Thermal Analysis

1. Thermal Analysis Dr. Basavaraj K. NanjwadeM. Pharm., Ph.D KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. Cell No: 00919742431000 E-mail: nanjwadebk@gmail.com Goa College of Pharmacy, Goa.

2. Thermal analysis • Thermal analysis is a branch of materials science where the properties of materials are studied as they change with temperature. • Several methods are commonly used – these are distinguished from one another by the property which is measured. Goa College of Pharmacy, Goa.

3. ABBREVIATIONS • ICTAC - International Confederation for Thermal Analysis and Calorimetry • DEA- Dielectric Analysis • DSC- Differential Scanning Calorimetry • TGA- Thermogravimetric Analysis • TMA- Thermomechanical Analysis • ÄHf- Heat of Fusion • Tm - Melting Temperature, extrapolated endothermic onset temperature • Tp- Peak Melting endothermic Temperature • ÄHc-Heat of exothermic Crystallization • Tc- Crystallization Temperature, extrapolated exothermic onset temperature • Tcp- Peak exothermic Crystallization temperature • ÄHv - Heat of endothermic Vaporization • Tv - Vaporization temperature, extrapolated endothermic onset temperature • Tvp - Peak Vaporization temperature • Tg -Glass transition temperature • ASTM- American Standards for Testing Materials Goa College of Pharmacy, Goa.

4. Thermal analysis • Dielectric thermal analysis (DEA): dielectric permittivity and loss factor • Differential thermal analysis (DTA): temperature difference • Differential scanning calorimetry (DSC): heat difference • Dilatometry (DIL): volume • Dynamic mechanical analysis (DMA) : mechanical stiffness and damping • Evolved gas analysis (EGA) : gaseous decomposition products • Laser flash analysis (LFA): thermal diffusivity and thermal conductivity • Thermogravimetric analysis (TGA): mass • Thermomechanical analysis (TMA): dimension • Thermo-optical analysis (TOA): optical properties Goa College of Pharmacy, Goa.

5. Common Thermal Analysis Methods and the Properties Measured Goa College of Pharmacy, Goa.

6. Introduction • Thermal analysis is defined as “series of techniques for measuring the temperature dependency of a physical property of a certain substance while varying the temperature of the substance according to a specific program.” • The substance referred to here includes reaction products. • Physical properties include mass, temperature, enthalpy, dimension, dynamic characteristics, and others, and depending on the physical properties to be measured, the techniques of thermal analysis. Goa College of Pharmacy, Goa.

7. Introduction • Conventionally thermal analysis has been mainly employed in measurements for research and development, but in recent times it is used in many practical applications, as the testing standards on the basis of thermal analysis have been established, for example, in quality control in the production field, process control, and material acceptance inspection. • It is also applied in wide fields, including polymer, glass, ceramics, metal, explosives, semiconductors, medicines, and foods. Goa College of Pharmacy, Goa.

8. Introduction • Introduce thermal analysis at an entry level chemist or a new function for the experienced pharmaceutical scientist. • This teaching tool describes the introductory use of Differential Scanning Calorimetry (DSC), Thermo-Mechanical Analysis (TMA) and to some extent Thermo-gravimetric Analysis (TGA) for characterizing pharmaceuticals. Goa College of Pharmacy, Goa.

9. OBJECTIVES • The main objective to introduce thermal analysis and its applications at an entry level in the pharmaceutical industry. • In the process, instruments were successfully calibrated using pharmaceuticals. • Studying the behavior of pharmaceuticals by different thermal analysis instruments, under different conditions and then compare the results was another objective. Goa College of Pharmacy, Goa.

10. Basic Principles of Thermal Analysis Goa College of Pharmacy, Goa.

11. Thermal Analysis of Pharma Materials • DSC,TG/DTA and TG/DTA-IR are often used for characterisation of pharma materials. • DSC, alone or in combination with hot-stage microscopy, is able to differentiate between different polymorphic structures and, by using different heating rates, can investigate the transformations which occur during the polymorphic transformation. Goa College of Pharmacy, Goa.

12. Thermal Analysis of Pharma Materials • By using appropriate heating rates, polymorphic purity can be determined, and can involve heating rates up to 750°C/min. • TGA is often used to measure residual solvents and moisture, but can also be used to determine solubility of pharma materials in solvents. • Analysis of pharma materials is probably the largest area of application for thermal analysis. Goa College of Pharmacy, Goa.

