UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Tradema rk Office
`
`January 17, 2013
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`
`THE RECOI~d)8 OF THIS OFFICE OF:
`
`U.S. PATENT: 7~700,645
`
`ISSUE DATE: April 20, 2010
`
`By Authority of the
`
`Under Secretary of Commerce for Intellectual Proper~,
`and Director of the United States Patent and Trademark Oftice
`
`P.R. GRA~ 3
`
`Certifying Officer
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`Lupin Ex. 1022 (Page 1 of 35)
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`US007700645B2
`
`(12) United States Patent
`Vermeersch et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,700,645 B2
`Apr. 20, 2010
`
`(54) PSEUDOPOLYMORPHIC FORMS OF A HIV
`PROTEASE INHIBITOR
`
`(75)
`
`Inventors: Hans Whn Pieter Vermeersch, Ghent
`(BE); Daniel Joseph Christiaan Then6,
`Beerse (BE); Luc Donn6 Marie-Louise
`Janssens, MaIM (BE)
`
`(73) Assignee: Tibotee Pharmaceuticals Ltd,, Little
`island, Co. Cork (IE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1320 days.
`
`(21)
`
`Appl. No.:
`
`10/514,352
`
`(22)
`
`PCT Filed:
`
`May 16, 2003
`
`(86)
`
`PCT No.:
`
`PCT/EP03/50176
`
`§ 371 (c)(1),
`(2), (4) Date:
`
`Nov. 12, 2004
`
`(87)
`
`PCT Pub. No.:
`
`WO03/106461
`
`PCT Pub. Date: Dee. 24, 2003
`
`(65)
`
`Prior Publication Data
`
`US 2005/0250845 A1 Nov. 10, 2005
`
`(30)
`
`Foreign Application Priority Data
`
`May 16, 2002
`
`(EP) .................................. 02076929
`
`(51) Int. C1.
`A61K 31/353
`(2006.01)
`(52) U.S. CL ....................................... 514f456; 549/396
`(58) Field of Classification Search ................. 514/456;
`549/396
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6,248,775 B1 6/2001 Vazquez et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`we
`we
`
`0715618 BI
`we 95/06030 A1
`we 99/67417 A2
`
`6/1996
`3/1995
`12/1999
`
`OTHER PUBLICATIONS
`
`Sodden "Pseudopolymorph... "Crystal growth & design 4(6)1087
`(2004),*
`Vermeersch et al. "Pseudo... "’ CA 140:47540 (2003).*
`Sodden "Pseudopolymorph: a polemic" Crystal Growth & design
`4(6) p. 1087-1087 (2004).*
`Kirk-Othmer"Encyclopedia of choral, tech" v..8, p. 95 -147 (2002).*
`Braga et al. "Making crystals flora... "Chem. Conunun. p. 3635-
`3645 (2005).*
`Giron D., et al, "Thermal analysis and calarimetric methods in the
`characterization of polymorphs and solvates," Thermochimica
`ACTA, Elsevier Science Publishers. Amsterdam, vol. 248, 1995, pp.
`1-59.
`Borka L, et al., "Crystal polymorphism of pharmaceuticals," ACTA
`Pharmaceutica Jugoslavica, Savez Farmaceutskih Drustava
`Jugoslavije, Zagre, Yu, vol. 40, 1990 pp. 71-94.
`Ghosh A.K., et at, "Potent HIV protease inhibitors incorporating
`high-affinity Pz-ligands and (R)-(hydroxycthylamino) sulfonamide
`isostere;’ Bioorganic & Medical Chemistry Letters, Oxford, GB, vol.
`8, No. 6, Mar. 17, 1998, pp. 687-690.
`Grunenberg A., et at., "Theoretical derivation and practival applica-
`tion of energy/temperature diagrams as an instrument in preformuta-
`tion studies ofpolymorphic drag substances:’ International Journal
`of Ph~tnaceufics 129 (1996) 147-158.
`Byrn, S. R, et at., "Solid-State Chemistry of Drags", Second Edition,
`1999, published by SSCI. Inc.. pp. 12-13.
`International Search Report dated Mar. 30, 2004 for PCT/EP03/
`50176.
`Sodden, K., Crystal Growth & Design, 4 (6), p. 1087 (2004).
`
`* cited by examiner
`
`Primary Examine~Cdia Chang
`
`(57)
`
`ABSTRACT
`
`New pseudopolymorphic forms of (3R,3aS,6aR)-hexahydro-
`furo[2,3 -b]furan-3-yl(1 S,2R)-3- [[(4-aminophenyl)sulfonyl]
`(isobutyl)amino] - 1 -benzyl-2-hydroxypropylcarbamate and
`processes for producing them are disclosed.
