Review ArticleReview

The Effect of Radiation on a Variety of Pharmaceuticals and Materials Containing Polymers

Mine Silindir and Yekta Özer
PDA Journal of Pharmaceutical Science and Technology March 2012, 66 (2) 184-199; DOI: https://doi.org/10.5731/pdajpst.2012.00774

Abstract

The interaction of radiation, whether it has natural or artificial, electromagnetic or particle-type characterizations, with materials causes different effects depending on the dose and type of radiation and physicochemical properties of the material. In the medical field, understanding the effect of radiation on a variety of materials including pharmaceuticals, medical devices, polymers as biomaterials, and packaging is crucial. Although there are many kinds of sterilization methods, the use of radiation in sterilization has many advantages such as being a substantially less toxic, safer terminal sterilization method. Radiosterilization is sterilization with an ionizing radiation such as gamma rays or electron beam (e-beam), the latter being a newer but less-frequently used technique. However, the need for large facilities with proper radiation protections for personnel and the environment from the effects of radiation and radioactive wastes makes this procedure highly costly. The effects of radiation on materials, especially pharmaceuticals and polymer-containing medical devices, cause degradation or chemical changes. The effects of radiation on a variety of different materials is a growing research area that can create safer techniques that reduce radiation damage and increase cost-effectiveness in the future.

LAY ABSTRACT: Radiation can be used for positive purposes such as medical applications and the sterilization of pharmaceutical products, medical devices, and food and agricultural products as well as clinical applications such as diagnosis and/or therapy of a variety of diseases. The dose rate, time, type and emitted energy of the radiation are critical issues for determining its benefit/damage ratio. The sterilization of pharmaceuticals and medical devices that contain polymers can be achieved safely and effectively by irradiation. The sterilization of materials at the terminal phase—that is, in its final packaging materials—and its suitability to a variety of different kinds of packaging materials have brought additional value to radiosterilization. However, radiation sterilization is more expensive than the other sterilization methods that require large facilities. Although this method is safe in application, the effects of radiation on drugs and polymers must be evaluated by various analytical methods. In the nuclear chemistry and radiochemistry field, more effective and novel methods are being developed to decrease the harmful effects of radiation on materials.

Introduction

As is commonly known, different radionuclides cause different effects within the body depending on different radioactivity emitting properties, physicochemical form of intake, half-life of the radioisotope, emission energy, and chemical nature of the element. Due to the different kinds of energies and penetration properties of alpha, beta, and gamma rays within tissues or materials, the organs, tissues, cells, and molecules are affected variously. In the case of high activity, aggregation may cause some undesired influences such as acute tissue damages, fibrosis in the lung, pneumonitis, and skin ulcerations. Malignant changes in tissues/organs may be formed depending on the long-term effect of the irradiation (1).

Radiation is currently used in a variety of fields. Some uses are for medical purposes such as the diagnosis and therapy of diseases, sterilization (primarily pharmaceuticals or medical devices) (2); food irradiation for conservation (3); research in agriculture and animal breeding; irradiation of domestic or industrial wastes, hospital wastes, and hood gases; and polymer processing such as polymerization, crosslinking, and controlled degradation/disintegration (2, 4).

Importance of Radiosterilization

Sterilization is one of the most important applications of radiation in industry and research. Radiation sterilization has been used for more than 50 years (5). With an increase in the use of disposable medical products, there has been a significant increase in radiation sterilization. Almost 160 commercial 60Co irradiators exist for sterilization with gamma radiation in 47 countries worldwide, including, contain research and development centers (6, 7). It is an essential process especially for pharmaceuticals such as parenteral solutions, emulsions, suspensions, ophthalmic preparations, and also for sterilizing water for injection used in the preparation of many parenteral pharmaceuticals. Gamma radiation sterilization is an officinal sterilization method and isothermal procedure, and it therefore produces no significant temperature rise within the sterilization process that may cause any degradation or chemical change. It is standard that any process provide a sterility assurance level of 10−6. Although there are number of different methods for the sterilization of pharmaceuticals and other materials used within the body (such as medical devices), radiosterilization is one of the most-selected methods due to its different advantages. Radiosterilization does not exhibit any of the toxicological and ecological problems that ethylene oxide (EtO) and formaldehyde sterilization do because of solvent residues that may stay on the material even after the quarantine process. Given this, radiosterilization is an effective, safe, easy, and rapid method for the sterilization of pharmaceuticals, active substances, and other ingredients and packaging materials that are sensitive to heat, steam, and pressure (8⇓⇓–11).

Like other sterilization methods, gamma radiation sterilization may also cause small amounts of degradation to the product during the inactivation process of microorganisms. Ion pairs may be formed that cause the formation of free radicals and excitation of electrons. The free radical reactions may cause gas release, double-bond formation or scission, electron migration, or crosslink formation in polymers. Polymerization is commonly formed at unsaturated compounds after irradiation. The mechanism of sterilization can be defined as the damage to the DNA chain and the membrane of the microorganisms that may cause cell death finally. Pharmaceuticals in the form of solutions such as parenterals are subject to radiation in two different ways, one directly from the radiation and the other indirectly from the transfer of the energy from the water to the solute material by the radiolysis products of water. Hydrogen, hydroxyl radicals, and hydrated electrons are the most important radiolysis products of water that are produced indirectly in radiation sterilization (12).

