.1 Ethyl Cellulose coating approach and its study in different dissolution

media

The coated pellets were then studied for the drug release in different medias like

phosphate buffer (pH 6.8), acetate buffer (pH 4.5) and HCl (0.1N).


Effexor XR®

Time

(hr)

Volume of Media 900mL

Apparatus USP type-1, 100 rpm


(0.l N)HCI 4.5 pH acetate buffer 6.8 pH phosphate

buffer

Effexor

XR 150

USB(113)-

42-01

Effexor

XR 150

USB(113)-

42-01

Effexor

XR 150

USB(113)-

42-01

0 0 0 0 0 0 0

1 4 10 4 10 4 11

2 15 21 14 21 15 22

4 35 36 35 36 39 37

6 51 46 52 46 55 46

8 61 53 62 53 66 53

12 73 63 75 63 78 63

16 81 68 81 68 84 69

20 85 73 86 73 88 73

24 88 76 88 76 91 75


221

Figure No 54: Comparison in different media of Effexor and U.S batches

Discussions:

Fines were generated during coating process. A suitable binder is required for desired

strength of spheroids. Drug release profile was slow compared to reference product in

all the three media’s.

5.2.6 Effect of binder on the drug release

5.2.6.1 Hypromellose as binder:

The first binder used was hypromellose 6 cps (Methocel E6) as binder at 1% w/w

Discussions:

Pellets collected in 12/30# fraction were only 55% and pellets over #12 mesh was

44%. Hence the batch was not further processed.

5.2.6.2 Povidone K30 as binders:

The other binder selected was povidone K30 as hypromellose 6cps did not give a

higher yield.


Efexor® XL

Time

(hr)

Volume of Media 900mL

Apparatus USP type-1, 100 rpm


222


(0.l N)HCI 4.5 pH acetate buffer 6.8 pH phosphate buffer

Effexor

XR 150

USB(113)-

45-01

Effexor

XR 150

USB(113)-

45-01

Effexor XR

150

USB(113)-

45-01

0 0 0 0 0 0 0

1 4 9 4 11 4 9

2 15 20 14 23 15 21

4 35 38 35 40 39 38

6 51 50 52 50 55 51

8 61 59 62 57 66 61

12 73 71 75 68 78 73

16 81 80 81 75 84 82

20 85 86 86 80 88 88

24 88 91 88 83 91 93

Figure No 55: Effect of Binder (Povidone K30)

Discussions:

• Batch size was 3000 capsules

• Bulkdensityofpremixwas0.16g/cc.Premixingconditions:5minutes,slow

impellerandchopperoffandsubsequentgranulationfor1minutewithimpeller and

chopper at slow speed.

• Drug release profile is comparable with the innovator in all three media.


223

5.2.7 Manufacturing set up process:

The manufacturing step involved various steps and at each step the optimization of

coating was done and studied for their dissolution profile as this process was taken up

for scale-up batches.

5.2.7.1 Effect of plasticizer

Different plasticizers such as triethylcitrate, dibutyl phthalate, dibutylsebacetate were

studied for the drug release profile.

Results:

Table no.152 Effect of plasticizer

Time (hr) %Drug release

Time (hr)

USB(113)-45-09

(Triethylcitrate)

USB(113)-46A-13

(Dibutyl phthalate)

USB(113)-46B-15

(Dibutylsebacate)

0 0 0 0

1 9 10 15

2 21 24 30

4 38 41 48

6 51 52 59

8 61 61 67

12 73 72 78

16 82 80 85

20 88 86 90

24 93 90 94


224

Figure No 56: Effect of Plasticizer

Discussions:

Drug release profile was similar with all the three plasticizers evaluated, hence,

Triethyl citrate was continued to be used in the formulation.

5.2.7.2 Optimization of extended release coat I

The coating of 6.5, 7.0, and 7.5 % w/w were studied for the drug release profile.

