CHAPTER 6.0 `6.

01 API CHARACTERIZATION

RESULTS AND DISCUSSION

The specifications of API are established with in-house controls. The API used for product development has been characterized by different physicochemical tests as given below: 6.1.1 Physical property of API: Table No. 6.01: Physical property of API A Bulk density Tapped density Carrs index Hausner ratio Angle of repose Table No. 6.02: Physical property of API B Bulk density Tapped density Carrs index Hausner ratio Angle of repose 6.1.2 Particle size determination by Malvern: Table No. 6.02: PSD of API A PSD D(0.1) D(0.5) D(0.9) Table No. 6.02: PSD of API B PSD D(0.1) D(0.5) D(0.9) 6.1.3 Determination of solubility: Table No. 6.03: pH Vs Solubility pH range Solubility 0.1N HCl Very soluble 4.5 pH Acetate buffer Soluble 5.5 pH Acetate buffer Slightly soluble 6.8 pH Phosphate buffer Very slightly soluble Water Very slightly soluble 6.1.4 API Potency calculation (Moisture and Assay compensation): SPS, Meerut 58 Result Result 2.031um 17.580um 45.084um

CHAPTER 6.0 Assay on dried basis = 100%

RESULTS AND DISCUSSION % LOD = 0.09%

The quantity is based on 100 % w/w assay on dried basis and Nil of LOD Strength X 100 X 100 = 50 x 100 x100 = 50.04mg (Assay on dried basis) X (100 - % LOD) 100 x (100-0.09) Conclusion: API complies as per the specification. Based on the above data it is concluded that the API has extremely poor compressibility and very, very poor flow property, Solubility of API is pH dependent and Dispensing of API was done on the basis of potency calculation and the compensation w/w is done by the non-functional diluent.

6.02 DRUG-EXCIPIENTS COMPATIBILITY STUDY DATA Table No. 6.04: Physical observations of drug excipients compatibility 25C2C /60%5% RH 04 OA, OD OA, OD OA, OD OA, OD OA, OD OA, OD A, OD OA, OD A, OD OA, OD

Sr. No.

Physical Admixture

40+ 2C/75+5%RH Weeks 01 02 OA,OD OA,OD OA,OD OA,OD OA,OD OA,OD OA,OD A, OD OA,OD A, OD OA,OD OA,OD OA,OD OA,OD OA,OD OA,OD A, OD OA,OD A, OD OA,OD

01 02 03 04 05 06 07 08 09 10

03 OA,OD OA,OD OA,OD OA,OD OA,OD OA,OD A, OD OA,OD A, OD A, OD

04 OA,OD OA,OD OA,OD A, OD OA,OD OA,OD A, OD OA,OD A, OD A, OD

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CHAPTER 6.0

RESULTS AND DISCUSSION

11 12 13 14 15

OA, OD OA, OD OA, OD OA, OD OA, OD

OA,OD OA,OD OA,OD OA,OD OA,OD

OA,OD OA,OD OA,OD OA,OD OA,OD

OA,OD OA,OD OA,OD OA,OD OA,OD

OA,OD OA,OD OA,OD OA,OD OA,OD

A: Agglomeration, OA: No Agglomeration, D: Discoloration, OD: No Discoloration Conclusion: From the above data it was observed that no significant physical changes were found. Table No. 6.05: Impurity data of drug excipients compatibility study 25C2C /60%5% RH 04 OA, OD OA, OD 01 OA,OD OA,OD

Sr. No.

