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- Mar 24
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Technical Review Article | Open Access | Published 26th March 2026
Photodegradation of Pharmaceuticals: Mechanisms, Influencing Factors, and Photostability Testing Approaches
Vignesh Perumal*, Padma Preetha J¹, Monisha A² | EJPPS | 311 (2026) https://doi.org/10.37521/ejpps31110
Abstract
Photodegradation is a critical pathway of drug instability that can compromise therapeutic efficacy, safety, and shelf life. Understanding the mechanisms of photochemical reactions is essential for predicting degradation behaviour and designing stable pharmaceutical formulations. Drugs may undergo a variety of light-induced reactions, including oxidation, isomerisation, cyclization, or bond cleavage, depending on their molecular structure and environmental conditions. Several factors influence the extent of photodegradation, such as wavelength and intensity of light exposure, drug concentration, pH and ionic strength, presence of oxygen, and excipients used in the formulation. To mitigate these risks, regulatory agencies such as the ICH have established specific guidelines for photostability testing of new drug substances and products. These standardized protocols involve forced degradation studies and confirmatory tests under controlled light sources to evaluate the susceptibility of pharmaceuticals to photolytic stress. This review provides a comprehensive overview of the mechanisms of drug photodegradation, key factors influencing photochemical stability, and the methodologies employed in photostability testing, with an emphasis on regulatory requirements and formulation strategies for developing photostable drug products.
Keywords: Photodegradation, Photostability, Stability indication method
Introduction
The ICH Q1B guideline on photostability testing was adopted in November 1996 and subsequently published by regulatory agencies including the FDA (Food and Drug Administration, India), MHWL (Ministry of Health and Labour Welfare, Japan), and EMEA (European Medical Agency) between May 1997 and January 1998.¹ Shelf-life determination is a regulatory mandate for pharmaceuticals and other products, necessitating rigorous adherence to stability testing protocols. Pharmaceutical product labels display shelf life (expiration date) to guarantee integrity, quality, and potency within the specified timeframe, based on stability data validated and approved by regulatory agencies. Expiration dates are legally required to ensure pharmaceutical products meet safety, efficacy, and quality standards throughout their specified shelf life. The stability profile of a pharmaceutical entity, a critical quality attribute, is primarily determined by the physicochemical characteristics of the drug substance and product.² Photochemical stability of pharmaceutical substances is crucial, as light-induced degradation can lead to loss of potency and formation of potentially toxic degradation products. Additionally, light exposure can contribute to adverse side effects in patients by interacting with endogenous substances after drug administration.³ Drugs sensitive to light can be impacted by both natural sunlight and artificial light sources, including UV irradiation and fluorescent light. This can cause not only photodegradation of the active ingredient but also changes in the product's physical and chemical properties, such as discolouration, cloudiness, viscosity loss, altered dissolution rate, or precipitation.⁴ Light energy can trigger and accelerate decomposition, making it crucial to determine whether instability is due to light or heat to guide proper storage conditions. Unlike thermal stability, photostability is complicated by formulation and reaction factors. To stabilize light-sensitive compounds, precautions such as protective packaging are necessary to minimize light exposure, but this is not the only solution to protect the drugs from light.⁵ Photodegradation conditions vary across solid and liquid preparations, packaging materials, administration routes, and storage environments. Understanding the nature and extent of photodegradation is crucial to stabilizing light-sensitive products. Hence photostress testing is an important component of the drug development process.
Photostability studies are essential to understand the impact of light on drug substances. These studies involve exposing a representative batch to specific light conditions, including 1.2 million lux hours of visible light and 200 watt hours/square meter of near UV, as per ICH Q1B guidelines.² Photostability studies may need to be repeated with changes in the drug substance or product, such as new synthesis routes or formulations. During method development, forced degradation samples are analyzed using HPLC with PDA and MS detection to track peaks, assess purity, and identify degradation products and impurities.⁷,⁸
Forced degradation testing intentionally degrades the sample to stress its stability. This study is necessary to develop or validate an analytical method that can detect potential photodegradants. Forced degradation studies also help understand degradation pathways and controls for manufacturing, packaging, and storage.¹
This review focuses on the overview of the mechanisms of drug photodegradation, key factors influencing photochemical stability, and the methodologies employed in photostability testing, with an emphasis on regulatory requirements and formulation strategies for developing photostable drug products.