Table no. 153 Optimization of coating weight build up of the extended release

Coat-I:

Time

(hr)

VKJ(113)-48-24

(6.5%w/w weight gain)

VKJ(113)-48-24


VKJ(113)-48-24


0 0 0 0

1 11 10 13

2 27 25 27

4 46 44 45

6 58 55 55

8 66 64 62

12 78 77 72

16 85 84 80

20 91 90 84

24 95 92 88


225

Figure No 57: Optimization of Extended release coat I

Discussion: At all the coating levels studied i.e. 6.5, 7.0, and 7.5% w/w, dissolution

remains unaffected by the extent of coating up to 7.5 % level.

5.2.7.3 Optimization of coating weight of the extended release coat -II

Table no 154.Optimization of coating weight build -up of the extended release

Coat-II

Time (hr) VKJ(113)-47-20C

(1.82% w/w weight gain)

VKJ(113)-47-20C

(2.40% w/w weight gain)

0 0 0

1 14 15

2 27 29

4 43 46

6 53 55

8 60 62

12 70 71

16 77 78

20 81 81

24 85 85


226

Figure No 58: Extended release coat II

Discussion: At all the coating levels studied i.e. 1.82% and 2.40% w/w, dissolution

remains unaffected by the extent of coating up to 2.40 % level.

5.2.8 Stability analysis

The batches were then put for stability analysis at 40°C/75%RH and

25°C/60%RH.

Table no.155 Stability data

Sr.

No.

Parameters Batch Number: VKJ(113)-47-20C

40°C/75%RH 25°C/60%RH

Time period

Initial 1 M 2 M 3 M 6 M 3 M 6 M

1 Assay (% w/w) 97.5 97.8 97.2 96.8 96.8 97.6 97.4

2 Water (% w/w) 3.26 3.29 3.19 3.45 3.13 3.18 3.29

3 Drug release(hr)

1 14 16 16 17 15 14 15

2 27 26 27 27 25 28 28

4 43 43 42 44 43 43 42

6 53 53 51 52 53 52 51

8 60 61 60 62 59 59 60

12 70 69 71 71 68 70 69

16 77 75 76 76 75 78 78

20 81 80 81 80 80 81 81

24 85 86 86 87 86 86 85

4 Related Substances (%w/w)

Impurity A ND ND ND ND 0.008 ND ND

Impurity C ND ND ND ND ND ND ND


227

Sr.

No.

Parameters Batch Number: VKJ(113)-47-20C

40°C/75%RH 25°C/60%RH

Time period

Initial 1 M 2 M 3 M 6 M 3 M 6 M

Impurity D ND ND ND ND ND ND ND

Impurity E ND ND ND ND ND ND ND

ImpurityF ND ND ND ND ND ND ND

Impurity G 0.004 0.005 0.005 0.007 0.006 0.004 0.004

ImpurityH ND ND ND ND ND ND ND

Hydroxynitrile ND ND ND ND ND ND ND

Highest

Unknown

impurities

0.022 0.023 0.022 0.021 0.023 0.022 0.022

Total impurities 0.032 0.035 0.032 0.033 0.043 0.031 0.031

5.2.9 Process optimization and scale-up batches: Scale-up Experience:

Scale-up 1:

5.2.9.1 Evaluation of reproducibility of parameter and characteristics of

formulation:

Observations and Discussions:

A) Granulation: Venlafaxine Hydrochloride used was not a uniform material

and consisted of flakes.

B) Drying Conditions: Pellets obtained were not spherical (dumbbell shaped

were obtained). This could be because of the physical nature of Venlafaxine

Hydrochloride (flakes). Hence it was decided to study the effect of milling of

active ingredient on the nature of spheroids and details are given below.

5.2.9.2 Effect of milling:

Observations and Discussions:

Pellets obtained with milled Venlafaxine hydrochloride were spherical and

uniform in comparison with the pellets obtained from unmilled Venlafaxine

hydrochloride.


228

Table no. 156 Particle size distribution

Mesh # (ASTM) % Retains

VKJ(113)-53-35 VKJ(113)-54-37

12 15.4 2.2

14 24.7 33.0

16 14.0 19.4

18 7.0 9.0

20 24.2 30.2

25 3.20 3.0

30 - -

Base Plate 0.6 0.4

Discussions: Pellets with milled Venlafaxine hydrochloride provides uniform

distribution of pellets compared to unmilled Venlafaxine hydrochloride. Hence milled

Venlafaxine hydrochloride could be used for fabrication of batches.

