Monographs

Radiopharmaceutical Preparations

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Radiopharmaceutical Preparations

Radiopharmaceutical Preparations comply with the requirements of the 3rd edition of the EuropeanPharmacopoeia [0125]. These requirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITIONS

The statements of this monograph are intended to be read in conjunction with the monographs onradiopharmaceutical preparations in the Pharmacopoeia.

For the purposes of this general monograph, radiopharmaceutical preparations cover: radiopharmaceutical: any medicinal product which, when ready for use, contains one or more

radionuclides (radioactive isotopes) included for a medicinal purpose, radionuclide generator: any system incorporating a fixed parent radionuclide from which is

produced a daughter radionuclide which is to be removed by elution or by any other methodand used in a radiopharmaceutical preparation.

kit for radiopharmaceutical preparation: any preparation to be reconstituted and/or combinedwith radionuclides in the final radiopharmaceutical preparation, usually prior to itsadministration,

radiopharmaceutical precursor: any other radionuclide produced for the radio-labelling ofanother substance prior to administration.

A nuclide is a species of atom characterised by the number of protons and neutrons in its nucleus(and hence by its atomic number Z, and mass number A) and also by its nuclear energy state.Isotopes of an element are nuclides with the same atomic number but different mass numbers.Nuclides containing an unstable arrangement of protons and neutrons will transformspontaneously to either a stable or another unstable combination of protons and neutrons with aconstant statistical probability. Such nuclides are said to be radioactive and are calledradionuclides. The initial unstable nuclide is referred to as the parent radionuclide and the resultingnuclide as the daughter nuclide.

The radioactive decay or transformation may involve the emission of charged particles, electroncapture (EC) or isometric transition (IT). The charged particles emitted from the nucleus may bealpha particles (helium nucleus of mass number 4) or beta particles (negatively charged, generallycalled electrons or positively charged, generally called positrons). The emission of chargedparticles from the nucleus may be accompanied by the emission of gamma rays. Gamma rays arealso emitted in the process of isomeric transition. These emissions of gamma rays may be partlyreplaced by the ejection of electrons known as internal conversion electrons. This phenomenon,like the process of electron capture, causes a secondary emission of X-rays (due to thereorganisation of the electrons in the atom). This secondary emission may itself be partly replacedby the ejection of electrons known as Auger electrons. Radionuclides with a deficit of neutrons maydecay by emitting positrons. These radionuclides are called positron emitters. Positrons areannihilated on contact with electrons, the process being accompanied by the emission of usuallytwo gamma photons, each with an energy of 511 keV, generally emitted at 180 to each other,termed annihilation radiation.

The decay of a radionuclide is governed by the laws of probability with a characteristic decayconstant and follows an exponential law. The time in which a given quantity of a radionuclidedecays to half its initial value is termed the half-life (T).

The penetrating power of each radiation varies considerably according to its nature and itsenergy. Alpha particles are completely absorbed in a thickness of a few micrometers to some tensof micrometers of matter. Beta particles are completely absorbed in a thickness of severalmillimetres to several centimetres of matter. Gamma rays are not completely absorbed but onlyattenuated and a tenfold reduction may require, for example, several centimetres of lead. For mostabsorbents, the denser the absorbent, the shorter the range of alpha and beta particles and thegreater the attenuation of gamma rays.

Each radionuclide is characterised by an invariable half-life expressed in units of time and by thenature and energy of its radiation or radiations. The energy is expressed in electron-volts (eV), kilo-electronvolts (keV) or mega-electronvolts (MeV).

Generally the term radioactivity is used to describe the phenomenon of radioactive decay andto express the physical quantity (activity) of this phenomenon. The radioactivity of a preparation isthe number of nuclear disintegrations or transformations per unit time.

In the International System (SI), radioactivity is expressed in becquerel (Bq) which is onenuclear transformation per second. Absolute radioactivity measurements require a specialisedlaboratory but identification and measurement of radiation can be carried out relatively bycomparing with standardised preparations provided by laboratories recognised by the competentauthority.

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Radionuclidic purity: the ratio, expressed as a percentage, of the radioactivity of the radionuclideconcerned to the total radioactivity of the radiopharmaceutical preparation. The relevantradionuclidic impurities are listed with their limits in the individual monographs.

Radiochemical purity: the ratio, expressed as a percentage, of the radioactivity of theradionuclide concerned which is present in the radiopharmaceutical preparation in the statedchemical form, to the total radioactivity of that radionuclide present in the radiopharmaceuticalpreparation. The relevant radiochemical impurities are listed with their limits in the individualmonographs.

Chemical purity: in monographs on radiopharmaceutical preparations chemical purity iscontrolled by specifying limits on chemical impurities.

Isotopic carrier: a stable isotope of the element concerned either present or added to the radio-active preparation in the same chemical form as that in which the radionuclide is present.

Specific radioactivity: the radioactivity of a radionuclide per unit mass of the element or of thechemical form concerned.

Radioactive concentration: the radioactivity of a radionuclide per unit volume.

Total radioactivity: the radioactivity of the radionuclide, expressed per unit (vial, capsule,ampoule, generator, etc).

Starting materials: all the constituents which make up the radiopharmaceutical preparations.

Period of validity: the time during which specifications described in the monograph must befulfilled. Expiry date and, if necessary, time must be clearly stated.

PRODUCTION

A radiopharmaceutical preparation monograph describes as precisely as possible the method ofproduction of the radionuclide. A radiopharmaceutical preparations contains its radionuclide: as an element in atomic or molecular form, e.g. [133Xe], [15O]O2, as an ion, e.g. [131I] iodide, [99mTc]pertechnetate, included in or attached to organic molecules by chelation, e.g. [111In]oxine or by covalent

bonding, e.g. 2-[18F]fluoro-2-deoxy-D-glucose.

The practical ways of producing radionuclides for use in, or as radiopharmaceutical preparationsare: neutron bombardment of target materials (generally in nuclear reactors), charged particles bombardment of target materials (in accelerators such as cyclotrons), nuclear fission of heavy nuclides of target materials (generally after neutron or particle

bombardment), from a radionuclide generator.

Neutron or charged particle bombardmentThe nuclear reaction and the probability of its occurrence in unit time are dependent on the natureand physical properties of the target material and the nature, energy and quantity of the incidentparticles.

The nuclear transformation occurring through particle bombardment may be written in theform:

target nucleus (bombarding particle, emitted particle or radiation) produced nucleus.

Examples: 58Fe(n,g)59Fe18O(p,n)18F

In addition to the desired nuclear reaction adventitious transformations may occur. These will beinfluenced by the energy of the incident particle and the purity of the target material. Suchadventitious transformations may give rise to radionuclidic impurities.

Nuclear fissionA small number of nuclides with a high atomic number are fissionable and the most frequently usedreaction is the fission of uranium-235 by neutrons in a nuclear reactor. Iodine-131, molybdenum-99 and xenon-133 may be produced by nuclear fission of uranium-235. Their extraction from amixture of more than 200 other radionuclides must be carefully controlled in order to minimise theradionuclidic impurities.

Radionuclide generatorsRadionuclide generator systems use a relatively long-lived parent radionuclide which decays to adaughter radionuclide, usually with shorter half-life.

By separating the daughter radionuclide from the parent radionuclide by a chemical or physicalprocess, it is possible to use the daughter at considerable distance from the production site of thegenerators despite its short half-life.

Target materialsThe isotopic composition and purity of the target material will determine the relative percentages of

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the principal radionuclide and radionuclidic impurities. The use of isotopically enriched targetmaterial in which the abundance of the required target nuclide has been artificially increased, canimprove the production yield and the purity of the desired radionuclide.

The chemical form, the purity, the physical state and the chemical additives, as well as thebombardment conditions and the direct physical and chemical environment will determine thechemical state and chemical purity of the radionuclides which are produced.

In the production of radionuclides and particularly of short-lived radionuclides it may not bepossible to determine any of these quality criteria before further processing and manufacture ofradiopharmaceutical preparations. Therefore each batch of target material must be tested in testproduction runs before its use in routine radionuclide production and manufacture of the radio-pharmaceutical preparations, to ensure that under specified conditions, the target yields theradionuclide in the desired quantity and quantity specified.

The target material is contained in a holder in gaseous, liquid or solid state in order to beirradiated by a beam of particles. For neutron bombardment, the material is commonly containedin quartz ampoules or high purity aluminium or titanium containers. It is necessary to ascertain thatno interaction can occur between the container and its contents under the irradiation conditions(temperature, pressure, time).

For charged particle bombardment, the holder for target material is usually built of aluminium oranother appropriate metal, with inlet and outlet ports, a surrounding cooling system and usually athin metal foil target window. The nature and thickness of the target window have a particularinfluence on the yield of the nuclear reaction and may also affect the radionuclidic purity.

The production procedure clearly describes: target material, construction of the holder for target material, loading of target material into the irradiation system, method of irradiation (bombardment), separation of the desired radionuclide,and evaluates all effects on the efficiency of the production in terms of quality and quantity of theproduced radionuclide.

The chemical state of the isolated radionuclide may play a major role in all further processing.

Precursors for synthesisGenerally, these precursors are not produced on a large scale. Some precursors are synthesised bythe radiopharmaceutical production laboratory, others are supplied by specialised producers orlaboratories.

Test for identity, for chemical purity and the assay must be performed by validated procedures.When batches of precursors are accepted using data from the certificates of analysis, suitable

evidence has to be established to demonstrate the consistent reliability of the suppliers analysesand at least one identity test must be conducted. It is recommended to test precursor materials inproduction runs before their use for the manufacture of radiopharmaceutical preparations, toensure that under specified production conditions, the precursor yields the radiopharmaceuticalpreparation in the desired quantity and quality specified.

