How to photostabilize molsidomine tablets

Different methods of photostabilization are presented for the very light sensitive molsidomine tablets. The incorporation of photostabilizers such as light absorber or pigments into the tablets considerably improved the photostability. Nevertheless, photodegradation was still detected after 12 h of intense light stress. Pigments are superior to colorants or ultraviolet absorbers. The use of titanium dioxide needs to be considered carefully. Preblending the pigment with the drug substance is very helpful for taking full advantage of its photostabilizing properties. Surface-treated titanium dioxide with reduced photocatalytic activity was less suitable than untreated. That was due to a change of particle agglomeration and adhesion behavior, which was demonstrated by scanning electron microscopy pictures. However, only the protection of the tablets by a cover, either by blistering or film coating, gave a photostable drug product.     

ICH guideline for photostability testing: aspects and directions for use

The ICH guideline Q1B for photostability testing gives guidance on the basic testing protocol required to evaluate the light sensitivity and stability of new drugs and products. The choice of the irradiation method, although complying with the guideline demands, may effect test results. High irradiances may shorten testing times, but can lead to enforcement of photodegradation, which was demonstrated for molsidomine tablets. The exposure to an artificial light source (xenon lamp) was compared and correlated to natural daylight. Suitable testing methods for nifedipine and molsidomine tablets were developed. Deviating from the guideline recommendations, the presentation of powder samples should be done in tiny aluminium pans, facilitating the test procedure, minimising the risk of falsified test results due to improper sampling and improving reproducibility. When using glass dishes for the presentation of tablets to photostability testing, they should be lined by e. g. aluminium foil to avoid influences of light reflected from the sample tray.     

The influence of formulation and manufacturing process on the photostability of tablets

The formulation and the manufacturing process can significantly influence the photostability of tablets. Investigations of various formulation and manufacturing parameters were done with tablets containing nifedipine and molsidomine as highly light sensitive drugs. The effect of relevant formulation factors are stated. Whereas the particle size of the drug substance and the choice of the lubricant had no effect, the drug content, the compression diluent and geometric alterations significantly affected the photoinstability. Depending on the formulation drug losses varied between 30 and 55% after 12 h irradiation in a light testing cabinet (Suntest CPS+). Manufacturing parameters like compression force and direct compression versus granulation showed less serious influences. Nevertheless, photostability changes up to 10% were registered.     

Improved photostability indicating ion-pair chromatography method for pergolide analysis in tablets and in the presence of cyclodextrins

Pergolide (PG) a semi-synthetic ergot alkaloid derivative used mainly for the treatment of Parkinson's disease is known to be a photosensitive drug substance. The major photodegradation products are PG sulphoxide (SX) and PG sulphone (SN), which are also the main impurities of the bulk drug substance. It is widely metabolized to more than 10 metabolites including SX and SN. In this work an improved photostability indicating ion-pair chromatography method for PG mesilate was developed. The method can be applied in the determination of PG and impurities in aqueous solutions and in tablets for routine analysis. This new method is appropriate for the quantitative determination of PG in the presence of its impurities and photodegradation products and can also be used for PG complexes with cyclodextrins (commonly used as photostabilizing agents). Furthermore it is suitable for the quantitation of its impurities and its thermal or photo-induced decomposition products. Separation was achieved on a ThermoQuest C(18) BDS column and Sodium octanosulphonate was used as ion-pairing agent. Analysis was performed at 223 nm. Validation parameters included: specificity, linearity, precision and accuracy, limit of quantitation and suitability. The method was found to be specific and linear for PG, as well as for SX and, SN impurities. The recovery was 100.83+/-0.46% for PG, 99.86+/-0.33% for SX and 99.77+/-1.84% for SN. Finally the photodegradation profile of PG mesilate was studied in different initial sample concentration. The obtained result revealed that: PG photolysis is catalyzed by its degradation products and that decrease of initial sample concentration reduces the rate of PG photoinduced degradation.     

Isolation and structure elucidation of photodegradation products of fexofenadine

The photostability of the antihistamine fexofenadine hydrochloride is described. The stress studies revealed the photostability of the drug as the most adverse stability factor. The main photodegradation products were isolated and its structures were elucidated by 1H, 13C, COSY, HSQC, HMBC NMR and mass spectrometry techniques. The drug was exposed to UVC light at 254 nm in methanolic solutions and the degradation was followed by HPLC and TLC. The photostability of fexofenadine tablets was studied and the same degradation products were observed. The two photodegradation products isolated were characterized as the isopropyl derivative, obtained by decarboxilation of fexofenadine, and a benzophenone compound, which was obtained by rearrangement of aromatic rings and oxidation reactions. The results show the importance of appropriate light protection during the drug development process, storage and handling.     

