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Collected ApplicationsThermal Analysis

PHARMACEUTICALS

METTLER TOLEDO Collected Applications TA PHARMACEUTICALS Page 1

Preface

Thermal Analysis (TA) is the term used to describe all the analytical techniques that measure the physicaland chemical properties of a sample as a function of temperature.

The potential applications of thermal analysis in the pharmaceutical industry are numerous on account ofthe different chemical-physical aspects of investigations. Amongst others these include method development,characterization and specification of active and inactive ingredients, safety analysis or routine analysis inquality control and stability studies.

This booklet describes applications of thermal analysis in the pharmaceutical industry with the help ofselected examples i.e. the possible uses of TA in the development of new pharmaceutical substances throughto the quality control of commercial products.

In particular we would like to thank Dr. Danièle Giron and Dr. Sabine Pfeffer (Novartis Pharma AG,previously TRD, Sandoz Pharma, Basle, Switzerland) for their expert assistance and support which contributedgreatly to the success of this booklet, and also to thank Dr. Thomas Gübeli for making facilities available inthe Chemical Development Department, Analytical Research, Sandoz Pharma, Basle, Switzerland.

We thank Professor Dr. P. C. Schmidt of the Department of Pharmaceutical Technology, Eberhard-Karls-University Tübingen, Germany for preparing numerous application examples.

In addition we would like to thank all the other people who were involved in the preparation of this bookletincluding Helga Judex who was responsible for the layout.

Elisabeth Schwarz, Basle Dr. Jürgen de Buhr, Schwerzenbach

This application booklet presents selected application examples. These have been tested with the utmost care using theanalytical instruments mentioned in the booklet. The experiments were conducted and the resulting data evaluated accordingto the current state of our knowledge.

The application booklet does not however absolve you from personally testing the suitability of the examples for your ownmethods, instruments and purposes. As the use and transfer of an application example are beyond our control, we cannotaccept any responsibility.

When chemicals and solvents are used, the safety rules and instructions of the manufacturer must be observed.

® ™ All names of commercial products can be registered trade marks even if they are not denoted as such.

PHARMACEUTICALS METTLER TOLEDO Collected Applications TA

Content

Preface .......................................................................................................................................................... 1

Introduction to Thermal Analysis ................................................................................................................. 4

Application Overview Pharmaceuticals ....................................................................................................... 8

Some Comments on the Pharmaceutical Industry ........................................................................................ 9

Applications of Thermal Analysis in the Pharmaceutical Industry ............................................................ 10

Applications and Techniques ...................................................................................................................... 15

1. Sample Preparation and Method Choice1 DSC Calibration, Temperature and Heat flow ....................................................................................16

2 TGA Calibration, Temperature ........................................................................................................... 18

3 DSC Calibration, Heating Rate Independence....................................................................................20

4 The Influence of Heating Rate on the Detection of Polymorphism, Butylated Hydroxyanisole........ 22

5 Influences on Crystallization Behavior, Saccharose Solutions ........................................................... 24

6 Influence of the Heating Rate on Moisture Content Determination, an O/W Cream ......................... 26

7 Influence of the Heating Rate on Decomposition, Metolazone .......................................................... 27

8 Influence of the Pan on Dehydration, Glucose Monohydrate ............................................................. 29

9 Sample Preparation, Butylated Hydroxyanisole ................................................................................. 31

10 Influence of the Sample Weight, Butylated Hydroxytoluene ............................................................. 32

11 Influence of the Pan on the Determination of Moisture Content, Cellulose ....................................... 33

12 Sample Storage and Hygroscopic Effects ........................................................................................... 35

13 Oxidation Stability of Oils .................................................................................................................. 36

14 Influence of Thermal History and the Evaluation of the Glass Transition, Polystyrene..................... 38

2. Identification and Characterization15 Melting Point Determination, Vanillin ................................................................................................ 40

16 Characterization of the Melting Behavior, Vanillin ............................................................................ 41

17 Phase Changes, Cholesteryl Myristate ................................................................................................ 42

18 Identification Based on Melting Behavior, Polyethylene Glycol........................................................ 44

19 Melting Point Depression of Water, Sugar Solutions.......................................................................... 46

20 DSC 'Fingerprint', O/W Cream ........................................................................................................... 47

