WO2014121901A1 - Polymorphic forms - Google Patents
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- WO2014121901A1 WO2014121901A1 PCT/EP2014/000205 EP2014000205W WO2014121901A1 WO 2014121901 A1 WO2014121901 A1 WO 2014121901A1 EP 2014000205 W EP2014000205 W EP 2014000205W WO 2014121901 A1 WO2014121901 A1 WO 2014121901A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- Phosphoinositide 3-kinases have a critical signalling role in cell proliferation, cell survival, vascularization, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (Cantley, 2000, Science, 296, 1655-1657).
- WO2011058149 describes a novel group Tricyclic Pyrazol Amine Derivatives which may be useful as inhibitors of Phosphoinositide 3-kinases (PI3Ks).
- Example 339 (p. 69, p. 307) of WO2011058149 discloses the compound 6-Fluoro-3- (morpholin-4-ylcarbonyl)-1-[4-(morpholin-4-ylmethyl) phenyl]-1 ,4- dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide, having the chemical structure given below:
- the salt forms of the present invention can be used in all PI3K related indications and treatments and specifically those disclosed in WO2011058149.
- the salt forms presented herein are particularly suited for the manufacture of solid oral dosage forms, such as tablets, preferably dry compression tablets and/or those obtained by dry granulation.
- the present invention thus relates to novel salt forms with improved manufacturability and solid-state properties of [6-Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo- 4,5-dihydro-1H-5l6-thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone, and to methods of their manufacture.
- Form Citrate-NF1 A novel crystalline form (further on to be named Form Citrate-NF1) of [6-Fluoro-1-(4- morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1 H-5l6-thiochromeno[4,3- c]pyrazol-3-yl]-morpholin-4-yl-methanone citrate salt has been found, which exhibits good crystallisation behaviour as well as beneficial solid state properties for different kind of applications.
- Form Besylate-NF1 A novel crystalline form (further on to be named Form Besylate-NF1) of [6-Fluoro-1- (4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1 H-5l6-thiochromeno[4,3- c]pyrazol-3-yl]-morpholin-4-yl-methanone besylate salt has been found, which exhibits good crystallisation behaviour as well as beneficial solid state properties for different kinds of applications. All forms can be characterized according to standard methods which can be found in e.g. in Rolf Hilfiker, 'Polymorphism in the Pharmaceutical Industry', Wiley-VCH.
- Fig. 1 Powder X-ray diffractogram of hemifumarate salt Form A1
- Fig. 2 Single crystal structure of Form A1 , viewed approx. along a-axis
- Fig. 3 FTIR spectrum of hemifumarate salt Form A1
- Fig. 4 FT Raman spectrum of hemifumarate salt Form A1
- Fig. 5 DSC scan of hemifumarate salt Form A1
- Fig. 6 TGA scan of hemifumarate salt Form A1
- Fig. 7 Water Vapour Sorption Isotherm (25 °C) of hemifumarate salt Form A1
- Fig. 8 Powder X-ray diffractogram of hemifumarate salt Form H1
- Fig. 9 Crystal structure of hemifumarate salt Form H
- Fig. 10 FTIR spectrum of hemifumarate salt Form H1
- Fig. 11 FT Raman spectrum of hemifumarate salt Form H1
- Fig. 12 DSC scan of hemifumarate salt Form H1
- Fig. 13 TGA scan of hemifumarate salt Form H1
- Fig. 14 Water Vapour Sorption Isotherm (25 °C) of hemifumarate salt Form H1
- Fig. 15 Powder X-ray diffractogram of hemifumarate salt Form S1
- Fig. 16 Powder X-ray diffractogram of hemifumarate salt Form S2
- Fig. 17 Powder X-ray diffractogram of hemifumarate salt Form S3
- Fig. 18 Powder X-ray diffractogram of citarte salt Form Besylate-NF1
- Fig. 19 FT Raman spectrum of besylate salt Form Besylate-NF1
- Fig. 20 DSC scan of besylate salt Form Besylate-NF1
- Fig. 21 TGA scan of besylate salt Form Besylate-NF1
- Fig. 22 Water Vapour Sorption Isotherm (25 °C) of besylate salt Form Besylate-NF1
- Fig. 23 Powder X-ray diffractogram of citrate salt Form Citrate-NF1
- Fig. 24 TGA scan of Citrate salt Form Citrate-NF1
- FaSSIF -120 ug/mL ; FeSSIF: -1100 pg/mL
- Powder X-ray peak list of hemifumarate salt Form A1 Powder X-ray peak list of hemifumarate salt Form A1 :
- Form A1 can be further characterized by infrared and Raman-spectroscopy.
- FT- Raman and FT-IR spectra have been obtained by standard techniques as described in the European Pharmacopeia 6 th Edition chapter 2.02.24 and 2.02.48.
