News & Trends for Thermal Analysis

Vietnam, October 2016

Võ Đình Vũ

Pharma Applications and Theory

TA-TechniquesDSC, Flash DSC, HPDSC TGA

TMA DMA

Agenda

� Compatibility and Interactions

- Eutectic Systems

- Compatible/Incompatible Mixtures

� Shelf life prediction

- Decomposition dynamics

- Kinetics of shelf life

� Overview

- Polymorphism

- Purity

- Sorption/Desorption

- Packaging material

4Interaction and compatibility

�The interaction between two or more components of a pharmaceutical preparation can be desirable or undesirable.

�Desirable interactions are purposely brought about in order to improve the solubility of an active ingredient.

�Undesirable interactions, i.e. incompatibility, can bring about a loss of activity or even a complete deactivation of a preparation. Even toxic decomposition products can be produced in the most unfavorable cases.

Are you interested in the study of compatibility between the active pharmaceutical ingredient and the excipient in the formulation?

5Interaction and compatibility

Principle:

�Pharmaceutical preparations can be investigated by DSC or TGA by comparing the results for the individual components and the mixture with each other.

� If the mixture exhibits thermal effects that are not apparent in the individual components, which indicates of an interaction.

�A eutectic system, however, shows thermal changes which are not caused by incompatibility.

� In real situation, the exposure of drug-excipient mixture to high temperatures is not experienced by the dosage form, therefore, the results should be interpreted carefully together with other test results e.g. Isothermal stress testing (IST)

Phase Diagram

Binary phase diagram

Example A: Benzoic acid

B: Dimethylter-ephthalate

T

xB0 1

liquid solution

crystals A+ liquid

crystals B+ liquid

crystals A + crystals B

T0A

T0B

solidus line

liquidus line

Phase Diagram

Binary phase diagram

DMT:Dimethyltereph-thalate

Benzoic acid

Eutectic mixture: 28 mol% DMT

Onset 122.00 °C

Onset 140.61 °C

Pure DMT

Pure benzoic acid

89 % BA

48 % BA

62 % BA

13 % BA

7 % BA

4 % BA

Onset 97.44 °C

Onset 97.49 °C

Onset 97.37 °C

Onset 97.53 °C

Onset 97.56 °C

Onset 97.38 °C

mW

50

°C90 100 110 120 130 140 150

exoexoexoexo Pharma: DMT/benzoic acidPharma: DMT/benzoic acidPharma: DMT/benzoic acidPharma: DMT/benzoic acid 21.11.2002 15:21:0921.11.2002 15:21:0921.11.2002 15:21:0921.11.2002 15:21:09

TA MSG31: R. RiesenTA MSG31: R. RiesenTA MSG31: R. RiesenTA MSG31: R. Riesen System System System SystemeeeeRRRRTATATATAMETTLER TOLEDO SMETTLER TOLEDO SMETTLER TOLEDO SMETTLER TOLEDO S

Phase Diagram

Binary phase diagram

DMT:Dimethyltereph-thalate

Benzoic acid

Eutectic mixture: 28 mol% DMT

9

0.26*!&Avicel 2nd+0.74*!&Aspirin

Nitrogen

73.7% ASA

Integral -808.92 mJ normalized -124.97 Jg^-1Onset 137.93 °C

Integral -1044.51 mJ normalized -169.45 Jg^-1Onset 138.07 °C

Aspirin/Avicel2, 6.4730 mgMixture

2. Heating

1. Heating

Aspirin, 6.1640 mgpure ASA

Aspirin 1000mg : Avicel 268mg

Sample Holder: Aluminum Standard 40ulwith pierced lid

Method: D 25...300/5 al std air 25.0-300.0°C 5.00°C/min

Avicel pure pH 1026.301 mg

Wg^-12

°C40 60 80 100 120 140 160 180 200 220 240 260 280

Acetyl salicylic acid

Avicel® PH:

microcrystalline cellulose, inactive excipient for direct compression formulations, lending superior compatibility and carrying capacity to tablets.

Interaction and compatibility

Compatibility between acetyl salicylic acid & Avicel

Interaction and compatibility

Interaction and compatibility

The mixture shows only one melting peak at much low er temperature compared to the pure components, indicates incompatibility d ue to strong interactions.

12Shelf Life

�Acetylsalicylic acid:

used to relieve pain and reduce fever and inflammation.

Are you interested in a rapid method to determine the shelf life of your products?

n-th Order Kinetics

Single dynamic measurement

Calculation of kinetic parameters k0, E and n from one single dynamic measurement with multiple linear regression (nth order kinetics):

Multiple dynamic measurements

The so called iso-conversional methods are based on several measurements using different heating rates.

Kissinger, Ozawa (ASTM E698) use the temperature of the peak maximum, Flynn-Wall (ASTM E1641).

)1(ed

d n/0 αα −= − RTEk

t

13Kinetics/Reaction Dynamics

n-th Order Kinetics

???

� autocatalytic reactions� competing, consecutive

reactions� diffusion, …

AB

C

A B C A B C+

14Kinetics/Reaction Dynamics

complex reactions

� Large number of parameters

� Practical no differences between differnt models

� The apparent activation energy is a function of conversion

∑=

⋅=q

ppp Tkf

t 1

)()(d

d αα

( )( )( )[ ]

( ) ( )( )etc.