21 Glass Transition, Poly (D,L-lactide)-Co-Glycolide (DLPLGGLU) ................................................... 48

22 Glass Transition and Moisture Content, Hydroxypropoxymethylcellulose Phthalate (HPMC-PH) .. 49

23 Quality Control, PE Films................................................................................................................... 51


3. Stability24 Decomposition, Hydrocortisone ......................................................................................................... 53

25 Decomposition at the Melting Point, Dihydroergotamine Mesylate .................................................. 54

26 Melting Behavior and Decomposition, Aspartame ............................................................................. 56

27 Total Decomposition, Malonic Acid ................................................................................................... 58

28 Kinetic Analysis of Decomposition, ................................................................................................... 59

29 Hydrate Stability, Theophylline .......................................................................................................... 61

30 Moisture, Starch/NaCMC (Primojel) .................................................................................................. 63

4. Polymorphism31 Polymorphism, Tripalmitin ................................................................................................................. 65

32 Polymorphism, Tolbutamide ............................................................................................................... 66

33 Polymorphic Modifications by Annealing, Butylated Hydroxyanisole .............................................. 68

34 DSC 'Fingerprint', Magnesium Stearate.............................................................................................. 70

35 Polymorphism, L-Polylactide ............................................................................................................. 71

36 Polymorphism, Sulfapyridine ............................................................................................................. 73

5. Pseudopolymorphism37 Pseudopolymorphism, Glucose Monohydrate .................................................................................... 75

6. Enantiomers38 Optical Purity, Ibuprofen..................................................................................................................... 77

7. Purity39 Purity using DSC and HPLC, 4-Hydroxybenzoic Acid and its Esters................................................ 79

40 Purity Determination, Phenacetin + 4-Aminobenzoic Acid ............................................................... 81

41 Purity and Recrystallization, Cholesterol ........................................................................................... 83

8. Phase Diagrams42 Phase Diagram, Tolbutamide and PEG 6000 ......................................................................................84

43 Eutectic Composition, Methyl-4-Hydroxybenzoate and 4-Hydroxybenzoic Acid ............................. 86

9. Quantification/Detection44 Solvent Detection by means of TG-MS, Pharmaceutically Active Substance .................................... 88

45 Quantification, O/W Creams with Different Water Content ............................................................... 90

46 Quantification,Theophylline Monohydrate ......................................................................................... 92

47 Determination of an Active Substance, Alcacyl .................................................................................. 94

Literature .................................................................................................................................................... 96

Index ........................................................................................................................................................... 98

Notes ......................................................................................................................................................... 100


1 DSC Calibration, Temperature and Heat flow

Sample Indium (calibration standard, purity > 99.999 %)

Application Standard for calibration

Conditions Measuring cell: DSC821e

Pan: Aluminum 40µl, with pierced lid

Sample preparation: Indium pellet, pressed flat , premelted

DSC measurement: Heating from 120°C to 180°C at 10 K/min

Atmosphere: Nitrogen, 50 cm3/min

Interpretation The DSC curve shows the melting of indium. A pure substance melts at an exactly definedtemperature, its melting point. The melting point is taken to be the start or onset of themelting process which is defined as the temperature given by the intercept of the extrapolatedslope of the melting curve and the continuation of the base line.

Evaluation The onset temperature and the heat of fusion of indium are determined. The fully automatedevaluation performs a validation which compares the measured values with literature values.If, as in this case, the values lie within the allowed limits then the message ‘The DSC moduleis within specifications’ is displayed.

Measured Ref. value Tolerance

Melting point (onset) 156.75 156.60 ± 0.3 ° C

Heat of fusion 28.42 28.45 ± 0.6 J/g


Conclusion The so-called indium-check is a quick and easy method to check the temperature and heatflow calibration of an instrument. The results are automatically compared with referencevalues. The instrument displays the appropriate message if an adjustment of the instrumentis required.

If the instrument is frequently used in other temperature ranges, then further checks withadditional standards suitable for those temperature ranges are recommended.

The tolerances given in this example are standard values and can be individually adapted.


