FreeThink Technologies, Inc. 2015 freethinktech.com 1
FreeThink Technologies, Inc
Drug Product Stability—Accelerated Decision Making for
Selecting a Package
Kenneth Waterman, Ph.D.
[email protected] 2015 2
Complex Kinetics
• >50% Products show complex kinetics: cannot be fit to simple linear approach • Heterogeneous systems • Secondary degradation • Autocatalysis • Inhibitors
[email protected] 2015 3
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 7 14 21 28
%D
egr
adan
t
Time (days)
Complex Kinetics—Example Drug → primary degradant → secondary degradant
%Deg Prod
Time
30°C
60°C
70°C
Spec. Limit
1 month
Constant Time ‘k’ = Slope of line
Traditional Accelerated Stability
Copyright FreeThink Technologies, Inc. 2015 Freethinktech.com
4
-4
-3.8
-3.6
-3.4
-3.2
-3
-2.8
0.0029 0.00295 0.003 0.00305 0.0031 0.00315 0.0032 0.00325 0.0033
ln k
1/T
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50°C
60°C
30°C?
70°C More unstable
• Appears very non-Arrhenius • Impossible to predict shelf-life
from high T results
Traditional Accelerated Stability
%Deg Prod
Time
30°C
60°C
70°C
Spec. Limit
3 days 14 days
Isoconversion
‘k’ = Slope of line
Isosconversion Accelerated Stability
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• Isoconversion: Time to “edge of failure” • Time to specification limit (specific degradant, total
degradant, potency, color change, etc.)
-7.5
-6.5
-5.5
-4.5
-3.5
-2.5
-1.5
0.0029 0.00295 0.003 0.00305 0.0031 0.00315 0.0032 0.00325 0.0033
ln k
1/T
Using 0.5% isoconversion
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50°C
60°C
30°C
70°C
Using 0.2% isoconversion
Accurate predictions do not depend on the kinetic form
Isosconversion Accelerated Stability
Assumption for ASAPprime models is that the shape of the curve (i.e. degradation kinetics) is similar across different stability conditions, just the timescale is different Real world example (G. Scrivens, 2015)
3.1x faster
3.1x faster
Etc.
11.7x faster
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Isoconversion Assumption
9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
0.00280 0.00290 0.00300 0.00310 0.00320 0.00330 0.00340
ln(k
)
1/T (K)
30C
70C
60C 50C
80C
CP-456,773/60%RH
Real time data
ASAPprime Shelf Life 1.2 yrs Experimental Shelf Life 1.2 yrs
[email protected] 2015
Accelerated Aging—Isoconversion Approach Complex Kinetics—Real Example
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Humidity Corrected Arrhenius
Equation
ln k = ln A - Ea/(RT) + B(RH)
equilibrium relative humidity
Spec. limit/(isoconversion time)
collision frequency
activation energy
1.986 cal/deg
humidity sensitivity factor
[email protected] 2015
11
B 60%RH in PVC
Blister
65%RH in PVC
Blister
0.00
low moisture sensitivity
5.0 yrs 5.0 yrs
0.04
average moisture
sensitivity
5.0 yrs 3.8 yrs
0.09
high moisture sensitivity
5.0 yrs 3.0 yrs
[email protected] 2015
Impact of B Factor on Shelf-Life
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Packaging
• Moisture in package equilibrates between headspace + internal components
• Ability of materials to hold moisture depends
on RH (moisture sorption isotherm) • Transfer of moisture into or out of packaging
depends on package permeability • Stability in package linked to ASAP fitting
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Packaging for Moisture Protection
H2O H2O
H2O H2O
FreeThink Technologies, Inc. 2015 freethinktech.com
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Moisture Sorption Isotherm
• Weight% water as a function of equilibrium RH
• Measured using dynamic vapor sorption
(DVS) • Mixture weighted average of components • Minor temperature dependence (25-40°C)
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Moisture Sorption Isotherm: Crystalline Materials
• Predominantly surface-bound water
• Described by Langmuir Equation: 𝑊𝑡%𝐻2𝑂 =𝐾𝑒𝑞(𝑅𝐻)
1+𝐾𝑒𝑞(𝑅𝐻)
0
0.05
0.1
0.15
0.2
0 20 40 60
Wt%
Wat
er
%RH
Langmuir Fitting of Sorption
Average sorption isotherm of 35 crystalline APIs
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Moisture Sorption Isotherm: Amorphous Materials