Physical admixture

40+ 2C/75+5%RH Weeks 02 OA,OD OA,OD

01 02

API

03 OA,OD OA,OD

04 OA,OD OA,OD

03 04 05 06 07 08 09

OA, OD OA, OD OA, OD OA, OD A, OD OA, OD A, OD

OA,OD OA,OD OA,OD OA,OD A, OD OA,OD A, OD

OA,OD OA,OD OA,OD OA,OD A, OD OA,OD A, OD

OA,OD OA,OD OA,OD OA,OD A, OD OA,OD A, OD

OA,OD A, OD OA,OD OA,OD A, OD OA,OD A, OD

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CHAPTER 6.0 10 11 12 13 14 15 OA, OD OA, OD OA, OD OA, OD OA, OD OA, OD OA,OD OA,OD OA,OD OA,OD OA,OD OA,OD

RESULTS AND DISCUSSION OA,OD OA,OD OA,OD OA,OD OA,OD OA,OD A, OD OA,OD OA,OD OA,OD OA,OD OA,OD A, OD OA,OD OA,OD OA,OD OA,OD OA,OD

Conclusion: From the above data it was observed that no significant impurity was found. 6.03 TABLETS IN PROCESS RESULT Table No. 6.06: In process blend results of anti-epileptic ER tablets Batch No. PRTSR-01 PRTSR-02 PRTSR-03 PRTSR-04 PRTSR-05 PRTSR-06 PRTSR-07 PRTSR-08 PRTSR-09 PRTSR-10 Angle of Bulk Tapped Compressibility repose density density index (%) (Degrees) (gm/ml) (gm/ml) Hausner ratio LOD (%L)

25.03

0.616

0.734

16.129

1.192

Table No. 6.07: PSD by sieve analysis

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CHAPTER 6.0

RESULTS AND DISCUSSION

Mesh Size % Retained 30 40 60 80 100 Collector Conclusion: All the above data were found satisfactory.

6.04 DISSOLUTION RESULTS OF FORMULATIONS 6.4.1 Results of dissolution studies of batch PRT-SR-01 in 4.5 Acetate Buffer: Dissolution Parameters: USP- / 4.5 pH acetate buffer /900ml/ 50 rpm. Batches: Innovator 200, Innovator 50, PRT-SR-01A200, PRT-SR-01B50 Strength: 200mg/50mg. Type: Diffusion controlled matrix tablets. Table No. 6.08: Dissolution data of batch No.PRT-SR-01
Time(mins) Innovator200 PRT-SR-02A200 0 0 0 15 6 4 30 10 14 45 14 23 60 19 30 75 23 37 90 26 43 120 34 56 150 40 66 180 45 75 240 56 89 Similarity factor, f2 36.35046 Innovator50 0 6 11 15 20 23 27 35 40 44 54 PRT-SR-02B50 0 3 13 22 29 36 42 55 65 73 86

37.62717

F2= Similarity Factor Figure No. 6.01: Dissolution profile of batch No. PRT-SR-01 SPS, Meerut 62

CHAPTER 6.0

RESULTS AND DISCUSSION

dissolution profile of formulation in 4.5 pH acetate buffer at 50rpm paddle agitation speed
% cumulative drug released 100 80 Innovator200 60 40 20 0 0 100 200 300 time(mins) PRT-SR-02A200 Innovator50 PRT-SR-02B50

Conclusion: In comparison between pouring and spraying method of granulation, Pouring method granules were hard and difficult to mill and dissolution release pattern was slow in comparison with Innovator (F2: 45).Granules prepared by spraying method were easy to mill and showed acceptable dissolution release pattern (F2: 64).Rapid mixer granulator (RMG) with top spray granulation process was finalized to carry out further trials using wet granulation using aqueous solvent. 6.4.2 Results of dissolution studies of batch PRT-SR-01 in 0.1N HCL: Dissolution Parameters: USP- / 0.1N HCl /900ml/ 50 rpm. Batches: Innovator 200, PRT-SR-01A200, Innovator 50, PRT-SR-01B50 Strength: 200mg/50mg. Type: Diffusion controlled matrix tablets. Table No. 6.09: Dissolution data of batch No. 03-200 ERT Time(mins) Innovator 200 PRT-SR-01A200 Innovator 50 PRT-SR-01B50 0 0 0 0 0 15 23 15 23 14 30 39 36 38 36 45 53 54 52 53 60 67 68 65 67 75 77 79 75 78 90 84 88 81 86 120 93 98 90 96 150 98 101 94 98 180 100 101 97 99 240 102 103 98 100 Similarity SPS, Meerut 63

