Table of Contents
The pharmaceutical industry is faced with the continuous challenge of precisely evaluating the stability and thermal behavior of active pharmaceutical ingredients. Especially for APIs (pharmaceutically active ingredients) in solid or crystalline form, thermal analysis has proven to be an important tool. thermal analysis e has established itself as an indispensable tool, as it Thermogravimetry (TG) and dynamic differential scanning calorimetry (DSC) in a single analysis step. This combination of methods makes it possible to record mass changes and caloric effects simultaneously on the same sample, enabling direct correlation of the results without the uncertainties of separate measurements. Particularly when the sample quantity is limited, as is often the case in the research and development of high-quality active pharmaceutical ingredients, the STA enables an almost complete characterization of complex pharmaceutical systems. As both analyses are carried out under exactly the same conditions – same atmosphere, temperature control and heating rate – STA provides highly reproducible and reliable data for quality control and development.
Identification of critical transition points
The Simultaneous Thermal Analysis (STA) is a key method for identifying critical thermal transition points that are of great importance for pharmaceutical development and quality control.
These transition points significantly determine the processing conditions and the storage stability of pharmaceutically active substances (API).
Key transition points:
- Melting point: Crucial for the processing and storage of active ingredients.
- Glass transition temperature (Tg): Describes the temperature range in which amorphous or semi-crystalline substances soften. It indicates the limit above which the stable, solid appearance is lost and storage safety can therefore be impaired.
- Decomposition temperature: Precise determination of the onset temperature to establish stable process and storage temperatures.
- Phase transitions: Characterization of polymorphic crystal forms based on specific melting or transformation temperatures.
The DSC component of the STA recognizes these transitions as characteristic endothermic or exothermic peaks, while the TG curve documents corresponding mass losses. A decrease in the glass transition temperature for example through moisture absorption, can lead to unwanted phase transformations or recrystallization. recrystallization recrystallization. This in turn can change the crystal structure – with possible consequences such as loss of efficacy, altered bioavailability or, in the simplest case, the need to reclassify and relabel the preparation.
Evaluation of moisture sensitivity
Many active pharmaceutical ingredients exhibit pronounced hygroscopic behavior, whereby even small changes in relative humidity can significantly influence water absorption and thus stability. The STA enables quantitative determination of moisture loss through evaporation or release of water of crystallization (1).
The analysis of moisture sensitivity includes several critical parameters that are essential for stability assessment. The adsorption and desorption of water is visible in the TG signal as discrete mass changes, while accompanying heat or temperature changes allow conclusions to be drawn about the binding form of the water.
Important valuation parameters:
- Water absorption capacity: ratio of the amount of water absorbed to the sample mass
- Equilibrium moisture content: state of moisture equilibrium under defined conditions
- Sorption-desorption isotherms: Relationship between moisture quantity and relative humidity
- Crystal water content: proportion of structurally bound water
- Kinetics of moisture absorption: rate of water absorption/release The absorption of moisture leads to a lowering of the glass transition temperature in amorphous API crystals, which can result in a region with an increased tendency to recrystallize during storage or transport (2).
Thermal decomposition and storage stability
Thermal decomposition has a decisive influence on the storage stability of active pharmaceutical ingredients, as it can directly affect the chemical integrity and thus the efficacy. The Simultaneous Thermal Analysis (STA) enables the early identification of such processes through the simultaneous detection of mass changes as well as endothermic and exothermic effects.
In addition to classic thermal decomposition, oxidation reactions can also play a central role. These often lead to an increase in mass, as oxygen is incorporated into the molecular structure. Even partial oxidation can change the chemical structure and thus impair the pharmacological effect – often long before actual decomposition occurs.
Another critical factor is denaturation: thermal or oxidative influences cause biotechnologically produced or protein-based active ingredients in particular to lose their native structure. This can lead to a loss of activity, aggregate formation or altered release and thus have a massive impact on the stability of the preparation.
The precise determination of the onset temperature of decomposition or denaturation is essential for research and quality control, as it defines the upper limit for storage, transportation and processing. Even brief exceedances can cause irreversible structural changes. With the help of the STA and corresponding kinetic modeling, the shelf life of a drug substance can also be reliably predicted under defined storage conditions.
Influences on storage stability:
- Degradation and loss of efficacy: reduction in the concentration of active ingredients due to chemical decomposition or denaturation
- Oxidation: Mass increase and structural change due to oxygen incorporation
- Formation of degradation products: Formation of chemically or toxicologically relevant by-products
- Interaction with moisture: Reduced thermal stability and possible hydrolysis processes with increased humidity
- Long-term prognosis: Prediction of shelf life under defined conditions through thermokinetic modeling
Conclusion
The Simultaneous Thermal Analysis provides laboratories, researchers and engineers in the pharmaceutical industry with a highly sensitive, reproducible and time-efficient tool. It enables the in-depth and reliable evaluation of moisture sensitivity, thermal transitions and decomposition processes of API crystals. Especially under GMP conditions and in the context of quality assurance, STA enables the development and storage of APIs at the highest scientific level. The method provides precise identification of critical transition points, reliable assessment of moisture sensitivity and complete characterization of thermal and chemical-structural decomposition behaviour. This significantly increases both the safety of active ingredient analysis and the efficiency of development, quality control and stability testing.
List of sources
(1) DocCheck Flexikon: Stability of pharmaceutical crystals.
https://flexikon.doccheck.com/de/Stabilit%C3%A4tspr%C3%BCfung_(Pharmacy)
(2) Deutsche Apotheker Zeitung: Mastering decomposition reactions.
https://www.deutsche-apotheker-zeitung.de/daz-az/2015/daz-52-2015/zersetzungs-reaktionen-beherrschen
