(11)
`
`EP 1 567 529 B1
`
`(12)
`
`EUROPEAN PATENT SPECIFICATION
`
`(45) Date of publication and mention
`of the grant of the patent:
`18.06.2014 Bulletin 2014/25
`
`(21) Application number: 03753571.3
`
`(22) Date of filing: 16.05.2003
`
`(51) Int CI.:
`C07D 493104 (2oo6.o~)
`
`C07D 3071061~oo~.0~)
`
`(86) International application number:
`PCTIEP2003!050176
`
`(87) International publication number:
`WO 2003/106461 (24.12.2003 Gazette 2003/52)
`
`(54) PSEUDOPOLYMORPHIC FORMS OF A HIV PROTEASE INHIBITOR
`
`PSEUDOPOLYMORPHE FORMEN EINES HIV PROTEASE INHIBITORS
`
`FORMES PSEUDOPOLYMORPHIQUES DE L’INHIBITEUR DE LA PROTEASE DU VIH
`
`(84)
`
`(3O)
`
`(43)
`
`Designated Contracting States:
`AT BE BG CH CY CZ DE DK EE ES FI FRGB GR
`HU IE IT LI LU MC NL PT RO SE SI SK TR
`Designated Extension States:
`AL LT LV MK
`
`Priority: 16.05.2002 EP 02076929
`
`Date of publication of application:
`31.08.2005 Bulletin 2005/35
`
`(60) Divisional application:
`10180831.9 ! 2 314 591
`
`(73) Proprietor: Janssen R&D Ireland
`Eastgate, Little Island, County Cork (IE)
`
`(72) Inventors:
`¯ VERMEERSCH, Hans, Wim, Pieter
`B-9000 Gent (BE)
`¯ THONI~, Daniel, Joseph, Christiaan
`B-2340 Beerse (BE)
`¯ JANSSENS, Luc, Donn~, Marie-Louise
`B-2390 Malle (BE)
`¯ Wigerinck, Piet Bert Paul
`Terhagen B-2840 (BE)
`
`(74) Representative: Jansen, Cornelis Marinus et al
`V.O.
`Johan de Wittlaan 7
`2517 JR Den Haag (NL)
`
`(56) References cited:
`WO-A-95/06030 WO-A-99/67417
`
`¯ GRUNENBERG A ET AL: "THEORETICAL
`DERIVATION AN D PRACTICALAPPLICATION OF
`ENERGY/TEMPERATURE DIAGRAMS AS AN
`INSTRUMENT IN PREFORMULATION STUDIES
`OF POLYMORPHIC DRUG SUBSTANCES"
`INTERNATIONAL JOURNAL OF
`PHARMACEUTICS, AMSTERDAM, NL, vol. 129,
`1996, pages 147-158, XP000909867 ISSN:
`0378-5173
`¯ GIRON ETAL: "Thermalanalysisand calorimetric
`methods in the characterisation of polymorphs
`and solvates" THERMOCHIMICA ACTA,
`ELSEVIER SCIENCE PUBLISHERS,
`AMSTERDAM, NL, vol. 248, 1995, pages 1-59,
`XP002101808 ISSN: 0040-6031
`¯ BORKA L ET AL: "Crystal polymorphism of
`pharmaceuticals" ACTA PHARMACEUTICA
`JUGOSLAVICA, SAVEZ FARMACEUTSKIH
`DRUSTAVAJ UGOSLAVIJE,ZAGREB,YU,voI.40,
`1990, pages 71-94,XP002195530 ISSN: 0001-6667
`¯ GHOSH A K ET AL: "Potent HIV protease
`inhibitors incorporating high-affinity P2-1igands
`and (R)-(hydroxyethylamino)sulfonamide
`isostere" BIOORGANIC & MEDICINAL
`CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no.