CHAPTER 6.0 factor, f2 72.22761

RESULTS AND DISCUSSION 68.78395

dissolution profile of formulation in 0.1N HCL at 50 rpm paddle agitation speed

%cumulative drug release 120 100 80 60 40 20 0 0 100 time(min) 200 300 Innovator 200 PRT-SR-01A200 Innovator 50 PRT-SR-01B50

Figure No. 6.01: Dissolution profile of batch No. 03-200 ERT Conclusion: The dimensions of the dosage form including its size and shape does not have influence on the rate of release of the active agent from the dosage form. Among above 3 trials, trial 1 has comparable dissolution release profile and similarity factor (F2: 67) as compare to other 2 trials. Therefore, next trial was planned with 9.5mm, standard concave, circular shape punches. 6.4.3 Results of dissolution studies of batch PRT-SR-02 : 1.0 Dissolution data: Dissolution in: USP- / 0.1N HCl /900ml/ 50 rpm. Batches: Innovator 200,Innovator50, PRT-SR-02A200, PRT-SR-02B50 Strength: 200mg/50mg. Stage: Diffusion controlled matrix tablets. Table No. 6.10: Dissolution data of core tablet of batch No. 04 to 07-200 ERT in 0.1 N HCl
Time (min) 0 15 30 45 60 75 90 120

Innovator 200 PRT-SR-02A200 Innovator 50 PRT-SR-02B50

0 23 39 53 67 77 84 93 0 13 27 38 48 56 64 77 0 23 38 52 65 75 81 90 0 12 26 38 48 56 64 76

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CHAPTER 6.0
150 180 Similarity factor, f2 98 100 87 94 41.97558

RESULTS AND DISCUSSION

94 97 86 93 44.32856

Dissolution profile of the formulation in 0.1N HCL at 50rpm paddle agitation speed
120 %cumulative drug release 100 80 60 40 20 0 0 50 100 time(min) 150 200 Innovator 200 PRT-SR-02A200 Innovator 50 PRT-SR-02B50

Figure No. 6.03: Dissolution profile of core tablet of batch No. 04 to 07-200 ERT in 0.1 N HCl Conclusion: Drug release of batch No. 04-200ERT with 9.5% Methocel E4M found better than 05-200ERT, 06-200ERT and 07-200ERT in 0.1N HCl. 2.0 PRT-SR-03: Dissolution in: USP- / 0.1N HCl /900ml/ 50 rpm. Batches: Innovator 200, 04-200 ERT, 05-200 ERT, 06-200 ERT and 07-200 ERT. Strength: 200mg. Stage: Coated tablet (3% Coat with 20% PVP K-30 and 20% Aerosil 200 ) Table No. 6.11: Dissolution data of coated tablet of batch No. 04 to 07-200 ERT in 0.1 N HCl Time (min) Innovator 200 PRT-SR-03A200 Innovator 50 PRT-SR-03B50
0 15 30 45 60 75 90 120 150 180 0 23 39 53 67 77 84 93 98 100 0 13 34 49 61 70 77 88 94 99 0 23 38 52 65 75 81 90 94 97 0 12 33 49 61 70 77 88 95 99

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RESULTS AND DISCUSSION

dissolution profile of formulation in 0.1N HCL at 50 rpm paddle agitation speed

120 % cumulative drug release 100 80 60 40 20 0 0 50 100 Time(min) 150 200 Innovator 200 PRT-SR-03A200 Innovator 50 PRT-SR-03B50