Table no. 157 Drug release profile of Venlafaxine hydrochloride Extended

Release capsules: Method: pH6.8phosphatebuffer, 900ml, typeI, 100rpm

Time (hr) % drug released

0 0

1 10

2 27

4 48

6 60

8 68

12 78

16 87

Figure No 59: Effect of critical control parameters


229

Conclusions and Identification of critical process parameters

• Milling of Venlafaxine hydrochloride resulted in spherical and uniform pellets

• Spray granulation to avoid localized wetting.

• Cold water circulation in extruder jacket to prevent sticking tendency of dough

mass.

• Retained pellets on #12mesh and passed pellets through #30mesh can be

extruded and spheronized to increase yield. This fraction is suitable for

coating.

• Spheronization of extrudes at 600-900 rpm for 5 minutes is optimum.

• Weight gain of extended release coating.

5.2.10 Sampling Data of Test Bathces

The sample batches were then analyzed for the optimized conditions of the critical

control parameters:

1. Drying of pellets:

Table no. 158 For Batch number LFS12182:

Tests Acceptance criteria Pooled sample data

Lot-I Lot-II Lot-III

Loss on drying

(at 105ºC) (%w/w)

Not more than 2.0 1.78 1.78 1.80

Table no. 159 For Batch number LFS12183:

Tests Acceptance criteria Pooled sample data


Loss on drying

(at 105ºC) (%w/w)

Not more than 2.0 1.63 1.70 1.54

Table no. 160 For Batch number LGS10751:


230

Tests

Acceptance criteria

Pooled sample data


Loss on drying

(at 105ºC) (%w/w)

Not more than 2.0 1.80 1.77 1.77

2. Table no. 161 Lubricated pellets (After coating II):

Tests

Acceptance criteria

Batch number

LFS12182

Batch number

LFS12183

Batch number

LGS10751

Description White to offwhite pellets Complies Complies Complies

Identification

(by HPLC)

The retention time of the

major peak in the

chromatogram of the assay

preparationcorrespondto

thatinthe chromatogram of the

standard preparation, as

obtained in the assay

Complies Complies Complies

Water (by KF)

(%w/w)

Not more than 4.0 % w/w 3.75 3.69 3.53

Blend Not less than 90.0% and 101.6, 101.4, 96.1, 95.8, 96.3, 100.7, 97.0,

(by HPLC) not more than 110.0% of 101.6, 101.7, 95.7, 95.8, 95.8, 97.2, 97.1, 96.8,

the labeled amount of 101.2, 101.7, 95.7, 95.7, 95.6, 97.9, 96.9, 96.1,

Venlafaxinewith relative 95.5, 99.8, 95.8 97.5, 92.7

standard deviation of not 100.7, 101.3 (% RSD: 0.2) (% RSD: 2.01)

more than 5.0% (% RSD: 1.9)

Residual

solvents

(By GC)

(ppm)

Isopropylalcohol:NMT

1000

95.5 128 95.5

Methylene chloride: NMT

600

Not Detected Not Detected Not Detected

Assay

(by HPLC)

(%w/w)

Not less than 90.0% and

not more than 110.0% of the

labeled amount of Venlafaxine

97.2 95.9 97.7


231

3. Table no. 162 Encapsulation: The in-process control parameters

followed during encapsulation stage as tabulated below:

Tests

Acceptance criteria Monitoring

Frequency

Results 75 mg strength 150 mg strength

Average weight

of filled capsule

Target fill weight ± 5% Target fill weight ± 5% Every 30

minutes

Passes

Weight of 20

filled capsules

± 5% of (20X

Average weight)

± 5% of (20X

Average weight)

Every 30

minutes

Passes

Locked length 19.4±0.3 mm 21.7±0.3 mm 2 hours Passes

Weight variation ±5% of average weight ±5% of average weight 2 hours Passes

During encapsulation, samples were collected at the beginning, middle and towards

the end and analyzed for the following parameters. The data of the samples collected

is as given in the tables below.

