WO 2004/059661
`
`PCT/US2002/041676
`
`Example 7 - Rubidium and Rubidium Chloride Target Solutions
`
`The processing of either rubidium chloride or rubidium metal targets follows a
`
`similar procedure once the target has been successfully dissolved. In essence, 82Sr needs to
`be selectively extracted from a solution of RbCl in a 0.1 M NH3 I O. lM NH4Cl buffer
`adjusted to a pH of between 9 and 10. Batch experiments were perfom1ed in simulated buffer
`
`solutions to determine the strontium selectivity in the presence of high concentrations of
`
`rubidium ions. Only the ion exchange materials that exhibited high strontium selectivities in
`
`the initial scoping studies with NaCl solutions were evaluated. ~values were obtained as
`
`described previously. Two rubidium chloride solutions were selected which represent typical
`
`rubidium concentrations obtained during the processing of rubidium metal (1.95 M Rb+) and
`
`rubidium chloride targets (0.68 M Rb+). In both cases, Chelex 100 is used in the preliminary
`
`step to remove the 82Sr from the buffered mbidium solutions. The ~ values for the ion
`
`exchange materials are shown in Figure 1.
`
`In the buffered rubidium solutions, there is little difference between the different
`
`nonatitanates evaluated. This is in stark contrast to the sodium molybdate solutions where a
`
`large variation in the performance of the titanates was observed. The nonatitanates were
`
`clearly the most effective materials at removing strontium from the buffered solutions with
`
`strontium Kd values of around 15,000 mL!g in 0.68 M Rb+ solutions and approximately
`
`5,000 mL/g in 1.96 M Rb+ solutions. By contrast, Chelex 100 ion exchange resin gave ~
`
`values of less than 1,000 mL/g in both solutions. Hydrous titanium oxide and hydrous tin
`
`oxide also exhibited appreciable ~ values, but they performed less efficiently than the
`
`nonatitanates in both solutions. Consequently, this data demonstrates that using sodium
`
`nonatitanate in place of Chelex 100 ion exchange resin will greatly increase the amount of
`
`strontium extracted from the target solutions.
`
`The ion exchange materials were also evaluated for their rubidium selectivity from
`0.1 M NH3 / O. lM NH4Cl buffer solution. The buffer was prepared, spiked with 86Rb and the
`pH adjusted to approximately 9.25 with concentrated ammonia. 86Rb Kd values were then
`
`determined following the method described earlier. All of the sodium nonatitanates had a Kd
`< 20 mL/g. The very low rubidium selectivity in the pure buffer is almost certainly due to
`competition from NH4+ ions for the available ion exchange sites. Consequently, absorption
`of rubidium during the processing of rubidium and rubidium chloride targets will be minimal,
`and any rubidium absorbed will be readily removed by washing with additional 0.1 M NH3 I
`O. lM ~Cl buffer solution. Thus, a clean separation of 82Sr from these targets can be
`
`obtained using sodium nonatitanate.
`
`16
`
`1201 of 2987
`
`

