Photostability Testing Research Articles

Photoprotective efficacy and photostability of fifteen sunscreen products having the same label SPF subjected to natural sunlight

The first objective of this study is to show how different can be photoprotection by sunscreens with an identical SPF given on the packaging, when subjected to sunlight radiation. The second objective is to highlight the need for global harmonization of photostability testing and UVA protection labelling. Fifteen products with various combinations of UV filters marketed in Europe were assessed based on transmission measurements of 0.75mgcm−2 layer covered onto polymethylmethacrylate plate roughness 2μm. Two absolute UV spectroscopic indices (in vitro SPF, UVA-PF), four well-known relative UVA indices: the UVA-PF/SPF ratio and critical wavelength by European Commission (EC); UVA/UVB ratio by Boots Star Rating system; UVA1/UV ratio by FDA Proposed Ruling and one new relative indices the Spectral Uniformity Index (SUI) by Diffey, were compared before and after sunlight exposure with dose about 42 SEDs. The UVA-PF values before exposure proved a high degree of variation among samples. After exposure only five sunscreens observed UVA protection standard by EC and the same products showed compliance with the first UVA rating by Boots system (three stars). According to the UVA1/UV ratio, except for one product, all sunscreens manifested certain UVA protection level (low, medium or high). In compliance with criteria of new rating proposed by Diffey, exactly all fifteen sunscreens gave some UVA rating exhibited as SUI (low, medium or high). These results mean that the different UVA protection indices can exhibit various data and be confusing for consumer. Photostability of each product was assessed with three indices: the Area under curve (Auc) Index for the total UV range, and UVB, UVA, UVA2, UVA1 range separately; the residual effectiveness of in vitro SPF and UVA-PF. All fifteen sunscreens were photostable in the UVB region. Seven products exhibited photoinstability in the total UV range (290–400nm); all of them contained a combination of the ethylhexyl methoxycinnamate (EHMC) and butyl methoxydibenzoylmethane (BMBM) together with other UV filters. Eight products lacked their stability in the UVA1 range (340–400nm) thus confirmed that photodegradation of some current sunscreens is primarily problem of this region. The most photoinstability showed sunscreens S1 (EHMC, BMBM and phenylbenzimidazole sulphonic acid) and S6 (EHMC, BMBM, phenylbenzimidazole sulphonic acid and ethylhexyl triazone); Auc-UVA1 Index was 0.15 only. Excellent UVA1 photostability showed sunscreen S8 (EHMC, EHT and methylene bis-benzotriazolyl tetramethylbutylphenol); Auc-UVA1 Index was of 1.00. Three sunscreens showed very good UVA1 photostability (Auc-UVA1 Index ranged from 0.98 to 0.93). The fact that these products applied only in the layer of 0.75mgcm−2 were photostable under the sunlight dose, which corresponds to layer of 2mgcm−2, is proof of their quality. Comparison of the residual effectiveness of in vitro SPF and UVA-PF values with the Auc-Index showed that methods give a similar ranking of the sunscreens’ photostability.

Considerations on the quinine actinometry calibration method used in photostability testing of pharmaceuticals

This paper addresses two critical issues concerning the guidelines adopted by the ICH on the photostability testing: the quinine actinometry method and the light/radiation exposure map distribution of the photostability chamber. Using a qualified non-commercial photostability chamber tests were performed using quinine and physical actinometry and compared the results to those which are used as the basis of the ICH guidelines. The statistical analysis on the results showed that: (i) the calibration curve of the quinine solution depends on its concentration and on its location in the chamber; (ii) the quinine actinometry method currently recommended by the ICH guidelines should not be generalized to any photostability chamber.

A Critical Assessment of the ICH Guideline on Photostability Testing of New Drug Substances and Products (Q1B): Recommendation for Revision

The ICH guideline on photostability (ICH Topic Q1B) was published in November 1996 and has been implemented in all three regions (US, EU, and Japan). The guideline describes a useful basic protocol for testing of new drug substances and associated drug products for manufacturing, storage, and distribution, but it does not cover the photostability of drugs under conditions of patient use. The pharmaceutical industry now has considerable experience in designing and carrying out photostability studies within the context of this guideline, and issues have been identified that would benefit from the revision process. The purpose of this commentary is to accomplish the following: (i) highlight issues proposed for consideration in the ICH revision process, (ii) offer a rationale for why these issues may compromise the design of a testing protocol and/or the results of the testing program, and (iii) provide recommendations for clarification of the guideline.