Figure No. 6.04: Dissolution profile of coated tablet of batch No.04 to 07-200 ERT in 0.1 N HCl Conclusion: Coated tablets with 20% PVP K-30 and 20% Aerosil 200 as a wicking agent in enteric coating system at 3 % weight gain, Dissolution results in 0.1N HCl for all the batches were found faster as compare to innovator. Among above 4 batches 07-200 ERT was found to be better than 04-200 ERT, 05-200 ERT and 06-200 ERT. 3.0 Dissolution data: Dissolution in: USP- / 0.1N HCl/ 900ml/ 50 rpm. Batches: Innovator 200, 04-200 ERT, 05-200 ERT, 06-200 ERT and 07-200 ERT. Strength: 200mg. Stage: Coated tablet (6% Coat with 20% PVP K-30 and 20% Aerosil 200 ) Table No. 6.12: Dissolution data of coated tablet of batch No. 04 to 07-200 ERT in 0.1 N HCl
Time PRT-SR(mins) Innovator200 03A200 0 0 0 15 6 4 30 10 17 45 14 27 60 19 35 75 23 42 90 26 50 120 34 60 150 40 71 180 45 79 240 56 91 Innovator50 0 6 11 15 20 23 27 35 40 44 54 PRT-SR-03B50 0 4 16 27 34 42 49 60 69 77 87

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RESULTS AND DISCUSSION

dissolution profile of the formulation in pH4.5 Acetate Buffer at 50rpm paddle agitation speed
100 %cumulative drug released 80 Innovator200 60 40 20 0 0 100 Time(min) 200 300 PRT-SR-03A200 Innovator50 PRT-SR-03B50

Figure No. 6.05: Dissolution profile of coated tablet of batch No. 04 to 07-200 ERT in 0.1 N HCl Conclusion: Core tablets coated with 20% PVP K-30 and 20% Aerosil 200 as a wicking agent in enteric coating at 6 % weight gain level to retard the release of drug. Drug release results in 0.1N HCl for all the batches still observed faster compared to innovator. Among above 4 batches 07-200 ERT was found to be better result than other batches. 4.0 Dissolution data: Dissolution in: USP- / 0.1N HCl/ 900ml/ 50 rpm. Batches: Innovator 50, 08-50 ERT, 09-50 ERT, 10-50 ERT and 11-50 ERT Strength: 50mg. Stage: Core tablet Table No. 6.13: Dissolution data of core tablet of batch No.08 to11-50 ERT in 0.1 N HCl Time points Innovator 08-200 ERT 09-200 ERT 10-200 ERT 11-200 ERT in hours 1 23 26 24 25 25 3 41 47 40 44 43 5 58 63 56 59 63 8 72 87 71 81 77 10 79 95 81 87 86 12 84 100 90 93 94 15 92 100 95 97 98 18 96 101 98 101 101 F2 49 77 61 62

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RESULTS AND DISCUSSION

120 110 100 90 80 Release % 70 60 50 40 30 20 10 0 0 1 3 5 8 10 Time in hours 12 15 18

1 1 -50ERT (Core: 24% ) 1 0-50ERT (Core: 24% ) 09-50ERT (Core: 24% E4M ) Innovator 50 (CoreRem oved coating) 08-50ERT (Core: 22% E4M )

Figure No. 6.06: Dissolution profile of core tablet of batch No. 08 to11-50 ERT in 0.1 N HCl Conclusion: Drug release of batch No. 09-50 ERT and subsequent reproducible trials 10-50 ERT and 11-50 ERT with 24% Methocel E4M CR was found to be better result than 08-50 ERT-with 22% Methocel E4M CR in 0.1N HCl. 5.0 Dissolution data: Dissolution in: USP- / 0.1N HCl /900ml/ 50 rpm. Batches: Innovator 50, 08-50 ERT (6%), 09-50 ERT (Trial-1 and 2), 10-50 ERT (Trial-1 and 2) and 11-50 ERT (Trial-1 and 2) Strength: 50mg. Stage: Coated tablet
Table No. 6.14: Dissolution data of coated tablet of batch No. 08 to 11-50 ERT in 0.1 N HCl

Time points in hours Coating (%) 1 3 5 8 10 12 15 18 20 SPS, Meerut

Inno vator 5 2 5 9 15 19 23 31 39 43

0850 ERT 6 7 18 26 42 51 65 78 85 90

09-50 ERT Trial1 3 1 4 6 7 11 17 26 28 35 Trial2 5 0 8 17 31 41 48 60 70 77

10-50 ERT Trial1 3 0 0 4 14 20 31 35 49 53 Trial2 5 0 1 7 17 22 29 39 45 51

11-50 ERT Trial1 3 2 4 5 10 15 21 28 35 40 68 Trial2 4 5 15 25 40 49 60 73 87 90

CHAPTER 6.0 22 24 F2
120 110 100 90 80 70 60 50 40 30 20 10 0 0 1 3 5 8 10 12 15 18 20 Time in hours