`
`8 Claims, 18 Drawing Sheets
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`U.S. Patent
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`Apr. 20, 2010 Sheet 1 of 18
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`US 7,700,645 B2
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`U.S. Patent
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`Apr. 20, 2010 Sheet 2 of 18
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`US 7,700,645 B2
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`U.S. Patent
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`Apr. 20, 2010 Sheet 3 of 18
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`U.S. Patent
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`Apr. 20, 2010 Sheet 4 of lS
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`US 7,700,645 B2
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`O!
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`01
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`C2
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`C16
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`C15
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`C14
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`C4 C13
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`C18
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`N10 C12
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`Figure 4
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`C25
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`U.S. Patent
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`Apr. 20, 2010 Sheet 5 of 18
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`US 7,700,645 B2
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`Figure 5
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`.... P25
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`-" .’ .’ P68
`P69
`P72
`--o P81
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`600
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`500 . . ’.: 400
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`300
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`.
`wavenumbers [era:~]
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`Figure 6
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`U.S. Patent
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`Apr. 20, 2010 Sheet 6 of 18
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`US 7,700,645 B2
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`Figure 7
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`U.S. Patent
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`Apr. 20, 2010 Sheet 7 of 18
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`U.S. Patent
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`Apr. 20, 2010 Sheet 8 of 18
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`US 7,700,645 B2
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`Figure 9
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`21~0
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`U.S. Patent
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`U.S. Patent
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`Apr. 20, 2010 Sheet 11 of 18
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`US 7,700,645 B2
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`U.S. Patent
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`Apr. 20, 2010 Sheet 13 of 18
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`US 7,700,645 B2
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`Figure 15
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`115
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`Figure 16
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`U.S. Patent
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`US 7,700,645 B2
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`U.S. Patent
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`US 7,700,645 B2
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`Figure 19
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`Figure 20
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`Figure 21
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`Apr. 20, 2010 Sheet 16 of 18
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`US 7,700,645 B2
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`U.S. Patent
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`Apr. 20, 2010 Sheet 17 of 18
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`US 7,700,645 B2
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`Figure 23
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`Figure 24
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`U.S. Patent
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`Apr. 20, 2010 Sheet 18 of 18
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`US 7,700,645 B2
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`Figure 25
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`Figure 26
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`US 7,700,645 B2
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`1
`PSEUDOPOLYMORPHIC FORMS OF A HIV
`PROTEASE INI3IBITOR
`
`This application is the national stage of Application No.
`PCT/EP03/50176, filed May 16, 2003, which application
`claims priority fi’om European Patent Application No.
`02076929.5, filed May 16, 2002.
`
`TECHNICAL FIELD
`
`This invention relates to novel pseudopolymorphic forms
`of (3R,3aS,6aR)-hexahydro-furo[2,3-bl furan-3-yl( 1S,2R)-
`3 -[[(4-aminophenyl)sulfonyl] (isobutyl)amino]- 1 -benzyl-2-
`hydroxypropylcarbamate, a method for their preparation as
`well as their use as a medicament.
`
`BACKGROUND OF THE INVENTION
`
`Virus-encoded proteases, which are essential for viral rep-
`lication, are required for the processing of viral protein pre-
`cursors. Interference with the processing of protein precur-
`sors inhibits the formation of infections vifions. Accordingly,
`inhibitors of viral proteases may be used to prevent or treat
`chronic and acute viral infections. (3R,3aS,6aR)-hexahydro-
`furo[2,3 -b] furan-3-yl(1 S,2R)-3 - [ [(4-aminophenyl)sulfonyl]
`(isobutyl)amino] - 1 -benzyl-2-hydroxypropylcarbamat e has
`HIV protease inhibitory activity and is particularly well
`suited for inhibiting HIV-1 and HIV-2 viruses.
`The structure of (3R,3aS,6aR)-hexahydrofuro[2,3-blfu-
`ran-3 -yl(1 S,2R)-3- [[(4-phenyl)sulfonyl] (isobutyl)amino] - 1-
`banzyl-2-hydroxypropylcarbamate, is shown below:
`
`Formul~ (X)
`
`CK3
`
`OK
`
`050
`
`NH2
`
`Compound of formula (X) and processes for its preparation
`are disclosed in EP 715618, WO 99/67417, U.S. Pat. No.
`6,248,775, and in Bioorganic and Chemistry Letters, Vol. 8,
`pp. 687-690, 1998, "Potent HIV protease inhibitors incorpo-
`rating high-aft-rally Pz-ligands and (R)-(hydroxyethylamino)
`sulfonamide isostere", all of which are incorporated herein by
`reference.
`Drugs utilized in the preparation of pharmaceutical formu-
`lations for commercial use must meet certain standards,
`including GMP (Good Manuthcturing Practices) and ICH
`(Iuteruational Conference on Harmonization) guidelines.