Indigotine, azorubine, and cochineal red as photoprotectors of manidipine

Background: The calcium antagonists from the group of 1,4-dihydropyridine (DHP) derivatives are photolabile, and the products of their photochemical decomposition have no pharmacological activity. Like the other DHP derivatives, after exposure to light, manidipine undergoes decomposition leading to a weakening of the pharmacological activity. Method: The protective influence of selected dyes on manidipine has been tested. The photodegradation of manidipine was performed according to the first version of the ICH Guideline for photostability testing. The solutions were illuminated by a high-pressure lamp HBO-200, and the methods used for evaluation of manidipine photodegradation were HPLC, HPLC–MS, and UV–vis spectrophotometry. Quantitative evaluation of photodegradation was made on the basis of the quantum yields of the processes with the use of Reinecke salt as a chemical actinometer. Results: Results have shown that all the dyes studied, indigotine, azorubine, and cochineal red, slow down the process of manidipine photodegradation, and the most effective is azorubine. The role of the dyes has been determined on the basis of the Stern–Volmer dependence. Conclusion: The dyes studied, indigotine, azorubine, and cochineal red, can be potential photoprotectors of manidipine as they quench the excited states of the compound.

Solid State Photodegradation Study of Fexofenadine Hydrochloride

The photodegradation of solid-state fexofenadine hydrochloride, H1 receptor antagonist, was investigated under UV light conditions as per option 2 of ICH photostability testing guidelines. The amount of drug remaining intact after photodegradation was estimated using a newly developed and validated HPTLC method employing ethyl acetate: methanol: ammonia (30%) as a mobile phase in proportion of (6:3.5:0.5v/v/v). In solid state, after 1800watt.hrs/m2 of UV light illumination, fexofenadine hydrochloride concentration was reduced to 57% following a first-order kinetic with t1/2 of 2221.5watt.hrs/m2 and a degradation rate constant (k) of 3.12(watt.hrs/m2)−1. The results indicate that fexofenadine hydrochloride should be protected from light.

Indigotine, azorubine, and cochineal red as photoprotectors of manidipine

The calcium antagonists from the group of 1,4-dihydropyridine (DHP) derivatives are photolabile, and the products of their photochemical decomposition have no pharmacological activity. Like the other DHP derivatives, after exposure to light, manidipine undergoes decomposition leading to a weakening of the pharmacological activity. The protective influence of selected dyes on manidipine has been tested. The photodegradation of manidipine was performed according to the first version of the ICH Guideline for photostability testing. The solutions were illuminated by a high-pressure lamp HBO-200, and the methods used for evaluation of manidipine photodegradation were HPLC, HPLC-MS, and UV-vis spectrophotometry. Quantitative evaluation of photodegradation was made on the basis of the quantum yields of the processes with the use of Reinecke salt as a chemical actinometer. Results have shown that all the dyes studied, indigotine, azorubine, and cochineal red, slow down the process of manidipine photodegradation, and the most effective is azorubine. The role of the dyes has been determined on the basis of the Stern-Volmer dependence. The dyes studied, indigotine, azorubine, and cochineal red, can be potential photoprotectors of manidipine as they quench the excited states of the compound.

Prochlorperazine tablets repackaged into dose administration aids: can the patient be assured of quality?

Patients are increasingly requiring their medications to be repackaged into dose administration aids because of the positive outcomes associated with reduction in medication related hospitalization and adverse effects due to improved medicines management. Since the stability of these repackaged medications is not the responsibility of manufacturer, it is important that drug substances with potential stability issues be identified. Thus the objective of this study was to evaluate the stability of prochlorperazine, a light sensitive drug repackaged into dose administration aids (DAAs), in order to provide guidelines to the pharmacist and advice to the patient on appropriate storage. Prochlorperazine tablets were stored repackaged in DAAs and in their original packaging for 8 weeks at ambient (25 +/- 1 degrees C; 60 +/- 1.5% RH), accelerated (40 +/- 1 degrees C; 75 +/- 1.5% RH) and in-use conditions encountered in situ both in a pharmacy and the patients' home. They were assessed for both chemical (using a validated HPLC method) and physical stability according to British Pharmacopoeial (BP) standards. In addition, photostability testing was undertaken under ICH conditions. Chemical and physical stability was confirmed to be within BP Limits. There were, however, noticeable organoleptic changes in the tablets stored under in-use conditions with a progressive grey discolouration over the 8 weeks, starting in week 2. Despite the confirmation of physical and chemical stability within BP limits, the discoloration and the potential for photodegradants to cause adverse effects in patients must lead us to draw the conclusion that the quality of this medication has been compromised. Pharmacists thus need to take this into account in repackaging and storage of prochlorperazine in DAAs and advise patients to store their DAA protected from light, heat and humidity.