- a Bruker Vector 22 and a Bruker RFS 100 spectrometer have been used for measurement of the FT-IR and FT-Raman-spectra .
- FT-IR spectra and FT-Raman spectra have been base-line corrected using Bruker OPUS software.
- Hemifumarate salt Form A1 is a crystalline anhydrous form, which is further characterised by the following physical properties:
- DSC (Fig. 5) and TGA (Fig. 6) profiles are displayed below.
- DSC scan of Form A1 was acquired on a Mettler- Toledo DSC 821 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.
- TGA scan of Form A1 was acquired on a Mettler- Toledo TGA 851 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.
- - Water Vapour Sorption behaviour small water uptake levels ⁇ 1 wt% in the relative humidity (rh) range 0-90% rh.
- Form A1 can be classified as slightly hygroscopic acc. to Ph.
- hemifumarate salt Form A1 reveals very good solid-state properties (very good crystallinity, slightly hygroscopic, high thermal stability) with sufficient solubility in biorelevant intestinal media and very good manufacturability in larger scale.
- FaSSIF -150 Mg/mL ; FeSSIF: -1100 pg/mL
- Hemifumarate salt Form H1 can be further characterized by infrared and Raman- spectroscopy.
- FT-Raman and FT-IR spectra have been obtained by standard techniques as described in the European Pharmacopeia 6 th Edition chapter 2.02.24 and 2.02.48.
- FT-IR spectra have been base-line corrected using Bruker OPUS software.
- FT-Raman spectra have been vector normalized using the same software.
- Hemifumarate salt Form H1 is a crystalline anhydrous form, which is further characterised by the following physical properties:
- Form H1 shows overlapped multiple dehydration processes ⁇ 30-120 °C, followed by exothermic re-crystallisation of anhydrous form A1 at -150-180 °C.
- DSC (Fig. 12) and TGA Fig. 13) profiles are displayed below.
- DSC scan of Form H1 was acquired on a Mettler-Toledo DSC 821 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.
- TGA scan of Form A2 was acquired on a Mettler-Toledo TGA 851 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.
- Form H1 can be considered a more stable form in aqueous suspensions, and reveals similar good solubility as anhydrous form A1 in biorelevant intestinal media.
- a Powder X-Ray Diffraction pattern of besylate salt Form Besylate-NF1 has been obtained by standard techniques as described in the European Pharmacopeia 6 th Edition chapter 2.9.33, and is characterised by the following X-ray powder
- Besylate salt Form Besylate-NF1 can be further characterized by Raman- spectroscopy.
- FT-Raman spectrum has been obtained by standard techniques as described in the European Pharmacopeia 6 th Edition chapter 2.02.48.
- FT-Raman-spectrum a Bruker RFS 00 spectrometer has been used.
- FT-Raman spectrum has been base-line corrected using Bruker OPUS software.
- Besylate salt Form Besylate-NF1 Raman band positions +2 cm "1 (relative intensity*):
- Besylate salt Form Besylate-NF1 is a crystalline anhydrous form, which is further characterised by the following physical properties:
- Besylate-NF1 reveals very good solid-state properties (very good crystallinity, slightly hygroscopic, high thermal stability). Also, good manufacturability in scales up to 10 g are demonstrated (see Example 8).
- Citrate salt Form Citrate-NF1 is a crystalline anhydrous form, which is further characterised by the following physical properties:
- TGA profile is displayed in Fig. 24. TGA scan of Form Citrate-NF1 was acquired on TA
- Example 1 Processes for preparation of free base (forms NF1 and NF2)
- Approx. 50 mg free base (following procedure AD from WO2011058149) were dissolved in approx. 600 ⁇ _ of hot 2-Propanol and re-crystallised at RT.
- XRD data suggested potential salt formation from experiments in Chloroforme, Isopropylether, and THF, respectively (all re-crystallised from solutions at 4 °C).
- TGA data on samples obtained from Isopropylether and THF revealed strong weight loss, strongly indicating solvate forms being formed.
- XRD data suggested potential salt formation from experiments in 2-Butanone and THF (both from fast solvent evaporation), and from experiment in Acetonitrile (slow solvent evaporation).
- TGA data on sample obtained from 2-Butanone revealed strong weight loss, strongly indicating a solvate form being formed.
- XRD data suggested potential salt formation from experiments in THF, Acetone, Acetonitrile, Chloroform, Dichloromethane, and Isopropylether (all from crystallisation at 4 °C), from experiments in Acetone, Dichloromethane, and Isopropylether (fast solvent evaporation), and from experiment in Ethanol (slow solvent evaporation).
- TGA data on sample obtained from Acetonitrile revealed strong weight loss, strongly indicating a solvate form being formed.
