USOO926.0393B2
(12) United States Patent (10) Patent No.: US 9.260,393 B2 Becker et al. (45) Date of Patent: Feb. 16, 2016
(54) SOLID STATE FORMS OF (58) Field of Classification Search N-((S)-2,3-DIHYDROXY-PROPYL)- None 3-(2-FLUORO-4-IODO-PHENYLAMINO)- See application file for complete search history. SONICOTNAMIDE (56) References Cited (71) Applicant: Merck Patent GmbH, Darmstadt (DE) U.S. PATENT DOCUMENTS (72) Inventors: Axel Becker, Darmstadt (DE); Christoph Saal, Otzberg (DE); Clemens 7.956,191 B2 6, 2011 Abel et al. 8, 198457 B2 6, 2012 Abel et al. Kuehn, Darmstadt (DE); Donald 8,524,911 B2 9/2013 Abel et al. Bankston, Dracut, MA (US); Marco 8,841,459 B2 9/2014 Abel et al. Poma, Rome (IT) 2009/0093462 A1 4/2009 Abel et al. 2011/0224.192 A1 9, 2011 Abel et al. (73) Assignee: Merck Patent GmbH, Darmstadt (DE) 2012fO295889 A1 11, 2012 Abel et al. 2014/0051686 A1 2/2014 Abel et al. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. WO 2006O45514 A1 5, 2006 (21) Appl. No.: 14/404,060 OTHER PUBLICATIONS (22) PCT Fled: May 7, 2013 Morissette et al. Advanced Drug Delivery Reviews, 56 (2004), pp. 275-3OO.* (86) PCT NO.: PCT/EP2013/001352 International Search Report from PCT Application No. PCT/ EP2013/001352 dated Aug. 29, 2013. S371 (c)(1), Kihyun Kimetal. “Blockade of the MEK/ERK signalling cascade by (2) Date: Nov. 26, 2014 AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic PCT Pub. No.: WO2O13/17832O anti-myeloma activity in vitro and in vivo”. British Journal of (87) Haematology, 2010), vol. 149, pp. 537-549. PCT Pub. Date: Dec. 5, 2013 * cited by examiner (65) Prior Publication Data US 2015/O152059 A1 Jun. 4, 2015 Primary Examiner — Zinna Northington Davis (74) Attorney, Agent, or Firm — Millen, White, Zelano and Related U.S. Application Data Branigan, P.C. (60) Provisional application No. 61/653,037, filed on May 30, 2012. (57) ABSTRACT The invention relates to solid state forms of N—((S)-2,3- (51) Int. C. Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isoni CO7D 23/8. (2006.01) cotinamide, processes for their preparation, and medical uses A6 IK3I/44 (2006.01) thereof. (52) U.S. C. CPC ...... C07D 213/81 (2013.01) 16 Claims, 21 Drawing Sheets U.S. Patent Feb. 16, 2016 Sheet 1 of 21 US 9.260,393 B2
F.G.
g Powder X-ray diffractogram of Form A1 (Cu-Ko, radiation, = 1.5406 A, Stoe Stadip 611 KL diffractometer) F.G. 2
Single crystal structure of Form Al viewed alonga-axis (XCalibur diffractometer from Oxford Diffraction equiped with graphite monochromator and CCD Detector using Mo K, radiation at 301 K U.S. Patent Feb. 16, 2016 Sheet 2 of 21 US 9.260,393 B2
FIG. 3 H-- 68 OO
s 4 O
20
: 0 : 4000 3500 3000 2500 2000 1500 OOO 500 Wavenumber (cm) FTIR spectrum of Form At
FG. 4
i - 0.9
- 0.8
- 0.7
- 0.6
- 0,5
- 0.4 - 0.3
- 0.2
- 0,1
3500 3000 2500 2000 500 OOO 500 Wavenumber (cm) FT Raman spectrum of Form At U.S. Patent Feb. 16, 2016 Sheet 3 of 21 US 9.260,393 B2
-4
-10 . . . . . 25 50 75 00 25 150 175 200 225 250 275 300 Temperature C DSC SCan Of Form A
FIG. 6 100 90 80 i 70 60 50 i------25 50 75 100 25 50 175 200 225 250 275 300 Temperature C
TGA Scan of Form. A U.S. Patent Feb. 16, 2016 Sheet 4 of 21 US 9.260,393 B2
FG. 7 0,5 s - - - Cycle 1 Sorp -Cycle Desorp -- Cycle 2 Sorp. OO 3,4
0, 2
O ,
Relative humidity (%) Water Vapour Sorption isotherm (25 °C) of Form A1
F.G. 8
Powder X-ray diffractogram of Form A2 (Cu-Ko, radiation, = 1.5406 A, Stoe StadiP 611 KL diffractometer) U.S. Patent Feb. 16, 2016 Sheet 5 of 21 US 9.260,393 B2
F.G. 9
Crystal structure of Form A2 (calculated from Powder data) viewed along c-axis
FG. O.
- 80
- 60
- 40
- 20
4000 3500 3OOO 2500 2000 500 OOO 500 Wavenumber (cm) FTIR spectrum of Form A2 U.S. Patent Feb. 16, 2016 Sheet 6 of 21 US 9.260,393 B2
F.G. 1
- 0.4
- 0,3
- 0.2
- 0,1
I 3500 3000 2500 2000 500 1000 500 Wavenumber (cm) FT Raman spectrum of Form A2
FIG. 2
3,
-4, 5 ------I...... ------...... 25 50 75 100 125 150 75 200 225 250 275 300 Temperature C
DSC SCan Of Form A2 U.S. Patent Feb. 16, 2016 Sheet 7 of 21 US 9.260,393 B2
FIG. 13
100 90 80 i 70 60 50 i------25 50 75 100 25 150 175 200 225 250 275 300 Temperature C
TGA Scan of Form A2
FIG. 14
0, 4. O, 2
Water Vapour Sorption isotherm (25 °C) of Form A2 U.S. Patent Feb. 16, 2016 Sheet 8 of 21 US 9.260,393 B2
F.G. 5
Powder X-ray diffractogram of Form A-NF6 U.S. Patent Feb. 16, 2016 Sheet 9 of 21 US 9,260,393 B2
d w wy My V W. .