i) For 75 mg strength:

1. Table no. 163 Batch Number LFS13264:

Sr. No. Test Acceptance criteria Beginning Middle End

1 Description Size ‘1’ hard gelatin capsules

with cream colored opaque cap

and cream opaque body filled

with white to off white pellets,

imprinted with ‘W’on cap in red


2 Average fill

weight

180.182mg±5.0 % 180.37mg 180.96mg 181.01mg

3 Content Between 85.0% and 115.0% of 99.3% 102.1% 103.8% Uniformity the label claim of Venlafaxine 97.6 % 100.4% 104.8%

With RSD not more than6.0 %. 104.8% 98.5 % 102.6% 102.3% 101.7% 102.5% 98.6 % 102.3% 99.0 % 100.3% 100.4% 102.5% 102.2% 100.0% 99.7 % 102.8% 101.7% 102.0% 101.2% 102.2% 102.3% 101.9% 101.8% 100.9% RSD=2.2 % RSD=1.2 % RSD=1.7 %


232

4 Assay Not less than 95.0% and not

more than 110.0% of the

labeled amount of Venlafaxine.

98.6 % 99.2 % 98.8 %


Sr.

No.

Test Acceptance criteria Beginning Middle End

1 Description Size ‘1’ hard gelatin capsules with

cream colored opaque cap and cream

opaque body filled with white to off

white pellets, imprinted with ‘W’ on

cap in 717 red color.


2 Average fill

weight

182.624mg±5.0 % 182.35mg 180.78 mg 181.89mg

3 Content

Uniformity

Between 85.0% and 115.0% of the 102.6% 100.9% 100.9% label claimof Venlafaxine with RSD 99.7 % 101.2% 101.2% Not more than6.0 %. 99.6 % 99.1 % 99.9 %

99.4 % 100.8% 100.8% 100.0% 105.8% 105.8% 103.7% 102.7% 102.7% 102.3% 101.8% 101.8% 102.3% 99.6 % 99.6 % 100.4% 101.6% 101.6% 95.8 % 101.0% 101.0% RSD=2.3 % RSD=1.8% RSD=1.8 %

4 Assay Not less than 95.0% and not more

than 110.0% of the labeled amount

of Venlafaxine.

100.5% 99.9% 99.9 %

3. Table no. 165 Batch Number LGS10756:

Sr.

No.



cream opaque cap and cream opaque

body filled with white to off white

pellets, imprinted with ‘W’oncapin

redcolor.



233

2 Average fill

weight

179.26mg±5.0 % 181.8 mg 178.4 mg 180.6 mg

3 Content Between 85.0% and 115.0% of the 98.9 % 99.8 % 98.2 % Uniformity labelclaimofVenlafaxinewithRSDnot 94.3 % 100.2% 98.4 %

morethan6.0%. 97.3 % 96.9 % 97.1 % 97.2 % 97.6 % 99.3 % 98.0 % 101.1% 93.7 % 101.4% 99.0 % 99.2 % 103.4% 100.5% 97.9 % 101.6% 98.7 % 95.4 % 97.8 % 99.1 % 95.2 % 100.0% 99.1 % 97.0 % RSD=2.7 % RSD=1.3 RSD=1.9 %

4 Assay Not less than 95.0% and not more than

110.0%of the labeled amount of

Venlafaxine.

101.1% 99.7% 101.7%

ii) For 150mg strength


Sr.

No.



light brown colored cap and light

brown colored opaque body filled

with white to off white pellets,

imprinted with ‘W’718 on cap in

white color.


2 Average fill

weight

360.264mg±5.0 % 353.88mg 353.95mg 356.48mg

3 Content

Uniformity

Between 85.0% and 115.0%of the

label claim of Venlafaxine

With RSD not more than

6.0%.

98.3 %

96.3 %

95.2 %

98.2 %

97.8 %

98.4 %

98.6 %

99.2 %

99.2 %

96.3 %

98.0 %

98.6 %

95.3 %

98.8 %

99.6 %

97.9 %

99.2 %

96.3 %

98.7 %

99.2 %

98.6 %

95.8 %

100.8%

100.1%


234

4 Assay Not less than 95.0% and not more

than110.0% of the labeled amount

of Venlafaxine.