Mechanism of photochemical reaction
Photochemical reactions are complex and typically occur in two stages. The primary reaction happens when molecules directly absorb light. Secondary reactions involve intermediates such as radicals, which can react further through thermal processes. Unlike primary reactions, secondary reactions can proceed without light through 'dark' reactions to form stable products. Drug molecules can be impacted directly or indirectly by light, depending on how energy is transferred to the substance.⁹,¹⁰ In direct photochemical reactions, the molecule absorbs radiation that overlaps with its absorption spectrum. In indirect reactions, energy is absorbed by other molecules, such as excipients or impurities, which then affect the drug. The photosensitizer absorbs energy and transfers it to the active ingredient, causing degradation. While the photosensitizer can sometimes transfer energy without changing itself, it often undergoes degradation in the process.⁵
Factors affecting drug photodegradation
Excipients and formulation
The impact of excipients and stabilizers on photostability can be hard to predict, making stability testing crucial. Assessing drug-light interactions is essential during new drug development. Excipients and formulation types can influence the photodecomposition of active compounds.¹¹ Excipients can trigger, accelerate, or take part in photochemical reactions. For liquid preparations, buffer selection and pH are determined by solution kinetics, and buffers can also influence photodegradation reactions, as seen with riboflavin in aqueous solution.¹² For parenterals, factors such as metal ion contamination and packaging compatibility can impact photostability, even if the drug molecule isn't sensitive to light above 300 nm. Even if a drug molecule isn't light-sensitive, factors such as citrate buffer, iron levels, oxygen, and light exposure can impact photostability. Chlorphenesine solutions undergo photodehalogenation, forming different degradation products depending on the solvent. Excipients in the formulation significantly impact the rate of photodegradation and the structure of the resulting degradation products.¹³
Solid dosage form
In solid dosage forms such as tablets and capsules, photochemical reactions occur on the surface, leaving the interior unaffected. The degradation rate on the surface depends on several factors. The photostability of solid drug preparations is understudied, largely due to the slower degradation rates compared to solutions. However, ICH guidelines (Q1B, 2002) now require photostability testing as part of stress testing, resulting in more light-sensitive drugs being identified.⁵
Particle size
Smaller particle sizes lead to faster degradation due to increased surface area. But when the powder is made into tablets, particle size no longer affects degradation.
Drug content
In solutions, higher drug concentrations slow down decomposition due to self-absorption of light, shielding inner molecules. In contrast, tablets become more photostable with increasing drug content.