Powder X-ray diffractogram of Form A-NF9
FG. 18
“. |
38 s - - - 38: 3: Powder X-ray diffractogram of Form A-NFO U.S. Patent Feb. 16, 2016 Sheet 10 of 21 US 9.260,393 B2
F.G. 19
5. 33 2. s 3i *2: Powder X-ray diffractogram of Form A-NF1
FG. 20
s 5 2 25 3. 2. Powder X-ray diffractogram of Form Bi (Cu-Ko, radiation, = 1.5406 A, Stoe StadiP 611 KL diffractometer) U.S. Patent Feb. 16, 2016 Sheet 11 of 21 US 9.260,393 B2
F.G. 2
Crystal structure of Form Bi (calculated from Powder data) viewed along c-axis
F.G. 22
80
60
40
20
-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-T------,T------,------, AO 35 30 2500 2000 1500 OOO 500 Wavenumber (cm) FTIR spectrum of Form B1 U.S. Patent Feb. 16, 2016 Sheet 12 of 21 US 9.260,393 B2
FIG. 23 0,12
- O 1
0.08
Wavenumber (cm) FT Raman spectrum of Form B1
FIG. 24
1 4. ------1------1------25 50 75 OO 125 150 75 200 225 250 275 3OO Temperature C
DSC Scan of Form B U.S. Patent Feb. 16, 2016 Sheet 13 of 21 US 9.260,393 B2
FIG. 25
1 OO
- s
-: s
i 7 O --
--s 50 his------1------1------25 50 75 100 125 150 75 200 225 250 275 300 Temperature C
TGASCan Of Form B
FIG. 26
- A Cycle 2 Desorpe-cycle Sorp - El- Cycle 1 Desorp.
3
2
Relative humidity (%) Water Vapour Sorption isotherm (25 °C) of Form B1 U.S. Patent Feb. 16, 2016 Sheet 14 of 21 US 9.260,393 B2
F.G. 27
5 8 5 20 25 30 Powder X-ray diffractogram of Form 82 (Cu-Ko, radiation, = 1.5406 A, Stoe Stadip 611 KL diffractometer)
F.G. 28
Crystal structure of Form B2 (calculated from Powder data) viewed alonga-axis U.S. Patent Feb. 16, 2016 Sheet 15 of 21 US 9.260,393 B2
FIG. 29
80 |
- 60 R
40
- 20
--9mammammammammam1------T------AOOO 3500 300 2500 2OOO 500 OOO SOD Wavenumber (cm) FTIR spectrum of Form B2
FIG. 30
- 0,16
- 0,14
- 0,12
- 0,1
Wavenumber (cm) FT Raman spectrum of Form B2 U.S. Patent Feb. 16, 2016 Sheet 16 of 21 US 9.260,393 B2
FIG. 3
-2-o-0,1
3 -3,5 25 SO 75 100 125 150 175 200 225 250 275 300 Temperature C DSC scan of Form B2 (Type 1)
FIG. 32
1 OO - 90 -
80 - 70 - i 60 - 50 -
40 -
30 m-m-m-m-m-m-m-m-m-m-m-m-m-m-m-m --j-----j-r-j-. 25 50 75 OO 125 150 75 200 225 250 275 300 Temperature C TGA scan of Form B2 (Type 1) U.S. Patent Feb. 16, 2016 Sheet 17 of 21 US 9.260,393 B2
-8 H------25 50 75 00 25 SO 175 200 225 250 275 300 Temperature C DSC DSC scan of Form B2 (Type 2)
F.G. 34
1 OO --
90 -
8O --- 7 O --
6 O al
5 O -- i 4 O --
30 --
20 -- 10 l------1------1------r------25 50 75 1 OO 25 150 75 200 225 250 275 300 Temperature C TGA scan of Form B2 (Type 2) U.S. Patent Feb. 16, 2016 Sheet 18 of 21 US 9.260,393 B2
F.G. 35
- E - Cycle 1 Desorp-e-cycle 1 sorp-A-cycle 2 Desorp
3.