Performance of the production systemAll operations, from the preparation of the target to the dispensing of the final radiopharmaceuticalpreparation, must be clearly documented including their impact on the purity of the final productand the efficiency of the procedure. Where possible, in-process controls are performed and theresults recorded at each production step to identify at which level a possible discrepancy from thenormal production pathway may have occurred.

a) The production of radiopharmaceutical preparations may make use of mechanical andautomated processes that are used in the pharmaceutical industry, subject to adapting theseto the specificity of the radioactive starting material and to the requirements ofradioprotection.

b) For radiopharmaceutical preparations containing short-lived radionuclides, such as certainpositron emitters, remotely controlled production and automated radiosynthesis aregenerally used. For radionuclides with a very short half-life (less than 20 min) the control ofthe performance of the production system is an important measure to assure the quality ofthe radiopharmaceutical preparation before its release.

c) Any production procedure must be validated in test production runs before its use in routinemanufacture of radiopharmaceutical preparations, to ensure that under specified productionconditions, the production system yields the radiopharmaceutical preparation in the desiredquantity and specified quality.

d) The preparation of the dosage form of the final radiopharmaceutical preparation in thepractice of nuclear medicine generally involves limited radioactivity starting from ready-to-

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use radiopharmaceutical preparations, generators, kits and radioactive precursors. Allconditions which may affect the quality of the product (e.g. radiochemical purity andsterility) must be clearly defined and must include appropriate measures for radiationprotection.

IDENTIFICATION

Radioactive decay: radioactivity decays at an exponential rate with a decay constant characteristicof each radionuclide.

The curve of exponential decay (decay curve) is described by the equation:

tt

= eAA

At = the radioactivity at time t,Ao = the radioactivity at time t = 0,l=the decay constant characteristic of each radionuclidee =the base of Napierian logarithms.

The half-life (T) is related to the decay constant (l) by the equation:

( )69302ln2ln .T =The radionuclide is generally identified by its half-life or by the nature and energy of its radiation orradiations or by both, as prescribed in the monograph.

Measurement of half-life. The half-life is measured with a suitable detection apparatus such as anionisation chamber, a Geiger-Mller counter, a scintillation counter (solid crystal, liquid) or asemiconductor detector. The preparation to be tested is used as such or diluted or dried in acapsule after appropriate dilution. The radioactivity chosen, having regard to experimentalconditions, must be of a sufficiently high level to allow detection during several estimated half-lives,but not too high to minimise count rate losses, for example due to dead time.

The radioactive source is prepared in a manner that will avoid loss of material during handling. Ifit is a liquid (solution), it is contained in bottles or sealed tubes. If it is a solid (residue from dryingin a capsule), it is protected by a cover consisting of a sheet of adhesive cellulose acetate or of someother material.

The same source is measured in the same geometrical conditions and at intervals usually corres-ponding to half of the estimated half-life throughout a time equal to about three half-lives. Thecorrect functioning of the apparatus is checked using a source of long half-life and, if necessary,corrections for any changes of the count rate have to be applied (see Measurement of Radioactiv-ity).

A graph can be drawn with time as the abscissa and the logarithm of the relative instrumentreading (e.g. count rate) as the ordinate. The calculated half-life differs by not more than 5 percent from the half-life stated in the Pharmacopoeia, unless otherwise stated.

Determination of the nature and energy of the radiation The nature and energy of theradiation emitted may be determined by several procedures including the construction of anattenuation curve and the use of spectrometry. The attenuation curve can be used for analysis ofelectron radiation; spectrometry is mostly used for identification of gamma rays and detectable X-rays.

The attenuation curve is drawn for pure electron emitters when no spectrometer for beta rays isavailable or for beta/gamma emitters when no spectrometer for gamma rays is available. Thismethod of estimating the maximum energy of beta radiation gives only an approximate value. Thesource, suitably mounted to give constant geometrical conditions, is placed in front of thethinwindow of a Geiger-Mller counter or a proportional counter. The source is protected asdescribed above. The count rate of the source is then measured. Between the source and thecounter are placed, in succession, at least six aluminium screens of increasing mass per unit areawithin such limits that with a pure beta emitter this count rate is not affected by the addition offurther screens. The screens are inserted in such a manner that constant geometrical conditionsare maintained. A graph is drawn showing, as the abscissa, the mass per unit area of the screenexpressed in milligrams per square centimeter and, as the ordinate, the logarithm of the count ratefor each screen examined. A graph is drawn in the same manner for a standardised preparation.The mass attenuation coefficients are calculated from the median parts of the curves, which arepractically rectilinear.

The mass attenuation coefficient m, expressed in square centimetres per milligram, depends on theenergy spectrum of the beta radiation and on the nature and the physical properties of the screen.It therefore allows beta emitters to be identified. It is calculated using the equation:

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12

21

mm

AlnAlnm

=

m1 =mass per unit area of the lightest screen,m2 =mass per unit area of the heaviest screen, m1 and m2 being within the rectilinear part of

the curve,A1 =count rate for mass per unit area m1,A2 =count rate for mass per unit area m2.

The mass attenuation coefficient m thus calculated does not differ by more than 10 per cent fromthe coefficient obtained under identical conditions using a standardised preparation of the sameradionuclide.

The range of beta particles is a further parameter which can be used for the determination of thebeta energy. It is obtained from the graph described above as the mass per unit area correspondingto the intersection of the extrapolations of the descending rectilinear part of the attenuation curveand the horizontal line of background radioactivity.

Liquid scintillation counting may be used to obtain spectra of a- and b-emitters (see measurement ofradioactivity).

Gamma spectrometry is used to identify radionuclides by the energy and intensity of their gamma raysand X-rays.

The preferred detector for gamma and X-ray spectrometry is a germanium semiconductordetector. A thallium-activated sodium iodide scintillation detector is also used but this has a muchlower energy resolution.

The gamma detector has to be calibrated using standard sources because the detection efficiencyis a function of the energy of the gamma and X-rays as well as the form of the source and thesource-to-detector distance. The detection efficiency may be measured using a calibrated source ofthe radionuclide to be measured or, for more general work, a graph of efficiency against gammaand X-ray energy may be constructed from a series of calibrated sources of various radionuclides.

The gamma and X-ray spectrum of a radionuclide which emits gamma and X-rays is unique tothat nuclide and is characterised by the energies and the number of photons of particular energiesemitted per transformation from one energy level to another energy level. This propertycontributes to the identification of radionuclides present in a source and to their quantification. Itallows the estimation of the degree of radionuclidic impurity by detecting peaks other than thoseexpected.

It is possible to establish the rate of the decay of radioactivity using gamma spectrometry sincethe peaks diminish in amplitude as a function of the half-life. If, in such a source, a radioactiveimpurity with a different half-life is present, it is possible to detect the latter by identification of thecharacteristic peak or peaks whose amplitudes decrease at a different rate from that expected forthe particular radionuclide. A determination of the half-life of the additional peaks by repeatedmeasurements of the sample will help to identify the impurity.

The Table of physical characteristics of radionuclides mentioned in the European Pharmacopoeia (5.7)(reproduced at the end of this monograph) summarises the most commonly accepted physicalcharacteristics of radionuclides used in preparations which are the subject of monographs in theEuropean Pharmacopoeia. In addition, the Table states the physical characteristics of the mainpotential impurities of the radionuclides mentioned in the monographs.

By transition probability is meant the probability of the transformation of a nucleus in a givenenergy state, via the transition concerned. Instead of probability the terms intensity andabundance are frequently used.

By emission probability is meant the probability of an atom of a radionuclide giving rise to theemission of the particles or radiation concerned.

Irrespective of whether the one or the other meaning is in intended, probability is usuallymeasured in terms of 100 disintegrations.

MEASUREMENT OF RADIOACTIVITY

The radioactivity of a preparation is stated at a given date and, if necessary, time.The absolute measurement of the radioactivity of a given sample may be carried out if the decay

scheme of the radionuclide is known, but in practice many corrections are required to obtainaccurate results. For this reason it is common to carry out the measurement with the aid of aprimary standard source. Primary standards may not be available for short-lived radionuclides e.g.positron emitters. Measuring instruments are calibrated using suitable standards for the particularradionuclides. Standards are available from the laboratories recognised by the competentauthority. Ionisation chambers and Geiger-Mller counters may be used to measure beta and beta/gamma emitters; scintillation or semiconductor counters or ionisation chambers may be used formeasuring gamma emitters; low-energy beta emitters require a liquid-scintillation counter. For thedetection and measurement of alpha emitters, specialised equipment and techniques are required.

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For an accurate comparison of radioactive source, it is essential for samples and standards to bemeasured under similar conditions.

Low-energy beta emitters may be measured by liquid-scintillation counting. The sample isdissolved in a solution containing one or more often two organic fluorescent substances (primaryand secondary scintillators), which convert part of the energy of disintegration into photons oflight, which are detected by a photomultiplier and converted into electrical impulses. When using aliquid-scintillation counter, comparative measurements are corrected for light-quenching effects.Direct measurements are made, wherever possible, under similar condition, (e.g. volumes and typeof solutions) for the source to be examined and the standard source.

All measurements of radioactivity must be corrected by subtracting the background due to theradioactivity in the environment and to spurious signals generated in the equipment itself.

With some equipment, when measurements are made at high levels of radioactivity, it may benecessary to correct for loss by coincidence due to the finite resolving time of the detector and itsassociated electronic equipment. For a counting system with a fixed dead time t following eachcount, the correction is:

=

obs

obs

1 NN

N

N =the true count rate per second,Nobs = the observed count rate per second,

t=the dead time in seconds.

