Linking Drug Stability to Manufacturing
Physical Chemical Foundations
Gabapentin
L. E. Kirsch
Stability team leader
Stability Team
Group
Team member
Minnesota
Raj Suryanarayanan (Co-PI)
Aditya Kaushal (post-doc)
Kansas
Eric Munson (Co-PI)
Dewey Barich (post-doc)
Elodie Dempah, Eric Gorman (grad. students)
Iowa
Lee Kirsch (Co-PI)
Greg Huang (Analytical Chemist)
Salil Desai, Zhixin Zong, Tinmanee Radaduen, Hoa
Nguyen, Jiang Qiu (grad students)
Duquesne
(Unit-op team
Interface)
Ira Buckner
Linking manufacturing to stability
(Unstable form)
(Stable form)
3
Gabapentin as a model drug substance
• Multiple crystalline forms
• Susceptible to stress-induced physical
transformations
• Susceptible to chemical degradation
KEY QUESTIONS
1. Are physical and chemical instability
linked?
2. How can manufacturing-induced stress be
incorporated in a quantitative chemical
instability model?
4
Some Crystalline Forms of Gabapentin
Ibers., Acta Cryst c57, 2001 and Reece and Levendis., Acta Cryst. c64 2008
API form
Crystalline
Hydrate
I
II
III
Stable polymorph
(API)
Intramolecular
H-bonding
IV
Transition between forms by mechanical stress, humidity, and thermal stress
5
Physical transformation by
Mechanical Stress
Form II
Milled
Gabapentin
Form III
4
6
8
10
12
2Theta
14
16
18
20
22
Physical transformation by Humidity
Intensity
47 hrs in 40C 31 %RH
29 hrs
17 hrs
7 hrs
0 hr
2theta
7
Physical transformation by Thermal Stress
Kaushal and Suryanarayanan., Minnesota Univ. AAPS poster 2009
8
Chemical Degradation of Gabapentin
– nucleophilic attack of nitrogen on carbonyl
O
NH
Gabapentin
Gabapentin _lactam
toxic
USP limit: < 0.4%
9
Aqueous degradation kinetics
Irreversible cyclization
O
OH
O
NH2
NH
+ H2O
gabapentin lactam
Solid state degradation kinetics
40 C 5% RH, milled gabapentin
7
Lactam (mole %)
6
autocatalytic lactam formation
5
4
3
2
1
rapid degradation of process-damaged gaba
initial lactam
0
0
100
200
300
hours
400
500
600
Solid state Degradation Model
autocatalytic branching
k1GD  L
spontaneous dehydration
GABA (G)
GABA (D)
(stable form)
(unstable form)
k3 G D 
k2 D
LACTAM (L)
branching termination
Hypothesis:
Manufacturing stress determines initial conditions (G0, D0 and L0)
Environmental (storage) stress determines kinetics (k1, k2 and k3)
12
Building a quantitative model
Environmental
Stress
Drug
Stability
Manufacturing
Stress
Compositional
Factors
(e.g. excipients)
13
Effects of Manufacturing Stress:
Initial Lactam and Instability
Thermal stressed at 50 °C, 5%RH
2.5
60 min milled
Milling caused faster
degradation rate
2.0
% lactam
45 min milled
1.5
1.0
15 min milled
0.5
Lactam generated
during milling
(in-process lactam)0.0
API as received
0
5
10
15
20
time(days)
14
25
30
Effects of Milling Stress:
Specific Surface Area
Is the increase of lactamization rate solely due to
increase of Surface Area?
20
2
Surface Area(m /g)
16
12
8
4
0
0
20
40
Milling Time (min)
15
60
Can Surface Area account for
Lactamization Rate Changes upon
Mechanical Stess?
Lactamization Rate(mole%/day 50 °C)
1
0.8
Samples milled for
different time
0.6
0.4
Sieved aliquots of 15min milled sample
0.2
Sieved aliquots of unmilled sample
0
0
5
10
15
20
Specific Surface Area(m2/g)
NO, ALSO increased regions of crystal disorder caused by the mechanical
stress.
