A Simple Explanation

What is Radiolysis?

Radiolysis is like a chemical breakdown caused by high-energy radiation . This radiation can split molecules apart . In water, this process creates very reactive particles.   

How Does it Affect Drug Development?

Radiolysis can be a problem for drugs, especially those that contain radioactive elements (radionuclide drugs). The radiation from these drugs can cause them to:   

• Break down and become less effective.   
• Become impure.   
• Have a shorter shelf life.   

Other drugs, not just radioactive ones, can also be affected by radiation, for example, during sterilization.   

How Do Radionuclide Drugs Deal with Radiolysis?

To protect themselves from radiolysis, radionuclide drugs often use:

• Antioxidants: These are like protectors that grab the harmful particles created by radiation. Examples include ethanol, ascorbic acid, and gentisic acid.   
• Careful Design: Scientists try to design the drug molecules to be more resistant to radiation damage.   
• Special Formulations: They might change the drug’s recipe, for example, by diluting it or keeping it at a low temperature.   

What Technologies Are Used to Reduce Radiolysis?

Besides the methods above, other technologies help reduce radiolysis:

• Using antioxidants during manufacturing and storage.   
• Choosing the right packaging that can block out harmful things like light and oxygen.   
• Storing drugs in controlled conditions, like specific temperatures and without much oxygen or light.   

What Are Some New Techniques?

Scientists are always looking for new ways to fight radiolysis, such as:

• Developing better antioxidants.   
• Using tiny particles (nanotechnology) to protect drugs.   
• Using small devices (microfluidics) to make and handle drugs, which can reduce radiolysis.   

In short, radiolysis is a chemical process that can damage drugs, especially radioactive ones. Scientists use various methods and technologies to prevent or reduce this damage to ensure that medications are safe and effective for patients.

If you like to dive into the topic, please continue with the below in-depth report.

1. Introduction: Defining Radiolysis and its Significance in Pharmaceutical Science

Radiolysis, a process involving the dissociation of molecules by ionizing radiation, represents a fundamental chemical phenomenon with far-reaching implications across various scientific disciplines, notably within the realm of pharmaceutical science.¹ This phenomenon is characterized by the cleavage of one or more chemical bonds resulting from the absorption of energy from a high-energy flux of ionizing radiation.¹ Unlike photolysis, which utilizes ultraviolet or visible light to induce molecular dissociation, radiolysis involves higher energy radiation such as gamma rays, X-rays, or accelerated particles.² The chemistry of solutions subjected to ionizing radiation can become exceedingly complex, with radiolysis capable of locally altering redox conditions and consequently influencing the speciation and solubility of constituent compounds.²

In the specific context of pharmaceuticals, and particularly concerning radionuclide drugs, radiolysis introduces a unique and significant challenge.⁷ These therapeutic and diagnostic agents inherently incorporate radioactive isotopes, which, through their decay processes, emit ionizing radiation. This internal source of radiation can trigger a process of self-irradiation, leading to the degradation of the drug molecule itself or its associated components.⁷ The stability and efficacy of these radiopharmaceuticals are therefore intrinsically linked to their ability to withstand or circumvent the effects of radiolysis over their intended shelf life and during their application.

This report aims to provide a comprehensive analysis of radiolysis, specifically focusing on its impact within pharmaceutical development, with a particular emphasis on radionuclide drugs. It will explore the underlying mechanisms of radiolysis, detail its detrimental effects on the stability and efficacy of pharmaceutical compounds, and critically examine the diverse strategies that are employed to mitigate its potentially adverse consequences. By understanding these challenges and the innovative solutions being developed, the pharmaceutical industry can continue to advance the field of radionuclide therapy and diagnostics, ensuring the delivery of safe and effective treatments to patients.

2. Understanding the Fundamentals of Radiolysis: A Chemical and Physical Perspective

Radiolysis, at its core, is the process by which chemical bonds within molecules are broken down due to the absorption of energy from a high-energy flux of ionizing radiation.¹ This energetic radiation can take various forms, including gamma rays, X-rays, alpha particles, beta particles, and accelerated particles, all possessing sufficient energy to cause ionization of atoms and molecules.¹ For instance, alpha radiation has been shown to induce the dissociation of water into hydrogen and oxygen.³ A key application of controlled electron beam irradiation, known as pulse radiolysis, allows for the initiation and study of fast chemical reactions occurring on timescales too rapid for conventional mixing techniques.²

In aqueous solutions, which are common in pharmaceutical formulations, the radiolysis process typically commences with the ionization of water molecules.² This ionization leads to the formation of a cascade of highly reactive species, including free radicals such as hydroxyl radicals (●OH), hydrated electrons (e⁻aq), and hydrogen atoms (H●), as well as molecular products like hydrogen peroxide (H₂O₂) and molecular hydrogen (H₂).² The yield and behavior of these radiolytic products are influenced by several factors, including the pH of the solution, the type and energy of the radiation, the dose rate, and the presence of any dissolved solutes.⁴ The overall reaction for water radiolysis illustrates the generation of this array of reactive species.¹⁰

The process of radiolysis can be broadly divided into distinct stages. The initial physical stage involves the deposition of energy by the ionizing particle and the subsequent ionization of water molecules.² Following this, a physico-chemical stage occurs, characterized by numerous processes such as the solvation of electrons and the splitting of ionized water molecules into hydroxyl radicals and hydrogen molecules.² Finally, in the chemical stage, the primary products of radiolysis react with each other and with their surrounding environment, giving rise to various reactive oxygen species that can diffuse through the solution.² These reactive species are the primary drivers of degradation in pharmaceutical compounds present in the solution.

The central role of water radiolysis in the degradation of pharmaceuticals formulated in aqueous solutions underscores the critical importance of understanding and controlling this process. The high reactivity of the products of water radiolysis necessitates the development of strategies that either prevent their formation or neutralize them before they can interact with and degrade the active pharmaceutical ingredient. This understanding forms the basis for many of the mitigation strategies employed in the development and storage of radiopharmaceuticals.

