(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`
`
`(43) International Publication Date
`
`20 January 2005 (20.01.2005)
`
`(10) International Publication Number
`
`WO 2005/005447 A2
`
`(51) International Patent Classification7:
`
`C07F 9/02
`
`(21) International Application Number:
`PCT/US2004/021626
`
`(22) International Filing Date:
`
`6 July 2004 (06.07.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/484,876
`
`3 July 2003 (03.07.2003)
`
`US
`
`(71) Applicant (for all designated States except BB, US):
`TEVA PHARMACEUTICAL INDUSTRIES LTD.
`
`[IL/IL]; Basel Street 5, PO. Box 3190, 49131 Petah Tiqva
`(IL).
`
`(71) Applicant (for BB only): TEVA PHARMACEUTICALS
`USA, INC. [US/US]; 1090 Horsham Road, PO. Box 1090,
`North Wales, PA 19454—1090 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): ARONHIME, Ju-
`dith [IL/IL]; Rehov HaraV Maor Isodef 5a, 76217 Rehovot
`(IL). LIFSHITZ-LIRON, Revital [IL/IL]; 12A Kibbush
`H’aavoda St., Apt. #8, 46322 Herzlia (IL).
`
`(74) Agents: BRAINARD, Charles, R. et a1.; Kenyon &
`Kenyon, One Broadway, New York, NY 10004—1050 (US).
`
`(81) Designated States (unless otherwise 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, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`ZW.
`
`(84) Designated States (unless otherwise 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, IT, LU, 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—
`ance Notes on Codes and Abbreviations ” appearing at the begin—
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: ZOLEDRONIC ACID CRYSTAL FORMS, ZOLEDRONATE SODIUM SALT CRYSTAL FORMS, AMORPHOUS
`ZOLEDRONATE SODIUM SALT, AND PROCESSES FOR THEIR PREPARATION
`
`(57) Abstract: The invention relates to polymorphs of zoledronic acid and zolidronate sodium salts, amorphous zoledronate sodium
`salts, processes for making the polymorphs and amorphous zoledronate sodium salt and pharmaceutical compositions containing the
`polymorphs and amorphous zoledronate sodium salt
`
`Grun. Exh. 1035
`
`PGR for US. Patent No. 9,539,268
`
`
`
`05/005447A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`c 0
`
`2
`
`Grun. Exh. 1035
`PGR for U.S. Patent No. 9,539,268
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`ZOLEDRONIC ACID CRYSTAL FORMS, ZOLEDRONATE SODIUM SALT
`CRYSTAL FORMS, AMORPHOUS ZOLEDRONATE SODIUM SALT, AND
`PROCESSES FOR THEIR PREPARATION
`
`CROSS REFERENCE TO RELATED APPLICATIONS,
`
`This application claims the benefit of US. provisional application Serial No.
`
`60/484,876, filed July 3, 2003, the contents of all of which is incorporated herein.
`
`FIELD OF THE INVENTION
`
`The invention relates to polymorphs of zoledronic acid and zoledronate sodium
`
`salts, amorphous zoledronate sodium salt, processes for making the polymorphs and
`
`amorphous zoledronate sodium salt and pharmaceutical compositions containing the
`
`polymorphs and amorphous zoledronate sodium salt.
`
`BACKGROUND OF THE INVENTIQN
`
`Zoledronic acid is a bisphosphonic acid, which is an inhibitor of osteoclastic bone
`
`resorption. Zoledronic acid, designated chemically as (l-Hydroxy-2—imidazol-1—yl-
`
`phosphonoethyl) phosphonic acid is marketed in the US. under the name Zometa®
`
`(zoledronic acid for injection). Zometa® is available in vials as a sterile powder for
`reconstitution for intravenous infusion. The prescribing information for Zometa® states
`that each vial of Zometa® contains 4.264 mg of zoledronic acid monohydrate
`
`(corresponding to 4 mg zoledronic acid on an anhydrous basis).
`
`US. patent 4,939,130 discloses a method for making substituted
`
`10
`
`15
`
`20
`
`25
`
`30
`
`alkanediphosphonic acids. Example 10 describes a method for making zoledronic acid.
`
`In this example, at the end of the reaction, the product, which is recrystallized from water,
`
`35
`
`has a melting point of 239°C with decomposition. However, repetition of the procedure
`
`described in Example 10 (which requires stirring under reflux imidazol—l-ylacetic acid,
`
`hydrochloride and phosphoric acid in chlorobenzene) did not lead to zoledronic acid“,
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`instead, the starting material was collected at the end of the reaction. Moreover, the last ‘
`step of crystallization could not be repeated exactly since the detailed experimental
`
`'
`
`parameters are not given (different cooling regimes, for instance, can produce different
`
`polymorphs when crystallized in the same solvent).