RESULTS AND DISCUSSION 45 47 93 101 24 40 44 60 82 89 35 55 59 63 58 66 66 45 49 73 92 105 26

Innovator 50 5%coat

08-50ERT (25%P VP k30 & 20%Aerosil) 6%coat

Release %

09-50ERT (Trial 1 ) (Calciumsilicate 15%in coating) 3%coat 09-50ERT coat (Trial 2) (Opadry enteric pink) 5%

1 0-50ERT (Trial 1) (Seal +Cal.ilicate 1 5%in coating) 3%coat 1 0-50ERT (Trial 2) (Seal + Opadry enteric coating) 5%coat 1 1-50ERT (Trial 1 ) (Seal +Cal.ilicate 20%in coating) 3%coat 1 1-50ERT (Trial 2) (Seal + Opadry enteric coating) 4%coat

22 24

Figure No. 6.07: Dissolution profile of coated tab. of batch No. 08 to11-50 ERT in 0.1 N HCl

Conclusion: Batch No.11-50 ERT (Trial 1) tablets coated with 20% calcium silicate as wicking agent in enteric coating at 3 % weight gain had better release profile and similarity factor among all above batches (F2:73%). 6.0 Dissolution data: Dissolution in: USP- / 6.8 phosphate buffer/ 900ml/ 50 rpm. Batches: Innovator 50, 09-50 ERT (Trial-1 and 2), 10-50 ERT (Trial-1 and 2) and 1150 ERT (Trial-1 and 2) Strength: 50mg. Stage: Coated tablet Table No. 6.15: Dissolution data of coated tablet of batch No. 09 to11-50 ERT in 6.8 phosphate buffer Time points Innoin hours vator Coating (%) 5 1 14 3 26 5 37 8 52 10 62 12 70 15 80 18 88 20 92 F2 09-50 ERT Trial-1 Trial-2 3 5 7 7 22 22 38 37 59 59 72 70 83 81 93 90 98 96 99 98 52 56 10-50 ERT Trial-1 Trial-2 3 5 9 7 26 20 42 33 65 54 79 65 89 75 99 88 104 95 105 98 43 62 11-50 ERT Trial-1 Trial-2 3 4 9 10 25 25 39 42 62 64 74 78 84 88 95 98 100 103 101 104 49 45

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120 110 100 90 Release % 80 70 60 50 40 30 20 10 0 0 1 3 5 8 10 Time in hours 12 15 18 20

09-50ERT (Trial 1 ) (Calciumsilicate 1 5%in coating) 3%coat 09-50ERT (Trial 2) (Opadry enteric pink) 5% coat 1 0-50ERT (Trial 1 ) (Seal +Cal.ilicate 1 5%in coating) 3%coat 1 0-50ERT (Trial 2) (Seal + Opadry enteric coating) 5%coat 1 1 -50ERT (Trial 1 ) (Seal +Cal.ilicate 20%in coating) 3%coat 1 1 -50ERT (Trial 2) (Seal + Opadry enteric coating) 4% coat Innovator 50 5%coat