Photomutagenic Properties of Terfenadine as Revealed by a Stepwise Photostability, Phototoxicity and Photomutagenicity Testing Approach ¶

Photomutagenic Properties of Terfenadine as Revealed by a Stepwise Photostability, Phototoxicity and Photomutagenicity Testing Approach ¶

Photostabilization of 1,4-Dihydropyridine Antihypertensives by Incorporation into β-Cyclodextrin and Liposomes

Inclusion compounds of eleven dihydropyridine drugs were formed and investigated for protection against photo-induced drug degradation. Formulations of cyclodextrins and liposomes were prepared and their photoprotective ability for the encapsulated drug was monitored. Drug photodegradation was spectrophotometrically followed during exposure of the formulations to light of a Xenon lamp. ICH guidelines for photostability testing were applied. A comparison with common pharmaceutical formulations revealed optimal protection for both formulations. The use of the liposome and cyclodextrin inclusion complexes resulted in a mean drug recovery of 77 and more then 90% respectively, after a light exposure until to 30 minutes with an intensity of 21 kJ x min(-1) m(-2). Lercanidipine and Manidipine only did not show a satisfactory increase of photostabilization in the studied supramolecular complexes, due to their low inclusion in both the systems.

Surface treatment: A potential approach for enhancement of solid-state photostability

The potentials of a simple surface treatment technique aiming at modifying solid-state properties with emphasis on photostability were investigated using methyldopa (MD), a photosensitive drug substance. MD was treated with a preselected solvent by stirring a drug suspension in the solvent in a predetermined solid/solvent ratio under controlled conditions. At the end of the solvent treatment period, MD powder was separated, dried and screened. Changes in the solid-state properties of surface-treated MD were monitored using flowability measurements, scanning electron microscopy, thermal analysis and dissolution rate. Further, photostability testing, according to the ICH guidelines, was conducted using compressed disks of MD treated with solvents in the absence and presence of antioxidants, namely ascorbic acid, butylated hydroxytoluene (BHT) and cysteine HCl. The color change (Δ E) was determined according to the CIELAB system. Surface treatment of MD drug substance with ethanol, methanol and isopropanol resulted in a marked improvement in flowability which was associated with morphological crystalline changes. Treatment of MD with methanol provided free flowing spherical agglomerates. Disks of solvent-treated MD showed improved photostability which was further potentiated by the inclusion of antioxidants, although only traces of the antioxidant were retained in the treated powder. Tablets containing MD surface treated with methanol containing a mixture of 2% ascorbic acid and 0.2% BHT were prepared by direct compression using a simple formula. The tablets conformed to official requirements.

Accelerated photostability study of tretinoin and isotretinoin in liposome formulations

The photodegradation of retinoic acids, tretinoin and isotretinoin, in ethanol and liposomes was studied. The light irradiation was performed according to the conditions suggested by the ICH Guideline for photostability testing by using a Xenon lamp within a wavelength range of 300–800 nm. The photodegradation process was monitored by UV spectrophotometry. In ethanol solution, tretinoin and isotretinoin undergo complete isomerization just within a few seconds of light exposure to give 13- cis and 9- cis isomers, respectively. The 13- cis isomer from tretinoin undergoes in turn a slow isomerization to the same 9- cis isomer. Both retinoic acids incorporated in liposome complexes showed an increased stability in comparison to the ethanol solutions. In particular for tretinoin, a residual concentration of 60% was still present after a light irradiance of 3470 kJ/m 2, by means of a 250 W/m 2 light power for 240 min, versus a residual value of just 8% measured at the same time in ethanol solution. Moreover, the isomerization rate in liposomes resulted reduced for isotretinoin and practically irrelevant for tretinoin. The degradation rate was found to be dependent on the drug concentration. The better stability of the tretinoin in liposome complex was supposed to be related to its higher incorporation value due to the linear structure of the molecule.