97.6 % 96.7 % 97.9 %

2. Tale no. 167 Batch Number LFS13267:

Sr.

No.


1 Description Size ‘0’hard gelatin capsules With light

brown cap and light brown opaque body

filled with white to off white pellets,

imprinted with ‘W’on cap in white color.


2 Average fill

weight

365.249mg±5.0 % 367.31mg 365.23mg 362.10mg

3 Content

Uniformity

Between 85.0% and 115.0% of the label

claim of Venlafaxine with RSD not

More than 6.0%.

97.8 % 99.9 % 102.3% 99.5 % 102.1% 101.5% 100.1% 101.1% 100.8% 97.8 % 98.4 % 100.6% 99.2 % 100.5% 103.1% 99.5 % 101.1% 102.0% 98.7 % 101.9% 100.9% 99.3 % 101.5% 102.3% 99.9 % 99.8 % 101.9% 100.6% 102.3% 101.4% RSD=0.9 % RSD=1.2 % RSD=0.8 %

4 Assay Not less than 95.0% and not More than

110.0% of the labeled amount of

Venlafaxine.

100.4%

100.3%

99.0 %

3. Table no. 168 Batch Number LGS10757

Sr.

No.


1 Description Size ‘0’hard gelatin capsules with light

brown colored cap and light brown

colored paque body filled with white to

off white pellet imprinted wit‘W’ 718

on cap in white color.



235

2 Average fill

weight

358.52mg±5.0 % 360.84mg 360.1 mg 359.29mg

3 Content

Uniformity

Between 85.0% and 115.0%of the

label claim of Venlafaxine with RSD

not more than 6.0%.

100.3%

99.2 %

101.6%

100.3%

98.8 %

101.3%

101.8%

100.0%

100.6%

102.0%

101.4%

100.3%

98.4 %

98.8 %

101.2%

101.7%

101.3%

100.9%

99.2 %

98.8 %

100.2% 4 Assay Not less than 95.0% and not more

than110.0%of the labeled amount of

Venlafaxine.

100.3%

100.0%

98.9 %

Discussions:

All the sample batches were tested and analysed for critical control parameters as well

as the analytical parameters such as the assay and content uniformity and were found

to comply within the limits. The values for all the tests fall within the acceptance

criteria and specifications.


236

5.13 Evaluation of test batches of venlafaxine hydrochloride 75mg vs Effexor 75mg capsules

Table no. 169 COMPARATIVE EVALUATION OF TEST BATCHES VS. EFEXOR® XL 75 MG CAPSULES

Tests

Regulatory

Specifications (Shelf

life)

Wockhardt’s test batch numbers

Reference product’s

(Efexor®XL,75mg)

batch number

LFS13264 LFS13265 LGS10756 P4213C

Water (byKF) (%w/w) Not more than 6.0 3.60 3.90 4.00 3.42

Drug

release

(in % of

the labeled

amount)

1Hour

6Hours

16 Hours

24 Hours

Not more than 25 %

40%-70%

60% - 90%

Not less than 75%

14,16,17,16,20,17

58,63,63,64,68,62

76,82,80,82,85,81

81,87,84,86,90,85

18,13,15,20,20,16,

62,57,64,66,65,61,

82,82,89,89,87,83

87,87,94,92,91,90

13,13,13,12,15,12

60,61,61,60,60,60

82,81,83,82,82,82

88,88,90,90,88,89

9,9, 8,10,10,9

53,55,53,54,54,55

85,83,85,85,84,85

92,90,92,91,91,92

Assay

(by HPLC) (%w/w)

Not less than 90.0%

and not more than

110.0%of the labeled

amount of Venlafaxine

99.0 98.8 102.7 101.2

Related substances(by HPLC) (%w/w)