`Such standards include technical requirements that encom-
`pass a heterogeneous and wide range of physical, chemical
`and pharmaceutical parameters. It is this variety of param-
`eters to consider, which make pharmaceutical tbrmulations a
`complex technical discipline.
`For instance, and as example, a drug utilized for the prepa-
`ration of pharmaceutical formulations should meet an accept-
`able purity. There are established guidelines that define the
`limits and qualification of impurities in new drug substances
`
`5
`
`2
`produced by chemical synthesis, i.e. actual and potential
`impurities most likely to arise during the synthesis, purifica-
`tion, and storage of the new drug substance. Guidelines are
`instituted for the amount of allowed degradation products of
`the drug substance, or reaction products ofthe drug substance
`with an excipient and]or immediate container/closure system.
`Stabilily is also a parameter considered in creating phar-
`maceutical formulations. A good stability will ensure that the
`desired chemical intcgrity of drug substances is maintained
`10 during the shelf-life of the pharmaceutical formulation,
`which is the time frame over which a product can be relied
`upon to retain its quality characteristics when stored under
`expected or directed storage conditions. During this period
`the drug may be administered with little or no risk, as the
`presence of potentially dangerous degradation products does
`15 not pose prejudicial consequences to the health of the
`
`receiver, nor the lower content of the active ingredient could
`cause under-medication.
`Different factors, such as light radiation, temperature, oxy-
`gen, humidity, pH sensitivity in solutions, may influence sla-
`20 bility and may determine shelf-life and storage conditions.
`Bioavailability is also a parameter to consider in drug
`delivery design ofpharmacentically acceptable formulations.
`Bioavailability is concerned with the quantity and rate at
`which the intact form of a particular drug appears in the
`25 systemic circulation following administration of the drug.
`The bioavailability exhibited by a drug is thus of relevance in
`determining whether a therapeutically effective concentra-
`tion is achieved at the site(s) ofacfion of the drug.
`Physico-chemical factors and the pharmaco-technical for-
`30 mulation can have repercussions in the bioavailabilily of the
`drug. As such, several properties of the drug such as disso-
`ciation constant, dissolution rate, solubility, polymorphic
`form, parlicle size, are to be considered when improving the
`bioavailability.
`It is also relevant to establish that the selected pharmaceu-
`tical formulationis capable of manufacture, more suitably, of
`large-scale manufacture.
`In view of the various and many technical requirements,
`and its influencing parameters, it is not obvious to foresee
`40 which pharmaceutical formulations will be acceptable. As
`such, it was unexpectedly found that certain modifications of
`the solid state of compound of formula (X) positively influ-
`enced its applicability in pharmaceutical formulations.
`
`35
`
`45
`
`SUMMARY OF THE INVENTION
`
`5o
`
`Present invention concerns pseudopolymorphic forms of
`compound of formula (X) for the preparation of pharmaceu-
`tical formulations. Such pseudopolymorphic forms contrib-
`ute to pharmaceutical formulations in improved stability and
`bioavailability. They can be manufactured in sufficient high
`purity to be acceptable for pharmaceutical use, more particu-
`larly in the manufacture ofa medicanaent for inhibiting H1V
`protease activity in mammals.
`In a first aspect, the present invention provides pseudopoly-
`55 morphs of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl
`
`(1 S,2R)-3 -[[(4-aminophenyl)sul fonyl] (isobutyl)amino] - 1-
`benzy1-2 -hydroxypropylcarbamate.
`Pseudopolymorphs provided include alcohol solvates,
`more in particular, C1-C4 alcohol solvates; hydrate solvates;
`60 alkane solvates, more in particular, C1-C4 chlorealkane sol-
`
`vales; ketone solvates, more in particular, C1-C5 ketone sol-
`vales; ether solvates, more in particular, C 1 -C4 ether solvates;
`cycloether solvates; ester solvates, more in particular, C1-C5
`ester solvates; and sulfonic solvates, more in particular, C1-4
`65 sulfonic solvates, of the compound of formula (X). Pretbrred
`pseudopolymorphs are pharmaceutically acceptable solvates,
`such as hydrate and ethanolate.
`
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`US 7,700,645 B2
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`4
`FIG. 15: DSC Thermograph curves of Form A (curve D),
`Form A after Adsorption/Desorption (ADS/DES) (curve E),
`and Form A after ADS/DES hydratation tests (curve F)
`FIG. 16: Thermogravimetric (TG) curves of FormA (curve
`5 D), Form A after ADS/DES (curve E), and Form A after
`ADS/DES hydratation tests (curve F)
`FIG. 17: TG curve of Form A at 25° C. under dry nitrogen
`atmosphere in function of time
`FIG. 18: ADS/DES curves of Form A.