3. The Detrimental Effects of Radiolysis on Pharmaceutical Compounds

• 3.1. Mechanisms of Radiolytic Degradation
  Radiolytic degradation of pharmaceutical compounds can occur through two primary mechanisms: direct damage and indirect damage.¹⁰ Direct damage arises from the direct interaction of ionizing radiation with the drug molecule, causing ionization or excitation that can lead to bond breakage and molecular transformation.¹⁰ However, in aqueous solutions, indirect damage is often the dominant pathway.⁷ This indirect mechanism involves the highly reactive species generated from the radiolysis of the solvent, primarily water.⁷ These species, such as hydroxyl radicals, hydrated electrons, and hydrogen atoms, can readily react with dissolved pharmaceutical compounds, initiating a cascade of chemical reactions that result in their degradation.⁷ This process can lead to a loss of the drug’s intended potency and the formation of degradation products, some of which may be potentially toxic.⁷ The prevalence of indirect damage highlights the critical need for strategies that can effectively target and neutralize these highly reactive species before they can interact with the pharmaceutical compound.
• 3.2. Types of Chemical Damage Induced by Radiolysis
  The interaction of ionizing radiation and its byproducts with pharmaceutical compounds can induce a wide array of chemical transformations.⁷ These include oxidation, where drug molecules lose electrons; reduction, where they gain electrons; hydrolysis, involving the cleavage of bonds by water; direct bond cleavage, leading to smaller molecular fragments; cross-linking, where molecules become interconnected; and isomerization, resulting in a change in the molecule’s structure.⁷ For instance, studies have shown that essential vitamins like thiamine, nicotinamide, riboflavine, and pyridoxine are susceptible to radiolytic decomposition, which can significantly diminish their potency.¹⁵ In the context of peptide-based radiopharmaceuticals, the interaction with water radiolysis products can lead to structural changes that alter their intended pharmacokinetic and receptor-specific properties, thereby affecting their efficacy.⁷ Furthermore, radiolysis can sometimes result in the formation of entirely new chemical entities that may possess altered biological activities or even exhibit toxicity.⁷ The diverse nature of these radiolytic transformations underscores the complexity of managing radiolysis and emphasizes the importance of employing sophisticated analytical techniques to identify and quantify the resulting degradation products to ensure the safety and efficacy of the pharmaceutical product.
• 3.3. Key Factors Influencing the Severity of Radiolysis in Pharmaceutical Formulations
  The extent to which a pharmaceutical compound undergoes radiolytic degradation is influenced by a multitude of factors.⁴ These include the fundamental characteristics of the radiation itself, such as its type (alpha, beta, gamma, X-ray), its energy, the total absorbed dose, and the rate at which the dose is delivered.⁴ Generally, higher radiation activity and prolonged exposure durations lead to a greater degree of degradation.⁷ Environmental conditions within the formulation also play a critical role. Temperature is a significant factor, with higher temperatures typically accelerating chemical reactions, including those induced by radiolysis.⁴ The pH of the solution can also influence the types and yields of reactive species formed during water radiolysis.⁴ The presence of dissolved oxygen is another crucial parameter, often enhancing radiation damage by promoting the formation of highly reactive oxygen species.⁴ Moreover, the intrinsic chemical structure of the pharmaceutical compound dictates its inherent susceptibility to radical attack, with certain functional groups being more prone to degradation than others.⁷ The concentration of the drug within the formulation can also affect the extent of radiolysis.⁸ Finally, the presence of other components in the formulation, such as solvents and excipients, can either exacerbate or mitigate the effects of radiolysis.⁴ A comprehensive understanding of the complex interplay of these factors is paramount in the design of stable pharmaceutical formulations and the optimization of storage conditions to minimize the detrimental impact of radiolysis.

4. Strategies Employed by Radionuclide Drugs to Mitigate Radiolysis

• 4.1. The Role of Stabilizers and Antioxidants in Radiopharmaceutical Formulations
  A cornerstone of mitigating radiolysis in radionuclide drugs is the incorporation of stabilizers, antioxidants, or radical scavengers, often referred to as quenchers, into their formulations.⁷ These agents are designed to preferentially react with the highly reactive species, particularly free radicals, generated during the radiolysis of water, thereby protecting the active pharmaceutical ingredient from degradation.⁷ Several excipients are commonly employed for this purpose, including ethanol, ascorbic acid, and gentisic acid, all of which have demonstrated effectiveness in scavenging free radicals.⁷ For example, ethanol is a well-known radical scavenger and has been shown to suppress radiolysis in various diagnostic and therapeutic radiopharmaceuticals.⁷ Ascorbic acid has been proposed as a particularly useful excipient due to its ability to act as both a buffer agent for pH control and a radiolytic stabilizer in metal-based radiopharmaceuticals.⁷ Gentisic acid is another popular antioxidant that has proven effective in preventing radiolytic degradation in several 177Lu-radiopharmaceuticals used in clinical practice.⁷ Beyond these, other stabilizing agents such as DMSA, cysteine, vanillin, methionine, adenine, dobesilic acid, thymine, uracil, nicotinamide, meglumine, and mannitol have been evaluated, exhibiting varying degrees of success in suppressing radiolysis in specific radiopharmaceuticals like [¹⁷⁷Lu]Lu-PSMA-617.⁷ However, the selection and optimization of these stabilizers are critical, as their presence and concentration can sometimes interfere with the radiolabeling process or introduce their own stability concerns within the formulation.⁷
• 4.2. Design Considerations for Chemical Structures to Enhance Radiostability
  A proactive approach to mitigating radiolysis in radionuclide drugs involves the careful design of their chemical structures to minimize their inherent susceptibility to radiolytic degradation.³⁸ This can be achieved by incorporating specific functional groups or structural motifs that are known to be more resistant to attack by free radicals.³⁸ For instance, the choice of the chelator used to bind the radiometal is crucial; employing more stable chelators can prevent the release of the radionuclide due to radiolytic bond breakage, which could lead to unwanted biodistribution and potential toxicity.²⁸ The selection of the radionuclide itself is another important design consideration, as its decay mode and the energy of the emitted particles can influence the extent of radiolysis.⁷ Alpha-emitting radionuclides, while highly effective for targeted therapy due to their high linear energy transfer, may also pose a greater risk of inducing radiolysis due to the high energy of their emissions.² Therefore, the rational design of the entire radiopharmaceutical molecule, taking into account the inherent stability of its components under irradiation, represents a critical strategy for minimizing the impact of radiolysis.
• 4.3. Formulation Approaches to Minimize Radiolytic Degradation
  Beyond the incorporation of stabilizers and the design of stable molecules, various formulation approaches can be employed to minimize radiolytic degradation in radionuclide drugs.⁴ Adjusting the pH and ionic strength of the formulation can influence the yields and reactivity of radiolytic species.⁴ Maintaining the radiopharmaceutical at low temperatures, including refrigeration or freezing, is a highly effective method for slowing down the kinetics of radiolytic reactions.⁷ Formulations with lower radioactive concentrations, achieved through higher dilution, generally exhibit less radiolysis due to a reduced absorbed dose rate ⁷; however, this must be balanced with the need to deliver a therapeutically or diagnostically effective dose. The use of specific buffer systems, such as ascorbic acid, can serve a dual purpose by controlling the pH of the formulation and simultaneously acting as a radiolytic stabilizer.⁷ Optimizing the formulation environment through a combination of carefully selected excipients and controlled physical conditions represents a multifaceted strategy for enhancing the radiostability of radionuclide drugs.

