Thermal Analysis of Pharmaceuticals – Techniques and Applications
On Demand Webinar

Thermal Analysis of Pharmaceuticals

On Demand Webinar

Thermal analysis of pharmaceuticals presents various techniques for characterizing pharmaceuticals

Thermal analysis of pharmaceuticals
Thermal analysis of pharmaceuticals

Thermal Analysis is often used to investigate pharmaceutical substances. Polymorphism, pseudo-polymorphism, phase diagrams, stability, and purity determination can all be measured by thermal analysis.
The four main techniques of thermal analysis, DSC, TGA, TMA, and DMA are ideal for characterizing such substances. The chief advantage is that properties can be measured as a function of the temperature or time over a wide temperature range, from –150 to 1600 °C.

In this Webinar, we will show how thermal analysis is used to investigate pharmaceutical substances. We will present some typical examples measured by DSC, TGA, TMA or DMA.

39:30 min
English

The Webinar covers the following topics:

  • Introduction to thermal analysis
  • Relevant effects and properties
  • Instrumentation and applications
    - Differential Scanning Calorimetry (DSC)
    - Thermogravimetry (TGA)
    - Thermomechanical Analysis (TMA)
    - Dynamic Mechanical Analysis (DMA)
  • Summary

A number of interesting application examples, presented in the "Thermal Analysis of Pharmaceuticals" webinar, demonstrate the use of thermal analysis techniques in the pharmaceutical industry. These have to do with the measurement and testing of physical properties. Typical examples include the investigation of polymorphic transitions, decomposition behavior, loss of weight on drying, and many other applications.

Thermal analysis of pharmaceuticals – important applications
Thermal analysis is mainly used to investigate polymorphism and the melting behavior of crystalline materials, or to measure the glass transition of amorphous fractions. The determination of the purity of active pharmaceutical ingredients is often used in quality control.

Thermal analysis also provides information on the compatibility of excipients, shelf life, and thermal degradation.

The moisture content and influence of relative humidity can also be studied. The testing of primary and secondary packaging materials, coatings, and blister packages is another important field.

Important effects and properties measured by thermal analysis
The most important effects that can be analyzed by DSC are the melting point, melting range and melting behavior.

DSC is also used to determine the heat of fusion, purity, polymorphism, the glass transition, and oxidation stability.

The main applications of TGA are evaporation, desorption and vaporization behavior, thermal stability, decomposition kinetics, and the analysis of composition.

TOA or thermo-optical analysis is used to study the melting point, melting range and polymorphism using visual observation and video recording.

MP indicates the automatic detection of the melting point or melting range.

TMA is normally used to study the expansion or shrinkage of materials and the glass transition.

DMA is the most sensitive method for characterizing the glass transition of materials.

Thermal Analysis in the Field of Pharmaceuticals

Slide 0: Thermal Analysis in the Field of Pharmaceuticals

Ladies and Gentlemen,

Welcome to the METTLER TOLEDO webinar on “Thermal Analysis in the Field of Pharmaceuticals”.

 

During the course of the webinar, I would like to describe a number of interesting application examples that demonstrate the use of thermal analysis techniques in the pharmaceutical industry. These have to do with the measurement and testing of physical properties. Typical examples include the investigation of polymorphic transitions, decomposition behavior, loss of weight on drying, and many other applications that we will discuss later on.

 

Slide 1: Contents

The slide lists the topics I want to cover.

 

I will first discuss the most important effects and properties that can be investigated by thermal analysis in the pharmaceutical industry, and the techniques used to measure them.

The techniques include:

Differential Scanning Calorimetry, or DSC as it is usually called;

DSC-Microscopy and Hot-stage microscopy

Melting point instruments

Thermogravimetric Analysis, or TGA;

Thermomechanical Analysis, or TMA;

and Dynamic Mechanical Analysis, or DMA.

 

I will then present applications that illustrate the use of thermal analysis in the pharmaceutical industry and briefly discus 21-CFR-Part-11 regulations.

                                                            twenty-one see eff arr Part eleven

 

Finally, I will summarize the different thermal analysis techniques and their application fields and list a number of useful references for further information and reading.

 

Slide 2: Introduction

Typical questions that arise in connection with pharmaceutical substances are:

 

How can the same substance, for example paracetamol, exist in different crystalline forms in the solid state?   The leads us into the topic of polymorphism.

