Simulated space radiation: Investigating ionizing radiation effects on the stability of amlodipine besylate API and tablets.

Efficacious pharmaceuticals with the adequate shelf life are essential for the well-being of the space explorers and successful completion of a space mission. Space is brimming with different types of radiations, which penetrate inside the spacecraft despite the shielding material. Such radiations can alter the stability of the pharmaceuticals during long duration space missions. The literature reporting the space radiation effects on the pharmaceuticals is scarce in a public domain. Ground-based simulation studies can be useful to predict the influence of the space radiations on the stability of the pharmaceuticals. Based upon these facts, the main objective of the present preliminary work was to investigate the effect of different types of ionizing radiations on the stability of amlodipine besylate API and tablets. Amlodipine besylate samples were irradiated by protons, neutrons (thermal and fast), gamma and heavy ion (56Fe) radiations with their different doses. The samples were also irradiated with UV-visible radiation to compare the effect of selected ionizing radiations with photodegradation. The physical stability was examined through organoleptic evaluation and the chemical stability was evaluated by FTIR and HPLC. The results of the organoleptic evaluation showed colour changes from colourless to yellow in proton irradiated solid API and gamma irradiated API aqueous solution. The FTIR spectrum of proton irradiated API showed one additional absorption band at 1728 cm-1 due to degradation products. HPLC analysis revealed that amlodipine degraded up to 10% and 21% after the highest doses of proton and gamma irradiation, respectively. No physical or chemical changes were observed after neutron and 56Fe irradiation. The structures of major radiolytic products were elucidated using LC-MS/MS. Two new impurities were found in the API aqueous solution as a result of gamma irradiation. The drug degradation pathways were postulated by proposing the plausible mechanism of formation.

Degradation kinetics and pathways of three calcium channel blockers under UV irradiation.

Calcium channel blockers (CCBs) are a group of pharmaceuticals widely prescribed to lower blood pressure and treat heart diseases. They have been frequently detected in wastewater treatment plant (WWTP) effluents and downstream river waters, thus inducing a potential risk to aquatic ecosystems. However, little is known about the behavior and fate of CCBs under UV irradiation, which has been adopted as a primary disinfection method for WWTP effluents. This study investigated the degradation kinetics and pathways of three commonly-used CCBs, including amlodipine (AML), diltiazem (DIL), and verapamil (VER), under UV (254 nm) irradiation. The chemical structures of transformation byproducts (TBPs) were first identified to assess the potential ecological hazards. On that basis, a generic solid-phase extraction method, which simultaneously used four different cartridges, was adopted to extract and enrich the TBPs. Thereafter, the photo-degradation of target CCBs was performed under UV fluences typical for WWTP effluent disinfection. The degradation of all three CCBs conformed to the pseudo-first-order kinetics, with rate constants of 0.031, 0.044 and 0.011 min(-1) for AML, DIL and VER, respectively. By comparing the MS(2) fragments and the evolution (i.e., formation or decay) trends of identified TBPs, the degradation pathways were proposed. In the WWTP effluent, although the target CCBs could be degraded, several TBPs still contained the functional pharmacophores and reached peak concentrations under UV fluences of 40-100 mJ cm(-2).

Mechanism of the photochemical degradation of amlodipine.

A mechanistic investigation on the photodegradation of amlodipine, the corresponding besylate and a simple analogue lacking the beta-aminoethoxy group has been carried out in water and in organic solvents. Irradiation leads to aromatization to the corresponding pyridines through an oxygen-independent process. The quantum yield for amlodipine base is Phi congruent with 0.001 under UV-A light, about one order of magnitude larger than that for the model bearing no amino group, supporting intramolecular assistance by that group. The value of Phi increases up to ca. 0.01 at shorter wavelength. The photolability of this drug according to ICH criteria is justified by the high absorptivity in the UV-A range (epsilon(UV-A)), despite the low quantum yield. Some comments are added about the fact that product Phi x epsilon(UV-A) is more significative than Phi alone for the photolability (in solution) and about the lacking possibility to quench the photoreactivity where, as in the present case, this involves only short-lived intermediates.

Effect of gamma radiation on amlodis and its potential for radiosterilization.

In the present work, radiation sensitivity of amlodis (AML) and its active ingredient Amlodipin Besylate (AML-B) were separately investigated by electron spin resonance (ESR) spectroscopy using radiolytic products induced in these drugs. Irradiation in the dose range of 2.5-25kGy did not create any ESR resonance line in AML-B, but it create five characteristic ESR resonance lines associated with more than one radical species in the case of AML. This signal is attributed to the radical species created upon irradiation of inactive ingredients such as microcrystalline cellulose and sodium starch glycolate of AML. Five resonance lines were observed to be divided into three sub groups of different characteristic behaviors associable with three different radical species. Radical species responsible from observed ESR lines were unstable at room and above room temperatures, however, they conserved their identities over a storage period of 92 days. This permitted to discriminate irradiated AML from unirradiated one. A quadratic function was found to describe best the variations of the intensities of observed resonance lines with applied radiation dose. A model based on three tentative radical species with a pyranose ring formed by the rapture of CH bonds in positions 1 and 4 was proposed to explain the observed five lines experimental ESR spectra. AML was considered not providing the characteristic features of a good dosimetric material due to its low radiation yield and relatively fast decays of the created radical species, but very low radiation sensitivity of its active ingredient, namely AML-B makes AML a good candidate for radiosterilization.

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 kJm(-2).