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Jian-Hwa Han USP Expert Panel Meeting May 29-30, 2013 Using Enzymes for Dissolution - The Understandings from Gelatin to Enzymes SUB-TITLE, DATE

USP EP Meeting_2013 Final

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Page 1: USP EP Meeting_2013 Final

Jian-Hwa HanUSP Expert Panel Meeting

May 29-30, 2013

Using Enzymes for Dissolution - The Understandings from Gelatin to Enzymes

SUB-TITLE, DATE

Page 2: USP EP Meeting_2013 Final

• Dissolution Equipment and Apparatus• Gelatin Dissolution in Various Media• Reference Compound – Acetaminophen

o Tablet vs. OE Capsule (Over-encapsulated Tablet sample)• Tier-2 Testing Performance Evaluation

o Enzymes Informationo Control of Experimentso Setting the Reference Point - <711> Pepsin o Equivalent Performance of other Enzymeso Reproducibility of Bromelain and Papain o Disintegration Evaluation

• Summary & Next Step

Presentation Outline

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 2

Page 3: USP EP Meeting_2013 Final

Dissolution by FO-UV System

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 3

• System 1: Distek Opt-Diss FO-UV Dissolution System

• System 2: Sotax with Rainbow FO-UV System

• Advantage: Direct detection with details profiles (and w/o Sampling errors)

• Apparatus 2 @ 50 rpm

• Samples

• Hard Gelatin Shell

• Tylenol Tablet

• OE Tylenol Sample

• Cross-linked OE Tylenol Sample

Page 4: USP EP Meeting_2013 Final

Gelatin Dissolution – The Basics

Page 5: USP EP Meeting_2013 Final

Gelatin Dissolution – Typical Media

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 5

• Data clearly show much faster dissolution rate in 0.1N HCl

• The dissolution rates in pH 4.5, pH 6.8, and water are similar

Dissolution of Hard Gelatin Shell - App 2 @ 50 rpmin Typical Dissolution Media

0.0

20.0

40.0

60.0

80.0

100.0

120.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0

Time, Minutes

%LC

0.1N HCl Acetate, pH 4.5 Phosphate, pH 6.8 Water

Page 6: USP EP Meeting_2013 Final

Gelatin Dissolution – Surfactant Impact in Water

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 6

• Surfactants do slow down the dissolution of gelatin

• The impact from POE and CTAB are not significant

• SDS posts more impact, but it still within the variability

Dissolution of Hard Gelatin Shell - App 2 @ 50 rpmSurfactant Impact in Water

0.0

20.0

40.0

60.0

80.0

100.0

120.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0

Time, Minutes

%LC

Water 0.5% SDS in Water 0.5% POE in Water 0.2% CTAB in Water

Page 7: USP EP Meeting_2013 Final

Gelatin Dissolution – Surfactant Impact in pH 6.8 Phosphate Media

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 7

• No significant impact observed in pH 6.8 Phosphate media with either SDS or POE10LE

Dissolution of Hard Gelatin Shell - App 2 @ 50 rpmSurfactant Impact in pH 6.8 Phophaste Buffer

0.0

20.0

40.0

60.0

80.0

100.0

120.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0

Time, Minutes

%LC

0.5% SDS in pH 6.8 pH 6.8 Buffer 0.5% POE in pH 6.8

Page 8: USP EP Meeting_2013 Final

Gelatin Dissolution – Surfactant Impact in 0.1N HCl Media

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 8

• No significant impact observed for POE in 0.1N HCl media

• Significant impact observed for SDS in 0.1N HCl media!!!

Dissolution of Hard Gelatin Shell - App 2 @ 50 rpmSurfactant Impact in 0.1N HCl

0.0

20.0

40.0

60.0

80.0

100.0

120.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0

Time, Minutes

%LC

0.5% SDS in HCl 0.1N HCl 0.5% POE in HCl

Page 9: USP EP Meeting_2013 Final

Comparison of Gelatin Dissolution Time in Various Media

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 9

Note – In general, the capsule opens within 2 minutes in 0.1N HCl.

