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Applying Microcalorimetry to Characterize the Stability Applying Microcalorimetry to Characterize the Stability and Compatibility of Pharmaceutical Systemsand Compatibility of Pharmaceutical Systems
Time/s0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000
HeatFlow/mW
-0.35
-0.30
-0.25
-0.20
-0.15
-0.10
-0.05
0.00
0.05
0.10
0.15
-0.35
-0.30
-0.25
-0.20
-0.15
-0.10
-0.05
0.00
0.05
0.10
0.15
Figure:25/11/2002 Mass (mg):674.8
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure: 35 37.5 40 42.5 45 3 hours each (Zone 2)Micro DSC III
Exo Exo
Exo
35C 37.5C 40C 42.5C 45C
ThermalCal International
OutlineOutlineMicrocalorimetry: The Universal Detector
Overview of Microcalorimetry Stability and Compatibility Testing
Overview of Commercially Available Microcalorimeters
∆G = ∆ H - T ∆ S
Microcalorimetry: The Universal DetectorMicrocalorimetry: The Universal DetectorIsothermal Microcalorimetry
Heat Flow Measured as Difference Between Sample and Reference
Isothermal Temperature Usually Maintained by Large Volume Constant Temperature Bath
Typical Detection Limit ~ +/-0.5 uJ/sec
Sample Sizes Range from 1ml to 150ml
Temperature Range ~ 5 to 90 °C
dQ/dt = ∆H *dn/dt
∆G = ∆ H - T ∆ S
Microcalorimetry: The Universal DetectorMicrocalorimetry: The Universal DetectorIsothermal Microcalorimetry
Chemical ProcessesHydrolysis, oxidation, free radical, etc. all have large
heats of reaction.
Ideally, degradation rates of less than 1% per year can be predicted in a matter of days.
Physical and Bio ProcessesCrystallization, polymorph conversions, bacterial
growth.
∆G = ∆ H - T ∆ S
Microcalorimetry: The Universal DetectorMicrocalorimetry: The Universal DetectorIsothermal Microcalorimetry
Closed or Open Systems
Batch BatchMixing Pressure
FluidMixingFluid
∆G = ∆ H - T ∆ S
Microcalorimetry: The Universal DetectorMicrocalorimetry: The Universal DetectorIsothermal Microcalorimetry
Qox = ∆ Hox*nox
Qhyd = ∆ Hhyd*nhyd
etc.
etc.
Qmeasured = Σi∆ Hi*ni
Standard Addition
∆G = ∆ H - T ∆ S
Microcalorimetry: The Universal DetectorMicrocalorimetry: The Universal DetectorScanning Microcalorimetry (HSDSC)
Heat Flow Measured as Difference Between Sample and Reference
Temperature Ramped by Peltier Elements or Fluid Circulation. Heat/Cool. Isothermal.
Typical Detection Limit ~.2-5 uJ/sec
Sample Sizes Range from .3 ml to 1 ml
Slow Scan Rates .001 – 1 °C /min
Temperature Range ~ -45 to 120 °C
d(dQ/dt)/dT = ∆H *d(dn/dt)/dT
∆G = ∆ H - T ∆ S
Microcalorimetry: The Universal DetectorMicrocalorimetry: The Universal DetectorScanning Microcalorimetry (HSDSC)
Chemical ProcessesThermally induced chemical reactions.
Physical and Bio ProcessesGlass transitions, thermally induced crystallization and polymorph conversions, protein denaturation.
∆G = ∆ H - T ∆ S
Microcalorimetry: The Universal DetectorMicrocalorimetry: The Universal DetectorScanning Microcalorimetry (HSDSC)
Closed or Open Systems
BatchMixing
Batch
Wetting
Fluid FluidMixing∆G = ∆ H - T ∆ S
Microcalorimetry: The Universal DetectorMicrocalorimetry: The Universal DetectorDetection LimitsDetection Limits
•If a significant signal of 1 µW is detectable, and if it is assumed that the reaction enthalpy ∆HR, is 50 kJ/mole for the compound, it is possible to estimate the rate of reaction x :•x = (10-6 J/s / 50x103 J/mole) = 2x10-11 mole/sec,
or 1.2x10-9 mole/min, or 1.7x10-6 mole/day, or 6.3x10-4 mole/year
•It is also possible to use the Arrhenius law for different temperatures : dα/dt = k (1- α)n = k0 exp(-E/RT) (1- α)n
•dα/dt is proportional to the calorimetric signal (dH/dt)•Plotting Log(dH/dt) versus 1/T yields the kinetic parameters of the reaction.