Tablet geometry
Tablet size and diameter are determined by drug content, and increasing diameter slightly improves photostability. Biconvex tablets degrade more than biplanar ones, although the difference is small but significant.²
Solutions
Concentration
Highly concentrated drug solutions absorb most light near the surface, shielding inner molecules (inner filter effect) and increasing stability. The inner filter effect occurs when a drug absorbs light, shielding inner molecules and increasing stability in concentrated solutions. Dilute solutions, such as diltiazem in aqueous solutions (pH 4-7), are more photolabile, forming diltiazem-S oxide as a primary degradation product. This can also pose challenges in infusion therapy where diluted solutions are common.¹⁴,¹⁵
pH and Ionisation
pH plays a crucial role in photodegradation. Diltiazem's stability varies with pH, showing slow degradation at acidic to neutral pH (4.0 and 7.4) and rapid degradation at alkaline pH (9.0) [16] Fluoroquinolones are amphoteric due to their amino acid structure, existing as cations at pH 5-5.5 and anions above pH 9. This pH-dependent ionization affects their photochemistry. Gatifloxacin is most stable at pH 4.5, with degradation increasing above this pH, highlighting the impact of ionization on photostability. Compounds that modify pH, such as phosphate buffer, can alter stability by affecting photochemical reactions. Phosphate buffer can enhance proton transfer, influencing the degradation of certain compounds.²
Ionic strength
Higher ionic strength can have varying effects on drug photostability. While it can stabilize some drugs by forming a protective ion layer, a study on lomefloxacin found that increased ionic strength and dielectric constant actually accelerated photodegradation, likely due to more drug molecules being in ionic form.⁵
Oxidation
Oxygen plays a key role in photochemical degradation, so reducing oxygen levels can enhance stability. However, the impact of antioxidants and chelating agents is variable and depends on specific conditions, requiring careful assessment. Fe(III) EDTA chelates are rapidly reduced by superoxide, rendering EDTA ineffective in inhibiting photodegradation. However, adding coloured substances that absorb similar wavelengths as the drug can stabilize it. For instance, nifedipine has demonstrated improved photostability through various methods.¹⁷,¹⁸
Stabilisation of light sensitive formulations
Drugs can be stabilized through photoprotection methods such as spectral overlay with excipients or coating solid dosage forms with opaque films, effectively blocking harmful light exposure.¹⁹ Protective packaging, such as amber containers or market packs, is the most widely used method to safeguard photosensitive drugs from light exposure. Clear glass or plastic provides little photoprotection. For highly sensitive drugs such as molsidomine, amber glass is not enough, and further protection measures are needed.²⁰
If oxygen plays a role in degradation, an inert atmosphere may be beneficial. But first, a comprehensive study on oxygen's impact on the specific formulation's photoreaction is required. Quenchers and scavengers can potentially stabilize products by neutralizing excited states and free radicals, provided they are non-toxic and don't interfere with the therapeutic effect. Substances such as α-tocopherol, ascorbic acid, and BHT can act as free radical scavengers and weak singlet oxygen quenchers. These compounds are already approved as food additives. L-Histidine is an efficient singlet oxygen quencher, but may affect a patient's amino acid balance. β-Carotene is effective in lipid preparations but can add a strong yellow colour.²
Another strategy is to modify drug photoreactivity through complexation with suitable carriers. Cyclodextrins, for instance, can form inclusion complexes that reduce photodegradation of various drugs.²¹ The stabilizing effect of cyclodextrins can vary significantly, and some may even catalyse photodegradation instead of stabilizing the drug. Cyclodextrin-liposome combinations or liposomes alone have shown improved photostability. Additionally, complexing with organic acids and salts can stabilize certain substances.²²,²³
Liposomal encapsulation protected tretinoin from photodegradation, with degradation rates about 1.8 times lower than in castor oil. This is likely due to light scattering by the liposome surface, reducing tretinoin's exposure to light.²⁴
Microspheres and microcapsules are being explored for controlled release and protecting photosensitive drugs. Amlodipine-loaded microspheres, for instance, offered superior light protection compared to cyclodextrins (CD) or liposomes, significantly reducing drug degradation. Microcapsules enhanced pantoprazole's stability and quality. Solid dispersions with Eudragit E also provided effective photoprotection for the drug.²⁵
Photostability testing of new drug substances and products
Photostability testing of drug substances and final dosage forms is crucial to ensure product quality throughout its lifespan. The ICH Guideline for photostability testing, implemented in January 1998, outlines a basic protocol for testing new drug substances and products prior to submission. According to the guideline, photostability testing is a key component of stress testing. For drug substances, this involves two stages: forced degradation (stress testing) and confirmatory testing.²⁶