- XRD data further suggested at least two different polymorphic forms being present from potential L-Tartrate salt.
- Example 5 Processes for preparation of hemifumarate salt form A1
- Example 6 Processes for preparation of hemifumarate salt form H1
- Approx. 320 mg hemifumarate salt A1 (following example 5) was dispersed in 10 mL MeOH and stirred at RT for approx. 45 hours. After adding further 10 mL MeOH, the suspension was further stirred for approx. 27 hours. Small amounts of water (50 pL) was added to the suspension, and further stirred for approx. 90 hours. The suspension was filtered, and dried under vacuum overnight at RT.
- Approx. 37 mg hemifumarate salt A1 (following example 5) was dispersed in 0.6 ml_ USP Gastric Juice (pH 1.2) and stirred at RT for approx. 7 days. The suspension was centrifuged, and dried at ambient conditions overnight.
- Approx. 15 mg hemifumarate salt A1 (following example 5) was dispersed in 0.4 ml_ Dl Water and stirred at RT for approx. 5 weeks. The suspension was centrifuged, and dried at ambient conditions overnight.
- Example 7 Solubility determinations of hemifumarate salt forms (A1 and H1)
- hemifumarate salt (form A1 , form H1) were dispersed in 1-2 ml_ FaSSIF medium (pH 6.5) or FeSSIF medium (pH 5.0), respectively, in Whatman Uniprep Syringless Filter vials.
- Example 8 Processes for preparation of besylate salt form Besylate-NF1 a) Method 1 :
- Approx. 10 g free base (following procedure AD from WO2011058149) was dissolved in approx. 90 mL anhydrous acetonitrile under reflux.
- Approx. 3.3 g Benzensulfonic Acid which was pre-dissolved in approx. 10 mL anhydrous acetonitrile was added to the refluxing solution of free base. After starting crystallisation under reflux, the heating bath was removed and the mixture was stirred at RT for 1 hour, and then at 0°C for 30 minutes.. The suspension was filtered off and dried under vacuum to give an off-white powder. After concentration of the mother liquors under vacuum, the resulting precipitate was also filtered off and washed with acetonitrile and acetone.
- Both separated powder fractions were re-combined in water (200 mL), and heated to 70 °C. After addition of further 30 mL water, the resulting fine suspension was removed by filtration as hot solution. The hot clear filtrate was concentrated down to approx. 80 mL at 70 °C, and then cooled down to RT. Resulting suspension was filtered off, washed with water, and dried under vacuum.
- Example 9 Processes for preparation of citrate salt form Citrate-NF1
Abstract
The present invention relates to novel salt forms with improved manufacturability and solid-state properties of [6-Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5- dihydro-1 H-5l6-thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone, and to methods of their manufacture.
Description
Polymorphic Forms
Field of the invention
Phosphoinositide 3-kinases (PI3Ks) have a critical signalling role in cell proliferation, cell survival, vascularization, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (Cantley, 2000, Science, 296, 1655-1657).
WO2011058149 describes a novel group Tricyclic Pyrazol Amine Derivatives which may be useful as inhibitors of Phosphoinositide 3-kinases (PI3Ks).
Example 339 (p. 69, p. 307) of WO2011058149 discloses the compound 6-Fluoro-3- (morpholin-4-ylcarbonyl)-1-[4-(morpholin-4-ylmethyl) phenyl]-1 ,4- dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide, having the chemical structure given below:
and the following NMR and MS data: 1 H NMR (DMSO-d6) δ 7.43-7.63 (m, 6H), 6.64- 6.67 (d, = 9 Hz, 1 H), 5.01 (s, 2H), 3.95 (m, 2H), 3.59-3.68 (m, 12H), 2.41 (m, 4H). MS (ESI+): 527.4.
According to a different nomenclature, which is adhered to in the following, the same compound is named [6-Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5- dihydro-1 H-5l6-thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone. Its free base can be obtained according to procedure AD (as described on pp. 304-305 of WO2011058149), with ethanol disclosed as solvent for final re-crystallisation step of the free base.
Solid-state characterization of [6-Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo- 4,5-dihydro-1 H-5l6-thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone free base revealed two anhydrous polymorphic forms (termed NF1 and NF2, both obtained from ethanol crystallisation processes, see Example 1). A monotropic relationship can clearly be established between both forms, with form NF2 being identified as thermodynamically more stable form (see Example 2). However, upon up-scaling, the desired more stable form NF2 could not be obtained in sufficient purity, despite intensive attempts to prepare this form (see Example 3).
Detailed description of the invention
It has now been found that specifically selected crystalline salt forms of 6-Fluoro-1-(4- morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1H-5l6-thiochromeno[4,3- c]pyrazol-3-yl]-morpholin-4-yl-methanone may be advantageously employed in pharmaceutical development.