2 TGA Calibration, Temperature

Samples Indium and aluminum (calibration standards, purity > 99.999 %)

Application Standards for temperature calibration

Conditions Measuring cell: TGA850

Pan: Alumina 70 µl

Sample preparation: Two indium pellets, one piece of aluminum wire. The metals arepressed flat. Weight of each sample approx. 12 mg. The pure metalsare put in the pan well separated from each other.

TGA measurement: Heating from 100°C to 200°C at 10 K/min, from 200°C to600°C at 50 K/min, from 600°C to 700°C at 10 K/min (indium-aluminium check).


Interpretation The SDTA signal shows the melting of both metals. The automatic evaluation determinesthe melting points (onsets) of both metals and compares them with the reference values. Ifthe deviations are too large then the appropriate message is displayed. In this example theresults lie within the specifications. The two peaks at 230°C and 600°C are caused by thechange of heating rate.

The weight curve is not shown because no effects would be observed.


Evaluation Determination of the melting points (onsets) of indium and aluminum using theSDTA curve.

Indium Aluminum

measured Ref. value measured Ref. value

Melting point 1) 156.5 156.6± 1 660.3 660.3± 1.5 ° C

Melting point 2) 156.7 156.6± 2 660.4 660.3± 3 ° C

1) based on the thermocouple of the sample holder (sample temperature)2) based on the thermocouple of the furnace (abscissa unit)

Conclusion The so called indium-aluminium check is a quick and easy method to check the temperaturecalibration of the thermobalance. If the measured values lie outside the given tolerances,then the settings can be adjusted. If the thermobalance (as in the case of the TGA850 orTGA/SDTA851e) is equipped with a suitable sample temperature sensor, then the check isperformed using the melting of known standards. Otherwise the method using the Curiepoint transition temperatures of different metals is used.

A special weight calibration is not usually be performed, because many balances alreadyhave an automatic internal test procedure available. A certified weight can be weighed atdefined intervals. For GMP investigations the use of reference materials to check the weightcalibration is recommended e.g. calcium oxalate monohydrate (Pharma Eur. 1997).


3 DSC Calibration, Heating Rate Independence

Sample Zinc (calibration standard, purity > 99.999 %)

Application Standard for calibration

Conditions Measuring cell: DSC821e

Pan: Alumina 40µl, with pierced lid

Sample preparation: Zinc pellet, pressed flat and premelted

DSC measurement: Heating from 350°C to 475°C at 5, 10 and 20 K/min. Allmeasurements are performed with the same sample. Cooling rateis 5 K/min.


Interpretation The DSC curves show the melting of zinc at different heating rates. If displayed with respectto temperature, the peak area increases with increasing heating rates. The heat of fusion ishowever the integral of the heat flow with respect to time. This is just as independent of theheating rate as the melting point.

Evaluation The onset temperature and the heat of fusion of zinc are determined.

Measured Measured Measured Ref. value

Heating rate 5 10 20 K/min

Melting point (onset) 419.5 419.6 419.8 419.7 ° C

Heat of fusion 107.0 107.0 107.1 107.0 J/g


Conclusion The calibration data of an instrument are affected by many factors such as the heating rate,the purge gas used, the sample pan material and the temperature range used. Only whenthese effects can be taken into account in the calibration data, are results obtained that areindependent of measurement parameters, as is shown in this example of the melting pointand the heat of fusion.


5 Influences on Crystallization Behavior, SaccharoseSolutions

Sample D(+) Saccharose solution,20 weight % in water (= 1.05 mole %)

Application Inactive ingredient (solution stabilizer)

Conditions Measuring cell: DSC820

Pan: Aluminum 40µl, hermetically sealed

Sample preparation: One drop of solution is weighed into the pan using a fine pipette,sample weight 2.260 mg.

DSC measurement: Cooling from 25°C to -50°C at -1, -2, -5, -10, -20 K/min. Thesame sample is used for all the measurements. Heating from-50 °C to 25°C at 5 K/min.


Interpretation The curves show that crystallization and melting processes can be measured with the DSC.At low cooling rates, the onset temperatures are almost constant, but are displaced to lowervalues (supercooling) at higher cooling rates. At very high cooling rates it is even possiblethat the solution does not crystallize but vitrifies i.e. is transformed to glassy state.

The melting point depression and the ‘purity’ of the water can be calculated from the meltingpeak.