Although the radiation sterilization of pharmaceuticals may be performed by gamma ray, e-beam, X-ray, and ultraviolet (UV) light, the most commonly applied and officinal sterilization method is gamma radiation sterilization (8⇓⇓⇓–12). Pharmaceuticals have been sterilized by these radiosterilization methods for almost 40 years by producers and drug companies. Although gamma radiation sterilization is the most commonly used one, X-ray and e-beam sterilization can also be used in different fields of pharmaceutical productions in industry (12). Generally, e-beam radiation causes less radiolysis than gamma irradiation, and less breakdown of the material is the result of the application of shorter process times with higher irradiation dose rates. On the contrary, application of higher dose rates of gamma photons may cause enhanced damage (12, 13). While gamma irradiation delivers a certain dose over a period of minutes to hours to a large volume of product, e-beam irradiation delivers the same dose in a few seconds but to a very small volume. Generally, similar radicals are formed when irradiating the materials by gamma radiation and e-beam; the only difference is the amount of formed radicals. For assessing the radiolytic properties of ionizing radiation, radicals should be identified with the help of instruments for observing the benefit/damage ratio. The dosimetry and the detection of radiosterilization of pharmaceuticals are significant for different regulatory agencies all around the world. Electron spin resonance (ESR) is commonly used for the identification of the free radicals that are formed by the irradiation of pharmaceuticals and other materials (14⇓–16).

There are some points that should be considered for radiosterilization, such as the quantitative relationship between the applied radiation dose and obtained microbicidal effect, radiosensitivity of different microorganisms to radiation, effect of environmental conditions on microorganism lethality, and penetration power of the radiation. Radiosterilization was first applied in late 1950s commercially. It is applied to plastic- and rubber-based materials that are the basic materials of syringes, sutures, implants, infusion and transfusion sets, surgical gloves, catheters, blood-collecting sets, pharmaceutical containers, Petri dishes, and other products such as ready-to-use kits for operating rooms, dressings, gowns, linens, surgical towels, bandages, swabs, and even biological tissues. For sterilization processes, these items should be packed individually or as a group with special materials that are hermetically sealed before sterilization (17, 18). Gamma irradiation as a sterilization method was first approved in 1963 by British Pharmacopoeia (BP) and was later accepted by United States Pharmacopeia (USP) XVII and the European Agency for the Evaluation of Medicinal Products. The dose is generally chosen as 25 kGy if there is no information about the microbial load of the material before irradiation and if the product is resistant to the radiation. But, lesser doses can also be chosen if it can be validated. Validation of radiation sterilization is essential for good manufacturing process applications. The application of novel validation methodologies using fewer samples for qualifying lower sterilization doses is not accepted as a positive approach by the radiaton sterilization community (19, 20). The determination of radiation dose is one of the most crucial parameters to control. Dose mapping for performance qualification is another essential issue in radiation sterilization. Minimum and maximum doses should be identified by dosimeters for establishing dose location and magnitude. It is recommended that B1 and B2 methods should be used, as described in the Process Control Guidelines for Radiation Sterilization of Medical Devices of the Association for Advancement of Medical Instrumentation (AAMI) (8, 13, 21, 22). The stability of the compound and the pharmaceutical should be designated depending on the exposure to the radiation before radiosterilization. Prior to applying radiosterilization, it is necessary to assess the stability of the compounds and pharmaceuticals. Higher doses such as 50 kGy may be used for the feasibility studies indicating the type of radiolytic decomposition. The accelerated aging studies should be done during the inspection by regulatory authorities, such as the Food and Drug Administration (FDA) in the U.S. For assessing the acceptable limits of the radiolysis products, formed products should be evaluated to ensure there were no adverse effects in that concentration. The products formed by the irradiation are not unique to the irradiation process. In this way, the radiolysis products are the same when the drug is subjected to a variety of different sterilization procedures separately and in similar concentrations (8, 9, 13, 21⇓–23).

The Effects of Radiation on Pharmaceuticals

Radiation sterilization may be safely applied on pharmaceuticals. The only disadvantage is the necessity of constructing an advanced process unit that causes high costs. The pharmaceuticals should be stable until the end of their expiration dates after sterilization with gamma radiation. Only a very small amount of change may occur depending on the irradiation process, but physical, chemical, microbiological, therapeutical, and toxicological changes should be in acceptable limits for organic materials used in the pharmaceutical industry. The main attention should be paid on the color change, potency loss, acid formation, and the production of UV-absorbing species. While color alterations are very commonly seen, changes in pH are also seen in solutions (8, 13, 24, 25).

It is commonly believed that many pharmaceuticals are more stable to irradiation in a dry solid state than in other forms, especially in aqueous form. Radiolysis species produced by radiation sterilization may react with product's active ingredients, other excipients, or both. Water-containing pharmaceuticals are generally more sensitive to radiolysis products such as hydrogen, hydroxy radicals, hydrated electrons, and hydrogen peroxide. Therefore, it can be assumed that although these drugs can be sterilized alone, some undesired chemical alterations and degradations can be formed due to the vehicles in the formulation. However, studies show that the drugs themselves generally are not degradated by gamma radiation sterilization that depends on quite low levels of hydrogen peroxide (13, 24). Gamma radiation sterilization affects both the active pharmaceutical ingredients and the drug carrier systems (26).

