Radiostability of Florfenicol in the solid state

Abstract

The effect of ionizing radiation on florfenicol (FF), an antibiotic with wide antibacterial properties was investigated to determine whether it can be sterilized using high-energy radiation. FF was irradiated by E-beam radiation to doses of 25-800kGy,andthenchangesinthephysico-chemicalpropertieswereexaminedusingchromatographicmethods(TLC andHPLC),spectroscopicmethods(NMRandMS)andhyphenatedmethods(HPLC-MS).Itwasfoundthatastandard sterilizingdoseof25kGyledtotheformationoftwonewproductsofradiolysisaswellasloweringthecontentofFFby 0.95%.Withhigherdosesofradiation,thecontentofFFfurtherdecreased(by12.27%withadoseof800kGy),andnew products of radiolysis appeared (up to five with a dose of 800kGy). However, there were no differences between the NMRandMSspectraofirradiatedandnon-irradiatedsamplesofFF.Alineardependencewasfoundbetweenthedose ofradiationandtheFFcontent(correlationcoefficientof0.9951)aswellasbetweenthemeltingpointandthesumof productsofradiolysis(correlationcoefficientof0.9975).ItwasfoundthataradiodegradationofFFtookplacebythe breaking of an amide bond, leading to the formation of an aliphatic amine, which was subsequently oxidized to 4-methylsulfonylbenzoic acid. The radiolytic yield for the radiodegradation of FF was calculated to be 10.24 molecules/100eVforadoseof25kGy.Asaresultofourinvestigation,wecanconcludethatFFshowsareasonably goodradiostabilityintherangeofdosesusedforsterilization,i.e.25kGyandbelow,andthereforeitcanbesterilized usinghigh-energyradiationwithoutchangingitsphysicochemical,propertiesandhenceitstherapeuticefficacy. The difference in the structure between florfenicol and thiamphenicol,i.e.thepresenceofaFatomatC3insteadofthe hydroxylgroup,protectsFFagainstdeactivationastheresultof acetylationoftheOHgroup.Thisreactioniscatalyzedbythe plasmidacquiredacetylotransferaseofchloramphenicol,andis oneofthemechanismsmostfrequentlyresponsibleforantibiotic resistanceofchloramphenicolderivatives. 1,4 FFisusedintheformofaninjection,andthereforemustbe sterile.Oneofthemethodsofsterilizationisionizingradiation, which has antibacterial properties. Despite being a fast and efficient method, the exposure of drugs to ionizing radiation may lead to changes in the physicochemical properties of the drug,andthereforealteritstherapeuticproperties.Itistherefore, necessarytodeterminetheradiostabilityofadrugbeforeusing ionizingradiationasamethodofsterilization. [5][6][7] Thechangesthattakeplacearemainlyduetotheproduction of free radicals, which can lead to chain reactions and the formationofstableproductsofdecomposition,includingoptical andstructuralisomers.Thesechangestakeplacepredominantly inaqueoussolutions,andtheproductsofwaterradiolysis(free radicals and H2O2) speed up the decomposition of sterilized drugs. For this reason the method of choice is currently sterilization in the solid state. In this state drugs are far less susceptibletoradiolyticdamage.However,somechangescan take place. The most frequently occurring effects in drugs irradiated in the solid state are: the formation of crystal-lattice defects,associat...