With some equipment this correction is made automatically. Corrections for loss by coincidencemust be made before the correction for background radiation.

If the time of an individual measurement, tm is not negligibly short compared with the half-life,T, the decay during this measurement time must be taken into account. After having corrected theinstrument reading (count rate, ionisation current, etc.) for background and, if necessary, forlosses due to electronic effects, the decay correction during measurement time is:

=

m

m

corr 2ln1

2ln

T

texp

T

tR

R

Rcorr = instrument reading corrected to the beginning of the individual measurement,R=instrument reading before decay correction, but already corrected for background, etc.

The results of determinations of radioactivity show variations which derive mainly from the randomnature of nuclear transformation. A sufficient number of counts must be registered in order tocompensate for variations in the number of transformations per unit of time. The standarddeviation is the square root of the counts, so at least 10,000 counts are necessary to obtain arelative standard deviation of not more than 1 per cent (confidence interval: 1 sigma).

All statements of radioactive content are accompanied by a statement of the date and, ifnecessary, the time at which the measurement was made. This statement of the radioactive contentmust be made with reference to a time zone (GMT, CET). The radioactivity at other times may becalculated from the exponential equation or from tables.

The radioactivity of a solution is expressed per unit volume to give the radioactive concentration.

RADIONUCLIDIC PURITY

In most of the cases, to state the radionuclidic purity of a radiopharmaceutical preparation, theidentity of every radionuclide present and their radioactivity must be known. The most generallyuseful method for examination of radionuclidic purity is that of gamma spectrometry. It is not acompletely reliable method because alpha- and beta-emitting impurities are not usually easilydetectable and, when sodium iodide detectors are employed, the peaks due to gamma emittingimpurities are often obscured by the spectrum of the principal radionuclide.

The individual monographs prescribe the radionuclidic purity required (for example, the gamma-ray spectrum does not significantly differ from that of a standardised preparation) and may setlimits for specific radionuclidic impurities (for example, cobalt-60 in cobalt-57). While theserequirements are necessary, they are not in themselves sufficient to ensure that the radionuclidicpurity of a preparation is sufficient for human use. The manufacturer must examine the product indetail and especially must examine preparations of radionuclides of short half-life for impurities oflong half-life after a suitable period of decay. In this way, information on the suitability of hismanufacturing processes and the adequacy of the testing procedures may be obtained. In caseswhere two or more positron emitting radionuclides need to be identified and/or differentiated, ase.g. 18F-impurities in 13N-preparations, half-life determinations need to be carried out in addition togamma spectrometry.

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Due to differences in the half-lives of the different radionuclides present in a radiopharmaceuticalpreparation, the radionuclidic purity changes with time. The requirement of the radionuclidicpurity must be fulfilled throughout the period of validity. It is sometimes difficult to carry out thesetests before authorising the release for use of the batch when the half-life of the radionuclide in thepreparation is short. The test then constitutes a control of the quality of production.

RADIOCHEMICAL PURITY

The determination of radiochemical purity requires separation of the different chemical substancescontaining the radionuclide and estimating the percentage of radioactivity associated with thedeclared chemical substance. Radiochemical impurities may originate from: radionuclide production, subsequent chemical procedures, incomplete preparative separation, chemical changes during storage.

The requirement of the radiochemical purity must be fulfilled throughout the period of validity.In principle, any method of analytical separation may be used in the determination of

radiochemical purity. For example, the monographs for radiopharmaceutical products may includepaper chromatography (2.2.26), thin-layer chromatography (2.2.27), electrophoresis (2.2.31), size-exclusion chromatography (2.2.30), gas chromatography (2.2.28) and liquid chromatography(2.2.29). The technical description of these analytical methods is set out in the monographs.Moreover certain precautions special to radioactivity must also be taken for radiation protection.

In a hospital environment thin-layer and paper chromatography are mostly used. In paper andthin-layer chromatography, a volume equal to that described in the monograph is deposited on thestarting-line as prescribed in the general methods for chromatography. It is preferable not to dilutethe preparation to be examined but it is important to avoid depositing such a quantity of radioactiv-ity that counting losses by coincidence occur during measurement of the radioactivity. On accountof the very small quantities of the radioactive material applied, a carrier may be added whenspecified in a particular monograph. After development, the support is dried and the positions ofthe radioactive areas are detected by autoradiography or by measurement of radioactivity over thelength of the chromatogram, using suitable collimated counters or by cutting the strips andcounting each portion. The positions of the spots or areas permit chemical identification bycomparison with solutions of the same chemical substances (non-radioactive) using a suitabledetection method.

Radioactivity may be measured by integration using an automatic-plotting instrument or a digitalcounter. The ratios of the areas under the peaks give the ratios of the radioactive concentration ofthe chemical substances. When the strips are cut into portions, the ratios of the quantities ofradioactivity measured give the ratio of concentrations of the radioactive chemical species.

SPECIFIC RADIOACTIVITY

Specific radioactivity is usually calculated taking into account the radioactive concentration (radio-activity per unit volume) and the concentration of the chemical substance being studied, afterverification that the radioactivity is attributable only to the radionuclide (radionuclidic purity) andthe chemical species (radiochemical purity) concerned.

Specific radioactivity changes with time. The statement of the specific radioactivity thereforeincludes reference to a date and, if necessary, time. The requirement of the specific radioactivitymust be fulfilled throughout the period of validity.

CHEMICAL PURITY

The determination of chemical purity requires quantification of the individual chemical impuritiesspecified in the monograph.

ENANTIOMERIC PURITY

Where appropriate, the stereoisomeric purity has to be verified.

PHYSIOLOGICAL DISTRIBUTION

A physiological distribution test is prescribed, if necessary, for certain radiopharmaceutical prepa-rations. The distribution pattern of radioactivity observed in specified organs, tissues or other bodycompartments of an appropriate animal species (usually rats or mice) can be a reliable indication ofthe expected distribution in humans and thus of the suitability for the intended purpose.

The individual monograph prescribes the details concerning the performance of the test and thephysiological distribution requirements which must be met for the radiopharmaceutical prepara-tion. A physiological distribution conforming to the requirements will assure appropriatedistribution of the radioactive compounds to the intended biological target in humans and limits itsdistribution to non-target areas.

In general, the test is performed as follows.Each of three animals is injected intravenously with the preparation to be tested. If relevant, the

species, sex, strain and weight and/or age of the animals is specified in the monograph. The test

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injection is the radiopharmaceutical preparation as it is intended for human use. Where applicable,products are reconstituted according to the manufacturers instructions. In some cases, dilutionimmediately before injection may be necessary.

The administration will normally be made via the intravenous route for which purpose the caudalvein is used. Other veins such as the saphenous, femoral, jugular or penile veins may be used inspecial cases. Animals showing evidence of extravasation of the injection (observed at the time ofinjection or revealed by subsequent assay of tissue radioactivity are rejected from the test.

Immediately after injection each animal is placed in a separate cage which will allow collection ofexcreta and prevent contamination of the body surface of the animal.

At the specified time after injection, the animals are killed by an appropriate method anddissected. Selected organs and tissues are assayed for their radioactivity using a suitable instrumentas described elsewhere in this monograph. The physiological distribution is then calculated andexpressed in terms of the percentage of the radioactivity which is found in each of the selectedorgans or tissues. For this purpose the radioactivity in an organ may be related to the injectedradioactivity calculated from the radioactive content of the syringe measured before and afterinjection. For some radiopharmaceutical preparations it may be appropriate to determine the ratioof the radioactivity in weighed samples of selected tissues (radioactivity/mass).

For a preparation to meet the requirements of the test, the distribution of radioactivity in at leasttwo of the three animals must comply with all the specified criteria.

STERILITY

Radiopharmaceutical preparations for parenteral administration must be prepared usingprecautions designed to exclude microbial contamination and to ensure sterility. The test forsterility is carried out as described in the general method for sterility (2.6.1). Special difficultiesarise with radiopharmaceutical preparations because of the short half-life of some radionuclides,small size of batches and the radiation hazards. It is not always possible to await the results of thetest for sterility before authorisation of the release for use of the bath concerned. Parametricrelease (5.1.1) of the product manufactured by a fully validated process is the method of choice insuch cases. When aseptic manufacturing is used, the test for sterility has to be executed as a controlof the quality of production.

When the size of a batch of the radiopharmaceutical preparation is limited to one or a fewsamples (e.g. therapeutic or very short-lived radiopharmaceutical preparation), sampling the batchfor sterility testing may not be applicable. If the radiopharmaceutical preparation is sterilised byfiltration and/or aseptically processed (5.1.1) process validation is critical.

When the half-life of the radionuclide is very short (e.g. less than 20 min), the administration ofthe radiopharmaceutical preparation to the patient is generally on-line with a validated productionsystem.

For safety reasons (high level of radioactivity) it is not possible to use the radiopharmaceuticalpreparations as required in the test for sterility (2.6.1). The method by membrane filtration is to bepreferred to limit irradiation of personnel.

Notwithstanding the requirements concerning the use of antimicrobial preservatives in Parenteralpreparations (0520), their addition to radiopharmaceutical preparations in multidose container is notobligatory, unless prescribed in the monograph.

BACTERIAL ENDOTOXINSPYROGENS

For certain radiopharmaceutical preparations a test for bacterial endotoxins is prescribed. The testis carried out as described in the general method (2.6.14), taking the necessary precautions to limitirradiation of the personnel carrying out the test.

The limit for bacterial endotoxins is indicated in the individual monograph.When the nature of the radiopharmaceutical preparation results in an interference by inhibition

or activation and it is not possible to eliminate the interfering factor(s), the test for pyrogens (2.6.8)may be specifically prescribed.

