(12) United States Patent
`Vermeersch et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,518,987 B2
`Aug. 27, 2013
`
`US00851.8987B2
`
`(54) PSEUDOPOLYMORPHIC FORMS OF A HIV
`PROTEASE INHIBITOR
`
`(75) Inventors: Hans Wim Pieter Vermeersch, Ghent
`(BE); Daniel Joseph Christiaan Thone,
`Beerse (BE); Luc Donne Marie-Louise
`Janssens, Malle (BE); Piet Tom Bert
`Paul Wigerinck, Terhagen (BE)
`
`(*) Notice:
`
`(73) Assignee: Janssen R&D Ireland, Little Island, Co.
`Cork (IE)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 276 days.
`(21) Appl. No.: 12/536,807
`(22) Filed:
`Aug. 6, 2009
`
`(65)
`
`Prior Publication Data
`US 2010/020431.6 A1
`Aug. 12, 2010
`Related U.S. Application Data
`(62) Division of application No. 10/514.352, filed as
`application No. PCT/EP03/50176 on May 16, 2003,
`now Pat. No. 7,700,645.
`Foreign Application Priority Data
`
`(30)
`
`May 16, 2002 (EP) ..................................... O2O76929
`
`(2006.01)
`
`(51) Int. Cl.
`A6 IK3I/353
`(52) U.S. Cl.
`USPC ........................................... 514/456; 549/396
`(58) Field of Classification Search
`USPC .......................................... 514/456; 549/396
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,413,999 A
`5, 1995 Vacca et al.
`6,071,916 A
`6, 2000 Askin et al.
`6,096,779 A
`8, 2000 Chikaraishi et al.
`6,248,775 B1
`6/2001 Vazquez et al.
`6,281,367 B1
`8/2001 Al-Farhan et al.
`6,287,693 B1
`9, 2001 Savoir et al.
`7,700,645 B2
`4/2010 Vermeersch et al.
`2013,0029945 A1
`1/2013 Phull et al. .................... 514,158
`
`FOREIGN PATENT DOCUMENTS
`O715618 B1
`6, 1996
`05-230044
`9, 1993
`WO95/06030 A1
`3, 1995
`WO98,56781
`12/1998
`WO99,51618
`10, 1999
`WO99.67254
`12/1999
`WO99,67417 A2 12/1999
`WOOO,29390
`5, 2000
`WOOOf 47551
`8, 2000
`WOO3 (106461 A1 12/2003
`
`EP
`JP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`OTHER PUBLICATIONS
`Seddon “Pseudopolymorph/\ ...” Crystal Growth & design v.4(6) p.
`1087 (2004) (2 pages from internet).*
`
`Gyseghem et al. “Solid state chara...” AAOSAnnual meeting abs.
`(2009).*
`Gao “Physical chemical . . .” AAPS PharmSci. 3(1) p. 1-8 (2001).*
`Gyseghem “Solid state. . .” Eu. J.Pharm. Sci. 38 p. 489-497 (2009).*
`Vermeersch “Pseudopo . . .” CA140:47540 (2003).*
`International Search Report re: PCT/EP03/50176, dated May 16,
`2003.
`Giron D. et al., “Thermal analysis and calorimetric 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.
`Ghosha.K., et al., “Potent HIV protease inhibitors incorporating
`high-affinity P2-ligands and (R)-(hydroxyethylamino) sulfonamide
`isostere.” Bioorganic & Medical Chemistry Letters, Oxford, GB, vol.
`8, No. 6, Mar. 17, 1998, pp. 687-690.
`Grunenberg A. et al., “Theoretical derivation and practival applica
`tion of energyftemperature diagrams as an instrument in preformula
`tion studies of polymorphic drug Substances.” International Journal
`of Pharmaceutics 129 (1996) 147-158.
`Byrn, S.R., et al., “Solid-State Chemistry of Drugs'. Second Edition,
`1999, published by SSCI, Inc. pp. 12-13.
`Seddon, K., Crystal Growth & Design, 4 (6), p. 1087 (2004).
`Braga, D., et al. “Making Crystals from Crystals: A Green Route to
`Crystal Engineering and Polymorphism'. Chem. Commun., pp.