`
`In the paper Drugs ofthefuture 2000, 25(3): 259-268 the following forms of
`
`Zoledronate are listed:
`
`1) Zoledronie acid disodium salt tetrahydrate CAS No. 165 800-07-7
`
`2) Zoledronie acid magnesium salt CAS No. 157432-59—2
`
`3) Zoledronie acid zinc salt CAS No. 157432-58—1
`
`10
`
`4) Zoledronie acid disodium salt anhydrous CAS No. 131654-46-1
`
`5) Zoledronie acid anhydrous CAS No. 118072-93-8
`
`6) Zoledronie acid monohydrate CAS No. 165800-06-6
`
`It is also disclosed in the paper that the free acid has a melting point of 239°C with
`
`decomposition, and the disodium salt dihydrate has a melting point of 291-293 °C with
`
`15,
`
`decomposition. However, the paper does not describe any procedure to obtain the forms
`
`mentioned therein, nor does it give any additional data by which they can be identified.
`
`Moreover, there is nothing in the literature that discloses polymorphs or different crystal
`
`forms of zoledronic acid.
`The solid state physical properties of a compound can be influenced by controlling
`
`20
`
`the conditions under which the compounds are obtained in solid form. Solid state physical
`
`properties include, for example, the flowability of the milled solid. Flowability affects
`
`the ease with which the material is handled during processing into a pharmaceutical
`
`product. When particles of the powdered compound do not flow past each other easily, a
`
`formulation specialist must take that fact into account in developing a tablet or capsule
`
`25
`
`formulation, which may necessitate the use of glidants such as colloidal silicon dioxide,
`
`talc, starch or tribasic calcium phosphate.
`
`Another important solid state property of a pharmaceutical compound is its rate of
`
`dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient’s
`
`stomach fluid can have therapeutic consequences since it imposes an upper limit on the
`
`30
`
`rate at which an orally-administered active ingredient can reach the patient’s bloodstream.
`
`The rate of dissolution is also a consideration in formulating syrups, elixirs and other
`
`liduid medicaments. The solid state form of a compound may also affect its behavior on
`
`compaction and its storage stability.
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`These practical physical characteristics are determined by the conformation and
`
`orientation of molecules in the unit cell, which defines a particular polymorphic form of a
`
`substance. The polymorphic form may give rise to thermal behavior different fitom that
`
`of the amorphous material or another polymorphic form. Thermal behavior is measured
`
`in the laboratory by such techniques as capillary melting point, thermogravimetric
`analysistTGA) and differential scanning calorimetry (DSC) and can be used to
`
`distinguish some polymorphic forms from others. A particular polymorphic form may
`
`also give rise to distinct spectroscopic properties that may be detectable by powder X—ray
`
`diffraction (PXRD), solid state 13C NMR spectrometry and infrared spectrometry.
`
`10
`
`The discovery of new polymorphic forms of a pharrnaceutically useful compound
`provides a new opportunity to improve the performance characteristics of a
`
`pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist
`
`has available for designing, for example, a pharmaceutical dosage form of a drug with a
`
`targeted release profile or other desired characteristic. The invention provides for new
`
`15
`
`polymorphic forms of zoledronic acid and zoledronate sodium, and for amorphous
`
`zoledronate sodium.
`
`BRIEF DESERIPTIQN @F THE FIGURE§
`
`Fig.1 is a representative PXRD pattern of zoledronic acid Form 1.
`
`20
`
`Fig. 2 is a representative DSC curve of zoledronic acid Form I.
`
`Fig. 3 is a representative PXRD pattern of zoledronic acid Form II.
`
`Fig. 4 is a representative PXRD pattern of zoledronic acid Form XII.
`
`Fig. 5 is a representative PXRD pattern of zoledronic acid Form XV.
`
`Fig. 6 is a representative PXRD pattern of zoledronic acid Form XVIII.
`
`25
`
`Fig. 7 is a representative PXRD pattern of zoledronic acid Form XX.
`Fig. 8 is a representative PXRD pattern of zoledronic acid Form XXVI.
`
`Fig. 9 is a representative PXRD pattern of zoledronate monohydrate Form VIII.
`
`Fig. 10 is a representative PXRD pattern of zoledronate monosodium Form XVI.
`
`Fig. 11 is a representative PXRD pattern of zoledronate monosodium Form XVII.
`
`30
`
`Fig. 12 is a representative PXRD pattern of zoledronate disodium Form V.
`
`Fig. 13 is a representative PXRD pattern of zoledronate disodium Form VI.
`
`\Fig. 14 is a representative PXRD pattern of zoledronate disodium Form VII.
`
`Fig. 15 is a representative PXRD pattern of zoledronate disodium Form X.
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`' Fig. 16 is a representative PXRD pattern of zoledrOnate disOdium Form XIII.’
`Fig. 17 is a representative PXRD pattern‘of zoledronate disodium Form XIV.