Gelatin Dissolution Comparison

0

5

10

15

20

25

30

0.1 N

HCl, 9

00 m

L

0.5% S

DS/0.1N

HCl

0.5% P

OE/0.1N

HCl

Phosp

hate,

pH 6.

8

0.5% S

DS/pH 6.

8

0.5% P

OE/pH 6.

8

Wate

r, 90

0 mL

0.5% S

DS/Wate

r

0.5% P

OE/Wate

r

0.2% C

TAB/Wate

r

Tim

e, M

inut

es

>~25% Dissolved

>~50% Dissolved

Page 10: USP EP Meeting_2013 Final

Reference DrugAcetaminophen(Tylenol IR Tablet):

Q: NLT 80% in 30 min.

Page 11: USP EP Meeting_2013 Final

Reference Compound – Acetaminophen

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 11

• Tylenol 250 mg Tablet was used as the test drug

• Size 0 HGC Used for the OE sample without filler

Page 12: USP EP Meeting_2013 Final

Tablet vs. OE Capsule Dissolution – Typical Media

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 12

Gelatin Dissolution Research - Acetaminophen, 0.1N HCl

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time, Min.

%LC

HGC Shell Tylenol OE Capsule Tylenol Tablet

Gelatin Dissolution Research - Acetaminophen, Water

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time, Min.

%LC

HGC Shell Tylenol OE Capsule Tylenol Tablet

Gelatin Dissolution Research - Acetaminophen, pH 6.8

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time, Min.

%LC

HGC Shell Tylenol OE Capsule Tylenol Tablet

Gelatin Dissolution Research - Acetaminophen, pH 4.5

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time, Min.

%LC

HGC Shell Tylenol OE Capsule Tylenol Tablet

Full release (>85%) within 3 minutes from Tablet (for all conditions)

Once capsule opens, the residual gelatin does not impact dissolution for this product.

Full release (>85%) within 10 minutes from OE Capsule (for all conditions)

0.1N HCl pH 4.5

pH 6.8 Water

Page 13: USP EP Meeting_2013 Final

Acetaminophen OE Capsule Dissolution – Surfactant Impact (in Water)

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 13

• Surfactant somewhat delays the drug release

• SDS: high capsule-to-capsule variability

• However, all conditions release >85% in 10 minutes

Gelatin Dissolution Research - Acetaminophen OE Capsule, Surfactant Impact (in Water)

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time, Min.

%LC

Water Only 0.5% Tween-80 0.5% POE 0.5% CTAB 0.5% SDS

Page 14: USP EP Meeting_2013 Final

Acetaminophen OE Capsule Dissolution – Surfactant Impact (in 0.1N HCl)

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 14

• Surfactants do NOT slow down the drug release in 0.1N HCL

• CTAB and POE show slightly faster drug release rate

(Very low gelatin dissolution rate in 0.5% SDS/HCl does not impact the drug release from OE Capsules – see slide #16)

Gelatin Dissolution Research - Acetaminophen OE Capsule, Surfactant Impact (in 0.1N HCl)

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time, Min.

%LC

0.1N HCl only 0.5% SDS 0.5% CTAB 0.5% POE Gelatin_SDS/HCl

Page 15: USP EP Meeting_2013 Final

Acetaminophen OE Capsule Dissolution – Surfactant Impact (in pH 6.8 Phosphate)

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 15

• CTAB delays the capsule opening (> 5minutes)

• SDS shows very high capsule-to-capsule variability, and did not release >85% at 10 minutes

Gelatin Dissolution Research - Acetaminophen OE Capsule, Surfactant Impact (in pH 6.8 Phosphate)

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time, Min.