`3635-3645 (2002).
`Kirk-Othmer Encyclopedia of Chemical Technology, “Crystalliza
`tion”, vol. 8 (2002) pp. 95-147 (2002).
`Vermeersch, H., et al. “Pseudopolymorphic Forms of a HIV Protease
`Inhibitor', Caplus No. 1006987 (2003).
`“Defendants Lupin Limited's, Lupin Pharmaceuticals, Inc.'s, Mylan
`Pharmaceuticals Inc.'s and Mylan Inc.'s Joint Invalidity Contentions
`Pursuant to Local Patent Rule 3.6(b)', in the United States District
`Court District of New Jersey, Consolidated Civil Action No.
`10-5954-WHW-MCA, Nov. 18, 2011 (Redacted), 178 pages.
`“Hetero Drugs, Ltd.'s Certification of Non-Infringement and/or
`Invalidity of United States Patent Nos. 5,843,946, 6,037,157,
`6,248,775, 6,335,460, 6,703,403, 7,470,506, and 7,700,645”, Feb.
`10, 2011 (Redacted), 73 pages.
`“Lupin Ltd.'s Notification of Certification of U.S. Patent Nos.
`6,037,157, 6,703,403, 7,470,506, and 7,700,645 Pursuant to S
`505(1)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act”. Jun.
`3, 2011 (Redacted), 96 pages.
`"Teva Pharmaceuticals USA, Inc.'s and Teva Pharmaceutical Indus
`tries, Ltd.'s Invalidity Contentions Under Local Patent Rules 3.3 and
`3.6”, Nov. 18, 2011 (Redacted), 123 pages.
`Ansel et al., “Pharmaceutical Dosage Forms and Drug Delivery Sys
`tems”. LippinOott Williams & Wilkins, 7" ed., 1999, 297-304.
`Bauer, “Ritonavir an Extraordinary Example of Conformational
`Polymorphism', vol. 18, Pharmaceutical Res., 2001, 859-866.
`Berstein, J., “Polymorphism in Molecular Crystals'. Oxford Univer
`sity Press, pp. 4-8, 2002.
`Brittain, H.G., “Polymorphism in Pharmaceutical Studies'. Discov
`ery Laboratories, Inc., 1999, pp. 205-208.
`Byrn, S. et al., Pharmaceutical Solids A Strategic Approach to Regu
`latory Considerations, Pharmaceutical Res., vol. 12, No. 7, 1995,
`945-954.
`
`(Continued)
`Primary Examiner — Celia Chang
`(74) Attorney, Agent, or Firm — Woodcock Washburn LLP
`(57)
`ABSTRACT
`New pseudopolymorphic forms of (3R,3aS,6aR)-hexahydro
`furo2,3-blfuran-3-yl (1S,2R)-3-(4-aminophenyl)sulfonyl
`(isobutyl)amino-1-benzyl-2-hydroxypropylcarbamate and
`processes for producing them are disclosed.
`
`19 Claims, 18 Drawing Sheets
`
`Merck Exhibit 2253, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 8,518,987 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Center for Drug Evaluation and Research, "Guideline for Submitting
`Supporting Documentation in Drug Applications for the Manufac
`ture of Drug Substances'. Feb. 1987. 20 pages.
`Chemburkar, S.R. et al., “Dealing with the Impact of Ritonavir
`Polymorphs on the Late Statges of Bulk Process Development”.
`Organic Process Research and Development, vol. 4, No. 5, 2000, pp.
`413-417.
`Chikaraishi, Y. et al., “Preparation of Piretanide Polymorphs and
`Their Physicochemical Properties and Dissolution Behaviors'.
`Chem. Pharm. Bull, vol. 42(5), May 1994, pp. 1123-1128.
`Datta, S. et al., “Crystal structures of drugs: advances in determina
`tion, prediction, and engineering. Nature Reviews Drug Discovery,
`vol. 3, Jan. 2004, pp. 42-57.
`Ghosh et al., “Structure Based Design: Novel Spirocyclic Ethers as
`Nonpeptidal P2-Ligands for HIV Protease Inhibitors'. Bioorganic
`and Med. Chem. Letters 8, Feb. 1998, 687-90.