5. Current Technologies and Methods for Radiolysis Mitigation in Pharmaceutical Manufacturing and Storage

• 5.1. Application of Antioxidants and Radical Scavengers
  The application of antioxidants and radical scavengers is a well-established technology for mitigating radiolysis in pharmaceutical manufacturing and storage, particularly for radiopharmaceuticals.⁷ Compounds like ascorbic acid, gentisic acid, and ethanol are routinely used during both the manufacturing process and the subsequent storage of many radiopharmaceuticals to effectively scavenge the free radicals that are generated by radiolysis.⁷ The effectiveness of these scavengers is contingent upon their concentration within the formulation, the specific radiopharmaceutical being protected, and the prevailing storage conditions.⁷ In some instances, employing a combination of different antioxidants can lead to synergistic effects, providing enhanced protection against radiolysis compared to using a single agent.⁷ While these established antioxidants are widely used and effective, ongoing research continues to explore novel compounds that may offer even superior radical scavenging properties and improved biocompatibility for future applications in radiopharmaceuticals.⁷
• 5.2. Selection of Appropriate Packaging Materials with Barrier Properties
  The selection of appropriate packaging materials is a critical technology for mitigating radiolysis in the storage of pharmaceuticals, particularly those that are radiosensitive.²⁸ The packaging serves not only to contain the drug but also to protect it from external factors that can exacerbate radiolysis, such as exposure to light and oxygen.²⁸ For instance, the use of amber glass vials can significantly minimize the amount of light that penetrates the container, thereby reducing light-induced degradation.²⁸ Similarly, packaging radiopharmaceuticals under an inert atmosphere, such as nitrogen or argon, can effectively reduce the potential for oxidative degradation caused by the presence of oxygen.⁷ It is also essential that the packaging materials themselves are compatible with the radiopharmaceutical formulation and do not undergo significant degradation or leaching of harmful substances due to irradiation.⁵⁰ For the safe transport of radioactive materials, regulatory bodies mandate specific packaging requirements that are designed to ensure both the containment of the radioactive material and adequate shielding to minimize radiation exposure to handlers and the environment.⁵² Thus, the careful selection of packaging materials with appropriate barrier properties is an integral part of the strategy to maintain the stability of radiopharmaceuticals by controlling environmental factors that can influence radiolysis.
• 5.3. Importance of Controlled Environmental Conditions (Temperature, Atmosphere, Light)
  Maintaining strictly controlled environmental conditions during both the manufacturing and storage of radiopharmaceuticals is paramount for minimizing the impact of radiolysis.⁷ Temperature control is particularly critical, with storage at recommended temperatures, often involving refrigeration or even freezing, significantly slowing down the rate of radiolytic reactions.⁷ Controlling the atmospheric composition, especially by minimizing exposure to oxygen during manufacturing processes and within storage containers, can substantially reduce the occurrence of oxidative radiolytic degradation.⁷ Furthermore, for radiopharmaceuticals that are known to be sensitive to light, protection from exposure to light sources that can initiate or accelerate degradation is an essential practice.²⁸ Adherence to these recommended storage conditions is a fundamental aspect of radiolysis mitigation that directly influences the shelf life and ultimately the efficacy of radiopharmaceuticals.⁵⁸