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingReaction in Solution: pH EffectReaction in Solution: pH Effect
Furnace temperature /°C30 35 40 45 50 55 60 65 70 75 80
-0.30
-0.25
-0.20
-0.15
-0.10
-0.05
0.00
0.05
0.10
pH 4
pH 6
pH 8
pH 10
Figure:Mass (mg):15.43
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure: scan 10C to 95C (Zone 7)
Exo
Exo Exo
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingReaction in Solution: pH EffectReaction in Solution: pH Effect
2.75 2.80 2.85 2.90 2.95 3.00 3.05 3.106.2
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8
Linear Regression for ph8_B:Y = A + B * X
Parameter Value Error------------------------------------------------------------A 19.9813 0.44947B -4.41783 0.1539------------------------------------------------------------
R SD N P-------------------------------------------------------------0.98056 0.08826 35 <0.0001------------------------------------------------------------
ln(u
W/g
)
1/T(K)*10002.7 2.8 2.9 3.0 3.1 3.2
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Linear Regression for ph10scan_B:Y = A + B * X
Parameter Value Error------------------------------------------------------------A 26.25509 0.06499B -6.03829 0.0226------------------------------------------------------------
R SD N P-------------------------------------------------------------0.99982 0.00817 28 <0.0001------------------------------------------------------------
Linear Regression for ph10scan_B:Y = A + B * X
Parameter Value Error------------------------------------------------------------A 40.67733 1.19214B -10.71188 0.37892------------------------------------------------------------
R SD N P-------------------------------------------------------------0.99565 0.02975 9 <0.0001------------------------------------------------------------
ln(u
W/g
)
1/T(K)*1000
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingReaction in Solution: Solvent EffectReaction in Solution: Solvent Effect
Hydrolysis of Ester with NaOH at 25C
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
1.1
0 200 400 600 800 1000 1200time (sec)
Q/Q
tot
0% DMF4.8% DMF17% DMF
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingAPI Stability in PEG: Effect of BHTAPI Stability in PEG: Effect of BHT
Time/s0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000
0.0 0.0
35C 37.5C 40C 42.5C 45C
Red: API/PEG (no BHT) - Placebo
Blue: API/PEG (with BHT) - Placebo
Figure:29/10/2002 Mass (mg):715.8
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure: 35 37.5 40 42.5 45 3 hours each (Zone 2)
ExoExo
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingSolution Stability: Impact of PreservativeSolution Stability: Impact of Preservative
Effect of Preservative on Bacteria Growth
0
10
20
30
40
50
60
70
80
0 5 10 15 20 25 30 35 40
Time (hours)
Ther
mal A
ctivit
y (uJ
oules
/sec)
Biological Solution
Biological Solution + Propyl Gallate
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingSolid State Stability: RealSolid State Stability: Real--time Monitoring of Polymorph Conversiontime Monitoring of Polymorph Conversion
Time/h2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 14.5
-0.4
-0.2
-0.0
0.2
0.4
HeatFlow/mW
-0.4
-0.2
-0.0
0.2
0.4Blue:Sample= .5g aluminaReference= steel cell
Black:Sample= 472.9 mg form 1Reference= steel cell
Red:Sample= 460.0 mg form I Reference= steel cell
Thermal Activity
60C 70C 80C
89C
Figure: 22/10/2002 Mass (mg):472.9
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure:
ExoExo
Blank
Thermal disturbances caused by temperature
ramping
Time/h2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 14.5
HeatFlow/mW
-0.4
-0.2
-0.0
0.2
0.4
-0.4
-0.2
-0.0
0.2
0.4
Blue:Sample= .5g aluminaReference= steel cell
Red:Sample= 352.7mg form II Reference= steel cell