The effects of radiosterilization on the physicochemical characteristics of the carriers and on the biological properties for brucellosis of the entrapped antigen complex from Brucella ovis were investigated by Martins et al. (27). The antigen was sterilized after entrapment in the conventional and mannosylated polyanhydride nanoparticles for ophthalmic delivery. Although the size, morphology, antigen entrapment, integrity, and antigenicity of nanoparticles were not affected by sterilization with both 10 and 25 kGy doses, the antigen release was affected negatively by the 25 kGy dose. These vaccine systems were found to be effective after sterilization with a 25 kGy radiation dose of gamma radiation. The effect of different doses of gamma irradiation such as 5, 15, 25, and 50 kGy on poly(ethylene glycol)-co-Poly(d,l lactide) (PEGd, lPLA) and poly(ethylene glycol)-co-Poly(d,l lactic and glycolic acid) (PEG-PLGA) multiblock copolymers was investigated by Dorati et al. (28). A decrease in the molecular weight of polymer samples was observed by the application of increasing doses. The major effect of gamma radiation on polymers was found to be the chain scission due to the increase in ―OH and ―COOH groups after irradiation. It was also observed that the effect of gamma radiation continued for a while after the irradiation was determined. Some degradation reactions were also observed during storage.

Biodegradable microparticulate systems containing levonorgestrel for parenteral contraception were prepared and sterilized with gamma radiation by Puthli et al. (29). For evaluating the sterilization, a sterility test was performed based on USP 2006 on particles subject to a 25 kGy dose of gamma irradiation previously. The optimum drug-to-polymer ratio was found as 0.3:1 (w:w) and the drug-loading capacity was calculated as 52%. The release kinetics of microparticulate systems was observed normally to obey a sustained release, but fitted to zero-order release kinetics only for a period of 1 month. In this way, cheaper and more stable microparticulate systems were obtained. The effect of radiosterilization on doxorubicin-loaded poly(butyl cyanoacrylate) nanoparticles was studied by Maksimenko et al. (16). Gamma radiation and e-beam doses of 10–35 kGy were applied and the optimum dose was found to be 15 kGy for the sterilization of the nanoparticles for both methods. The stability and physicochemical properties of empty and drug-loaded nanoparticles were not affected by either of the sterilization methods, even when applying a high dose (35 kGy). A study was performed by Martinez-Sancho et al. (30) on the effect of gamma irradiation on acyclovir PLGA microspheres containing gelatin that are administered by a different application route (intravitreal route). The physicochemical properties such as surface properties, mean diameter, encapsulation efficiency, and drug release properties were not affected by radiosterilization with a dose of 25 kGy. Another study was made by Bozdag et al. (31) about the effect of gamma radiation sterilization and freeze drying with additional cryoprotectants on the physicochemical properties of PLGA nanoparticles containing ciprofloxacin HCl. No significant change was observed after the sterilization process. Similar to that study, another study was performed by Shameem et al. (32) about investigating the effect of gamma radiation sterilization on peptide-containing hydrophilic PLGA microspheres. Both studies showed that the physicochemical properties were not affected significantly by gamma radiation sterilization.

Some important issues about the effect of irradiation on a variety of pharmaceutical dosage forms, drugs, and packaging materials and the effect of decontamination on vegetarian raw materials are given below (8, 24).

1. The Effects of Irradiation on Aqueous Solutions and Suspensions

Most of the effects of irradiation on aqueous solutions, suspensions, and water-containing pharmaceuticals result from the radiolysis of water by ionization and the excitation effect of high-energy gamma rays. This causes decomposition of active substances and other ingredients that exist in the pharmaceutical formulation. For this reason, many water-containing pharmaceuticals cannot be sterilized by irradiation. However, as an exception, the aqueous solutions of chloride and phosphates of alkali elements and alkaline earth elements, lactates, and sitrates of alkali metals can be sterilized by irradiation. Some solutions such as insulin and heparin solutions may be sterilized by gamma irradiation by freezing before sterilization. The disadvantages of this application are that it is a long and expensive process (8, 24). A study was performed by Maquille et al. (33) investigating the effect of irradiation on drugs that are in frozen aqueous solution. Metoclopramide hydrochloride and metoprolol tartarate were chosen as model drugs. Drugs in frozen solution were irradiated by a variety of different high doses. The radiosterilization process was found safe for both of the drugs in frozen solutions.

2. The Effects of Irradiation on Oily Solutions and Ointments

Oily solutions may be sterilized by either irradiation or heat application. But some vegetative oily solutions cannot be sterilized by heat due to hydrocarbon formation. Some steroids such as hydrocortisone acetate, prednisolone, and testosterone propionate; some antibiotics such as neomycin, sodium benzyl peniciline, and tetracycline hydrochloride; and some alkaloids are more resistant to radiation in their oily matrix form than in their dry powder form. Some synthetic ointment excipients such as PEG, silicon, Vaseline, and paraffin may also be sterilized by irradiation. The effect of ionization on oily pharmaceuticals was observed by some researchers and almost no crucial alteration was assessed in their taste and potency (8, 24).

3. The Effects of Irradiation on Active Pharmaceutical Ingredients and Other Ingredients in Solid Form

Many of the ingredients used in the preparation of pharmaceutical formulations may safely be sterilized in a dry solid state, based on different studies of this issue. Antibiotics are one of the most significant areas of concern, and especially semisynthetic penicillins. For example, powders of parenteral pharmaceuticals of beta-lactam antibiotics such as flucloxacillin sodium and amoxicillin trihydrate, and cephalosporins such as cefadroxil sodium, cephalexin, and cephotaxim, do not exhibit any degradation and activity loss in solid-state conditions. There are also some other antibiotics such as gentamycine, tetracycline hydrochloride, chloramphenicol, and neomycin that do not exhibit any degradation by sterilization with radiation. Apart from antibiotics, some alkaloids such as neostigmine bromide, pilocarpine, morphine sulfate, atropine sulfate, caffeine, some multivitamins, enzymes such as papain, anesthetics such as Novocaine, and other ingredients such as talc, lactose, and sodium carboxymethylcellulose are also resistant to radiation in dry powder form. Radiation sterilization is a considerably proper method for powders for injection to obtain aseptic process (8, 13, 24).