`
`Fig. 18 is a representative PXRD pattern of zoledronate disodium Form XIX.
`
`Fig. 19 is a representative PXRD pattern of zoledronate disodium Form XXV.
`
`Fig. 20 is a representative PXRD pattern of zoledronate disodium Form XXVII.
`Fig. 21 is a representative PXRD pattern of zoledronate disodium Form IX.
`
`Fig. 22 is a representative PXRD pattern of zoledronate disodium Form XI.
`
`Fig. 23 is a representative PXRD pattern of zoledronate sodium amorphous.
`
`Fig. 24 is a representative TGA curve of zoledronic acid Form I.
`
`10
`
`Fig. 25 is a representative TGA curve of zoledronic acid Form II.
`
`Fig. 26 is a representative TGA curve of zoledronic acid Form XII.
`
`Fig. 27 is a representative TGA curve of zoledronic acid Form XV.
`
`Fig. 28 is a representative TGA curve of zoledronic acid Form XVIII.
`
`Fig. 29 is a representative TGA curve of zoledronic acid Form XX.
`
`15
`
`Fig. 30 is a representative TGA curve of zoledronic acid Form XXVI.
`
`Fig. 31 is a representative TGA curve of zoledronate monosodium Form VIII.
`
`Fig. 32 is a representative TGA curve of zoledronate monosodium Form XVI.
`
`Fig. 33 is a representative TGA. curve of zoledronate monosodium Form XVII.
`Fig. 34 is a representative TGA curve of zoledronate disodium Form V.
`
`20
`
`Fig. 35 is a representative TGA curve of zoledronate disodium Form VI.
`
`Fig. 36 is a representative TGA curve of zoledronate disodium Form VII.
`
`Fig. 37 is a representative TGA curve of zoledronate disodium Form X.
`
`Fig. 38 is a representative TGA curve of zoledronate disodium Form XIII.
`
`Fig. 39 is a representative TGA curve of zoledronate disodium Form XIV.
`
`25
`
`Fig. 40 is a representative TGA curve of zoledronate disodium Form XIX.
`
`Fig. 41 is a representative TGA curve of zoledronate disodium Form XXV.
`
`Fig. 42 is a representative TGA curve of zoledronate disodium Form XXVII.
`
`Fig. 43 is a representative TGA curve of zoledronate disodium Form IX.
`
`Fig. 44 is a representative TGA curve of zoledronate disodium Form XI.
`
`30
`
`SUMMARY OF THE INVENTION
`
`The invention relates to polymorphs of zoledronic acid and zoledronate sodium
`
`salts, amorphous zoledronate sodium salt, processes for making the polymorphs and
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`amorphous zoledronate sodium salt and pharmaceutical compbsitions containing the
`
`polymorphs and amorphous zoledronate sodium salt. The invention can be understood by
`
`reference to the following numbered embodiments.
`
`5
`
`l.
`
`Crystalline solid zoledronic acid (Form 1) characterized by a powder
`
`X—ray diffiaction pattern having peaks at 12.1, 12.8, 15.7, and 18.9 i
`
`0.2 °20.
`
`2.
`
`The
`
`crystalline
`
`solid zoledronic
`
`acid of embodiment
`
`1
`
`further
`
`characterized by a powder XRD pattern with peaks at 20.9, 21.3, 21.8,
`
`10
`
`22.2, 25.8, 27.6, 29.2, 32.5, and 32.9 i0.2 °20.
`
`15
`
`3.
`
`4.
`
`5.
`
`The crystalline solid zoledronic acid of embodiment l, which contains less
`
`than about 5% of other polymorphic forms of zoledronic acid.
`
`The crystalline solid zoledronic acid of embodiment 1, of which no more
`
`than about 5% transforms to zoledronic acid Form II upon exposure to
`
`100% relative humidity (RH) for 7 days.
`
`The crystalline solid zoledronic acid of embodiment 4, of Which no more
`than about 5% transforms to other polymorphic forms of zoledronic acid
`upon exposure to 100% relative humidity (RH) for 7 days.
`
`6.
`
`The crystalline solid zoledronic acid of embodiment 1, which, upon
`
`20
`
`exposure to 100% relative humidity GRH) for 7 days, absorbs less than
`
`about 0.2% water.
`
`7.
`
`The crystalline solid zoledronic acid of embodiment 1, which, upon
`
`exposure to 100% relative humidity (RH) for 7 days, retains its X—ray
`
`diffraction pattern substantially as shown in figure no. 1.
`
`25
`
`8.
`
`The crystalline solid zoledronic acid of embodiment l, of which no more
`
`than about 5% transforms to zoledronic acid form II upon exposure to 75%
`
`relative humidity (RH) at 40°C for 3 months.
`
`9.
