DSC Purity Analysis
On Demand Webinar

DSC Purity Determination

On Demand Webinar

DSC purity analysis is an important application that can be performed using this versatile technique

DSC purity
DSC purity

Differential Scanning Calorimetry (DSC) is the most widely used thermal analysis technique. A well-established application is the purity determination of organic substances. The method is based on the van’t Hoff law of melting point depression of eutectic systems. Purities between 90 and 100 mol% can be reliably determined.
Purity determination is used in the chemical and pharmaceutical industries and also for additives in the food and plastics industries.

In this Webinar, we will discuss the basic principles of DSC purity determination and present some interesting applications.

25:26 min
English

The Webinar covers the following topics:

  • Basic principles
  • Why use DSC Purity Determination?
  • Industries and applications
  • Application examples

DSC purity analysis of substances in drugs or foodstuffs is an important issue. In general, substances with significant amounts of impurity may produce unexpected reactions, lose their efficiency, or create toxic compounds. In the worst case, even just a few percent of an impurity could be toxic or even lethal.

 

Definition of Purity

According to the International Union of Pure and Applied Chemistry,

 

“A sample is sufficiently pure when the amount of each of the impurities which may interfere with the specific purpose for which the sample is required is so low that their combined effect is negligible within the desired limits of accuracy”.

 

The amount and nature of impurities in a substance is usually expressed as a percentage or in mole percent.

 

DSC purity analysis

Purity determination by DSC is based on the thermodynamics of an ideal eutectic system. This can be shown in the form of a phase diagram, explained in this webinar. Many mixtures of organic substances exhibit this type of behavior.

DSC Purity Determination

DSC Purity Determination

Ladies and Gentlemen

Welcome to the METTLER TOLEDO webinar on DSCPurity Determination.

 

Differential Scanning Calorimetry, or DSC as it is commonly called, is the most frequently used technique in thermal analysis. It is widely employed to study the behavior and properties of materials as a function of temperature or time.

The determination of the purity of organic substances is an important application that can easily be performed using this versatile technique.

Contents

In the course of this webinar, I would like to discuss:

what we mean by purity,

why and where the purity of a substance might be of interest,

and explain the basic principles of purity determination by DSC.

 

I also want to point out why purity determination is important,

explain the applicability of the method,

and briefly discuss the advantages of purity determination by DSC in comparison with other analytical techniques.

Finally, I will present several application examples to illustrate the determination of purity by DSC in practice.

 

Why Do We Need To Determine Purity?

Why, then, do we need to determine purity?

The purity of a substance is particularly important in connection with active pharmaceutical ingredients in the pharmaceutical industry.

For example, would you want to risk taking an impure aspirin pill? Depending on the storage conditions, aspirin can decompose to acetic acid and salicylic acid in the presence of moisture. This could cause stomach irritation and the substance would in any case lose its effect.

In general, substances with significant amounts of impurity may produce unexpected reactions, lose their efficiency, or create toxic compounds. In the worst case, even just a few percent of an impurity could be toxic or even lethal. The determination of the purity of substances in drugs or foodstuffs is therefore an important issue.

In laboratory or industrial syntheses, the quality of end-products is at risk if chemical substances are not sufficiently pure.

Purity is therefore an important quality characteristic for products used in the pharmaceutical and food industries, as well as in chemical laboratories and production.

 

Definition of Purity

So, what exactly is purity, and what does purity mean?

 

According to the International Union of Pure and Applied Chemistry,

 

“A sample is sufficiently pure when the amount of each of the impurities which may interfere with the specific purpose for which the sample is required is so low that their combined effect is negligible within the desired limits of accuracy”.

 

There are of course many other definitions of purity and impurities depending on the actual circumstances or particular application.

On the one hand, impurities can interact with the main constituent or with other impurities and affect the properties of the substance, for example, lower the melting point. They can, however, also be inert and have no effect on the substance other than dilution, for example a residue of aluminum oxide in aspirin.

In general, impurities are unwanted and undesirable and lower the quality of the substance in question.

 

The amount and nature of impurities in a substance is usually expressed as a percentage or in mole percent.

Possible techniques

How is purity determined in practice?

Fortunately, a number of well-known analytical techniques are available, depending on the sample and the concentration of the impurities:

  • For organic impurities, we can use chromatographic methods such as High-Performance Liquid Chromatography (HPLC) and Gas Chromatography (GC), or thermal methods such as DSC;
  • for inorganic impurities, we can determine the residual ash content, or use Inductively Coupled Plasma (ICP), or Thermogravimetric Analysis (TGA);
  • for water, we can measure the density and refractive index, or use titration methods or TGA, and
  • for residual solvents, there is mass spectrometry and FTIR spectroscopy possibly combined with TGA.

