AU9817400 89 Quality Control Methods of Strontium Chloride SrCl2, Radiopharmaceutical for Palliative Treatment of Bone Metastases. CZ DEPTULA, T KEMPISTY, A MARKIEWICZ, R MKOLAJCZAK, S STEFANCZYK, T TERLDCOWSKA, W ZULCZYK Radioisotope Centre POLATOM, 05-400 Otwock - Swierk, Poland SUMMARY 89 Strontium chloride, SrCl2, a radiopharmaceutical used for palliative therapy of bone metastases from breast and prostate cancer is produced by irradiation in a nuclear reactor. Radionuclidic purity of the preparation is well over 99.6%. Extraction chromatography on strontium and rare earth elements specific resins is used for separation of the *°Y (daughter of ^Sr) and y-impurities for the radionuclidic purity analysis of the 89SrCl2 solution. Complexometric determination of strontium and argentometric titration of chlorides are used to confirm chemical composition of the preparation and its specific 89 activity. The quality control protocol is established to confirm the suitability of the obtained SrCl2 as the radiopharmaceutical. l.INTRODUCTION and surrounding tissue which gives in effect pain palliation (5). 89Sr-Strontium chloride is a radiopharmaceuti- Strontium-89 can be produced either in a cal used for palliative therapy of multiple cyclotrone or by irradiation of strontium-88 in malignant metastases to the skeleton, mainly a nuclear reactor (n,y reaction). When the latter from breast or prostate cancer. Therapeutic option is used, depending on the purity of the action of 89Sr is known for over 50 years, as target material and irradiation parameters reported by Pecher (1) but its application several long- and short lived y-radionuclides can became popular in recent years because of be produced as impurities. increasing number of patients suffering from Strontium-90, a p-emiter produced in a malignant bone neoplasm. In Europe the secondary reaction (89Sr (n,y) ^Sr) contributes preparation is offered by Amersham under the to the impurities. It accumulates in the bones as name Metastron. well and has a very long (Tm - 28.5 years) half Internal radiotherapy gives a selectively directed life. Two parameters, besides its sterility and and effective radiation dose in the painful isotonicity, are critical when the therapeutical osseous metastases whereas the radiation risk to usefulness of the preparation is concerned: normal tissue is minimal. Several specific activity and radionuclidic purity. The radiopharmaceuticals were used for therapy of aim of the work presented below was to bone metastses: 32P, 89Sr, 131I, *Y (2) and establish analytical quality control procedures recently 186Re-HEDP and 153Sm-EDTMP (3). to confirm the radionuclidic purity as well as Among them 89Sr seems to be the most effective chemical composition and specific activity of and gives long lasting pain palliation (4). the 89SrCl2 preparation obtained by irradiation Strontium-89 is practically a pure beta emitting in a nuclear reactor. radionuclide (P-particle energy of 1.46 MeV = and T1/2 50.5 days). In bone tissue this 2.EXPERIMENTAL radiation penetrates to about 0.8 cm. In normal bones the biological half life of strontium is 2.1.Materials about 14 days, in malignant bone tissue about 89 Strontium-88 carbonate, isotopic enrichment 50 days (4). Radiotherapeutic action of SrCl2 99.8%, Cambridge Isotope Laboratories, US. is probably based on irradiation of metastases 90Sr and ^(carrier free), produced at the 90 89 Radioisotope Centre POLATOM were used for 2.5. Y separation from SrCl2 solution spiking the analysed solutions. on Sr-Spec and RE-Spec resins. The solutions to be analyzed on Sr-Spec or RE- Extraction chromatography resins with organic Spec were acidified correspondingly to either extractants supported on nonionic acrylic ester 3M or 2M with nitric acid. Aliquots of the polymer: analysed solution were loaded onto a column, Sr-Spec : 4\4"(5") di-t-butylcyclohexane-18- rinsed with an appropriate nitric acid solution crown-6 in N-octanol and finally a stripping of the column with dilute RE-Spec : octyl(phenyl) -N,N-diisobutyl nitric acid was made. Aliquots of the load, rinse carbamoylmethylphosphine oxide [CMPO] in and strip fractions were collected and subjected tributyl phosphate (TBP) to analysis by y or p-counting. The capacity of Pre-filter material (AmberlitXAD-7) resin in the column is about 6 mg of Sr while ©Spec resins and pre-filter material are the aliquots of the analysed solution contained commercially available from EICHroM up to 3 mg of Sr. Industries, Inc. II.US. Carrier-free ^Y solution and its mixture with All reagents used were of analytical grade. 