An ionization chamber is an instrument in which an electric field is applied across a volume of gas for the purpose of collecting ions produced by a radiation field. The positive ions and negative electrons drift along the lines of force of the electric field, and are collected on electrodes, producing an ionization current. In a properly designed well-type ionization chamber, the ionization current should not be too dependent on the position of the radioactive specimen, and the value of the current per unit activity, known as the calibration factor, is characteristic of each gamma-ray-emitting radionuclide.

The ionization current produced in an ionization chamber is related to the mean energy of the emitted radiation and is proportional to the intensity of the radiation. If standard sources of known disintegration rates are used for efficiency calibration, the ionization chamber may then be used for activity determinations between several microcuries and several hundred millicuries or more. The upper limit of activity that may be measured in an ionization chamber usually is not sharply defined and may be limited by saturation considerations, range of the amplifier, and design of the chamber itself. The data supplied with or obtained from a particular instrument should be reviewed to ascertain the useful ranges of energies and intensities of the device.

Reproducibility within approximately 5% or less can be readily obtained in about 10 seconds, with a deep re-entrant well-type chamber. The most commonly used form of ionization chamber for measurement of the activities of radiopharmaceuticals is known as a dose calibrator.

Although the calibration factor for a radionuclide may be interpolated from an ionization chamber energy-response curve, there are a number of sources of error possible in such a procedure. It is therefore recommended that all ionization chamber calibrations be performed with the use of authentic reference sources of the individual radionuclides, as described hereinafter.

The calibration of a dose calibrator should be maintained by relating the measured response of a standard to that of a long-lived performance standard, such as radium 226 in equilibrium with its daughters. The instrument must be checked daily with the 226Ra or other source to ascertain the stability over a long period of time. This check should include performance standard readings at all radionuclide settings employed. To obtain the activity (Ax) of the radionuclide being measured, use the relationship:

in which Rn is the new reading for the radium or other source, Rc is the reading for the same source obtained during the initial calibration procedure, and R is the observed reading for the radionuclide specimen. Obviously, any necessary corrections for radioactive decay of the reference source must first be applied. Use of this procedure should minimize any effects due to drift in the response of the instrument. The recommended activity of the 226Ra or other monitor used in the procedure described above is 75 to 150 µCi. It is recommended also that the reproducibility and/or stability of multirange instruments be checked for all ranges with the use of appropriate standards.

The size and shape of a radioactive source may affect the response of a dose calibrator, and it is often necessary to apply a small correction when measuring a bulky specimen.

When all or part of the energy of beta or gamma radiation is dissipated within scintillators, photons of intensity proportional to the amount of dissipated energy are produced. These pulses are detected by an electron multiplier phototube and converted to electrical pulses, which are subsequently analyzed with a pulse-height analyzer to yield a pulse-height spectrum related to the energy spectrum of the radiation emitted by the source. In general, a beta-particle scintillation pulse-height spectrum approximates the true beta-energy spectrum, provided that the beta-particle source is prepared in such a manner that self-absorption is minimized. Beta-ray spectra may be obtained by using calcium fluoride or anthracene as the scintillator, whereas gamma-ray spectra are usually obtained with a thallium-activated sodium iodide crystal or a large-volume lithium-drifted germanium semiconductor detector. The spectra of charged particles also may be obtained using silicon semiconductor detectors and/or gas proportional counters. Semiconductor detectors are in essence solid-state ionization chambers, but the energy required to create an electron-hole pair or to promote an electron from the valence band to the conduction band in the semiconductor is about one-tenth the energy required for creation of an ion-pair in a gas-filled ionization chamber or proportional counter and is far less than the energy needed to produce a photon in a NaI(Tl) scintillation crystal. In gamma-ray spectrometry, a Ge(Li) detector can yield an energy resolution of 0.33% for 1.33 MeV gamma-rays from 60Co, while a 3- × 3-inch NaI(Tl) crystal can give a value of 5.9% for the same gamma-ray energy. The energy resolution is a measure of the ability to distinguish the presence of two gamma rays closely spaced in energy and is defined by convention as the full width of the photopeak at its half maximum (FWHM), expressed in percentage of the photopeak energy.