`FIG. 19: ADS/DES curves of the hydratation test of Form
`
`10
`
`15
`
`2O
`
`A
`
`FIG. 20: ADS/DES curves of Form B
`FIG. 21: IR spectrnm of Form K
`FIG. 22: Raman spectrum of Form K
`FIG. 23: DSC curve of Foma K
`FIG. 24: TG curve of Form K
`FIG. 25: ADS/DES isotherm of Form K, batch 1
`FIG. 26: ADS/DES isotherm of Form K, batch 2
`
`DETAILED DESCRIPTION
`
`3
`Particular pseudopolymorphs are Form A (ethanolate),
`Form B (hydrate), Form C (methanolate), Form D (aceto-
`hate), Form E (dichloromethanate), Form F (ethylacetate sol-
`vale), Form G (1-methoxy-2-propanolate), Form H (anise-
`late), Form I (tetrahydrofuranate), Form J (isopropanolate) of
`compound of formula (X). Another particular pseudopoly-
`morph is Form K (mesylate) of compound of formula (X).
`In a second aspect, present invention relates to processes
`for preparing pseudopolymorphs. Pseudopolymorphs of
`compound of formula (X) are prepared by combil~ing com-
`pound of formula (X) with an organic solvent, water, or
`mixtures of water and water miscible organic solvents, and
`applying any suitable tectmique to induce crystallization, to
`obtain the desired pseudopolymorphs.
`In a third aspect, the invention relates to the use of the
`present pseudopolymorphs, in the manufacture of pharma-
`ceutical formulations for inkibiting HW pretense activity in
`mammals. ~n relation to the therapeutic field, a preferred
`embodiment of this invention relates to the use of pharma-
`ceutically acceptable pseudopolymorphic forms of com-
`pound o f formula (X) for the treatment o fan HW viral disease
`in a mammal in need thereof, which method comprises
`administering to said mammal an effective amount era phar-
`maceutically acceptable pseudopolymorphic form of eom-
`pound of formula (X).
`The following drawings provide additional information on
`the characteristics of the pseudopolymorphs according to
`present invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1, FIG. 2 and FIG. 3 are the powder X-ray diffraction
`patterns of the Form A (1:1).
`FIG. 4 depicts Form A (1:1) in three dimensions with the
`atoms identified.
`FIG. 5 is a comparison of the Raman spectra of Forms A, B,
`D, E, F, H, (1:1) and the amorphous form at the earbonyl
`stretching region of 1800-100 cm- 1 and the region 3300-2000
`cm-1.
`FIG. 6 is a comparison of the expanded Raman spectra of
`Forms A, B, D, E, F, H, (1:1) and the amorphous form at the
`carbonyl stretching region of 600-0 cm-1.
`FIG. 7 is a comparison of the expanded Raman spectra of
`Forms A, B, D, E, F, H, (1:1)and the amorphous form at the
`earbonyl stretching region of 1400-800 cm-~.
`In FIGS. 5, ~i, and 7, P1 corresponds to Form A, P18
`corresponds to Form B, P19 corresponds to amorphous form,
`P25 corresponds to Form E, P27 corresponds to Form F, P50
`corresponds to Form D, P68 corresponds to Form H, P69
`corresponds to Form C, P72 corresponds to Form I, and PS1
`corresponds to Form (3.
`FIG. 8 is the Differential Scanning Calorimetric (DSC)
`thermograph of Form A (1:1).
`FIG. 9 is the Infrared (IR) spectrum that reflects the vibra-
`tional modes of the molecular structure of Form A as a crys-
`talfine product
`FIG. 10 is the IR spectrum that reflects the vibrational
`modes of the molecular structure of Form B as a crystalline
`product
`FIG. 11: IR spectrum of forms A, B, and amorphous form,
`at spectral range 4000 to 400 cm-~.
`FIG. 12: ~R spectrum of forms A, B, and amorphous form,
`at spectral range 3750 to 2650 cm-~.
`FIG. 13: IR spectrum of forms A, B, and amorphous form,
`at spectral range 1760 to 1580 cm-.
`FIG. 14: IR spectrum of forms A, B, and amorphous form,
`at spectral range 980 to 720 cm-~.
`In FIGS. 11, 12,13 and 14, curveA corresponds to FormA,
`curve B corresponds to Form B, and curve C corresponds to
`the amorphous form.
`
`The term "polymorphism" refers to the capacity of a
`chemical structure to occur in different forms and is known to
`occur in many organic compounds including drugs. As such,
`"polymorphic forms" or "polymorphs" include drug sub-
`25 stances that appear in amorphous form, in crystalline form, in
`anhydrous form, at various degrees of hydration or solvation,
`with entrapped solvent molecules, as well as substances vary-
`hag in crystal hardness, shape and size. The different poly-
`morphs vary in physical properties such as solubility, disso-
`3o lution, solid-state stability as well as processing behaviour in
`terms of powder flow and compaction during tabletting.