6. Emerging Techniques and Research in Radiolysis Mitigation for Pharmaceuticals

• 6.1. Novel Chemical and Material Approaches
  Ongoing research continues to explore novel chemical compounds and materials that can offer superior protection against radiolysis in pharmaceuticals.⁷ This includes the search for new chemical entities with enhanced radical scavenging properties and improved biocompatibility for use as radioprotectants.⁷ For instance, the use of nitrones, which are known to be non-toxic radical scavengers, has shown promising results in inhibiting radiolytic decomposition in certain compounds.¹⁷ Another emerging approach involves the exploration of sacrificial ligand grafts. The concept here is to incorporate molecules within the formulation that are preferentially targeted by the reactive species produced during radiolysis, thereby protecting the main pharmaceutical compound from degradation.⁵⁹ These novel chemical and material approaches represent the forefront of research aimed at developing more effective and safer strategies for mitigating radiolysis in pharmaceutical applications.
• 6.2. Applications of Nanotechnology in Radioprotection
  The field of nanotechnology is offering potential novel solutions for protecting radiopharmaceuticals from the damaging effects of radiolysis, although the precise mechanisms by which this protection is afforded are still under active investigation.¹⁴ One hypothesis suggests that encapsulating radiopharmaceutical molecules within nanocarriers could provide a physical barrier, reducing their direct exposure to the reactive species generated by radiolysis.¹⁴ Interestingly, radiolysis itself is being explored as a technique for the synthesis of nanoparticles with precisely controlled properties that can be utilized in drug delivery systems.⁶³ This dual role of radiolysis in both potentially damaging and creating solutions for radiopharmaceuticals highlights the complexity and potential of nanotechnology in this field. Further research is crucial to fully elucidate and harness the protective capabilities of nanotechnology in mitigating radiolysis in pharmaceutical applications.
• 6.3. Microfluidic Systems for Radiopharmaceutical Synthesis and Handling
  Microfluidic technology is emerging as a powerful tool in the synthesis and handling of radiopharmaceuticals, offering several advantages, including the potential to reduce the extent of radiolysis.⁷⁰ Due to the very small volumes of reagents involved in microfluidic systems, a larger fraction of the positron energy emitted by radionuclides can be absorbed by the walls of the microfluidic device rather than by the tracer solution itself, thus minimizing radiolysis.⁷⁰ The small dimensions of these systems also enable better control over reaction conditions and facilitate faster processing times, which can significantly reduce the overall exposure time of the radiopharmaceutical to high levels of radiation.⁷⁰ Furthermore, the development of digital microfluidic platforms allows for automated and highly precise handling of microliter volumes of radiopharmaceuticals, potentially minimizing human intervention and radiation exposure while simultaneously enhancing the stability of the synthesized products.⁷⁰ Microfluidic systems thus represent a significant advancement in the field of radiopharmaceutical production, offering a promising avenue for minimizing radiolysis and improving the quality of the final drug product.

7. Case Studies: Examples of Pharmaceutical Drugs Particularly Susceptible to Radiolysis and Their Management

Several pharmaceutical drugs have been identified through research as being particularly susceptible to the effects of radiolysis. For instance, glucagon has been shown to experience a significant decrease in its potency following irradiation, highlighting its sensitivity to this process.¹⁶ Similarly, erythromycin and dobutamine exhibit a slight reduction in potency and an increase in absorbance after exposure to radiation.¹⁶ In the case of cefazolin sodium, studies have indicated that trapped radicals formed as a result of irradiation play a crucial role in the subsequent formation of radiolytic products, suggesting a complex degradation pathway.¹⁶ Technetium-99m-d,l-HMPAO, a radiopharmaceutical used in medical imaging, has been found to suffer from reduced radiochemical purity when subjected to gamma irradiation, underscoring the need for careful handling and stabilization.²⁷ Certain aryl amines labeled with carbon-11 and fluorine-18, commonly used as PET tracers, have also demonstrated rapid decomposition due to radiolysis, necessitating the development of specific stabilization strategies.¹⁷ Interestingly, the physical form of the drug can significantly impact its radiostability, as seen with insulin and heparin, where aqueous solutions are sensitive to radiolysis, but freeze-dried formulations exhibit greater resistance.²⁶ Chloramphenicol, an antibiotic, undergoes degradation in both its powder form and in eye ointment formulations, with the extent of radiolysis being influenced by the surrounding microenvironment and the presence of solvents.²⁰ In a unique example, minaprine, an anti-depressant, can be intentionally modified by radiolysis to produce a novel derivative with enhanced anti-inflammatory properties, demonstrating the potential for controlled radiolytic transformation.²²

The management of radiolysis in these susceptible drugs often involves a combination of strategies tailored to the specific drug and its intended use. Formulation adjustments, such as opting for freeze-dried forms instead of aqueous solutions, can enhance stability.²⁶ The addition of specific stabilizers or antioxidants, like ethanol or sodium ascorbate, has been shown to effectively inhibit radiolytic decomposition in certain compounds.¹⁷ Strict control over storage conditions, including temperature, atmosphere, and light exposure, is also critical in minimizing degradation.²⁶ Furthermore, when sterilization by irradiation is required, optimizing the radiation dose to achieve sterility while minimizing damage to the drug is essential.²⁰ These case studies illustrate the diverse ways in which pharmaceutical compounds can be affected by radiolysis and the importance of developing targeted strategies to address these challenges and ensure the quality and efficacy of the final drug product.

8. Regulatory Landscape and Quality Control Measures Pertaining to Radiolysis in the Pharmaceutical Industry

Radiopharmaceuticals, due to their inherent radioactivity and medical applications, are subject to stringent regulatory guidelines to ensure their safety and efficacy.⁷⁶ In the United States, the Food and Drug Administration (FDA) plays a primary role in regulating radiopharmaceuticals, overseeing their manufacturing, testing, and approval processes through its Center for Drug Evaluation and Research (CDER).⁷⁶ Similarly, in the European Union, the European Medicines Agency (EMA) establishes and enforces regulations for these specialized drugs.⁷⁶ These regulatory bodies emphasize the need for comprehensive quality control measures to verify critical attributes of radiopharmaceuticals before they are administered to patients. These attributes include radiochemical purity, which is directly affected by radiolysis, as well as radionuclidic purity, chemical purity, sterility, and apyrogenicity.⁵⁸

Pharmacopoeias, such as the United States Pharmacopeia (USP) and the European Pharmacopoeia (Ph. Eur.), provide detailed standards and test methods for radiopharmaceuticals, including specifications related to their stability and potential degradation products formed through processes like radiolysis.¹⁸ While general protocols exist within these pharmacopoeias for analyzing related substances in drugs, specific adaptations may be required for radiosterilized drugs due to the unique profiles of impurities that can arise from ionizing radiation.¹⁸ Techniques such as high-performance liquid chromatography (HPLC) are often employed to identify and quantify these radiolysis-induced degradation products.¹⁹ The FDA has also established specific regulations concerning drugs that are sterilized by irradiation, although some of these requirements have been updated or repealed over time as the understanding of radiation sterilization technology has advanced.⁸⁷ These regulatory frameworks underscore the critical importance of robust quality control measures in detecting and managing radiolysis-induced degradation in radiopharmaceuticals, ultimately ensuring patient safety and the effectiveness of these vital diagnostic and therapeutic agents.