13. Thermal Analysis of Polymers • Polymers represent another large area in which thermal analysis finds strong applications. • Thermoplastic polymers are commonly found in everyday packaging and household items, but for the analysis of the raw materials, effects of the many additive used (including stabilisers and colours) and fine-tuning of the moulding or extrusion processing used can be achieved by using DSC. Goa College of Pharmacy, Goa.

14. Thermal Analysis of Polymers • An example is oxidation induction time (OIT) by DSC which can determine the amount of oxidation stabiliser present in a thermoplastic (usually a polyolefin) polymer material. • Compositional analysis is often made using TGA, which can separate fillers, polymer resin and other additives. • TGA can also give an indication of thermal stability and the effects of additives such as flame retardants Goa College of Pharmacy, Goa.

15. Thermal Analysis Methods Used in Pharmaceutical • Even though most of the thermal analysis methods can handle samples such as solids, semi-solids or liquids, an evaluation of the contemporary literature would recommend that solid-state portrayal could apply to most of the pharmaceutical research applications. • Common applications used in thermal analysis incorporate the categorization of the physicochemical attributes of crystalline solids and the discovery and classification of polymorphic forms. Goa College of Pharmacy, Goa.

16. Thermal Analysis Methods Used in Pharmaceutical • With the usage of solid dispersions and other polymeric dosage forms in an increased manner, thermal analytical techniques have been required more frequently to assist researchers with the characterization and development. • Thermal analytical techniques are also utilized for studying the results of lyophilization and developing optimal lyophilization formulations and cycles. • Differential techniques are also used to review kinetics in the solid-state, which includes accelerated stability, decomposition and the aging effects on various formulations. Goa College of Pharmacy, Goa.

17. Thermal Analysis Methods Used in Pharmaceutical • If any laboratory - be it a pharmaceutical industry or an academic research institute, needs to purchase no more than one piece of thermal analysis equipment, it is most likely to be a DSC. • These instruments can be purchased from numerous manufacturers with wide options of price and applications. Goa College of Pharmacy, Goa.

18. Thermal Analysis Methods Used in Pharmaceutical • The DSC concept was formerly derived from earlier DTA instruments. While DTA measures the difference in temperature, DSC grants for the measurement of a modification in enthalpy. • ‘The International Confederation for Thermal Analysis and Calorimetry’ (ICTAC) has defined DSC as a technique where “the heat flow rate difference into a sample and reference material is measured." Goa College of Pharmacy, Goa.

19. Thermal Analysis Methods Used in Pharmaceutical • Two types of basic DSC instruments are available today commercially - heat-flux DSC (hf-DSC) and power compensation DSC (pc-DSC). • As per the latest audits, both the instruments are extremely versatile and very comparable. • While engaging different techniques to inspect the measurement, both the types of instruments are employed to measure heat flow and this seems to be certified as DSC under the ICTAC(International Confederation for Thermal Analysis and Calorimetry) definition. • Originally the term heat-flux DSC was used to illustrate quantitative DTA instruments. Goa College of Pharmacy, Goa.

20. Thermal Analysis Methods Used in Pharmaceutical • Now, it is universally denoted as a DSC method. • This progress was an improvement over DTA, which allowed for a measurement in the changes in heat flow as compared to only temperature. • This was reached by the accumulation of a second sequence of thermocouples in order to measure the temperature of a furnace and a heat sensitive plate. • By measuring the capacity of the heat sensitive plate as a task of temperature during the process of manufacturing, an estimation of the enthalpy of transition can be prepared by the incremental temperature fluctuation. Goa College of Pharmacy, Goa.

21. Thermal Analysis Methods Used in Pharmaceutical • Power-compensation DSC is different from hf-DSC in operating principle as well as in basic instrument design.   • Just as the name can notes, pc-DSC measures the change in power or energy essential to preserve the sample and references material at the identical temperature all through the heating or cooling cycle. • This is carried out through an instrument design which is different than that normally found in hf-DSC instruments. Goa College of Pharmacy, Goa.

22. Thermal Analysis Methods Used in Pharmaceutical • Two individual heaters are used with pc-DSC to control the flow of heat to the sample and reference holders. • Individual resistance sensors are positioned within each holder and temperature is measured at the base of each. • When a phase change takes place in a in thermal analysis and a temperature difference is observed between the sample and reference, energy is removed or supplied until the temperature difference is lower than the threshold. Goa College of Pharmacy, Goa.