`The term "amorphous form" is defined as a form in which
`a three-dimensional long-range order does not exist. In the
`amorphous form the position of the molecules relative to one
`another are essentially random, i.e. without regular arrange-
`35 ment of the molecules on a lattice structure.
`
`The term "crystalline" is defined as a form in which the
`position of the molecules relative to one another is organised
`according to a three-dimensional lattice structure.
`The term "anhydrous fbrm" refers to a particular form
`40 essentially free of water. "Hydration" refers to the process of
`adding water molecules to a substance that occurs in a par-
`tieular tbrm and "hydrates" are substances that are formed by
`adding water molecules. "Solvafing" refers to the process of
`incorporating molecules of a solvent into a substance occur-
`45 ring in a crystalline form. Therefore, the term "solvate" is
`defined as a crystal form that contains either stoichiometric or
`non-stoichiometric amounts of solvent. Since water is a sol-
`vent, solvates also include hydrates. The term. "pseudopoly-
`morph" is applied to polymorphic crystalline forms that have
`50 solvent molecules incorporated in their lattice structures. The
`term pseudopolymerphism is used frequently to designate
`solvates (Byrn, Pfeiflbr, Stowell, (1999) Solid-state Chemis-
`try of Drugs, 2nd Ed., published by SSCI, Inc).
`The present invention provides pseudopolymorphs of(3R,
`55 3aS.,6aR)-hexahydrofuro[2,3-b]furan-3 -yl(1 S,2R)-3- [[(4-
`ammophenyl)sulfonyl] (isobutyt)amino]-l-benzyl-2-hydrox-
`ypropylcarbamate.
`In one embodiment pseudopolymorphs are alcohol sol-
`vales, more in particular, C1-C~ alcohol solvates; hydrate
`solvates; alkane solvates, more in particular, C~-C,~ chloroal-
`60 kane solvates; ketone solvates, more in particular, C~-Cs
`ketone solvates; ether solvates, more in particular Ct -C4 ether
`solvates; cycloether solvates; ester solvates, more in particu-
`lar C~-Cs ester solvates; or sultbnie solvates, more in particu-
`lar, C~-C4 sulfonic solvate.s of the compound of formula (X).
`6~ The term "Cr-C4 alcohol" defines straight and/or branched
`chained saturated and unsaturated hydrocarbons having from
`1 to 4 carbon atoms substituted with at least a hydroxyl group,
`
`Copy provided by USPTO from the PIRS Image Database on 01/10/2013
`
`Lupin Ex, 1022 (Page 22 of 35)
`
`

`

`US 7,700,645 B2
`
`6
`As such, .X-ray powder diffraction spectra were collected
`on a Phillips PW 1050/80 powder diffractometer, model
`Bragg-Brentano. Powders of Form A (1:1), around 200 mg
`each sample, werepacked in 0.5 mm glass capillary tubes and
`were analysed according to a standard method in the art. The
`X-ray generator was operated at 45 Kv and 32 mA, using the
`copper Ka line as the radiation source. There was no rotation
`of the sample along the chi axis and data was collected
`between 4 and 60° 2-theta step size. Form A (1:1) has the
`characteristic two-theta angle positions of peaks as shown in
`FIGS. 1, 2 and 3 at: 7.04°+0.50, 9.240_*0.5°, 9.960_*0.5°
`12.82°_+0.5°.
`11.30°,-0.5°
`13.80°±0.5°
`10.66°_+0.5°,
`17.30°--0.5°
`18.28°±0.5°
`16.66°±0.5°
`14.56°±0.5°,
`20.500_+0.5°
`20.000+0.5°
`21.22°_+0.5°
`19.10°_+0.5°,
`23.660_-,-0.5°.
`25.080_*0.5°
`23.080_*0.5°
`22.680±0.5°,
`26.280±0.5°
`27.18°±0.5°.
`28.22°±0.5°
`25.580±0.5°,
`31.340_+0.5°
`32.68°_+0.5°.
`33.820_+0.5°
`30.200_+0.5°,
`39.18°_.0.5°, 41.20°±0.5°, 42.060±0.5°, and 48.740±0.5°.
`In another set of analytical experiments, X-ray single dif-
`fraction was applied to FormA (1:1), which resulted in the
`following crystal configuration, listed in the table below.