It is sometimes difficult to carry out these tests before releasing the batch for use when the half-life of the radionuclide in the preparation is short. The test then constitutes a control of the qualityof production.

STORAGE

Store in an airtight container in a place that is sufficiently shielded to protect personnel fromirradiation by primary or secondary emissions and that complies with national and internationalregulations concerning the storage of radioactive substances. During storage, containers maydarken due to irradiation. Such darkening does not necessarily involve deterioration of the prepa-rations.

Radiopharmaceutical preparations are intended for use within a short time and the end ofthe period of validity must be clearly stated.

LABELLING

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The labelling of radiopharmaceutical preparations complies with the relevant national andEuropean legislation.

The label on the direct container states: the name of the preparation and/or its reference, the name of the manufacturer, an identification number,

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for liquid and gaseous preparations: the total radioactivity in the container, or the radioactiveconcentration per millilitre at a stated date and, if necessary, time, and the volume of liquid onthe container,

for solid preparations (such as freeze-dried preparations): the total radioactivity at a stateddate and, if necessary, time. After reconstitution with the appropriate solution, the prepara-tion is considered as a liquid preparation,

for capsules: the radioactivity per capsule at a stated date and, if necessary, time and thenumber of capsules in the container.

The labelling can be adapted in certain cases (e.g. radiopharmaceutical preparations containingshort-lived radio-nuclides.

In addition, the label on the outer package states: the route of administration, the period of validity or the expiry date, the name and concentration of any added antimicrobial preservative, where applicable, any special storage conditions.

__________________________________________________________________________________________________________ Ph Eur

Table of Physical Characterisitics of Radionuclides Mentioned in theEuropean PharmacopoeiaThe following table is given to complete the general monograph on Radiopharmaceutical Preparations(0125).

The values are obtained from the database of the National Nuclear Data Center (NNDC) atBrookhaven National Laboratory, Upton. N.Y., USA, directly accessible via Internet at theaddress:http://www.nndc.bnl.gov/nndc/nudat/radform.html.

In case another source of information is preferred (more recent values), this source is explicitlymentioned.

Other data sources:

* DAMRI (Dpartement des Applications et de la Mtrologie des Rayonnements Ionisants,CEA Gif-sur-Yvette, France),

** PTB (Physikalisch-Technische Bundesanstalt, Braunschweig, Germany),

*** NPL (National Physical Laboratory, Teddington, Middlesex, UK).

The uncertainty of the half-lives are given in parentheses. In principle the digits in parentheses arethe standard uncertainty of the corresponding last digits of the indicated numerical value Guide tothe Expression of Uncertainty in measurement, International Organisation for Standardisation (ISO),1993, ISBN 92-67-10188-9).

The following abbreviations are used:

eA = Auger electrons

ce = conversion electrons

b = electronsb+ = positrons

70-12

g = gamma raysX = X-rays

Radionuclide Half-life Electron emission Photon emission

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Tritium (3H) *12.33 (6)years

* *0.006 (I)(max: 0.019)

*100

Carbon-11 (11C) 20.385 (20)min

+ 0.386 (I)(max: 0.960)

99.8 0.511 199.5(II)

Nitrogen-13 (13N) 9.965 (4) min + 0.492(I)(max: 1.198)

99.8 0.511 199.6(II)

Oxygen-15 (15O) 122.24 (16) s + 0.735 (I)(max: 1.732)

99.9 0.511 199.8(II)

Fluorine-18 (18F) 109.77 (5)min

+ 0.250 (I)(max: 0.633)

96.7 0.511 193.5(II)

Phosphorus-32 (32P) 14.26 (4)days

0.695 (I)(max: 1.71)

100

Phosphorus-33 (33P) 25.34 (12) days 0.076 (I)(max: 0.249)

100

Sulphur-35 (35S) 87.51 (12) days 0.049 (I)(max: 0.167)

100

Chromium-51 (51Cr) 27.7025 (24)days

eA 0.004 67 X

0.005

0.320

22.3

9.9

Cobalt-56 (56Co) 77.27 (3 days) eA

+0.006

0.179 (I)

0.631 (I)

47

0.9

18.1

X

0.006-0.007

0.511

0.8471.0381.1751.2381.3601.7712.0152.0352.5983.2023.253

25

38.0(II)

100.014.12.266.14.315.53.07.817.03.17.6

(I) Mean energy of the spectrum.(II) Maximum emission probability corresponding to a total annihilation in the source per 100 disintegrations.

70-13

Radionuclide Half-life Electron emission Photon emission

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Cobalt-57 (57Co) 271.79 (9) days eA+ ce

ce

0.006-0.007

0.0140.1150.129

177.4

7.41.81.3

X

0.006-0.007

0.0140.1220.1360.692

57

9.285.610.70.15

Cobalt-58 (58Co) 70.86 (7) days eA

+0.006

0.201 (I)49.4

14.9

X

0.006-0.007

0.5110.8110.8641.675

26.3

29.9(II)99.40.70.5

Cobalt-60 (60Co) 5.2714 (5)years

0.096(I)(max: 0.318)

99.9 1.1731.333

100.0100.0

Gallium-66 (66Ga) 9.49 (7) hours eA

+0.008

0.157(I)0.331(I)0.397(I)0.782(I)1.90(I)

21

10.73.80.350

X

0.009-0.010

0.5110.8341.0391.3331.9192.1902.4232.7523.2293.3813.7924.0864.2954.807

19.1

112(II)5.9371.22.15.61.923.41.51.51.11.34.11.8

Gallium-67 (67Ga) 3.2612 (6) days eA

ce

0.008

0.082-0.0840.090-0.0920.175

62

30.43.60.3

X

0.008-0.010

0.091-0.0930.1850.2090.3000.3940.888

57

42.421.22.416.84.70.15

Germanium-68 (68Ge)in equilibrium withGallium-68 (68Ga)

270.82 (27)days

(68Ga: 67.629(24) min)

eA

+0.008

0.353(I)0.836(I)

42.4

1.288.0

X

0.009-0.010

0.5111.077

44.1

178.33.0

Gallium-68 (68Ga) 67.629 (24)min

eA

+0.008

0.353(I)0.836(I)

5.1

1.288.0

X

0.009-0.010

0.5111.077

4.7

178.33.0

Krypton-81m (81Kr) 13.10 (3) s ce 0.1760.189

26.44.6

X

0.012-0.014

0.190

17.0

67.6

Rubidium-81 (91Rb) inequilibrium withKrypton-81m (91mKr)

4.576 (5) hours

(91mKr: 13.10(3) s)

eA

ce

+

0.011

0.1760.188

0.253(I)

0.447(I)

31.3

25.04.3

1.825.0

X

0.013-0.014

0.1900.4460.4570.5100.5110.538

57.2

6423.23.05.354.22.2

(I)Mean energy of the spectrum.(II)Maximum emission probability corresponding to a total annihilation in the source per 100 disintegrations.

70-14

Radionuclide Half-life Electron emission Photon emission

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Strontium-89 (89Sr)in equilibrium withYttrium-89m (89Y)

50.53 (7) days

(89Y: 16.06(4) s)

0.583(I)(max: 1.492)

99.99 0.909 0.01

Strontium-90 (90Sr)in equilibrium withYttrium-90 (90Y)

28.74 (4) years

(90Y: 64.10 (8)hours)

0.196(I)(max: 0.546)

100

Yttrium-90 (90Y) 64.10 (8)hours

0.934(I)(max: 2.280)

100

Molybdenum-99(99Mo) in equilibriumwith Technetium-99m(99mTc)

65.94 (1) hours

(99mTc: 6.01(1) hours)

0.133(I)0.290(I)

0.443(I)

16.4(I)

1.1(I)

82.4(I)

X

0.018-0.021

0.0410.1410.1810.3660.7400.778

3.6

1.14.561.212.14.3

Technetium-99m(99mTc)

6.01 (1) hours ce

eA

ce

0.002

0.015

0.1200.137-0.140

74

2.1

9.41.3

X

0.018-0.021

0.141

7.3

89.1

Technetium-99 (99Tc) 2.11 105

years 0.085(I)

(max: 0.294)100

Ruthenium-103(103Ru) in equilibriumwith Rhodium-103m(103mRh)

39.26 (2) days

(103mRh:56.114 (20)min)

eA+ ce

ce

0.017

0.030-0.039

0.031(I)

0.064(I)

12

88.3

6.6(I)

92.2(I)

X

0.020-0.023

0.4970.610

9.0

915.8

Indium-110 (110In) 4.9 (1) hours eA 0.019 13.4 X

0.023-0.026

0.6420.6580.8850.9380.997

70.5

25.998.392.968.410.5

Indium-110m (110mIn) 69.1 (5) min eA

+0.019

1.015(I)5.3

61

X

0.023-0.026

0.511(I)

0.6582.129

27.8

123.4(II)

97.82.1

Indium-111 (111In) 2.8047 (5) days eA

ce

0.019

0.145

0.167-0.1710.2190.241-0.245

15.6

7.8

1.34.91.0

X

0.0030.023-0.026

0.1710.245

6.982.3

90.294.0

Indium-114m (114mIn)in equilibrium withIndium-114 (114In)

49.51 (1) days

(114In: 71.9(1) s)

ce

*

0.1620.186-0.190

0.777(I)

(max: 1.985)

4040

95

X

0.023-0.027

0.1900.5580.725

36.3

15.63.23.2

(I)Mean energy of the spectrum.(II)Maximum emission probability corresponding to a total annihilation in the source per 100 disintegrations.