`Haleblian, J. et al., “Pharmaceutical Applications of Polymorphism',
`J. Pharm. Sci., vol. 64, No. 8, Aug. 1975, pp. 1269-1288.
`ICH Harmonized Tripartite Guideline, “Specifications: Test Proce
`dures and Acceptance Criteria for New Drug Substances and New
`Drug Products: Chemical Substances, Q6A', Oct. 6, 1999, 35 pages.
`Jesley, et al., “Organic Phase Analysis, II. Two Unexpected cases of
`Pseudopolymorphism'. Arch. Pharm. Chemi. Sci. Ed., vol. 9, May
`1981, 123-130.
`Johnson et al., “Indinavir Sulfate” Analytical Profiles of Drug Sub
`stances and Excipients, vol. 26, Academic Press, 1999, 319-357.
`Jozwiakowski, Water-Insoluble Drug Formation; Chapter 15: Alter
`ation of the Solid State of the Drug Substance: Polymorphs, Solvates,
`and Amorphous Forms, Interpharm Press, Jan. 5, 2001, 525-568.
`
`Matsuda et al., “Physicochemical Characterization of Sprayed-Dried
`Phenylbutazone Polymorphs”. J. Pharm. Sci., vol. 73, No. 2, Feb.
`1984, pp. 173-179.
`McCrone, W.C., “Physics and chemistry of the Organic Solids State;
`Chapter 8: Polymorphism', vol. 2, eds. D. Fox, M.M. Labes, and A.
`Weissberger, Wiley Interscience, New York, 1965, 725-767.
`Salole, E.G., “The Physicochemical Properties of Oestradiol”, J.
`Pharm. Biomed. Anal., vol. 5, No. 7, 1987, pp. 635-648.
`Ghosh, et al., Nonpeptidal P. Ligands for HIV Protease Inhibitors:
`Structure-Based Design, Synthesis, and Biological Evaluation, J.
`Med. Chem, 39, 1996, 3278-3290.
`European Patent Application No. 10180831.9: Extended European
`Search Report dated Feb. 28, 2011, 8 pages.
`Japanese Patent Application No. 513292/04: Official Action dated
`Sep. 1, 2009, 3 pages.
`Ogata, “Operation of Chemical Experiment Procedures.” K.K.
`Nankodo, 1963, 367-377 and 297-399.
`Lupin's Detailed Factual and Legal Basis for Lupin's Paragraph IV
`Certification that U.S. Patent Nos. 6,037, 157; 6,703,403; 7.470,506,
`and 7.700,645 are Invalid, Unenforceable, and/or Not Infringed, Oct.
`1, 2010, 96 pages, Redacted.
`Mylan’s Paragraph IV Certification that U.S. Patent Nos. 7,470,506
`and 7,700,645 are Invalid, Unenforeceable, and/or Not Infringed,
`Oct. 1, 2010, 38 pages, Redacted.
`Plaintiffs Response to Invalidity Contentions of Defendants Lupin
`Limited, Lupin Pharmaceuticals, Inc., Mylan Pharmaceuticals Inc.,
`and Mylan Inc. Concerning U.S. Patent No. 7,700,645 Pursuant to
`Local Patent Rules 34A and 3.6(i), Mar. 29, 2012, 62 pages.
`Plaintiffs Response to Invalidity Contentions of Defendants Teva
`Pharmaceuticals USA, Inc. and Teva Pharmaceutical Industries, Ltd.
`Concerning U.S. Patent No. 7,700,645 Pursuant to Local Patent
`Rules 34A and 3.6(i), Mar. 29, 2012, 51 pages.
`* cited by examiner
`
`Merck Exhibit 2253, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 1 of 18
`
`US 8,518,987 B2
`
`3.
`
`S.
`
`VN
`
`s CD Na U
`
`S
`
`Se
`
`R
`
`Merck Exhibit 2253, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 2 of 18
`
`US 8,518,987 B2
`
`3
`
`s
`
`GN
`
`S CD N U
`
`S
`
`Se
`
`MM
`
`s
`
`Merck Exhibit 2253, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 3 of 18
`
`US 8,518,987 B2
`
`g
`
`S.