`
`TABLE 1
`
`Crystal Data
`
`Crystal shape
`Crystal dimensions
`Crystal color
`Space Group
`Temperature
`Cell constants
`
`0.56 x 0.38 × 0.24 mm
`Colorless
`P 212z 21 ortherhombic
`293 K
`a = 9.9882(6)
`b = 16.1697(8) A
`e = 19.~2M(9)
`~pha (a) = 90~
`~e~ (~) = 90~
`g~ 0) = 90~
`3158.7(3)
`4
`1.248
`1.340
`1272
`Intensity Measurements
`
`Volume
`Molecules/tmlt cell (Z)
`Density, in Mg/ms
`p~ (linear absorption coefficient)
`
`Diffraetometer
`Radiation
`
`Siemens P4
`
`Ca Ka (~, = 1.54184/~)
`ambient
`Ternp eratttre
`138.14°
`20~x
`Empirical via ~-seans
`Correction
`Total: 39!2
`Number of Reflections Measured
`Structure Solution and Refinement
`
`Nmnber of Observations
`Residual (K)
`
`3467 [F2 > 2 a(F2)]
`0.0446
`
`5
`and optionally substituted with an alkyloxy group, such as,
`for example, methanol, ethanol, isopropanol, butanol,
`1-methoxy-2-propano] and the like. The term "C1-C4 chloro-
`alkane" defines straight and/or branched chained saturated
`and unsaturated hydrocarbons having from 1 to 4 carbon 5
`atoms substituted with at least one chloro atom, such as, for
`example, dichloromethane. The term "Cz-C5 ketone" defines
`solvents of the general formula W--C(~----O)--R wherein R
`and R’ can be the same or different and are methyl or ethyl,
`such as, acetone and the like. The term "C1-C4 ether" defines 10
`solvents of the general formula R’~--R wherein R and R’
`can be the same or different and are a phenyl group, methyl or
`ethyl, such as, anisole and the like. The term "cycloether"
`defines a 4- to 6-membered monocyclic hydrocarbons con-
`taining one or two oxygen ring atoms, such as tetrahydrofuran 15
`and the like. The term "CI-C5 ester" defines solvents of the
`general formula R’--O~(~---O)--R wherein R and R’ can
`be the same or different and are methyl or ethyl, such as
`ethylaeetate and the like. The term "Cz-C4 sulfonic solvent"
`defines solvents of the general formula ~SO~H wherein R
`can be a straight or branched chained saturated hydrocarbon 2o
`having from 1 to 4 carbon atoms, such as mesylate, ethane-
`sulfonate, butanesulfonate, 2-methyl-l-propanesulfonate,
`and the like.
`Pseudopolymorphs of the present invention, which are
`pharmaceutically acceptable, for instance hydrates, alcohol 25
`solvates, such as, ethanolate, are preferred forms.
`Several pseudopolymorphs are exemplifiedinthis applica-
`tion and include Form A (ethanolate), Form B (hydrate),
`Form C (methanolate), Form D (acetonate), Form E (dichlo-
`romethanate), Form F (ethylacetate solvate), Form G 3o
`(1-methoxy-2-propanolate), Form H (anisolate), Form I (tet-
`rahydrofuranate), Form J (isopropanolate), or Form K (mesy-
`late) of compound of formula (X).
`Solvates can occur in different ratios of solvation. Solvent
`content of the crystal may vary in different ratios depending 35
`onthe conditions applied. Solvate crystal forms of compound
`of formula (X) may comprise up to 5 molecules of solvent per
`molecule of compound of formula (X), appearing in different
`solvated states including, amongst others, hemisolvate,
`monosolvate, disolvate, trisolvate crystals, intermediate sol- 40
`rates crystals, and mixtures thereof. Conveniently, the ratio of
`compound of formula (X) to the solvent may range between
`(5:1) and (1:5). In particular, the ratio may range from about
`0.2 to about 3 molecules of solvent per 1 molecule of com-
`pound of formula (X), more in particular, the ratio may range 45
`from about 1 to about 2 molecules of solvent per 1 molecule
`of compound of formula (X), preferably the ratio is 1 mol-
`ecule of solvent per 1 molecule of compound of formula (X).
`Solvates may also occur at different levels of hydration. As
`such, solvate cryslal forms of compound of formula (X) may
`in addition comprise under certain circumstances, water mol-
`ecules partially or fidly in the crystal structures. Conse-
`quently, the term "Form A" will be used herein to refer to the
`ethanolate forms of compound of formula (X) comprising up
`to 5 molecules of solvent per 1 molecule of compound of
`formula (X), intermediate solvates crystals, and the mixtures
`thereof; and optionally comprising additional water mol-
`ecules, partially or fully in the crystal structures. The same
`applies for Form B through Form K. In case a particular
`"Form A" needs to be denoted, the ratio of solvafion will
`follow the "Form A", for instance, one molecule of ethanol 60
`per one molecule of compound (X) is denoted as Form A
`(1:1).