89Sr bulk solution were analysed on Sr-Spec column. The elution profile of ^ rinsed with 2.2.Column preparation 3M HNO3 is presented in Figure 1. Glass columns of 6 mm internal diameter were filled to about 50 mm height with Spec resin which was preliminary conditioned in the acidic solution for 24 hours. The Sr-Spec resin 120 Sr-Spec column was prepared in 3M HNO3 and RE-Spec in 2M 100 HNO3 according to the suppliers recommendations (6). I °° 2.3. Instrumentation 7~A •luted with 3M HNO, LSC counter WALLAC (LKB) with i 40 7 V application of liquid scintillator Ultima Gold 20 (Hewlett Packard) Gamma-spectrometer with HPGe detector of 70 cm3 volume and resolution of 0.8 keV at FCV energy 122keV from 57Co and 1.8 keV at 1332 keV from ^Co. Detection limits for y-impurities Fig.l **¥ elution efficiency on Sr-Spec by this apparatus are within 5* 10"3and 5»10"5 %. column. PU 8745 UV/VIS spectrophotometer (Philips) The effluent volume necessary to rinse loaded as carrier free solution and with PGS-2 spectrograph (Carl Zeiss, Jena). addition of strontium carrier was not more than 2ml (up to 3 free column volumes FCV). 89 2.4.Method of SrCI2 preparation Fractions eluted with 3M HNO3 did not contain 89Sr was obtained by neutron bombardment of 89Sr but y-impurities such as I56Eu, 51Cr, 54Mn, 65 89 SrCO3 (enriched in strontium-88 over 99.8%) ^Co and Zn present in the SrCl2 solution in a reactor at 1015 n*cm'2*s'1 neutron flux. were eluted together with 90Y. Under these Irradiated target material was dissolved in 1 M conditions the measurement of '"Y activity by HC1, evaporated to dryness and dissolved in the LSC method was not possible. water (bulk solution). After correction of RE-Spec resin (RE is for rare earth elements) specific activity and isotonicity by addition of retains yttrium selectively when eluted with 2M natural SrCk and NaCl the solution was filtered HNO3. To strip yttrium from the column the on 0.22jam filter, dispensed into glass vials, eluent is changed to diluted 0.2M HNO3. sealed and autoclaved. Europium isotopes are retained on the RE-Spec column and neither 2M HN03 nor 0.2M HN03 10l/47 removes them (see Table 1). Carrier free 156Eu and 154Eu, other y-impurities are eluted solution of known activity was loaded on the with 2M HNO3 (fractions 1-5) while trace 59 RE-Spec column and rinsed with 2M HNO3. amounts of ^Co and Fe (which was Any ^f activity was present in the effluent. previously not observed) are detected next to the Then the column was rinsed with 0.2M HNO3. '"Y (fractions 6-9). The elution profile of 'Y from the RE-Spec column is shown in Fig.2. The strip of yttrium 3. RESULTS from the RE-Spec column is rapid and not more 90 89 than 8 free column volumes of eluent are 3.1. Determination of the Sr in the SrCl2 needed for its complete recovery. solution 89 The ^Sr activity in the SrCl2 solution is 60 calculated on the basis of '"Y activity. Prior to the measurement by LSC method 90Y must be RE-Spec column separated chemically. The system for separation A 90 89 of Y from the SrCl2 solution is presented in 40 / \ Figure 3. -O-"Y •luted with 0.2MHNO, 20 "SiCUbJMHNOl Dilution l» 2 M HNOi Elmnt2:Q.0SMHKOa Eloenl2:0.2HHN0) J -o—o 6 10 12 FCV Fig. 2 Recovery of from the RE-Spec column. I f SMg.Sr49.tr4a r-«U(Eu-1S6.Cr-51. Impuritlu The activities of radionuclides present in the Ma-M.Co-60.Z»-<5) collected fractions of effluent were measured. Five fractions of lml volume rinsed with concentrated HNO3 followed by four fractions Fig. 3 Extraction chromatography system for 90 89 of diluted HNO3 were collected. Y separation from SrCl2 product solution. 89 As shown in Table 1, bulk SrCl2 solution loaded on the RE-Spec column is purified from 89 Table 1. Radionuclidic impurities determined in fractions of effluent collected during SrCl2 solution chromatography on RE-Spec column (results obtained by y-spectrometry) Radionuclide Fractions eluted with 2M HNO3 Fractions eluted with RE- [kBq] 0.2M HNO3 Spec [kBq] resin HcBql 1 2 3 4 5 6-9 85Sr 0.44 7.03 0.041 51Cr 0.37 4.81 0.037 0.012 0.005 ^Co 0.013 0.37 0.003 0.008 ^Zn 0.011 0.28 S4Mn 0.14 0.016 103Ru 0.004 0.085 159Fe 0.006 154Eu + 156Eu 103.6 fil To separate 90Y from the product solution two /r(0.54MeV) steps of extraction chromatography are 90'Z- r involved. The analyzed solution is first purified 28y 64.0h from y-impurities (mostly 154Eu and I56Eu) on the Sr-Spec column. When eluted with 3M This reaction is widely used for production of 90 HNO3, the Sr-Spec column retains strontium carrier-free Y. The chemical separation isotopes while impurities i.e. 156Eu, 51Cr , 54Mn, techniques used by different authors were: 65Zn as well as 90Y are removed from the solvent extraction (9,10), precipitation (11) and column and the effluent collected.