NETZSCH-Gerätebau GmbH has recently published a new handook entitled “Thermal Analysis in the Pharmaceutical Field”.
Image credit: Netzsch GmbH
The book features more than 260 pages of content across eight chapters.
The topics include methods (including DSC, TGA, STA and gas analysis); the proper characterization of amorphous and crystalline phases; ensuring purity, thermal stability and oxidative stability; storage conditions and shelf life; and considerations around polymorphism and compatibility.
The book employs a range of distinct application experiments, illustrates the steps required to carry these out and highlights the conclusions that can be drawn from their results.
Each featured topic includes a preceding introduction, describing any definitions and methods covered and illustrating their relationships with specific pharmaceutical issues.
A number of chapters also include appendices, providing additional information; for example, the chapter on polymorphism includes an appendix outlining the relationship between polymorphism and thermodynamics.
The importance of thermal stability
One of the key topics covered in the “Thermal Analysis in the Pharmaceutical Field” handbook is the importance of stability to the quality of drugs and drug products. (Please note that the below is an excerpt of the full handbook)
Stability is critical to the development, manufacturing and commercialization of pharmaceuticals. It influences material attributes such as purity, efficacy, safety and product shelf life.
There are three key stability categories:
- Chemical stability
- Physical stability
- Microbial stability
It should be noted, however, that microbial stability cannot be covered using thermoanalytical methods.
A substance is considered to be chemically stable when it is not reactive during normal use.
Chemical instability occurs when a substance undergoes chemical reactions, for example, oxidations or interactions between excipients and APIs. Reaction products may be toxic, make a drug aesthetically unacceptable or reduce its potency. Chemical stability may be equated to thermodynamic stability.
Physical stability may be impacted by transitions in the crystalline state such as the crystallization of an amorphous drug, moisture adsorption, polymorphism or the loss of volatile matter.1
The packaging or preservatives used in the pharmaceutical preparation of finished drug products may also impact physical stability.
The ICH Guideline Q1A2 and the WHO Technical Report No. 10103 relate stability to environmental factors including light, temperature and humidity, highlighting that these may influence the quality of a drug substance or drug product over time.
In this context, ‘thermal stability’ refers to circumstances in which temperature is the key influencing factor.
Thermal stability also refers to the ability of compounds to resist heat treatment. A material is considered to be thermally stable so long as its structure and properties remain unaffected when exposed to higher temperatures.
ASTM E2550 states that “the assessment of material thermal stability” may be performed “through the determination of the temperature at which the material starts to decompose or react and the extent of the mass change using thermogravimetry”.4
Thermogravimetric analysis is typically employed in the investigation of thermal stability. This is generally performed under inert conditions, for example, under the exclusion of air. Thermogravimetric analysis is an essential tool in the estimation of maximum DSC test temperatures as well as for DSC curve interpretation.
Determining suitable characteristic temperatures
Various temperatures may characterize a degradation or decomposition effect:
- By the onset temperature
- By the extrapolated temperature
- By the DTG maximum (or minimum depending on the direction of presentation)
As stated in ASTM E2550, the onset temperature is defined as “the point on the TGA curve where a deflection is first observed from the established baseline prior to the thermal event”.
As mentioned in ISO 11358-15 and DIN 51006,6 the extrapolated onset temperature is “the point of intersection of the starting-mass baseline and the tangent to the TGA curve at the point of maximum gradient”.
The DTG curve can be understood as the first derivative of the TGA curve versus time, while the extremum represents the inflection point of the corresponding TGA curve.
Figure 1 provides examples of all three of these temperatures using an example of the thermal behavior of pullulan in a nitrogen atmosphere. Mass-loss steps can be explored using TGA-FT-IR, highlighting that the effects noted between room temperature and 200 °C are the result of water evaporation.
The substance illustrated here begins to decompose with the second mass-loss step: it occurs at 219 °C (onset temperature as per ASTM E2550), 299 °C (extrapolated onset temperature as per ISO 11358-1) and 315 °C (minimum of the DTG curve).
The optimal choice of temperature largely depends on the application and the accuracy of determination required.
A peak temperature (DTG peak) and the majority of extrapolated onset temperatures are always mathematically well defined.
The onset temperature, however, is highly dependent on the rate of data acquisition and the magnification of the displayed curve. Despite this, it can be understood as representing the beginning of the mass-loss step under the measurement conditions of choice.
The examples presented here utilize the extrapolated onset temperature of the TGA curve and the extremum of the DTG curve to describe mass-loss effects.
ASTM E2550 also restricts the application of the suggested method of thermal stability determination because this is considered “not suitable for materials that sublime or vaporize in the temperature of interest”.
It should be noted that decomposition and sublimation or vaporization can be differentiated via evolved gas analysis. This process involves coupling a gas detector to the thermobalance and using this to identify the gaseous products released during measurement.
Figure 1. TGA measurement curve of pullulan. The first mass-loss step is due to the release of surface water (see TGA-FT-IR measurement on page 118). The second mass loss describes the thermal decomposition of the sample. The characteristic temperatures of the decomposition are 299 °C (extrapolated onset temperature), 219 °C (onset temperature according to ASTM E2550. see blue inset) and 315 °C (maximum mass loss rate indicated by the DTG curve). Image Credit: NETZSCH-Gerätebau GmbH
About NETZSCH-Gerätebau GmbH
The NETZSCH Group is a mid-sized, family-owned German company engaging in the manufacture of machinery and instrumentation with worldwide production, sales, and service branches.
The three Business Units – Analyzing & Testing, Grinding & Dispersing, and Pumps & Systems – provide tailored solutions for highest-level needs. Over 3,300 employees at 210 sales and production centers in 35 countries across the globe guarantee that expert service is never far from our customers.
When it comes to Thermal Analysis, Calorimetry (adiabatic & reaction), and the determination of Thermophysical Properties, NETZSCH has it covered. Our 50 years of application experience, broad state-of-the-art product line, and comprehensive service offerings ensure that our solutions will not only meet your every requirement but also exceed your every expectation.
Make your choice from among our diverse variety of instruments for Thermal Analysis, Calorimetry (adiabatic & reaction), and the determination of Thermophysical Properties. NETZSCH Analyzing & Testing has consistently invested its long-time experience into innovative new developments and advanced technologies conceived for state-of-the-art application tasks in materials research and development, quality assurance, and process optimization.
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