237

i) Impurity A

ii) Impurity C

iii) Impurity D

iv) Impurity E

v) Impurity F

vi) Impurity G

vii) Impurity H

viii) Hydroxynitrile

ix) Any single unknown

impurity

x) Total impurities

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than1.0

0.011

ND

BL

ND

ND

0.064

ND

ND

0.039

0.158

0.017

ND

BL

ND

ND

0.073

ND

ND

0.045

0.135

0.013

ND

ND

ND

ND

0.062

ND

ND

0.045

0.187

ND

ND

ND

ND

ND

BLQ

ND

ND

0.008

0.026

Residual solvents

(By GC)

i) Isopropyl alcohol

ii) Methylene chloride

Not more than1000ppm

Not more than600 ppm

10

ND

15

ND

ND

ND

ND

ND

Discussions: The test batches of venlafaxine hydrochloride 75mg were found to comply within the limits of the analytical parameters and the

dissolution profile was similar to innovator.


238

Table no. 170 COMPARATIVE EVALUATION OF TEST BATCHES VS. EFEXOR® XL 150 MG CAPSULES

Tests

Regulatory Specifications

(Shelf life)

Wockhardt’s test batch numbers Reference product’s

(Efexor®XL,150mg) batch

number

LFS13266 LFS13267 LGS10757 A78941A

Water (byKF) (%w/w) Notmore than6.0 3.8 3.6 4.0 3.4

Drug release

(in % of the labeled

amount)

1Hour

6Hours

16 Hours

24 Hours

Not more than 25 % 40%-

70%

60% - 90%

Not less than 75%

17,15,17,14,17,17

67,64,67,62,66,65

86,82,86,82,86,84

91,87,92,88,91,89

18,17,18,16,18,14

68,66,65,63,62,62

89,87,85,83,79,83

95,93,90,89,84,88

13,14,13,14,12,11

59,62,61,61,60,59

83,85,83,83,82,82

90,91,88,88,88,88

3,3, 3,4,4,4

54,53,52,55,54,57

83,81,81,84,83,86

90,89,87,91,89,93

Assay

(byHPLC)(%w/w)

Not less than 90.0% and not

more than 110.0%of the

labeled amount of

Venlafaxine

98.2 99.9 98.9 101.2

Related substances(by HPLC) (%w/w)


239

Discussions: The venlafaxine hydrochloride 150mg capsules were found to comply within the limits of the analytical parameters and the

dissolution profile was similar to the innovator

i) Impurity A

ii) Impurity C

iii) Impurity D

iv) Impurity E

v) Impurity F

vi) Impurity G

vii) Impurity H

viii) Hydroxynitrile

ix) Any single unknown

impurity

x) Total impurities

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than0.2

Not more than1.0

0.014

0.005

0.009

ND

ND

0.060

ND

ND

0.04

0.154

0.014

ND

BLQ

ND

ND

0.07

ND

ND

0.04

0.146

0.014

ND

0.001

ND

ND

0.068

ND

ND

0.042

0.134

ND

ND

ND

ND

BLQ

0.017

ND

ND

0.019

0.104

Residual solvents(ByGC)

i) Isopropyl alcohol

ii) Methylene chloride

Not more than1000ppm

Not more than600 ppm

13

ND

15

ND

20

ND

ND

ND


240

5.2.11 Comparative 12 units drug release profile of effexor®

XL capsules, 75mg

versus venlafaxine hydrochloride modified release capsules, 75mg in various

media.

The drug profile was compared in various medias like pH 6.8 phosphate. pH 4.5

acetate and HCl (0.1N). The different strengths were compared like 150mg, 75mg and

respectively.

A) Table no. 171 Drug release in 900ml pH6.8 phosphate buffer for 24hours,

Ph.Eur.type1, 100 rpm

Time (hr)

Effexor®XL75mg Venlafaxine MR

Capsules75mg

Batch Number: P4213C Batch Number: LG10263#

0 0 0 1 8 13 2 18 29 4 37 49 6 54 60 8 65 68

12 78 77 16 85 82 20 90 86 24 92 89

Figure No. 60: Effexor 75mg vs venlafaxine 75mg in phosphate buffer (pH 6.8)


241

B) Table no. 172 Drug release in pH4.5 acetate buffer, 900ml, Ph.Eur.type1,

at100rpm

Time (hr)