1ln1)(112/3)(

1ln)()1()(

/)1(

13/1

1

nn

n

nff

ff

−

−−

−

−−−=−−=

−−=−=

ααααα

αααα

alternatively:

“Model Free” reaction dynamic

no explicit model functions have to be assumed

15Kinetics/Reaction Dynamics

Reaction Dynamic – „Model Free Kinetics“

� Isoconversional method reaction rate at a certain conversion = f(T)

� Use of Arrhenius temperature function

� Complex chemical reactions (e.g. with transport phenomena) show an activation energy that depends on the conversion

The resulting activation energy as a function of conversion is the basis of predictions

16Kinetics/Reaction Dynamics

Model Free Kinetics

Separation of the variables in the rate equation and integration with respect to t delivers g(α):

∫=∫==αα

ααααα t

0t0

tdk'd)'(f

1)(g )(f)T(ktd

d

Insertion of Arrhenius equation and of the definition of β:

TdRT

)(Eexp

k)(g

T

0

0 ∫

−=α α

βα

g(α) is assumed to be independent of β. Based on several experiments with different heating rates βi one finally has to solve numerically (Vyazovkin):

)T,E(Ik

...)T,E(Ik

)T,E(Ik

)(gn21 ,

n

0,

2

0,

1

0βααβααβαα βββ

α ====

I(Eα,Tα,β )

17Kinetics/Reaction Dynamics

Shelf Life - Stability

Decomposition kinetics

Acetylsalicylic acid:

TGA measurementfor kinetic purpose

TGA Curves

DTG Curves

1 K/min, 2.965 mg

2 K/min, 3.111 mg

5 K/min, 3.068 mg

10 K/min, 2.977 mg

mg

1

mg°C^-1

-0.04

-0.02

0.00

°C50 100 150 200 250

SDTA Curves

°C

2

exoexoexoexo Pharma: Acetylsalicylic AcidPharma: Acetylsalicylic AcidPharma: Acetylsalicylic AcidPharma: Acetylsalicylic Acid 21.11.2002 10:29:5421.11.2002 10:29:5421.11.2002 10:29:5421.11.2002 10:29:54

TA MSG31: R. RiesenTA MSG31: R. RiesenTA MSG31: R. RiesenTA MSG31: R. Riesen System System System SystemeeeeRRRRTATATATAMETTLER TOLEDO SMETTLER TOLEDO SMETTLER TOLEDO SMETTLER TOLEDO S

Stability

Storage conditions

Acetylsalicylic acid:

Model free kinetics for stability predictions

%

0

50

°C100 150 200

Conversion Curves

Activation EnergykJmol^-1

100

120

%50

Applied Kinetics: Iso-Conversion[°C] 1 % 2 % 10e+03 h 15.25 25.28 20e+03 h 10.62 20.72 30e+03 h 7.98 18.12

alpha(5%)

alpha(3%)alpha(2%)

alpha(1%)h

0

10000

20000

30000

°C0 20 40

Pharma: Kinetics, PredictionPharma: Kinetics, PredictionPharma: Kinetics, PredictionPharma: Kinetics, Prediction 21.11.2002 11:13:3021.11.2002 11:13:3021.11.2002 11:13:3021.11.2002 11:13:30

TA MSG31: R. RiesenTA MSG31: R. RiesenTA MSG31: R. RiesenTA MSG31: R. Riesen System System System SystemeeeeRRRRTATATATAMETTLER TOLEDO SMETTLER TOLEDO SMETTLER TOLEDO SMETTLER TOLEDO S

Agenda

� Compatibility and Interactions

- Eutectic Systems

- Compatible/Incompatible Mixtures

� Shelf life prediction

- Decomposition dynamics

- Kinetics of shelf life

� Overview

- Identification/Polymorphism

- Purity

- Decompostion

- Sorption/Desorption

- Packaging material

IdentificationPurity

DSC Purity:

Melting pointdepression

Van‘t Hoff

ASTM E928

Polymorphism

monotropictransition(exothermic)

liquid

high temperaturemodification (β)

low temperaturemodification (α)

liquid

stablemodification

metastablemodification

amorphous state

Enantiotropic Monotropic

metastablesolid state II

stable solidstate I

liquidstate

Tfus II Tfus I

Temperature

Vaporpressure

Polymorphism

Chlorpropamide:antidiabetic agent.

DSC is a simple and fast tool for detection of poly morphic transitions.

Polymorphism of Chlorpropamide

24

Cooled from 135 °C at 10 K/min and held isothermally at 80 °C.

Cooled from 135 °C at 10 K/min and held isothermally at 90 °C. Cooled from 135 °C at 10

K/min and held isothermally at 100 °C.

Crystallization of chlorpropamide

Polymorphism

Crystallization temperature ↑

� lower nucleation rate, less crystals

� higher crystal growth rate, bigger crystals

Hot-stage microscope enables visual observation of polymorphic transitions.

Polymorphism

Phase transitions

Thermo-microscopy,DSC

Sulfapyridine(amorphous, shock-cooled after melting)

Polymorphism

Phase transitions

L-Polylactic-acid (excipient)

A: melting metastab. mod.

B: crystallization

C: melting stab. modification

C

B

A

Integral -25.05 mJOnset 150.96 °CLeft Limit 135.90 °CRight Limit 161.81 °CLeft bl Limit 135.90 °CRight bl Limit 161.81 °CHeating Rate 10.00 °Cmin^-1Baseline Type Horiz. links

L-Polylactide1.0280 mg

Wg^-1

2

°C100 120 140 160 180 200

exoexoexoexo Pharma: L-PolylactidePharma: L-PolylactidePharma: L-PolylactidePharma: L-Polylactide 21.11.2002 15:54:2721.11.2002 15:54:2721.11.2002 15:54:2721.11.2002 15:54:27

TA MSG31: R. RiesenTA MSG31: R. RiesenTA MSG31: R. RiesenTA MSG31: R. Riesen System System System SystemeeeeRRRRTATATATAMETTLER TOLEDO SMETTLER TOLEDO SMETTLER TOLEDO SMETTLER TOLEDO S

27Polymorphism

Pseudopolymorphism of glucose

Glucose: inactive ingredient, filler for tablets and capsules

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