23. Techniques and Applications in the Pharmaceutical Sciences • The current field of thermal analysis is both diverse and dynamic. • Although not a new field, more advanced instrumentation, techniques and applications are constantly appearing on the market and in the literature. • Theoretically, almost any substance whether solid, semi-solid or liquid can be analyzed and characterized with thermal analytical techniques. • Common materials include foods, pharmaceuticals, electronic materials, polymers, ceramics, organic and inorganic compounds, even biological organisms. Goa College of Pharmacy, Goa.

24. Techniques and Applications in the Pharmaceutical Sciences • In theory, all thermal analytical techniques simply measure the change of a specific property of a material as a function of temperature. • This in turn allows researchers access to information regarding macroscopic theories of matter including, equilibrium and irreversible thermodynamics and kinetics. • While numerous techniques are available, the primary differences in the techniques are the properties of the material being studied. Goa College of Pharmacy, Goa.

25. Techniques and Applications in the Pharmaceutical Sciences • In the pharmaceutical sciences, only a handful of the techniques are commonly employed but the information gained and phenomena that can be explored are countless. • The primary workhorses in the pharmaceutical sciences include, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), differential thermal analysis (DTA) and thermomechnical analysis (TMA). • Admittedly, as the needs of the researcher change and new materials are identified in formulation development, less commonly used techniques are being utilized and developed resulting in a very dynamic and exciting field of research. Goa College of Pharmacy, Goa.

26. Techniques and Applications in the Pharmaceutical Sciences • The first will be thermal analytical methods commonly used in the pharmaceutical sciences, primarily DSC (including several specialized techniques), TGA and TMA. • The second will focus on applications in the pharmaceutical sciences including solid-state characterization of polymorphism, solid dispersions and polymeric dosage forms. Goa College of Pharmacy, Goa.

27. Thermal Analysis Techniques IUPAC: International Union of Pure and Applied Chemistry Goa College of Pharmacy, Goa.

28. Thermal Analysis • Differential Scanning Calorimetry (DSC) • Measure heat absorbed or liberated during heating or cooling • Thermal Gravimetric Analysis (TGA) • Measure change in weight during heating or cooling • Thermomechanical Analysis (TMA) • Measure change in dimensions during heating or cooling • Differential Thermal Analysis (DTA) • They are use for thermal investigation where thermal change can be observed and characterised Goa College of Pharmacy, Goa.

29. THERMOGAVIMETRIC ANALYSIS (TGA) Goa College of Pharmacy, Goa.

30. Thermogravimetric Analysis (TGA) • Principle: TGA measures the amount and the rate of weight change of a material with respect to temperature or time in controlled environments. • A TGA consists of three major parts a furnace, 1. A microgram balance, 2. An auto sampler and 3. A thermocouple. Goa College of Pharmacy, Goa.

31. GENERAL PRINCIPLES INVOLVED IN THERMOGRAVIMETRY • PRINCIPLE : Thermogravimetry is a technique in which a change in the weight of a substance is recorded as a function of temperature or time. • Instrument: Instrument used for thermogravimetry is “Thermobalance”. Data recorded in form of curve known as ‘Thermogram’. Goa College of Pharmacy, Goa.

32. Thermogravimetric Analysis (TGA) • The furnace can raise the temperature as high as 1000°C which is made of quartz. • The auto sampler helps to load the samples on to the microbalance. • The thermocouple sits right above the sample. • Care should be taken at all times that the thermocouple is not in touch with the sample which is in a platinum pan. Goa College of Pharmacy, Goa.

33. Thermogravimetric Analysis (TGA) • A technique that permits the continuous weighing of a sample as a function of temperature and/or as a function of time at a desired temperature Goa College of Pharmacy, Goa.

34. Differential Thermal Analysis Goa College of Pharmacy, Goa.

35. Thermogravimetric Analysis (TGA) Goa College of Pharmacy, Goa.

36. Interpretation of TG and DTG curves • The sample undergoes no decomposition with loss of volatile products over the temperature range shown but solid phase transformation, melting ,etc can not be detected by TG, • The rapid initial mass loss is characteristic of desorption or drying. If it is true, then re-run the sample should result in type (i) curves, • Single stage decomposition, • Multi-stage decomposition with relatively stable intermediates : provide information on the temperature limit of stability of reactants and intermediate products and also stoichiometry, • Multi-stage decomposition with no stable intermediate product. However heating-rate effect must be considered. At low heating rate, type (v) resemble type (iv). At high heating rate, type (iv) and (v) resemble type (iii) and lose all the details, • Gain in mass due to reaction with atmosphere, e.g. oxidation of metals, • Oxidation product decompose again at higher temperature; this is not often encountered. Goa College of Pharmacy, Goa.