Development and validation of a stability-indicating RP-HPLC method for duloxetine hydrochloride in its bulk and tablet dosage form

The objective of the present work was to develop a stability-indicating RP-HPLC method for duloxetine hydrochloride (DUL) in the presence of its degradation products generated from forced decomposition studies. The drug substance was found to be susceptible to stress conditions of acid hydrolysis. The drug was found to be stable to dry heat, photodegradation, oxidation and basic condition attempted. Successful separation of the drug from the degradation products formed under acidic stress conditions was achieved on a Hypersil C-18 column (250 mm ? 4.6 mm id, 5?m particle size) using acetonitrile: 0.01 M potassium dihydrogen phosphate buffer (pH 5.4 adjusted with orthophosphoric acid) (50:50, v/v) as the mobile phase at a flow rate of 1.0 ml/min. Quantification was achieved with photodiode array detection at 229 nm over the concentration range 1a25 ?g/ml with range of recovery 99.8a101.3 % for DUL by the RP-HPLC method. Statistical analysis proved the method to be repeatable, specific, and accurate for estimation of DUL. It can be used as a stability-indicating method due to its effective separation of the drug from its degradation products.     

硝苯啶的光解分析法及其在透皮吸收研究中的应用

A new method of analysis for low concentrations nifedipine was developed according to the principle of a photodegradation analytical method that has been reported by the authors previously, and was used to study percutaneous absorption. The absorbance of sample solution was measured before and after light irradiation at 237 nm for 2 h. In this method, calibration graph was linear in the range of 1～20μg/ml for △A₂₃₇. The average recovery for nifedipine was 98.80%. No interference from propylene glycol, azone, m-nifedipine, nitrendipine, verapamil and propranolol was observed. It is shown that azone can promote markedly percutaneous absorption of nifedipine.     

In-Use Photostability Practice and Regulatory Evaluation for Pharmaceutical Products in an Age of Light-Emitting Diode Light Sources

This article describes how the increased use of energy-efficient solid-state light sources (e.g., light-emitting diode [LED]-based illumination) in hospitals, pharmacies, and at home can help alleviate concerns of photodegradation for pharmaceuticals. LED light sources, unlike fluorescent ones, do not have spurious spectral contributions <400 nm. Because photostability is primarily evaluated in the International Council of Harmonization Q1B tests with older fluorescent bulb standards (International Organization for Standardization 10977), the amount of photodegradation observed can over-predict what happens in reality, as products are increasingly being stored and used in environments fitted with LED bulbs. Because photodegradation is premised on light absorption by a compound of interest (or a photosensitizer), one can use the overlap between the spectral distribution of a light source and the absorption spectra of a given compound to estimate if photodegradation is a possibility. Based on the absorption spectra of a sample of 150 pharmaceutical compounds in development, only 15% would meet the required overlap to be a candidate to undergo direct photodegradation in the presence of LED lights, against a baseline of 55% of compounds that would, when considering regular fluorescent lights. Biological drug products such as peptides and monoclonal antibodies are also expected to benefit from the use of more efficient solid-state lighting.     

Comparison of haemodynamic effects of nifedipine and molsidomine in patients with coronary artery disease

Summary The haemodynamic effects of oral nifedipine 20 mg and molsidomine 4 mg were compared in 24 patients with coronary artery disease.Molsidomine unlike nifedipine caused a significant fall in mean pulmonary artery pressure and left ventricular end-diastolic pressure. Both drugs caused a significant and comparable reduction in systolic and diastolic blood pressure. Although only nifedipine significantly reduced systemic vascular resistance the difference between the drugs was not significant. The heart rate was significantly increased by nifedipine but not by molsidomine. The ejection phase indices were all increased by molsidomine and the increment in the mean normalized systolic ejection rate was significantly greater than that due to nifedipine. The left ventricular end-systolic volume index decreased significantly after molsidomine but not nifedipine.Neither drug significantly affected left ventricular end diastolic volume index, stroke volume index, maximal rate of rise of left ventricular pressure or left ventricular stroke work index.     