`The X-ray powder diffraction is a technique to characterise
`polymorphic forms including pseudopolymorphs of com-
`pound of formula (X) and to differentiate solvate crystal 65
`forms from other crystal and non-crystal forms of compound
`of formula (X).
`
`The resulting three-dimensional structure of Form A (1:1)
`50 is depicted in FiG. 4.
`
`Table 2 shows the atomic coordinates (x 104) and equiva-
`lent isotropic displacement parameters (/~ 2x103) for Form A
`(1:1).Atoms are numbered as exhibited in FIG. 4. The x, y and
`z fractional coordinates indicate the position of atoms relative
`55 to the origin of the unit cell. U(eq) is defined as one third of the
`trace of the orthogonalized Uo tensor.
`
`x
`
`y
`
`z
`
`u(eq)
`
`Ol
`C2
`C3
`C3A
`C4
`C5
`06
`C6A
`
`7778(3)
`7171(4)
`6831(3)
`7953(3)
`7527(4)
`7425(5)
`8501(3)
`8582(4)
`
`2944(2)
`3513(2)
`3046(2)
`2411(2)
`1533(2)
`124i(2)
`1642(2)
`2416(2)
`
`9946(1)
`9487(2)
`8823(2)
`8793(2)
`8708(2)
`9457(2)
`9809(1)
`9534(2)
`
`70(1)
`64(1)
`52(1)
`55(1)
`65(1)
`70(1)
`76(1)
`62(1)
`
`Copy provided by USPTO from the PIRS Image Database on 01/10/2013
`
`Lupin Ex. 1022 (Page 23 of 35)
`
`

`

`US 7,700,645 B2
`
`7
`-continued
`
`07
`08
`C9
`N10
`Cll
`C12
`C13
`C14
`C15
`C16
`C17
`C18
`C19
`020
`C21
`N22
`C23
`C24
`C25
`C26
`$27
`028
`029
`C30
`C31
`C32
`C33
`C34
`C35
`N36
`C37
`C38
`039
`
`5533(2)
`5168(2)
`4791(3)
`3590(2)
`2638(3)
`2223(3)
`3381(3)
`3937(4)
`4989(5)
`5494(5)
`4975(6)
`3926(5)
`1423(3)
`494(2)
`1829(3)
`699(3)
`521(4)
`-61(4)
`-1453(5)
`-47(7)
`510(1)
`572(3)
`-693(2)
`1854(3)
`1803(3)
`2871(4)
`4033(4)
`4063(4)
`2998(4)
`5076(3)
`1920(10)
`1310(10)
`1768(4)
`
`2702(1)
`2636(1)
`2534(1)
`2256(1)
`1916(2)
`1071(2)
`501(2)
`340(2)
`-200(2)
`-581(3)
`-413(3)
`126(2)
`2464(2)
`2112(1)
`3307(2)
`3880(1)
`4312(2)
`3785(2)
`3497(3)
`4247(3)
`4414(1)
`3860(1)
`4873(1)
`5080(2)
`5825(2)
`6341(2)
`6133(2)
`5385(2)
`4869(2)
`6667(2)
`2231(7)
`1590(6)
`1393(2)
`
`8945(1)
`7768(1)
`8368(1)
`8562(1)
`8068(2)
`8310(2)
`8387(2)
`9038(2)
`9111(3)
`8530(3)
`7881(3)
`7810(2)
`7976(2)
`7502(1)
`7740(2)
`7721(1)
`7048(2)
`6473(2)
`6654(2)
`5779(2)
`8440(1)
`9015(1)
`8345(1)
`8509(2)
`8159(2)
`8195(2)
`8564(2)
`8909(2)
`8883(2)
`8596(2)
`5258(4)
`5564(4)
`6249(2)
`
`51(1)
`53(I)
`42(1)
`43(1)
`44(1)
`58(1)
`56(1)
`67(1)
`80(1)
`96(2)
`98(2)
`78(1)
`45(1)
`61(1)
`48(1)
`49(1)
`58(1)
`67(1)
`86(2)
`102(2)
`50(1)
`61(1)
`65(1)
`50(1)
`54(1)
`56(1)
`55(1)
`59(1)
`56(1)
`72(1)
`232(6)
`191(5)
`94(1)
`
`Table 3 shows the anisotropic displacement parameters
`(A_2× 103) for Form A ( 1:1 ). The anisotropic displacement
`factor exponent takes the formula:
`