`
`The crystalline solid zoledronic acid of embodiment 8, of which no more
`
`than about 5% transforms to other polymorphic forms of zoledronic acid
`
`30
`
`upon exposure to 75% relative humidity (RH) at 40°C for 3 months.
`
`10.
`
`The crystalline solid zoledronic acid of embodiment 1, which, upon
`
`exposure to 75% relative humidity (RH) at 40°C for 3 months, absorbs less
`
`than about 0.2% water.
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`11.
`
`The crystalline solid wzoledronic acid of embodiment 1, which, upon
`
`exposure to 75% relative humidity (RH) at 40°C for 3 months, retains its
`
`X-ray diffraction pattern substantially as shown in figure no. 1.
`
`12.
`
`A pharmaceutical composition comprising the crystalline zoledronic acid
`
`5
`
`of any of embodiments 1-1 1.
`
`13.
`
`The crystalline solid zoledronic acid of embodiment 1, which is a
`
`monohydrate.
`
`14.
`
`Crystalline solid zoledronic acid (Form II) characterized by a powder
`
`X—ray diffiaction pattern having peaks at 14.6, 15.4, 19.1, 22.9, and
`
`10
`
`23.9 i 0.2 °20.
`
`15.
`
`The crystalline zoledronic acid of embodiment 14, further
`
`characterized by a powder X-ray diffraction pattern with peaks at 20.8,
`
`21.7, 25.1, 26.7, 29.5, 29.9, and i0.2 °20.
`
`16.
`
`The crystalline solid zoledronic acid of embodiment 14, which is a
`
`15
`
`monohydrate.
`
`17.
`
`Crystalline solid zoledronic acid (Form XII) characterized by a powder
`
`X-ray pattern having peaks at 9.0, 13.9, 14.8, 21.5, 24.7, and 29.8 i 0.2
`
`°20.
`
`18.
`
`The crystalline zoledronic acid of embodiment 17, further
`
`20
`
`characterized by a powder X-ray diffraction pattern with peaks at 17.0,
`
`20.6, 20.8, 22.4, 25.8, 27.7, 28.4, 28.7, 29.1, 30.8, 3.19, 32.3, and 32.9
`
`"$0.2, °20.
`
`19.
`
`The crystalline solid zoledronic acid of embodiment 17, which is a
`
`monohydrate.
`
`25
`
`20.
`
`Crystalline solid zoledronic acid (Form XV) characterized by a powder
`
`X—ray diffraction pattern having peaks at 10.1, 17.3, 19.3, and 23.2 i
`
`0.2 °20.
`
`21.
`
`The crystalline zoledronic acid of embodiment 20, further
`
`characterized by a powder X-ray diffraction pattern with peaks at 14.5,
`
`30
`
`16.7, 18.1, 24.5, 25.1, 25.7, 28.5, 29.1, 29.6, and 30.4 i0.2 °20.
`
`22.
`
`The crystalline solid zoledronic acid of embodiment 20, which is
`
`anhydrous.
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`23.
`
`Crystalline solid zoledronic acid (Form XVIII) characterized by a
`
`powder X—ray diffiaction pattern having peaks at 10.7, 13.0, 16.4, 17.4,
`
`and 28.5 i 0.2 °20.
`
`24.
`
`The crystalline zoledronic acid of embodiment 23, further
`
`5
`
`characterized by a powder X—ray diffraction pattern with peaks at 13 .3,
`
`18.1, 19.3, 21.3, 23.7, 25.9, 31.5, and 34.5 $0.2 °20.
`
`25.
`
`The crystalline solid zoledronic acid of embodiment 23, which is a
`
`monohydrate.
`
`26.
`
`Crystalline solid zoledronic acid (Form XX) characterized by a powder
`
`10
`
`X—ray diffraction pattern having peaks at 12.2, 19.3, 20.2, 21.3, 25.1, ,
`
`and 27.25 i 0.2 °20.
`
`27.
`
`The crystalline zoledronic acid of embodiment 26, further
`
`characterized by a powder X—ray diffraction pattern with peaks at 11.4,
`14.9, 15.5, 17.2, 18.2 and 30.5 i0.2 °20.
`
`15
`
`28.
`
`The crystalline solid zoledronic acid of embodiment 26, which is
`
`anhydrous.
`
`29.
`
`Crystalline solid zoledronic acid (Form XXVI) characterized by a
`
`powder X—ray diffraction pattern having peaks at 9.8, 14.5, 17.1, 17.6,
`
`and 18.3 i 0.2 °26.
`
`20
`
`30.
`
`. The crystalline zoledronic acid of embodiment 29, thither
`
`characterized by a powder X—ray diffiaction pattern with peaks at 18.8,
`
`19.7, 21.4, 25.7, 26.6, and 28.1 $0.2 °20.
`
`31.
`
`The crystalline solid zoledronic acid of embodiment 29, which is
`
`anhydrous.