9. Recent Scientific Literature and Reviews: Challenges and Advancements in Managing Radiolysis in Pharmaceutical Development, Including Novel Drug Delivery Systems

Recent scientific literature and reviews highlight the dynamic nature of radiopharmaceutical development, with significant attention being paid to managing the challenges posed by radiolysis, particularly in the context of emerging therapeutic modalities and novel drug delivery systems.⁷ The field of radiopharmaceutical theranostics, which combines diagnostic and therapeutic capabilities, and the growing interest in targeted alpha therapy, present unique challenges due to the use of high activity levels and highly energetic radionuclides, increasing the potential for radiolysis.⁷ Several recent reviews have focused on advancements in stabilizing radiopharmaceuticals through the use of various antioxidants and optimized formulation strategies to combat radiolysis.⁷ The application of nanotechnology in radiopharmaceutical development is also a prominent area of research, with the potential for targeted drug delivery and, potentially, radioprotection of the encapsulated drugs.¹⁴ Microfluidic systems continue to be explored and refined for their ability to improve the synthesis of radiopharmaceuticals, offering benefits such as reduced reaction times and the potential to minimize radiolysis due to the small volumes involved.⁷⁰ Despite these advancements, challenges persist, particularly concerning the reliable supply, efficient manufacturing, and effective distribution of radionuclides, especially for the increasingly sought-after alpha emitters.⁴⁹ Furthermore, the development and standardization of stability testing guidelines and the comprehensive identification and evaluation of radiolysis degradation products remain important aspects of ongoing research to ensure the quality and safety of these advanced therapies.¹⁸

10. Conclusion

Radiolysis poses a significant and ongoing challenge in the development and handling of pharmaceutical drugs, particularly in the rapidly advancing field of radionuclide-based therapies. The inherent radioactivity of these agents introduces a constant risk of self-irradiation, leading to degradation that can compromise their stability and efficacy. However, the pharmaceutical science community has responded with a multi-faceted approach to mitigate these effects. Careful formulation design, including the strategic use of stabilizers and antioxidants, forms a critical line of defense against radiolysis. The selection of appropriate packaging materials with robust barrier properties and the implementation of strictly controlled environmental conditions during manufacturing and storage further contribute to minimizing degradation.

The field continues to evolve with the exploration of emerging technologies and novel chemical entities. Research into new radioprotective agents with enhanced efficacy and safety profiles, the application of nanotechnology-based solutions for targeted delivery and potential radioprotection, and the optimization of microfluidic synthesis platforms all hold promise for future advancements in radiolysis mitigation. Moreover, ongoing refinements in analytical techniques and regulatory guidelines play a crucial role in ensuring the stability and efficacy of radiopharmaceuticals. Ultimately, the continued dedication to understanding and overcoming the challenges of radiolysis is essential for advancing the field of radionuclide therapy and diagnostics, paving the way for safer and more effective treatments for a wide range of diseases.