`

`WO 2004/059661
`
`PCT /US2002/041676
`
`The performance could also be improved by removing the buffer and increasing the
`
`pH to improve the amounts of strontium absorbed. (Buffers were initially utilized to
`
`maximize the performance of the organic ion exchange resins cwTently used and are not
`
`essential to the 82Sr recovery process.)
`
`Example 9 - Kinetic Experiments
`
`In order for the sodium nonatitanate materials to fmd applications in the processing
`
`of irradiated target solutions, they must exhibit fast ion exchange kinetics allowing solutions
`
`to be passed through an ion exchange column at an acceptable rate. The kinetics of strontium
`
`absorption from alkaline molybdate target solutions was evaluated using a simple batch
`
`procedure. Ion exchange material, in the amount of 0.05 g, was shaken with 10 mL of
`
`molybdate solution spiked with 89Sr to give a total activity of approximately 155,000
`
`cpm/mL. After an allotted time, the material was filtered through a 0.2 m syringe filter and
`
`the activity in the aqueous phase determined by LSC. The results are shown below in Figure
`2.
`
`From the data in Figure 2, it is clear that the reaction kinetics for the sodium
`
`nonatitanate powder is extremely rapid, with over 99 % of the 89Sr removed in only 1
`
`minute. By contrast, the reaction kinetics of the organic ion exchanged resins was much
`
`slower and the total amount of 89Sr removed after 1 hour was much less.
`
`The exceedingly rapid kinetics can partly be explained by the fact that the
`
`nonatitanate was in the form of a fine powder, whereas the two resins were in the form of
`
`beads (see Table 1). As a consequence, a relatively slow reaction rate would be expected for
`the beads because the uptake of 82Sr will be dependent upon the rate of diffusion of the 82Sr
`to the internal functional groups. The rate of uptake of a sample of sodium nonatitanate
`
`pellets (using hydrous titanium dioxide as a binder) was significantly slower than the
`
`powdered form, but the kinetics and amount of 82Sr absorbed was still significantly better
`
`than for either of the two organic resins. As the pelletization process is improved, it is
`
`expected that the kinetics and selectivity of the pelletized sodium nonatitanate will improve
`
`substantially. Other sodium nonatitanate powders of varying crystallinities also showed rapid
`
`kinetics. Other potentially suitable binders for forming suitable pellets include titanium
`
`isopropoxide or tetraethyl orthosilicate (TEOS) as a binder precursor.
`
`Example 10-82Sr Removal from Irradiated Targets Using
`Pelletized Sodium Nonatitanate
`
`17
`
`1202 of 2987
`
`

`

`WO 2004/059661
`
`PCT /US2002/041676
`
`A sample of sodium nonatitanate was mixed with titanium isopropoxide as a
`
`binder and the resulting paste dried at 105°C for 12 hours. The material was gently
`
`broken up using a mortar and pestle and then sieved to produce particles in the range
`
`40 to 60 mesh. The binder content was approximately 20%. These particles were then
`
`used to assess the extraction of 89Sr from simulated target solutions.
`
`1 mL of pelletized sodium nonatitanate was slurried into a column and the
`
`target simulant that had been spiked with 89Sr to give an activity of approximately
`
`200,000 cpm/mL was passed through the column at a flow rate of 15 mL per hour.
`
`The amount of activity removed from solution was then determined. The results are
`
`given below in Table 1.
`
`Table 1. Removal of 82Sr From Irradiated Target Solutions
`
`Solution Composition Volume(mL) 82Sr Removed
`
`Target
`(%)
`Rubidium Metal
`
`Rubidium Chloride
`
`1.95M RbCl in
`0. IM NH3/NH4Cl
`Buffer, pHlO
`
`0.68M RbCl in
`O.lMNH3~Cl
`Buffer, pH 10
`
`20
`
`20
`
`97.3
`
`98.8
`
`99.9
`
`Molybdenum Metal
`
`0.26MNa2MoQ4, pH 12
`
`20
`
`This data clearly shows the effectiveness of sodium nonatitanate at removing
`
`strontium isotopes :from 82Sr target materials. Rubidium absorption under these
`
`conditions is minimal.
`
`Example 11 - Elution of Strontium
`
`Strontium was quantitatively eluted from the sodium nonatitanate column of
`
`Example 10 using 6M nitric acid. Hydrochloric acid was found to be much less
`
`effective and also resulted in breakdown of the sodium nonatitanate particles and
`
`blocked the ion exchange column.
`
`While the foregoing is directed to the preferred embodiment of the present
`
`invention, other and further embodiments of the invention may be devised without
`
`18
`
`1203 of 2987
`
`

`

`WO 2004/059661
`
`PCT/US2002/041676
`
`departing from the basic scope thereof, and the scope thereof is determined by the
`
`claims that follow.
`
`19
`
`1204 of 2987
`
`