37. TGA Curve of Calcium Oxalate Goa College of Pharmacy, Goa.

38. Examples of TGA Curves Goa College of Pharmacy, Goa.

39. Sample Preparation • Sample preparation has a significant effect in obtaining good data. • It is suggested that maximizing the surface area of the sample in a TGA pan improves resolution and reproducibility of weight loss temperatures. • The sample weight affects the accuracy of weight loss measurements. • Typically 10-20mg of sample is preferred in most applications. • Whereas, if the sample has volatiles 50-100mg of sample is considered adequate. • It is to be noted that most TGA instruments have baseline drift of ±0.025mg which is ±0.25% of a 10mg sample. Goa College of Pharmacy, Goa.

40. Experimental Conditions • Heating Rate • Purge gas Goa College of Pharmacy, Goa.

41. Experimental Conditions -Heating Rate • Samples are heated at a rate of 10 or 20°C/min in most cases. • Lowering the heating rates is known to improve the resolution of overlapping weight losses. • Advances in the technology have made it possible for variable heating rates (High Resolution TGA) to improve resolution by automatically reducing the heating rate during periods of weight loss. Goa College of Pharmacy, Goa.

42. Experimental Conditions -Purge gas • Nitrogen is the most common gas used to purge samples in TGA due to its inert nature. • Whereas, helium provides the best baseline. • Air is known to improve resolution because of a difference in the oxidative stability of components in the sample. • Vacuum may be used where the sample contains volatile components, which helps improve separation from the onset of decomposition since the volatiles come off at lower temperatures in vacuum. • e.g. oil in a rubber tire product. Goa College of Pharmacy, Goa.

43. Miscellaneous Goa College of Pharmacy, Goa.

44. Calibration • Blank test • Calibration of mass changes • Calibration of temperature Goa College of Pharmacy, Goa.

45. Calibration- Blank test • Without sample, air is passed at 20 ml/mm, and the temperature is raised up to 1000 °C at heating rate of 10°C min-1. • By this blank test, the general condition of the apparatus can be known. • The TGA curve can drift slightly as the temperature is increased. • This is owing to the changes in the buoyancy and convection. Goa College of Pharmacy, Goa.

46. Calibration- Blank test • When noise appears in the TG curve, the possible cause may include contact between sample dish and thermocouple, contact between quartz suspension wire and purge gas feed pipe, and contact between weight pan and arid glass cap. • Vibration and shock may also cause noise. • When the sample pan or suspension wire is contaminated with deposit of decomposition product or the like, the TGA curve shows a slight decreasing curve. Goa College of Pharmacy, Goa.

47. Calibration- Calibration of mass changes • Since the TGA is usually measured by the rate of the weight change to the sample weight, calibration of absolute value of weight is hardly necessary. • A weight of 20 mg is read to a precision of 10 microgms by a precision balance, and the mean (So) is determined. • The furnace is put on, and when the TGA signal is stabilized, the instrument balance control is adjusted to set the automatic zero. Goa College of Pharmacy, Goa.

48. Calibration- Calibration of mass changes • Then the furnace is put into place and the furnace is set again, and the TGA signal value is read. This value is S1. • Repeating the same operation several times, the mean of S1 is obtained as S. • In this operation it is known that a signal corresponding to S1 mg is delivered with the weight of So mg is placed on the balance. • The measuring precision of TGA is within ±1 % of the range. • When calibrating the apparatus, the calibration function is utilized. Goa College of Pharmacy, Goa.

49. Calibration-Calibration of temperature • The temperature of the TGA may be calibrated in two manners: • The method of making use of the melting point of a pure metal, and the method of utilizing the Curie point temperature. • In the former method, one of the metals processed in a ribbon shape, and it is suspended on the TGA suspension wire, and a weight of about 100mg is attached at its tip. • When the pure metal is fused by heating, the weight drops, and a weight drop appears on the TGA curve. Goa College of Pharmacy, Goa.

50. Calibration-Calibration of temperature • In the latter method, the standard substance verified by International Congress on Thermal Analysis, ICTA, is measured. The standard substances are Ferromagnets, and have different Curie temperatures. • It is intended to calibrate by measuring the apparent weight change appearing in steps at Curie temperatures by making use of a permanent magnet. Goa College of Pharmacy, Goa.