16
Effects of Milling based on Change in
Initial Condition:
lactam formation (50 °C)
milling time effect
3.5
D0
Treatment (%)
Lactam mole %
3
60min mill
2.5
2
45min mill
1.5
15min mill
1
0.5
unstressed
0
0
200
400
600
unstressed
15min
milled
45min
milled
60min
milled
(%mole-1hr-1)
k2
(hr-1)
0.6
0.017
k1*104
0.02
0.59
1.28
1.62
800 1000 1200 1400
Time (hr)
17
Effects of Environmental Stress:
temperature and humidity
Environmental
Stress
Drug
Stability
Manufacturing
Stress
Compositional
Factors
(e.g. excipients)
18
15
Lactam (%mole)
Lactam
kinetics under
controlled
temperature
(40-60 C) and
humidity (550% RH)
20
10
5
0
0
100
200
300
400
Hours
500
600
700
800
Effects of Temperature:
predicted values based on parameterization of
autocatalytic model
25
Gaba 60C 5%RH
20
Gaba 50C 5%RH
Lactam mole%
15
10
Gaba 40C 5%RH
5
0
0
100
200
300
time(hours)
400
500
600
Effects of Moisture
21
Is the decreased lactam rate due to
reversible reaction?
• Thermal stress of solid state (milled) or
aqueous gabapentin_lactam
– No detectable loss of lactam and no appearance
of gabapentin in solution and solid state
O
NH
COOH
NH2
+H20
Gabapentin
Gabapentin_lactam
Zong et.al., Draft submitted to AAPS Pharm Sci Tech. 2010
22
Why moisture appears to slow and shut
down lactam formation?
• In general, effect of moisture is NOT to slow reaction
rates
• Analytical issue?
Most gaba-L could be recovered from solid powder, only ignorable gabaL was detected in saturated salt solution.
• Reversible reaction?
No gabapentin formed from gaba-L in solution or solid state
• Formation of stable hydrate?
No hydrate found from XRD patterns
Moisture-facilitated termination of branching
23
Effect of Moisture:
Shut down Lactam Formation
Thermal stress: 50°C 5%RH
Gaba-L Concentration (Mole %)
4
Pretreated at 5% RH 25°C for 24 hours before thermal stress
3
2
Pretreated at 81% RH 25°C for 24 hours before thermal stress
1
0
0
20
40
60
Hours
24
80
100
Effects of Moisture
moisture effect gaba simulation
5
k1
k2
(%mole-1hr-1) (hr-1)
D0
(%)
0.000021 0.0074 1.05
k3(%mole-1hr-1)
Lactam mole %
4
5%RH
3
̴0
40 C 5%RH
2
L0
(% mole)
0.37
11%RH 30%RH 50%RH
0.014
0.030
0.099
40 C 11%RH
40 C 30%RH
1
40 C 50%RH
0
0
100
200
300
400
500
Time (hr)
25
Effects of Compositional Factors:
excipient effects
Environmental
Stress
Drug
Stability
Manufacturing
Stress
Compositional
Factors
(e.g. excipients)
26
Excipient Effects
Comparison of lactam formation kinetics between neet gabapentin
and gabapentin/HPC
controlled temperature (40-60 C) and humidity (5-50% RH)
Gabapentin & 6.5% HPC
60
60
50
50
40
40
Lactam (% mole)
Lactam (%mole)
Gabapentin
30
20
10
30
20
10
0
0
0
100
200
300
400
Hours
500
600
700
800
0
100
200
300
400
Hours
500
600
700
800
Evaluation of the role of excipients in
gabapentin SS degradation
– Mixtures of gabapentin & excipients
– Co-milled
– Storage conditions: 5 to 50% RH at 50 ˚C
Saturated solution 50˚C
5RH 4:47:40 AM 10/22/2010
50
Lactam mole %
• Excipients (50% w/w)
– CaHPO4.2H20 (Emcompress)
– Corn starch
– Microcrystalline cellulose (Avicel PH101)
– HPMC 4000
– Colloidal SiO2 (Cab-O-Sil)
– Talc (Mg silicate)
– HPC (6.5% w/w)
40
CaHPO4
SiO2
30
HPC
Avicel
HPMC
Talc
20
Starch
10
Gaba
0
0
100
200
300
Time (hr)
400
500
ga
Av
HP
Ca
Ta
HP
Ca
co
ga
ca
co
Av
HP
Ca
Ta
HP
Model parameterization using
excipient-induced variation in crystal damage during
milling and termination rate
50
CaHPO
4
Excipient
k1
k2
SiO2
k3104
5.55
D0 (%)
21.1
40
SiO
MCC
Talc
0.016
Starch
0.000074
CaHPO4
2.37
10.6
2.62
Lactam (% mole)
2
7.80
1.35
HPMC
1.20
HPC (6.5%)
4.04
4.5
Starch
30
7.2
MCC
8.4