Figure No. 6.08: Dissolution profile of coated tablet of batch No. 09 to11-50 ERT in 6.8 pH Conclusion: Batch No.10-50ERT (Trial 2) tablets coated with opadry enteric coating at 5 % weight gain had better release profile and similarity factor among all above batches and drug release was observed comparable to innovator (F2: 62%). 7.0 Dissolution data: Dissolution in: USP- / 0.1N HCl followed by 6.8 phosphate buffer/900ml/ 50 rpm. Batches: Innovator 50, 09-50 ERT (Trial-1 and 2), 10-50 ERT (Trial-1 and 2) and 1150 ERT (Trial-1 and 2) Strength: 50mg. Stage: Coated tablet Table No. 6.16: Dissolution data of coated tablet of batch 09 to11-50 ERT in first 2hour 0.1N HCl followed by remaining hour in 6.8 Phosphate buffer Time points Innoin hours vator Coating 5 (%) 2hr7 0.1N HCl 1 hr-6.8 17 3hr-6.8 24 6hr-6.8 33 8hr-6.8 38 10hr-6.8 43 13hr-6.8 47 16hr-6.8 50 18hr-6.8 52 F2 SPS, Meerut 09-50 ERT Trial-1 Trial-2 3 0 17 19 25 32 36 45 51 55 63 5 4 13 20 28 31 36 42 51 53 65 10-50 ERT Trial-1 Trial-2 3 2 6 13 21 28 32 41 48 52 52 5 6 12 21 32 38 42 53 62 67 64 11-50 ERT Trial-1 Trial-2 3 5 11 20 30 36 41 47 61 65 65 70 4 9 23 27 36 39 46 53 61 67 63

CHAPTER 6.0

RESULTS AND DISCUSSION

120 110 100 90 80 70 60 50 40 30 20 10 0 0 2hr- 1 hr- 3hr0.1N 6.8 6.8 HCL 6hr- 8hr- 10hr- 13hr- 16hr- 18hr6.8 6.8 6.8 6.8 6.8 6.8 Time in hours

Innovator 50 5%coat

Release %

09-50ERT (Trial 1 ) (Calciumsilicate 1 5%in coating) 3%coat 09-50ERT (Trial 2) (Opadry enteric pink) 5%coat 1 0-50ERT (Trial 1 ) (Seal + Cal.ilicate 1 5%in coating) 3% coat 1 0-50ERT (Trial 2) (Seal + Opadry enteric coating) 5% coat 1 1 -50ERT (Trial 1 ) (Seal + Cal.ilicate 20%in coating) 3% coat 1 1 -50ERT (Trial 2) (Seal + Opadry enteric coating) 4% coat

Figure No. 6.09: Dissolution profile of coated tablet of batch No. 09 to11-50 ERT in first 2-hour 0.1N HCl followed by remaining hour in 6.8 phosphate buffer Conclusion: All the batches were found better release profile and similarity factor in 6.8 phosphate Buffer. 8.0 Dissolution data: (Coated tablets) Dissolution In: USP-/First 1 hour in 0.1 N HCl, Second hour in 4.5 acetate buffer and remaining hours in 6.8 phosphate buffer.(Fasting condition)/900ml/50 rpm. Batches: Innovator 50, 09-50 ERT (Trial-1 and 2), 10-50 ERT (Trial-1 and 2) and 1150 ERT (Trial-1 and 2) Strength: 50mg. Stage: Coated tablet Table No. 6.17: Dissolution data of batch No. 09 to11-50 ERT in Fasting condition Time points in hours Coating (%) 1hr-0.1N HCl 1hr-4.5 pH 1hr-6.8 pH 3hr-6.8 pH 6hr-6.8 pH 8hr-6.8 pH 10hr-6.8 pH 13hr-6.8 pH 16hr-6.8 pH 18hr-6.8 pH F2 09-50 ERT Innovator Trial-1 Trial-2 5 3 5 4 4 7 7 6 16 18 12 24 26 17 28 32 23 34 37 30 41 42 36 48 51 43 58 50 52 67 56 54 71 59 63 10-50 ERT Trial-1 Trial-2 3 5 1 2 1 2 4 4 10 9 19 20 25 28 34 35 40 51 47 53 53 54 48 50 11-50 ERT Trial-1 Trial-2 3 4 2 4 3 6 18 21 26 30 36 31 38 41 43 42 54 54 64 59 61 65 79 78

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120 110 100 90 80 70 60 50 40 30 20 10 0

1h r-0 1h 0 r-4 .1N .5 H CL pH Ac 1h e r-6 ate .8 Ph os 3h r-6 .8 6h r-6 .8 8h r-6 . 10 8 hr -6 13 .8 hr -6 16 .8 hr -6 18 .8 hr -6 .8