70-15

Radionuclide Half-life Electron emission Photon emission

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Tellurium-121m(121mTe) in equilibriumwith Tellurium-121(121Te)

154.0 (7) days

(121Te: 19.16(5) days)

eA

ce

0.0030.022-0.023

0.0500.0770.180

88.07.4

33.240.06.1

X

0.026-0.031

0.2121.102

50.5

81.42.5

Tellurium-121 (121Te) **19.16 (5)days

eA 0.022 11.6 X

0.026-0.030

0.4700.5080.573

75.6

1.417.780.3

Iodine-123 (123I) 13.27 (8) hours eA

ce

0.023

0.1270.1540.158

12.3

13.61.80.4

X

0.0040.027-0.031

0.1590.3460.4400.5050.5290.538

9.386.6

83.30.10.40.31.40.4

Iodine-125 (125I) 59.402 (14)days

eA + ce 0.0040.023-0.035

8033

X

0.0040.0270.031

0.035

15.511426

6.7

Iodine-126 (126I) 13.11 (5) days eA

+b(

b(

0.0230.3540.634

0.109(I)

0.290(I)

0.459(I)

0.530(I)

60.50.1

3.6(x)

32.1(x)

8.0(x))

1

X

0.0270.0310.3880.4910.511(x)

0.666(x)

0.754(x)

0.880(x)

1.420(x)

42.2342.92.3(II)

33(x)

4.2(x)

0.8(x)

0.3(x)

Iodine-131 (131I) 8.02070 (11)days

ce

0.460.330

0.069(I)

0.097(I)

0.192(I)

3.51.6

2.17.389.9

X

0.029-0.030

0.0800.2840.3650.6370.723

3.9

2.66.181.77.21.8

Xenon-131m (131mXe) 11.84 (7) days eA

ce

0.025

0.1290.1590.163

6.8

6128.58.3

X

0.0040.0300.034

0.164

8.344.010.2

2.0

Iodine-133 (133I)(decays to radioactiveXenon-133)

20.8 (1) hours 0.140(I)0.162(I)

0.299(I)

0.441(I)

3.83.24.283

0.5300.8751.298

874.52.4

Xenon-133 (133Xe) 5.243 (1) days eA

ce

0.026

0.0450.075-0.080

0.101(I)

5.8

55.19.9

99.0(I)

X

0.0040.0310.035

0.080

6.340.39.4

38.3

(I)Mean energy of the spectrum.(II)Maximum emission probability corresponding to a total annihilation in the source per 100 disintegrations.

70-16

Radionuclide Half-life Electron emission Photon emission

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Xenon-133m (133mXe)(decays to radioactiveXenon-133)

2.19 (1) days eA

ce

0.025

0.1990.2280.232

7

64.020.74.6

X

0.0040.0300.034

0.233

7.845.910.6

10.0

Iodine-135(135I)(decays toradioactive Xenon-135)

6.57 (2) hours 0.140(I)0.237(I)

0.307(I)

0.352(I)

0.399(I)

0.444(I)

0.529(I)

7.4(I)

8(I) (I

8.8(I) (

21.9(I)

8(I)

7.5(I)

23.8(I)

*0.527(I)0.547(I)

0.837(I)

1.039(I)

1.132(I)

1.260(I)

1.458(I)

1.678(I)

1.791(I)

13.8(I)

7.2(I)

6.7(I)

8.0(I)

22.7(I)

28.9(I)

8.7(I)

9.6(I)

7.8(I)

Xenon-135 (135Xe) 9.14 (2) hours ce

0.214

0.1710.308

5.5

3.196.0

X

0.031-0.035

0.2500.608

5.0

90.22.9

Caesium-137 (137Cs) inequilibrium withBarium-137m (137mBa)

30.04 (3) years

(137mBa: 2.552(1) min)

eA

ce

0.026

0.6240.656

0.174(I)

0.416(I)

0.8

8.01.4

94.4(I)

5.6(I)

X

0.0050.032-0.036

0.662

17

85.1

Thallium-200 (200Tl) 26.1 (1) hours ce

+

0.2850.353

0.495(I)

3.41.4

0.3(I)

X

0.0100.069-0.0710.08

0.3680.5790.8281.2061.2261.2741.3631.515

32.063.317.5

87.213.810.829.93.43.33.44.0

Lead-201 (201Pb)(decays to radioactiveThallium-201)

9.33 (3) hours eA

ce

0.055

0.2460.2760.316

3

8.522.3

X

0.070-0.0730.083

0.3310.3610.4060.5850.6920.7670.8260.9080.9461.0991.277

6919

799.92.03.64.33.22.45.77.91.81.6

Thallium-201 (201Tl) 72.912 (17)hours

ce 0.016-0.0170.027-0.0290.0520.0840.153

17.74.17.215.42.6

X

0.0100.069-0.0710.080

0.1350.167

46.073.720.4

2.610.0

Thallium-202 (202Tl) 12.23 (2) days eA

ce

0.054

0.357

2.8

2.4

X

0.0100.069-0.0710.080

0.440

31.061.617.1

91.4

(I)Mean energy of the spectrum.(II)Maximum emission probability corresponding to a total annihilation in the source per 100 disintegrations.

70-17

Radionuclide Half-life Electron emission Photon emission

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Type Energy (MeV) Emissionprobability(per 100disintegrations)

Lead-203 (203Pb) 51.873 (9)hours

eA

ce

0.055

0.194

3.0

13.3

X

0.0100.071-0.0730.083

0.2790.401

37.069.619.4

80.83.4

(I)Mean energy of the spectrum.(II)Maximum emission probability corresponding to a total annihilation in the source per 100 disintegrations.

70-18

Iodinated[125I] Albumin InjectionIodinated[125I] Human Albumin Injection

Definition Iodinated[125I] Albumin Injection is a sterile solution of albumin that has beeniodinated with iodine-125 and subsequently freed from iodide[125I] ion, made isotonic with bloodby the addition of Sodium Chloride and containing a suitable antimicrobial preservative such asBenzyl Alcohol. It is prepared from Albumin Solution and contains not less than 1% of protein.Before addition of carrier albumin, if this is added, the albumin is uniformly iodinated to an extentthat does not exceed the equivalent of one atom of iodine for each molecule of albumin. Thecontent of iodine-125 activity is not less than 85.0% and not more than 115.0% of the content ofiodine-125 stated on the label at the date stated on the label.

The injection complies with the requirements stated under Radiopharmaceutical Preparations and with thefollowing requirements.

Characteristics A clear, colourless or faintly yellow solution.Iodine-125 has a half-life of 60.1 days and emits gamma-radiation and X-rays.

IdentificationA. The gamma-ray and X-ray spectrum, measured in a suitable instrument, does not differsignificantly from that of a standardised iodine-125 solution other than any differences attributableto the presence of iodine-126. The most prominent gamma-photon of iodine-125 has an energy of0.027 MeV (corresponding to the K X-ray of tellurium). The presence of iodine-126 is shown bymajor gamma-photons of 0.388 and 0.666 MeV. Iodine-126 has a half-life of 13.0 days.

B. When examined in an ultracentrifuge, it has the sedimentation coefficient of normal humanalbumin.

Acidity or alkalinity pH, 6.5 to 8.5, Appendix V L.

Radionuclidic purity Measure the gamma-ray and X-ray spectrum in a suitable instrument bycomparison with standardised solutions of iodine-125 and caesium-137. Determine the relativeamounts of iodine-125 and iodine-126 present on the assumption that the 0.666 MeV gamma-photon of iodine-126 is emitted in 33% of disintegrations and that the 0.66 MeV gamma-photon ofcaesium-137 is emitted in 86% of disintegrations. Not more than 1.0% of the total activity is due toiodine-126 at the date stated on the label.

Radiochemical purity Submit a volume containing not less than 0.5 mg of albumin toelectrophoresis on a strip of filter paper (30 cm 5 cm) at 500 volts for 1 hour in a solutioncontaining 5 g of barbitone sodium, 3.25 g of sodium acetate, 4 g of sodium octanoate and 34.2 ml of0.1M hydrochloric acid in sufficient water to produce 100 ml. Allow the paper to dry and determinethe area of radioactivity using a suitable instrument. Not less than 95% of the activity on the paperoccurs in a position corresponding to that which would be occupied by treating normal humanalbumin at the same time and in the same manner.

ProteinA. To 1 ml in a 75-ml boiling tube add 1 ml of saline solution and carry out the method for the deter-mination of protein in blood products, Appendix VIII H, Method VI, beginning at the words add 2 ml and ending at the words as indicator and taking care to absorb liberated iodine-125. Eachml of 0.02M hydrochloric acid VS is equivalent to 1.75 mg of protein.

B. Carry out the test for Radiochemical purity using a volume containing 0.2 to 0.5 mg of albuminbut using a strip of cellulose acetate (30 cm 5 cm) in place of the paper. Dry the strip at about80 to 100 for 15 minutes and stain for 15 minutes in a solution of 0.2 g of naphthalene black 12B ina mixture of 10 ml of glacial acetic acid and 90 ml of methanol. Wash the strip in a mixture of 12 ml ofglacial acetic acid and 88 ml of methanol until the background is white and then wash for 10 minutesin 1M acetic acid and finally in water. Dry the strip between blotting paper pressed between glassplates. The distribution of the stained protein does not deviate significantly from that obtained bytreating normal human albumin at the same time and in the same manner.

Pyrogens Complies with the test for pyrogens, Appendix XIV D. Use per kg of the rabbits weighteither 0.1 ml or a quantity corresponding to 370 kBq at the date stated on the label, whichever isthe less.

Assay Determine the activity using suitable counting equipment by comparison with a standardisediodine-125 solution or by measurement in an instrument calibrated with the aid of such a solution.An instrument incorporating a scintillation detector, such as a thin sodium iodide crystal, should beemployed and the instrument should be set so that the contribution from iodine-126 is minimal.