 

or,        Are you interested in the compatibility of the active pharmaceutical ingredient (API) with the excipient in the formulation?

 

or,        How does moisture influence the stability and shelf life of the formulation?

 

Slide 3: Applications Related to Pharmaceuticals

Thermal analysis has many potential applications and is used in practically all fields of the pharmaceutical industry.

An important advantage is that only a small amount of sample is needed to perform an analysis.

 

The table summarizes different applications. It shows that thermal analysis is mainly used to investigate polymorphism and the melting behavior of crystalline materials, or to measure the glass transition of amorphous fractions. The determination of the purity of active pharmaceutical ingredients is often used in quality control.

 

Thermal analysis also provides information on the compatibility of excipients, shelf life, and thermal degradation.

The moisture content and influence of relative humidity can also be studied. The testing of primary and secondary packaging materials, coatings, and blister packages is another important field.

 

Slide 4: Thermal Analysis

What is Thermal analysis?

The ICTAC definition of thermal analysis is:

“A group of techniques in which a physical property of a substance is measured as a function of temperature whilst the substance is subjected to a controlled temperature program”.

The schematic diagram on the right shows a typical linear temperature program.

 

The lower half of the slide illustrates typical events that occur when a substance is heated. For example, initial melting, in which the sample changes from the solid to the liquid state. If the sample is exposed to air or oxygen, it will start to oxidize and finally decompose.

 

We use thermal analysis techniques to investigate these effects.

 

Slide 5: Thermal Analysis

The slide shows the most important techniques used in thermal analysis to characterize pharmaceutical substances and compounds, namely:

 

Differential Scanning Calorimetry, or DSC. This is the most widely used thermal analysis technique. The picture shows a DSC sensor with a crucible containing a sample (colored red), and a reference crucible.

 

Thermogravimetric Analysis, or TGA. This technique measures the weight of the sample using a highly sensitive electronic balance.

 

Thermomechanical Analysis, or TMA, is used to measure dimensional changes of a sample.

The picture shows the sample support with a sample (colored red) and the quartz probe.

 

Dynamic Mechanical Analysis, or DMA, provides information on mechanical properties.

The picture shows one of the several different sample-clamping assemblies.

 

DSC-Microscopy and Hot-stage Microscopy. These are thermo-optical analysis techniques that use a microscope to observe samples while they are heated.

 

Melting Point Determination. Modern melting point instruments can not-only investigate melting behavior but also detect and record color changes, clear points and decomposition temperatures by means of video recording.

 

I will explain these techniques in more detail in the following slides and describe some application examples.

 

Slide 6: Differential Scanning Calorimetry (DSC)

Let’s begin with DSC. This technique allows us to determine the energy absorbed or released by a sample as it is heated or cooled.

 

The standard METTLER TOLEDO DSC 1 instrument measures from minus one hundred and fifty to plus seven hundred degrees Celsius at heating rates of up to three hundred Kelvin per minute. The samples are normally contained in small crucibles made of aluminum, alumina or other materials, and usually weigh one to ten milligrams.

 

The schematic diagram on the left shows the typical DSC measurement curve of a crystalline substance. Exothermic effects point in the upward direction and endothermic effects downward. The curve is plotted as heat flow in milliwatts versus temperature. The different effects are numbered next to the curve and explained in the table below.

These are:

One, the initial deflection or start-up transient of the DSC. This is proportional to the heat capacity of the sample;

Two, the evaporation of moisture;

Three, part of the curve where no thermal effects occur. It is often called the baseline and is proportional to the heat capacity.

Four, melting of the crystalline fraction; and finally

Five, the onset of exothermic oxidation in air.

 

Slide 7: Differential Scanning Calorimetry (DSC)

DSC is used to study the thermal behavior of substances and in particular physical transitions and chemical reactions. Most of the events involved are related to enthalpy changes caused by increasing or decreasing temperature.

 

The table summarizes the analytical applications used to characterize pharmaceutical substances.

The main applications have to do with melting and crystallization behavior, and polymorphism. DSC measurements also provide information about transition enthalpies and heat capacity.

Evaporation, the effect of impurities or additives on melting behavior, and chemical reactions are also important applications of DSC.