2
Relative humidity (%) Water Vapour Sorption isotherm (25 °C) of Form B2
FG. 36
Powder X-ray diffractogram of Form B-S1 U.S. Patent Feb. 16, 2016 Sheet 19 of 21 US 9.260,393 B2
F.G. 37
Powder X-ray diffractogram of Form B-S2
F.G. 38 Dissolution of Compound C in Buffer pH 1.2
-A-HCl Salt Form A1 -E.-HCl Salt Form A2 -X- Free Base Form B
20 s 30 40 53 60 Time min U.S. Patent Feb. 16, 2016 Sheet 20 of 21 US 9.260,393 B2
F.G. 39 Dissolution of Compound C in Buffer pH 3.0
o C O % s |-A-HCl Salt Form A1 SQ -E-HCl Salt Form A2 -X - Free Base Forn B ------. 40 50 60 Time min
F.G. 40 Dissolution of Compound C in Buffer pH 5.0
d
"O : 2 --K-T-:K :
d -A-HCl Salt Form A1 : -E.-HCl Salt Form A2 -X-Free Base Form B1
O 10 2O 30 40 50 60 Time min U.S. Patent Feb. 16, 2016 Sheet 21 of 21 US 9.260,393 B2
FG. 4 issolution of Corporad it Buffer pi 6.8
i. s: :
3. : : irre it US 9,260,393 B2 1. 2 SOLID STATE FORMS OF invention encompass any composition made by admixing a N-(S)-2,3-DIHYDROXY-PROPYL)- compound of the present invention and a pharmaceutically 3-(2-FLUORO-4-IODO-PHENYLAMINO)- acceptable carrier. SONICOTNAMIDE A pharmaceutical composition of the present invention may additionally comprise one or more other compounds as CONTINUING DATA pharmaceutical active ingredients. The pharmaceutical compositions include compositions This application is a 371 of PCT/EP2013/001352 filed Suitable for oral, rectal, topical, parenteral (including Subcu May 7, 2013 which claims benefit of 61/653,037 filed May 30, 2012. taneous, intramuscular, and intravenous), ocular (oph 10 thalmic), pulmonary (nasal or buccal inhalation), or nasal FIELD OF THE INVENTION administration, although the most Suitable route in any given case will depend on the nature and severity of the conditions The invention relates to solid state forms of N—((S)-2,3- being treated and on the nature of the active ingredient. They Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)-isoni may be conveniently presented in unit dosage form and pre cotinamide, processes for their preparation, and medical uses 15 pared by any of the methods well-known in the art of phar thereof. macy. In one embodiment, said compounds and pharmaceutical SUMMARY OF THE RELATED ART composition are for the treatment of cancer Such as brain, lung, including non-Small cell lung cancer, colon, colorectal, N—((S)-2,3-Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phe epidermoid, squamous cell, bladder, gastric, pancreatic, nylamino)-isonicotinamide, for ease of reference hereinafter breast, head & neck, renal, kidney, liver, ovarian, prostate, referred to as Compound C, its use as a kinase inhibitor to uterine, oesophageal, testicular, gynecological, including treat cancer, and its manufacture is disclosed in WO 2006/ endometrial, thyroid cancer, melanoma, including NRAS or 0455 14, page 76. Example 115. However, no solid state form BRAF mutated melanoma, as well as hematologic malignan of Compound C is disclosed in WO 2006/045514, or has been 25 cies such as acute myelogenous leukemia, multiple myeloma, otherwise publicly disclosed to the best of applicants’ knowl chronic myelogneous leukemia, myeloid cell leukemia, edge, until the present date. Without a solid state form, how Kaposi's sarcoma, or any other type of solid or liquid tumors. ever, it is not possible to provide a pharmaceutical active Preferably, the cancer to be treated is chosen from colon, ingredient in a tablet, which is the dosage form of choice in lung, breast and hematological tumor types. terms of manufacturing, packaging, stability and patient com 30 Therefore, the present invention relates also to the use of pliance. the herein disclosed solid state forms of Compound C for the Therefore, in order to advance the development of Com treatment of the above mentioned diseases. pound C as a drug Substance, there is a high need to provide The anti-cancer treatment defined above may be applied as at least one solid state form of this compound. a monotherapy or may involve, in addition to the herein 35 disclosed solid state forms of Compound C, conventional DESCRIPTION OF THE INVENTION Surgery or radiotherapy or medicinal therapy. Such medicinal therapy, e.g. a chemotherapy or a targeted therapy, may Surprisingly, the inventors of the present patent application include one or more, but preferably one, of the following for the first time succeeded to provide a number of solid state anti-tumor agents: forms of C that are not only crystalline but also stable, i.e. do 40 Alkylating Agents not convert to other forms under the conditions of tablet Such as altretamine, bendamustine, buSulfan, carmustine, manufacturing and storage. chlorambucil, chlormethine, cyclophosphamide, dacarba In one specific aspect the invention relates to crystalline Zine, ifosfamide, improSulfan tosilate, lomustine, melphalan, forms A1 and A2 of the mono hydrochloride of C. In another mitobronitol, mitolactol, nimustine, ranimustine, temozolo specific aspect the invention relates to crystalline forms B1 45 mide, thiotepa, treosulfan, mechloretamine, carboquone, and B2 of the free base of C. apaziquone, fotemustine, glufosfamide, palifosfamide, pipo The crystalline forms are characterized, e.g., by X-ray pow broman, trofosfamide, uramustine; der diffractometry, single crystal diffractometry, FTIR spec Platinum Compounds troscopy, FT Raman spectroscopy, differential scanning calo Such as carboplatin, cisplatin, eptaplatin, miriplatine rimetry (DSC) and thermogravimetric analysis (TGA) as 50 hydrate, Oxaliplatin, lobaplatin, nedaplatin, picoplatin, satra hereinafter shown in the experimental section. platin; All forms are characterized by high crystallinity, absence DNA. Altering Agents of hygroscopicity and high thermal stability. Moreover, forms Such as amrubicin, bisantrene, decitabine, mitoxantrone, A1 and A2 show a higher solubility and faster dissolution procarbazine, trabectedin, clofarabine, amsacrin, brostalli kinetics as compared to forms B1 and B2. 