`
`CY
`
`8 CS N U
`
`S
`
`Se
`
`Merck Exhibit 2253, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 4 of 18
`
`US 8,518,987 B2
`
`
`
`Merck Exhibit 2253, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 5 of 18
`
`US 8,518,987 B2
`
`FIG. 5
`
`to
`
`---
`
`wavenumbers (cm) $:
`
`
`
`Merck Exhibit 2253, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 6 of 18
`
`US 8,518,987 B2
`
`
`
`FIG. 7
`
`wavenumbers (cm)
`
`Merck Exhibit 2253, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 7 of 18
`
`US 8,518,987 B2
`
`
`
`Merck Exhibit 2253, Page 9
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 8 of 18
`
`US 8,518,987 B2
`
`FIG. 9
`
`OO
`
`20
`10
`
`ico
`
`3000
`
`2000
`Wavenumbers (cm?)
`
`1OOO
`
`F.G. 10
`
`4000
`
`3000
`
`2000
`Wavenumbers (cm1)
`
`1000
`
`Merck Exhibit 2253, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 9 of 18
`
`US 8,518,987 B2
`
`
`
`s
`
`s
`
`Merck Exhibit 2253, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 10 of 18
`
`US 8,518,987 B2
`
`
`
`r???????r-~~~~); {
`
`}
`
`
`
`
`
`{
`
`|---?????
`
`O|'0-
`
`ZOO
`
`#00
`
`900
`
`800
`
`80UeCJOSCW
`
`000€
`
`00990079
`
`0098
`
`0099
`
`0018
`
`Merck Exhibit 2253, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 11 of 18
`
`US 8,518,987 B2
`
`
`
`
`
`Merck Exhibit 2253, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 12 of 18
`
`US 8,518,987 B2
`
`
`
`
`
`
`
`
`
`Merck Exhibit 2253, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 13 of 18
`
`US 8,518,987 B2
`
`FIG. 15
`
`3O
`
`40
`
`50
`
`60
`
`7O
`
`OO
`90
`8O
`Temperature (°C)
`
`110
`
`120
`
`130
`
`140
`
`150
`
`
`
`FIG 16
`
`25
`
`50
`
`75
`
`100
`
`125
`
`175
`150
`Temperature (°C)
`
`200
`
`225
`
`250
`
`275
`
`300
`
`Merck Exhibit 2253, Page 15
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 14 of 18
`
`US 8,518,987 B2
`
`OO
`
`FIG. 17
`
`26.0
`
`25.5
`
`250
`
`CS
`is
`3.
`2
`
`Residue.
`99.65% min
`\(07ong Residue.
`as 99.6 \
`99.45% 6min
`(10.68mg)
`g
`
`99.8
`
`99.4
`
`Residue.
`99.36% 10min (1067mg)
`N--
`
`Residue.
`9. bo?
`
`99.2
`
`99.0
`O
`
`300
`
`600
`
`900
`Time (min)
`
`1200
`
`1500
`
`1800
`
`24.0
`
`FIG. 18
`Adsorption/Desorption isothermat 25°C
`
`
`
`-- Dried (hour at 10°C)
`-- First run
`Second run
`
`"o
`
`to
`
`20
`
`30
`
`60
`50
`40
`% Relative Humidity
`
`io
`
`80
`
`go
`
`too
`
`Merck Exhibit 2253, Page 16
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 15 of 18
`
`US 8,518,987 B2
`
`FIG. 19
`Adsorption/Desorption isothermat 25°C
`
`"
`
`1.0
`0.5
`-
`-------------- - - - - -
`OO
`- -3
`05
`---
`...
`-
`4-s:
`1.0
`2.
`-
`s
`---
`- 5
`---
`:-
`e
`-
`-- -322
`ss -2.0
`--- -132
`25-
`- -3°
`25
`- 23:
`St -3.0
`33 - 13-
`--- 1.