`
`25
`
`32.
`
`A pharmaceutical composition comprising the crystalline solid
`
`33.
`
`34.
`
`zoledronic acid of any of embodiments 12-31.
`
`Crystalline solid zoledronate monosodium.
`
`Crystalline solid zoledronate monosodium hydrate.
`
`35.
`
`The crystalline solid zoledronate monosodium of embodiment 33,
`
`30
`
`characterized by a powder X—ray diffraction pattern having peaks at
`
`8.2, 15.5, 18.6, 23.6, and 26.8 i 0.2 °20 (Form VIII).
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`36.
`
`The crystalline solid zoledronate monosodium of embodiment 35,
`
`further characterized by a powder X—ray diffraction pattern with peaks
`
`37.
`
`38.
`
`at 11.8, 17.6, 20.1, 24.7, 25.0, 28.4, 31.7, and 32.8 i 0.2 °20.
`
`The crystalline solid zoledronate monosodium of embodiment 35,
`
`which is a trihydrate.
`
`The crystalline solid zoledronate monosodium of embodiment 33,
`
`characterized by a powder X—ray diffraction pattern having peaks at
`
`7.3, 8.8, 14.7, 21.8, and 29.6 i 0.2 °20 (form XVI).
`
`39.
`
`The crystalline solid zoledronate monosodium of embodiment 38,
`
`40.
`
`41.
`
`fithher characterized by a powder X-ray diffraction pattern with peaks
`
`at 13.8, 16.8, 20.4, 21.4, 24.4, 25.6, 27.5, 28.2, and 31.7 i 0.2 °20.
`
`The crystalline solid zoledronate monosodium of embodiment 38,
`
`which is a dihydrate.
`
`The crystalline solid zoledronate monosodium of embodiment 33,
`
`characterized by a powder X-ray diffraction pattern having peaks at
`
`8.2, 9.0, 14.5, 21.4, 24.5, and 29.2 i 0.2 °20 (Form XVII).
`
`42.
`
`The crystalline solid zoledronate monosodium of embodiment 41,
`
`further characterized by a powder X—ray diffiaction pattern with peaks
`
`at 13.9, 15.5, 16.8, 18.6, 22.3, 23.6, 26.7, 27.7, and 32.3 i 0.2 °20.
`
`The crystalline solid zoledronate monosodium of embodiment 41,
`
`which is a dihydrate.
`
`Crystalline solid zoledronate disodium.
`
`Crystalline solid zoledronate disodium hydrate.
`
`Crystalline solid zoledronate disodium anhydrous.
`
`The crystalline solid zoledronate disodium of embodiment 44,
`
`characterized by a powder X-ray diffraction pattern having at 1 1.3,
`
`14.8, 15.5, 17.4, and 19.9 i 0.2 °20 (Form V).
`
`The crystalline solid zoledronate disodium of embodiment 47, further
`characterized by a powder X—ray diffraction pattern with peaks at 18.0,
`
`43.
`
`44.
`
`45.
`
`46.
`
`47.
`
`48.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`18.9, 19.7, 22.7, 25.0, 26.7, 30.9, and 34.5 i 0.2 °20.
`
`49.
`
`The crystalline solid zoledronate disodium of embodiment 47, which is
`
`a dihydrate.
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`50.
`
`The crystalline solid zoledrOnatedisodium of embodiment 44,‘
`
`characterized by a powder X—ray diffiaction pattern having peaks at
`
`51.
`
`52.
`
`53.
`
`7.2, 13.3, 13.7, 14.5, and 21.7 i 0.2 °20 (Form VI).
`
`The crystalline solid zoledronate disodium of embodiment 50, further
`characterized by a powder X—ray diffraction pattern with peaks at 8 .2,
`
`16.6, 16.9, 17.3, 25.9, 26.6, 30.7, 31.9, and 32.9i 0.2 °20.
`
`The crystalline solid zoledronate disodium of embodiment 50, which is
`
`a trihydrate.
`
`The crystalline solid zoledronate disodium of embodiment 44,
`
`characterized by a powder X—ray diffiaction pattern having peaks at 6.2
`
`11.6, 12.6, 13.7 i 0.2 °20 (Form VII).
`
`“
`
`54.
`
`The crystalline solid zoledronate disodium of embodiment 53, further
`
`characterized by a powder X—ray diffraction pattern with peaks at
`
`55.
`
`56.
`
`22.0, 23.2, 26.4, 27.1, 28.6, 28.8, 34.2i 0.2 °20.
`
`The crystalline solid zoledronate disodium of embodiment 53, which is
`
`a tetrahydrate.
`
`The crystalline solid zoledronate disodium of embodiment 44,
`
`characterized by a powder X—ray diffraction pattern having peaks at
`
`6.7, 14.4, 18.2, 20.4, and 20.7 i 0.2 °29 (Form X).