The picture on the right of the slide shows an open DSC furnace with sample and reference crucibles.

 

Slide 8: Application 1: DSC                                Purity and melting behavior

The first application illustrates the effect of an impurity on the melting behavior of a pharmaceutical substance.

The diagram displays the DSC melting curves of pure phenacetinand samples of phenacetin containing small amounts of para-aminobenzoic acid, written PABA for short.

The sharp, black curve is that of pure phenacetin. The melting peak becomes broader and shifts to lower temperature with increasing amounts of para-aminobenzoic acid, which acts as an impurity. At the same time, the eutectic peak at about hundred and thirteen degrees Celsius becomes larger.

Purity determination by DSC is based on the van’t Hoff equation, which states that the melting point depression is proportional to the mole fraction of the impurity.

The advantage of using DSC for purity determination is that only one measurement is needed to get a result. This is shown for the sample containing 0.7% impurity – the red curve in the diagram. The purity is calculated in mol% and printed in the results-block together with the temperature, T-Fusion, at which the very last crystals melt.

 

Slide 9: Application 2: DSC                                            Polymorphism

The second application shows how polymorphism can be studied by DSC.

 

Many pharmaceutical substances exhibit polymorphic behavior. A substance can exist in several different crystalline forms depending upon the recrystallization and processing conditions used to prepare it. DSC is an extremely useful technique for identifying and quantifying the different polymorphic forms of a substance.

A good way to detect polymorphism is to first shock-cool a molten sample to a temperature below the glass transition temperature. A heating run is then performed at a rather low heating rate. The procedure is demonstrated here using sulfapyridine as an example.

 

The effects that occur are labeled A to F on the heating curve shown in the diagram:

The first effect is the glass transition, A, of the amorphous substance.

On further heating at a low rate, the substance has to time to crystallize and produces the exothermic peak, B.

According to the Ostwald rule, the metastable phase crystallizes out first. This phase may undergo transformation to another form via a solid-solid transition, indicated by C.

This form then melts at D. If there is enough time, it crystallizes to the stable form at E and finally melts giving rise to the large endothermic peak at F.

 

Slide 10: Application 3: DSC                                          Content determination

This application shows an example of content determination - in this case, the determination of the polymorphic Form II in Form I, of a glyburide drug sample.

(Speaker: for Form I: say Form one and for Form II: say Form two)

 

The main diagram on the left displays DSC heating curves of samples of Form 1 doped with different amounts of Form II. The areas under the small peaks due to Form II were integrated and the results plotted in the upper inserted graph. The response was linear in the range one (1) to seven-point-five (7.5) weight percent.

The red curve in the lower inserted graph displays the melting curve of a sample of Form I containing about 7% of glyburide Form II on a different scale.

 

The detection limit for Form II was found to be about 1.0%

The detection and separation of such low concentrations of polymorphic forms requires an instrument of high sensitivity, high resolution and a very flat and stable baseline. The DSC with the FRS5 detector is an excellent choice for this purpose.

 

Slide 11: Application 4: DSC                                                      Compatibility

In the pharmaceutical industry, the next step after the development of a new drug substance is the formulation of a drug product. The potential physical and chemical interactions between drugs and excipients can affect the chemical nature, the stability, and bioavailability of drugs.

DSC is an important method in preformulation studies to quickly obtain information about interactions between different constituents of a formulation. If the melting behavior of an active pharmaceutical ingredient in an excipient remains unchanged, and if the enthalpy of melting corresponds to that expected from the concentration of the substance, then the two substances are assumed to be compatible.

 

This is illustrated in the case of irbesartan and lactose monohydrate. The DSC heating runs display the endothermic melting curves of pure irbesartan (top), pure lactose (middle) and a 50/50 mixture of irbesartan and lactose (bottom). Pure irbesartan exhibits a melting peak at about one hundred and eighty-five degrees Celsius (185 °C), and pure lactose monohydrate a peak at about one hundred and forty six degrees, which is related to the evaporation of water.

It can be seen that the melting peak of irbesartan in the mixture shows no significant change or shift due to the presence of lactose. This indicates that irbesartan is compatible with lactose monohydrate.