Effexor®XL75mg Venlafaxine MR Capsules75mg


0 0 0 1 9 11 2 20 28 4 39 48 6 57 60 8 69 69

12 83 79 16 90 85 20 94 90 24 97 93

Graph:

Figure No. 61 Effexor 75mg vs Venlafaxine hydrochloride capsules 75mg in

acetate buffer (pH 4.5)


242

C) Table no. 173 Drug release in 0.1 N Hydrochloric acid, 900 ml, Ph. Eur.

type 1, at 100 rpm

Time (hr)



0 0 0

1 9 10

2 19 26

4 37 45

6 53 57

8 64 65

12 77 75

16 85 81

20 89 86

24 92 89

Graph:

Figure No: 62 Effexor vs Venlafaxine hydrochloride in HCl (0.1N)

D) Table no. 174 Drug release in water, 900 ml, Ph. Eur. type 1, at 100 rpm

Time (hr)

Effexor®XL75mg Venlafaxine MR Capsules 75mg


0 0 0 1 8 10 2 18 26 4 40 45


243

6 58 57 8 69 65

12 82 75 16 89 81 20 92 86 24 94 87

#: Corresponds to batch number LGS10756 at encapsulation stage.

Graph:

Fig 63: Effexor vs. venlafaxine Hydrochloride in water

5.2.11.1 Comparative 12 units drug release profile of Effexor®

XL capsules, 150

mg versus venlafaxine hydrochloride modified release capsules, 150 mg in

various media



Time (hr)

Effexor®XL150mg Venlafaxine MR Capsules 150mg

Batch Number:A78941A Batch Number: LG10272#

0 0 0 1 3 12 2 14 29 4 36 49 6 51 60 8 61 68 12 73 77 16 79 83 20 84 87 24 87 89


244


Figure No. 64: Effexor vs Venlafaxine 150mg in pH 6.8 phosphate

B) Table no. 176 Drug release in pH4.5 acetate buffer, 900ml, Ph.Eur.type1,

at100rpm

Time (hr)



0 0 0 1 4 11 2 13 26 4 34 45 6 51 57 8 61 66 12 73 75 16 80 82 20 84 87 24 87 90



245

Figure No. 65: Effexor vs Venlafaxine 150mg in acetate buffer (pH 4.5)


type 1, at 100 rpm

Time (hr)



0 0 0 1 4 11 2 13 26 4 34 45 6 49 56 8 60 64 12 72 73 16 78 79 20 83 83 24 86 86


Fig 66: Effexor vs Venlafaxine capsules in HCl (0.1N)


246


Time (hr)



0 0 0

1 3 12 2 14 28 4 38 47 6 55 59 8 65 68 12 77 77 16 83 83 20 87 86 24 89 89


Fig 67: Effexor vs Venlafaxine 150mg in water

5.2.11.2 Comparative 12 units drug release profile of venlafaxine hydrochloride

modified release capsules, 75 mg versus venlafaxine hydrochloride modified

release capsules, 150 mg in various media


Ph.Eur. type1, 100 rpm

Time (hr)

Venlafaxine MR Venlafaxine MR

Batch Number: LG10263 Batch Number: LG10272

0 0 0 1 13 12


247

2 29 29 4 49 49 6 60 60 8 68 68 12 77 77 16 82 83 20 86 87 24 89 89

Graph:

Fig 68: Effexor vs Venlafaxine HCl in pH 6.8 phosphate

B) Table no. 180: Drug release in pH 4.5 acetate buffer, 900ml, Ph. Eur. Type

1, at 100rpm

Time (hr)



0 0 0 1 11 11 2 28 26 4 48 45 6 60 57 8 69 66

12 79 75 16 85 82 20 90 87 24 93 90


248

Figure No. 69: Effexor vs Venlafaxine HCl in pH 4.5 acetate in E.P type 1


type 1, at 100 rpm

Time (hr)



0 0 0 1 10 11 2 26 26 4 45 45 6 57 56 8 65 64

12 75 73 16 81 79 20 86 83 24 87 86

Figure No. 70: Effexor vs Venlafaxine HCl in water in E.P type 1


249


Time (hr)



0 0 0 1 10 12 2 26 28 4 45 47 6 57 59 8 65 68

12 75 77 16 81 83 20 86 86 24 87 89

Figure No. 71: Effexor vs Venlafaxine HCl (12 units) in pH 6.8 (75mg)

5.2.11.3 Comparative 12 units drug release profile of all three batches of

venlafaxine hydrochloride modified release capsules, 75mg versus Effexor XL

capsules, 75mg in phosphate buffer (pH 6.8).


