Table of Contents
Thermogravimetric analysis (TGA) of gelatine capsules: basics and significance
Thermogravimetric analysis (TGA) is a key method in pharmaceutical and medical analysis to quantitatively monitor the moisture behavior and stability of materials such as gelatin capsules under real storage conditions. Especially with hygroscopic materials such as gelatine, knowledge of the moisture content is crucial, as this has a significant influence on capsule strength, release properties and overall stability during storage and transportation (1). TGA continuously measures the mass change of a sample at a controlled temperature rise, allowing precise characterization of the thermal properties of pharmaceutical materials. For gelatine capsules, it is possible to determine exactly how much water is contained in different types of binding and how this moisture evaporates when heated or during long-term storage. The method not only provides the pure moisture content, but also detailed information on the interaction between water and the capsule matrix as well as on the mechanics of relevant transitions such as glass transition and melting point (2).
Central aspects of the TGA application:
- Continuous mass monitoring with controlled temperature rise
- Differentiation between free and bound moisture in the gelatine matrix
- Quantification of water evaporation processes in the 40-150°C range
- Detection of thermal transitions and structural changes
- Correlation between mass loss and moisture loss of the samples
- Validation of storage stability under different environmental conditions
A model known as sorption-desorption moisture transfer describes the transfer of water between the capsule wall and the capsule filling during storage. The use of this model in conjunction with TG analysis data allows the prediction of the equilibrium moisture content in the system and helps to select storage conditions in such a way as to prevent the capsules from cracking or sticking together (3).
Residual moisture as a critical stability factor over longer storage periods
Gelatine capsules are characterized by a typical initial residual moisture content of around 13% – a value that is relatively stable after production but is subject to considerable fluctuations due to external influences such as temperature and humidity. The optimum residual moisture for gelatine capsules is ideally between 12-16%, which gives them the necessary flexibility and elasticity and acts as a natural plasticizer for the gelatine matrix (4). During a three-month storage period, TGA can be used to quantitatively monitor how the residual moisture is lost or absorbed under different environmental conditions. Published studies show that the residual moisture of the gelatine capsule increases significantly after just 24 hours under increased humidity and the material properties are affected. Over longer storage periods, moisture equalization with the environment tends to be completed, so that the capsules either increase in moisture or successively lose moisture under dry conditions (5).
Critical moisture areas and their effects:
- Residual moisture too low (<8-10%): Loss of flexibility, embrittlement, increased risk of breakage during handling
- Optimum residual moisture (12-16%): Balanced mechanical properties, stable release properties
- Excessive residual moisture (>16%): Increased plasticity, sticking, deformation of the capsule geometry
- Extreme humidity (>65% RH): deformation, mold growth, microbial growth, loss of function
- Long-term effects: Moisture equalization with the environment leads to permanent changes in properties
TGA-based evaluation of moisture changes:
- Quantitative determination of moisture loss through precise mass measurement in the temperature range 40-150°C
- Seamless tracking of changes in humidity over longer storage periods of 3 months and more
- Detection of critical moisture areas to avoid stability problems at an early stage
- Correlation between environmental conditions and resulting material changes
- Objective, scientifically sound basis for quality management and regulatory compliance
The ability of gelatine capsules to absorb or release water results from the molecular structure of the gelatine itself. The polymer matrix can become plasticized or brittle due to the moisture content, whereby the flexibility decreases with decreasing residual moisture and the capsule can become brittle.
Thermal properties and long-term stability of pharmaceutical gelatine capsules
The key thermal properties for the long-term stability of gelatine capsules include the glass transition temperature, melting point, behavior under humidity fluctuations, thermal decomposition and specific heat capacity. These parameters fundamentally determine how the capsule retains its mechanical integrity, flexibility and protective function over the entire storage period and during transportation (6). The glass transition temperature describes the critical temperature range in which gelatine changes from a glassy, brittle state to a flexible, rubbery state. If the storage moisture or temperature falls below a critical value, the capsule becomes brittle and susceptible to breakage. If the humidity is too high or the glass transition temperature is exceeded, it tends to deform, stick or release the contents of the capsule in an uncontrolled manner. The melting point marks the transition from solid to liquid, whereby temperatures above 30°C can already become problematic with long-term exposure.