`6, 17 March 1998 (1998-03-17), pages 687-690,
`XP004136945 ISSN: 0960-894X cited in the
`application
`
`Remarks:
`The file contains technical information submitted after
`the application was filed and not included in this
`specification
`
`Note: Within nine months of Lhe publication of the mention of the grant of the European patent in the European Patent
`Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
`Im plementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
`paid. (Art. 99(1) European Patent Convention).
`
`Printed by Jouve, 75001 PARIS (FR)
`
`Lupin Ex. 1018 (Page 1 of 47)
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`EP 1 567 529 B1
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`Description
`
`Technical Field
`
`[0001] This invention relates to novel pseudopolymorphic forms of (3R,3aS,6aR)-hexahydro-furo [2,3-b] furan-3-yl
`(1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2-hydroxypropylcarbamate, a method for their prepa-
`ration as well as their use as a medicament.
`
`Background of the invention
`
`[0002] Virus-encoded proteases, which are essential for viral replication, are required for the processing of viral protein
`precursors. Interference with the processing of protein precursors inhibits the formation of infectious virions. Accordingly,
`inhibitors of viral proteases may be used to prevent or treat chronic and acute viral infections.
`[0003] We-A-99/67417 discloses an assay for measuring anti-HIV activity of compounds. We-A-95/06030 discloses
`hydroxyethylamino sulfonamides as retroviral protease inhibitors.
`Bioorg.Med.Chem.Lett. 8,687 (1998) compares a HIV protease inhibitor to its 4-methoxy derivative.
`[0004] (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-ben-
`zyl-2-hydroxypropylcarbamate has HIV protease inhibitory activity and is particularlywell suited for inhibiting HIV-1 and
`HIV-2 viruses.
`[0005] The structure of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-amino-phenyl) sulfonyl] (isobutyl)
`amino]-l-benzyl-2-hydroxypropylcarbamate, is shown below:
`
`OH ;~0 CH3
`
`NH2
`
`Formula (X)
`
`[0006] Compound of formula (X) and processes for its preparation are disclosed in EP 715618, we 99/67417, US
`6,248,775, and in Bioorganic and Chemistry Letters, Vol. 8, pp. 687-690, 1998, "Potent HIV protease inhibitors incor-
`porating high-affinity P2-igands and (R)-(hydroxyethylamino)sulfonamide isostere".
`[0007] Drugs utilized in the preparation of pharmaceutical formulationsforcommercial use must meet certain standards,
`including GMP (Good Manufacturing Practices) and ICH (International Conference on Harmonization) guidelines. Such
`standards include technical requirements that encompass a heterogeneous and wide range of physical, chemical and
`pharmaceutical parameters. It is this variety of parameters to consider, which make pharmaceutical formulations a
`complex technical discipline.
`[0008] For instance, and as example, a drug utilized for the preparation of pharmaceutical formulations should meet
`an acceptable 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,
`purification, 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 contain-
`er/closure system.
`[0009] Stability is also a parameter considered in creating pharmaceutical 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.
`
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`EP 1 567 529 B1
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`[0010] Different factors, such as light radiation, temperature, oxygen, humidity, pH sensitivity in solutions, may influence
`stability and may determine shelf-life and storage conditions.
`[0011] Bioavailability is also a parameter to consider in drug delivery design of pharmaceutically acceptable form ula-
`tions. 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 concentration is achieved at the site(s) of action of the drug.
`[0012] Physico-chemical factors and the pharmaco-technical formulation can have repercussions in the bioavailability
`of the drug. As such, several properties of the drug such as dissociation constant, dissolution rate, solubility, polymorphic
`form, particle size, are to be considered when improving the bioavailability.
`[0013] Acta Pharm. Jogosl. 40, 71 (1990) compiles a listing of the various pharmaceutical substances which have
`been reported having crystal polymorphism.
`[0014] Int.J.Pharm. 129, 147 (1996) discusses the construction and interpretation of energy/temperature diagrams for
`the drugs nimodipine and acemetacin to show the practical application of energy/temperature diagrams as an instrument
`in a preformulation studies of polymorphic drug substances. Thermodhim. Acta 248, 1 (1995) teaches that thermal
`analysis and calorimetric methods are useful for the characterization of polymorphs and solvates.