O

CH2OH

OH

OH

OHO

CH2OH

OOH

CH2OHOH


Evaluation Cooling rate (K/min) Onset, °C ∆H, J/g Effect

-1 -15.0 173.2 crystallization

-1 -15.3 168.3 ‘

-5 -15.8 162.5 ‘

-10 -15.3 170.0 ‘

-20 -23.0 157.3 ‘

+5 -3.8 153.5 melting

Purity calculated using theMelting peak: 99.02 mole % (theoretical value: 98.95)Melting point depression: -1.76°C

Conclusion The onset temperatures of the melting and crystallization processes are different. Crystalli-zation processes are controlled kinetically by nucleation and are dependent on the coolingrate and the amount of sample (number of nuclei present). The onset temperatures of meltingpeaks are not normally subject to disturbing influences.


6 Influence of the Heating Rate on Moisture ContentDetermination, an O/W Cream

Sample O/W Cream sample 647-A

Application Basic material for the manufacture of creams

Conditions Measuring cell: TGA850

Pan: Aluminum 100µl, with pierced lid. The lid was automaticallypierced shortly before the measurement (sample changer withneedle, 1 mm diameter)

Sample preparation: As received, no preparation

TGA measurement: Heating from 20°C to 200°C at 2 and 5 K/min. Bothmeasurements are blank curve corrected.


Interpretation The TGA curves show the evaporation of the volatile components (mainly water) in theregion between 40°C and 140°C. At higher heating rates the evaporation is diplaced tohigher temperatures. The first derivative of the TGA curve is helpful for the determinationof the final step of the TGA signal.

Evaluation Heating rate Step, % Peak temperature DTG, °C2 K/min 59.4 102.15 K/min 58.5 122.4

Conclusion The influence of the mass and form of the sample, the heating rate and the type of pan haveto be considered when developing methods. The heating rate is of special importance wheninvestigating time and temperature dependent effects such as evaporation.


Interpretation A comparison of the two DSC curves of α-D-Glucose monohydrate shows the changes thatarise when the sample is measured in a sealed pan or in a pan with a pierced lid. In ahermetically sealed pan the sharp melting peak of the monohydrate can be observed. If apan with a pierced lid is used, the water of crystallization can escape. This is noticeable as ashift of the DSC curve at the beginning of the measurement and as a broad evaporationpeak. At the same time, a transition to β-D-Glucose anhydrate occurs, the melting point ofwhich is at about 158°C. Above 200°C the glucose starts to caramelize.

Evaluation DSC Measuring conditions Onset, °C EffectSealed pan 81.4 melting

Pan with pierced lid 157.4 melting

8 Influence of the Pan on Dehydration,Glucose Monohydrate

Sample α-D-Glucose monohydrate

Application Inactive ingredient, filler for tablets and capsules

Conditions Measuring cells: DSC820 or TGA850

Pan DSC: Aluminum 40 µl, hermetically sealed or with pierced lid

Pan TGA: Aluminum 100 µl, with pierced lid


DSC measurement: Heating from 30°C to 250°C at 20 K/min

TGA measurement: Heating from 30°C to 300°C at 20 K/min

Atmosphere: Nitrogen; DSC: 50 cm3/min, TGA: 80 cm3/min

O

OH

OH

CH2OH

OHOH

• H2O


Interpretation Thermogravimetric measurements using a pan with a pierced lid confirm the interpretationof the results obtained from the DSC curves, in particular the weight loss caused by theevaporation of the water of crystallization as well as the melting of the β-D-Glucose anhydrateafterwards. The weight loss step of 7% between 53°C and 134°C is somewhat less thanthat expected stoichiometrically. It can be explained however by a loss of water ofcrystallization during storage of the sample.

Evaluation TGA Temperature, °C EffectTGA, step 53-134 7.0% weight loss (water of crystallization)

SDTA, onset 59 endothermic peaks

SDTA, onset 154.2 melting peak

Conclusion A substance that contains water of crystallization and its anhydrous form normally havedifferent melting points (pseudopolymorphism). The melting point of the form containingthe water of crystallization can be determined in a hermetically sealed pan, provided that nodecomposition occurs. In an open pan the water of crystallization can escape so that themelting point of the anhydrous form is measured. The presence of a form with water ofcrystallization should always be confirmed by measuring the weight loss.