Antineoplastic, antibacterial, and anti-inflammatory agents are the three main classes of drugs having controlled delivery systems that compose 50% of total radiation sterilizable drugs (26). Polyesters are commonly used biodegradable polymers that are used for carriers in drug delivery systems. Homo or copolymers that are derived from poly(lactic acid) (PLA), poly(glycolic acid) (PGA), or their copolymers poly(lactic co-glycolic acid) (PLGA) are some of the main polymers of this family that were initially produced and used as synthetic absorbable sutures between 1960 and 1970. Drug-loaded micro and nanoparticulate and vesicular systems, implants, and inserts are utilized for a large variety of applications. However, polyesters are not stable in the presence of moisture and high temperature, so gamma irradiation is one of the most effective choices for their sterilization (34, 35).

The effect of gamma irradiation on the biopharmaceutical properties of PLGA microspheres containing SPf66 malarial antigen was studied by Igartua et al. (23). It was reported that gamma irradiation has no effect on the integrity of the antigen and the physicochemical properties of the formulation or on the formation of immune response after subcutaneous administration of the antigen-containing drug delivery system. Although the release rate of the SPf66 antigen from the drug delivery system was slightly changed by gamma irradiation, the antigenic properties remained immunogenic. The radioprotective effect of prednisolone-containing self-microemulsifying microemulsions and their phase transition systems against sterilization with gamma radiation was observed by El Maghraby et al. (36). After sterilization of both the control solutions and the formulations by gamma irradiation, it was observed that although the phase behaviors of the formulations were not affected, the viscosity of liquid crystalline property was reduced significantly. The degradation was seen more extensively in the control solution than the prednizolone in self-microemulsifying and microemulsion systems when exposed to a dose of 20 kGy. The effect of gamma irradiation on the biodistribution and pharmacokinetics of 111In-DTPA (diethylenetriaminepentaacetic acid)-labeled PEGylated liposomes (IDLPL) was evaluated by Harrington et al. (37) in tumor-bearing mice. Liposomes were injected in two different protocols, while some of the mice were taken 2 Gy radiation dose, others were taken 5 Gy dose, and the time courses were also different in both methods for evaluating the radiation effects. It was reported that the biodistribution of radiolabeled liposomes was not significantly changed in the tumor or other normal tissues. However, the uptake of IDLPL in the small intestine, stomach, musculoskeletal system, female reproductive tract, and adrenal glands was increased in irradiated mice. The effect of temperature during sterilization by gamma irradiation on indomethacin-containing PLGA/PEG-derivative microspheres was observed by Carballido et al. (38). A 25 kGy dose was applied for performing the sterilization. Some of the microspheres were sterilized and protected using the dry ice protection method in low temperature. While some alterations were observed in nonprotected microspheres such as morphological surfaces, polymer glass transition temperatures, molecular weights, and release rates after sterilization, no changes were reported for microspheres previously sterilized using the dry ice protection method. Indomethacin-loaded and PEGylated microspheres were observed to be sterilized successfully with gamma irradiation at lower temperatures using the dry ice protection method.

Another study was performed by Polat (15). The influence of gamma irradiation on amlodis (AML) and its active ingredient amlodipin besylate (AML-B) was evaluated with ESR. Although no ESR resonance line with the irradiation of AML-B was seen, five ESR resonance lines were observed due to radicals with inactive ingredients such as microcrystalline cellulose and sodium starch glycolate of AML in the dose range of 2.5 to 25 kGy. AML-B was found to be more stable than AML and as a result was found to be compatible with gamma radiation sterilization. Ibuprofen-containing microspheres for therapy of the knee joint cavity with a nonsteroidal anti-inflammatory drug (NSAID) were prepared and sterilized using gamma radiation by Carballido et al. (39). The sterilization procedure using a dose of 25 kGy was applied and it was observed that the physicochemical properties and dissolution profiles of the microspheres were not affected by low temperatures according to differential scanning calorimetry (DSC) and X-ray diffraction analyses. The kinetics and spectroscopic properties of radical species produced by the irradiation of sodium sulfacetamide were studied by Çolak et al. (40). Gamma radiation at a dose range of 5 to 50 kGy was applied. The effects of different temperatures were investigated by using ESR and it was found that although these species were generally stable at room temperature (RT), they were relatively unstable above RT. Although some slight changes were observed, sodium sulfacetamide itself and sodium sulfacetamide–containing drugs were safely sterilized by radiation without causing any significant difference.