Central thermal parameters and their significance:
- Glass transition temperature (Tg): Critical transition from brittle to flexible material behavior
- Melting point (Tm): Temperature limit for dimensional stability (>30°C permanently problematic)
- Thermal decomposition temperature: Structural degradation of the gelatine matrix above 150°C
- Specific heat capacity: measure of thermal reactivity and energy requirement
- Crystallization behaviour: Structural changes with temperature fluctuations
- Phase transitions: Reversible and irreversible changes of state of the capsule matrix
Effects of thermal properties on product stability:
- Mechanical integrity: Preservation of capsule shape and strength over the storage period
- Release properties: control of active substance release in a physiological environment
- Chemical stability: Protection against thermally induced degradation of the capsule matrix
- Solubility behavior: Influencing the dissolution kinetics in the gastrointestinal tract
- Cross-linking resistance: avoidance of irreversible cross-linking reactions
Above certain temperatures, thermal decomposition of the gelatine sets in, whereby this threshold is less relevant in practical storage, but must be taken into account in process steps or analytical methods. The purity and thermal stability of the gelatine used is crucial, as oxidation by light and heat can reduce the mechanical strength and integrity.
Influence of environmental factors on chemical stability and material integrity
Temperature and humidity are the two key environmental factors that significantly and often synergistically influence the chemical stability of gelatine capsules. Higher temperatures increase the mobility of the gelatine molecular chains and thus weaken the intermolecular bonds within the capsule matrix. This allows water and other small molecules to penetrate the gelatin structure more easily, which significantly increases the susceptibility to chemical degradation processes such as hydrolysis, oxidation and undesired cross-linking (7).
As the temperature rises, chemical reactions accelerate exponentially, with mechanical and chemical stability being significantly reduced from 35-40°C. In extreme cases, the gelatine matrix can collapse, leading to sticking, irreversible deformation or partial melting of the capsule. In extreme cases, the gelatine matrix can collapse, leading to sticking, irreversible deformation or partial melting of the capsule and thus compromising dosing safety and active ingredient protection. High storage temperatures also lead to fluctuations in the residual moisture in the gelatine capsule and to a decrease in the glass transition temperature, which makes the capsule softer and chemically more vulnerable.
Temperature-related stability risks:
- Acceleration of chemical reactions (hydrolysis, oxidation, cross-linking) from 35°C
- Increase in molecular mobility and weakening of intermolecular bonds
- Influencing the residual moisture and lowering the glass transition temperature
- Risk of matrix collapse, deformation and melting processes
- Compromising dosing safety and active ingredient protection
- Irreversible structural changes with prolonged exposure
Humidity-related degradation mechanisms:
- Hygroscopic behavior leads to uncontrolled water absorption at >60% rH
- Reduction of the glass transition temperature due to increased water content
- Promotion of chemical degradation processes due to excess moisture in the matrix
- Facilitation of hydrolysis and microbial decomposition of the gelatine structure
- Risk of leaks due to softer, more permeable and more unstable capsule walls
- Cross-linking processes at extreme humidity impair solubility and release
Gelatine is highly hygroscopic and absorbs moisture from the environment at high humidity, which leads to a significant increase in the water content of the capsule. This results in a reduction in the glass transition temperature and makes the gelatine matrix more flexible, but at the same time much more chemically unstable. Excess moisture facilitates both hydrolysis and microbial decomposition of the gelatine and can initiate harmful cross-linking processes.
Synergistic effects and optimal storage conditions:
- Synergistic effect of temperature and humidity increases degradation exponentially
- Optimal storage at 15-25°C and 30-60% relative humidity
- Avoidance of tropical conditions to maintain product quality
- Need for strict environmental monitoring in pharmaceutical logistics
- Importance of controlled storage conditions for regulatory compliance
The optimum storage conditions for pharmaceutical gelatine capsules are 15-25°C and a relative humidity of 30-60% in order to guarantee both chemical and mechanical stability over long periods of time. Deviations from these parameters, especially tropical conditions with high temperature and humidity, lead to a significant and often irreversible reduction in product quality.