Innovator 50 5%coat

Release %

09-50ERT (Trial 1 ) (Calciumsilicate 1 5%in coating) 3%coat 09-50ERT (Trial 2) (Opadry enteric pink) 5% coat 1 0-50ERT (Trial 1 ) (Seal +Cal.ilicate 1 5%in coating) 3%coat 1 0-50ERT (Trial 2) (Seal + Opadry enteric coating) 5%coat 1 1 -50ERT (Trial 1 ) (Seal +Cal.ilicate 20%in coating) 3%coat 1 1 -50ERT (Trial 2) (Seal + Opadry enteric coating) 4%coat

Time in hours

Figure No. 6.10: Dissolution profile of batch No. 09 to11-50 ERT in Fasting condition Conclusion: Batch No.11-50 ERT (Trial-1 and 2) showed better drug release profile and similarity factor among all above batches and drug release observed comparable to innovator F2: 79% and F2: 78% respectively. 9.0 Dissolution data: Dissolution in: USP-/First 2 hour in 4.5 acetate buffer then 2hour in 0.1N HCl followed by 6.8 Phosphate buffer. (Fed Condition) / 900ml/ 50 rpm. Batches: Innovator 50, 09-50 ERT (Trial-1 and 2), 10-50 ERT (Trial-1 and 2) and 1150 ERT (Trial-1 and 2) Strength: 50mg. Stage: Coated tablet Table No. 6.18: Dissolution data of coated tablet of batch 09 to11-50ERT in Fed Condition 09-50 ERT Time points Innoin hours vator Trial-1 Trial-2 Coating (%) 5 3 5 2hr-4.5 pH 2 6 3 2hr-0.1N HCl 11 24 20 1hr-6.8 pH 29 29 30 4hr-6.8 pH 44 49 43 6hr-6.8 pH 51 60 47 8hr-6.8 pH 55 64 51 11hr-6.8 pH 61 66 55 14hr-6.8 pH 66 67 64 16hr-6.8 pH 68 64 69 F2 57 67 10-50 ERT Trial-1 Trial-2 3 5 1 0 12 9 34 18 45 30 47 41 53 42 56 48 61 57 64 59 72 49 11-50 ERT Trial-1 Trial-2 3 4 0 3 17 21 40 39 58 59 62 67 63 68 69 69 71 79 78 83 52 47

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RESULTS AND DISCUSSION

120 110 100 90 80 70 60 50 40 30 20 10 0

0 Ac 2h e r-0 ate .1 N 1h r-6 H c l .8 Ph os 4h r-6 .8 6h r-6 .8 8h r-6 . 11 8 hr -6 14 .8 hr -6 16 .8 hr -6 .8

Innovator 50 5%coat

09-50ERT (Trial 1 ) (Calciumsilicate 1 5%in coating) 3%coat 09-50ERT (Trial 2) (Opadry enteric pink) 5%coat 1 0-50ERT (Trial 1 ) (Seal + Cal.ilicate 1 5%in coating) 3% coat 1 0-50ERT (Trial 2) (Seal + Opadry enteric coating) 5% coat 1 1 -50ERT (Trial 1 ) (Seal +Cal.ilicate 20%in coating) 3% coat 1 1 -50ERT (Trial 2) (Seal + Opadry enteric coating) 4% coat

Release %

2h r-4 .5

pH

Time in hours

Figure No. 6.11: Dissolution profile of coated tablet of batch No. 09 to11-50 ERT in Fed Condition Conclusion: Batch No.10-50ERT (Trial-1) showed better release profile and F2: 72% 10. Dissolution data: Dissolution apparatus: USP III (Reciprocating cylinder) Buffer: First 2 hour in 0.1N HCl then 2hour in 4.5 acetate buffer then 2hour in 5.5 acetate buffer followed by remaining hour in 6.8 phosphate buffer. Volume: 250 ml Speed: 15 dpm Strength: 50mg. Stage: Coated tablet