In particular, the salt forms of the present invention can be used in all PI3K related indications and treatments and specifically those disclosed in WO2011058149. The salt forms presented herein are particularly suited for the manufacture of solid oral dosage forms, such as tablets, preferably dry compression tablets and/or those obtained by dry granulation.
The present invention thus relates to novel salt forms with improved manufacturability and solid-state properties of [6-Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo- 4,5-dihydro-1H-5l6-thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone, and to methods of their manufacture.
Salt formation with numerous acid counter ions was attempted, however, revealing no successful salt formation in the vast majority of experiments comprising different solvents as well as different type of crystallisation set-ups (see Example 4).
Novel crystalline forms (further on to be named Forms A1 and H 1 , respectively) of [6- Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1H-5l6- thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone hemifumarate salt have been found, which exhibit very good and robust crystallisation behaviour as well as beneficial solid state properties for different kind of applications.
A novel crystalline form (further on to be named Form Citrate-NF1) of [6-Fluoro-1-(4- morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1 H-5l6-thiochromeno[4,3- c]pyrazol-3-yl]-morpholin-4-yl-methanone citrate salt has been found, which exhibits good crystallisation behaviour as well as beneficial solid state properties for different kind of applications.
A novel crystalline form (further on to be named Form Besylate-NF1) of [6-Fluoro-1- (4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1 H-5l6-thiochromeno[4,3- c]pyrazol-3-yl]-morpholin-4-yl-methanone besylate salt has been found, which exhibits good crystallisation behaviour as well as beneficial solid state properties for different kinds of applications.
All forms can be characterized according to standard methods which can be found in e.g. in Rolf Hilfiker, 'Polymorphism in the Pharmaceutical Industry', Wiley-VCH. Weinheim 2006 (Chapter 6: X-Ray Diffraction, Chapter 6: Vibrational Spectroscopy, Chapter 3: Thermal Analysis, Chapter 9: Water Vapour Sorption, and references therein) and H.G. Brittain, 'Polymorphism in Pharmaceutical Solids, Vol. 95, Marcel Dekker Inc., New York 1999 (Chapter 6 and references therein).
Brief description of the figures:
Fig. 1 : Powder X-ray diffractogram of hemifumarate salt Form A1
Fig. 2: Single crystal structure of Form A1 , viewed approx. along a-axis
Fig. 3: FTIR spectrum of hemifumarate salt Form A1
Fig. 4: FT Raman spectrum of hemifumarate salt Form A1
Fig. 5: DSC scan of hemifumarate salt Form A1
Fig. 6: TGA scan of hemifumarate salt Form A1
Fig. 7: Water Vapour Sorption Isotherm (25 °C) of hemifumarate salt Form A1
Fig. 8: Powder X-ray diffractogram of hemifumarate salt Form H1
Fig. 9: Crystal structure of hemifumarate salt Form H
Fig. 10: FTIR spectrum of hemifumarate salt Form H1
Fig. 11 : FT Raman spectrum of hemifumarate salt Form H1
Fig. 12: DSC scan of hemifumarate salt Form H1
Fig. 13: TGA scan of hemifumarate salt Form H1
Fig. 14: Water Vapour Sorption Isotherm (25 °C) of hemifumarate salt Form H1
Fig. 15: Powder X-ray diffractogram of hemifumarate salt Form S1
Fig. 16: Powder X-ray diffractogram of hemifumarate salt Form S2
Fig. 17: Powder X-ray diffractogram of hemifumarate salt Form S3
Fig. 18: Powder X-ray diffractogram of citarte salt Form Besylate-NF1
Fig. 19: FT Raman spectrum of besylate salt Form Besylate-NF1
Fig. 20: DSC scan of besylate salt Form Besylate-NF1
Fig. 21 : TGA scan of besylate salt Form Besylate-NF1
Fig. 22: Water Vapour Sorption Isotherm (25 °C) of besylate salt Form Besylate-NF1 Fig. 23: Powder X-ray diffractogram of citrate salt Form Citrate-NF1
Fig. 24: TGA scan of Citrate salt Form Citrate-NF1
The identified novel salt forms as well as certain solvates thereof, have the
advantageous physicochemical properties and characteristics described in the following:
Hemifumarate salt Form A1 :
- Crystalline morphic form, very good crystallinity
- Slightly hygroscopic acc. to Ph. Eur. (section 5.11.), physisorption processes only
- High thermal stability (m.pJdec. >220 °C)
- Solubility levels in biorelevant intestinal media:
FaSSIF: -120 ug/mL ; FeSSIF: -1100 pg/mL
- Good and consistent manufacturability also in large scale (kg)
Processes for preparation of hemifumarate salt Form A1 : see Example 5.