`
`10
`
`15
`
`20
`
`57.
`
`The crystalline solid zoledronate disodium of embodiment 56, further
`
`58.
`
`59.
`
`characterized by a powder X-ray diffraction pattern with peaks at 8.8,
`
`13.7, 17.0, 19.8, 21.3, 24.4, 27.5, 27.9, 30.9, and 33.4: 0.2 °20.
`
`The crystalline solid zoledronate disodium of embodiment 56, which is
`
`a hemihydrate.
`
`The crystalline solid zoledronate disodium of embodiment 44,
`
`characterized by a powder X—ray diffraction pattern having peaks at
`
`6.5, 13.0, 16.1, 17.2, and 30.7 i 0.2 °20 (Form XIII).
`
`60.
`
`The crystalline solid zoledronate disodium of embodiment 59, further
`
`characterized by a powder X-ray diffiaction pattern with peaks at 10.2,
`
`19.0, 20.0, 20.6, 22.3, 27.4, 28.6, 28.9, and 34.8i 0.2 °29.
`
`61.
`
`The crystalline solid zoledronate disodium of embodiment 59, which is
`
`a hemihydrate.
`
`25
`
`30
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`62.
`
`The crystalline solid zoledronate disodium of embodiment 44, '
`characterized by a powder X—ray diffraction pattern having peaks at
`
`6.6, 19.9, 28.5, and 34.8 i 0.2 °2e (Form XIV).
`
`63.
`
`The crystalline solid zoledronate disodium of embodiment 62, further
`
`64.
`
`65.
`
`characterized by a powder X-ray diffiaction pattern with peaks at 13.0,
`
`15.1, 17.1, 20.5, 27.7, 29.6, 30.7, and 33.5i 0.2 °20.
`
`The crystalline solid zoledronate disodium of embodiment 62, which is
`
`anhydrous.
`
`The crystalline solid zoledronate disodium of embodiment 44,
`
`characterized by a powder X—ray diffraction pattern having peaks at
`
`11.6, 12.5, 13.7, 22.0, and 23.1 i 0.2 °20 (Form XIX).
`
`66.
`
`The crystalline solid zoledronate disodium of embodiment 65, fin'ther
`
`characterized by a powder X—ray diffraction pattern with peaks at 6.2,
`
`67.
`
`68.
`
`14.3, 15.3, 16.0, 18.5, 24.3, and 28.6 i 0.2 °20.
`
`The crystalline solid zoledronate disodium of embodiment 65, which is
`
`a pentahydrate.
`
`The crystalline solid zoledronate disodium of embodiment 44,
`
`characterized by a powder X-ray difficaction pattern having peaks at
`
`7.4,13.7, 17.6, and 21.9 i 0.2 °20 (Form XXV).
`
`10
`
`15
`
`20
`
`69.
`
`The crystalline solid zoledronate disodium of embodiment 68, flirther
`
`characterized by a powder X—ray diffiaction pattern with peaks at 6.3,
`
`9.5, 12.6, 14.6, 26.2, 27.1, and 28.6 i 0.2 °20.
`
`70.
`
`71.
`
`The crystalline solid zoledronate disodium of embodiment 68, which is
`
`a sesquihydrate.
`
`‘
`
`The crystalline solid zoledronate disodium of embodiment 44, which is
`
`a monohydrate characterized by a powder X-ray diffraction pattern
`
`having peaks at 6.4, 8.2, 16.0, 17.4, 19.0, and 28.8 i- 0.2 °20 (Form
`
`XXVII).
`
`72.
`
`The crystalline solid zoledronate disodium of embodiment 71, further
`
`characterized by a powder X—ray diffraction pattern with peaks at 7.7,
`
`10.2, 17.2, 18.1, 21.6, 25.7, and 25.9 i 0.2 °20.
`
`25
`
`30
`
`10
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`73.
`
`The crystalline solid zoledronate disodium of embodiment 71, which is
`
`a monohydrate.
`
`Crystalline solid zoledronate trisodium.
`
`The crystalline solid zoledronate trisodiuni of embodiment 74,
`
`74.
`
`75.
`
`5
`
`characterized by a powder X—ray diffraction pattern having peaks at
`
`8.3, 10.9, 15.0, 16.6, and 22.8 i 0.2 °20 (Form IX).
`
`76.
`
`The crystalline solid zoledronate trisodium of embodiment 75, [flirther
`
`characterized by a powder X-ray diffraction pattern with peaks at 13.1,
`
`20.2, 20.6, 20.9, 25.0, 27.8, and 29.0 :t 0.2 °20.
`
`10
`
`77.
`
`The crystalline solid zoledronate trisodium of embodiment 75, which is
`
`a trihydrate.
`
`78.