The effect of sterilization with gamma radiation on the properties of a controlled-release formulation of insulin-like growth factor-I (IGF-I) was investigated by Carrascosa et al. (41). The controlled-release formulation was prepared with the encapsulation of recombinant human insulin-like growth factor-I (rhIGF-I) in PLGA microspheres. The in vitro release of the microspheres was affected by the irradiation process, which showed an increased burst effect. Although no significant change was observed in the size, morphology, or drug-loading capacity of microspheres, some very slight changes were seen after irradiation with a 25 kGy dose. The effect of both beta and gamma irradiation separately on the surface morphology, drug release, drug content, and stability of a bupivacaine-containing PLGA copolymer with a ratio of 50:50 was investigated by Montanari et al. (42). Microspheres containing 10, 25, and 40% (w/w) of bupivacaine were exposed to beta and gamma irradiation at a dose of 25 kGy. The microspheres were irradiated by gamma radiation in the presence of air using a 60Co source with a dose of 25 kGy and a dose rate of 516 Gy · h−1 at 25 °C. Beta irradiation was performed in the presence of air with the use of an e-beam accelerator with a dose of 25.1 kGy having an energy of 10 MeV at 25 °C. Although similar alterations were observed by atomic force microscopy (AFM) in morphological surface properties after irradiation by either gamma or beta radiation, slightly more alteration was seen after irradiation by gamma radiation. However, no alteration was observed in the particle size of microspheres. It was reported that bupivacaine was more sensitive to gamma radiation than beta radiation because drug content was found more in non-irradiated and beta radiation–irradiated microspheres. The drug release rate was found to be almost constant after irradiation with beta radiation, unlike gamma radiation, over a storage period of 9 months. Bupivacaine-containing microspheres were found to be more stable against beta irradiation than gamma irradiation. The effect of beta radiation for the purpose of sterilization on biodegradable polymers containing starch was evaluated by Oliveira et al. (43). Different doses of radiation were applied for evaluating the surface and mechanical properties of polymers. The surface properties were assessed using scanning electron microscopy (SEM). It was observed that the main effect of beta radiation sterilization on starch-based polymers was an increase in hydrophilicity, while almost no change was observed on mechanical properties. The effect of radioprotective excipients on the radiosterilization of drugs in aqueous solutions was assessed by Maquille et al. (14). While mannitol, nicotinamide, and pyridoxine were chosen for protecting drugs from degradation, metoclopramide was used as a model drug. Metoclopramide hydrochloride aqueous solutions with and without excipients were irradiated by gamma radiation or by high-energy electrons. No alteration was seen in the excipient containing metoclopromide solutions when sterilized using gamma irradiation and high-energy electrons with a dose of 15 kGy. The effect of gamma radiation on the physicochemical properties of solid-state ciprofloxacin was evaluated by Al-Mohizea et al. (13) after it was exposed to different gamma radiation doses, such as 0, 15, 25, 50, and 100 kGy. An alteration was seen in the enthalpy of ciprofloxacin while changing from a crystalline to a more amorphous state. It was reported that a smaller degree of crystallinity was observed in irradiated powders than in non-irradiated ones by X-ray diffraction analysis. The increase in the ciprofloxacin dissolution rate was found to be proportional with the irradiation dose, and the color of the ciprofloxacin powder was seen to have changed after irradiation. Although these slight changes were seen in powder ciprofloxacin, the drug was found chemically stable.

4. Decontamination of Herbal Raw Materials

Radiation can also be used for the decontamination of herbal raw materials such as extracts of belladon, ergot, and gummi arabicum that have a definite microbiological load. Studies show that a low dose rate such as 1 kGy can be sufficient for the decontamination of herbal raw materials without causing any change in their properties (8, 24).

5. Sterilization of Packaging Materials

Packaging materials of pharmaceutical formulations such as aluminum tubes and covers, polyethylene and polystyrene containers, bottles, and gelatin capsules and membranes can also be sterilized with gamma irradiation. The radiosterilization allows for the use of a variety of different materials for packaging. Generally, rigid containers made of fiberboard, plastic, metal, and glass are observed to be proper for radiation sterilization, but discoloration is generally seen with radiosterilization of glass containers. Although radiation sterilization can be applied to a variety of packaging materials, it has very few commercial applications, due to relatively higher unit costs and difficult automatic filling. Radiation sterilization can be applied not only to rigid materials but also to aerosol cans, valves, and flexible packaging materials before filling in aseptic conditions. For manufacturing a sterilized packaging material, some issues have to be considered such as the resistance of the packaging material to the bacteria, the suitability and strength of the package undergoing radiation sterilization, and the type of package and cap (8, 24, 44).

Many investigations have been made into improving the physicochemical properties of packaging materials subject to radiation sterilization. The effect of gamma irradiation was investigated by Soliman et al. (45) on zein-based films used as packaging materials because of their ability to provide a strong oxygen barrier. Gamma irradiation was observed to improve physicochemical properties such as appearance and strength.

Polymers Used for Medical Devices

Polymers are widely used in many applications in the medical fields, in clothing, housing materials, automotive, communication, and aerospace parts. Low molecular weight and low costs for processing are some of the superior properties of polymers in relation to other materials such as ceramics and metals, and these prevailing properties are why they are chosen for medical purposes (46⇓–48). Medical devices have been used for a long time, and the first successful study was the application of synthetic implants to skeleton cartilages for therapy. The replacement of blood vessels, the production of artificial heart valves in 1950, and the production of femur prostheses in 1960 were other early developments in this field. Polymer-based medical devices can be used in medical fields such as orthopaedics, cardiology, ophthalmology, and general surgery and in some diagnostic kits in hospitals. Medical devices are generally composed of biomaterials that are not only implants but also extracorporal devices that are in contact with the body. Biopolymers are a special group of polymers produced by living organisms. Those that are biodegradable and employed for medical applications are called advanced medical biopolymers. A biomaterial that is in contact with tissues or biological fluids should have certain properties, such as being biocompatible with the biological system; not causing any toxic, allergic, or carcinogenic effects; maintaining the desired functional, mechanical, and physicochemical properties; and being easily purified and sterilized with a proven method (4, 46, 49⇓⇓⇓–53). One of the most important issues is the time duration of usage of polymeric implants within the body, which may be used for long-term (chronic) or short-term (acute) applications. While small changes in physicochemical, mechanical, and biological properties induced by radiation can be tolerable for polymeric implants for short-term applications, they are often not tolerable for long-term (chronic) applications. Therefore, long-term polymeric implants should be carefully evaluated and examined for the effects of high-energy radiation sterilization (54, 55).