A Powder X-Ray Diffraction pattern of hemifumarate salt Form A1 has been obtained by standard techniques as described in the European Pharmacopeia 6th Edition chapter 2.9.33, and is characterised by the following X-ray powder diffractogram (Cu- Kat radiation, λ = 1.5406 A, Stoe StadiP 611 KL diffractometer) (see FIG. 1):
Powder X-ray peak list of hemifumarate salt Form A1 :
No. °2Θ (Cu-Κ , radiation) ±
0.2°
1 6.9
2 7.6
3 13.4
4 13.9
5 15.2
6 17.3
7 17.7
8 18.3
9 18.6
10 19.1
11 19.5
12 19.8
13 20.1
14 20.9
15 23.1
16 23.7
17 24.3
18 24.8
19 25.2
20 25.6
21 27.9
Single crystal X-Ray Structure data were obtained on hemifumarate salt Form A1 as well (SuperNova diffractometer from Agilent, equipped with CCD Detector using Cu Κα radiation at 302 K, Fig. 2).
Hemifumarate salt Form A1 crystallises in the triclinic space group P-1 with the lattice parameters a = 7.4±0.1 A, b = 13.8±0.1 A, c = 14.5±0.1 A, and a = 111.5±0.5°, β = 101.0±0.5°, and γ = 91.0±0.5° ±0.5. From the single crystal structure it is clear that Form A1 represents an anhydrous form.
Form A1 can be further characterized by infrared and Raman-spectroscopy. FT- Raman and FT-IR spectra have been obtained by standard techniques as described in the European Pharmacopeia 6th Edition chapter 2.02.24 and 2.02.48. For measurement of the FT-IR and FT-Raman-spectra a Bruker Vector 22 and a Bruker
RFS 100 spectrometer have been used. FT-IR spectra and FT-Raman spectra have been base-line corrected using Bruker OPUS software.
An FT-IR spectrum has been obtained using a KBr pellet as sample preparation technique. The FT-IR spectrum is presented in Fig. 3 and band positions are given below:
Form A1 IR band positions +2 cm"1 (relative intensity*)
3432 cnY1 (w), 3074 cm-1 (w), 3039 cm-1 (w), 2968 cm'1 (w), 2908 cm'1 (w), 2857 cm'1 (w), 1683 cm"1 (w), 1629 cm'1 (m), 1545 cm'1 (w), 1519 cm"1 (w), 1508 cm"1 (w), 1454 cm"1 (m), 1418 cm'1 (w), 1333 cm"1 (m), 1248 cm'1 (w), 1224 cm"1 (w), 1161 cm"1 (m), 1112 cm"1 (m), 1024 cm'1 (w), 884 cm"1 (w), 810 cm"1 (w), 726 cm"1 (w), 575 cm"1 (w), 534 cm"1 (w)
*"s" = strong (transmittance < 50 %), "m" = medium (50 % < transmittance < 70 %), "w" = weak (transmittance > 70 %).
The respective FT-Raman spectrum is presented in Fig. 4 and band positions are given below:
Hemifumarate salt Form A1 Raman band positions +2 cm-1 (relative intensity*):
3069 cm'1 (w), 3040 cm-1 (w), 2999 cm'1 (m), 2981 cm"1 (w), 2970 cm'1 (m), 2909 crrf 1 (m), 1612 cm"1 (m), 1597 cm"1 (s), 1545 cm'1 (s), 1478 cm"1 (s), 1369 cm"1 (s)
*"s" = strong (relative Raman intensity > 0.2), "m" = medium (0.2 > relative Raman intensity > 0.1), "w" = weak (relative Raman intensity < 0.1)
Hemifumarate salt Form A1 is a crystalline anhydrous form, which is further characterised by the following physical properties:
- 1H-NMR data reveal a molar ratio fumarate:base of 0.5:1
- Thermal behaviour of Form A1 shows an overlapped
melting/decomposition processes >220 °C, with no significant weight loss up to this temperature. DSC (Fig. 5) and TGA (Fig. 6) profiles are displayed below. DSC scan of Form A1 was acquired on a Mettler- Toledo DSC 821 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min. TGA scan of Form A1 was acquired on a Mettler- Toledo TGA 851 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.
- Water Vapour Sorption behaviour small water uptake levels <1 wt% in the relative humidity (rh) range 0-90% rh. Form A1 can be classified as slightly hygroscopic acc. to Ph. Eur. Criteria (section 5.11.). Water Vapor Sorption isotherm (25 °C) of Form A1 is displayed in Fig. 7. Water Vapour Sorption isotherm was acquired on a DVS-lntrinsic system from SMS.
- Solubility of Form A1 in biorelevant intestinal media at 37 °C was
determined to be approx. 120 g/mL (FaSSIF, pH 6.5) and approx. 1.1 mg/mL (FeSSIF, pH 5.0), respectively (see example 7).