• Surface-bound water at low RH • Water-water binding at higher RH: solid allows water
condensation
0
10
20
30
40
50
60
70
0 10 20 30 40 50 60 70 80
Wt%
Wat
er
%RH
MCC HEC PVP
Langmuir Region: surface-water interactions
Cooperative Adsorption Region: water-water interactions
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Moisture Sorption Isotherm: Amorphous Materials
• As more waters condense, more water-water interactions possible
• Exponential increase in water as a function of RH
1
1.5
2
2.5
3
3.5
4
4.5
35 45 55 65 75
ln(W
t% W
ate
r)
%RH
MCC HEC PVP
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Moisture Sorption Isotherm: Amorphous Materials • Condensation (cooperative adsorption) similar for many
excipients
• ln 𝑊𝑡%𝐻2𝑂 = ln+ 𝜷 𝑅𝐻
Excipient ß
Microcrystalline cellulose 0.018
Gelatin 0.021
Hydroxyproylcellulose 0.037
Mannitol 0.044
Hydroxyethylcellulose 0.045
Methylcellulose 0.028
Sodium starch glycolate 0.031
Lactose monohydrate 0.028
Croscarmellose sodium 0.027
Crospovidone 0.021
Povidone 0.029
Pregelatinized starch 0.016
Average 𝜷 = 0.03, same as the average ASAP B term
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0
5
10
15
20
25
30
35
10 20 30 40 50 60 70 80
% W
ate
r
%RH
Moisture Sorption by Desiccant (Silica)
Capacity depends on RH
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Moisture Equilibration in a Package
• Uncoated tablet: t½ 30 min (solid fraction 0.75) • Moisture barrier coated tablets: t½ 10 hr • Internal RH equilibrates fast: permeation into
package is rate-limiting step
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Moisture Vapor Transmission Rate
• MVTR standard term • USP24/NF18 23°C/75%RH • ASTM 3079 37.8°C [100°F]/90%RH
• More fundamental permeability (P) • P = MVTR/ΔRH • Follows Arrhenius temperature
dependence
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Pblister = Pdosage area*draw ratio
Draw ratio = surface areaformed/ surface areaunformed sheet
P proportional to V2/3
Permeability of Packaging
40%RH
10 tablets: 170 mg water
Headspace:
30-cc bottle 0.2 mg water
200-cc bottle 1.4 mg water
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Headspace
0
1
2
3
4
5
6
7
0 20 40 60
We
igh
t% W
ate
r
%RH
2:1 MCC:Lactose; 500 mg 40% RH
17 mg water/tablet
1
10
100
10 15 20 25 30 35 40
H2O
(m
g/L
)
T (ºC)
0.018 mg water/mL; 0.0072 mg water/mL @40%RH
Headspace: volume not significant! Surface area: permeability change is important
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Link to Stability • Drug degradation occurs predominantly in non-
crystalline domains • Amorphous • Solid-solution • Defect
• Water sorption in these regions is exponential with RH
• Reactivity increases proportionately to amount of water: reactivity depends exponentially on RH
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Packaging
• RH generally increases over time in packaging at ICH conditions
• Degradation rate increases exponentially with increased RH: ASAP predicts long-term behavior better than linear extrapolation from 1-year data
• Blisters: higher protection more expensive • Even aluminum-aluminum cold form blisters
cannot match bottles plus desiccant
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Excursions • T, RH excursions can impact stability
• Change in RH inside package • T impact directly on reaction
• Can be explicitly calculated using ASAPprime®
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Initial Dosage Water Content (Water Activity)
• Stability can be impacted by initial water
activity (water content) • Packaging decision can be linked to initial
water content (lower water release specifications can enable lower barrier protection)
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•RH inside packaging depends on moisture transfer and re-equilibration inside the package
•Packaging decisions dependent on humidity can be predicted by incorporating RH vs. time into ASAP data analysis
•ASAPprime® makes these determinations easy
FreeThink Technologies, Inc. 2015 freethinktech.com
Conclusions