Ph.Eur. type1, 100 rpm

Time (hr) Effexor®XL75mg Venlafaxine MR Capsules75mg

Bulk finished product- Batch numbers

Batch Number: P4213 LGS10756# LFS13264 LFS13265

0 0 0 0 0

1 8 13 16 17


250

6 54 60 63 63

12 78 77 76 78

16 85 82 81 86

24 92 89 86 90

#: Corresponds to batch number LG10263after blister packing.

Figure No. 72: Effexor vs Venlafaxine HCl (12 units) in pH 6.8(150mg)

5.2.11.4 Comparative 12 units drug release profile of all three batches of

venlafaxine hydrochloride modified release capsules, 150 mg versus Wyeth

pharmaceuticals’ Effexor XL capsules, 150mg in phosphate buffer (pH 6.8)



Time (hr) Effexor®XL150mg Venlafaxine MR Capsules150mg

Bulk finished product- Batch numbers

Batch Number:A78941A LGS10757# LGS10757# LFS13267

0 0 0 0 0

1 3 12 16 16

6 51 60 66 64

12 73 77 80 80

16 79 83 84 85

24 87 89 90 91

#: Corresponds to batch number LG10272after blister packing.


251

Discussions:

The comparison of 75mg, 150mg venlafaxine hydrochloride capsules compared with

the reference listed drug Effexor of different strengths like 75mg and 150mg in

different medias like pH 6.8 phosphate, pH 4.5 acetate and HCl (0.1N) and water. The

scale-up batches were found to be similar to the innovator’s drug release profile.

Container Closure System

Two packs, viz. blister pack and bulk (container) pack are intended to be used for

commercial and repackaging respectively, as detailed below:

i)BlisterPack: Blister pack consisting of 196mm white opaque PVD Ccoated PVC

film(0.25mm) and 192mm plain lidding aluminium foil (0.025mm) of 2x14 capsules

is proposed. The inherent protective property of PVDC coated PVC film from

moisture and other environmental factors makes it suitable for capsule blister packing.

Forming material structure-

The PVC layer will be in contact with capsules while PVDC layer in contact with

environment.

ii)Bulk Pack(for repackaging):

The bulk pack for repackaging at UK site is also proposed based on stability data of

bulk replica pack. The proposed bulk pack size for 75mg strength is12,000 capsules

and for 150 mg strength is 10,000 capsules. The bulk capsules are first packaged in


252

low density polyethylene bag with polypropylene strap seal. The bag is then kept in

triple laminated sachet with two silica gel bags on the top and thermo-sealed. The

thermo-sealed triple laminated bag is then kept in HDPE container.

Microbiological Attributes:

Wockhardt's Venlafaxine Hydrochloride Modified Release Capsules, 75mg & 150mg

come under category 3. A product as per Ph.Eur. general monograph, "Microbial

quality of pharmaceutical preparations", 5.1.4; hence microbial limits are monitored

as per Ph.Eur.,which are as follows:

Table no. 185 Microbiological analysis

Specification Acceptance criteria a)Total viable aerobic microbial count

Not more than103

per g.

b)Fungi Not more than 10

2per g

c)Escherichia coli Absent

Microbiological testing is conducted on test batches, and is also a part of stability

protocol; the results are satisfactory. This test will be performed on first three

validation batches and thereafter on every 10th

batch or annually whichever is

sooner.

Compatibility

No reconstitution diluents or dosage devices are required for administration of

Venlafaxine HCl MR Capsules, 75mg & 150mg; hence, no compatibility studies are

conducted.

Figure No 73: Images of Venlafaxine Capsules and Pellets.

5.1 results and discussion of aripiprazole...

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