Works cited

1. en.wikipedia.org, accessed April 5, 2025, https://en.wikipedia.org/wiki/Radiolysis#:~:text=Radiolysis%20is%20the%20dissociation%20of,exposure%20to%20high%2Denergy%20flux.
2. Radiolysis – Wikipedia, accessed April 5, 2025, https://en.wikipedia.org/wiki/Radiolysis
3. Radiolysis – chemeurope.com, accessed April 5, 2025, https://www.chemeurope.com/en/encyclopedia/Radiolysis.html
4. Fundamentals of Water Radiolysis – MDPI, accessed April 5, 2025, https://www.mdpi.com/2673-8392/5/1/38
5. RADIOLYSIS Definition & Meaning – Merriam-Webster, accessed April 5, 2025, https://www.merriam-webster.com/dictionary/radiolysis
6. RADIOLYSIS Definition & Meaning – Dictionary.com, accessed April 5, 2025, https://www.dictionary.com/browse/radiolysis
7. Radiolysis-Associated Decrease in Radiochemical Purity of 177Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against This Process – PubMed Central, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9967390/
8. Radiolysis-Associated Decrease in Radiochemical Purity of 177Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against This Process – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/368544897_Radiolysis-Associated_Decrease_in_Radiochemical_Purity_of_177Lu-Radiopharmaceuticals_and_Comparison_of_the_Effectiveness_of_Selected_Quenchers_against_This_Process
9. Water Radiolysis: Influence of Oxide Surfaces on H2 Production under Ionizing Radiation, accessed April 5, 2025, https://www.mdpi.com/2073-4441/3/1/235
10. Radiolysis – Knowledge and References – Taylor & Francis, accessed April 5, 2025, https://taylorandfrancis.com/knowledge/Engineering_and_technology/Chemical_engineering/Radiolysis/
11. 4. Radiation chemistry of liquid systems 4.1.Techniques in radiation chemistry 4.1.1. Steady-state techniques 4.1.2.Pulse – European Commission, accessed April 5, 2025, https://ec.europa.eu/programmes/erasmus-plus/project-result-content/23832f80-9d89-4660-9cb2-40487a2fe5f9/Dilek-whole.pdf
12. A quantitative model of water radiolysis and chemical production rates near radionuclide-containing solids, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5741314/
13. Radiolysis-Associated Decrease in Radiochemical Purity of 177 Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against This Process – MDPI, accessed April 5, 2025, https://www.mdpi.com/1420-3049/28/4/1884
14. Nano-radiopharmaceuticals as therapeutic agents – Frontiers, accessed April 5, 2025, https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1355058/full
15. studies on the radiolysis and radiation protection of vitamins in aqueous systems and the solid state – INIS, accessed April 5, 2025, https://inis.iaea.org/collection/NCLCollectionStore/_Public/09/404/9404840.pdf
16. Effect of gamma irradiation on drugs – IAEA INIS – International Atomic Energy Agency, accessed April 5, 2025, https://inis.iaea.org/records/58nx5-28z03
17. Studies into Radiolytic Decomposition of Fluorine-18 Labeled Radiopharmaceuticals for Positron Emission Tomography – PMC, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5938091/
18. Radiolysis of Solid-State Drugs – and the Analytical Tools Applicable to this Study, accessed April 5, 2025, https://www.farm.ucl.ac.be/Full-texts-FARM/Engalytcheff-2007-1.pdf
19. Radiolabeling and quality control of therapeutic radiopharmaceuticals: optimization, clinical implementation and comparison of radio-TLC/HPLC analysis, demonstrated by [177Lu]Lu-PSMA – PubMed, accessed April 5, 2025, https://pubmed.ncbi.nlm.nih.gov/36333648/
20. Identification and evaluation of radiolysis products of irradiated chloramphenicol by HPLC-MS and HPLC-DAD | Request PDF – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/225108906_Identification_and_evaluation_of_radiolysis_products_of_irradiated_chloramphenicol_by_HPLC-MS_and_HPLC-DAD
21. 98 RADIOLYSIS CHARACTERIZATION OF CHLORAMPHENICOL IN POWDER AND IN EYE OINTMENT L. HONG, H. R. ALTORFER Institute of Pharmaceuti – OSTI.GOV, accessed April 5, 2025, https://www.osti.gov/etdeweb/servlets/purl/20693058
22. Irradiation of pharmaceuticals: A literature review – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/354825607_Irradiation_of_pharmaceuticals_A_literature_review
23. The Effect of Radiation on a Variety of Pharmaceuticals and Materials Containing Polymers, accessed April 5, 2025, https://www.researchgate.net/publication/223974016_The_Effect_of_Radiation_on_a_Variety_of_Pharmaceuticals_and_Materials_Containing_Polymers
24. Radiolytic Elimination of Nabumetone from Aqueous Solution: Degradation Efficiency, and Degradants’ Toxicity – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/387647878_Radiolytic_Elimination_of_Nabumetone_from_Aqueous_Solution_Degradation_Efficiency_and_Degradants’_Toxicity
25. (PDF) Radiation effects on pharmaceuticals – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/286031199_Radiation_effects_on_pharmaceuticals
26. Radiation Effects on Pharmaceuticals, accessed April 5, 2025, http://dergi.fabad.org.tr/pdf/volum35/issue4/203-217.pdf
27. Sensitivity of technetium-99m-d,1-HMPAO to radiolysis in aqueous solutions – PubMed, accessed April 5, 2025, https://pubmed.ncbi.nlm.nih.gov/1988613/
28. Chapter 15: Radiopharmaceutical Preparation Problems | Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine, 4th Edition | PharmacyLibrary, accessed April 5, 2025, https://pharmacylibrary.com/doi/10.21019/9781582122830.ch15
29. Radiolysis-Associated Decrease in Radiochemical Purity of 177Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against This Process – PubMed, accessed April 5, 2025, https://pubmed.ncbi.nlm.nih.gov/36838872/
30. Prevention of Radiolysis of Monoclonal Antibody during Labeling – Journal of Nuclear Medicine, accessed April 5, 2025, https://jnm.snmjournals.org/content/jnumed/37/8/1384.full.pdf
31. Prevention of radiolysis of monoclonal antibody during labeling – PubMed, accessed April 5, 2025, https://pubmed.ncbi.nlm.nih.gov/8708780/
32. WO2020021310A1 – Stable, concentrated radionuclide complex solutions – Google Patents, accessed April 5, 2025, https://patents.google.com/patent/WO2020021310A1/en
33. US20030198593A1 – Radioprotectants for radiopharmaceutical formulations – Google Patents, accessed April 5, 2025, https://patents.google.com/patent/US20030198593A1/en
