Radiochemical impurities

Typical validation for radiochemical and radiopharmaceutical purity. Quality control is very important to ensure the safety and efficacy of radiopharmaceuticals. One important quality parameter is the radiochemical purity of the radiolabeled product. This is defined as the fraction of the total radioactivity in the desired chemical form in the radiopharmaceutical [56]. Radiochemical impurities come from incomplete labeling, shift of equilibrium, radiolysis ((3 decay), temperature or pH change, exposure to light,... 

A number of analytical methods are used to detect and determine the radiochemical impurities in a given radiopharmaceutical. Most commonly used are methods like paper (PC), thin-layer (TLC), and gel chromatography, paper and gel electrophoresis, HPLC, and precipitation. A common principle for the different methods is that they can chemically separate the different radiolabeled components in the radiopharmaceutical. It may sometimes be necessary to perform more than... 

The nature of our concern is best illustrated by a specific example. Blank and Kidwell use a cocaine solution of 100,000 ng/mL for their contamination experiments, to which they add approximately 1 pCi of tritium-labeled cocaine, i.e., approximately one million counts per minute. Therefore, they have approximately a sensitivity of 10 cpm/ng of sample. Decontamination of hair means that residual drug concentration must drop below the endogenous cutoff level of 5 ng/10 mg of hair, i.e., to 50 cpm/10 mg hair. Now if the labeled cocaine has a radiochemical impurity of as little as 0.1%, this corresponds to 1000 cpm or to 100 ng of residual cocaine equivalents. Since self-irradiation of tritium-labeled material tends to form polymeric impurities, and since these are likely to preferentially bind to hair, one incurs a major risk of concluding erroneously that the residual radioactivity represents residual cocaine contamination rather than contamination by polymeric degradation products. 

Quality is directly related to the labeling yield, which is measured by the amount of unbound Tc activity. Limits of radiochemical impurities are stated in the official monographs (Council of Europe 2005). 

ITLC plates are made of fiberglass sheets, impregnated with an adsorbent, usually silica gel (e.g., SG). Due to the fine mesh material, the migration properties are increased many-fold by the TLC materials. The time for the development of any chromatogram may be reduced to < 5 min, without affecting the separation of radiochemical impurities. 

The difference between activity measured at the start (A C D + E) in solvent II (saline) minus activity measured at the start (A C E) in solvent I (MEK) corresponds to the percentage of unbound lipophilic " Tc-HMPAO complex (D). Radioactivity measured at the solvent front in system II indicates the amount of free Tc-per-technetate (B). Thus, the major radiochemical impurities (B and D) are used as an approximation of the purity of " Tc-HMPAO-labeled leukocytes (E). 

The limit of radiochemical impurities at expiry (3 h) is <10%. Results of analysis (12 samples)... 

Noll B, Johannsen B, Spies H (1995) Sources of radiochemical impurities in the Tc/... 

Earlier work by Schrodt and Libby (1954) and MacKay and Libby (1957) reported non-statistical distribution of the hexanes. Radiochemical impurities in the hexanes were probably at fault here. 

A radiopharmaceutical has adequate radiochemical purity when the fraction in the form of the wanted chemical form is high enough to meet specifications. Radiolysis (degradation due to own radiation) and the usual factors that affect stability (light, oxidation, reduction, pH shifts), may cause incomplete or slow labelling, degradation and create radiochemical impurities. Thin layer chromatography is the most widely used technique for the analysis of radiochemical purity. HPLC techniques may also be used, for instance for the assessment of the radiochemical purity of PET radiopharmaceuticals. 

TLC is still useful for rapid assessment of HPLC methods, because it provides rapid analyses with different mobile phases in much less time than required for reequilibration of HPLC columns. TLC is also practical for rapid qualitative analysis of reaction products from synthetic or semisynthetic reactions and for confirming purity of concentrated solutions, in which impurities might escape detection by HPLC. TLC is in fact preferable to HPLC for analysis of radiochemical impurities (degradation products) in radiolabeled retinoids and carotenoids, since in HPLC some impurities might not be eluted and detected radioactivity on thin-layer plates may be detected by autoradiography (exposure of the plate to x-ray film (98)) or by cutting the TLC plate into short sections which can be counted individually in vials by liquid scintillation. 

A technique has been reported by Tenny et al. (1963) which gives cis-9,10-oleic add, labeled with a high degree of specificity at the double bond. The oleic acid obtained was free from radiochemical impurities and was obtained in good yields as well as in high specific activity. 

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