Gamma-ray spectra exhibit one or more sharp, characteristic photopeaks, or full-energy peaks, as a result of total absorption in the detector of the full energy of gamma radiations from the source; these photopeaks are useful for identification purposes. Other secondary peaks are observed as a consequence of backscatter, annihilation radiation, coincidence summing, fluorescent X-rays, etc., accompanied by a broad band known as the Compton continuum arising from scattering of the photons in the detector and from surrounding materials. Since the photopeak response varies with gamma-ray energy, calibration of a gamma-ray spectrometer should be achieved with radionuclide standards having well-known gamma-ray energies and emission rates. The shape of the gamma-ray spectrum is dependent upon the shape and size of the detector and the types of shielding materials used.

When confirming the identity of a radionuclide by gamma-ray spectrometry, it is necessary to make a comparison of the specimen spectrum with that of a specimen of known purity of the same radionuclide obtained under identical instrument parameters and specimen geometry. Where the radionuclides emit coincident X- or gamma-radiations, the character of the pulse-height distribution often changes quite dramatically because of the summing effect of these coincident radiations in the detector as the efficiency of detection is increased (e.g., by bringing the source closer to the detector). Such an effect is particularly evident in the case of iodine 125. Among the more useful applications of gamma-ray spectrometry are those for the identification of radionuclides and the determination of radionuclidic impurities.

Where confirmation of the identity of a given radionuclide by means of a direct comparison with the spectrum of a specimen of the same radionuclide of known purity is not possible, the identity of the radionuclide in question must then be established by the following method. Two or more of the following nuclear decay scheme parameters of the radionuclide specimen to be identified shall be measured, and agreement shall be within ±10%: (1) half-life, (2) energy of each gamma- or X-ray emitted, (3) the abundance of each emission, and (4) Emax for those radionuclides that decay with beta-particle emissions. Such measurements are to be performed as directed in the Identification and Assay sections of this chapter. Agreement of two or more of the measured parameters with the corresponding published nuclear decay scheme data constitutes confirmation of the identity of the radionuclide.

Alpha- and beta-emitting radionuclides may be assayed with the use of a liquid-scintillation detector system. In the liquid scintillator, the radiation energy is ultimately converted into light quanta that are usually detected by two multiplier phototubes so arranged as to count only coincidence radiation. The liquid scintillator is a solution consisting of a solvent, primary and secondary solutes, and additives. The charged particle dissipates its energy in the solvent, and a fraction of this energy is converted into fluorescence in the primary solute. The function of the secondary solute is to shift the fluorescence radiation to longer wavelengths that are more efficiently detected by the multiplier phototubes. Frequently used solvents are toluene and p-xylene; primary solutes are 2,5-diphenyloxazole (PPO) and 2-(4¢-tert-butylphenyl)-5-(4-biphenylyl)-1,3,4-oxadiazole (butyl-PBD); and secondary solutes are 2,2¢-p-phenylenebis[4-methyl-5-phenyloxazole] (dimethyl-POPOP) and p-bis(o-methylstrylyl)benzene (bis-MSB). As a means of attaining compatibility and miscibility with aqueous specimens to be assayed, many additives, such as surfactants and solubilizing agents, are also incorporated into the scintillator. For an accurate determination of radioactivity of the specimen, care must be exercised to prepare a specimen that is truly homogeneous. The presence of impurities or color in solution causes a decrease in photon output of the scintillator; such a decrease is known as quenching. Accurate radioactivity measurement requires correcting for count-rate loss due to quenching.

The disintegration rate of a beta-particle source may be determined by a procedure in which the integral count rate of the specimen is measured as a function of the pulse-height discriminator bias, and the emission rate is then obtained by extrapolation to zero bias. Energetic alpha-particle emitters may be similarly measured by this method.

The gamma-ray spectrum of a radionuclide is a valuable tool for the qualitative identification of gamma-ray emitting radionuclides. The full-energy peak, or the photopeak, is identified with the gamma-ray transition energy that is given in the decay scheme of the radionuclide.

In determining radionuclidic identity and purity, the gamma-ray spectrum of a radioactive substance is obtained with either a NaI(Tl) crystal or a semiconductor Ge(Li) detector. The latter has an energy resolution more than an order of magnitude better than the former and is highly preferred for analytical purposes. The spectrum obtained shall be identical in shape to that of a specimen of the pure radionuclide, measured with the same detection system and in the same geometry. The gamma-ray spectrum of the radiopharmaceutical shall contain only photopeaks identifiable with the gamma-ray transition energies found in the decay scheme of the same radionuclide. For low geometrical efficiencies, the areas under the photopeaks, after correction for the measured detector efficiency, shall be proportional to the abundances or emission rates of the respective gamma-rays in the radionuclide.