Standardised iodine-125 solutions available from Amersham International plc, Amersham, HP79LL, England, are suitable.

Storage Iodinated[125I] Albumin Injection should be stored at a temperature of 2 to 8.

Labelling The label states the concentration of albumin.

70-19

Ammonia[13N] Injection1/01

Ammonia[13N] Injection complies with the requirements of the 3rd edition of the European Pharmacopoeia[1492]. These requirements are reproduced after the heading Definition below.

Action and use Radiodiagnostic.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Ammonia (13N) injection is a sterile solution of [13N]ammonia for diagnostic use. The injectioncontains not less than 90.0 per cent and not more than 110.0 per cent of the declared nitrogen-13radioactivity at the date and time stated on the label. Not less than 99 per cent of the total radio-activity corresponds to nitrogen-13 in the form of [13N]ammonia. Not less than 99.0 per cent ofthe total radioactivity corresponds to nitrogen-13.

PRODUCTION

RADIONUCLIDE PRODUCTION

Nitrogen-13 is a radioactive isotope of nitrogen which may be produced by various nuclearreactions, such as proton irradiation of carbon-13 or oxygen-16, or deuteron irradiation ofcarbon-12.

RADIOCHEMICAL SYNTHESIS

[13N]Ammonia may be prepared by proton irradiation of water followed by the reduction of theresulting [13N]nitrates/nitrites mixture with a reducing agent. The [13N]ammonia formed is distilledfrom the reaction mixture and trapped in a slightly acidic solution.

Other methods may produce [13N]ammonia in-target by proton irradiation of water containinga small amount of ethanol or acetic acid, or by proton irradiation of a slurry of [13C]carbon powderin water. The resulting solution can be purified, to remove radionuclidic and radiochemicalimpurities, using anion and cation exchange columns.

Production systems and their performance comply with the requirements prescribed in themonograph on Radiopharmaceutical preparations (0125).

STARTING MATERIALS

Target materials comply with the requirements prescribed in the monograph on Radiopharmaceuticalpreparations (0125).

CHARACTERS

A clear, colourless solution.

Nitrogen-13 has a half-life of 9.96 min and emits positrons with a maximum energy of 1.198 MeV,followed by annihilation gamma radiation of 0.511 MeV.

IDENTIFICATION

A. Record the gamma-ray spectrum using a suitable instrument as described in the monographon Radiopharmaceutical preparations (0125). The only gamma photons have an energy of 0.511 MeVand, depending on the measurement geometry, a sum peak of 1.022 MeV may be observed.

B. It complies with test (a) for radionuclidic purity (see Tests).

C. Examine the chromatograms obtained in the test for radiochemical purity. The principal peak inthe radiochromatogram obtained with the test solution has approximately the same retention timeas the principal peak in the radiochromatogram obtained with the reference solution.

TESTS

pH (2.2.3). The pH of the injection is 5.5 to 8.5.

Chemical purityAluminium. In a test-tube about 12 mm in internal diameter, mix 1 ml of acetate buffer solution pH4.6 R and 2 ml of a 1 in 20 dilution of the preparation to be examined in water R. Add 0.05 ml of a10 g/l solution of chromazurol S R. After 3 min, the colour of the solution is not more intense thanthat of a standard prepared at the same time and in the same manner using 2 ml of a 1 in 20 dilutionof aluminium standard solution (2 ppm Al) R (2 ppm).

The injection may be released for use before completion of the test.

Radionuclidic purity

(a) Half-life. The half-life as measured by methods described in the monograph on Radiopharma-ceutical preparations (0125) is between 9 min and 11 min.

70-20

(b) Gamma emitting impurities. Retain a sample of the preparation to be examined for 2 h. Examinethe gamma-ray spectrum of the decayed material for the presence of radionuclidic impurities,which should, where possible, be identified and quantified. The total gamma radioactivity due tothese impurities does not exceed 1.0 per cent of the total radioactivity.

The injection may be released for use before completion of tests (a) and (b).

Radiochemical purity Examine by liquid chromatography (2.2.29).

Test solution. The preparation to be examined.

Reference solution. Dilute 1.0 ml of dilute ammonia R2 to 10.0 ml with water R.

The chromatographic procedure may be carried out using: a column 0.04 m long and 4.0 mm in internal diameter packed with cation exchange resin R

(10 m), as mobile phase at a flow rate of 2 ml/min 0.002M nitric acid, a suitable radioactivity detector, a conductivity detector, a loop injector,maintaining the column at a constant temperature between 20C and 30C.

Inject separately the test solution and the reference solution. The chromatogram obtained withthe radioactivity detector and the test solution shows a principal peak with approximately the sameretention time as the peak in the chromatogram obtained with the reference solution and theconductivity detector. Not less than 99 per cent of the total radioactivity corresponds to nitrogen-13 in the form of ammonia.

The injection may be released for use before completion of the test.

Sterility It complies with the test for sterility prescribed in the monograph on Radiopharmaceuticalpreparations (0125). The injection may be released for use before completion of the test.

Bacterial endotoxins (2.6.14). Not more than 175/V I.U. of endotoxin per millilitre, V being themaximum recommended dose in millilitres. The injection may be released for use beforecompletion of the test.

RADIOACTIVITYMeasure the radioactivity as described in the monograph on Radiopharmaceutical preparations

(0125) using suitable equipment by comparison with a standardised fluorine-18 solution or by usingan instrument calibrated with the aid of such a solution. Standardised fluorine-18 solutions areavailable from laboratories recognised by the competent authority.

STORAGE

See Radiopharmaceutical preparations (0125).

LABELLING

See Radiopharmaceutical preparations (0125).

IMPURITIESA. [13N]O2,

B. [13N]O3,

C. [18F],

D. H2[15O].__________________________________________________________________________________________________________ Ph Eur

70-21

Chromium[51Cr] Edetate Injection

Chromium[51Cr] Edetate Injection complies with the requirements of the 3rd edition of the EuropeanPharmacopoeia [0266]. These requirements are reproduced after the heading Definition below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Chromium (51Cr) edetate injection is a sterile solution containing chromium-51 in the form of acomplex of chromium(III) with ethylenediaminetetra-acetic acid, the latter being present in excess.It may be made isotonic by the addition of sodium chloride and may contain a suitable antimicrobialpreservative such as benzyl alcohol. Chromium-51 is a radioactive isotope of chromium and may beprepared by the neutron irradiation of chromium, either of natural isotopic composition orenriched in chromium-50. The injection contains not less than 90.0 per cent and not more than110.0 per cent of the declared chromium-51 radioactivity at the date and hour stated on the label.Not less than 95 per cent of the radioactivity corresponds to chromium-51 in the form of chromiumedetate. The injection contains a variable quantity of chromium (Cr) not exceeding 1 mg permillilitre.

CHARACTERS

A clear, violet solution.Chromium-51 has a half-life of 27.7 days and emits gamma radiation.

IDENTIFICATION

A. Record the gamma-ray spectrum using a suitable instrument as described in the monograph onRadiopharmaceutical preparations (0125). The spectrum does not differ significantly from that of astandardised chromium-51 solution. Standardised chromium-51 solutions are available fromlaboratories recognised by the competent authority. The gamma photon has an energy of0.320 MeV.

B. Examine the electrophoretogram obtained in the test for radiochemical purity. The distributionof radioactivity contributes to the identification of the preparation.

TESTS

pH (2.2.3). The pH of the solution is 3.5 to 6.5.

Radionuclidic purity Record the gamma-ray spectrum using a suitable instrument as described inthe monograph on Radiopharmaceutical preparations (0125). The spectrum does not differsignificantly from that of a standardised chromium-51 solution.

Radiochemical purity Examine by zone electrophoresis (2.2.31), using a paper strip as thesupport and a solution containing 0.2 g/l of barbital sodium R and 10 g/l of sodium nitrate R as theelectrolyte solution. A paper with the following characteristics is suitable: mass per unit area120 g/m2; thickness 0.22 mm; capillary rise 105 mm to 115 mm per 30 min.

Apply to the paper 10 l of the injection as a 3 mm band at a position 10 cm from the cathode.Apply an electric field of about 30 V per centimetre for 30 min using a stabilised current.[51Cr]chromium edetate moves about 5 cm towards the anode. [51Cr]Chromate moves about10 cm towards the anode and [51Cr] chromic ion moves about 7 cm towards the cathode.Determine the distribution of the radioactivity using a suitable detector. Not less than 95 per centof the total radioactivity is found in the band corresponding to [51Cr]chromium edetate.

Chromium Prepare a reference solution (1 mg per millilitre of Cr) as follows: dissolve 0.96 g ofchromic potassium sulphate R and 2.87 g of sodium edetate R in 50 ml of water R, boil for 10 min, cool,adjust to pH 3.5 to 6.5 using dilute sodium hydroxide solution R and dilute to 100.0 ml with water R.Measure the absorbance (2.2.25) of the injection to be examined and the reference solution at theabsorption maximum at 560 nm. The absorbance of the injection to be examined is not greater thanthat of the reference solution.

Sterility It complies with the test for sterility prescribed in the monograph on Radiopharmaceuticalpreparations (0125). The injection may be released for use before completion of the test.

RADIOACTIVITY

Measure the radioactivity as described in the monograph on Radiopharmaceutical preparations (0125)using suitable equipment by comparison with a standardised chromium-51 solution or bymeasurement in an instrument calibrated with the aid of such a solution.

STORAGE

See Radiopharmaceutical preparations (0125).

