usp ep meeting_2013 final
TRANSCRIPT
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Jian-Hwa HanUSP Expert Panel Meeting
May 29-30, 2013
Using Enzymes for Dissolution - The Understandings from Gelatin to Enzymes
SUB-TITLE, DATE
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• 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
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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
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Gelatin Dissolution – The Basics
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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
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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
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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
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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
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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
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Reference DrugAcetaminophen(Tylenol IR Tablet):
Q: NLT 80% in 30 min.
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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
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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
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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
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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
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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
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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
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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
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Tier-2 Testing Performance Evaluation
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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
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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
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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
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<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.
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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.
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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.
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<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
)
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<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
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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)
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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>
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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.
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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
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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>
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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
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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
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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>
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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
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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
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Stability of Bromelain Medium at 30 GDU/L
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• 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
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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
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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)
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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
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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
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• 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
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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
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Q&A
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