34. Ascorbic Acid: Useful as a Buffer Agent and Radiolytic Stabilizer for Metalloradiopharmaceuticals | Request PDF – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/10413296_Ascorbic_Acid_Useful_as_a_Buffer_Agent_and_Radiolytic_Stabilizer_for_Metalloradiopharmaceuticals
35. 68Ga-Labeling: Laying the Foundation for an Anti-Radiolytic Formulation for NOTA-sdAb PET Tracers – PMC – PubMed Central, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8151064/
36. Radiation Chemical Investigation of Antioxidant Activity of Biologically Important Compounds from Plant Materials | ACS Omega, accessed April 5, 2025, https://pubs.acs.org/doi/10.1021/acsomega.9b04335
37. Ascorbic Acid: Useful as a Buffer Agent and Radiolytic Stabilizer for Metalloradiopharmaceuticals | Bioconjugate Chemistry – ACS Publications, accessed April 5, 2025, https://pubs.acs.org/doi/10.1021/bc034109i
38. Radiotracer and Radiopharmaceutical Chemistry – Advancing Nuclear Medicine Through Innovation – NCBI Bookshelf, accessed April 5, 2025, https://www.ncbi.nlm.nih.gov/books/NBK11482/
39. Chapter 9: Radiopharmaceutical Chemistry: General Topics | Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine, 4th Edition | PharmacyLibrary, accessed April 5, 2025, https://pharmacylibrary.com/doi/10.21019/9781582122830.ch9
40. Stabilized compositions of radionuclides and uses thereof – Patent US-11707540-B2, accessed April 5, 2025, https://pubchem.ncbi.nlm.nih.gov/patent/US-11707540-B2
41. Stabiliser for radiopharmaceuticals – US7914768B2 – Google Patents, accessed April 5, 2025, https://patents.google.com/patent/US7914768B2/en
42. A Step-by-Step Guide for the Novel Radiometal Production for Medical Applications: Case Studies with 68Ga, 44Sc, 177Lu and 161Tb – PMC, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7070971/
43. Effect of radiolysis produced by high levels of radiation dose (Gy) delivered by alpha particles on the production and supply of Ac-225, and the labelling of radiopharmaceutical for therapy – INIS, accessed April 5, 2025, https://inis.iaea.org/records/hyh9d-nxj45
44. What are the different types of drugs available for Radionuclide Drug Conjugates (RDC)?, accessed April 5, 2025, https://synapse.patsnap.com/article/what-are-the-different-types-of-drugs-available-for-radionuclide-drug-conjugates-rdc
45. Production and Quality Control of Actinium-225 Radiopharmaceuticals, accessed April 5, 2025, https://www-pub.iaea.org/MTCD/publications/PDF/TE-2057web.pdf
46. What are Radiopharmaceuticals? An Insight into Their Role and Applications, accessed April 5, 2025, https://openmedscience.com/what-are-radiopharmaceuticals-an-insight-into-their-role-and-applications/
47. Stability Matters: Radiochemical Stability of Therapeutic Radiopharmaceutical 177 Lu-PSMA I&T – Journal of Nuclear Medicine Technology, accessed April 5, 2025, https://tech.snmjournals.org/content/50/3/244
48. Targeting tumours with novel radiopharmaceuticals – European Pharmaceutical Review, accessed April 5, 2025, https://www.europeanpharmaceuticalreview.com/article/187762/targeting-tumours-with-novel-radiopharmaceuticals/
49. Production and Supply of α-Particle–Emitting Radionuclides for Targeted α-Therapy, accessed April 5, 2025, https://jnm.snmjournals.org/content/62/11/1495
50. PACKAGING FOR FOOD IRRADIATION – INIS, accessed April 5, 2025, https://inis.iaea.org/records/0n98n-ykp73/files/38005202.pdf?download=1
51. PACKAGING OF IRRADIATED FOOD – Foods deteriorate as a result of physiological changes, activities of enzymes and attack by, accessed April 5, 2025, https://icpe.in/icpefoodnpackaging/pdfs/20_irradiated.pdf
52. Design, Construction and Testing of Packaging for the Transport of Radioactive Materials – International Atomic Energy Agency, accessed April 5, 2025, https://www.iaea.org/sites/default/files/publications/magazines/bulletin/bull21-6/21602542432.pdf
53. Regulatory Report on Irradiation of Food Packaging Materials – FDA, accessed April 5, 2025, https://www.fda.gov/food/ingredients-additives-gras-packaging-guidance-documents-regulatory-information/regulatory-report-irradiation-food-packaging-materials
54. Active Packaging Reimagined: Novel Technologies to Derisk Drug Product Stability, accessed April 5, 2025, https://www.pharmtech.com/view/active-packaging-reimagined-novel-technologies-to-derisk-drug-product-stability
55. Lutetium Radiopharmaceuticals in Medicine: A Comprehensive Review – Open MedScience, accessed April 5, 2025, https://openmedscience.com/lutetium-radiopharmaceuticals-in-medicine-a-comprehensive-review/
56. Container-content interactions with radiopharmaceuticals: Seeing is believing – PubMed, accessed April 5, 2025, https://pubmed.ncbi.nlm.nih.gov/38286343/
57. Understanding the Regulatory Standards for Radiation Sterilization of Medical Products, accessed April 5, 2025, https://www.complianceonline.com/resources/understanding-the-regulatory-standards-for-radiation-sterilization-of-medical-products.html
58. Radiopharmaceutical quality control (RTNM) | Canadian Association of Medical Radiation Technologists – CAMRT Best Practice Guidelines, accessed April 5, 2025, https://camrt-bpg.ca/quality-of-care/quality-assurance/radiopharmaceutical-qc-nm/
59. Dioctyl Ether Radiolysis Under Used Nuclear Fuel Reprocessing Conditions – OSTI, accessed April 5, 2025, https://www.osti.gov/servlets/purl/2279174
60. Nano-radiopharmaceuticals as therapeutic agents – PMC, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10978739/
61. Nanotechnology-Based Drug Delivery Systems, 2nd Edition – MDPI, accessed April 5, 2025, https://www.mdpi.com/1999-4923/17/1/110
62. IAEA Contribution to Nanosized Targeted Radiopharmaceuticals for …, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9146346/
63. Harnessing Radiation for Nanotechnology: A Comprehensive Review of Techniques, Innovations, and Application – MDPI, accessed April 5, 2025, https://www.mdpi.com/2079-4991/14/24/2051
64. Using Radiolysis to Synthesize Nanoparticles – AZoNano, accessed April 5, 2025, https://www.azonano.com/article.aspx?ArticleID=6388
65. Nanosized Delivery Systems for Radiopharmaceuticals | IAEA, accessed April 5, 2025, https://www.iaea.org/projects/crp/f22064
66. Advances in liposomal nanotechnology: from concept to clinics – RSC Publishing, accessed April 5, 2025, https://pubs.rsc.org/en/Content/ArticleLanding/2024/PM/D4PM00176A
67. Radiation sterilization of liposomes: A literature review | Request PDF – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/377987045_Radiation_sterilization_of_liposomes_A_literature_review