 

Slide 12: Application 5: DSC                                                      Incompatibility

The interactions between two or more components of a pharmaceutical formulation can be desirable or undesirable. Desirable interactions are for example used to improve the solubility of an active ingredient. In contrast, undesirable interactions may reduce the activity of active ingredient in a formulation.

The diagram shows the DSC heating curves of pure acetyl-salicyclic-acid and calcium-stearate together with a mixture of both substances in a one-to-one concentration.

The calcium-stearate-curve exhibits an endothermic melting peak at about one hundred and thirty degree Celsius and the acetyl-salicyclic-acid-curve shows a sharper peak at about one hundred and forty two degrees.

The curve of the mixture displays only one endothermic peak at a temperature much lower than the peaks of the two pure constituents. This is good evidence for incompatibility due to strong interactions between the two substances.

 

Slide 13: Thermo-Optical Techniques

METTLER TOLEDO has developed versatile optical techniques that allow you to observe changes that occur in a sample while it is heated or cooled. The techniques include DSC-Microscopy and a Hot-stage microscopy system.

 

DSC microscopy makes use of light reflected from the sample contained in an open crucible during a normal DSC run.

Hot-stage microscopy allows direct visual observation of the sample and the possibility of recording images using polarized transmitted light.

 

The table summarizes some typical analytical applications that can be measured using these optical techniques.

The main applications have to do with

the identification of solid-solid transitions,

the separation of overlapping effects,

the identification of the causes of artifacts (for example, dimensional changes of the sample, or movement of the sample in the crucible),

and morphological changes.

 

The pictures on the right show the microscopy accessory for the standard DSC instrument, and the hot-stage microscopy accessory with the ability to quickly store, evaluate and share information in digital format as images or videos.

 

Slide 14: Application: DSC-Microscopy              Polymorphism, crystal growth

The solubility and melting behavior of a crystalline substance is determined by the morphology of the crystals. The size and number of crystals formed on crystallization from the melt depend on the cooling rate, and, under isothermal conditions, on the actual crystallization temperature. Hot-stage microscopy can be used to check the morphology of crystals.

An overview of the melting behavior of a substance can be obtained by performing a DSC measurement. For example, the first heating run of chlorpropamide shown in the slide indicates the presence of at least two polymorphic transitions.

The images on the right show different crystalline forms of chlorpropamide that were obtained after cooling at ten Kelvin per minute from the melt to three different isothermal crystallization temperatures at one hundred, ninety, and eighty degrees Celsius.

At high temperatures, the nucleation rate is low and the crystal growth rate is high, so that a small number of large crystals are formed. The lower the crystallization temperature, the higher the nucleation rate. The effect of this can be seen in the increasing number of smaller crystals formed at lower temperatures.

 

Slide 15: Melting Point Instrument

The innovative METTLER TOLEDO melting point instrument automatically determines the melting point, or melting range of substances with excellent accuracy.

The instrument can in fact do a lot more than this: for example, it allows you to investigate color changes, clear points and decomposition temperatures with video observation and video recording.

The table summarizes the main analytical applications of the METTLER TOLEDO melting point instrument for pharmaceutical substances. The instrument provides information about the melting point and melting range according to different pharmacopeia standards and allows you to identify substances, determine purity by melting point depression and to observe unusual melting behavior or decomposition.

 

The picture on the right side shows a view of the instrument with substances filled in six melting point capillaries.

 

Slide 16: Application: Melting Point of Benzoic Acid

The melting point instrument provides a rapid and exact method for automated, unattended melting point determination.

Automatic measurement of transmitted light and visual camera observation using reflected light guarantee reliable results.

The figure displays the intensity curves of transmitted light measured during the melting of benzoic acid. Point A is the start of melting, B is a threshold value, and C is the end of melting for the six samples that can be simultaneously measured.

 

Slide 17: TGA/DSC

Now let’s turn our attention to thermogravimetric analysis, or TGA.

In this technique, the mass of a sample is continuously measured as it is heated in a defined atmosphere. We simply put a few milligrams of the sample into a crucible, heat it and continuously record the weight change. This allows us to obtain information about the composition of the sample.

The schematic curve on the left shows the typical TGA measurement curve of a pharmaceutical preparation. The different effects are numbered next to the curve and explained in the table. These are:

One: heating begins, and volatile components such as moisture and solvent residues vaporize;

Two: loss of water of crystallization;

Three: at about three hundred degrees Celsius, the sample undergoes decomposition;

Four: inorganic fillers or ash are left behind.