`

`WO 2004/059661
`
`What is claimed is:
`
`PCT/US2002/041676
`
`1.
`
`A rubidium-82 generator, comprising:
`
`(a) a strontium-82 support medium comprising sodium nonatitanate.
`
`2.
`
`The rubidium-82 generator of claim 1, wherein the sodium nonatitanate is
`
`characterized by a strontium selectivity greater than 250,000 mL/g at an alkaline pH.
`
`3.
`
`The rubidium-82 generator of claim 1, wherein the sodium nonatitanate is
`
`characterized by a rubidium selectivity less than 100 mLI g at an alkaline pH.
`
`4.
`
`The rubidium-82 generator of claim 1, wherein the sodium nonatitanate is
`
`characterized by a strontium/rubidium separation factor greater than 1,000.
`
`5.
`
`The rubidium-82 generator of claim 1, wherein the sodium nonatitanate is
`
`characterized by a strontium/rubidium separation factor greater than 100,000.
`
`6.
`
`A process for preparing a rubidium-82 generator, comprising:
`
`(a) preparing sodium nonatitanate from titanium isopropoxide and aqueous sodium
`
`hydroxide;
`
`(b) heating the sodium nonatitanate at a temperature between 100°C and 250°C for a
`
`period between 12 hours and 2 weeks; and
`
`( c) absorbing strontium-82 on the sodium nonatitanate from an aqueous solution
`
`comprising strontium-82 and sodium chloride, wherein the sodium chloride concentration is
`
`between 0.1 and I molar.
`
`7.
`
`The process of claim 6, wherein the molar ratio of aqueous sodium hydroxide to
`
`titanium isopropoxide is in excess of0.44.
`
`8.
`
`The process of claim 6, wherein the molar ratio of aqueous sodium hydroxide to
`
`titanium isopropoxide is between 2 and 6.
`
`9. A method of chemically isolating strontium-82 from a proton-irradiated molybdenum
`
`target, comprising:
`(a) dissolving the molybdenum metal target containing the strontium-82;
`
`(b) adjusting the pH of the dissolved molybdenum target solution to an alkaline pH;
`
`20
`
`1205 of 2987
`
`

`

`WO 2004/059661
`
`PCT /US2002/041676
`
`( c) removing precipitates from the solution; and then
`
`(d) absorbing the strontium-82 from the solution onto a support comprising sodium
`
`nonatitanate.
`
`10.
`
`A process for preparing a solution containing rubidium-82, comprising:
`
`(a) providing a solution containing strontium-82 at a pH between 10 and 14;
`
`(b) absorbing strontium-82 onto a sodium nonatitanate support medium; and
`
`( c) eluting rubidium-82 from the sodium nonatitanate support medium with a solvent.
`
`11.
`
`The process of claim 10, wherein the solvent is selected from the group consisting of
`
`water and saline solutions.
`
`12.
`
`The process of claim 10, wherein the solvent is an aqueous solution having a sodium
`
`chloride concentration between 0.001 molar and 1 molar.
`
`13.
`
`The process of claim 10, wherein the solvent is an aqueous solution having a sodium
`
`chloride concentration between 0.2 molar and 1 molar.
`
`14.
`
`The process of claim 10, wherein the solvent is a pharmaceutical-grade saline and
`
`buffer solution.
`
`15. A method of chemically isolating strontium-82 from a proton-irradiated rubidium or
`
`rubidium chloride target, comprising:
`
`(a) dissolving the target containing the strontium-82;
`
`(b) adjusting the pH of the dissolved target solution to an alkaline pH;
`
`( c) removing precipitates from the solution; and then
`
`( d) absorbing the strontium-82 from the solution onto a support comprising sodium
`
`nonatitanate without absorbing rubidium.
`
`21
`
`1206 of 2987
`
`

`

`WO 2004/059661
`
`PCT /US2002/041676
`
`E30.68M RbCI
`m1.95M RbCI
`
`~
`~
`z
`
`~
`z
`
`;;;
`
`0
`0
`~
`
`~ z
`
`ci
`&
`I= .,
`z
`
`~
`ci
`§.
`~ z
`
`Figure 1. 82Sr K.i Values for the ion exchange materials from simulated rubidium and
`rubidium chloride target solutions
`
`1/2
`
`1207 of 2987
`
`