Stents are one of the most commonly used medical devices applied during surgery. They are generally implanted intracoronarily during angioplasty for preventing thrombus and neointima formation. For producing biocompatible stents, polymer coatings can be used on metallic stents. In this way drug-containing stents are developed with the help of polymers as a matrix material. Additionally, radiotherapy has been improved through the use of radioactive stents, which has the advantages of delivering radiation with low and continuous dose rate (56).

The production of more developed medical devices is possible with the contribution of tissue engineering. Damaged tissues may be regenerated using tissue engineering that can combine protein delivery systems with biomaterial-based scaffolds generally composed of improved polymers (57). When designing novel polymers, it should be clear what the purpose is for the polymer, how it is affected by radiation, and what issues arise. Polymer morphology and temperature are some of the important factors changing the radiation effect on polymers. Generally, while the electronics and aerospace industries require radiation-induced scission or crosslinking for resistance applications, highly radiation-stable materials are required for medical applications (58, 59). Many investigations have been made into the effect of radiation on medical devices such as dental materials (60), orthopedic materials (61, 62), microfibrillar vascular grafts (63), and specifically of UV light on intraocular lenses (64).

Polymers may be in a variety of compositions and shapes such as fiber, film, gel, core, and nanoparticulates and used for different purposes. Polyethylene (PE), polyurethane (PU), polystyrene (PS), polytetrafluoroethylene (PTFE), polymethylmetacrilate (PMMA), polyethylene tereftalate (PET), silicon rubber (SR), polysulfon (PSU), polycarbonate (PC), PLA, and polyglycolic acid (PGA) are some of the commonly used polymers for medical applications (21, 50, 65, 66).

For investigating the effects of radiation on medical devices that are generally composed of polymers, the type of polymer used must be known, and they are classified as thermoplastics, thermosets, or elastomers. Thermoplastics comprise a large group of polymers and are used commonly in the production of medical devices and packages. A variety of thermoplastic polymers, especially radiation-stable polymers, are used in industry frequently. Some of these are acrylonitrile/butadiene/styrene (ABS), polyacetals, polyacrylics, polyamides, cellulosics, fluoropolymers, PC, polyesthers, PS, polyolephines, polysulphones, and polyvinyls. Thermosets are an important class of polymers commonly used in the production of medical devices, including phenol formaldehyde, epoxy, polyesther, polyimides, and PU. Elastomers, commonly referred as “rubber,” are depending on their properties used for the production of syringes, blood diffusion sets, dialyzers, and other devices that thermosets and thermoplastics are not suitable for. Although less radiation-resistant than thermoplastics, elastomers are crucial to the production of medical devices. The existence of plasticizers and stuffings in elastomers affect their radiation resistance primarily (50, 51, 53, 65, 66).

Polymers can also be classified depending on their in vivo degradation tendency and stability. Hydrophobic polymers are the most stable and do not contain any hydrolyzed bonds. Hydrophilic, hydrolyzed polymers also do not contain any bonds and swell easily but may fragment partially or totally. Hydrophobic and hydrolyzed polymers are generally composed of surface-active materials and show lesser stability. The degradation process of polymers usually shows monomer formation first. Carbon dioxide and water formation then occurs and they are excreted from the body (4). The degradation of polymers under ambient nuclear environments in which the dose rate is lower than 1 Gy · h−1 and the temperature is below 60 °C in the presence of air, generally causes oxidation that is formed by the effect of radiation. Oxidation and radiation aging are closely related with the dose rate. The diffusion limitation of oxygen into polymer materials during irradiation and the chain reaction of oxidation in the materials are two important factors related to dose rate (67).

For defining the sterilization dose, the type and energy of radiation and polymers used should be clearly defined. Some important parameters about the irradiation process are particulate or electromagnetic nature, pulse character, homogeneous or localized distribution, dose rate, and total dose amount. The time period of irradiation at a definite dose rate also has an essential role in this procedure. The physicochemical properties and morphology of polymers, such as molecular structure, molecular weight, and crystalline properties, have an effect on their stability when subject to irradiation. The physicochemical properties of the additive ingredients, free oxygen in the solid structure, oxygen in the irradiation medium, and the diffusibility of the oxygen in the polymer should also be taken into consideration. For the stability of the polymers, while thermosets are the most stable polymers, elastomers should be considered to have second-order stability. Thermoplastics are in the third order of stability but are the most resistant to heat (4, 53).

The stability properties of polymers when subject to irradiation are as follows (4, 21, 53, 68):

  • - Polymers exposed to crosslinking are more stable.

  • - Polymers containing less free radical yield are more stable.

  • - Polymers having an aromatic ring in their structure are more stable than polymers having only an aliphatic chain.

  • - Polymers having less density are more stable.

  • - Polymers having a higher crystalline phase ratio are more stable.

  • - Polymers having a smaller crystalline center are more stable.

  • - Polymers having elastomeric properties are more stable.

  • - Polymers containing antioxidants and plasticizers are more stable.

  • - Polymers containing no nucleation agents or soft plastics are less stable than polymers containing nucleation agents or hard plastics.

PE having high- or low-density PS, epoxypolymer, PU, and elastomers are very resistant to radiation and more stable. However, polypropylene (PP), polyvinyl chloride (PVC), polyester, and fluoroplastics are highly affected by irradiation, and Teflon, polymetacrilate, and polyasetal are very seriously affected by irradiation and therefore should not be exposed to it (4, 21, 66, 68).