`
`r
`
`-a-hydratation test
`
`O
`
`10
`
`20
`
`3O
`
`6O
`50
`40
`% Relative Humidity
`
`70
`
`80
`
`90
`
`100
`
`
`
`FIG. 20
`Adsorption/Desorption isothermat 25°C
`
`--Drted (1 hour at 10°C)
`-a-First run
`Second run
`
`O
`
`O
`
`2O
`
`30
`
`60
`50
`40
`% Relative Humidity
`
`70
`
`80
`
`90
`
`100
`
`Merck Exhibit 2253, Page 17
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 16 of 18
`
`US 8,518,987 B2
`
`FIG. 21
`
`50
`
`4000
`
`3OOO
`
`2000
`Wavenumber (cm-1)
`
`1000
`
`FIG. 22
`
`20
`
`10
`
`3000
`
`2OOO
`Wavenumber (cm-1)
`
`1OOO
`
`Merck Exhibit 2253, Page 18
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 17 of 18
`
`US 8,518,987 B2
`
`FIG. 23
`
`156,96°C
`8827mg
`158.47°C
`
`150
`
`175
`
`200
`
`25
`
`50
`
`75
`
`125
`100
`Temperature (C)
`
`FIG. 24
`
`
`
`0.1969%
`(0.01445mg)
`
`0.086%
`(0.007938mg)
`
`25
`
`50
`
`75
`
`100
`Temperature (C)
`
`125
`
`150
`
`175
`
`Merck Exhibit 2253, Page 19
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`U.S. Patent
`
`Aug. 27, 2013
`
`Sheet 18 of 18
`
`US 8,518,987 B2
`
`FIG. 25
`Adsorption/Desorption isothermat 25°C
`
`--Dried (hour at 10°C)
`--First run
`Second run
`
`f
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`OO
`
`% Relative Humidity
`
`
`
`
`
`2
`O
`s 0.8
`g 0.6
`0.4
`
`O2
`
`O
`-02
`
`Adsorption/Desorption ISOthermat 25°C
`18O Fo -- Dried (hour at 10°C)
`
`200
`
`160
`140
`120
`-
`s 100
`& O.80
`O60
`O40
`O20
`
`-- First Un
`. . . . . . Second run
`|
`|
`l
`
`60
`50
`% Relative Humidity
`
`70
`
`80
`
`90
`
`100
`
`Merck Exhibit 2253, Page 20
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`1.
`PSEUDOPOLYMORPHC FORMS OF A HIV
`PROTEASE INHIBITOR
`
`US 8,518,987 B2
`
`2
`including GMP (Good Manufacturing Practices) and ICH
`(International 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 formulations 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
`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 of the drug Substance
`with an excipient and/or immediate container/closure system.
`Stability is also a parameter considered in creating phar
`maceutical formulations. A good Stability will ensure that the
`desired chemical integrity of drug Substances is maintained
`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
`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 sta
`bility and may determine shelf-life and storage conditions.
`Bioavailability is also a parameter to consider in drug
`delivery design of pharmaceutically acceptable formulations.
`Bioavailability is concerned with the quantity and rate at
`which the intact form of a particular drug appears in the
`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) of action of the drug.
`Physico-chemical factors and the pharmaco-technical for
`mulation can have repercussions in the bioavailability of the
`drug. As such, several properties of the drug such as disso
`ciation constant, dissolution rate, solubility, polymorphic
`form, particle size, are to be considered when improving the
`bioavailability.
`It is also relevant to establish that the selected pharmaceu
`tical formulation is 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
`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.
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional of pending U.S. application
`Ser. No. 10/514,352, filed Nov. 12, 2004, now U.S. Pat. No.
`7,700,645 which in turn is a national stage of PCT Applica
`tion No. PCT/EP2003/50176, filed May 16, 2003, which
`application claims priority from European Patent Application
`No. 02076929.5, filed May 16, 2002, the entire disclosures of
`which are hereby incorporated in their entirely.
`
`TECHNICAL FIELD
`
`10
`
`15
`
`This invention relates to novel pseudopolymorphic forms
`of (3R,3aS,6aR)-hexahydrofuro2,3-blfuran-3-yl (1S,2R)-3-
`(4-aminophenyl)sulfonyl(isobutyl)amino-1-benzyl-2-hy
`droxypropylcarbamate, 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 infectious virions. Accordingly,
`inhibitors of viral proteases may be used to prevent or treat
`chronic and acute viral infections. (3R.3aS,6aR)-hexahydro
`furo2.3-blfuran-3-yl (1S,2R)-3-(4-aminophenyl)sulfonyl
`(isobutyl)amino-1-benzyl-2-hydroxypropylcarbamate has
`HIV protease inhibitory activity and is particularly well
`suited for inhibiting HIV-1 and HIV-2 viruses.