55 cin, pixantrone, laromustine; Furthermore, the present invention relates to pharmaceuti Topoisomerase Inhibitors cal compositions comprising a solid state form of the present Such as etoposide, irinotecan, razoxane, Sobuzoxane, teni invention, together with at least one pharmaceutically accept poside, topotecan, amonafide, belotecan, elliptinium acetate, able carrier. Voreloxin; "Pharmaceutical composition” means one or more active 60 Microtubule Modifiers ingredients, and one or more inert ingredients that make up Such as cabazitaxel, docetaxel, eribulin, ixabepilone, the carrier, as well as any product which results, directly or paclitaxel, vinblastine, Vincristine, Vinorelbine, Vindesine, indirectly, from combination, complexation or aggregation of Vinflunine, fosbretabulin, tesetaxel: any two or more of the ingredients, or from dissociation of Antimetabolites one or more of the ingredients, or from other types of reac 65 Such as asparaginase, azacitidine, calcium levofolinate, tions or interactions of one or more of the ingredients. capecitabine, cladribine, cytarabine, enocitabine, floXuridine, Accordingly, the pharmaceutical compositions of the present fludarabine, fluorouracil, gemcitabine, mercaptopurine, US 9,260,393 B2 3 4 methotrexate, nelarabine, pemetrexed, pralatrexate, azathio mide, procodaZol, ridaforolimus, tasquinimod, telotristat, prine, thioguanine, carmofur, doxifluridine, elacytarabine, thymalfasin, tirapazamine, tosedostat, trabedersen, uben raltitrexed, sapacitabine, tegafur, trimetrexate; imex, Valspodar, gendicine, picibanil, reolysin, retaspimycin Anticancer Antibiotics hydrochloride, trebananib, virulizin. Such as bleomycin, dactinomycin, doxorubicin, epirubi In practical use, the compounds of the present invention cin, idarubicin, levamisole, miltefosine, mitomycin C, can be combined as the active ingredient in intimate admix romidepsin, Streptozocin, valrubicin, Zinostatin, Zorubicin, ture with a pharmaceutical carrier according to conventional daunurobicin, plicamycin, aclarubicin, peplomycin, piraru pharmaceutical compounding techniques. The carrier may bicin; take a wide variety of forms depending on the form of prepa Hormones/Antagonists 10 ration desired for administration, e.g., oral or parenteral (in Such as abarelix, abiraterone, bicalutamide, buserelin, cluding intravenous). In preparing the compositions for oral calusterone, chlorotrianisene, degarelix, dexamethasone, dosage form, any of the usual pharmaceutical media may be estradiol, fluocortolone, fluoxymesterone, flutamide, fulves employed, such as, for example, water, glycols, oils, alcohols, trant, goserelin, histrelin, leuprorelin, megestrol, mitotane, flavoring agents, preservatives, coloring agents and the like. nafarelin, nandrolone, nilutamide, octreotide, prednisolone, 15 In the case of oral liquid preparations, any of the usual phar raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilos maceutical media may be employed, such as, for example, tane, triptorelin, diethylstilbestrol, acolbifene, danazol, Suspensions, elixirs and solutions; or carriers such as deslorelin, epitioStanol, orteronel, enZalutamide; starches, Sugars, microcrystalline cellulose, diluents, granu Aromatase Inhibitors lating agents, lubricants, binders, disintegrating agents and Such as aminoglutethimide, anastroZole, exemestane, the like. In the case of oral Solid preparations the composition fadrozole, letrozole, testolactone, formestane; may take forms such as, for example, powders, hard and soft Small Molecule Kinase Inhibitors capsules and tablets, with the Solid oral preparations being Such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, preferred over the liquid preparations. nilotinib, paZopanib, regorafenib, ruXolitinib, Sorafenib, Because of their ease of administration, tablets and cap Sunitinib, Vandetanib, Vemurafenib, boSutinib, gefitinib, axi 25 Sules represent the most advantageous oral dosage unit form tinib, afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, in which case Solid pharmaceutical carriers are obviously dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsi employed. If desired, tablets may be coated by Standard aque tinib, masitinib, midostaurin, motesanib, neratinib, orantinib, ous or nonaqueous techniques. Such compositions and prepa perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivan rations should contain at least 0.1 percent of active com tinib, tivozanib, trametinib, pimasertib, brivanib alaninate, 30 pound. The percentage of active compound in these cediranib, apatinib, cabozantinib S-malate, carfilzomib, ibru compositions may, of course, be varied and may conveniently tinib, icotinib; be between about 2 percent to about 60 percent of the weight Photosensitizers of the unit. The amount of active compound in Such therapeu Such as MethoXSalen, porfimer Sodium, talaporfin, tically useful compositions is such that an effective dosage temoporfin; 35 will be obtained. The active compounds can also be admin Antibodies istered intranasally as, for example, liquid drops or spray. Such as alemtuzumab, besilesomab, brentuximab vedotin, The tablets, pills, capsules, and the like may also contain a cetuximab, denosumab, ipilimumab. ofatumumab, panitu binder Such as gum tragacanth, acacia, corn starch or gelatin: mumab, rituximab, to