Design and monitoring of photostability systems for amlodipine dosage forms

Photostability of amlodipine (AML) has been monitored in several pharmaceutical inclusion systems characterized by plurimolecular aggregation of the drug and excipients with high molecular weight. Several formulations including cyclodextrins, liposomes and microspheres have been prepared and characterized. The photodegradation process has been monitored according to the conditions suggested by the ICH Guideline for photostability testing, by using a light cabinet equipped with a Xenon lamp and monitored by spectrophotometry. The formulations herein tested have been found to be able to considerably increase drug stability, when compared with usual pharmaceutical forms. The residual concentration detected in the inclusion complexes with cyclodextrins and liposomes was 90 and 77%, respectively, while a very good value of 97% was found for microspheres, after a radiant exposure of 11,340 kJ m −2.

アルギン酸ナトリウム液中のポラプレジンクの安定性についての検討

Cancer chemotherapy and radiation therapy-induced stomatitis often involves symptoms severe enough that the oral ingestion of food may become difficult. We therefore prepared a polaprezinc (zinc N- (3-aminopropionyl) -L-histidine) suspension dispersed in sodium alginate solution (P-AG) as a specific treatment and agent for the prophylaxis of severe stomatitis, and examined the chemical and physico-chemical stability of P-AG for clinical use.The chemical and physico-chemical stability of P-AG was established from its appearance, the percentage polaprezinc content and viscosity immediately after steam sterilization and uniformity after being left to stand for14 days at 25 and 5°C. Similarly, these parameters were examined in photostability testing (40°C, 2000lux) for14 days at the same time. As a result, a change in appearance was observed after steam sterilization according to photostability testing. However, the percentage of polaprezinc contents did not decline after either steam sterilization, photostability testing or after being left to stand for 14 days regardless of the storage temperature. On the other hand, the viscosity of P-AG declined after steam sterilization according to the findings of photostability testing.

Photomutagenic properties of terfenadine as revealed by a stepwise photostability, phototoxicity and photomutagenicity testing approach.

Administration of the second-generation antihistamine, terfenadine, is sometimes associated with photosensitivity and other skin reactions. To obtain information on its photoreactivity, we used a stepwise experimental approach involving tests for photostability, phototoxicity (PT) (mouse fibroblast cell line [3T3] neutral red uptake [NRU] test) and photomutagenicity (with standard Ames salmonella tester strains TA98, TA100 and TA102). Terfenadine was not phototoxic to cultured mammalian cells under the conditions used (i.e. 5000/161 mJ cm(-2) UVA-UVB). Natural sunlight and UV radiations caused considerable drug decomposition and formation of several photoproducts. Addition of the irradiated terfenadine solution (i.e. a mixture of photoproducts) to the tester did not significantly increase background mutation frequency. Irradiation of terfenadine coplated with the TA102 strain induced a clear-cut photomutagenic response, the magnitude of which was dependent upon the precursor compound concentration and the UV dose (212/7 to 339/11 mJ cm(-2) UVA-UVB). These findings demonstrate that in vitro terfenadine is photomutagenic in absence of PT. Further in vitro and in vivo studies are therefore needed to provide an adequate safety assessment of the photochemical genotoxicity--carcinogenicity potential of terfenadine. In the meantime, patients should be advised to avoid excessive exposure to sunlight.

Pharmaceutical Development of a Parenteral Lyophilized Formulation of the Investigational Polymer-Conjugated Platinum Anticancer Agent AP 5280

AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water. However, as aqueous solutions of AP 5280 proved to be labile upon sterilization by moist heat, it was decided to develop a lyophilized dosage form. Initially, glass vials were used as primary packaging, but this led to a high breakage rate, which could be completely prevented by the use of CZ® resin vials. Stability studies to date show that the lyophilized product in glass vials is stable for at least 12 months when stored at 2–8°C in the dark and the lyophilized product in CZ resin vials is stable for at least 6 months under these conditions. Photostability testing revealed photolability of AP 5280 drug substance and lyophilized product in both types of primary container, necessitating storage in the dark. The first clinical experiences indicate that the proposed formulation is fully applicable for use in the clinical setting.

SELECTIVE ASSAYS FOR QUANTITATION OF TENOXICAM IN PRESENCE OF ITS PHOTODEGRADATION PRODUCTS

ABSTRACT Tenoxicam, a thienothiazine oxicam, is a potent anti- inflammatory and antirheumatic drug. A comprehensive study on the photostability of tenoxicam is presented, including a comparison of three different methods (HPTLC/densitometry, HPLC, CE) developed for the photostability testing of the title compound. The stability indicating capability of the respective assays is proven with sample solutions forcedly degraded by artificial irradiation from a xenon source. The chromatograms and the electropherogram of the resulting solution, show tenoxicam well resolved from the degradation products. The methods are applied for testing the photostability of solutions containing tenoxicam in various concentrations (2 mg mL−1; 250 μg mL−1; 40 μg mL−1), and stored under different conditions. The stability of tenoxicam was found to be dependent on the nature of the light source, as well as on the concentration of the sample solution. The assays are validated and compared with respect to performance and precision.