`The structure of (3R.3aS,6aR)-hexahydrofuro2.3-bfu
`ran-3-yl
`(1S,2R)-3-(4-aminophenyl)sulfonyl(isobutyl)
`amino-1-benzyl-2-hydroxypropylcarbamate, is shown
`below:
`
`25
`
`30
`
`35
`
`40
`
`Formula (X)
`
`Ott,
`
`O
`
`(- O) 2
`
`O
`
`O
`
`N
`
`H
`
`OH
`
`CH
`
`N
`
`r
`CH
`S
`2 so
`3
`
`NH2
`
`45
`
`50
`
`55
`
`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-affinity P-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,
`
`SUMMARY OF THE INVENTION
`
`60
`
`65
`
`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 of a medicament for inhibiting HIV
`protease activity in mammals.
`
`Merck Exhibit 2253, Page 21
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`3
`In a first aspect, the present invention provides pseudopoly
`morphs of (3R.3aS,6aR)-hexahydrofuroI2,3-blfuran-3-yl
`(1S,2R)-3-(4-aminophenyl)sulfonyl(isobutyl)amino-1-
`benzyl-2-hydroxypropylcarbamate.
`Pseudopolymorphs provided include alcohol solvates,
`more in particular, C1-C4 alcohol solvates; hydrate solvates:
`alkane Solvates, more in particular, C1-C4 chloroalkane Sol
`Vates; ketone Solvates, more in particular, C1-C5 ketone sol
`vates: ether solvates, more in particular, C1-C4 ether solvates:
`cycloether solvates; ester solvates, more in particular, C1-C5
`ester Solvates; and Sulfonic Solvates, more in particular,
`C1-C4 sulfonic solvates, of the compound of formula (X).
`Preferred pseudopolymorphs are pharmaceutically accept
`able solvates, such as hydrate and ethanolate. Particular
`pseudopolymorphs are Form A (ethanolate), Form B (hy
`drate). Form C (methanolate), Form D (acetonate). Form E
`(dichloromethanate), Form F (ethylacetate solvate), Form G
`(1-methoxy-2-propanolate). Form H (anisolate). Form I (tet
`rahydrofuranate), Form J (isopropanolate) of compound of
`formula (X). Another particular pseudopolymorph 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 combining com
`pound of formula (X) with an organic solvent, water, or
`25
`mixtures of water and water miscible organic solvents, and
`applying any suitable technique 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 inhibiting HIV protease activity in
`mammals. In relation to the therapeutic field, a preferred
`embodiment of this invention relates to the use of pharma
`ceutically acceptable pseudopolymorphic forms of com
`pound of formula (X) for the treatmentofan HIV viral disease
`35
`in a mammal in need thereof, which method comprises
`administering to said mammal an effective amount of a phar
`maceutically acceptable pseudopolymorphic form of com
`pound of formula (X).
`The following drawings provide additional information on
`the characteristics of the pseudopolymorphs according to
`present invention.
`
`10
`
`15
`
`30
`
`40
`
`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 carbonyl
`stretching region of 1800-100 cm and the region3300-2000
`cm.
`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
`55
`carbonyl stretching region of 600-0 cm.
`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
`carbonyl stretching region of 1400-800 cm.
`In FIGS. 5, 6, 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 P81
`corresponds to Form). G.
`FIG. 8 is the Differential Scanning Calorimetric (DSC)
`thermograph of Form A (1:1).
`
`45
`
`50
`
`60
`
`65
`
`US 8,518,987 B2
`
`4
`FIG. 9 is the Infrared (IR) spectrum that reflects the vibra
`tional modes of the molecular structure of Form A as a crys
`talline 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: IR 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, curve A corresponds to Form A.
`curve B corresponds to Form B, and curve C corresponds to
`the amorphous form.