situmomab, trastuzumab, bevaci excipients such as dicalcium phosphate; a disintegrating Zumab, catumaXomab, elotuZumab, epratuZumab, farletu 40 agent Such as corn starch, potato starch, alginic acid; a lubri Zumab, mogamulizumab, necitumumab, nimotuZumab, cant such as magnesium Stearate; and a Sweetening agent obinutuzumab, ocaratuZumab, oregovomab, ramucirumab, Such as Sucrose, lactose or saccharin. When a dosage unit rillotumumab, siltuximab, tocilizumab, Zalutumumab, Zano form is a capsule, it may contain, in addition to materials of limumab, matuZumab, dalotuZumab, onartuzumab, pertu the above type, a liquid carrier Such as a fatty oil. Zumab, racotumomab, tabalumab; 45 Various other materials may be present as coatings or to Cytokines modify the physical form of the dosage unit. For instance, Such as aldesleukin, interferon alfa, interferon alfa2a, tablets may be coated with shellac, Sugar or both. A syrup or interferon alfa2b, tasonermin, teceleukin, oprelvekin; elixir may contain, in addition to the active ingredient, Drug Conjugates Sucrose as a Sweetening agent, methyl and propylparabens as Such as denileukin diftitox, ibritumomab tiuxetan, ioben 50 preservatives, a dye and a flavoring Such as cherry or orange guane I123, prednimustine, trastuzumab emtansine, estra flavor. mustine, gemtuzumab ozogamicin, aflibercept, cintredekin Compounds of the present invention may also be adminis besudotox, edotreotide, inotuZumab ozogamicin, naptumo tered parenterally. Solutions or Suspensions of these active mab estafenatox, oportuZumab monatox, technetium compounds can be prepared in water Suitably mixed with a (99mTc) arcitumomab, vintafolide; 55 Surfactant such as hydroxy-propylcellulose. Dispersions can Vaccines also be prepared in glycerol, liquid polyethylene glycols and Such as Sipuleucel, Vitespen, emepepimut-S, oncoVAX. mixtures thereof in oils. Under ordinary conditions of storage rindopepimut, troVax, stimuVax; and use, these preparations contain a preservative to prevent Miscellaneous the growth of microorganisms. alitretinoin, bexarotene, bortezomib, everolimus, iban 60 The pharmaceutical forms suitable for injectable use dronic acid, imiquimod, lenalidomide, lentinan, metirosine, include sterile aqueous solutions or dispersions and sterile mifamurtide, pamidronic acid, pegaspargase, pentostatin, powders for the extemporaneous preparation of sterile inject sipuleucel, sizofiran, tamibarotene, temsirolimus, thalido able solutions or dispersions. In all cases, the form must be mide, tretinoin, Vismodegib, Zoledronic acid, thalidomide, sterile and must be fluid to the extent that easy syringability Vorinostat, celecoxib, cilengitide, entinostat, etanidazole, 65 exists. It must be stable under the conditions of manufacture ganetespib, idronoxil, iniparib, ixazomib, lonidamine, and storage and must be preserved against the contaminating nimorazole, panobinostat, peretinoin, plitidepsin, pomalido action of microorganisms such as bacteria and fungi. The US 9,260,393 B2 5 6 carrier can be a solvent or dispersion medium containing, for FIG. 29: FTIR spectrum of Form B2 example, water, ethanol, polyol (e.g., glycerol, propylene FIG. 30: FT Raman spectrum of Form B2 glycol and liquid polyethylene glycol), Suitable mixtures FIG. 31. DSC scan of Form B2 (Morphological Type 1) thereof, and vegetable oils. Any suitable route of administration may be employed for FIG. 32: TGA scan of Form B2 (Morphological Type 1) providing a mammal, especially a human, with an effective FIG.33: DSC scan of Form B2 (Morphological Type 2) dose of a compound of the present invention. For example, FIG. 34: TGA scan of Form B2 (Morphological Type 2) oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and FIG.35: Water Vapour Sorption Isotherm (25°C.) of Form the like may be employed. Dosage forms include tablets, B2 troches, dispersions, Suspensions, solutions, capsules, 10 FIG. 36: Powder X-ray diffractogram of Form B-S1 creams, ointments, aerosols, and the like. Preferably com pounds of the present invention are administered orally. FIG. 37: Powder X-ray diffractogram of Form B-S2 The effective dosage of active ingredient employed may FIG.38: Dissolution of Compound C solid state forms at vary depending on the particular compound employed, the pH 1.2 mode of administration, the condition being treated and the 15 FIG. 39: Dissolution of Compound C solid state forms at severity of the condition being treated. Such dosage may be pH 3.0 ascertained readily by a person skilled in the art. FIG. 40: Dissolution of Compound C solid state forms at When treating inflammatory, degenerative or hyperprolif pH 5.0 erative diseases for which compounds of the present inven FIG. 41: Dissolution of Compound C solid state forms at tion are indicated, generally satisfactory results are obtained pH 6.8 when the compounds of the present invention are adminis tered at a daily dosage of from about 0.01 milligram to about 100 milligram per kilogram of body weight, preferably given ABBREVIATIONS as a single daily dose. For most large mammals, the total daily dosage is from about 0.1 milligrams to about 1000 milli 25 Some abbreviations that may appear in this application are grams, preferably from about 0.2 milligram to about 50 mil as follows: ligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.2 milligrams to about 200 milligrams. This dosage regimen may be adjusted to provide Designation the optimal therapeutic response. 