 

The METTLER TOLEDO TGA/DSC 1 instrument can also simultaneously measure heat flow and thereby detect effects that involve heat exchange.

 

Slide 18: Thermogravimetric Analysis (TGA)

The table summarizes the main analytical applications of TGA for pharmaceutical materials. TGA is used to investigate processes such as vaporization or decomposition. It allows us to check thermal stability, the kinetics of reactions, and reaction stoichiometry.

 

The combination of TGA with a mass spectrometer or a Fourier-transform-infrared-spectrometer allows us to analyze gaseous compounds evolved from a sample. This provides information about the nature and composition of the sample.

 

The picture on the right shows a view of the open furnace of a TGA/DSC instrument, and in particular the sample holder with positions for the sample and reference crucibles. The standard crucibles are made of alumina.

 

Slide 19: Application 1: TGA/DSC                                               Loss on drying

Thermogravimetric analysis is the easiest way to investigate the loss of water from a pharmaceutical compound. This is often performed using a standard method such as the USP, or United States Pharmocopeia, loss on drying test.

 

The first TGA application example shows the mass loss curve of amiloride hydrochloride dihydrate performed according to USP 26 guidelines. The mass loss up to two hundred degrees Celsius is due to a small amount of adsorbed moisture and the loss of the water of crystallization. The mass loss must not be less than eleven percent and not greater than thirteen percent according to the specification given in the USP test method. The evaluation result of eleven point eight percent falls well within these limits.

 

The simultaneously recorded SDTA curve shows that the anhydrous substance melts at approximately two hundred and ninety two degrees Celsius and then immediately decomposes.

 

Slide 20: Application 2: TGA                                                                   Shelf life

Stability testing is necessary to ensure that the quality of a product is acceptable throughout its entire storage lifetime. TGA provides a method for determining the shelf life of pharmaceutical products and requires only a small amount of substance. It is based on accelerated testing and reaction kinetics

The application example shows the results obtained for the storage lifetime of acetylsalicylic acid using the model-free kinetics or MFK evaluation method.

The decomposition of several samples is first measured by TGA at different heating rates and yields the conversion curves shown in the upper left part of the diagram.

The conversion curves are then used to calculate the activation energy as a function of conversion as shown in the lower left part of the diagram. Due to the complexity of the decomposition process, the activation energy is not constant but changes from about one hundred and thirty (130 kJ/mol) to one hundred kilo joules per mole. Knowledge of the activation energy allows the decomposition reaction to be simulated for other conditions. This is shown graphically or in tabular form using so-called iso-conversion curves and tables.

The applied kinetics iso-conversion table shows predictions for storage times at different storage temperatures for selected degrees of conversion (alpha). For example, for 1% decomposition, a storage lifetime of ten thousand (10000) hours would necessitate a maximum storage temperature of about fifteen degrees Celsius (15 °C).

The iso-conversion curve labeled alpha 2% shows that a degree of conversion (alpha) of two percent is reached when the substance is stored at twenty degrees Celsius for about twenty thousand (20000) hours, or twenty-seven (27) months.

 

Slide 21: Application 3: TGA-MS                                                 Solvates

The next slide shows how TGA-MS can be used to detect the presence of solvents in pharmaceutical compounds.

Many pharmaceutical substances are recrystallized from solvents. As a result of this, residues of solvents often remain in the product. Combined techniques such as TGA-MS are ideal for detecting and identifying such undesired residues.

In this example, methanol and acetone were used to recrystallize the active substance. The presence of these two substances is confirmed by the peaks in the m/z 31 and m/z 43 MS fragment ion curves. The results indicate that the weight loss step at 200 °C is almost entirely due to the elimination of acetone.

Definite analytical information like this can only be obtained using a mass spectrometer coupled to a TGA instrument.

 

Slide 22: Application 4: TGA-Sorption                 Hydration and dehydration

This application shows the advantages of using a TGA-Sorption-Analyzer-System to study the behavior of substances with regard to drying, moisture uptake, and moisture content.