Photochemical stabilities of some dihydropyridine calcium-channel blockers in powdered pharmaceutical tablets

Photostabilities of some dihydropyridine calcium-channel blockers in pulverized pharmaceutical tablets were studied. Powdered tablets including amlodipine, nifedipine, or nilvadipine were exposed to D65 daylight lamp radiation according to an ICH guideline (ICH Q1B). The photodegradation of pharmaceutical components and their degradation products were monitored by HPLC using a reversed phase column with UV detection; their peak components were identified using MS analysis. Photochemical reactions involved in the photodegradation of these pharmaceuticals include aromatization of the dihydropyridine moiety and conversion to nitroso group from the nitro group in benzene rings. Chemical stability studies of these drugs indicate that nifedipine is the most photosensitive. The rate constant of nifedipine is indicated as seven times higher than those of the other two drugs.     

Photoreactivity of biologically active compounds. XVIII. Photostability of ofloxacin in the solid state and in a tablet formulation

The photostability of ofloxacin in the solid state has been investigated. The change in colour of uncoated and film coated ofloxacin tablets and compressed ofloxacin was studied as a function of irradiance level and total exposure energy. The degradation of ofloxacin in the various preparations was quantified by HPLC and the antimicrobial activity was determined for selected tablets. The structure of two main degradation products from ofloxacin in the solid state has been postulated from LC-MS analysis. Both products have an absorption cut-off below 400 nm and cannot explain the observed change in tablet colour. There was no apparent relationship between the change in colour and the loss of active substance or antibacterial activity for the preparations investigated. The change in colour was easily detectable at rather low exposure levels. Apparently, there was a difference in light sensitivity between the two film-coated tablet batches investigated. The results obtained were partly dependent on the conditions within the radiation chamber (e.g., exposure time and irradiance level), which emphasizes the importance of testing the samples under various conditions unless the results are unequivocal. The tablets were sensitive to visible light although ofloxacin only has a neglectible absorption above 400 nm. The film coated ofloxacin tablets did, however, absorb above 400 nm with a cut-off at approximately 520 nm. A change in tablet coating to include a component that filters visible light in addition to UV radiation might provide a solution to the discolouration problem and prevent batch to batch variations with respect to light sensitivity.     

The role of excipients and package components in the photostability of liquid formulations

A phenyl ether-based drug substance exhibits photochemical degradation in citrate buffers with both ultraviolet (300-450 nm range) and visible light (380-700 nm range) exposure, even though the drug molecule itself is non-light absorbing at wavelengths > 300 nm. The major contributors to the observed photosensitivity are the citrate buffer, parts per billion (ppb) levels of iron, oxygen, and light exposure level. Although a primary phenol photodegradate is generated, there are at least eight other species formed as well. The molecular weights and abundance of these species suggest that the product distribution is generated by the reaction of hydroxyl radicals with the drug substance. The generation of the primary photodegradate is linearly proportional to the light exposure amount for a fixed concentration of iron present in the formulation. Conversely, the amount of photodegradation is also nearly linear with iron concentration (through 200 ppb levels) for a fixed amount of light exposure. The proposed mechanism for the photochemical generation of hydroxyl radicals has precedence in the literature for similar combinations of iron, oxygen, carboxylate buffers, and light. Since the buffer salt and oxygen molecular equivalents in the product are significantly higher than the ppb levels of iron employed and more difficult to remove, the control of the extent of photodegradation largely rests on the control of trace levels of iron in the formulated product and control of light exposure. Exposure of drug solutions to a series of transition metals clearly indicates that iron is the key transition metal involved in the observed photochemistry. At manufacture, the primary source of iron is the raw materials (water, drug or excipients) used in the formulation. The level of iron for product stored in glass increases with sample age and can be attributed to iron leaching from borosilicate glass vials. Consideration of adequate light control during the manufacturing and packaging processes will be discussed and can only be defined as a function of the amount of iron present at the time of manufacture in the formulation. The generality of this chemistry to other drug candidates and in the presence of other common buffers will also be discussed.     

Stability Behaviour of Molsidomine-containing Pellet Formulations

Molsidomine in mixtures with different inactive ingredients has been subjected to a stability test. The fingerprint chromatogram obtained by HPLC with diode-array detection of mixtures of molsidomine with povidone 25 revealed decomposition products; the detection wavelength of 210 nm resulted in easy detection of the degradation products. Molsidomine-containing pellets were manufactured according to a compact procedure and by applying the active ingredient to placebo pellets. Compared with the nonpareil pellet formulations, compact pellets have a considerably higher water content and undergo decomposition of the active ingredient after storage for 50 months under different conditions. It is assumed that the decomposition of molsidomine is accelerated by the peroxide found in povidone.     