`

`WO 2004/059661
`
`PCT/US2002/041676
`
`160000
`
`140000
`
`120000
`
`100000
`
`....I
`
`E e 80000
`0. u
`
`60000
`
`40000
`
`20000
`
`0
`
`0
`
`-+--AG50W
`- - Chelex 100
`1-"-· ·NaTi (Honeywell)
`-i<-Pellelized nonalitanale
`
`10
`
`20
`
`30
`Time (minutes)
`
`40
`
`50
`
`60
`
`Figure 2. The reduction of 82Sr activity with increasing time.
`
`2/2
`
`1208 of 2987
`
`

`

`l.RNATIONAL SEARCH REPORT
`
`-
`
`lnu9ional Application No
`PCT/US 02/41676
`
`A. CLASSIFICATION OfcUBJECT MATTER
`IPC 7
`G21G4 08
`
`According to International Patent Classification (IPC) or to both national classification and IPC
`
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followea by classification symbols)
`IPC 7
`G21G
`
`Documentation searched other lhan minimum documentation lo the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
`EPO-Internal, WPI Data, INSPEC, COMPENDEX
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category 0
`
`Citation of document, with indication, where approptiale, of the relevant passages
`
`Relevant to claim No.
`
`A
`
`A
`
`A
`
`A
`
`EP 0 043 650 A (SQUIBB & SONS INC)
`13 January 1982 (1982-01-13)
`the whole document
`---
`us 3 953 567 A (GRANT PATRICK M ET AL)
`27 Apri 1 1976 (1976-04-27)
`the whole document
`---
`us 4 406 877 A (NEIRINCKX RUDI D ET AL)
`27 September 1983 (1983-09-27)
`the whole document
`---
`us 3 957 945 A (GRANT PATRICK M ET AL)
`18 May 1976 (1976-05-18)
`the whole document
`---
`
`-/--
`
`1-15
`
`1-15
`
`1-15
`
`9
`
`[!] Further documents are listed in the continuation of box C.
`
`[] Patent family members are listed in annex.
`
`0 Special categories of cited documents :
`
`'A" document defining the general state o• the art which Is not
`considered to be of particular relevance
`"E" earner document but published on or after the international
`filing dale
`'L' document which may throw doubts on priority claim(s) or
`which is cited to establish the publication date of another
`citation or other special reason (as specified)
`•o• document referring to an oral disclosure, use, exhibition or
`other means
`•p• document published prior to the international filing dale but
`later than the priority date claimed
`
`"T' later document published after the international filing date
`or priority date and not in conflict with the application but
`cited to understand !he principle or theoiy underlying the
`invenlion
`·x- document of particular relevance; the claimed invention
`cannot be considered novel or cannot be considered to
`involve an inventive step when the document is taken alone
`'Y" document of particular relevance; the claimed invention
`cannot be considered to involve an inventive step when the
`document is combined with one or more other such doou-
`ments, such combination being ohvious lo a person skilled
`in !heart
`'&' document member of the same patent family
`
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`15 September 2003
`
`Name and mailing address of the ISA
`European Patent Office, P.B. 5818 Patentlaan 2
`NL - 2280 HV Rijswijk
`Tel. (+31-70) 340-2040, Tx. 31 651 epo nl,
`Fax: (+31-70) 340-3016
`
`Form PCTllSA/210 /second sheell (July 1992)
`
`25/09/2003
`
`Authorized officer
`
`Ludi, M
`
`1209 of 2987
`
`