The diagram displays the uptake and release of moisture of a pharmaceutical substance as a function of the relative humidity at twenty-five degrees Celsius. The sample was amiloride hydrochloride dihydrate, a drug used to treat high blood pressure.

It was first dried at one hundred and twenty five (125) degrees Celsius to convert it to the anhydride and then cooled to twenty-five degrees. The dashed blue line shows the temperature program and the black TGA curve the loss of water.

After drying, the relative humidity was increased in steps of 10% allowing sufficient time for equilibrium to be reached at each step. The red curve shows the steps of the relative humidity curve and the black curve the resulting increase in mass. At a relative humidity of about 50%, the sample has regained its original water of crystallization. A further increase in relative humidity results in the uptake of free water, which is released when the relative humidity is decreased. This process is clearly shown on the right side of the slide. At twenty-five (25) degrees Celsius, the water of crystallization remains bound in the sample and can only be liberated by increasing the temperature.

Slide 23: Thermomechanical Analysis (TMA)

We now move on to thermomechanical analysis, or TMA. This technique measures the dimensional changes of a sample as it is heated or cooled.

 

The schematic curve on the left shows a typical TMA measurement curve of the coating of a capsule on heating. The two main effects are numbered next to the curve and explained in the table. These are:

One: expansion below the glass transition;

Two: softening with plastic deformation;

 

Slide 24: Thermomechanical Analysis (TMA)

The table summarizes different analytical applications of TMA for pharmaceutical materials.

The main application is to measure changes in the thickness or length of a sample due to heating or cooling, and in particular to determine the coefficient of thermal expansion, or CTE.

The technique is excellent for determining the glass transition temperature, and for studying softening behavior, especially for thin layers or coatings. Measurements of the swelling of materials in solvents are usually performed isothermally.

The picture on the right shows the typical TMA experimental setup with a ball-point probe in contact with the sample specimen resting on a flat support.

The following slide describes a specific application example.

 

Slide 25: Application 1: TMA                                          Swelling measurements

Capsules and tablets are often coated with polymers to provide a means for the controlled release of active ingredients. It has been shown that the rate of release correlates with the degree of swelling of the coating. This behavior can be measured and characterized in different solutions using the TMA swelling accessory.

As an example, a typical polymer such as a polymethacrylate based-film was investigated in different salt solutions.

At time zero, the liquid was filled into the vial containing the film and the swelling process measured. The inserted schematic diagram shows the experimental setup. Due to the uptake of liquid, the thickness of the film increases with time. The degree of swelling was lower with increasing ionic strength. Expansion in pure water is fastest and is completed after about twenty-five (25) minutes. The film then starts to dissolve.

 

Slide 26: Dynamic Mechanical Analysis (DMA)

Dynamic Mechanical Analysis is a technique that is used to measure the mechanical properties of a viscoelastic material as a function of time, temperature and frequency when the material is deformed under a periodic oscillating stress.

 

The schematic diagram on the left shows the results of a DMA measurement of a shock-cooled semicrystalline polymer. The curves display the storage modulus, gee prime (G′), the loss modulus, gee double prime (G″),and the loss factor tan delta as a function of temperature.

The different effects given by changes in the curves are numbered next to the curve and explained in the table. These are:

One: secondary relaxation, observed as a peak in the tan delta curve;

Two: the glass transition, seen as a peak in the tan delta curve and as a decrease in the storage modulus curve;

Three: cold crystallization of the polymer. The stiffness and hence the storage modulus, gee prime (G′), increase.

Four: recrystallization accompanied by a peak in tan delta;

Five: melting of the crystalline fraction with a decrease in the storage modulus.

 

Slide 27: Dynamic Mechanical Analysis (DMA)

The table lists the main analytical applications of DMA for polymers and biopolymers.

 

In general, DMA provides information about the glass transition of amorphous components, about viscoelastic behavior, and the elastic modulus.

 

It also gives information on the softening temperature, the effect of moisture on the modulus, and the dynamic mechanical behavior of polymer coatings and coating materials.

 

The picture on the right shows a sample installed in the DMA ready for measurement in a bending mode.

 

Slide 28: Application: DMA

The application displays the results obtained from the measurement of a polyamide thread immersed in water using DMA in the tension mode.