LABELLING

See Radiopharmaceutical preparations (0125).__________________________________________________________________________________________________________ Ph Eur

70-22

Cyanocobalamin[57Co] Capsules

Cyanocobalamin[57Co] Capsules comply with the requirements of the 3rd edition of the EuropeanPharmacopoeia [0710]. These requirements are reproduced after the heading Definition below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Cyanocobalamin (57Co) capsules contain [57Co]-a-(5,6-dimethylbenzimidazol-1-yl)cobamidecyanide and may contain suitable auxiliary substances. Cobalt-57 is a radioactive isotope of cobaltand may be produced by proton irradiation of nickel. Cyanocobalamin (57Co) may be prepared bythe growth of suitable micro-organisms on a medium containing (57Co) cobaltous ion. Not less than90 per cent of the cobalt-57 is in the form of cyanocobalamin. The capsules comply with therequirements for hard capsules in the monograph on Capsules (0016), unless otherwise justified andauthorised.

CHARACTERS

Hard gelatin capsules.Cobalt-57 has a half-life of 271 days and emits gamma radiation.

IDENTIFICATION

A. Record the gamma-ray spectrum using a suitable instrument as described in the monographon Radiopharmaceutical preparations (0125). The spectrum does not differ significantly from that of astandardised cobalt-57 solution. Standardised cobalt-57 and cobalt-58 solutions are available fromlaboratories recognised by the competent authority. The most prominent gamma photon of cobalt-57 has an energy of 0.122 MeV.

B. Examine the chromatograms obtained in the test for radiochemical purity. The principal peak inthe radiochromatogram obtained with the test solution has a retention time similar to that of thepeak in the chromatogram obtained with the reference solution.

TESTS

Radionuclidic purity Record the gamma-ray spectrum as described in the monograph on Radio-pharmaceutical preparations (0125) using a suitable instrument calibrated with the aid of standardisedcobalt-57 and cobalt-58 solutions. The spectrum does not differ significantly from that of thestandardised cobalt-57 solution. Determine the relative amounts of cobalt-57, cobalt-56 andcobalt-58 present. Cobalt-56 has a half-life of 78 days and its presence is shown by gamma photonsof energy 0.847 MeV. Cobalt-58 has a half-life of 70.8 days and its presence is shown by gammaphotons of energy 0.811 MeV. Not more than 0.1 per cent of the total radioactivity is due tocobalt-56, cobalt-58 and other radionuclidic impurities.

Radiochemical purity Examine by liquid chromatography (2.2.29).

Test solution. Dissolve the contents of a capsule in 1.0 ml of water R and allow to stand for 10 min.Centrifuge at 2000 r/min for 10 min. Use the supernatant.

Reference solution. Dissolve 10 mg of cyanocobalamin CRS in the mobile phase and dilute to 100 mlwith the mobile phase. Dilute 2 ml of the solution to 100 ml with the mobile phase. Use within 1 h.

The chromatographic procedure may be carried out using: a stainless steel column 0.25 m long and 4 mm in internal diameter packed with octylsilyl silica

gel for chromatography R (5 m), as mobile phase at a flow rate of 1.0 ml per minute a mixture prepared as follows: mix 26.5

volumes of methanol R and 73.5 volumes of a 10 g/l solution of disodium hydrogen phosphate R,adjust to pH 3.5 using phosphoric acid R and use within 2 days,

a radioactivity detector adjusted for cobalt-57, as detector a spectrophotometer set at 361 nm, a loop injector.

Inject 100 l of the test solution and record the chromatogram for three times the retention timeof cyanocobalamin. Determine the peak areas and calculate the percentage of cobalt-57 present ascyanocobalamin. Inject 100 l of the reference solution and record the chromatogram for 30 min.

Disintegration The capsules comply with the test for disintegration of tablets and capsules (2.9.1)except that one capsule is used in the test instead of six.

Uniformity of content Determine by measurement in a suitable counting assembly and underidentical geometrical conditions the radioactivity of each of not less than ten capsules. Calculate theaverage radioactivity per capsule. The radioactivity of no capsule differs by more than 10 per cent

70-23

from the average. The relative standard deviation is less than 3.5 per cent.

RADIOACTIVITY

The average radioactivity determined in the test for uniformity of content is not less than 90.0 percent and not more than 110.0 per cent of the declared cobalt-57 radioactivity, at the date stated onthe label.

STORAGE

Store in an airtight container, protected from light, at a temperature of 2C to 8C, in theconditions prescribed in the monograph on Radiopharmaceutical preparations (0125).

LABELLING

See Radiopharmaceutical preparations (0125).__________________________________________________________________________________________________________ Ph Eur

70-24

Cyanocobalamin[58Co] Capsules

1/01

Cyanocobalamin[58Co] Capsules comply with the requirements of the 3rd edition of the EuropeanPharmacopoeia [1505]. These requirements are reproduced after the heading Definition below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Cyanocobalamin (58Co) capsules contain [58Co]-a-(5,6-dimethylbenzimidazol-1-yl)cobamidecyanide and may contain suitable auxiliary substances. Cobalt-58 is a radioactive isotope of cobaltand may be produced by neutron irradiation of nickel. Cyanocobalamin (58Co) may be prepared bythe growth of suitable micro-organisms on a medium containing (58Co) cobaltous ion. Not less than84 per cent of the cobalt-58 is in the form of cyanocobalamin. The capsules comply with therequirements for hard capsules in the monograph on Capsules (0016), unless otherwise justified andauthorised. The average radioactivity is not less than 90.0 per cent and not more than 110.0 percent of the declared cobalt-58 radioactivity at the date stated on the label.

CHARACTERS

Hard gelatin capsules.Cobalt-58 has a half-life of 70.9 days and emits beta (b+) radiation and gamma radiation.

IDENTIFICATION

A. Record the gamma-ray spectrum using a suitable instrument as described in the monographon Radiopharmaceutical preparations (0125). The spectrum does not differ significantly from that of astandardised cobalt-58 solution. Standardised cobalt-58 solutions are available from laboratoriesrecognised by the competent authority. The most prominent gamma photons of cobalt-58 haveenergies of 0.511 MeV (annihilation radiation) and 0.811 MeV.

B. Examine the chromatograms obtained in the test for radiochemical purity. The principal peak inthe radiochromatogram obtained with the test solution has a retention time similar to that of thepeak in the chromatogram obtained with the reference solution.

TESTS

Radionuclidic purity Record the gamma-ray spectrum as described in the monograph on Radio-pharmaceutical preparations (0125) using a suitable instrument calibrated with the aid of standardisedcobalt-58, cobalt-57 and cobalt-60 solutions. The spectrum does not differ significantly from thatof the standardised cobalt-58 solution. Standardised cobalt-58, cobalt-57 and cobalt-60 solutionsare available from laboratories recognised by the competent authority. Determine the relativeamounts of cobalt-58, cobalt-57 and cobalt-60 present. Cobalt-57 has a half-life of 272 days and itspresence is shown by gamma photons of energy 0.122 MeV. Cobalt-60 has a half-life of 5.27 yearsand its presence is shown by gamma photons of energies 1.173 MeV and 1.333 MeV. Not morethan 1 per cent of the total radioactivity is due to cobalt-60 and not more than 2 per cent of thetotal radioactivity is due to cobalt-57, cobalt-60 and other radionuclidic impurities.

Radiochemical purity Examine by liquid chromatography (2.2.29).

Test solution. Dissolve the contents of a capsule in 1.0 ml of water R and allow to stand for 10 min.Centrifuge at 2000 r/min for 10 min. Use the supernatant.

Reference solution. Dissolve 10 mg of cyanocobalamin CRS in the mobile phase and dilute to 100 mlwith the mobile phase. Dilute 2 ml of the solution to 100 ml with the mobile phase. Use within 1 hof preparation.

The chromatographic procedure may be carried out using: a stainless steel column 0.25 m long and 4 mm in internal diameter packed with octylsilyl silica

gel for chromatography R (5 m), as mobile phase at a flow rate of 1.0 ml/min a mixture prepared as follows: mix 26.5 volumes of

methanol R and 73.5 volumes of a 10 g/l solution of disodium hydrogen phosphate R, adjusted topH 3.5 with phosphoric acid R and use within 2 days,

a radioactivity detector adjusted for cobalt-58, as detector a spectrophotometer set at 361 nm, a loop injector.

Inject 100 l of the test solution and record the chromatogram for three times the retention timeof cyanocobalamin. Determine the peak areas and calculate the percentage of cobalt-58 present ascyanocobalamin. Inject 100 l of the reference solution and record the chromatogram for 30 min.

Disintegration The capsules comply with the test for disintegration of tablets and capsules (2.9.1)except that one capsule is used in the test instead of six.

70-25

Uniformity of content Determine by measurement in a suitable counting assembly and underidentical geometrical conditions the radioactivity of each of not less than ten capsules. Calculate theaverage radioactivity per capsule. The radioactivity of no capsule differs by more than 10 per centfrom the average. The relative standard deviation is less than 3.5 per cent.

RADIOACTIVITY

The average radioactivity determined in the test for uniformity of content is not less than 90.0 percent and not more than 110.0 per cent of the declared cobalt-58 radioactivity, at the date stated onthe label.

STORAGE

Store in an airtight container, protected from light, at a temperature of 2C to 8C, in theconditions prescribed in the monograph on Radiopharmaceutical preparations (0125).