Because they are extremely toxic, alpha-emitting nuclides must be strictly limited in radiopharmaceutical preparations. Procedures for identifying beta- and gamma-active radionuclides as given in the foregoing text are applicable to the detection of gamma and usually beta contaminants.

The gross alpha-particle activity in radiopharmaceutical preparations can be measured by the use of a windowless proportional counter or a scintillation detector employing a silver-activated zinc-sulfide phosphor or by the techniques of liquid-scintillation counting.

The heavy ionization caused by alpha particles allows the measurement of alpha-emitting radionuclides in the presence of large quantities of beta- and gamma-active nuclides by the use of appropriate techniques for discriminating the amplitudes of signal pulses. In proportional counting, the operating voltage region for counting alpha particles, referred to as the “alpha plateau,” is considerably lower than the “beta plateau” for counting beta and gamma radiations. Typical “alpha plateau” and “beta plateau” voltage settings with P-10 counting gas are 900 to 1300 and 1600 to 2000 volts, respectively.

When silver-activated zinc-sulfide phosphor is employed for alpha-particle detection, the alpha particles can be distinguished from other interfering radiation by pulse-height discrimination. Care must be exercised to minimize self-absorption at the source whenever specimens are prepared for alpha-particle counting.

For the assay of gamma-emitting radionuclides, three methods are provided. The selection of the preferred method is dictated by the availability of a calibration standard of the radionuclide to be assayed and the radionuclidic purity of the article itself.

Direct comparison with a calibration standard is required if a calibration standard of the radionuclide to be assayed is available and if the upper limit of conceivable error in the activity determination arising from the presence of radionuclidic impurities has been determined to be less than 3%. If the required calibration standard is not routinely available, as would probably be the case for a short-lived radionuclide, but was available at some time prior to the performance of the assay for determination of efficiency of the counting system for the radionuclide to be assayed, use a calibrated counting system, provided the radionuclidic impurity content of the specimen meets the requirements stated for the direct comparison method. If the requirements for either of the first two methods cannot be met, use the method for determination of activity from a calibration curve.

With the exception of the first method, the counting systems used are monitored for stability. This requirement is met by daily checks with a long-lived performance check source and weekly checks with at least three sources covering a broad range of gamma-ray emission energies (e.g., 57Co, 137Cs, and 60Co). If a discrepancy for any of the aforementioned measurements is found, either completely recalibrate or repair and recalibrate the system prior to further use.

Selection of a Counting Assembly— A gamma-ray spectrometer is used for the identification of radionuclides that emit X-rays or gamma rays in their decay. Requirements for an assembly suitable for identification and assay of the radionuclides used in radiopharmaceuticals are that (a) the resolution of the detector based on the 662-keV photopeak of 137Cs-137mBa must be 8.0% or better, (b) the detector must be equipped with a specimen holder designed to facilitate exact duplication of counting geometry, and (c) the pulse-height analyzer must have enough channels to delineate clearly the photopeak being observed.

Procedure— Minimal requirements for the maintenance of instrument calibrations shall consist of weekly performance checks with a suitable reference source and a complete recalibration semi-annually. Should the weekly performance check deviate from the value determined at the time of calibration by more than 4.0%, a complete recalibration of the instrument is required at that time.

photopeak efficiency calibration— Radionuclides such as those listed in the accompanying table together with some of their nuclear decay data are available as certified reference standards.* A sufficient number of radioactive standard reference sources should be selected in order to obtain the calibration curve over the desired range. Where possible, standard sources of those radionuclides that are to be assayed should be included.

determination of specimen activity— In the same manner as in the preparation of the calibration curve, determine the fractional area (F) of the principal photopeak of the specimen under assay or an accurately measured aliquot adjusted to the same volume in an identical container as used for the standards. From the calibration curve, find the value of p for this radionuclide. Using the equation G = F/p, calculate the gamma-ray emission rate (G). Calculate the activity (A), in disintegrations per second, of the specimen using the equation A = (G/b)(D), in which b is the number of gamma rays per disintegration and D is the dilution factor. To obtain the activity, in µCi or mCi, divide A by 3.7 × 104 or 3.7 × 107, respectively. The above relationship is equally valid for obtaining the activity of an undiluted specimen or capsule; in this case, the dilution factor, D, is unity.