`

`l.RNATIONAL SEARCH REPORT
`
`~onal Appl/cation No
`PCT/US 02/41676
`
`C.(Contlnuatlon) DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category ° Citation of document, with indication.where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`A
`
`A
`
`"AN ASSESSMENT OF
`SYLVESTER P ET AL:
`INORGANIC ION-EXCHANGE MATERIALS FOR THE
`REMOVAL OF STRONTIUM FROM SIMULATED
`HANFORD TANK WASTESn
`SEPARATION SCIENCE AND TECHNOLOGY,
`DEKKER,,NEW YORK,NY,, US,
`vol. 34, no. 10, 1999, pages 1981-1992,
`XP009013438
`ISSN: 0149-6395
`the whole document
`SAHA G B ET AL:
`"USE OF THE 82SR/82RB
`GENERATOR IN CLINICAL PET STUDIES"
`INTERNATIONAL JOURNAL OF RADIATION
`APPLICATIONS AND INSTRUMENTATION PART B:
`NUCLEAR MEDICINE AND BIOLOGY, ELSEVIER
`SCIENCE PUBLISHERS, NEW YORK, NY, US,
`vol. 17, no. 8, 1990, pages 763-768,
`XP000166064
`ISSN: 0883-2897
`the whole document
`
`1-15
`
`1
`
`Form PCTIJSN210 (conlinuatlon of second sheet} (July 1992)
`
`1210 of 2987
`
`

`

`l.RNATIONAL SEARCH REPORT
`Information on patent family members
`
`lnt-onal Application No
`PCT/US 02/41676
`
`Patent family
`member(s)
`
`4400358 A
`22188 T
`548918 B2
`7135281 A
`1176618 Al
`3175292 Dl
`0043650 A2
`51449 Bl
`1662587 c
`3025760 B
`57030545 A
`8103677 A
`1057946 Al
`591750 AS
`2542415 Al
`2286480 Al
`51060900 A
`
`7068681 A
`1171354 Al
`0041356 Al
`57031624 A
`8103320 A
`
`I Publication
`
`date
`
`23-08-1983
`15-09-1986
`09-01-1986
`07-01-1982
`23-10-1984
`16-10-1986
`13-01-1982
`24-12-1986
`19-05-1992
`08-04-1991
`18-02-1982
`30-06-1982
`
`10-07-1979
`30-09-1977
`15-04-1976
`23-04-1976
`27-05-1976
`
`10-12-1981
`24-07-1984
`09-12-1981
`20-02-1982
`26-05-1982
`
`Patent document
`cited in search report
`EP 0043650
`
`I
`
`A
`
`Publication
`date
`
`13-01-1982
`
`us 3953567
`
`A
`
`27-04-1976
`
`us 4406877
`
`A
`
`27-09-1983
`
`I
`
`us
`AT
`AU
`AU
`CA
`DE
`EP
`IE
`JP
`JP
`JP
`ZA
`
`CA
`CH
`OE
`FR
`JP
`
`AU
`CA
`EP
`JP
`ZA
`
`us 3957945
`
`A
`
`18-05-1976
`
`NONE
`
`Fomi p::T/ISA/210 (patentfamlly annex) (July 1992)
`
`1211 of 2987
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED L'NDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`(43) International Publication Date
`9 March 2006 (09.03.2006)
`
`PCT
`
`(10) International Publication Number
`WO 2006/026603 A2
`
`(51) International Patent Classification:
`A61K 51100 (2006.01)
`
`(21) International Application Number:
`PCT/US2005/030796
`
`(22) International Filing Date: 30 August 2005 (30.08.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/605,481
`
`30 August 2004 (30.08.2004) US
`
`(71) Applicant
`(for all designated States except US):
`BRACCO DIAGNOSTICS INC. [US/US]; 107 College
`Road East, Princeton, NJ 08540 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BALESTRACCI,
`Ernest [US/US]; Woodbridge Hills, 404 Hampton Lane,
`Iselin, NJ 08830 (US). MELCHORE, James, A., Jr.
`[US/US]; 12 Staats Road, Bloomsbury, NJ 08804 (US).
`MONTEFERRANTE, Jo, Anna [US/US]; 18 Johnston
`Drive, Flemington, NJ 08822 (US). KUCHAREWICZ
`ROPIAK, Irene [US/US]; 15122 East Run Drive,
`Lawrenceville, NJ 08648 (US). SCHRAMM, Ernest
`[DE/US]; 815 Prospect Avenue, Milltown, NJ 08850 (US).
`ZODDA, Julius, P. [US/US]; 3 Tigers Court, Mercerville,
`NJ 08619 (US).
`
`---iiiiiiiiiiiiiii -iiiiiiiiiiiiiii ---
`
`(74) Agents: SUTTON, Paul, J. et al.; Greenberg Traurig,
`LLP, Met Life Building, 200 Park Avenue, New York. NY
`10166 (US).
`
`(81) Designated States (unless otheTWise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
`MD, MG, MK, MN, JvfW, MX, MZ, NA, NG, NI, NO, NZ,
`OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
`SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC,
`VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (unless ntheTWise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning o_f each regular issue o_f the PCT Gazette.
`
`(54) Title: IMPROVED CONTAIJ\inRS FOR PHARMACEUTICALS, PARTICULARLY FOR USE IN RADIOISOTOPE GEN(cid:173)
`ERATORS
`
`--
`
`22
`
`1
`
`2
`
`13
`
`is directed
`invention
`The
`(57) Abstract:
`to
`improved containers for pharmaceuticals
`and
`any
`tubing
`and
`tubing
`connectors
`associated therewith, particularly containers for
`pharmaceuticals which are irradiated, heated or
`otherwise subjected to increased pressure. In a
`preferred embodiment, the invention is directed
`to an improved container for use in a radioisotope
`generator, such as a rubidium-82 generator.
`
`1212 of 2987
`
`