`
`The crystalline solid zoledronate trisodium of embodiment 74,
`
`15
`
`79.
`
`characterized by a powder X—ray diffraction pattern having peaks at
`
`6.2, 7.9, 8.8, 10.6, and 12.2 i 0.2 °20 (Form XI).
`The crystalline solid zoledronate trisodium of embodiment 78, further
`characterized by a powder X—ray diffraction pattern with peaks at 15.0,
`
`15.4, 17.5, 18.8, 19.6, 20.5, 22.3, 23.7, 25.7, 29.6, and 31.7 0.2 °20.
`
`80.
`
`The crystalline solid zoledronate trisodium of embodiment 78, which is
`
`a dihydrate.
`
`20
`
`81.
`
`A process for preparing a solid crystalline zoledronate sodium salt
`
`comprising:
`
`a)
`
`b)
`
`c)
`
`dissolving zoledronic acid in water to form a solution;
`
`adding a base, preferably sodium hydroxide, to the solution; and
`
`cooling the solution, optionally with the addition of an organic
`
`25
`
`solvent such as isopropyl alcohol, to precipitate crystalline zoledronate
`
`sodium.
`
`82.
`
`The process of embodiment 81, wherein the crystalline solid zoledronate
`
`sodium salt is the monosodium salt.
`
`83.
`
`The process of embodiment 82, wherein the crystalline solid zoledronate
`
`30
`
`monosodium is selected from the group consisting of Form VIII, Form
`
`XVI and Form XVII.
`
`ll
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`84.
`
`The process of embodiment 81, wherein the crystalline solid zoledronate
`
`sodium salt is the disodium salt.
`
`85.
`
`The process of embodiment 84, wherein the crystalline solid zoledronate
`
`disodium is selected from the group consisting of Form V, Form VI, Form
`
`5
`
`VH, Form X, Form XIII, Form XIV, Form XIX, Form XXV, and Form
`
`XXVII.
`
`86.
`
`The process of embodiment 81, wherein the crystalline solid zoledronate
`
`sodium salt is the trisodium salt.
`
`87.
`
`The process of embodiment 86, wherein the crystalline solid zoledronate
`
`lO
`
`trisodium is selected from the group consisting of Form IX and Form XI.
`
`88.
`
`A process for preparing a crystalline solid zoledronate sodium salt
`
`comprising:
`
`a)
`
`suspending zoledronic acid in a mixture of alcohol/water,
`
`preferably at reflux temperature
`
`15
`
`b)
`
`adding to the suspension of a) a solution of a base, preferably
`
`sodium hydroxide, in an equivalent mixture of alcohol/water as that used in
`
`the suspension of a), to form a reaction mixture; and
`
`c)
`
`stirring the reaction mixture for a time sufficient to precipitate a
`
`crystalline solid zoledronate sodium salt.
`
`20
`
`89.
`
`The process of embodiment 88, wherein the reaction mixture is stirred at
`
`reflux for about 10 to about 20 hours, preferably about 14-16.
`
`90.
`
`The process of embodiment 88, wherein the volume ratio of alcohol/water
`
`to zoledronic acid in a) and b) is 6-14 volumes, preferably 10 voumes.
`
`91.
`
`The process of embodiment 88, wherein the alcohol in a) and b) is selected
`
`25
`
`from the group consisting of methanol, ethanol, isopropanol and
`
`dimethylformamide.
`
`92.
`
`The process of embodiment 88, wherein the zoledronic acid is zoledronic
`
`acid Form I and the ratio of acid to base is 1:1.
`
`93.
`
`The process of embodiment 88, wherein the zoledronic acid is zoledronic
`
`30
`
`acid Form I and the ratio of acid to base is 1:2.
`
`94.
`
`The process of embodiment 88, wherein the zoledronic acid is zoledronic
`
`acid Form XII and the ratio of acid to base is 1:1.1.
`
`12
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`95.
`
`The process of embodiment 92, wherein the crystalline solid zoledronate
`
`sodium salt is the monosodium salt.
`
`96.
`
`The process of embodiment 95, wherein the crystalline solid zoledronate
`
`monosodium is selected from the group consisting of Form VIII, Form
`
`5
`
`XVI and Form XVII.
`
`97.
`
`The process of embodiment 93 or embodiment 94, wherein the crystalline
`
`solid zoledronate sodium salt is the disodium salt.
`
`98.
`
`The process of embodiment 97, wherein the crystalline solid zoledronate
`
`disodium is selected from the group consisting of Form V, Form VI, Form
`
`10
`
`VII, Form X, Form XIII, Form XIV, Form XIX, Form XXV, and Form
`
`XXVII.
`
`99.
`
`The process of embodiment 0, wherein the zoledronic acid is zoledronic
`
`acid Form XII and the ratio of acid to base is 1:2.l.
`
`100.