LABELLING

See Radiopharmaceutical preparations (0125).__________________________________________________________________________________________________________ Ph Eur

70-26

Cyanocobalamin[57Co] Solution

Cyanocobalamin[57Co] Solution complies with the requirements of the 3rd edition of the EuropeanPharmacopoeia [0269]. These requirements are reproduced after the heading Definition below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Cyanocobalamin (57Co) solution is a solution of [57Co]-a-(5,6-dimethylbenzimidazol-1-yl)cobamidecyanide and may contain a stabiliser and an antimicrobial preservative. Cobalt-57 is a radioactiveisotope of cobalt and may be produced by the irradiation of nickel with protons of suitable energy.Cyanocobalamin (57Co) may be prepared by the growth of suitable micro-organisms on a mediumcontaining (57Co) cobaltous ion. The solution contains not less than 90.0 per cent and not morethan 110.0 per cent of the declared cobalt-57 radioactivity at the date stated on the label. Not lessthan 90 per cent of the cobalt-57 is in the form of cyanocobalamin.

CHARACTERS

A clear, colourless or slightly pink solution. Cobalt-57 has a half-life of 271 days and emits gammaradiation.

IDENTIFICATION

A. Record the gamma-ray spectrum using a suitable instrument as described in the monographon Radiopharmaceutical preparations (0125). The spectrum does not differ significantly from that of astandardised cobalt-57 solution. Standardised cobalt-57 and cobalt-58 solutions are available fromlaboratories recognised by the competent authority. The most prominent gamma photon of cobalt-57 has an energy of 0.122 MeV.

B. Examine the chromatograms obtained in the test for radiochemical purity. The principal peak inthe radiochromatogram obtained with the solution to be examined has a retention time similar tothat of the peak in the chromatogram obtained with the reference solution.

TESTS

pH (2.2.3). The pH of the solution is 4.0 to 6.0.

Radionuclidic purity Record the gamma-ray spectrum as described in the monograph on Radio-pharmaceutical preparations (0125) using a suitable instrument calibrated with the aid of standardisedcobalt-57 and cobalt-58 solutions. The spectrum does not differ significantly from that of thestandardised cobalt-57 solution. Determine the relative amounts of cobalt-57, cobalt-56 andcobalt-58 present. Cobalt-56 has a half-life of 78 days and its presence is shown by gamma photonsof energy 0.847 MeV. Cobalt-58 has a half-life of 70.8 days and its presence is shown by gammaphotons of energy 0.811 MeV. Not more than 0.1 per cent of the total radioactivity is due tocobalt-56, cobalt-58 and other radionuclidic impurities.

Radiochemical purity Examine by liquid chromatography (2.2.29).

Reference solution. Dissolve 10 mg of cyanocobalamin CRS in the mobile phase and dilute to 100 mlwith the mobile phase. Dilute 2 ml of the solution to 100 ml with the mobile phase. Use within 1 h.

The chromatographic procedure may be carried out using: a stainless steel column 0.25 m long and 4 mm in internal diameter packed with octylsilyl silica

gel for chromatography R (5 m), as mobile phase at a flow rate of 1.0 ml per minute a mixture prepared as follows: mix 26.5

volumes of methanol R and 73.5 volumes of a 10 g/l solution of disodium hydrogen phosphate R,adjust to pH 3.5 using phosphoric acid R and use within 2 days,

a radioactivity detector adjusted for cobalt-57, as detector a spectrophotometer set at 361 nm, a loop injector.

Inject 100 l of the solution to be examined and record the chromatogram for three times theretention time of cyanocobalamin. Determine the peak areas and calculate the percentage ofcobalt-57 present as cyanocobalamin. Inject 100 l of the reference solution and record thechromatogram for 30 min.

RADIOACTIVITY

Measure the radioactivity as described in the monograph on Radiopharmaceutical preparations (0125)using suitable counting equipment by comparison with a standardised cobalt-57 solution.

STORAGE

Store protected from light at a temperature of 2C to 8C under the conditions prescribed in themonograph on Radiopharmaceutical preparations (0125).

70-27

LABELLING

See Radiopharmaceutical preparations (0125).__________________________________________________________________________________________________________ Ph Eur

70-28

Cyanocobalamin[58Co] Solution

Cyanocobalamin[58Co] Solution complies with the requirements of the 3rd edition of the EuropeanPharmacopoeia [0270]. These requirements are reproduced after the heading Definition below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Cyanocobalamin (58Co) solution is a solution of [58Co]-a-(5,6-dimethylbenzimidazol-1-yl)cobamidecyanide and may contain a stabiliser and an antimicrobial preservative. Cobalt-58 is a radioactiveisotope of cobalt and may be produced by neutron irradiation of nickel. Cyanocobalamin (58Co)may be prepared by the growth of suitable micro-organisms on a medium containing (58Co) cobalt-ous ion. The solution contains not less than 90.0 per cent and not more than 110.0 per cent of thedeclared cobalt-58 radioactivity at the date stated on the label. Not less than 90 per cent of thecobalt-58 is in the form of cyanocobalamin.

CHARACTERS

A clear, colourless or slightly pink solution.Cobalt-58 has a half-life of 70.8 days and emits beta (b+) radiation and gamma radiation.

IDENTIFICATION

A. Record the gamma-ray spectrum using a suitable instrument as described in the monographon Radiopharmaceutical preparations (0125). The spectrum does not differ significantly from that of astandardised cobalt-58 solution. Standardised cobalt-58, cobalt-57 and cobalt-60 solutions areavailable from laboratories recognised by the competent authority. The most prominent gammaphotons of cobalt-58 have energies of 0.511 MeV (annihilation radiation) and 0.811 MeV.

B. Examine the chromatograms obtained in the test for radiochemical purity. The principal peak inthe radiochromatogram obtained with the solution to be examined has a retention time similar tothat of the peak in the chromatogram obtained with the reference solution.

TESTS

pH (2.2.3). The pH of the solution is 4.0 to 6.0.

Radionuclidic purity Record the gamma-ray spectrum as described in the monograph on Radio-pharmaceutical preparations (0125) using a suitable instrument having adequate resolution andcalibrated with the aid of standardised cobalt-58, cobalt-57 and cobalt-60 solutions. The spectrumdoes not differ significantly from that of the standardised cobalt-58 solution. Determine the relativeamounts of cobalt-58, cobalt-57 and cobalt-60 present. Cobalt-57 has a half-life of 271 days and itspresence is shown by gamma photons of energy 0.122 MeV. Cobalt-60 has a half-life of 5.27 yearsand its presence is shown by gamma photons of energies 1.173 MeV and 1.332 MeV. Not morethan 1 per cent of the total radioactivity is due to cobalt-60 and not more than 2 per cent of thetotal radioactivity is due to cobalt-57, cobalt-60 and other radionuclidic impurities.

Radiochemical purity Examine by liquid chromatography (2.2.29).

Reference solution. Dissolve 10 mg of cyanocobalamin CRS in the mobile phase and dilute to 100 mlwith the mobile phase. Dilute 2 ml of the solution to 100 ml with the mobile phase. Use within 1 h.

The chromatographic procedure may be carried out using: a stainless steel column 0.25 m long and 4 mm in internal diameter packed with octylsilyl silica

gel for chromatography R (5 m), as mobile phase at a flow rate of 1.0 ml per minute a mixture prepared as follows: mix 26.5

volumes of methanol R and 73.5 volumes of a 10 g/l solution of disodium hydrogen phosphate R,adjust to pH 3.5 using phosphoric acid R and use within 2 days,

a radioactivity detector adjusted for cobalt-58, as detector a spectrophotometer set at 361 nm, a loop injector.

Inject 100 l of the solution to be examined and record the chromatogram for three times theretention time of cyanocobalamin. Determine the peak areas and calculate the percentage ofcobalt-58 present as cyanocobalamin. Inject 100 l of the reference solution and record thechromatogram for 30 min.

RADIOACTIVITY

Measure the radioactivity as described in the monograph on Radiopharmaceutical preparations (0125)using suitable counting equipment by comparison with a standardised cobalt-58 solution or bymeasurement in an instrument calibrated with the aid of such a solution.

70-29

STORAGE

Store protected from light at a temperature of 2C to 8C under the conditions prescribed in themonograph on Radiopharmaceutical preparations (0125).

LABELLING

See Radiopharmaceutical preparations (0125).__________________________________________________________________________________________________________ Ph Eur

70-30

Fludeoxyglucose[18F] Injection

O

CH2OH

[18F]

OH

HO

OH

Fludeoxyglucose[18F] Injection complies with the requirements of the 3rd edition of the EuropeanPharmacopoeia [1325]. These requirements are reproduced after the heading Definition below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Fludeoxyglucose (18F) injection is a sterile solution of 2-[18F]fluoro-2-deoxy-D-glucopyranose(2-[18F]fluoro-2-deoxy-D-glucose) for diagnostic use. The injection contains not less than 90.0 percent and not more than 110.0 per cent of the declared fluorine-18 radioactivity at the date andtime stated on the label. Not less than 95 per cent of the radioactivity corresponds to fluorine-18 inthe form of 2-[18F]fluoro-2-deoxy-D-glucose and 2-[18F]fluoro-2-deoxy-D-mannose, with the2-[18F]fluoro-2-deoxy-D-mannose fraction not exceeding 10 per cent of the total radioactivity. Notless than 99.0 per cent of the radioactivity corresponds to fluorine-18. The content of 2-fluoro-2-deoxy-D-glucose is not more than 10 mg per maximum recommended dose of injection.

PRODUCTION

RADIONUCLIDE PRODUCTION

Fluorine-18 is a radioactive isotope of fluorine which may be produced by various nuclearreactions induced by proton irradiation of oxygen-18, deuteron irradiation of neon-20, helium-3 orhelium-4 irradiation of oxygen-16.

RADIOCHEMICAL SYNTHESIS

2-[18F]Fluoro-2-deoxy-D-glucose may be prepared by various chemical synthetic pathways, whichlead to different products in terms of specific radioactivity, by-products and possible impurities.

Most widely used is the method of phase tran