`[0015] It is also relevant to establish that the selected pharmaceutical formulation is capable of manufacture, more
`suitably, of large-scale manufacture.
`[0016] 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 modifi-
`cations of the solid state of compound of formula (X) positively influenced its applicability in pharmaceutical formulations.
`
`Summary of the invention
`
`[0017] Present invention concerns pseudopolymorphic forms of compound of formula (X) for the preparation of phar-
`maceutical formulations. Such pseudopolymorphic forms contribute to pharmaceutical formulations in improved stability
`and bioavailability. They can be manufactured in sufficient high purity to be acceptable for pharmaceutical use, more
`particularly in the manufacture of a medicament for inhibiting HIV protease activity in mammals.
`[0018] In a first aspect, the present invention provides pseudopolymorphs of (3R,3aS,6aR)-hexahydrofuro [2,3-b]
`furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2-hydroxypropylcarbamate.
`Preferred pseudopolymorphs are pharmaceutically acceptable solvates, such as hydrate and ethanolate.
`Particular pseudopolymorphs are Form A (ethanolate) and Form B (hydrate) of compound of formula (X).
`[0019] In a second aspect, present invention relates to processesfor preparing pseudopolymorphs. Pseudopolymorphs
`of compound of formula (X) are prepared by combining compound of formula (X) with an organic solvent, water, or
`mixtures of water and water miscible organic solvents, and applying any suitable technique to induce crystallization, to
`obtain the desired pseudopolymorphs.
`[0020] In a third aspect, the invention relates to the use of the present pseudopolymorphs, in the manufacture of
`pharmaceutical formulations for inhibiting HIV protease activity in mammals. In relation to the thera peutic field, a preferred
`embodiment of this invention relates to the use of pharmaceutically acceptable pseudopolymorphic forms of compound
`of formula (X) for the treatment ofan HIVviraldisease in a mammal in need thereof, which method comprises administering
`to said mammal an effective amount of a pharmaceutically acceptable pseudopolymorphic form of compound of formula
`(X).
`[0021] The following drawings provide additional information on the characteristics of the pseudopolymorphs according
`to present invention.
`
`5
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`Brief Description of the Drawings
`
`[0022]
`
`50
`
`55
`
`FIGURE 1, FIGURE 2 and FIGURE 3 are the powder X-ray diffraction patterns of the Form A (1:1).
`FIGURE 4 depicts Form A (1:1) in three dimensions with the atoms identified.
`FIGURE 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-1 and the region 3300-2000 cm-1.
`FIGURE 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.
`FIGURE 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-1.
`In Figures 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, P66 corresponds to
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`Lupin Ex. 1018 (Page 3 of 47)
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`EP 1 567 529 B1
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`Form H, P69 corresponds to Form C, P72 corresponds to Form I, and P81 corresponds to Form G.
`FIGURE 8 is the Differential Scanning Calorimetric (DSC) thermograph of Form A (1:1).
`FIGURE 9 is the Infrared (IR) spectrum that reflects the vibrational modes of the molecular structure of Form A as
`a crystalline product
`FIGURE 10 is the IR spectrum that reflects the vibrational modes of the molecular structure of Form B as a crystalline
`product
`FIGURE 11: IR spectrum of forms A, B, and amorphous form, at spectral range 4000 to 400 cm-1.
`FIGURE 12: IR spectrum of forms A, B, and amorphous form, at spectral range 3750 to 2650 cm-1
`FIGURE 13: IR spectrum of forms A, B, and amorphous form, at spectral range 1760 to 1580 cm-1
`FIGURE 14: IR spectrum of forms A, B, and amorphous form, at spectral range 980 to 720 cmq
`In fig ures 11, 12, 13 and 14, curve A corresponds to Form A, curve B corresponds to Form B, and cu rve C corres ponds
`to the amorphous form.
