Applying Microcalorimetry to Characterize the Stability Applying Microcalorimetry to Characterize the Stability and Compatibility of Pharmaceutical Systems and Compatibility of Pharmaceutical Systems Time/s 0 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 Hastelloy Atmosphere: Air Experimentation: 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
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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
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
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
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
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
Microcalorimetry: Stability TestingMicrocalorimetry: Stability TestingSolid State Stability: Influence of HumiditySolid State Stability: Influence of Humidity