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Disintegration Test a Surrogate

Disintegration Test a Surrogate


for
for
Dissolution Testing
Dissolution Testing
Some Practical Considerations
Some Practical Considerations
Vilayat A. Sayeed, Ph.D.
Director, Division of Chemistry III
Office of Generic Drugs
OPS/CDER/FDA
April 28-30, 2008
Crystal City, Arlington, VA
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Objectives
To understand the influence of formulation and
processing variables on the dissolution and
disintegration time of IR tablets
To determine the relationship, if any, between
dissolution and disintegration time for IR tablets of
a highly soluble drug
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Disintegration vs. Dissolution
De-aggregation
Dissolution
Tablet
Granules or
Aggregates
Particles
Drug in Solution
(in-vitro/in-vivo)
Disintegration
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ICH Q6A Decision Tree 7(1)
Disintegration acceptance criteria with an upper
time limit are acceptable if the following conditions
are satisfied:
Dosage form is not designed to produce modified
release
Dose/ solubility < 250 mL through out the
physiological pH range (pH 1.2 - 6.8) at 37C
Dissolution > 80% in 15 min at pH 1.2, 4.0, and 6.8
A relationship has been determined between
disintegration and dissolution
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Drug Selection
Verapamil HCl used as model drug
Product Classification
Dose / Solubility < 250 mL at pH range 1.2 - 6.8
Solubility at different pH (Analytical Profiles)
Solvent Water/pH solubility (mg/mL)
pH 2.32 82
pH 3.05 78
pH 4.65 89
pH 4.86 82
pH 5.59 76
pH 6.35 83
pH 6.54 46
pH 6.76 11
pH 7.32 0.44
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Experiment Design
Verapamil HCl used as model drug
Product Classification
Dose / Solubility < 250 mL at pH range 1.2 - 6.8
Formulation ingredients
Drug 10.0%
Filler 75.0%
Binder 4.0%
Disintegrating agent (or absent) 10.0% (0%)
Magnesium stearate 0.5%
Talc 0.5%
2x2x3x2 (24 batches) full-factorial design used
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Variables and Batch Codes
Different batches of IR tablets prepared by varying
Filler DCP / LMH
Binder PVP / HPMC
Disintegrating Agent NaCMC / MCC / None
Tablet hardness 6 Kgf / 10 Kgf
Each batch assigned a five digit alpha-numeric
code V*
1
*
2
*
3
*
4
, where
*
1
= D for DCP L for LMH
*
2
= P for PVP H for HPMC
*
3
= A for NaCMC M for MCC X for None
*
4
= 1 for 6 Kgf 2 for 10 Kgf (tablet hardness)
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Manufacturing Process
Drug + filler blended for 5 min in a planetary mixer
Granulation performed in a fluidized- bed
granulator
Aqueous binder solution sprayed at constant rate
Dried granules blended with the disintegrating
agent (if present), talc and magnesium stearate
for 5 minutes in a V-blender
Granules compressed on a tablet press to obtain
tablets with 6 and 10 Kgf hardness
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Test Procedures
USP30 <701> Disintegration procedure for
uncoated tablets. n = 6
USP30 Dissolution test procedure for Verapamil
HCl tablets. n = 6
USP method II (Paddle method) at 50 rpm
Media: 900 mL 0.01 N HCl
UV analysis at 278 nm at 15 and 30 minutes
USP limit: Q NLT 75% in 30 min
Dissolution test also performed in pH 4.0 and pH
6.8 phosphatebuffers for selected batches
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Results
Disintegration Time ranged from <1 to >60 min
Dissolution @ 30 min ranged from 18.1 to 100.5%
Q < 75% for 14 batches (failed as per USP criteria)
Variable analysis of the 14 failed batches:
DCP: LMH 12:2 NaCMC: MCC: None 4:4:6
PVP: HPMC 6:8 6 Kgf: 10 Kgf (Hardness) 7:7
Dissolution @ 15 min at pH 4.0, 6.8 & 0.1N HCL
Q > 80% for VLHA1 and VLHA2
Q < 80% for at least one tablets at all pHs for VLPA1,
VLPA2, VLPX1 and VLPM1
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Variation in Disintegration Time
0
10
20
30
40
50
60
A1 A2 M1 M2 X1 X2
Disintegrating Agent and Tablet Hardness
D
i
s
i
n
t
e
g
r
a
t
i
o
n

T
i
m
e

(
m
i
n
)
DH LH DP LP Filler - Binder
Dark color: DCP; Light color: LMH; (Horizontal): HPMC;
[|]
(Vertical)
:
PVP
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Dissolution (at 30 min)
0
20
40
60
80
100
120
A1 A2 M1 M2 X1 X2
Disintegrating Agent and Tablet Hardness
D
i
s
s
o
l
u
t
i
o
n

a
t

3
0

m
i
n
u
t
e
s

(
%

w
/
w
)
DH LH DP LP
Filler - Binder
USP limit
Dark color: DCP; Light color: LMH; (Horizontal): HPMC;
[|]
(Vertical): PVP
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Dissolution vs. Disintegration
0
20
40
60
80
100
0 4 8 12 16 20
Disintegration Time (minutes)
D
i
s
s
o
l
u
t
i
o
n

(
%
w
/
w
)
30 min
15 min
>
USP limit
ICH Q6A Dicision Tree 7(1)
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Q 80% @ 15 minutes
70
75
80
85
90
95
100
105
0 1 2 3 4 5 6
Disintegration Time (minutes)
D
i
s
s
o
l
u
t
i
o
n

(
%
w
/
w
)
VLHA1
VLHA2
VLPA1
VLPA2
VLPM1
VLPX1
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Effect of Filler
0
20
40
60
80
100
0 4 8 12 16 20
Disintegration Time (min)
D
i
s
s
o
l
u
t
i
o
n

(
%
w
/
w
)
DCP 15 min LMH 15 min
DCP 30 min LMH 30 min
>
16
Effect of Disintegrating Agent
0
20
40
60
80
100
0 4 8 12 16 20
Disintegration Time (min)
D
i
s
s
o
l
u
t
i
o
n

(
%
w
/
w
)
A-15 M-15 X-15
A-30 M-30 X-30
>
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Effect of Binder
0
20
40
60
80
100
0 4 8 12 16 20
Disintegration Time (minutes)
D
i
s
s
o
l
u
t
i
o
n

(
%
w
/
w
)
H-15 P-15
H-30 P-30
>
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Variable Effect Analysis
Dissolution (at 15 and 30 min) influenced by
Filler L > D p < 0.0001
Disintegrating agent A > M > X p = 0.002
Binder P > H p = 0.02
Disintegration time influence by
Disintegrating agent A > M > X p < 0.0001
Filler L > D p = 0.0002
Binder P > H p = 0.004
Hardness 1 > 2 p = 0.02
Filler * Disintegrating Agent p = 0.0004
Filler * Binder p = 0.008
Binder * Disintegrating Agent p = 0.03
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Conclusions
Dissolution influenced by formulation variables
Disintegration time influenced by all four variables
Filler and disintegrating agent showed most
significant influences on both test parameters
No relationship observed between dissolution and
disintegration time
Only two test batches (out of 24) met the criteria for
using disintegration test for drug release
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Acknowledgement
Abhay Gupta, Robert Hunt, Mansoor A. Khan,
Gary Buehler, Helen Winkle