`FIGURE "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)
`FIGURE 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)
`FIGURE 17: TG curve of Form A at 25°C under dry nitrogen atmosphere in function of time
`FIGURE 18: ADS/DES curves of Form A.
`FIGURE 19: ADS/DES curves of the hydratation test of Form A
`FIGURE 20: ADS/DES curves of Form B
`FIGURE 21: IR spectrum of Form K
`FIGURE 22: Raman spectrum of Form K
`FIGURE 23: DSC curve of Form K
`FIGURE 24: TG curve of Form K
`FIGURE 25: ADS/DES isotherm of Form K, batch 1
`FIGURE 26: ADS/DES isotherm of Form K, batch 2
`
`"/0
`
`"/5
`
`20
`
`25
`
`Detailed description
`
`30
`
`35
`
`[0023] 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-
`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 varying in crystal hardness, shape and size. The different
`polymorphs vary in physical properties such as solubility, dissolution, solid-state stability as well as processing behaviour
`in terms of powder flow and compaction during tabletting.
`[0024] 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
`arrangement of the molecules on a lattice structure.
`[0025] 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.
`[0026] 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 particular 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
`occurring 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 solvent, solvates also include hydrates. The term "pseudopol-
`ymorph" is applied to polymorphic crystalline forms that have solvent molecules incorporated in their lattice structures.
`The term pseudopolymorphism is used frequently to desig nate solvates (Byrn, Pfeiffer, Stowell, (1999) Solid-state Chem-
`istry of Drugs, 2nd Ed., published by SSCI, Inc).
`[0027] The present invention provides pseudopolymorphs of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-
`5o 3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2-hydroxypropylcarbamate.
`[0028] Examples of pseudopolymorphs are alcohol solvates, more in particular, C1-C4 alcohol solvates; hydrate sol-
`vates; alkane solvates, more in particular, C1-C4 chloroalkane solvates; ketone solvates, more in particular, C~-C5 ketone
`solvates; ether solvates, more in particular C~-C4 ether solvates; cycloether solvates; ester solvates, more in particular
`C~-C5 ester solvates; or sulfonic solvates, more in particular, Cl-C4 sulfonic solvates, of the compound of formula (X).
`The term "Cl-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, and optionally substituted with an alkyloxy group,
`such as, for example, methanol, ethanol, isopropanol, butanol, 1-methoxy-2-propanol and the like. The term "Cl-C4
`chloroalkane" defines straight and/or branched chained saturated and unsaturated hydrocarbons having from 1 to 4
`
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`EP 1 567 529 B1
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`carbon atoms substituted with at least one chloro atom, such as, for example, dichloromethane. The term "Cl-C5 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 "Cl-C4 ether" defines solvents of the general formula R’-O-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 containing one or two oxygen ring atoms, such as
`tetrahydrofuran and the like. The term "Cl-C5 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 "Cl-C4 sulfonic
`solvent" defines solvents of the general formula R-SO3H wherein R can be a straight or branched chained saturated
`hydrocarbon having from 1 to 4 carbon atoms, such as mesylate, ethanesulfonate, butanesulfonate, 2-methyl-l-pro-
`panesulfonate, and the like.
`[6029] Pseudopolymorphs of the present invention, which are pharmaceutically acceptable, for instance hydrates,
`alcohol solvates, such as, ethanolate, are preferred forms.
`[0030] Several pseudopolymorphs are exemplified in this application and include 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 (tetrahydrofuranate), Form J (isopropanolate), or Form K
`(mesylate) of compound of formula (X).
`[0031] 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 solvates crystals, and mixtures thereof. Conven-
`iently, 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 compound of formula (X), more in particular, the
`ratio may range from about 1 to about 2 molecules of solvent per 1 molecule of compound of formula (X), preferably the
`ratio is 1 molecule of solvent per 1 molecule of compound of formula (X).