Overall, hemifumarate salt Form A1 reveals very good solid-state properties (very good crystallinity, slightly hygroscopic, high thermal stability) with sufficient solubility in biorelevant intestinal media and very good manufacturability in larger scale.
Hemifumarate salt Form H1
- Crystalline morphic form, very good crystallinity
- Slightly hygroscopic acc. to Ph. Eur. (section 5. 1.)
- Stable form in aqueous suspension media
- Solubility levels in biorelevant intestinal media:
FaSSIF: -150 Mg/mL ; FeSSIF: -1100 pg/mL
Processes for preparation of hemifumarate salt Form H1 : see Example 6.
A Powder X-Ray Diffraction pattern of hemifumarate salt Form H1 has been obtained by standard techniques as described in the European Pharmacopeia 6fh Edition chapter 2.9.33, and is characterised by the following X-ray powder diffractogram (Cu- Koti radiation, λ = 1.5406 A, Stoe StadiP 611 KL diffractometer, Fig. 8).
Powder X-ray peak list of hemifumarate salt Form H1
No. °2Θ (Cu-Koci radiation) ± 0.2°
1 6.6
2 7.6
3 8.3
4 10.2
5 1 1.6
6 14.4
7 15.6
8 16.5
9 16.7
10 18.8
1 1 19.1
12 19.6
13 20.5
14 20.8
15 21.6
16 21.8
17 22.2
18 22.6
19 23.0
20 24.1
21 25.9
Single crystal X-Ray Structure data were obtained on hemifumarate salt Form H1 as well (SuperNova d iff ractometer from Agilent, equipped with CCD Detector using Cu K« radiation at 302 K, Fig. 9).
Hemifumarate salt Form H1 crystallises in the triclinic space group P-1 with the lattice parameters a = 9.4±0.1 A, b = 13.1 ±0.1 A, c = 14.6±0.1 A, and a = 102.0±0.5°, /? = 103.6±0.5°, and γ = 110.9±0.5° ±0.5. From the single crystal structure it is clear that Form H1 represents a hydrate form.
Hemifumarate salt Form H1 can be further characterized by infrared and Raman- spectroscopy. FT-Raman and FT-IR spectra have been obtained by standard techniques as described in the European Pharmacopeia 6th Edition chapter 2.02.24 and 2.02.48. For measurement of the FT-IR and FT-Raman-spectra a Bruker Vector 22 and a Bruker RFS 100 spectrometer have been used. FT-IR spectra have been base-line corrected using Bruker OPUS software. FT-Raman spectra have been vector normalized using the same software.
An FT-IR spectrum has been obtained using a KBr pellet as sample preparation technique. The FT-IR spectrum and band positions are given in Fig. 10.
Hemifumarate salt Form H1 IR band positions +2 cm"1 (relative intensity*)
3440 cm-1 (m), 3062 cm-1 (w), 2958 cm-1 (m), 2909 cm'1 (w), 2865 cm-1 (m), 1639 cm" 1 (w), 1626 cm'1 (s), 1547 cm'1 (m), 1515 cm'1 (m), 1503 cm'1 (w), 1459 cm'1 (m), 1432 cm'1 (m), 1371 cm'1 (m), 1326 cm' (m), 1265 cm'1 (m), 1252 cm'1 (m), 1159 cm'1 (m), 1110 cm'1 (m), 1025 cm'1 (w), 879 cm'1 (w), 812 cm'1 (m), 670 cm'1 (w), 521 cm"1 (w),
*"s" = strong (transmittance < 50 %), "m" = medium (50 % < transmittance < 70 %), "w" = weak (transmittance > 70 %)
FT-Raman spectrum and band positions are given in Fig. 11.
Hemifumarate salt Form H1 Raman band positions +2 cm"1 (relative intensity*):
3078 cm-1 (w), 3064 cm-1 (w), 3039 cm-1 (w), 3010 cm'1 (w), 3001 cm'1 (w), 2960 cm-1 (w), 2910 cnT1 (w), 2865 cm'1 (w), 1612 cm-1 (m), 1597 cm'1 (m), 1546 cm-1 (m), 1486 cm'1 (m), 1371 cm"1 (m)
*"s" = strong (relative Raman intensity > 0.2), "m" = medium (0.2 > relative Raman intensity > 0.1), "w" = weak (relative Raman intensity < 0.1)
Hemifumarate salt Form H1 is a crystalline anhydrous form, which is further characterised by the following physical properties:
- 1H-NMR data reveal a molar ratio fumarate.base of 0.5:1
- Thermal behaviour of Form H1 shows overlapped multiple dehydration processes ~30-120 °C, followed by exothermic re-crystallisation of anhydrous form A1 at -150-180 °C. DSC (Fig. 12) and TGA Fig. 13) profiles are displayed below. DSC scan of Form H1 was acquired on a Mettler-Toledo DSC 821 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min. TGA scan of Form A2 was acquired on a Mettler-Toledo TGA 851 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.
