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. This solution various forms of chromatography (12,13,14). is diluted with water to get 2M HNO3 The properties of solid phase extraction environment and then placed on the RE-Spec chromatography on Spec resins were used for column. Rinsing with 2M HNO3 is continued to ^ separation. Extraction chromatography remove impurities while yttrium is retained. combines the advantages of solvent extraction Then ^Y is stripped from the column with (selectivity) and ion exchange chromatography 0.2M HNO3. The fraction containing *Y is (ease of use). The Sr and RE-Spec resins are collected for measurement by the LSC method stable and easy to regenerate. The effect of and its activity recalculated for ^Sr and related resins irradiation was carefoly studied by to the 89Sr activity in the original sample. The Horowitz (15) and their stability proved. The results of the ^Sr determinations varied in the organic extractant is well bound to the range from 1.9»1(T* % to 2. l*104%. supporting resin and if freed can be removed from the effluent when passing it through a bed 89 of uncoated nonionic acrylic ester polymer (pre- 3.2. Determination of SrCI2 chemical composition filter material from Eichrom). The contamination with ^Sr determined in the 89 4 The chemical concentration of strontium in the SrCl2 solution at the value of about 2 *10" % product is determined by complexometry with conforms with the data published by Laing et arsenazo III. In acetone solution Sr+2 forms with all (5) and with the value calculated on the arsenazo III a complex which maximum basis of activation parameters. absorbance can be measured at 640 nm (7). When the radionuclidic purity measurements in the bulk solution indicate relatively high level of The assay of chlorides is determined by 89 potentiometric titration with silver nitrate (8) y-impurities (<0.4% relative to Sr is the upper limit for the product) it is possible to extend the The sum of chlorides coming from SrCl2 and period of cooling the short lived radionuclides NaCl present in the solution is determined. 89 The chemical purity of the preparation is (shorter than that of Sr). Among the measured by DC graphite spark spectrography. radionuclides detected in the bulk solution only the half lifes of 54Mn(312,5d), 60Co(I926d) and With this technique the limits for 65 89 contamination with the following elements: As, Zn(244d) are longer than that of Sr. Cooling Ba, Cd, Pb and Te are 5 ng/ml of each and might be practical when the level of the summaricaly not more than 1 Oug/ml. impurities is at the limit, when it is higher the benefit of increase in radionuclidic purity is 89 4. DISCUSSION OF RESULTS counterweighed by loss of Sr activity. The possibilities of the technology optimization in the aim to reduce contamination with y- The radionuclidic purity of the radionuclides were carefully studied (data not radiopharmaceutical (when y-impurities are shown). The radionuclidic purity of the concerned) can be determined directly in the obtained preparation is about 99.9%. The y- product solution by y-spectrometry but the impurities determined are: 85Sr at the level of activity of ^Sr by p-counting is not 65 51 89 0.09 - 0.1% and Zn, Cr, ^Mn^Co^'Re at measureable against Sr. We proposed the 2 the level of MO' to W0\ indirect method of ^Sr determination by The quality of the obtained product was separation of yttrium-90 which is in equilibrium investigated. Table 2 specifies the tests included with ^Sr and can be separated chemicaly from 89 into quality control procedure of SrCl2 as the parent nuclide. well as the results of the determinations The decay scheme of ^Sr is as follows: performed on the 3 production batches.

4 Table 2. Quality control protocol of the 3 production batches of SrCl2

TESTS ! SPECIFICATIONS ! Batch 1A ! Batch IB . Batch 2A Identification: Characters clear, colourless liquid complies comphes complies

P-ray spectrum Eroax= 1.49 MeV complies complies complies spectra identification y-ray spectrum Emax= 910 keV

4-7 5.5 5.5 6.0 pH Radionuclidic purity y-impurities < 0.4% <0.1 <0.1 <0.1 ^Sr 2.0*10^ 2.04*10^ Radioactive concentration 37.5 MBq/ml 37.5 37.5 37.5 not more than lOpgAnlof: <10 <10 <10 Chemical purity Cd,Ba,As,TSuPb, Assay: strontium chloride 10.8-19.4 mgAnl 10.8 11.3 10.9 sodium chloride 0 - 3.0 mgAnl 2.9 2.9 3.0

Specific activity 3.5 - 6.3 MBq/mg Sr 6.2 6.3 6.2

89 The SrCl2 preparation forms a sterile and References isotonic water solution. The specific activity of 1. Pecher C: Univ. Calif. Publ. Pharmacology 89 SrCl2 falls in the range from 3.5 to 6.3 11,1942,117-149 MBq/mg Sr while chemical concentration of 2. Reddly E.K. et all: J. Nucl. Med. Assoc. 7, strontium is about 10.8 mg/ml and NaCl about 1986, 27-32 3.0 mg/ml. The radionuclidic purity with 3. Volkert W.A. et all: Drugs of Future. 14, respect to y-impurities is not less than 99.6%. 1989, 779-881 The radioactive concentration is 37.5 MBq/ml 4. Bloke S.M. et al.: European J. Nucl. Med. which gives a standard single patient dose of 12, 1986, 447-454 150 MBq in 4 ml solution. The preparation is 5. Laing A.H.: The British Journal of stable over the period of not less than 4 weeks. Radiology. 64,1991, 816-822 After this time the 89Sr activity decreases by 6. Eichrom Analytical Products Description, about 32% of its initial value and the specific Eichrom Industries Inc., 1995 activity decreases to its lower limit but the 7.Marczenko Z.: Spektrofotometryczne therapeutical usefulness of the preparation is oznaczaniepierwiastk6w.PWN;Warszawa 1979 not lost. 8. European Pharmacopoeia 3rd edition, 1997. 9. Peppard D.F. et all: J. more. Nucl. Chem. 5, 5. CONCLUSIONS 1957, 141-144 10. Goldin A.S. and Velten R.J.: Anal. Chem. 89 The obtained solution of SrCl2, produced by 33, 1961, 149-152 88 irradiation of SrCO3 in a nuclear reactor 11. Kanapilly G.M. and Newton G.J.: Int. J. fulfills the requirements of a medical Appl. Radiat. Isot. 22. 1971, 567-575 preparation. The radionuclidic purity of the 12. Suzuki Y.: Int. J. Appl. Radiat. Isot. 15, preparation with respect to y-impurities is about 1964, 599-602 89 99.9%. ^Sr strontium assay in the SrCl2 13.Sraba W.J. et all: IntJ. Appl. Radiat. Isot. solution determined by its daughter nuclide 90Y 29, 1978,91-94 separation on the selective extraction 14. Dietz MX. and Horowitz E.P.: Appl. chromatography resins is at the level of 2*10"*% Radiat. Isot. 9. 1992, 1093-1101 and the toxicological risk from contamination 15. Horowitz E.P. et all: Analytica Chimica with this isotope can be neglected. Acta. 266, 1992, 25-29