Radiation processing of polymers is not economic in many countries. The utilization of low irradiation doses within the process can reduce the effects of degradation. In this way, the quality of the end product may also be improved. Ammonium persulfate, potassium persulfate, or H2O2 can be used as additives during the irradiation process to reduce the dose required for the degradation process of some natural polymers. Degradation and cross-linking of natural polymers can be controlled by radiation (69).

When sterilizing polymers with radiation, some instable intermediate products may be formed due to exposure to high-energy radioactive rays. These instable intermediate products may then be turned into stable radiolysis products via certain reactions. After this, some changes in the physical, chemical, and surface properties of the polymer may be formed. Some of these changes are given in Table I (46, 51⇓–53, 58).

View this table:
TABLE I

Changes observed after irradiation of polymers (50, 53, 65, 66, 70, 71)

Commonly seen chemical changes formed by irradiation are chain scission and crosslinking, which cause alterations in molecular weight. These are accompanied by the effects of volatiles such as hydrogen and the formation of double bonds. The results depend on both the sensitivity of the structure of the repeating unit and the sample preparation method (72). However, a complete breakdown of the chain and crosslinking is seen very rarely after the irradiation of the polymers. Most of the polymers show both of the reactions, depending on the radicals formed by irradiation. The irradiation of the polymers in the existence of oxygen may cause the formation of radiolysis products and further degradation of the polymers. Radiation-induced reactions are mostly radical, and oxygen has a powerful radical-quenching effect. Depending on the properties of the polymer, double-bond formations may also a result, which may cause color formation or color change if conjugated double-bonds are formed (50, 53, 65, 66, 70, 71).

While the hardness, fragility, and elastic modulus are subject to crosslinking, the tension force and elastic modulus are subject to breakdown of the chain. Crosslinking causes an increase in hardness, fragility, and elastic modulus. Thermal transitions generally arise, depending on the effect of tempurature on the mobility of the molecules. Amorphous polymers are hard and fragile in normal conditions and become soft and flexible when warmed up. The glass transition temperature increases in relation to the formation of crosslinking by irradiation but decreases in relation to the chain scission of the polymer (50, 53, 65, 66, 70, 71).

Irradiation also causes alterations in surface roughness. Changes in surface porosity and surface roughness depend on the dose level of the high-energy irradiation of the polymer, the polymer conformation, and dose rate. The surface porosity of the material affects the binding affinity of the proteins and biochemical intermediate products on the surface, which helps to define the biocompatibility of the material. Surface porosity also affects interactions with body tissues and fluids. Surface wettability is another important parameter affecting biocompatibility of the substance in contact with a biological system. Depending on the application purpose of the biomaterial, it should have a definite surface hydrophilicity/hydrophobicity ratio, which may be affected by irradiation (50, 53, 65, 66, 70, 71).

Some Instances of the Effect of Radiation on Polymeric Materials

Changes in the structure, color, surface roughness and porosity, and crystalline properties of polymers due to radiation can be detected and measured with a variety of analytical methods such as high-performance liquid chromatography (HPLC), viscosimetry, gel permeability chromatography (GPC), mass spectroscopy (MS), ESR, UV-visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, DSC, thermogravimetric analysis (TGA), SEM, and AFM (50, 65, 66, 70, 71).

The formation of hydrogen fluoride and dissociated fluoride ions in dialyzers containing perfluoroheptane by gamma and beta sterilization was monitored by Zundorf et al. (73) for toxic effects on patients after the sterilization process. The effect of 20–500 kGy doses of both gamma and beta radiation sterilization on perfluoroheptane, which is a toxic decomposition product of hexadecafluoroheptane, was investigated. The decomposition of perfluoroheptane was found to depend on the dose of irradiation and the degree of decomposition and was found to be higher after beta irradiation than after gamma irradiation of the same dose. After irradiation with 100 and 500 kGy doses, almost no change was observed in the chemical properties that lead to the formation of any fluorinated hydrocarbons. The sterilization of PEG hydrogels containing cyclosporine by EtO, hydrogen peroxide (H2O2), and gamma irradiation was investigated by Kanjickal et al. (74). The release properties of cyclosporine and the swelling ratios of polymers were found to be affected by both the sterilization procedure and the type of agent. Although no change was observed in the surface roughness by EtO, a reduction was seen in sterilization with H2O2 and gamma irradiation by AFM. Increased radical formation was reported in polymers sterilized with gamma irradiation and H2O2 than in polymers sterilized with EtO or unsterilized polymers. In a study by Jayabalan et al. (75), the effect of gamma radiation sterilization with repeated irradiation on the stability of PU potting compounds containing castor oil/dicyclohexyl methane diisocyanate (SMDI) and caprolactone polyol/SMDI, which are used for hollow-fiber hemodialyzers, was evaluated. Castor oil–based PU was found to contain higher amounts of low molecular weight fragments formed by radiation-induced degradation and leaching than caprolactone polyol–based PU. Sterilization at a dose higher than 50 kGy was found to cause reduced leaching in caprolactone polyol–based PU, leading to crosslinking. However, with castor oil–based PU, higher dose rates such as 100 kGy of gamma radiation were found to cause cleavage in the crosslinks. Another study was performed by Ishaki et al. (10) in which the degradation by irradiation of PP was observed by measuring the chemiluminescence formed by the recombination of peroxy radicals with the increasing irradiation dose and the degree of oxidation. The degree of oxidation of PP when sterilized using with e-beam irradiation was found to be half what it was when using gamma radiation. Less degradation was seen in the samples irradiated with e-beam than gamma irradiation during storage, and the degradation was reported higher at the surface area of the film. E-beam irradiation with a dose of 25 kGy was found to cause degradation during storage due to oxidation. Additionally, the degradation during both irradiation time and storage was observed to be higher with gamma irradiation than with e-beam irradiation.