`

`WO 2006/026603
`
`PCT /US2005/030796
`
`IMPROVED CONTAINERS FOR PHARMACEUTICALS,
`PARTICULARLY FOR USE IN RADIOISOTOPE GENERATORS
`
`TECHNICAL FIELD OF THE INVENTION
`
`The invention is directed to improved containers for pharmaceuticals and the tubing
`
`and tubing connectors associated therewith, particularly containers for pharmaceuticals which
`
`are heated, irradiated or otherwise subjected to increased pressure.
`
`In a preferred
`
`embodiment, the invention is directed to an improved container for use in a radioisotope
`
`generator. Specifically, the designs and materials of the column container and its closure and
`
`associated tubing and tubing connectors have been improved.
`
`1
`
`1213 of 2987
`
`

`

`WO 2006/026603
`
`PCT /US2005/030796
`
`SUMMARY OF THE INVENTION
`
`The invention includes improved pharmaceutical containers, particularly improved
`
`containers for pharmaceuticals that are subjected to increased pressure (such as by heating or
`
`other means) and/or are subjected to radioactivity. In a prefen-ed embodiment, the invention
`
`is directed to an improved container, also called a column, for use in a radioisotope generator.
`
`In an especially preferred embodiment, the improved column is for use with rubidiurn-82
`
`generator such as those disclosed in U.S. Patent Nos. 3,953,567; 4,400,358; 4,406,877;
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`4,562,829; 4,585,009; 4,585,941; and 5,497,951, incorporated herein by reference in their
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`entirety. In a particularly preferred embodiment, the improved column is used in a rubidium-
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`82 generator such as that sold under the trade name CardioGen®.
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`The improved pharmaceutical container of the invention includes an improved seal
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`and crimping process, as well as changes to the design of the stopper and the container to
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`prevent blockages and improve consistency in packing and closing the container, which
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`improves flow rate and elution from the column.
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`Further improvements include constructing the container and stopper out of radiation
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`resistant or tolerant materials. In addition, flexible tubing used with the container is made of
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`a radiation resistant or tolerant material, and the Luer locks used to fasten the flexible tubing
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`to the container is made of a radiation resistant or tolerant material and is further improved to
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`insure a tight, secure lock which will not inadvertently loosen or disconnect.
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`Specifically, the improved container has a new, stronger seal which is used to crimp
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`the stopper in a pharmaceutical container and particularly, which is used to seal a
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`radioisotope generator column/stopper assembly system, such as the CardioGen® system.
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`This improved seal prevents leakage, even at increased pressure, and reduces ballooning of
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`the rubber stopper material. The seal has a configuration similar to one of those shown in
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`Fig. 5B through Fig. SF and Fig. 6 and is made of any suitably strong material including
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`metal or plastic. A pneumatically operated automatic or semi-automatic crimper, set at
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`optimized pressure, is preferably used to crimp the seal during assembly of a pharmaceutical
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`container such as a radioisotope generator column/stopper assembly system. The invention
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`includes identification of optimized crimping pressure(s) for crimping the seal (regardless of
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`material) to a pharmaceutical container such as a glass or plastic vial or column and thus
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`securing in place a rubber closure(s) when using an automatic crimping system and/or
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`manual crimping.
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`The stopper which is crimped into place is also improved. Specifically, it is made of a
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`material which is radiation resistant or tolerant, is resistant to ballooning and can withstand at
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`least the pressures at which the container operates. Additionally, the configuration and
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`placement of the stopper are improved. For example, the improved stoppers form tight seals
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`with the column and reduce the "dead volume" at the bottom of the column- space where
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`non-radioactive, decayed eluate could mix with (and dilute) fresh, radioactive eluate,
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`reducing the efficacy of the eluent.
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`The improved pharmaceutical container also includes improvements to the design
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`which improve its packing/assembly and thus ensure specified flow of eluent through the
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`container.
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`These improvements are illustrated in the context of a radioisotope generator column
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`container. Flow rate of the eluent through the column could be partially or completely
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`blocked if the stopper blocks the outlet arm of the column. As shown in Figure 1, the outlet
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`arm of the container of the invention has been repositioned slightly and a small piece of