`
`The process of embodiment 99, wherein the crystalline solid zoledronate
`
`15
`
`sodium salt is the trisodium salt.
`
`101.
`
`The process of embodiment 100, wherein the crystalline solid zoledronate
`
`trisodium is selected from the group consisting of Form IX and Form XI.
`
`102. A process for preparing a solid crystalline zoledronate sodium salt
`
`comprising:
`
`20
`
`a)
`
`dissolving a crystal form of zoledronate sodium in water,
`
`preferably at reflux, to form a solution; and
`
`b)
`
`cooling the solution to precipitate a crystal form of zoledronate
`
`sodium which is different from the starting form in a).
`
`103.
`
`The process of embodiment 102, wherein the water is added in an amount
`
`25
`
`of between 20-30 volumes, preferably 25 volumes, per volume of zoledronate sodium.
`
`104. A process for preparing crystalline solid zoledronate monosodium Form
`
`VIII comprising:
`
`a)
`
`adding a solution of a base in an 80%/20% v/v mixture of
`
`water/ethanol to a suspension of zoledronic acid form I in an 80%/20% WV
`
`30
`
`mixture of water/ethanol at elevated temperature, preferably reflux
`
`temperature;
`
`b)
`
`stirring the mixture of a) at reflux temperature for about 10 to 20
`
`hours, preferably 14—16 hours; and
`
`13
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`c)
`
`precipitating zoledronate monosodium Form VIII.
`
`105. The process of embodiment 104, wherein the base is sodium hydroxide, which is
`
`added in an amount of a 1:1 molar ratio to the zoledronic acid.
`
`106.
`
`The process of embodiment 104, wherein the volume ratio of
`
`5
`
`water/ethanol to zoledronic acid form I in the suspension and the solution is between 6-
`
`14, preferably 10.
`
`107. A process for preparing crystalline solid zoledronate monosodium Form
`
`VIII comprising:
`
`a)
`
`adding a solution of a base in an 80%/20% V/V mixture of
`
`10
`
`water/methanol to a suspension of zoledronic acid form I in an 80%/20% v/V
`
`mixture of water/methanol at elevated temperature, preferably reflux
`
`temperature;
`
`b)
`
`stirring the mixture of a) at reflux temperature for about 10 to 20
`
`hours, preferably 14—16 hours; and
`
`15
`
`c)
`
`precipitating zoledronate monosodium Form VIII.
`
`108.
`
`The process of embodiment 107, wherein the base is sodium hydroxide,
`
`which is added in an amount of a 1:1 molar ratio to the zoledronic acid.
`
`109.
`
`The process of embodiment 107, wherein the volume ratio of
`
`water/methanol to zoledronic acid form I in the suspension and the solution is between 6—
`
`20
`
`14, preferably 10.
`
`110. A process for preparing crystalline solid zoledronate monosodium Form VIII
`
`comprising:
`
`a)
`
`adding a solution of a base in an 60%/40% v/v mixture of
`
`water/isopropanol to a suspension of zoledronic acid form I in an 60%/40%
`
`25
`
`V/V mixture of water/isopropanol at elevated temperature, preferably reflux
`
`temperature;
`
`b)
`
`stirring the mixture of a) at reflux temperature for about 10 to 20
`
`hours, preferably14-16 hours; and
`
`c)
`
`precipitating zoledronate monosodium Form VIII.
`
`30
`
`111.
`
`The process of embodiment 110, wherein the base is sodium hydroxide,
`
`which is added in an amount of a 1:1 molar ratio to the zoledronic acid.
`
`14
`
`

`

`WO 2005/005447
`
`PCT/US2004/021626
`
`112.
`
`The process of embodiment 110, wherein the volume ratio of
`
`water/isopropanol to zoledronic acid form I in the suspension and the solution is between
`
`6-14, preferably 10.
`
`113. A process for preparing crystalline solid zoledronate monosodium Form
`
`XVI comprising:
`
`a)
`
`adding a solution of a base in a 50%/50% v/V mixture of
`
`water/ethanol to a suspension of zoledronic acid form I in a 50%/50% V/V
`
`mixture of water/ethanol at elevated temperature, preferably reflux
`
`temperature;
`
`10
`
`b)
`
`stirring the mixture of a) at reflux temperature for about 10 to 20
`
`hours, preferab1y14—16 hours; and
`
`c)
`
`precipitating zoledronate monosodium Form XVI.
`
`114.
`
`The process of embodiment 113, wherein the base is sodium hydroxide,
`
`which is added in an amount of a 1:1 molar ratio to the zoledronic acid.
`
`15
`
`115.
`
`The process of embodiment 113, wherein the volume ratio of
`
`water/ethanol to zoledronic acid form I in the suspension and the solution is between 6-
`
`14, preferably 10.
`
`116. A process for preparing crystalline solid zoledronate monosodium Form