68. Novel Multifunctional Theranostic Liposome Drug Delivery System: Construction, Characterization, and Multimodality MR, Near-Infrared Fluorescent, and Nuclear Imaging | Bioconjugate Chemistry – ACS Publications, accessed April 5, 2025, https://pubs.acs.org/doi/abs/10.1021/bc300175d
69. A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives – PubMed Central, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8879473/
70. Digital microfluidics – a new paradigm for radiochemistry – PMC, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4734895/
71. Microfluidic reactor geometries for radiolysis reduction in … – PubMed, accessed April 5, 2025, https://pubmed.ncbi.nlm.nih.gov/22750198/
72. First Human Use of a Radiopharmaceutical Prepared by Continuous-Flow Microfluidic Radiofluorination: Proof of Concept with the Tau Imaging Agent [18F]T807 – Steven H. Liang, Daniel L. Yokell, Marc D. Normandin, Peter A. Rice, Raul N. Jackson, Timothy M. Shoup, Thomas J. Brady, Georges – Sage Journals, accessed April 5, 2025, https://journals.sagepub.com/doi/10.2310/7290.2014.00025?icid=int.sj-abstract.citing-articles.505
73. Microfluidics in radiopharmaceutical chemistry | Request PDF – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/236918741_Microfluidics_in_radiopharmaceutical_chemistry
74. A Digital Revolution in Radiosynthesis | Journal of Nuclear Medicine, accessed April 5, 2025, https://jnm.snmjournals.org/content/55/2/181
75. Microfluidic reactor geometries for radiolysis reduction in radiopharmaceuticals | Request PDF – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/228101872_Microfluidic_reactor_geometries_for_radiolysis_reduction_in_radiopharmaceuticals
76. The Regulatory Landscape of Radiopharmaceuticals: Ensuring Safety and Effectiveness, accessed April 5, 2025, https://regulink.com/media-centre/the-regulatory-landscape-of-radiopharmaceuticals-ensuring-safety-and-effectiveness/
77. Position paper to facilitate patient access to radiopharmaceuticals: considerations for a suitable pharmaceutical regulatory framework – PMC – PubMed Central, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10761641/
78. FAQs: <825> Radiopharmaceuticals – US Pharmacopeia (USP), accessed April 5, 2025, https://www.usp.org/frequently-asked-questions/radiopharmaceuticals
79. Regulatory Guidance for Drug Interaction Studies – Solvo Biotechnology, accessed April 5, 2025, https://www.solvobiotech.com/regulatory-guidance/FDA_EMA_Guidance_for_Drug_Interaction_Studies
80. In-depth look at the differences between EMA and FDA – Mabion, accessed April 5, 2025, https://www.mabion.eu/science-hub/articles/similar-but-not-the-same-an-in-depth-look-at-the-differences-between-ema-and-fda/
81. United States | European Medicines Agency (EMA), accessed April 5, 2025, https://www.ema.europa.eu/en/partners-networks/international-activities/bilateral-interactions-non-eu-regulators/united-states
82. QUALITY ASSURANCE AND QUALITY CONTROL OF RADIOPHARMACEUTICALS: AN OVERVIEW – DergiPark, accessed April 5, 2025, https://dergipark.org.tr/en/download/article-file/2399654
83. Fundamental concepts of radiopharmaceuticals quality controls – Pharmaceutical and Biomedical Research, accessed April 5, 2025, https://pbr.mazums.ac.ir/article-1-198-en.pdf
84. (PDF) Fundamental concepts of radiopharmaceuticals quality controls – ResearchGate, accessed April 5, 2025, https://www.researchgate.net/publication/331635329_Fundamental_concepts_of_radiopharmaceuticals_quality_controls
85. Chapter 14: Quality Control of Radiopharmaceuticals | Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine, 4th Edition | PharmacyLibrary, accessed April 5, 2025, https://pharmacylibrary.com/doi/10.21019/9781582122830.ch14
86. 825 RADIOPHARMACEUTICALS—PREPARATION, COMPOUNDING, DISPENSING, AND REPACKAGING – USP-NF, accessed April 5, 2025, https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/gc-825-postponement-rb-notice-20191122.pdf
87. Regulation Requiring an Approved New Drug Application for Drugs Sterilized by Irradiation, accessed April 5, 2025, https://www.federalregister.gov/documents/2019/12/16/2019-27046/regulation-requiring-an-approved-new-drug-application-for-drugs-sterilized-by-irradiation
88. 18. Validation of the Radiation Sterilization of Pharmaceuticals – Regulations.gov, accessed April 5, 2025, https://downloads.regulations.gov/FDA-2017-N-6924-0002/content.pdf
89. Radiopharmaceuticals Emerging as New Cancer Therapy – NCI, accessed April 5, 2025, https://www.cancer.gov/news-events/cancer-currents-blog/2020/radiopharmaceuticals-cancer-radiation-therapy
90. Attacking Cancer Targets with Radiotherapeutics | The Scientist, accessed April 5, 2025, https://www.the-scientist.com/attacking-cancer-targets-with-radiotherapeutics-72449
91. Editorial: Recent advances in radiotheranostics – Frontiers, accessed April 5, 2025, https://www.frontiersin.org/journals/nuclear-medicine/articles/10.3389/fnume.2024.1520778/full
92. Radiopharmaceutical Industry Outlook: Growth Trends and Future Prospects – BioSpace, accessed April 5, 2025, https://www.biospace.com/radiopharmaceutical-industry-outlook-growth-trends-and-future-prospects
93. Special Issue : Advancements in Radiopharmaceutical Theranostics – MDPI, accessed April 5, 2025, https://www.mdpi.com/journal/pharmaceuticals/special_issues/QP1OMHA3R2
94. A decade of incremental advances in radiopharmaceuticals: a promising future ahead, accessed April 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11616306/
95. Commercial and business aspects of alpha radioligand therapeutics – Frontiers, accessed April 5, 2025, https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.1070497/full
96. Pharmaceutical stability testing, Part 1: An overview of stability – RAPS, accessed April 5, 2025, https://www.raps.org/News-and-Articles/News-Articles/2024/6/Pharmaceutical-stability-testing,-Part-1-%C2%A0An-overv
97. Guideline for the Stability Testing of Nonprescription (OTC) Drug Products Not Regulated by an NDA/ANDA, accessed April 5, 2025, https://www.chpa.org/public-policy-regulatory/voluntary-codes-guidelines/guideline-stability-testing-nonprescription-otc
98. Annex 10 – ICH, accessed April 5, 2025, https://database.ich.org/sites/default/files/Q1F_Stability_Guideline_WHO_2018.pdf
99. Quality Guidelines – ICH, accessed April 5, 2025, https://www.ich.org/page/quality-guidelines