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`plastic removed from the inside edge of the column to create a recess or notch where the
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`outlet arm enters the column lumen to prevent a stopper from blocking flow. See Figure 4.
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`A small reinforcement piece of resin is added to the outside of the column between the outlet
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`arm and column body to provide additional strength.
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`Another improvement in the containers of the inv~ntion addresses consistency of
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`assembly and packing of the containers. In prior columns for a radioisotope generator, a
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`plastic basket or spacer was supplied separately and was placed on the top of the column
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`packing before the seal was inserted and the seal crimped into place. h1 these prior columns,
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`placement of the baskets or spacers, which hold the column packing in place, could vary
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`significantly, potentially creating some problems with consistency in packing.
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`In the
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`improved columns, two small orientation knobs have been added to the outside of the top
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`basket/spacer and the orientation knobs are positioned 180° apart. These knobs fit into two
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`small slots cut into the wall of the column. This combination eliminates the potential
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`variability of manual alignment and depth placement of the basket/spacer into the column and
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`ensures a consistent fit every time. Critical to the function of the column is the alignment of
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`the basket/spacer openings with the column inlet in the top arm. This prevents potential
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`misalignment and consequent restricted flow and possible back pressure and also ensures
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`consistent and timely output of eluent to the patient.
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`Another improvement is to make the column assembly out of a radiation resistant or
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`tolerant material, such as radiation resistant polypropylene. Likewise, the flexible tubing and
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`Luer connector are made of radiation resistant or tolerant materials, such as radiation resistant
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`polyvinylchloride. Furthermore, the Luer connector on the flexible tube and its counterpart
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`Luer connector on the column assembly are configured to provide for a tight lock which will
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`not leak and which will not loosen or inadvertently disconnect during use.
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`THE TECHNICAL PROBLEM AND ITS SOLUTION
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`The invention was designed to solve a number of technical problems experienced with
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`prior art pharmaceutical containers.
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`1.
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`Leakage From the Stopper/Column Interface
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`Leakage from the flange (or other area) of the seal of prior pharmaceutical
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`containers such as column/stopper assembly systems was found to occur when the system
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`was exposed to increasing pressure.
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`The new seal, consisting of a stronger material crimped at optimized crimping
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`pressure, prevents leakage at the flange seal area even at increasing pressure.
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`2.
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`Ballooning
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`Ballooning and/or burst of rubber materials (both before and after irradiation)
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`through the center hole of current aluminum seals has been observed when they are subject to
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`repeated pulsations of pressure cycling. The seals of the invention, which are stronger and
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`are crimped at optimized pressure, reduce the likelihood of this problem. However, in a
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`preferred embodiment the seal used in the improved container of the invention has a center
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`hole of reduced size. For example, a seal with the configuration of those in Fig. SB, Fig. 5C,
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`Fig. SE or Fig. 6 may preferably be used. Due to the small center hole and strength of these
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`seals, and crimping at optimized pressure, ballooning and/or burst of rubber materials is
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`prevented. Consequently, pharmaceutical containers of the invention, and particularly
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`column/stopper systems of the invention, can be exposed to much higher pressures during use
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`of the system in the field.
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`In addition, the larger surface area of the crimp resulting from the reduction of
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`the diameter of the center hole serves as additi,onal support for the rubber closure and inhibits
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`possible rupture as it is weakened over time due to the cumulative effect of exposure to