`[0032] Solvates may also occur at different levels of hydration. As such, solvate crystal forms of compound of formula
`(X) may in addition comprise under certain circumstances, water molecules partially or fully in the crystal structures.
`Consequently, 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 molecules, 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 will
`follow the "Form A", for instance, one molecule of ethanol per one molecule of compound (X) is denoted as Form A (1:1).
`[0033] The X-ray powder diffraction is a technique to characterise polymorphic forms including pseudopolymorphs of
`compound of formula (X) and to differentiate solvate crystal forms from other crystal and non-crystal forms of compound
`of formula (X). 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, were packed 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 Krz 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 FIG. 1,2and 3at: 7,04° + 0,5°, 9,24° + 0,5°, 9,96° + 0,5°, 10,66° + 0,5°, 11,30° + 0,5°, 12,82° +
`0,5°, 13,80° + 0,5°, 14,560 + 0,5°, 16,66° + 0,5°, 17,30° + 0,5°, 18,28° + 0,5°, 19,100 + 0,5°, 20,000 + 0,5°, 20,50°
`+ 0,5°, 21,22° + 0,5°, 22,68° + 0,5°, 23,08° + 0,5°, 23,66° + 0,5°, 25,08° + 0,5°, 25,58° + 0,5°, 26,28° + 0,5°, 27,18°
`+ 0,5°, 28,22° + 0,5°, 30,20° + 0,5°, 31,34° + 0,5°, 32,68° + 0,5°, 33,82° + 0,5°, 39,18° + 0,5°, 41,20° + 0,5°, 42,06°0
`0,5°, and 48,74° + 0,5°.
`[0034] In another set of analytical experiments, X-ray single diffraction was applied to Form A (1:1), which resulted in
`the following crystal configuration, listed in the table below.
`
`Crystal Data
`
`Crystal shape
`
`Table 1
`
`Prism
`
`Crystal dimensions
`
`0.56 x 0.38 x 0.24 mm
`
`Crystal color
`
`Space Group
`
`Temperature
`
`Cell constants
`
`Colorless
`
`P 212121 orthorhombic
`
`293K
`
`a = 9.9882(6) ,&,
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`(continued)
`
`Crystal Data
`
`b = 16.1697(8)
`
`c = 19.0284(9)
`
`alpha (o0 = 90°
`
`beta (~) = 90°
`
`gamma (3,) = 90°
`
`3158.7(3)
`
`4
`
`1.248
`
`Volume
`
`Molecules/unit cell (Z)
`
`Density, in Mg/m3
`
`#, (linear absorption coefficient)
`
`1.340 mm-1
`
`F(000)
`
`1272
`
`Intensity Measurements
`
`Diffractometer
`
`Radiation
`
`Temperature
`
`20max
`
`Correction
`
`Siemens P4
`
`Cu Kc~ (X= 1.54184 ~,)
`
`ambient
`
`138.140
`
`Empirical via 1~’-scans
`
`Number of Reflections Measured Total: 3912
`
`Structure Solution and Refinement
`
`Number of Observations
`
`3467 [F2>2 o-(F2)]
`
`Residual (R)
`
`0.0446
`
`[0035] The resulting three-dimensional structure of Form A (1:1) is depicted in Figure 4.
`
`Table 2 shows the atomic coordinates (x 104) and equivalent isotropic displacement parameters (,~2 x 103) for Form
`A (1:1). Atoms are numbered as exhibited in Figure 4. The x, y and z fractional coordinates indicate the position of
`atoms relative to the origin of the unit cell. U(eq) is defined as one third of the trace of the orthogonalized Uii tensor.