30 API Active Pharmaceutical Ingredient DI Deionized BRIEF DESCRIPTION OF THE DRAWINGS DMF Dimethylformamide DMSO Dimethyl Sulfoxide DSC Differential Scanning Calorimetry FIG. : Powder X-ray diffractogram of Form A1 FTIR Fourier Transform Infrared Spectroscopy FIG. : Single crystal structure of Form A1 35 h Hour FIG. : FTIR spectrum of Form A1 HPLC High Pressure Liquid Chromatography FIG. M Molar (unit of concentration) : FT Raman spectrum of Form A1 MTBE Methyl tertiary-butyl ether FIG. : DSC Scan of Form A1 N Normal (unit of concentration) FIG. : TGA scan of Form A1 NMP N-methylpyrrollidone FIG. : Water Vapour Sorption Isotherm (25°C.) of Form 40 PBS Phosphate Buffered Saline A1 PTFE Polytetrafluoroethylene RT Room Temperature (-23 °C.) FIG. 8: Powder X-ray diffractogram of Form A2 TGA Thermogravimetric Analysis FIG. 9: Crystal structure of Form A2 (calculated from THF Tetrahydrofurane Powder data) USP U.S. Pharmacopeia FIG.10: FTIR spectrum of Form A2 45 FIG. 11: FT Raman spectrum of Form A2 FIG. 12: DSC Scan of Form A2 FIG. 13: TGA scan of Form A2 EXAMPLES FIG. 14:Water Vapour Sorption Isotherm (25°C.) of Form A2 50 The working examples presented below are intended to FIG. 15: Powder X-ray diffractogram of Form A-NF3 illustrate particular embodiments of the invention, and are not FIG. 16: Powder X-ray diffractogram of Form A-NF6 intended to limit the scope of the specification or the claims in FIG. 17: Powder X-ray diffractogram of Form A-NF9 any way. FIG. 18: Powder X-ray diffractogram of Form A-NF10 By mono hydrochloride form is meant a stoichiometric FIG. 19: Powder X-ray diffractogram of Form A-NF11 55 ratio of Compound C to HCl between 0.8:1 and 1.2:1, pref FIG. 20: Powder X-ray diffractogram of Form B1 erably between 0.9:1 and 1.1:1. Most preferred is a ratio of FIG. 21: Crystal structure of Form B1 (calculated from 1:1. Powder data) 1. Mono-Hydrochloride Form A1 FIG.22: FTIR spectrum of Form B1 1.1 Characterization of Form A1 FIG. 23: FT Raman spectrum of Form B1 60 FIG. 24: DSC Scan of Form B1 1.1.1 X-Ray Powder Diffractometry FIG. 25: TGA scan of Form B1 A powder X-ray Diffraction pattern of Form A1 was FIG. 26: Water Vapour Sorption Isotherm (25°C.) of Form obtained by standard techniques at RT as described in the B1 European Pharmacopeia 6" Edition chapter 2.9.33, which is FIG. 27: Powder X-ray diffractogram of Form B2 65 shown in FIG. 1. FIG. 28: Crystal structure of Form A2 (calculated from A list of characteristic X-ray peaks derived from this pat Powder data) tern is provided in Table I: US 9,260,393 B2 7 8 TABLEV 20 (Cu-KC. hk0 orientation No. radiation) + 0.2° 20 (Cu-KC. 1 5.5 No. radiation) + 0.2° 2 15.9 1 15.9 3 16.8 2 19.1 4 18.5 3 24.9 5 19.1 6 19.5 10 7 20.1 Therefore, in a preferred aspect the present invention 8 21.1 relates to crystalline form A1 having characteristic peaks at 9 22.6 the 20 angles provided in Table I. 10 23.0 In a more preferred aspect the invention relates to formA1 11 24.4 15 having characteristic peaks at the 20 angles provided in Table II. 12 24.9 In an equally preferred aspect the invention relates to form 13 25.2 A1 having characteristic peaks at the 20 angles provided in 14 25.7 one or more of Tables III, IV and V. 15 27.1 1.1.2 X-Ray Singe Crystal Diffractometry 16 28.4 In addition, single crystal X-ray structure data were 17 29.2 obtained on Form A1, from which the spacial arrangement of 18 29.6 the A molecules in the crystal was computed as shown in FIG. 2. 25 Form A1 crystallises in the chiral monoclinic space group The most significant X-ray peaks from Table I are listed in P2, with the lattice parameters a=9.6+0.1 A, b=11.2+0.1 A, Table II: c=16.6+0.1 A, and B=104.4+0.5° (C Y-90°). From the single crystal structure it is obvious that Form A1 represents an anhydrous form. 20 (Cu-KC. 30 In a specific aspect, the invention relates to a crystalline NO. radiation) + 0.2° form of the mono hydrochloride of Compound C character 5.5 ized by these crystallographic parameters. 16.8 1.1.3 Vibrational Spectroscopy 18.5 19.1 Form A1 can be further characterized by infrared and 22.6 35 Raman-spectroscopy. FT-Raman and FT-IR spectra were 23.0 obtained by standard techniques as described in the European 24.9 25.2 Pharmacopeia 6" Edition chapter 2.02.24 and 2.02.48. For 28.4 measurement of the FT-IR and FT-Raman-spectra a Bruker 1 29.2 Vector 22 and a Bruker RFS 100 spectrometer were used. 40 FT-IR spectra and FT-Raman spectra were base-line cor rected using Bruker OPUS software. Broken down by sample orientation, the most characteris An FT-IR spectrum was obtained using a KBr pellet as tic peaks are as listed in Tables III, IV and V: sample preparation technique. The FT-IR spectrum is shown in FIG. 3 from which band positions were derived as given TABLE III 45 below. Form A1 IR band positions (+2 cm", relative intensity) Okl orientation 3.108 cm (m), 2935 cm (m), 2772 cm (m), 1655 20 (Cu-KC. cm (s), 1539 cm (s), 1493 cm (s), 1380 cm (m), 1269 No. radiation) + 0.2° cm (s), 1118 cm (m), 1036 cm (m), 808 cm (m), 773 50 1 5.5 cm (m) 2 16.8 *s'=strong (transmittances50%), “m' medium 3 19.5 (50%
40 r % oHCI I 2-PrOH:DI Water (20:1, w 45 OH --" O N H 50 F r 55 % oHCI