9 Sample Preparation, Butylated Hydroxyanisole

Sample Butylated hydroxyanisole

Application Inactive ingredient (antioxidant)

Conditions Measuring cell: DSC820


Sample preparation: As received (1) or crystals ground in a mortar (2)

DSC measurement: Heating from 30°C to 70°C at 2.5 K/min


Interpretation The two curves show the effects that sample preparation can have on the results. In bothcases, two melting peaks can be observed that differ noticeably in temperature range and inthe heats of fusion. The explanation lies in the polymorphic behavior of butylatedhydroxyanisole. The two peaks correspond to the possible crystal modifications.

Evaluation Sample preparation Onset 1, ° C ∆H, J/g Onset 2, ° C ∆H, J/g

as received 59.3 78.2 63.3 27.6

ground in a mortar 55.1 96.8 61.7 1.7

Conclusion A difference in sample preparation (especially mechanical treatment) can lead to differentresults. This is particularly the case with substances that exhibit polymorphism.

OHH3CO

C(CH3)3


10 Influence of the Sample Weight,Butylated Hydroxytoluene

Sample Butylated hydroxytoluene

Application Inactive ingredient (antioxidant)

Conditions Measuring cell: DSC821e with IntraCooler



DSC measurement: Heating from 50°C to 80°C at 2.5 K/min

Atmosphere: Air, stationary environment, no flow

Interpretation The curves show the melting peaks as a function of sample weight. As expected, the peaksin the original presentation (ordinate in mW) increase in height but also in width withincreasing weight. Because of this the resolution decreases. In contrast, the normalizedpresentation shows that the lowest sample weight gives the highest peaks.

Evaluation The onset temperature and heat of fusion of the peaks are determined. The mean values ofa number of measurements are presented in the table.

Sample weight Onset, ° C Heat of fusion ∆H, J/g

18 ± 0.3 mg 69.4 ± 0.1 85.6, 84.7, 85.6

8.5 ± 0.3 mg 69.6 ± 0.1 83.9, 84.5

4.0 ± 0.4 mg 69.5 ± 0.1 82.6, 84.1, 83.6

Conclusion The sample weight influences the shape of the melting peak. The time required for meltingis longer for larger samples because a greater amount of heat has to be transferred. As aresult of this, the peaks are shifted to higher temperature. For comparison purposes, themeasurement of samples of similar weight is recommended. Samples that are too large aredisadvantageous: the peaks become broad (lower resolution) and non-uniform melting leadsto irregularly shaped peaks.

C(CH3)3

OH

C(CH3)3

H3C


11 Influence of the Pan on the Determination of MoistureContent, Cellulose

Sample Microcrystalline Cellulose (Avicel)

Application Inactive ingredient (gel binder, adsorption agent, flow improver)

Conditions Measuring cell: TGA850 with sample robot

Pan: Aluminum 100µl, without a lid or with a pierced lid. The lid waspierced automatically immediately before the measurement (needlediameter 1 mm).


TGA measurement: Heating from 30°C to 300°C at 20 K/min, all measurements areblank curve corrected.


O

OH

HOH2C

HOHO

OO

OO

OO

HOH2C

OH

HO

HO

HOH2C

OH

OH

HOH2C

HOOH

n

Interpretation Cellulose and its derivatives easily take up water from the surroundings or release waterdepending on the humidity in the laboratory.


At the same heating rate, the release of moisture during the measurement occurs morerapidly if no lid is used than with a pierced lid. This has to be taken into account whencomparing methods using open pans to methods in which pierced lids are used (samplechanger operation). Samples which are in open pans on the sample changer turntable canlose moisture because of the relatively low humidity of the surroundings. The true moisturecontent of samples can be determined using sealed pans whose lids are pierced immediatelybefore the measurement.

Evaluation Pan Step, % Initial value of the curve Correctedsample weight *, % step, %

Sealed, lid pierced immediately -4.8 99.9 -4.9before the measurement

Without lid -4.1 99.1 -5.0

* Original sample weight = 100%

Conclusion The possible effect of the delay between the weighing out and the actual measurement ofthe sample must be investigated when determining the moisture content with TGA. Whenusing pans with pierced lids, the smaller the hole in the lid the more the weight loss step isshifted to higher temperature.

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