Evaluation of chemical stability of St. John's wort commercial extract and some preparations

Thermal and photostability of a commercial dried extract and capsules of St. John's wort ( Hypericum perforatum L.) were evaluated under the ICH test conditions. The extract was considered as drug substance and its preparations as drug products. In addition, capsules of different colours corresponding to different opaficient and pigment contents were also evaluated as primary package of drug product and the tests in the secondary pack were performed with amber containers, as well. A selective high-performance liquid chromatography (HPLC) for determination of stability of all the characteristic constituents, namely flavonols, hyperforins and hypericins, was carried out. Photostability testing showed all the constituents to be photosensitive in the tested conditions. However, different opaficients and pigments present in the capsules influenced the stability of the different classes of constituents. Amber containers suggested as secondary packages influenced only in part the photostability of the investigated constituents. Long-term thermal stability testing showed a very low (less than 4 months) hyperforins and hypericins t 90, even if ascorbic and citric acids were added to the formulation. From the results we have obtained it is clear that for St. John's wort preparations, a mere translation of the ICH guidelines to the field of herbal products, as suggested by the WPHMP of the EMEA, cannot be accepted. A revision and adaptation of the storage conditions should be elaborated.

2-Nitrobenzaldehyde: a convenient UV-A and UV-B chemical actinometer for drug photostability testing

We report the development of a new 'photochemical titration' actinometric method for measurement of UV-B (290-320 nm) and UV-A (320-400 nm) light dose during drug photostability testing. It is based upon photolysis of aqueous 2-nitrobenzaldehyde solution, a well-characterized reaction that has been previously demonstrated to be useful as an accurate and reliable actinometric method. Our new method can be performed by a chemical technician using only common reagents. It has been developed for use with xenon arc lamp illumination chambers which are commonly employed for drug photostability testing, but can be readily modified for use with the other illumination sources.

Influence of temperature and storage time after light exposure on the quinine monohydrochloride chemical actinometric system.

The ICH guideline on photostability has proposed quinine monohydrochloride chemical actinometric system as a standard method for measuring light exposure during photostability testing. A change in the absorption at 400 nm of quinine monohydrochloride after light exposure corresponds to a defined dose of light. The present work investigated the effect of temperature, light exposure level and the dark reactions following light exposure on the change of absorbance obtained. The change in the absorbance was linear with respect to time, the rate increased threefold in the temperature range of 25–52°C, and the calculated activation energy was 30 kJ/mol as calculated by the Arrhenius equation. For the dark reactions the change in absorbance was non-linear with respect to time. The rate of the dark reactions was smaller than during light exposure and dependent on the light exposure level prior to the dark reactions. The calculated activation energy of the dark reactions was 18 kJ/mol when calculated by the Arrhenius equation on the initial reaction rates. The different activation energy of the light reaction and the dark reactions indicated different degradation patterns of the two reactions. The present study shows that the absorbance change of quinine monohydrochloride chemical actinometric system is dependent on temperature during light exposure and on storage time and storage temperature after light exposure. The method proposed in the ICH guideline should therefore be optimized in terms of definition of temperature and limitations in storage time after light exposure.

Stability indicating assays for the determination of piroxicam—comparison of methods

Photodegradation of piroxicam, a 1,2-benzothiazine oxicam, is studied laying special emphasis on the investigation of the correlation between concentration of the sample solution and stability. A comparison of three different methods (HPTLC/densitometry, HPLC, CE) developed for the photostability testing of the title compound is presented. The stability indicating capability of the assays is proved using forced degradation by exposing a sample solution to artificial irradiation from a xenon source. The chromatograms and the electropherogram of the resulting solution show piroxicam well resolved from the degradation products. For quantitation external calibration is employed, all calibration curves being linear in the respective concentration range of interest. Piroxicam solutions of three different concentrations (2 mg ml −1; 250 μg ml −1; 40 μg ml −1) are subjected to simulated sunlight for 480 min. The stability is investigated by quantitation of piroxicam by the methods mentioned. The methods are compared in respect of performance and precision. Costs and time of analysis are regarded also.