%LC

pH 6.8 Phosphate only 0.5% SDS 0.5% CTAB 0.5% POE

Page 16: USP EP Meeting_2013 Final

Acetaminophen OE Capsule Dissolution – SDS (at 0.5%) Impact in Different Media

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 16

• More variable in water and pH 6.8 Phosphate

• SDS/pH 6.8: did not release >85% at 10 minutes

• However, all conditions can release >85% of drug in 15 minutes

Gelatin Dissolution Research - Acetaminophen OE Capsule, SDS Impact in Various Media

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time, Min.

%LC

Water Only SDS in Water SDS in HCl SDS in pH 6.8

Page 17: USP EP Meeting_2013 Final

Comparison of Acetaminophen Dissolution Time: Tablet vs. OE Capsule in Various Media

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 17

• The Tablet full releases the drug within 3 minutes (> 90% for all media tested)• The OE Capsule releases >85% drug within 10 minutes for all conditions tested

Acetaminophen Dissolution Comparison - Tablet vs. OE Capsule (Tier-1)

0123456789

10

0.1N H

Cl, Tab

let

0.1N H

Cl, OE C

apsu

le

0.5% S

DS/0.1N

HCl_C

ap

pH 4.

5, Tab

let

pH 4.

5, OE C

apsu

le

pH 6.

8, Tab

let

pH 6.

8, OE C

apsu

le

0.5% C

TAB/pH 6.

8_Cap

Wate

r, Ta

blet

0.5% T

ween-8

0, Tab

let

Wate

r, OE C

apsu

le

0.5% T

ween-8

0, OE C

ap

0.5% S

DS, OE C

apsu

le

0.5% P

OE, OE C

apsu

le

0.5% C

TAB, OE C

apsu

le

Tim

e, M

inut

es

>=5% Release >=85% Released

Page 18: USP EP Meeting_2013 Final

Tier-2 Testing Performance Evaluation

Page 19: USP EP Meeting_2013 Final

Enzymes Information (Currently in USP <711>)

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 19

Pepsin:

• Manufacture: American Laboratories Inc.

• Product: Pepsin, 1:10,000 Powder

• Lot No: 00511010

• Pepsin Activity: 1:10,400

Pacreatin:

• Manufacture: American Laboratories Inc.

• Product: Pancreatin 8X USP Powder

• Lot No: 52320708

• Activity: Protease: 8.1X USP (203 USP units/mg)

Amylase: 10.2X USP

(255 USP units/mg)

Lipase: 33.7 USP Units/mg

Page 20: USP EP Meeting_2013 Final

Enzymes Information (New)

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 20

Bromelain:

• Manufacture: American Laboratories Inc.

• Product: Bromelain 2400 GDU

• Lot No: 55920701-A

• Proteolytic Activity: 2,482

GDU/g

Papain:

• Manufacture: American Laboratories Inc.

• Product: Papain Full Strength

• Lot No: 70310665-B

• Proteolytic Activity: 66,900

USP units/mg

Page 21: USP EP Meeting_2013 Final

Control of Experiments

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 21

Need to get Reproducible results! (Consistency!)• Same Equipment and Apparatus• Same Analyst• Consistent Execution of Dissolution Runs • Direct Detection – Avoid sampling errors

• Precise operation for generating cross-linked capsule samples: 2-hour Treatment with Formaldehyde

Page 22: USP EP Meeting_2013 Final

<711> Tier-1 vs. Tier-2: Non-cross-linked Capsules

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 22

• No significant difference after 10 minutes

Normal Capsule - 0.1N HCl

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

0.1N HCl/Pepsin 0.1N HCl

Normal Capsule - pH 6.8

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

pH 6.8 pH 6.8/Pancreatin

Q: NLT 80% in 30 min.

Page 23: USP EP Meeting_2013 Final

Tier-1, 0.1N HCl: Non-cross-linked Capsule vs. Cross-linked Capsule

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 23

• Fails Stage-3!

• The ~same level of cross-linked capsule samples (i.e. 2-hour treated) were used for all Tier-2 experiments

Tier-1, 0.1N HCl: Normal Capsule vs. X-linked Capsule

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-1_HCl Xlinked_Tier-1_HCl

Q: NLT 80% in 30 min.

