(T1230-08-45) Multiscale Thermo-Kinetic Aging Model of Complex Systems: Application to Device Materials and Interfaces including Implications in Drug Stability

Purpose: In previous work [1,2] we introduced a multiscale thermo-kinetic aging model to describe the behavior of complex systems (e.g., a medical device or primary container). The model considers the functional and chemical behavior of the system and the scale of activation energies involved in such behavior. Using chemical kinetic theory [3], we established that such activations energies translate in actual time scales for the aging of such complex systems [4.5]. Traditionally, the design of accelerated aging protocols has been based on several regulatory guidance [6-8] or literature [9-10] where only the acceleration of the aging processes by thermal energy is considered. The relationship between the Q₁₀ factor, and the activation energy of the aging processes is shown below. It is customary to use of a Q₁₀ factor of 2.0 based solely on thermal energy without a thorough analysis of the different mechanism contributing to the failure mode (mechanical failure, chemical degradation). This study will present further experimental and theoretical analysis of a new multiscale thermo-kinetic aging model of complex systems involving many components made from elastomers, polymers, and metals. The model predicts the presence of different time and energy scales for the behavior the system’s components and the overarching system.

Methods: The main approach consists of using Dynamic Mechanical Analysis (DMA), Differential Scanning Calorimetry: Oxidative Induction Time (DSC-OIT) and Thermo-Gravimetric Analysis (TGA) to evaluate the functional and chemical aging of complex systems. The exact methodology and implementation will depend on each application considered. The correlation between functional aging and the different relaxation modes of polymers, as well as chemical aging and reaction mechanisms, is evaluated and the mechanisms prioritized based upon their impact on the system’s functionality and user’s safety.

Results: Figure 1 shows the results for the DMA-strain relaxation of the elastomeric (butyl-1) molded part under 0.35 MPa tensile stress loading/unloading at different temperatures between 2 and 70^oC. Figure 2 shows the DMA-Time Temperature Superposition results for the strain relaxation under tensile stress of butyl-1 elastomeric part as molded. The predicted reduced time for the strain relaxation correspond to typical shelf lives of the part having activation energy of 215.3±0.6 kJ/mol kJ for a Q₁₀ factor of 12.6±0.1. Similar analysis of another elastomeric (TPE-1) part produced significantly different results: activation energy of 107.9±2.2 kJ/mol kJ for a Q₁₀ factor of 3.6±0.1. Figure 3 shows the oxidative-induction time results for the same butyl-1 elastomeric molded parts corresponding to activation energies of 172.5±16.0 kJ/mol and a Q₁₀ factor of 8.1±1.2. Similarly, TPE-1 molded parts showed activation energies of 103.4±16.2 kJ/mol kJ for a Q₁₀ factor of 3.5±1.2 under the same analysis

Conclusion: The results confirm the presence of different energy and time scales during the aging of systems and depending on each application either functional or chemical aging will dominate. Furthermore, they also show that in the overall aging of a system, a variety of physico-chemical phenomena are interrelated and must be considered to predict the system’s aging behavior. These considerations are also valid for the aging/degradation of drug products. We will outline how this modeling may be extended to such cases and suggest relevant analytical techniques for such applications.

References: 1. “Adhesion, friction and viscoelastic properties for non-aged and aged Styrene” N. Rodriguez a, L. Dorogin, K.T. Chew, and B.N.J. Persson, Tribology International 121 (2018) 78–83
2. “Aging of Complex Systems: Fundamental Theory and Implications in the Aging of Primary Containers and Medical Devices: Components and Systems”, N Rodriguez, T Bankston, B. N J Persson, PDA-2018 Conference, Orlando, FL.
3. Chemical Kinetics and Reaction Dynamics, P. L. Houston, Dover Publications, Inc (2001)
4. “Temperature dependance of rate processes Beyond Arrhenius and Eyring: Activation and Transitivity”, V. H. Carvalho-Silva, N. D. Coutinho, and V Aquilanti, Frontiers in Chemistry, 7-380 (2019)
5. “Activation Energies and Beyond”, Z. A. Piskulich, O. O. Mesele, and W. H. Thompson, Jou. Phys. Chem. A 2019, 123, 7185-7194
6. ASTM F1980-16:Accelerated aging for Sterile barrier systems for medical devicesI
7. ICH Q1A(R2): Stability testing of New Drug Substances and Products
8. 21CFR 211.166: Stability testing
9. “General Aging Theory and Simplified Protocol for Accelerated Aging of Medical Devices,” Hemmerich, K. J., Medical Plastics and Biomaterials, July/August 1998, pp. 16–23
10. “Stability Testing of Pharmaceutical Products”, S. Bajaj, D. Singla and N. Sakhuja, Jou. of Appl. Pharm. Scie., 02 (03); 2012: 129-138


Figure 1. DMA-strain relaxation of butyl-1 elastomeric molded part under 0.35 MPa tensile stress.


Figure 2. TTS plot of static deformation (StatD) vs. reduced time for butyl-1 elastomeric molded part under 0.35 MPa tensile stress loading/unloading between 2 and 70oC.


Figure 3. Arrhenius plot of the oxidative-induction time (tonset) vs. inverse of temperature for butyl-1 molded parts. The slope of the linear fit is proportional to the activation energy of the oxidative processes.