`
`O1
`C2
`
`C3
`C3A
`C4
`C5
`O6
`C6A
`
`O7
`O8
`C9
`N10
`Cll
`C12
`
`C13
`
`x
`
`7778(3)
`7171(4)
`
`6831(3)
`7953(3)
`7527(4)
`7425(5)
`8501(3)
`8582(4)
`
`5533(2)
`5168(2)
`4791(3)
`3590(2)
`2638(3)
`2223(3)
`
`3381(3)
`
`y
`
`2944(2)
`3513(2)
`
`3046(2)
`2411 (2)
`1533(2)
`1241(2)
`1642(2)
`2416(2)
`
`2702(1)
`2636(1)
`2534(1 )
`2256(1)
`1916(2)
`1071(2)
`
`501(2)
`
`z
`
`9946(1 )
`9487(2)
`
`8823(2)
`8793(2)
`8708(2)
`9457(2)
`9809(1)
`9534(2)
`
`8945(1 )
`7768(1)
`8368(1)
`8562(1)
`8068(2)
`8310(2)
`
`8387(2)
`
`U(eq)
`
`70(1)
`64(1)
`
`52(1)
`55(1)
`65(1)
`70(1)
`76(1)
`62(1)
`
`51(1)
`53(1)
`42(1)
`43(1)
`44(1 )
`58(1)
`
`56(1)
`
`Lupin Ex. 1018 (Page 6 of 47)
`
`

`

`EP 1 567 529 B1
`
`(continued)
`
`C14
`
`C15
`
`C16
`
`C17
`C18
`C19
`O2O
`C21
`N22
`C23
`C24
`C25
`C26
`S27
`028
`
`029
`C30
`C31
`C32
`C33
`
`C34
`C35
`N36
`C37
`C38
`039
`
`X
`
`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)
`51o(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)
`
`Y
`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)
`
`Z
`
`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 )
`85O9(2)
`8159(2)
`8195(2)
`8564(2)
`
`8909(2)
`8883(2)
`8596(2)
`5258(4)
`5564(4)
`6249(2)
`
`U(eq)
`
`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 (,&2 x 103) for Form A (1:1). The anisotropic displacement
`factor exponent takes the formula: -2~2[h2a*2U11 + -.- + 2 h k a* b’U12]
`
`O1
`C2
`C3
`C3A
`C4
`C5
`
`O6
`C6A
`O7
`O8
`C9
`N10
`Cll
`C12
`C13
`C14
`C15
`C16
`
`Ull
`
`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)
`
`U22
`
`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)
`
`U33
`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)
`
`U23
`-4(1)
`-7(2)
`4(1)
`9(1)
`-4(2)
`
`8(2)
`
`16(1)
`5(2)
`0(1)
`3(1)
`1(1)
`-1(1)
`-4(1)
`2(1)
`0(1)
`0(2)
`18(2)
`26(3)
`
`U!3
`
`-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)
`34(3)
`
`U! 2
`
`-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)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`50
`
`55
`
`Lupin Ex. 1018 (Page 7 of 47)
`
`

`

`EP 1 567 529 B1
`
`(continued)
`
`U11
`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)
`50(2)
`59(2)
`57(2)
`56(2)
`
`63(2)
`67(2)
`290(10)
`280(10)
`99(2)
`
`U22
`
`72(2)
`
`60(2)
`44(1)
`56(1)
`42(1)
`47(1)
`50(1)
`
`59(2)
`83(2)
`99(3)
`47(1)
`58(1)
`58(1)
`
`46(1)
`48(1)
`45(1)
`55(2)
`63(2)
`
`52(1)
`70(2)
`260(10)
`187(7)
`91(2)
`
`U33
`I0g(3)
`
`85(2)
`61(1)
`83(1)
`64(2)
`57(1)
`64(2)
`
`62(2)
`101(3)
`65(2)
`61(1)
`61(1)
`92(2)
`
`54(1)
`64(2)
`65(2)
`52(1)
`59(2)
`
`53(1)
`80(2)
`145(7)
`104(4)
`93(2)
`
`023
`
`-6(2)
`-4(2)
`-3(1)
`-6(1)
`2(1)
`1(1)
`7(1)
`
`1(1)
`6(2)
`14(2)
`2(1)
`9(1)
`-4(1)
`
`2(1)
`6(1)
`4(1)
`-4(1)
`6(1)
`
`5(1)
`4(2)
`68(7)
`1(5)
`1(2)
`
`U13
`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)
`-4(2)
`2(2)
`1(1)
`-13(2)
`
`-8(2)
`-5(2)
`67(8)
`-53(6)
`-13(2)
`
`U12
`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(1)
`
`1(1)
`6(1)
`1(1)
`-3(1)
`-3(2)
`
`-2(2)
`-19(2)
`120(10)
`-80(10)
`-28(2)
`
`C17
`
`C18
`C19
`O2O
`C21
`N22
`C23
`
`C24
`C25
`C26
`$27
`028
`O29
`
`C30
`C31
`C32
`C33
`C34
`
`C35
`N36
`C37
`C38
`039
`
`10
`
`15
`
`20
`
`25
`
`30
`
`[0036] Raman spectroscopy has been widely used to elucidate molecular structures, crystallinity and polymorphism.