7.4
Talc
20
6.5
HPC (6.5%)
HPMC
10
Excipient effects
•Crystal damage (D0) during milling 0 0
•Kinetics of branching and termination(k3)
100
200
300
Hours
400
500
Effect of Excipients based on Change in
Initial Conditions and Rate Constants:
under
low
humidity
4
k1 *10
SiO2
Talc
0.27
0.33
0.0208
0.0116
D0
(%)
21.16
8.44
Starch
HPMC
Avicel
0.35
0.41
0.49
0.0150
0.0123
0.0148
4.54
7.42
7.21
0.30
0.30
0.26
HPC (6.5%)
Gaba
0.55
0.74
0.0209
0.0149
6.52
1.05
0.30
0.37
(%mole-1hr-1)
k2
(hr-1)
L0
(% mole)
2.6
0.98
30
Effect of Excipients based on Change in
Rate Constants: under low humidity
k2
k3*102
HPMC
Talc
0.012
0.014
D0
(%)
7.42
8.44
CaHPO4
0.023
10.6
0.60
0.041
0.056
0.078
0.260
̴0
6.52
21.1
7.21
4.54
1.05
0.30
2.60
0.26
0.30
0.37
k1
(hr-1)
0.016
HPC (6.5%)
SiO2
Avicel
Starch
Gaba
0.000074
(%mole-1hr-1)
(%mole-1hr-1)
L0
(% mole)
0.30
0.98
31
B
D
F
H
Moisture and excipient effects
0RH
11RH
30RH
50RH
Data 10
moisture effect gaba50RH
No excipient
20
Co-milled excipient (SiO2)
50
30 %RH
Lactam mole %
40
15
5 %RH
11 %RH
30
10
50 %RH
20
5 %RH
5
0
0
11 %RH
30 %RH 10
50 %RH
0
0
100 200 300 400 500 600 700 800
100
200
300
400
500
600
Time (hr)
32
Linking Stability in Design Space
Manuf.
Design
Space
Model
L0
D0
PostManuf.
Degradation
Model
Lt
End
of
Expiry
• Key Research Findings
• Manufacturing Stress impacts drug stability upon storage:
 L0 (in-process lactam)
 D0 (unstable gabapentin)
• Predictive model for drug stability includes:
•
•
•
Environment factor: temperature () & humidity ()
Compositional factors: both kinetic and initial condition
effects
Manufacturing factors: L0 and D0
• Model validation: completion of long term stability
Measuring the manufacturing stress effects
• Physical methods
– Raj Suryanarayanan (University of Minnesota)
– Eric Munson (University of Kentucky)
• Chemical and kinetic measurements
– Lee Kirsch (University of Iowa
Solid State NMR
Raman spectroscopy
Powder x-ray diffraction (XRD)
DSC/TGA
Water vapor sorption
HPLC
Kansas
Minnesota
Minnesota
All
Minnesota
Iowa
Chromatographic methods
1.50
Detector 1-210nm
hydBt24H
Area
Name
Retention Time
Detector 1-210nm
hydAt0H
1.25
Area
Name
Retention Time
4
20
Detector 1-210nm
lotAHbefore
Area
Name
Retention Time
20
1.00
1
2
4
5
6
7
8
9
10
Minutes
Comparison of HPLC
chromatograms before (black) and
after (red) thermal stress:
∆ lactam = 0.004%.
1
2
10
3.618
Lactam
10
1
5
0
3
5
6
7
8
9
10
Minutes
1
2
3
5
287843
0
4
7.572
(Lactam)
Gabapentin
0
0.00
15
m AU
7.307
0.25
3
8278
m AU
1
2
15
4635741
0.00
2
3.668
9.117
2388
Gabapentin
0.25
3
0.50
3853
5.390
3.658
0.50
0.75
4339
0.75
m AU
Lactam
7.288
3
4093741
m AU
Detector 1-210nm
lotAH
m AU
m AU
1.00
4
Detector 1-210nm
hydAt24H
Gabapentin
1.25
Detector 1-210nm
hydBt0H
2801635
1.50
4
5
6
7
0
8
9
10
Minutes
Comparison of HPLC
chromatograms before (black)
and after (red) thermal stress:
Comparison of HPLC
chromatograms before (black) and
after (red) thermal stress:
∆ lactam = 0.059%.
∆ lactam = 0.174%.
Manufacturing-stability measurements
• In process lactam (L0)
– Change in lactam levels during specific treatment or unit
operation in % lactam/gabapentin on molar basis
• Initial Rate of Lactam Formation (V0 or STS)
– Daily rate of lactam formation upon thermal stress at 50°C
under low humidity
• D0 from Chemical Analysis
V0  k 2 D0
V0
D0 
k2
k 2 (50o C )  0.37 / %day
Insert Sury
Insert Eric
Applied Manufacturing-stability Measurements to
Design Space and Risk Assessment
• Laboratory scale stability design space
• Pilot scale stability design space
• Risk assessment using Manufacturingstability Measurements