Table No. 6.19: Dissolution data of coated tablet of batch No. 09 to11-50 ERT in USP III Time points in hours Coating (%) 2hr-0.1N HCl 2hr-4.5 pH 2hr-5.5 pH 2hr-6.8 pH 2hr-6.8 pH 5hr-6.8 pH F2 Innovator 5 5 13 15 30 45 88 09-50 ERT Trial-1 3 2 3 7 31 52 96 58 Trial-2 5 8 16 19 45 64 106 45 10-50 ERT Trial-1 3 1 4 8 29 49 94 62 Trial-2 5 8 17 22 43 65 107 44 11-50 ERT Trial-1 3 2 3 10 31 51 94 61 Trial-2 4 5 11 15 37 46 97 64

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RESULTS AND DISCUSSION

120 110 100 90 80 Release % 70 60 50 40 30 20 10 0 0 2hr-0.1N HCL 2hr-4.5 2hr-5.5 2hr-6.8 Acetate Acetate Phos. Time in hours 2hr-6.8 Phos. 5hr-6.8 Phos.
09-50ERT (Trial 1 ) (Calcium silicate 1 5%in coating) 3%coat 09-50ERT (Trial 2) (Opadry enteric pink) 5%coat 1 0-50ERT (Trial 1 ) (Seal + Cal.ilicate 1 5%in coating) 3%coat 1 0-50ERT (Trial 2) (Seal + Opadry enteric coating) 5%coat 1 1 -50ERT (Trial 1 ) (Seal + Cal.ilicate 20%in coating) 3%coat 1 1 -50ERT (Trial 2) (Seal + Opadry enteric coating) 4% coat Innovator 50 5%coat

Figure No. 6.12: Dissolution profile of coated tablet of batch No.09 to11-50 ERT in USP III Observation: Table No. 6.20: Observation of coated tablet of batch No. 09 to11-50 ERT in USP III 11-50 ERT Trial-1 2 hour in 0.1 N HCl Tablet slightly swelled and tablet coating intact. Tablet coating slightly separated at the peripheral surface or edges of tablet. 2 hour in 4.5 acetate buffer Tablet more hydrate as compare to 0.1 N HCl but tablet coat not opened. Tablet coating slightly more separated at the peripheral surface or edges of tablet. Trial-2

2 hour in 5.5 acetate buffer Tablet more hydrate as compare to 4.5 Acetate buffer but tablet coat not opened. Tablet coating more separated at the peripheral surface or edges of tablet.

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Remaining hour in 6.8 phosphate buffer Tablet coating was completely dissolved within 10 mins. Gel like structure (Transparent layer) formed around the core tablet. Tablet coating was completely dissolved within 10 mins. Gel like structure (Transparent layer) formed around the core tablet.

After 15 hour small quantity of residue of core tablet remaining reciprocating cylinder.

Conclusion: Batch 11-50 ERT (Trial 1 and Trial 2) were found to be better release profile and similarity factor among all above batches and F2:61 and 64 respectively. Decision: Batch No.11-50 ERT Trial 1 were found better drug release profile in all the buffers and also comparable with innovator means F2 were found grater than 50% in all buffers. Therefore, this trial was selected for the bioequivalence study and further subjected to stability in different packs. 6.05 ASSAY RESULTS Table No. 6.21: Assay results of batch No.09 to 11-50 ERT InnoBatch No. vator Assay (%) 6.06 STABILITY DATA Table No. 6.22: Dissolution data of stability batch No.11-50 ERT Trial 1 Time in hrs Initial 40C 2C and 75 %RH 5%RH 1 Month 40 cc HDPE white opaque bottle

F2 SPS, Meerut 75

CHAPTER 6.0

RESULTS AND DISCUSSION

Table No. 6.23: Impurity data and assay result of stability batch 40C 2C and 75 %RH 5%RH 1 Month 40 cc HDPE white opaque bottle

Impurities

Initial

6.07 SUMMARY AND DISCUSSION Table No. 6.24: Summary and discussion Changes from Batch No. Objective of the batch previous experiment Observations

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RESULTS AND DISCUSSION

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