`The low-frequency Raman modes are particularly useful in distinguishing different molecular packings in crystal. As
`such, Raman spectra were recorded on a Bruker FT-Raman RFS100 spectrometer equipped with a photomultiplier tube
`and optical multichannel detectors. Samples placed in quartz capillary tubes were excited by an argon ion laser. The
`
`35 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 A, B, D, E, F, and H, (1:1) and the amorphous form have the Raman spectra which appear in Figures 5, 6, and 7.
`[0037] In addition, Forms A and B were characterized using a FATR (Micro-Attenuated Total Reflectance) accessory
`(Harrick Split-Pea with Si crystal). The infrared spectra were obtained with a Nicolet Magna 560 FTIR spectrophotometer,
`a Ge on KBr beamsplitter, and a DTGS with KBr windows detector. Spectra were measured at 1 cm-1 resolution and 32
`scans each, in a wavelength range of from 4000 to 400 cm-1, and application of baseline correction. The wavenumbers
`for Form A obtained are exhibited in the following Table 4.
`
`4o
`
`Table 4
`
`Wavenumbers(cm-1)and relativeintensities ofabsorption bands(1)
`
`3454w, 3429w, 3354w, 3301w, 3255w, 3089w, 3060w, 3041w, 3028w
`
`2964w, 2905w, 2875w, 2856w, 2722vw, 2684vw, 2644vw, 2603vw, 2234vw
`
`1704s, 1646w, 1595s, 1550m, 1503m, 1466w, 1453w, 1444w, 1413w
`
`1373w, 1367w, 1340w, 1324m, 1314m, 1306m, 1290w, 1266m, 1244m, 1229m
`
`1187w, 1146s, 1124m, 1104m, 1090m, 1076m, 1052m, 1042s, 1038m, 1024s
`
`987s, 971m, 944m, 909w, 890w, 876w, 841m,792w, 768s, 742s, 732w, 697m, 674s, 645w, 630m
`
`598w~593w~574m~564s~553vs~538m~533m~531m~526m~5~8m~5~1m~491m~471m~458w~445w~442w~436w~
`428w, 418w
`
`vs = very strong, s = strong, m = medium, w =weak, vw = very weak, br= broad
`
`45
`
`50
`
`55
`
`Lupin Ex. 1018 (Page 8 of 47)
`
`

`

`[0038] The IR spectrum in Figure 9 reflects the vibrational modes of the molecular structure as a crystalline product.
`[0039] The wavenumbers obtained for Form B are exhibited in the following Table 5.