In this seminar, I will focus on DSC puritydetermination and show how it complements HPLC, which is nowadays the most widely used technique for determining the purity of organic substances.

Principles of DSC

Before we go into this, let me first briefly explain how a Differential Scanning Calorimeter works.

Differential Scanning Calorimetry measures the heat flow produced in a sample when it is heated, cooled, or held at constant temperature. The heat flow from the furnace to the Sample crucible is measured relative to the heat flow to a Reference crucible. The sample and reference crucibles are identical except that the reference crucible is usually empty. A sample may undergo one or more phase changes during heating or cooling. A good example of a phase change is the melting of ice, which can be easily measured by DSC.

 

The schematic diagram in the upper part of the slide shows the sample area of a heat flux DSC. In this particular design, the sample and reference crucibles are heated from below; the heat flow is indicated by the red dots in the diagram. The sample is contained in a crucible, or pan, that sits on top of the sensor. Both the sample and reference crucibles are surrounded by a heated chamber or furnace.

 

The sensor is the heart of the DSC and detects the heat flow. An enlarged view of a METTLER TOLEDO sensor with its typical star-shaped arrangement of thermocouples is shown in the lower left corner of the slide. The thermocouples guarantee that the heat flow is accurately measured.

 

The measurement curve in the lower right corner of the slide displays a typical melting peak. Evaluation of the curve yields valuable information such as the enthalpy of fusion, the melting point, and the specific heat capacity.

 

DSC Purity Determination

Purity determination by DSC is based on the thermodynamics of an ideal eutectic system. This can be described by the phase diagram shown on the left of the slide. Many mixtures of organic substances exhibit this type of behavior.

 

In a phase diagram, the ordinate axis is usually the temperature, and the abscissa the concentration of impurity expressed as a mole fraction. This is the ratio of the number of moles of impurity to the sum of the moles of the main component and the impurity.

Below the solidus temperature, the material is solid.

If an impure substance is slowly heated, the eutectic melts completely at the eutectic temperature, Teu. (Speaker, say “Tee you”). At this temperature, the sample consists of a liquid containing the entire impurity in the eutectic ratio with the main component, together with a crystalline residue of the main component. The solidus line is the boundary between the areas where liquid and solid phases coexist and the completely solid phase.

On further heating, more and more crystals melt in the liquid phase and the concentration of the impurity in the liquid phase decreases. In the temperature range between the liquidus and the solidus lines, pure solid and impure liquid phases coexist. Finally, all the crystals have melted and the final melting temperature T is reached. In this diagram, T0 (Speaker, say “Tee zero”) denotes the melting temperature of the pure main component.

A typical DSC curve describing these processes is shown in the diagram on the right. The first, usually fairly small peak, corresponds to the melting of the eutectic and is followed by the melting of the remaining part of the major component at a higher temperature.

 

If the purity of the sample is high, the final melting temperature T is very close to T0. In this case, the liquidus line can be approximated by the well-known van’t Hoff equation shown in the upper part of the slide.

In this equation, T is the temperature in Kelvin at which a fraction F of the sample has melted, T0 is the melting point of the pure substance in Kelvin, R is the gas constant, DH isthe enthalpy of fusion of the main component in joules per mole (J/mol) and x impurity (ximp) (Speaker, say “eks impurity”) is the initial concentration of the impurity in mole percent.

The van’t Hoff equation shows that there is a linear relationship between T and one over F (1/F). For a given system, the only unknown is the initial concentration of the impurity. This allows us to calculate its value from the slope of the van’t Hoff curve. This can easily be determined from a single DSCexperiment.

 

Purity Determination in Practice

This slide explains how purity is evaluated from a DSC measurement.

 

The diagram on the left displays a single DSC melting curve. The software usually evaluates the fraction which has melted, F, between 10% and 50% of the peak height in order to avoid melting rates that are too high. For each value of F, the corresponding temperature is plotted as a function of the reciprocal value of the molten fraction, F. The resulting one-over-F (1/F) plot allows visual assessment of the raw data and the linearization correction to be applied.

The van’t Hoff equation shows that there is a linear relationship between T and one-over-F (1/F). However, in practice, it is found that the curve calculated from DSC measurements for T as a function of one-over-F (T = f(1/F)) is not a straight line. There is a marked departure from linearity at high impurity levels. The reason for this is that the baseline for the integration of the DSC curve is not exactly known. This systematic deviation from linearity can be corrected mathematically. As a result, one obtains the amount of the impurity calculated from the slope of the corrected one-over-F (1/F) plot and the final melting point of the impure substance at one-over-F-equals 1 (1/F = 1).