Forced degradation testing evaluates photosensitivity and helps develop methods or understand degradation pathways. The choice of reaction medium and photon source is critical for accurately assessing a drug's photoreactivity. Using a single medium can lead to loss of valuable information, as organic solvents may not distinguish between different protonation forms. To capture all possible degradation products, including those from sensitized reactions, samples should be irradiated across all absorbing wavelengths using a broad-spectrum source.¹⁹
Pre-formulation kinetic studies typically involve drug substances in solutions or simple formulations. To compare degradation rates, the absorbed photons must be calculated, considering both wavelength and irradiation time. Low drug concentrations are recommended to ensure first-order kinetics. Without proper conditions, reaction rates are limited by light intensity rather than drug concentration. Stirring solutions and careful sampling help maintain experimental integrity.²⁷
Confirmatory photostability testing simulates real-world exposure to glass-filtered natural and indoor light. This study aims to assess product photostability under standardized conditions, typically conducted late in product development. The goal is to identify suitable packaging and labelling to maintain product quality during manufacturing, handling, and storage. Photostability testing results are qualitative, serving as a limit test rather than providing quantitative data. Despite the test's simplicity, key factors such as irradiation source, irradiance levels, temperature, and lamp calibration require close consideration.⁴
The ICH guideline specifies overall illumination but not irradiance levels, allowing for adjustments based on specific needs. Using high irradiance levels can reduce the test results' correlation with real-world conditions. Increased irradiance can raise temperatures, affecting degradation rates. High irradiance levels may alter degradation mechanisms, even with consistent spectral distribution. Tests at different irradiance levels shouldn't be compared without established correlation. Calibrating the light source and monitoring its irradiance is crucial for achieving the desired exposure. Some light cabinets have built-in sensors for calibration, while others require manual calibration. Manual calibration can be done using devices such as UV filter-radiometers, lux-meters, thermopiles, or chemical actinometers. Most devices require specific calibration for each light source to ensure accurate measurements.²⁸
Drug substances and products should be exposed to the light source in a way that maximises surface area. The containers used should be specified based on their light transmittance properties.
Tablets or capsules should be arranged in a single layer to ensure maximum exposure. The ICH guideline recommends a sample thickness of no more than 3 mm for solid drug substances. Using a protective container can lead to a significant temperature increase. A covered glass dish can reach temperatures of 40 °C, even if the surrounding chamber is at room temperature. Some test chambers offer water cooling, but this can cause condensation inside the container if the chamber surface becomes too cold.
Photostability testing indicates whether drug substances or products are likely to degrade photochemically during their shelf-life. The term 'acceptable change' is not defined in the ICH guideline. Impurity limits should be justified based on relevant ICH guidelines for drug substances and products. If a product is at risk of photodegradation, it should be labelled 'protect from light'.⁴,²⁶
A Stability Indicating Method (SIM) is a validated analytical procedure that accurately measures active ingredients, free from impurities and degradation products. The FDA recommends that all stability assays use Stability Indicating Methods. The FDA recommends SIMs for stability studies to ensure safety, efficacy, and quality.
Three basic steps to develop a SIM are:
Generation of degraded samples for testing selectivity of the method.
Method development
Method validation
Conclusion
Combining drug delivery systems with light offers promising potential for targeted drug delivery. Photochemical reactions are being explored for activating new drug delivery systems. Assessing drug-light interactions is essential for pharmaceutical development. Light-stability testing provides valuable information for product use. Photostability testing predicts potential degradation during shelf-life. Test results guide labelling decisions for pharmaceutical products. Data on sunlight conditions can inform handling recommendations for products.
Insights about the drug-light interactions is essential for developing stable, high-quality dosage forms with potential for targeted therapy.
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Author Information
Authors:
Vignesh Perumal*, Padma Preetha J¹, Monisha A²
*Master of Pharmacy, Department of Pharmaceutics, KMCH College of Pharmacy, Coimbatore-641 048.
1Associate Professor, Department of Pharmaceutics KMCH College of Pharmacy, Coimbatore-641 048.
2Master of Pharmacy, Department of Pharmaceutics, KMCH College of Pharmacy, Coimbatore-641 048.
Corresponding Author:
Vignesh Perumal
Address: Master of Pharmacy, Department of Pharmaceutics, KMCH College of Pharmacy, Coimbatore-641 048
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