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`radiation from the column or container content.
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`Also, the stopper is made of a radiation resistant or tolerant material. This also
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`helps prevent ballooning and bursting.
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`3.
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`Leakage Through Puncture Points
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`Leakage through puncture points has been observed in prior art pharmaceutical
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`containers. Such leakage may be eliminated in containers of the invention through a
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`combination of the stronger seal material, preferably a smaller center hole, and crimping at
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`optimized pressure.
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`4.
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`Splitting of the Seal
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`Splitting or tearing of current aluminum seals has been observed at pressures
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`intended for use with a pharmaceutical container system (or pressures to which the system
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`can potentially be exposed during intended usage in the field).
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`Due to the strength of the new seal material, no splitting or rupture of seal
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`material is observed at pressures intended for use. For example, the seals on the columns of
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`the invention do not split or rupture when used in, for example, a rubidium generator at
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`intended pressures.
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`5.
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`Inconsistent Manual Crimping Procedure
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`The manual crimping procedure commonly used with many prior container
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`systems, including radioisotope column systems, is not always consistent and thus may not
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`result in reproducible crimping pressures. Over-pressuring can result in buckling and
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`collapse of the skirt of the seal material, the closure and/or the container. Under-pressuring
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`can result in a loose overseal. Use of the automatic or semi-automatic crimping procedure of
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`the invention with compressed or pressurized air results in consistent/reproducible crimping
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`pressures, and enables selection of optimized crimping pressures when crimping various seal
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`materials.
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`6.
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`Maintenance of Consistent Flow/Reduction of Back Pressure
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`In some prior pharmaceutical columns, flow rate of the eluent through the
`
`column could be partially or completely blocked because the stopper blocked the outlet arm
`
`of the column. The outlet arm of the container of the invention has been repositioned slightly
`
`and a small piece of plastic removed from the inside edge of the column to create a recess or
`
`notch where the outlet arm enters the column lumen to prevent a stopper from blocking flow.
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`A small reinforcement piece of resin is added to the outside of the column between the outlet
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`arm and column body to provide additional strength. The recessed outlet arm and notch near
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`the bottom of the column body greatly reduces the chance of back pressure due to a stopper
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`blocking the outlet arm.
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`7.
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`Inconsistent Positioning Within Column
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`In a column for a radioisotope generator, a plastic basket or spacer is supplied
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`separately and is placed on the top of the packed column before the seal or closure is inserted
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`and the seal crimped into place.
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`In prior columns, the baskets/spacers, which hold the
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`column packing in place, were not easily positioned consistently both in terms of depth and
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`orientation. In the improved columns of the invention, two small orientation knobs have been
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`added to the outside of the top b,asket/spacer and these orientation knobs are positioned 180°
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`apart. These knobs fit into two small slots cut into the wall of the column. This combination
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`eliminates the potential variability of manual placement of the basket into the column,
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`ensuring a consistent fit from generator to generator and reducing the variability in packing
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`density associated with this manual process.
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`8.
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`Degradation Due To Radiation
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`Many materials degrade when exposed to radiation. Degradation includes possible
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`changes in color, loss of flexibility, increased brittleness and the leaching out of various
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`substances from the materials. To avoid these potential problems, the column assembly,
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`stopper, flexible tubing and Luer connecto