F 1.2.1 Method 1 S’ A solution of acetonide-protected Compound C as free N base (1.0 wt) in methanol (20.0 Vol) was clarified through a 60 0.7 um glass microfibre filter paper. Clarified ca. 2 M hydro 2 chloric acid in diethyl ether (5.3 Vol) was added to the metha nolic solution at 16 to 25°C. The mixture was stirred for 60 to 90 minutes at 16 to 25° C. and filtered. The filter-cake was washed with a clarified mixture of methanol/diethyl ether 4:1 65 (1.0 vol) and pulled dry on the pad for 60 to 90 minutes. The filter-cake was transferred to a suitable vessel and clarified propan-2-ol (20.0 vol) and clarified water (1.0 vol) was US 9,260,393 B2 11 12 charged. The mixture was heated to and stirred at 75 to 85°C. for 30 to 50 minutes. The mixture was cooled to 0 to 5°C. Over 20 (Cu-KC. 60 to 90 minutes and aged at 0 to 5° C. for 20 to 30 minutes NO. radiation) + 0.2° and filtered. The filter-cake was washed with clarified propan 5.4 2-ol (1.0 vol) and pulled dry on the filter under nitrogen for up 9.6 to 24 hours to give a pre-blend of Compound C hydrochlo 18.4 18.6 ride. A mixture of the pre-blend Form A1 (1.0 wt %) and 20.9 propan-2-ol (3.0 Vol) was charged to a Suitable flask and 21.6 Stirred for 60 to 90 minutes at 16 to 25°C. The mixture was 23.9 filtered and the filter-cake was washed with propan-2-ol (1.0 10 24.4 Vol) and pulled dry on the filter under nitrogen for up to 24 2S.O hours. 1 26.0 The filter-cake was transferred to drying trays and dried under vacuum at up to 40° C. until the propan-2-ol content Broken down by sample orientation, the most characteris was 0.2 wt % to give Form A1. 15 tic peaks are as listed in Tables VIII, and IX: 1.2.2 Method 2 TABLE VIII Approx. 800g of Form A2 (see Example 2) were dispersed in 16 L 2-Propanol and 0.8 L Water, and heated to 80°C. The hO orientation reaction mixture was kept at 80° C. for 3 hours, and slowly 20 (Cu-KC. cooled down to room temperature. The dispersion was then No. radiation) + 0.2° kept at room temperature for 3 hours, and then further cooled 18.4 down to 0° C. The dispersion was then filtered, and the 18.6 obtained filter residue was dried at 40° C. under vacuum 19.2 overnight. 25 2O2 1.2.3 Method 3 21.6 Approx. 25 mg of Compound C mono hydrochloride were dispersed in 0.3 mL DMF, and heated to 50° C. The resulting Solution was then cooled to RT in approx. 1 h, resulting in TABLE IX yellow crystals. 30 hk0 orientation 2. Mono-Hydrochloride Form A2 2.1 Characterization of Form A2 No. 20 (Cu-KC radiation) + 0.2 2.1.1 X-Ray Powder Diffractometry 1 9.6 2 11.3 35 A Powder X-Ray Diffraction pattern of Form A2 was 3 17.8 obtained by standard techniques at RT as described in the 4 23.9 European Pharmacopeia 6" Edition chapter 2.9.33, which is 5 2S.O shown in FIG. 8. A list of characteristic X-ray peaks derived from this pat Therefore, in a preferred aspect the present invention tern is provided in Table VI: 40 relates to crystalline form A2 having characteristic peaks at the 20 angles provided in Table VI. In a more preferred aspect the invention relates to form A2 20 (Cu-KC. having characteristic peaks at the 20 angles provided in Table No. radiation) + 0.2° VII. 45 In an equally preferred aspect the invention relates to form 1 5.4 2 9.6 A1 having characteristic peaks at the 20 angles provided in 3 11.3 one or more of Tables VIII and IX. 4 13.5 X-ray structural data were calculated from powder X-ray 5 16.O data of Form A2 as shown in FIG. 9. 6 16.4 50 7 16.7 Form A2 crystallises in the chiral orthorhombic space 8 17.8 group P222 with the lattice parameters (measured at 301 K) 9 18.4 a=32.3+0.1 A, b=11.2+0.1 A, c=4.8+0.1 A (C-B-Y=90°). 10 18.6 From the crystal structure it is obvious that Form A2 repre 11 19.2 12 2O2 sents an anhydrous form. 13 20.9 55 In a specific aspect, the invention relates to a crystalline 14 21.6 form of the mono hydrochloride of Compound C character 15 22.9 ized by these crystallographic parameters. 16 23.3 17 23.9 2.1.2 Vibrational Spectroscopy 18 24.4 Form A2 can be further characterized by infrared and 19 2S.O 60 Raman-spectroscopy. FT-Raman and FT-IR spectra were 2O 26.O obtained by standard techniques as described in the European 21 26.7 22 27.5 Pharmacopeia 6" Edition chapter 2.02.24 and 2.02.48. For 23 27.9 measurement of the FT-IR and FT-Raman-spectra a Bruker Vector 22 and a Bruker RFS 100 spectrometer were used. 65 FT-IR spectra were base-line corrected using Bruker OPUS The most significant X-ray peaks from Table VI are listed Software. FT-Raman spectra were vector normalized using in Table VII: the same Software. US 9,260,393 B2 13 An FT-IR spectrum was obtained using a KBr pellet as sample preparation technique. The FT-IR spectrum is shown in FIG. 10 from which band positions were derived as given below. O - Form A2 IR band positions (+2 cm, relative intensity*) 5 -- 3086 cm (s), 2931 cm (s), 2724 cm (s), 1663 cm (s), O NH MeOH, F 2M HCl (in diethylether) 1544 cm (s), 1492 cm (s), 1383 cm (s), 1282 cm (s), Hs 1035 cm (s), 810 cm (s), 782 cm (m) *s'=strong (transmittances50%), “m'-medium (50%
2.2 Processes for the Preparation of A2 65 3.1 Dioxane Solvate Form A-NF3 Reaction scheme to obtain HCl salt Form A2 from From the powder X-ray diffractogram of Form NF3 shown acetonide-protected A: in FIG. 15 the following peaks were derived Table X: US 9,260,393 B2 15 16 3.4 NMP Solvate Form A-NF10 20 (Cu-KC radiation) + 0.2° From the powder X-ray diffractogram of Form A-NF10 shown in FIG. 18 the following peaks were derived Table 4.2 XIII: 8.1 14.7 16.2 17.8 No. 20 (Cu-KC radiation) + 0.2 18.8 19.6 1 4.3 20.1 2 8.0 20.8 10 3 1O.O 21.6 4 16.7 22.3 5 18.8 22.9 6 20.1 23.2 7 20.7 24.2 8 21.2 9 21.6 25.2 15 10 22.1 25.4 11 22.9 3O.O 12 23.5 13 24.8 14 25.2 3.2 Acetic Acid Solvate Form A-NF6 15 25.5 16 26.0 From the powder X-ray diffractogram of Form A-NF6 17 26.6 shown in FIG. 16 the following peaks were derived Table XI: 3.5 NMP Solvate Form A-NF11 From the powder X-ray diffractogram of Form A-NF11 25 shown in FIG. 19 the following peaks were derived Table 20 (Cu-KC radiation) + 0.2 XIV: 4.5