Practical application, industrial relevance and quality management
TGA offers the pharmaceutical industry a precise and scientifically sound way of answering critical practical questions: How much residual moisture remains after several months of storage under specific climate conditions? How stable is the capsule structure under real transportation and storage conditions during the entire supply chain? How can storage and manufacturing processes be optimized to ensure consistent quality? For research departments, laboratories and development teams in the pharmaceutical industry, the integration of TGA for moisture measurement and material characterization is now state-of-the-art and a critical component of comprehensive quality management (8).
TGA data provides a scientifically robust basis for assessing the product safety of gelatine capsules over longer periods of time and enables the prediction of material behavior under different environmental conditions. If the moisture content of the capsule is reduced due to unfavorable storage conditions, care must be taken to ensure that the water content does not fall below critical values in order to avoid brittleness and fragility. If, on the other hand, the capsule remains too moist, the glass transition temperature will drop, plasticity will increase and the contents of the capsule may be released in an uncontrolled manner.
Comprehensive practical recommendations for the industry:
- Constant storage at 15-25°C and 35-65% relative humidity in controlled environments
- Use of high-quality moisture and light-proof packaging materials such as aluminum composite films
- Implementation of regular visual inspections for discoloration, deformation or mold growth
- Carrying out random TGA analyses for continuous quality monitoring
- Comprehensive validation of stability over the entire declared shelf life
- Systematic protection from light exposure to prevent photochemical degradation
- Integration into quality management systems and regulatory compliance programs
Strategic industrial advantages and applications:
- Objective, scientifically comprehensible basis for comprehensive stability assessments
- Data-driven optimization of storage, transport and manufacturing processes
- Proactive compliance with regulatory requirements and international product specifications
- Development and validation of improved packaging systems and protection concepts
- Continuous quality assurance along the entire pharmaceutical supply chain
- Risk minimization through preventive stability analysis and material characterization
- Cost optimization by avoiding product losses and complaints
Another critical risk associated with changing moisture levels concerns the integrity of the capsule filling, especially if it is hygroscopic. A balanced moisture balance ensures the necessary flexibility and stability, which is also highly relevant from a regulatory perspective in order to ensure compliance with specifications throughout the entire product life cycle and to meet international quality standards.
Conclusion
Thermogravimetric analysis is proving to be an indispensable analytical tool for scientifically recording, quantifying and comprehensively documenting moisture losses and the resulting changes in the mechanical and thermal stability of gelatine capsules in the pharmaceutical industry. These detailed findings flow directly into the systematic optimization of storage and production conditions as well as the evidence-based development of safe and reliable pharmaceutical dosage forms.
TGA not only makes the complex moisture profile in pharmaceutical gelatine capsules precisely measurable and traceable within typical and critical storage times, but also provides an objective, scientifically sound and regulatory accepted basis for comprehensive stability assessments, targeted material optimization and reliable compliance in modern pharmaceutical manufacturing. For the pharmaceutical industry, the integration of TGA into quality management systems is a critical success factor for product safety, regulatory compliance and economic efficiency.
List of sources
(1) Investigating the effect of novel capsule materials on the stability of soft capsules, AIP Advances, 2025. https://pubs.aip.org/aip/adv/article/15/4/045209/3342879/Investigating-the-effect-of-novel-capsule
(2) Comparative Evaluation of Gelatin and HPMC Inhalation Capsule Shells Exposed to High Humidity, PMC12299881, 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC12299881/
(3) Chang RK et al, A Study on Gelatin Capsule Brittleness: Moisture Transfer Between the Capsule Shell and its Content, J Pharm Sci, 1998. https://pubmed.ncbi.nlm.nih.gov/9572904/
(4) Ensuring Quality and Shelf Life: Optimal Storage. http://de.gdlcapsule.com/info/ensuring-quality-and-shelf-life-optimal-stora-17198404475266048.html
(5) What is the Shelf Life of Medicine Gelatin Capsules. https://de.gaohuacapsule.com/blog/what-is-the-shelf-life-of-medicine-gelatin-capsules-134787.html
(6) Differential Scanning Calorimetry (DSC) Analysis. https://torontech.com/de/differential-scanning-calorimetry-dsc-analysis/
(8) Formulation with soft gelatine capsules. https://www.saintyco.com/de/formulierung-mit-weichgelatinekapseln/