- Water Vapour Sorption behaviour shows strong water uptake of ~7 wt% in low relative humidity (rh) range 0-20% rh, which can be assigned to hydrate formation. The reversible adsorption/desorption behaviour is in line with the channel structure. Form H1 can be classified as slightly hygroscopic acc. to Ph. Eur. Criteria (section
5.11.). Water Vapor Sorption isotherm (25 °C) of Form H1 is displayed in Fig. 14. Water Vapour Sorption isotherm was acquired on a DVS- Intrinsic System from SMS.
- Solubility of Form H1 in biorelevant intestinal media at 37 °C was
determined to be approx. 150 pg/mL (FaSSIF, pH 6.5) and approx. 1.1 mg/mL (FeSSIF, pH 5.0), respectively (see example 7).
Overall, Form H1 can be considered a more stable form in aqueous suspensions, and reveals similar good solubility as anhydrous form A1 in biorelevant intestinal media.
Hemifumarate salt, solvate forms:
Several solvate forms have also been found, which are identified by their respective Powder X-ray diffractograms as disclosed in the following. a) Hemifumarate salt Acetic Acid solvate form S1 (Fig. 15)
Powder X-ray peak list of hemifumarate salt Form S1
No. °2Θ (Cu-Και radiation) ±
0.2°
1 7.6
2 9.8
3 10.7
4 13.1
5 13.6
6 14.0
7 14.2
8 14.5
9 16.2
10 17.7
11 18.2
12 18.8
13 20.2
14 20.7
15 21.5
16 21.6
17 22.2
22.5
18
19 24.0
20 24.9
21 25.3
b) Hemifumarate salt Acetic Acid solvate form S2 (Fig. 16):
Powder X-ray peak list of hemifumarate salt Form S2
No. °2θ (Cu-Kcci radiation) ±
0.2°
1 7.7
2 9.8
3 10.8
4 10.9
5 13.2
6 13.5
7 14.1
8 14.4
9 15.8
10 17.0
11 17.4
12 18.3
13 18.7
14 19.2
15 20.4
16 20.7
17 21.0
18 21.2
19 21.7
20 22.8
21 24.1
22 25.2
23 26.0
c) Hemifumarate salt Dioxane solvate form S3 (Fig. 17): Powder X-ray peak list of hemifumarate salt Form S3
No. °2Θ (Cu-Kcci radiation) ±
0.2°
1 6.0
2 11.5
4 15.2
5 16.4
6 16.9
7 17.3
8 18.0
9 18.3
10 19.2
11 19.4
12 19.9
13 20.7
14 21.9
15 23.0
16 23.8
17 24.3
18 24.6
19 24.9
20 25.3
21 25.9
22 26.1
23 26.9
Form Besylate-NF1 :
- Crystalline morphic form, very good crystallinity
- Slightly hygroscopic acc. to Ph. Eur. (section 5.11.), physisorption processes only
- High thermal stability (m.p./dec. >250 °C)
- Good manufacturability also in larger scale (10 g)
Processes for preparation of besylate salt Form Besylate-NF1: see Example 4 and Example 8.
A Powder X-Ray Diffraction pattern of besylate salt Form Besylate-NF1 has been obtained by standard techniques as described in the European Pharmacopeia 6th Edition chapter 2.9.33, and is characterised by the following X-ray powder
diffractogram (Cu-Kct] radiation, λ = 1.5406 A, Stoe StadiP 611 KL diffractometer, Fig. 18).
Powder X-ray peak list of citarte salt Form Besylate-NF1
No. °2Θ (Cu-Koci radiation) ±
0.2°
1 6.5
2 8.1
3 9.7
4 11.6
5 13.0
6 13.8
7 14.8
8 15.4
9 17.4
10 17.6
11 17.9
12 18.3
13 18.6
14 18.8
15 19.7
16 20.0
17 22.2
18 22.3
19 23.5
20 24.1
21 26.0
22 27.5
Besylate salt Form Besylate-NF1 can be further characterized by Raman- spectroscopy. FT-Raman spectrum has been obtained by standard techniques as described in the European Pharmacopeia 6th Edition chapter 2.02.48. For
measurement of the FT-Raman-spectrum a Bruker RFS 00 spectrometer has been used. FT-Raman spectrum has been base-line corrected using Bruker OPUS software.
FT-Raman spectrum and band positions are given in Fig. 19.