9.0 No. 20 (Cu-KC radiation) + 0.2 13.6 30 15.7 1 4.3 16.1 2 8.0 18.0 3 10.1 20.6 4 11.6 21.2 5 15.2 21.7 35 6 19.0 24.O 7 20.3 25.3 8 20.6 26.6 9 21.0 28.1 10 21.5 28.5 11 22.0 29.7 12 22.4 29.9 40 13 23.5 14 24.3 15 24.8 3.3 NMP Solvate Form A-NF9 16 25.1 17 25.4 From the powder X-ray diffractogram of Form A-NF9 18 25.9 45 19 27.4 shown in FIG. 17 the following peaks were derived Table 2O 29.4 XII: 4. Free Base Form B1 20 (Cu-KC radiation) + 0.2 4.1 Characterization of Form B1 50 4.1.1 X-Ray Powder Diffractometry 4.3 A Powder X-Ray Diffraction pattern of Form B1 was 8.6 obtained by standard techniques at 301 Kas described in the 10.1 European Pharmacopeia 6" Edition chapter 2.9.33, which is 11.6 shown in FIG. 20. 15.1 55 16.O A list of characteristic X-ray peaks derived from this pat 19.0 tern is provided in Table XV: 20.3 21.O 21.5 NO. 20 (Cu-KC radiation) + 0.2 23.4 24.2 60 7.0 24.8 14.0 25.1 17.1 25.4 18.3 25.9 19.0 27.4 19.2 29.4 65 20.6 21.2 US 9,260,393 B2 17 18 -continued 3081 cm (w), 2918 cm (w), 1604 cm (s), 1553 cm (m), 1323 cm (m), 1253 cm (m), 1228 cm (m), 1134 No. 20 (Cu-KC radiation) + 0.2 cm (w), 1077 cm (m), 935 cm (w), 785 cm (w), 630 9 21.6 cm (w), 529 cm (w) 10 22.1 s'=strong (relative Raman intensity-0.1), “m'-medium 11 23.1 (0.1 >relative Raman intensity 0.02), “w”-weak (relative 12 24.2 Raman intensity.<0.02) 13 25.1 14 25.4 4.1.3. Other Analytical Methods 15 26.2 It could be shown that Form B1 is a crystalline anhydrous 16 27.3 10 form, which is further characterised by the following physical 17 27.9 properties: 18 29.0 Thermal behaviour of Form B1 shows a melting peak at 19 29.3 approx. 165° C., with very small weight loss up to this temperature only. DSC and TGA profiles are displayed The most significant X-ray peaks from TableX are listed in 15 in FIGS. 24 and 25, respectively. DSC scan of Form B1 Table XVI: was acquired on a Mettler-Toledo DSC 821 with a heat ing rate of 5 K/min, using nitrogen purge gas at 50 mL/min. TGA scan of Form B1 was acquired on a Met NO. 20 (Cu-KC radiation) + 0.2 tler-Toledo TGA 851 with a heating rate of 5 K/min, 7.0 using nitrogen purge gas at 50 mL/min. 14.O Water Vapour Sorption behaviour shows small water 18.3 uptake levels<1 wt % in the relative humidity (RH) 19.0 20.6 range 0-80% RH, and slightly enhanced water uptake at 21.2 elevated RH. Form A1 can be classified as slightly 24.2 25 hygroscopic acc. to Ph. Eur, criteria. Water Vapor Sorp 25.1 tion isotherm (25°C.) of Form B1 is displayed in FIG. 25.4 26. Water Vapour Sorption isotherm was acquired on a 1 27.9 DVS-1 System from SMS. From solvent-mediated competitive slurry conversion Therefore, in a preferred aspect the present invention 30 experiments with binary phase mixtures of forms B1 and relates to crystalline form B1 having characteristic peaks at the 20 angles provided in Table XV. B2 in different solvents at ambient and at 50° C., Form In a more preferred aspect the invention relates to form B1 B1 is clearly shown to result as solid-state residue at the having characteristic peaks at the 20 angles provided in Table expense of Form B2, thus confirming Form B1 as ther XVI. modynamically more stable free base form (see X-Ray Structural data were calculated from powder X-Ray 35 Example 6). data of Form B1 as shown in FIG. 21. Solubility in USP phosphate buffer (pH 7.4) at 37° C. was Form B1 crystallises in the chiral orthorhombic space determined to be approx. 50 ug/mL (see Example 7). group P2,2,2 with the lattice parameters a=20.8+0.1 A, Overall, Form B1 reveals very good solid-state properties b=15.7+0.1A, c=5.0+0.1 A C-BY=90) at 301 K. From the (good crystallinity, slightly hygroscopic only, Sufficient ther crystal structure it is obvious that Form B1 represents an 40 mal stability), which are favourable properties for solid dos anhydrous form. age formulations. In a specific aspect, the invention relates to a crystalline Moreover, Form B1 can be considered as thermodynami form of the free base of Compound C characterized by these cally stable crystalline form of the free base. crystallographic parameters. 4.2 Processes for the Preparation of B1 4.1.2 Vibrational Spectroscopy 45 4.2.1 Method 1 Form B1 can be further characterized by infrared and Approx. 260 g of Compound C hydrochloride salt were Raman-spectroscopy. FT-Raman and FT-IR spectra have dispersed in 6.5 L Water at RT, and stirred for 5 minutes. After been obtained by standard techniques as described in the addition of approx. 598 mL aqueous NaOH solution (1 N), a European Pharmacopeia 6" Edition chapter 2.02.24 and thick Suspension is formed. The Suspension is further agitated 2.02.48. For measurement of the FT-IR and FT-Raman-spec 50 for approx. 10 minutes, before approx. 2.6L Ethylacetate are tra a Bruker Vector 22 and a Bruker RFS 100 spectrometer added. The dispersion is further agitated for 20 minutes at RT, have been used. FT-IR spectra and FT-Raman spectra have and is then filtrated and washed twice with approx. 260 mL been base-line corrected using Bruker OPUS software. water. The resulting filter residue is then dried under vacuum An FT-IR spectrum has been obtained using a KBrpellet as at 40°C. overnight. sample preparation technique. The FT-IR spectrum is shown 55 4.2.2 Method 2 in FIG. 22 from which the following band positions were Approx. 20 mg of Compound C form B1 were dispersed in derived (+2 cm, relative intensity*): 1 mL 2-Propanol at RT. The dispersion was heated to 60°C., 3329 cm (s), 2935 cm (w), 1638 cm (s), 1604 resulting in a clear solution, which was further filtrated over a cm (s), 1585 cm (s), 1555 cm (s), 1516 cm (s), 1422 0.2 um syringe filter. The clear warm solution was then cooled cm (s), 1398 cm (m), 1337 cm (s), 1228 cm (m), 1098 60 down to 4°C. at 0.1° C./min, resulting in a dispersion with cm (m), 1071 cm (m), 1028 cm (s) crystals. Crystals were separated by filtration from the mother *s'=strong (transmittances50%), “m'-medium liquor, and left open at ambient conditions to evaporate (50%