DSC Purity Applicability and Advantages

As already mentioned, DSC purity determination is based on the van’t Hoff law for eutectic systems. This assumes that the main component has a high level of purity, displays a single melting point, is thermally stable, and that the sample is in a state of equilibrium. Impurity in this context refers to the sum of all impurities and not to a single species.

 

DSC purity measurements are rapid and easy to perform compared with standard chromatographic methods such as high-performance liquid chromatography or gas chromatography. Regular calibration is not needed so that certified reference materials, which are sometimes expensive and difficult to obtain, are not required.

A further advantage is that the method is very sensitive to small deviations in the purity level.

Industries and Applications

As previously mentioned, purity determination of organic substances is very important in the pharmaceutical and food industries as well as in chemical laboratories. It is mainly used for quality control of active pharmaceutical ingredients, preservatives, additives or excipients.

 

I now want to present several different application examples that illustrate the various points we have discussed up until now.

 

Application 1                                   Purity determination of ibuprofen

This slide summarizes the results obtained from the purity determination of a sample of ibuprofen, an anti-inflammatory drug used to treat fever and pain.

As described in the ASTM E928 standard test method, a low heating rate is generally used for the determination of purity by DSC in order to achieve quasi-equilibrium conditions.

The DSC melting curve displayed in the slide was measured at a heating rate of one Kelvin per minute (1 K/min).The curve is fully evaluated and lists the maximum number of results: In addition to

  • the purity, the confidence limits for the calculated purity, and the clear melting point,

these include

  • the melting point depression T zero minus T (T0T),
  • the linearization correction in %,
  • the corrected heat of fusion in joules per gram (J/g) and kilojoules per mole (kJ/mol),
  • the suggested maximum heating rate determined from the peak shape,
  • the cryoscopic constant, which is the percentage of impurity that depresses the melting point by one Kelvin (1 °C)
  • and the melting temperature at 10% liquid fraction.

 

The melting temperature with a liquid fraction of 10% is significant because it corresponds to the melting temperature when the melting process is measured in a melting point apparatus. This is the temperature at which melting is visually observed.

 

The graph in the lower left part of the diagram also shows the one-over-F plot, obtained by plotting the equilibrium melting temperature against one-over-F.

Application 2           Purity determination of p-Hydroxybenzoic acid    pHB

This slide shows the purity determination of a very pure sample of para-hydroxy-benzoic acid. The diagram on the left shows its chemical structure and summarizes the results obtained by DSC using a heating rate of 1 K/min.

The methyl, ethyl, propyl, and butyl esters of para-hydroxybenzoic acid are known as parabens and are used as preservatives in the cosmetics, pharmaceutical and food industries. The melting curves of the four substances are shown in the small inset diagram on the right of the DSC diagram.

 

For comparison, the same batch of para-hydroxybenzoic acid was also analyzed by high-performance liquid chromatography (HPLC). Quantitative determination by HPLC requires certified reference substances, the preparation of standard solutions, and several measurements to construct and check the accuracy of the calibration curve used for the analysis. This takes more time and effort than a DSC measurement. On average, the purity analysis of a sample by HPLC took more than 30 minutes compared with about 15 minutes by DSC.

 

In this example, the purity of the para-hydroybenzoic acid sample was found to be 99.83 mole percent (mol%) by DSC and 99.77% by HPLC. These results are the same within the limits of experimental error.

 

Application 3a                                 Purity determination of phenacetin

The slide displays DSC heating runs of samples of phenacetin that contained increasing amounts of para-aminobenzoic acid abbreviated to PABA as an impurity. Phenacetin was introduced in 1887 and is mainly used as an analgesic.

As before, the samples were measured at a heating rate of one Kelvin per minute (1 K/min).

The curves show that the melting peak of phenacetin at around 134 degrees Celsius (134 °C) becomes broader and shifts to lower temperature as the level of impurity increases. In addition, the eutectic peak at about 114 degrees (114 °C) becomes larger.

 

Finally, the degree of purity of each sample was evaluated. The values obtained were used to construct the so-called Error Plot shown in the next slide.

 

Application 3b                                 Purity determination of phenacetin

The slide shows the Error Plot for the phenacetin/PABA system. The error plot is constructed by plotting the difference between the impurity measured and the impurity added on the y-axis against the impurity added on the x-axis.

The plot allows you to determine the maximum impurity level that can be accurately measured.