Black:Sample= 410.6 mg Reference= steel cell
80C 60C 70C 89C
Thermal Activity
Figure: 23/10/2002
Crucible: Standard HastelloyAtmosphere:AirExperimentation: Procedure:
Exo Exo
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingSolid State Stability: RealSolid State Stability: Real--time Monitoring of Polymorph Conversiontime Monitoring of Polymorph Conversion
Time/h2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 14.5
-0.4
-0.2
-0.0
0.2
0.4
HeatFlow/mW
-0.4
-0.2
-0.0
0.2
0.4Blue:Sample= .5g aluminaReference= steel cell
Black:Sample= 472.9 mg form 1Reference= steel cell
Red:Sample= 460.0 mg form I Reference= steel cell
Thermal Activity
60C 70C 80C
89C
Figure: 22/10/2002 Mass (mg):472.9
Crucible: Standard HastelloyAtmosphere:AirExperimentation: Procedure:
ExoExo
Blank
Time/h2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5 14.5
Heat Flow - 2 - red3 970011 isotherms at 50,60,70,80,89/mW
-0.4
-0.2
-0.0
0.2
0.4
-0.4
-0.2
-0.0
0.2
0.4Blue:Sample= .5g aluminaReference= steel cellBlack:Sample= 338.5 mg mixedReference= steel cellRed:Sample= 520.2 mg mixed Reference= steel cell
Thermal Activity
Figure: 24/10/2002 Mass (mg):409.4
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure:
Exo
338.5mg
520.2mg
Blank
60C 70C80C
89C
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingProtein Stability: Impact of StabilizerProtein Stability: Impact of Stabilizer
Furnace temperature /°C30 35 40 45 50 55 60 65 70 75 80
HeatFlow/mW
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8 Peak 1 :66.6557 °CPeak 2 :70.9494 °COnset Point :61.7528 °C Enthalpy /J : 0.0378 (Endothermic effect) (0.0562 + -0.0185)
Peak 1 :67.2049 °C Peak 2 :73.3009 °C Onset Point :62.2572 °C Enthalpy /J : 0.0331 (Endothermic effect) (0.0549 + -0.0217)
1 % BSA
1% BSA + 4% Manitol
Figure:17/06/2002 Mass (mg):0
Crucible: batch Atmosphere:AirExperimentation:1% BSA Procedure: BSA scan 22 to 90 (Zone 2)
Exo
Exo
∆G = ∆ H - T ∆ S
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingSolid State Stability: Influence of HumiditySolid State Stability: Influence of Humidity
Time/h0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
HeatFlow/mW
0.0
0.5
1.0
1.5
0.0
0.5
1.0
1.5
Red: Lot AGreen: Lot BBlue: Lot C1.4 hr
4.7 hr
2.4 hr
Figure:14/01/2003 Mass (mg):599.6
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure:
Exo
Exo
Exo
∆G = ∆ H - T ∆ S
Microcalorimetry: Compatibility TestingMicrocalorimetry: Compatibility TestingGeneral ConceptGeneral Concept
+Time ---> TA of API q1
+Time ---> TA of Excipient q2
+Time ---> TA of Mix qmix
qmix = x1q1 + x2q2 ?
∆G = ∆ H - T ∆ S
Microcalorimetry: Compatibility TestingMicrocalorimetry: Compatibility TestingHSDSCHSDSC
Furnace temperature /°C20 40 60 80 100
HeatFlow/mW
-16
-14
-12
-10
-8
-6
-4
-2
-16
-14
-12
-10
-8
-6
-4
-2
114 C
Red: Placebo
Blue: API
Black: Formulation
Figure:01/03/2003 Mass (mg):500.2
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure: scan 15C to 119C (Zone 4)
Exo Exo
Exo Exo
∆G = ∆ H - T ∆ S
Microcalorimetry: Compatibility TestingMicrocalorimetry: Compatibility TestingHSDSCHSDSC
Furnace temperature /°C30 40 50 60 70 80 90
-16
-14
-12
-10
-8
-6
-4
-2
0
-0.8
-0.6
-0.4
-0.2
-0.0
0.2
0.4
Formulation
Amorphous
Figure:15/01/2003 Mass (mg):26.2
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure: scan 15-119 (Zone 7)
ExoExo
∆G = ∆ H - T ∆ S
Microcalorimetry: Compatibility TestingMicrocalorimetry: Compatibility TestingIsothermal Thermal ActivityIsothermal Thermal Activity
Time/h0 2 4 6 8 10 12 14 16 18
HeatFlow/mW
-0.5
-0.4
-0.3
-0.2
-0.1
-0.0
0.1
0.2
0.3
0.4
-0.5
-0.4
-0.3
-0.2
-0.1
-0.0
0.1
0.2
0.3
0.4
Red: placeboBlue: Salt Form ABlack: Salt Form B
Figure:12/11/2002 Mass (mg):599.4
Crucible: Standard HastelloyAtmosphere:AirExperimentation:Procedure: 50 60 70 3 hours each (Zone 2)
Exo Exo
Exo Exo
∆G = ∆ H - T ∆ S