`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 Form A (curve
`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
`A
`FIG. 20: ADS/DES curves of Form B
`FIG. 21: IR spectrum of Form K
`FIG.22: Raman spectrum of Form K
`FIG. 23: DSC curve of Form 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
`
`The term “polymorphism' refers to the capacity of a
`chemical structure to occur in different forms and is knownto
`occur in many organic compounds including drugs. As such,
`"polymorphic forms' or “polymorphs' include drug sub
`stances that appearinamorphous form, in crystalline form, in
`anhydrous form, at various degrees of hydration or Solvation,
`with entrapped solvent molecules, as well as Substances vary
`ing in crystal hardness, shape and size. The different poly
`morphs vary in physical properties Such as solubility, disso
`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
`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 form” refers to a particular form
`essentially free of water. “Hydration” refers to the process of
`adding water molecules to a Substance that occurs in a par
`ticular form and “hydrates' are substances that are formed by
`adding water molecules. “Solvating refers to the process of
`incorporating molecules of a solvent into a Substance occur
`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
`
`Merck Exhibit 2253, Page 22
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`US 8,518,987 B2
`
`5
`morph” is applied to polymorphic crystalline forms that have
`solvent molecules incorporated in their lattice structures. The
`term pseudopolymorphism is used frequently to designate
`solvates (Byrn, Pfeiffer, Stowell, (1999) Solid-state Chemis
`try of Drugs, 2nd Ed., published by SSCI, Inc).
`The present invention provides pseudopolymorphs of (3R,
`3aS,6aR)-hexahydrofuro2,3-blfuran-3-yl (1S,2R)-3-(4-
`aminophenyl)sulfonyl(isobutyl)amino-1-benzyl-2-hydrox
`ypropylcarbamate.
`In one embodiment pseudopolymorphs are alcohol Sol
`Vates, more in particular, C-C alcohol Solvates; hydrate
`Solvates; alkane Solvates, more in particular, C-C chloroal
`kane Solvates; ketone Solvates, more in particular, C-Cs
`ketone solvates; ether solvates, more in particular C-C ether
`Solvates; cycloether Solvates; ester Solvates, more in particu
`lar C-C ester Solvates; or sulfonic solvates, more in particu
`lar, C-C Sulfonic Solvates, of the compound of formula (X).
`The term "C-C alcohol defines straight and/or branched
`chained Saturated and unsaturated hydrocarbons having from
`1 to 4 carbonatoms Substituted with at least a hydroxyl group,
`and optionally substituted with an alkyloxy group. Such as,
`for example, methanol, ethanol, isopropanol, butanol,
`1-methoxy-2-propanol and the like. The term "C-C chloro
`alkane' defines straight and/or branched chained Saturated
`and unsaturated hydrocarbons having from 1 to 4 carbon
`atoms Substituted with at least one chloro atom, Such as, for
`example, dichloromethane. The term "C-C ketone' defines
`solvents of the general formula R' 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 "C-C ether defines
`solvents of the general formula R' O—R wherein Rand 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
`and the like. The term "C-C ester defines solvents of the
`general formula R O C(=O)—R wherein R and R' can
`be the same or different and are methyl or ethyl, such as
`ethylacetate and the like. The term "C-C sulfonic solvent
`defines solvents of the general formula R SOH wherein R
`40
`can be a straight or branched chained saturated hydrocarbon
`having from 1 to 4 carbon atoms, such as mesylate, ethane
`Sulfonate, butanesulfonate, 2-methyl-1-propanesulfonate,
`and the like.
`Pseudopolymorphs of the present invention, which are
`pharmaceutically acceptable, for instance hydrates, alcohol
`Solvates, such as, ethanolate, are preferred forms.
`Several pseudopolymorphs are exemplified in this applica
`tion and include Form A (ethanolate), Form B (hydrate),
`Form C (methanolate). Form D (acetonate), Form E (dichlo
`50
`romethanate), Form F (ethylacetate solvate), Form G
`(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
`on the 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
`vates 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
`65
`pound of formula (X), more in particular, the ratio may range
`from about 1 to about 2 molecules of solvent per 1 molecule
`
`30
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`60
`
`6
`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 occurat different levels of hydration. As
`Such, Solvate crystal forms of compound of formula (X) may
`in addition comprise under certain circumstances, water mol
`ecules partially or fully 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 solvation wi