Polyamide threads are used in microsurgery for stitching wounds because of their high tensile strength, even with very small thread diameters. Polyamides can absorb up to 10% water. As a consequence of water uptake, the glass transition temperature decreases from about plus seventy (70 °C) to minus ten degrees Celsius (‑10 °C).

To investigate these effects, measurements were performed on a polyamide thread immersed in an immersion bath connected to the DMA.

The elastic modulus was first measured in the tension mode in air. A specimen was then immersed in water at 40 °C at a time indicated by the vertical blue line. The polyamide began to soften as soon as it was immersed in the water. The elastic modulus decreased from 4.5 giga-pascals (GPa) to a minimum of 1.3 giga-pascals (GPa) at 40 °C. The experiment was then repeated using a new thread at 20 °C. The modulus curves show that the softening process is faster at higher temperature.

 

Slide 29: 21 CFR Part 11

 

(21-CFR-Part-11) “Twenty-one cee eff arr Part eleven” refers to regulations issued by the

the U.S Food and Drug Administration (FDA) concerning the use of electronic records and electronic signatures.

“Part eleven”, as it is commonly called, defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and equivalent to paper records.

 

Incorporating 21 CFR Part 11 into the STARe software reduces costs by simply moving from paper to electronic documents.

Direct on-line access to electronic documents reduces the time and costs required for document retrieval during an audit situation or for resolving internal problems.

Electronic documents, with supporting audit trail and electronic signatures, present auditors with a clear and accurate picture of the results, thereby simplifying audit procedures. 

 

The METTLER TOLEDO STARe 21 CFR Part 11 software option ensures that the technical controls are compliant.

 

Slide 30: Summary

The table summarizes the most important thermal events that characterize pharmaceutical materials as well as the techniques recommended for investigating the effects. A box marked red means that the technique is recommended as a first choice; a box marked blue indicates that the technique can also be used.

 

The most important effects that can be analyzed by DSC are the melting point, melting range and melting behavior.

 

DSC is also used to determine the heat of fusion, purity, polymorphism, the glass transition, and oxidation stability.

 

The main applications of TGA are evaporation, desorption and vaporization behavior, thermal stability, decomposition kinetics, and the analysis of composition.

 

TOA or thermo-optical analysis is used to study the melting point, melting range and polymorphism using visual observation and video recording.

 

MP indicates the automatic detection of the melting point or melting range.

 

TMA is normally used to study the expansion or shrinkage of materials and the glass transition.

 

DMA is the most sensitive method for characterizing the glass transition of materials.

 

Slide 31: Summary

This slide gives an overview of the temperature ranges of the METTLER TOLEDO DSC, TGA, TMA, DMA and thermo-optical analysis instruments

 

In general, DSC experiments are performed at temperatures between minus one hundred and fifty degrees Celsius and plus seven hundred degrees. The temperature ranges may be different if special equipment or accessories are used.

 

TGA measurements normally begin at room temperature. The maximum possible temperature is sixteen hundred degrees. For pharmaceutical applications, the low temperature range up to four hundred degrees (400 °C) is most important.

 

TMA experiments can be performed between minus one hundred and fifty degrees and plus eleven hundred degrees.

 

DMA samples are measured in the range minus one hundred and fifty degrees to plus six hundred degrees.

 

Thermo-optical analysis includes Hot-stage microscopy and DSC-Microscopy: Measurements can be performed in the range minus sixty to plus three hundred and seventy five degrees.

 

Slide 32: For More Information on Pharmaceuticals

Finally, I would like to draw your attention to information about pharmaceutical applications that you can download from the Internet.

METTLER TOLEDO publishes articles on thermal analysis and applications from different fields twice a year in UserCom, the well-known METTLER TOLEDO biannual technical customer magazine. Back issues can be downloaded as PDFs from www.mt.com/usercoms as shown at the bottom of the slide.

Our “Pharmaceuticals” and “Thermal Analysis in Practice” handbooks contain many other examples and are recommended for further reading.

 

Slide 33: For More Information on Thermal Analysis

In addition, you can download details about webinars, application handbooks or information of a more general nature from the Internet address given on this slide and so ensure that you are always fully up-to-date in thermal analysis.

 

Slide 34: Thank You

This concludes my presentation on the thermal analysis of pharmaceuticals. Thank you very much for your interest and attention.

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