Modern sterilization techniques are widely used in medical industry, but they may have harmful effects on polymers. Some commonly seen examples of these alterations are polymer chain scission, which reduces molecular weight, and crosslinking, which produces large polymer networks that may cause changes in the physical properties, appearances, and functions of the devices composed of these materials (76). The effect of sterilization by gamma radiation on a variety of the materials used in RTP Company's thermoplastic elastomers (TPE) division for the U.S. healthcare industry was investigated by Killian et al. (77). TPEs are commonly used in medical fields depending on some of their advantages especially being more ergonomic. Although most of RTP Company's TPE products remained unchanged with various levels of radiation exposure, different responses were seen in all TPE variations to sterilization with gamma irradiation. Gamma radiation sterilization was found to be a safe process, and almost no significant changes were observed in the properties of these TPE products used as medical devices. A novel method was developed for decreasing the calcification effect and increasing the lifetime of the artificial cardiac bio-valve-OX-pericardium valve by Fengmei et al. (78). Gluteraldehyde was applied to OX-pericardium valves and then sterilized by gamma radiation. The application of 0.1% gluteraldehyde and gamma radiation with a dose of 25 kGy was reported to sterilize OX-pericardium sufficiently, and the mechanical properties of OX-pericardium were preserved. It was observed that by the application of this method, the formation of calcification was reduced significantly. The application of 0.1% gluteraldehyde and 25 kGy of gamma irradiation was found to be a better choice than the application of gluteraldehyde itself in higher concentrations.

Physical and Chemical Methods for Preventing the Harmful Effects of Radiation

The use of additives depends on the utilization purpose of the polymer. However, the effect of irradiation on the polymers in the presence of additives is still not defined clearly. For decreasing the indirect effects of radiation, such as radiolysis, radical formation, and oxidative degradation, materials should be irradiated under anoxia and at low temperatures, or by using additives. These additives may be antioxidants, radioprotectors, or preservatives designed especially for drugs, which should remain nontoxic and not interfere with the efficacy of the drug due to the use of certain energy transfer systems, ―SH containing molecules, or scavengers (13, 14, 50, 53, 65, 66, 70, 71). The protection of polymers against high-radiation doses such as 20–1000 kGy is necessary when using efficient additives such as primary and secondary antioxidants to prevent chain-reaction oxidative degradation (79). Plasticizers can be used as antirads, which have a relatively smaller chain size, are more active, transfer energy easily, and inactivate oxygen radicals by binding easily. Crosslinking agents can also be used as chemical methods for decreasing harmful effects and degradation. Hindered amines and phenols, phosphate-containing solids, phosphites, thio-esthers, epoxides, and piperidyl compounds are some of these chemical agents (80).

Physical methods can also be utilized for preventing the harmful effects of radiation. Collision, including the use of polymer mixtures, is the easiest and most commonly used one. Molding, rapid cooling after manufacturing, and quenching are other methods. Quenching may be done by decreasing the crystalline property and thus decreasing the effect of the linear energy transfer. Irradiation and storage in an oxygen-free medium is a good method for preventing oxidation reactions and radical formation. Incubation at proper solutions for preventing the harmful effect of radicals and irradiation with a maximum possible dose rate can also be applied for this purpose (80).

Conclusion

The effect of radiation on pharmaceuticals and polymer materials is a growing area for both the health industry and the research institutes, as is very well known. The effect of irradiation on pharmaceuticals can be significant when they are sterilized with gamma radiation or e-beam radiation. Sterilization of pharmaceuticals by gamma radiation or e-beam radiation affects their stability, depending on the physicochemical properties of the active substances and other ingredients and their physical state, whether solid, liquid, or gas. Although gamma radiation sterilization is an officinal and a more frequently used technique, e-beam sterilization is a promising process and several researchers are investigating its effects on different drugs and materials. The choice of sterilization method should be determined according to the structure of the substance, the microbial load (bioburden) of the substance, and the effects of the process on the substance. With improvements in technology, more resistant polymers can be produced that are not affected by radiation sterilization. In the medical field, improved medical devices may be produced along with the contributions of enhancements in the polymer industry. Disposable products such as syringes, catheters, blood bags, and transfusion sets may be sterilized by irradiation in their final packed form and with minimum risk of contamination. According to studies about the effect of radiation on pharmaceutical formulations and medical devices containing polymers, although some slight chemical changes may occur, generally no significant alteration is observed. Recently, a large number of different novel analytical methods have become available for determining even very slight physical and chemical changes, and the harmful effects related to degradation may be easily prevented by the use of antioxidants, preservatives, and radioprotectors such as antirads.

Conflict of Interest Declaration

The authors declare that we have no financial or nonfinancial competing interests related to this paper. It has not been previously published and is not currently under consideration by another journal. The authors take public responsibility for the legality and originality of the work.

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The Effect of Radiation on a Variety of Pharmaceuticals and Materials Containing Polymers
Mine Silindir, Yekta Özer
PDA Journal of Pharmaceutical Science and Technology Mar 2012, 66 (2) 184-199; DOI: 10.5731/pdajpst.2012.00774
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