Structural elucidation of rabeprazole sodium photodegradation products

Rabeprazole sodium is a proton pump inhibitor, used in acid-related disorders, like peptic ulcers and gastroesophageal reflux. It is known to be an acid-labile drug, however, few data about its stability under other factors are available. The aim of this work was to study the photodegradation of rabeprazole, to determine its kinetics and to elucidate the structures of the main degradation products. UVC-254 nm and metal-halide lamps were used. The analysis of the samples was carried out by HPLC. When the drug was in methanol solution, one main degradation product was formed; the degradation rate followed zero-order kinetics. The (1)H and (13)C NMR spectroscopic determinations revealed the product was the benzimidazolone. Another isolated product was identified as benzimidazole. The latter was confirmed against an authentic sample. A third photodegradation product was identified as the [4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl]methanol, by (1)H and (13)C NMR of the reaction mixture in chloroform-d. When powdered commercial tablets were exposed to UVC irradiation, they showed the same degradation products along with other unidentified, which appeared as traces; the degradation rate was slower than in solution. The intact tablets were stable after 50 days of exposition to the same light source.     

不同辅料对硝苯地平缓释片光稳定性影响研究

目的 考察硝苯地平缓释片中原料药与辅料的相容性,为更好地设计处方,控制和提高质量提供依据和信息。方法 采用中国药典2015年版二部硝苯地平原料药项下有关物质检查方法,考察有关物质变化,作为不同辅料对硝苯地平缓释片光稳定性的影响指标。结果 在光照条件下,硝苯地平易产生光降解杂质2,且微晶纤维素和硬脂酸镁会加速杂质2的产生。结论 在满足相关制剂要求的条件下,建议尽量少加或不加微晶纤维素和硬脂酸镁。     

差示分光光度法测定制剂中硝苯啶的含量

利用硝苯啶溶液对光不稳定的性质,在波长350nm处测其光照前后的吸收度差值(△A),△A与硝苯啶乙醇溶液浓度在10～60μg/ml范围内呈线性关系。使用本法对硝苯啶片进行了含量测定,并对其类似物进行了干扰试验,排除了组分的干扰。该法的精密度日内为1.3%,日间为1.9%,平均回收率为99.96%。方法简便、快速,不需色谱等分离手段即可达到分析目的,专一性、重复性均较好,是分析硝苯啶制剂的一种新途径。     

The influence of food on the pharmacokinetics of ''biphasic'' nifedipine at steady state in normal subjects.

Previous studies following single dose administration have suggested that the pharmacokinetics of various nifedipine formulations could be influenced by the timing of associated food consumption. In order more closely to reflect the clinical situation we have carried out a study at steady state using a 'biphasic' formulation comprising 'rapid' and 'retarded' drug release components. Fifteen normal subjects took 20 mg 'biphasic' nifedipine 12 hourly for 10 days. Studies were carried out on days 4, 7 and 10. On these days the nifedipine was taken 2 h or 1 h before or immediately following a light breakfast. A light breakfast influenced neither the rate nor the extent of nifedipine absorption nor the rate or extent of major metabolite appearance. We conclude that at steady state the timing of a light meal is unlikely to alter in any clinically important manner the pharmacokinetics of nifedipine released from 'biphasic' tablets.     

羟丙甲纤维素QbD样品对硝苯地平骨架片释放的影响

目的：研究羟丙甲纤维素的不同关键材料属性（CMAs）的样品（QbD样品）对以难溶性药物硝苯地平（溶解度11μg/ml）为模型药物的亲水凝胶骨架缓释片的药物释放的影响。方法：采用直接压片的方式,分别使用粘度、粒度和羟丙基含量等属性分别接近标准上下限范围的羟丙甲纤维素QbD样品和其他辅料一起制成硝苯地平骨架缓释片,并按标准规定的方法对体外释放曲线进行测定。结论：在标准规定范围内羟丙甲纤维素的粘度、粒度和羟丙基含量的波动对硝苯地平亲水凝胶骨架缓释片的释放没有显著的影响。     

Complex formation between menadione and cetylethylmorpholinium ethosulfate: effect on UV photodegradation of menadione.

The process of menadione photodegradation can be enhanced or diminished by other compounds. The presence of the quaternary ammonium compound cetylethylmorpholinium ethosulfate (I) in solutions of minadione was found to slow the rate of photodegradation by UV light (253.7 nm). The mechanism of this effect may be due to complex formation between menadione and I. Complex formation was demonstrated by a shift in the absorption peaks of menadione from 245 and 260 nm to 251.5 and 261.5 nm, respectively. The equilibrium constant of this complex was calculated to be 1.647 M.