`-2~2/7~a *~UI t+... +2hka*b
`
`O1
`C2
`C3
`C3A
`C4
`C5
`06
`C6A
`07
`08
`C9
`N10
`Cll
`C12
`C13
`C14
`C15
`C16
`C17
`C18
`C19
`020
`C21
`N22
`C23
`C24
`C25
`C26
`S27
`028
`029
`C30
`
`UII
`
`U]2
`
`U33
`
`U23
`
`Uls
`
`UI2
`
`65(2)
`53(2)
`38(2)
`37(2)
`61(2)
`72(3)
`78(2)
`47(2)
`34(1)
`42(1)
`35(2)
`31(1)
`32(2)
`44(2)
`50(2)
`64(2)
`68(3)
`77(3)
`114(4)
`89(3)
`30(2)
`44(1)
`36(2)
`42(1)
`59(2)
`79(3)
`75(3)
`143(5)
`44(1)
`64(2)
`46(1)
`50(2)
`
`89(2)
`68(2)
`63(2)
`78(2)
`74(2)
`67(2)
`80(2)
`80(2)
`69(1)
`68(1)
`41(1)
`50(1)
`41(1)
`42(1)
`39(1)
`56(2)
`72(2)
`68(2)
`72(2)
`60(2)
`4~(1)
`56(1)
`42(1)
`47(1)
`50(1)
`59(2)
`83(2)
`99(3)
`47(1)
`58(1)
`58(1)
`46(1)
`
`55(1)
`71(2)
`55(2)
`49(1)
`61(2)
`71(2)
`70(1)
`59(2)
`50(1)
`50(1)
`49(1)
`49(1)
`57(1)
`87(2)
`78(2)
`80(2)
`100(3)
`143(4)
`109(3)
`85(2)
`61(1)
`83(1)
`64(2)
`57(l)
`64(2)
`62(2)
`101(3)
`65(2)
`61(1)
`6t(1)
`92(2)
`54(1)
`
`-4(I)
`-7(2)
`4(1)
`9(1)
`-4(2)
`8(2)
`16(t)
`5(2)
`0(1)
`3(1)
`1(1)
`-i(1)
`-4(1)
`2(1)
`0(1)
`0(2)
`18(2)
`26(3)
`-6(2)
`-4(2)
`-3(1)
`-6(1)
`2(1)
`1(1)
`7(1)
`1(i)
`6(2)
`14(2)
`2(1)
`9(1)
`-4(1)
`2(1)
`
`-12(1)
`-8(2)
`-2(1)
`1(1)
`-6(2)
`-11(2)
`-21(1)
`-6(2)
`-1(1)
`2(1)
`-3(1)
`1(1)
`0(1)
`2(2)
`8(2)
`5(2)
`7(2)
`340)
`32(3)
`10(2)
`-5(1)
`-18(1)
`-4(1)
`0(1)
`-8(2)
`-11(2)
`-30(3)
`-15(3)
`2(1)
`3(1)
`6(1)
`1(1)
`
`-3(1)
`-11(2)
`-12(1)
`-3(2)
`10(2)
`-7(2)
`-8(2)
`-7(2)
`-9(1)
`-12(1)
`3(1)
`-2(1)
`-2(1)
`-4(1)
`0(1)
`9(2)
`12(2)
`28(2)
`38(3)
`10(2)
`-5(1)
`-6(1)
`-1(1)
`3(1)
`1(2)
`6(2)
`-5(2)
`-6(3)
`1(1)
`-7(1)
`10(I)
`1(1)
`
`-continued
`
`5 C31
`C32
`C33
`C34
`C35
`N36
`10 C37
`C38
`039
`
`UII
`
`U22
`
`U33
`
`U23
`
`UI3
`
`UI2
`
`50(2)
`59(2)
`57(2)
`56(2)
`63(2)
`67(2)
`290(10)
`280(10)
`99(2)
`
`48(1)
`45(1)
`55(2)
`63(2)
`52(1)
`70(2)
`260(10)
`187(7)
`91(2)
`
`64(2)
`65(2)
`52(1)
`59(2)
`53(1)
`80(2)
`145(7)
`104(4)
`93(2)
`
`6(1)
`4(1)
`-4(1)
`6(1)
`5(1)
`4(2)
`68(7)
`1(5)
`1(2)
`
`-4(2)
`2(2)
`1(1)
`-13(2)
`-8(2)
`-5(2)
`67(8)
`-53(6)
`-13(2)
`
`6(1)
`1(1)
`-3(1)
`-3(2)
`-2(2)
`-19(2)
`120(10)
`-80(10)
`-28(2)
`
`Raman spectroscopy has been widely used to elucidate
`!5 molecular structures, crystallinity and polymorphism. The
`low-l~equency Raman modes are particularly useihl in dis-
`tinguishing different molecular packings in crystal. As such,
`Raman spectra were recorded on a Bruker FT-Raman RFS
`100 spectrometer equipped with a photomultiplier tube and
`2o optical multichannel detectors. Sanaples placed in quartz cap-
`illary tubes were excited by an argon ion laser. The laser
`power at the samples was adjusted to about 100 mW and the
`spectral resolution was about 2 cm-1. It was found that Forms
`