Page 24: USP EP Meeting_2013 Final

Tier-1, pH 6.8: Non-cross-linked Capsule vs. Cross-linked Capsule

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 24

• Fails Stage-3!Tier-1, pH 6.8: Normal Capsule vs. X-linked Capsule

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-1_pH 6.8 Xlinked_Tier-1_pH 6.8

Q: NLT 80% in 30 min.

Page 25: USP EP Meeting_2013 Final

<711> Pepsin, 750,000 Units/L

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 25

• Current <711> 750,000 units/L is equivalent to 16,000,000 FCC units/L

• For X-linked capsule (2-hour treated with formaldehyde), Tier-2 result at 30 minutes is 92% (± 6.2%)May Pass S-1 of Tier-2

<711> Pepsin @ 750,000 Units/L

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-1_HCl Xlinked_Tier-2_HCl

(Use

as R

efer

ence

)

Page 26: USP EP Meeting_2013 Final

<711> Pancreatin, 1750 Units/L

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 26

• Current <711> 1750 units/L

• For X-linked capsule (2-hour treated with formaldehyde), Tier-2 result at 30 minutes is 83% (± 10.6%)Will go to Stage-2 of Tier-2

<711> Pacreatin @ 1750 Units/L

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-1_pH 6.8 Xlinked_Tier-2_pH 6.8

Page 27: USP EP Meeting_2013 Final

Finding Equivalent Pancreatin Level to Match Pepsin Performance

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 27

• Current <711> 1750 units/L (1X)

• Levels tested: [Units/L]

1750 (1X), 2000, 2500, 3500 (2X), and 5250 (3X)

• For 2000 Units/L, Tier-2 result at 30 minutes is 93% (± 4.0%) May Pass S-1 of Tier-2

pH 6.8 / Pancreatin

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-2 Normal_Tier-1 Xlinked_Tier-1

Xlinked_Tier-2_3X Xlinked_Tier-2_2X Xlinked_Tier-2_1X

Xlinked_Tier-2_2500U Xlinked_Tier-2_2000U

1750 Units/L

2000 Units/L

5250 Units/L (3X)

Page 28: USP EP Meeting_2013 Final

pH 6.8 / Pancreatin

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-1 Xlinked_Tier-1 Xlinked_Tier-2_1XXlinked_Tier-2_2000U Pepsin, <711>

Pancreatin vs. Pepsin Performance

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 28

1750

Unit

s/L

2000

Uni

ts/L

Pepsin, <711>

Page 29: USP EP Meeting_2013 Final

Tier-1, pH 4.5: Non-cross-linked Capsule vs. Cross-linked Capsule

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 29

• Fails Stage-3!Tier-1, pH 4.5: Normal Capsule vs. X-linked Capsule

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-1_pH 4.5 Xlinked_Tier-1_pH 4.5

Q: NLT 80% in 30 min.

Page 30: USP EP Meeting_2013 Final

Screening Bromelain at pH 4.5 to Match Pepsin Performance

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 30

• Starting point: 0.5 g/L (i.e. ~1250 GDU/L)

• Levels tested: [GDU/L]

1250, 500, 100, 50, 40, 30, and 25 GDU/L

• For 30 GDU/L, Tier-2 result at 30 minutes is 91% (± 7.0%) Will Pass S-2 of Tier-2

pH 4.5 / Bromelain

0

20

40

60

80

100

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-1 X_Tier-1 X_Tier-2 (1250U)X_Tier-2 (500U) X_Tier-2 (100U) X_Tier-2 (50U)X_Tier-2 (40U) X-Tier-2 (30U) X-Tier-2 (25U)

Very Effective!