 

Ideally, the plot should be a horizontal line with 0% difference as indicated by the dashed black line. In general, a relative error of 10% of the impurity level is acceptable for DSC purity determination. These limits are indicated by the two blue lines in the graph.

The red dots indicate the actual deviations between the measured and the true impurity values. The diagram shows that there is a good agreement between the two values up to an impurity level of about 1.75 mole percent (mol%).

For this system, one can therefore conclude that the acceptable range for purity determination is limited to a maximum level of impurity of 1.75 mole percent (mol%).

Application 4a:              Dimethyl terephthalate/Benzoic acid

The diagram in this slide shows the DSC curves of the dimethyl terephthalate/benzoic acid eutectic system. Here, benzoic acid is the eutectic impurity.

 

In the diagram, dimethyl terephthalate is abbreviated to DMT, and benzoic acid to BA. DMT is used in the production of polyesters including polyethylene terephthalate.

 

In this series of measurements, the DMT contained different percentages of benzoic acid ranging from 4 to 89 percent. Pure DMT and pure benzoic acid were also measured. The melting points of these two substances are approximately 141 and 122 degrees Celsius (°C).

The curves show that the melting peak of DMT becomes broader and shifts to lower temperature with increasing amounts of benzoic acid impurity, and that the eutectic peak at about 97 degrees (°C) increases up to a certain level and then decreases.

The eutectic composition can be obtained by integrating the area of the eutectic peak and recording its enthalpy of fusion for each percentage composition. In addition, the phase diagram can be plotted by recording the melting point of the major constituent.

The eutectic composition and phase diagram of DMT/benzoic acid are shown in the next slide.

Application 4b:                                Dimethyl terephthalate/Benzoic acid

As discussed in the previous slide, the eutectic composition and the phase diagram of a eutectic system can be obtained using data from DSC measurements.

In the upper diagram, the enthalpy of fusion of the eutectic peak is plotted against the level of impurity, that is, against the mole fraction of benzoic acid. The eutectic composition corresponds to the point of intersection of the linear extrapolation of the data points.

 

The lower diagram shows the phase diagram of the DMT/benzoic acid system. The solidus line is a horizontal line at the onset-melting-temperature of the eutectic. The eutectic composition is also recorded.

The liquidus line is obtained by plotting the melting peak temperatures of the main component against the level of eutectic impurity. The melting points of pure DMT and pure benzoic acid are also used.

Application 5                                   API and the effect of decomposition

This slide shows the purity determination by DSC and thermogravimetric analysis of an active pharmaceutical ingredient and illustrates the effect of decomposition. The continuous black line is the DSC curve and the dashed red line the TGA curve.

 

As already mentioned, DSC purity determination is usually performed at a low heating rate in order to achieve quasi-equilibrium conditions. In this example, however, the substance undergoes partial decomposition during the melting process if a low heating rate is used. This is often the case with active pharmaceutical ingredients. This behavior makes purity determination by DSC impossible.

In cases like this, one can try using higher heating rates so that there is less time for decomposition to occur during melting. In this example, the measurement was performed at ten Kelvin per minute (10 K/min). The TGA curve measured at the same heating rate confirms that decomposition then takes place above the melting temperature.

This makes purity analysis feasible at higher heating rates. One must, however, be careful regarding the accuracy of the value obtained for the purity because the analysis is performed at a heating rate that no longer satisfies the previously mentioned assumptions. It nevertheless allows differences in the purity levels of samples from different production batches to be compared.

 

Summary

This slide summarizes the features and benefits of DSC purity determination.

 

Differential scanning calorimetry is an excellent technique for characterizing the purity of organic substances in pharmaceuticals, foodstuffs, plastics and chemicals.

 

The method is based on the van't Hoff law for eutectic systems.

DSC purity determination is rapid and easy to perform, and very sensitive especially in monitoring small deviations of purity, for example from batch to batch.

Regular calibration and certified reference materials are not needed. This makes it a very reliable technique for research and for quality control.

 

For More Information

Finally, I would like to draw your attention to information about DSC purity determination 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 technical customer magazine. Back issues can be downloaded as PDF files from the Internet.

 

Individual applications can be also searched for on the METTLER TOLEDO homepage.

In addition, you can download information about application handbooks, webinars or of a more general nature from the Internet addresses given on this slide.

Thank You

This concludes my presentation on Purity Determination by DSC. Thank you for your interest and attention.

Thank you for visiting www.mt.com. We have tried to optimize your experience while on the site, but we noticed that you are using an older version of a web browser. We would like to let you know that some features on the site may not be available or may not work as nicely as they would on a newer browser version. If you would like to take full advantage of the site, please update your web browser to help improve your experience while browsing www.mt.com.