`
`EP 1 567 529 B1
`
`Table 5
`
`Wavenumbers (cm-1) and relative intensities of absorption bands (1)
`
`3614w, 3361 m, 3291 m, 3088w, 3061w, 3043w, 3028w
`
`2967w, 2905w, 2872w, 2222vw
`
`1703s, 1631w, 1595s, 1553m, 1502w, 1467w, 1453w, 1444w, 1436w
`
`1388vw, 1374vw, 1366w, 1355vw, 1340w, 1308m, 1291w, 1267m, 1245m
`
`1187w, 1148s, 1125m, 1105m, 1091m, 1077m, 1052m, 1044m, 1025s
`
`990m, 972w, 944m, 912w, 891w, 876vw, 862w, 843w, 836w, 792w, 769m, 757w, 743m, 717w, 699m, 672m
`
`598w, 591w, 585w, 576m, 566m, 553vs, 536m, 509w, 502m, 484w, 471w, 432vw, 425w, 418w
`
`(1) vs = very strong, s = strong, m = medium, w = weak, vw = very weak, br = broad
`
`[0040] The IR spectrum in Figure 10 reflects the vibrational modes of the molecular structure of Form B as a crystalline
`product.
`[0041] Following the same analytical IR method, Form B and the amorphous form were characterised and compared
`with Form A, as shown in Figures 11 to 14. IR spectra of the different physical forms showed distinct spectral differences,
`most relevant are those in Table 6:
`
`Wavenumbers(cm-1) and relativeintensities ofabsorption bands(1)
`
`Table 6
`
`Form A
`
`Form B
`
`Amorphousform
`
`3454m,3429m, 3353m,
`3255m,3089w,3060m, 3041w, 3028w
`
`3615m,3356m, 3291m,
`3089m,3061m, 3043w,
`3027w
`
`3462m, 3362m, 3249m,3062m,
`3026m
`
`2963m,2905m, 2869m, 2856m
`
`2966m,2905m, 2873m
`
`2959m,2871m
`
`1704s, 1646m, 1596s, 1549s, 1503s
`
`1703s, 1630m, 1595s, 1552s,
`1502m
`
`1704s, 1628s, 1596s, 1525s,
`1502s
`
`1306s, 1266s, 1244s
`
`1308s, 1267s, 1245s
`
`1312s, 1259s
`
`1146s, 1104s, 1090s, 1076s, 1052s, 1042s,
`1038s, 1023s
`
`1148s, 1105s, 1090s, 1077s,
`1052s, 1044s, 1024s
`
`1143s, 1090s, 1014s
`
`987s, 971s, 954s, 945s, 912m, 909m, 891s,
`876s, 841s, 827s
`
`960s, 953s, 950s, 944s, 937s,
`989s, 972s, 944s, 925m,
`915m, 912s, 891s, 862s, 843s 922s, 832s
`
`792m, 768s, 742s, 697s, 674s
`
`792s, 769s, 744s, 699s, 672s 750br, 792s, 672s
`
`(1)s = strong, m = medium, w =weak, vw= ve~ weak, br= broad
`
`[0042] The physical Forms A, B, and amorphous form are identified through spectral interpretation, focused on ab-
`sorption bands specific for each form. Unique and specific spectral differences between forms are noticed in 3 spectral
`ranges: from 3750 to 2650 cm-1 (range 1), from 1760 to 1580 cm-1 (range 2) and from 980 to 720 cm-1 (range 3).
`
`Range 1 (from 3750 to 2650 cm-1)
`
`[0043] Figure 11: Form A shows a double band with absorption maxima at 3454 cm-~ and 3429 cm-1. Form B shows
`a single absorption band at 3615 cm-1 and amorphous form shows a single absorption band at 3362 cm-1.
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`4O
`
`45
`
`5O
`
`55
`
`Lupin Ex. 1018 (Page 9 of 47)
`
`

`

`Range 2 (from 1760 to 1580 cm-~)
`
`EP 1 567 529 B1
`
`[0044] Figure 12: Form A shows a single absorption band at 1646 cm-1, Form B shows a single absorption band at
`1630 cm-1 and amorphous form shows a single absorption band at 1628 cmq with a clearly higher intensity compared
`to the Form B band. Additionally, amorphous form shows a less intense, broad band at 1704 cm 1 compared to both
`forms A and B bands at about 1704 cm-1.
`
`Range 3(fr