25 GDU/L

30 GDU/L

100

GDU/

L

Page 31: USP EP Meeting_2013 Final

Bromelain vs. Pepsin Performance

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 31

pH 4.5 / Bromelain

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_Tier-1 Xlinked_Tier-1 Xlinked-Tier-2 (30U)

Xlinked-Tier-2 (25U) Pepsin, <711>

30 G

DU/L

25 GDU/L

Pepsin, <711>

Page 32: USP EP Meeting_2013 Final

Screening Papain at pH 4.5 to Match Pepsin Performance

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 32

• Starting point: 9 mg/L (i.e. ~600,000 U/L)

• Levels tested: [KU/L]

600, 550, 525, and 500 KU/L

• Very small amount of Papain Used:

pH 4.5 / Papain

0

20

40

60

80

100

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_T1 X_T1 X_Tier-2 (600KU)X_Tier-2 (550KU-1) X_Tier-2 (550KU-2) X_Tier-2 (525KU-1)X_Tier-2 (525KU-2) X_Tier-2 (500KU)

Units/L mg / 6L600,000 53.8550,000 49.3525,000 47.1500,000 44.9

Page 33: USP EP Meeting_2013 Final

Screening Papain at pH 4.5 to Match Pepsin Performance (cont.)

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 33

• The results seem more variable than Bromelain

• For 550 KU/L, Tier-2 result at 30 minutes is 95% (± 3.0%) Too Good?

• For 525 KU/L, Tier-2 result at 30 minutes is 85% (± 9.9%) Will go to Stage-2 of Tier-2

pH 4.5 / Papain

0

20

40

60

80

100

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_T1 X_T1 X_Tier-2 (600KU)

X_Tier-2 (550KU, N=12) X_Tier-2 (525KU, N=12)

525 KU/L550 KU/L

Page 34: USP EP Meeting_2013 Final

Papain vs. Pepsin Performance

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 34

pH 4.5 / Papain

0

20

40

60

80

100

120

0 10 20 30 40 50 60

Time, Minutes

%LC

Normal_T1 Xlinked_T1Xlinked_Tier-2 (550KU, N=12) Xlinked_Tier-2 (525KU, N=12)Pepsin, <711>

550 K

U/L52

5 KU/L

Pepsin, <711>

Page 35: USP EP Meeting_2013 Final

Stability of Papain Medium at 550,000 Units/L

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 35

• X-linked Capsule / Tier-2 Testing: Levels = 550 KU/L

• After 7 hours, Tier-2 result at 30 minutes is 78% (± 15.3%) May Fail the Tier-2

pH 4.5 / Papain, ~550 KU/L

0

20

40

60

80

100

0 10 20 30 40 50 60

Time, Minutes

%LC

Papain 550 kU-1 Papain 550 kU-2 Papain 550 kU_7 Hours

Page 36: USP EP Meeting_2013 Final

Stability of Papain Medium at 525,000 Units/L

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 36

• X-linked Capsule / Tier-2 Testing: Levels = 525 KU/L

• Up to 4 hours, the dissolution rate did not slow down

• Overall, it shows high variability from run-to-run using Papain at 550 KU/L and 525 KU/L

pH 4.5 / Papain, ~525 KU/L

0

20

40

60

80

100

0 10 20 30 40 50 60

Time, Minutes

%LC

Papain 525 kU-1 Papain 525 kU-2 Papain 525 kU_4 Hours

Page 37: USP EP Meeting_2013 Final

Stability of Bromelain Medium at 30 GDU/L

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 37

• X-linked Capsule / Tier-2 Testing: Levels = 30 GDU/L

• The dissolution rate are very consistent up to 4 hours

• After 7 hours, Tier-2 result at 30 minutes is 70% (± 9.6%) May Fail the Tier-2

pH 4.5 / Bromelain, ~30 GDU/L

0

20

40

60

80

100

0 10 20 30 40 50 60

Time, Minutes

%LC

Bromelain 30GDU-1 Bromelain 30GDU-2

Bromelain 30GDU_4-hour Bromelain 30GDU_7-hour

Page 38: USP EP Meeting_2013 Final

Solution Stability of Enzyme Media

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 38

• Enzyme activity will drop over time in solution• From the observations of Bromelain and Papain media, it

suggests that the dissolution run should start within 4 hours after the media is made. The media is no longer good after 7 hours.

• Pepsin and Pancreatin had not been tested for solution stability, but the general rule from above may apply to them

Page 39: USP EP Meeting_2013 Final

Disintegration Evaluation:Another Look from Different Hydrodynamics

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 39

• Bromelain @30 GDU/L and Papain @525 KU/L have much longer disintegration time than Pepsin

• @6X works well (6 capsules in 1 beaker)

Disintegration of Cross-linked Capsules(Individual Data)

0

5

10

15

20

25

30

Water SGF

SIF

Pepsin

, 1X

Pancre

atin, 1

X

Bromela

in, 1X

Papain

, 1X

Bromela

in, 6X

Papain

, 6X

Disi

nteg

ratio

n Ti

me,

Min

.

02468

101214161820

Water SGF SIF

Pepsin

, 1X

Pancre

atin, 1

X

Bromela

in, 1X

Papain

, 1X

Bromela

in, 6X

Papain

, 6X

Disintegration of Cross-linked Capsules (Mean, N=6)• Water can not open the X-linked

capsules within 15 minutes• Pancreatin @1750 units/L is

weaker than SGF and Pepsin (similar to dissolution results)

Page 40: USP EP Meeting_2013 Final

Summary: Recommended Levels of these four Enzymes

Recommended levels of Enzymes:

•Pepsin: 750,000 Units/L (<711>), i.e. 16,000,000 FCC units/L

•Pancreatin: 2000 Units/L

•Bromelain: 30 GDU/L

•Papain: 550,000 Units/L(525,000 U/L may be slightly too weak and too variable.)

40USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013

Tier-2 Performance Comparison - All 4 Enzymes (N=12)

0

20

40

60

80

100

0 10 20 30 40 50 60

Time, Minutes

%LC

Pepsin/750000 U Pancreatin/2000 UBromelain/30 GDU Papain/550000 UNormal Capsule (pH 6.8)

Tier-2 Performance Comparison - All 4 Enzymes (N=12)

0

20

40

60

80

100

0 10 20 30 40 50 60

Time, Minutes

%LC

Pepsin/750000 U Pancreatin/2000 U Bromelain/30 GDU Papain/525000 U

Page 41: USP EP Meeting_2013 Final

Summary and Next Step • The gelatin dissolves faster in 0.1N HCl than pH 4.5 & pH 6.8• SDS may interact with gelatin and show more variable results. The

impact is not significant for fast dissolving formulations• Pepsin in 0.1N HCl is used as the reference, and identified the

appropriate levels for the other three enzymes

Next Steps:• Verify these experiment results from other labs• Verify working pH ranges for each enzymes• Find the best way to express the enzyme activity, and be consistent

from various suppliers

41USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013

Page 42: USP EP Meeting_2013 Final

• The design, study conduct, and financial support for the study were provided by Abbvie. Abbvie participated in the interpretation of data, review, and approval of the presentation.

• Abbvie is the sole source of funding for the related studies in this presentation. No other entity has provided any funding for the related studies in this presentation.

Disclosures

USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 42

Page 43: USP EP Meeting_2013 Final

Acknowledgement• Dr. Jian-Hwa Han is employed at Abbvie. Dr. Han is the primary

investigator for this study.

• Mr. Daniel Bonilla is employed at Abbvie. Mr. Bonilla provided technical assistance for this study.

• Ms. Susan George and Dr. Paul D. Curry, Jr. are employed at Abbvie who have contributed for scientific discussions and reviewing the presentation materials.

• Mr. Thomas Langdon of American Laboratories, Inc. provided all four enzymes for this study, and the technical information about these materials.

43USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013

Page 44: USP EP Meeting_2013 Final

Q&A

Page 45: USP EP Meeting_2013 Final