Besylate salt Form Besylate-NF1 Raman band positions +2 cm"1 (relative intensity*):
3076 cnr1 (w), 3058 cm"1 (w), 3023 cm"1 (w), 3002 cm"1 (w), 2990 cm"1 (w), 2955 cm"1 (m), 2901 cm"1 (w), 2870 cm"1 (w), 1611 cm"1 (m), 1604 cm"1 (m), 1590 cm"1 (w), 1544 cm"1 (w), 1481 cm"1 (m), 1368 cm"1 (w), 999 cm"1 (m)
*"s" = strong (relative Raman intensity > 0.2), "m" = medium (0.2 > relative Raman intensity > 0.1), "w" = weak (relative Raman intensity < 0.1)
Besylate salt Form Besylate-NF1 is a crystalline anhydrous form, which is further characterised by the following physical properties:
- 1H-NMR data reveal a molar ratio besylate:base of :1 .
- Thermal behaviour of Form Besylate-NF1 shows a melting peak >250 °C, with no significant weight loss up to this temperature. DSC (Fig. 20) and TGA profiles (Fig. 21) are displayed below. DSC scan of Form Besylate-NF1 was acquired on a Mettler-Toledo DSC 821 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min. TGA scan of Form Besylate-NF1 was acquired on a Mettler-Toledo TGA 851 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.
- Water Vapour Sorption behaviour small water uptake levels≤1 wt% in the relative humidity (rh) range 0-90% rh. Form Besylate-NF1 can be classified as slightly hygroscopic acc. to Ph. Eur. Criteria (section 5.11.). Water Vapor Sorption isotherm (25 °C) of Form Besylate-NF1 is displayed in Fig. 22. Water Vapour Sorption isotherm was acquired on a DVS-lntrinsic system from SMS.
Overall, besylate salt Form Besylate-NF1 reveals very good solid-state properties (very good crystallinity, slightly hygroscopic, high thermal stability). Also, good manufacturability in scales up to 10 g are demonstrated (see Example 8).
Form Citrate-NF1 :
- Crystalline morphic form, good crystallinity
- High thermal stability (dec. >150 °C)
- Good manufacturability
Processes for preparation of citrate salt Form Citrate-NF1 : see Example 9.
A Powder X-Ray Diffraction pattern of citrate salt Form Citrate-NF1 has been obtained by standard techniques as described in the European Pharmacopeia 6' Edition chapter 2.9.33, and is characterised by the following X-ray powder
diffractogram (Cu-Κα radiation, λ = 1.5418 A, X'Pert PRO-MPD, PANalytical, SPRI, Fig. 23).
Powder X-ray peak list of citrate salt Form Citrate-NF1
No. °2Θ (Cu-Κα
radiation) ±
0.2°
1 4.9
2 7.5
3 9.7
4 10.4
5 13.3
6 13.9
7 14.8
8 15.1
9 15.8
10 17.7
11 18.6
12 19.1
13 19.4
14 20.2
15 20.8
16 21.9
17 22.9
19 24.4
20 24.6
21 28.0
Citrate salt Form Citrate-NF1 is a crystalline anhydrous form, which is further characterised by the following physical properties:
- 1 H-NMR data reveal a molar ratio citrate:base of 1 : 1.
- Thermal behaviour of Form Citrate-NF1 shows small weight loss
processes up to ~150 °C, being indicative for high thermal stability and no solvate or hydrate form being present. The TGA profile is displayed in Fig. 24. TGA scan of Form Citrate-NF1 was acquired on TA
Instrumenets Q500 with a ating rate of 20 K/min, using nitrogen purge gas atmosphere.
Examples
Example 1 : Processes for preparation of free base (forms NF1 and NF2)
a) Free base form NF1
Approx. 33 g free base (following procedure AD from WO2011058149) was
suspended in EtOH (ethanol, approx. 250 mL) and redissolved by addition of DCM (dichloromethane, approx. 250 mL).DCM was distilled (oil bath temperature 80°C then 120°C), the heating was switched off and the solution was stirred overnight at RT. The precipitatewas filtered off and dried under vacuum to afford a yellow solid.
1H NMR (DMSO-d6) δ 7.69 - 7.37 (m, 6H), 6.66 (d, J = 7.9 Hz, 1 H), 5.00 (s, 2H), 3.95 (d, J = 5.6 Hz, 2H), 3.78 - 3.53 (m, 12H), 2.46 - 2.30 (m, 4H)
b) Free base form NF2
Approx. 6-7 g free base (following procedure AD from WO20 1058149) was dissolved in 800 mL EtOH and re-crystallised under reflux. The resuling suspension was filtered and dried under vacuum at 00 °C for 1.5 h to afford a white powder.
1H NMR (DMSO-d6) δ 7.71 - 7.33 (m, 6H), 6.77 - 6.56 (m, 1 H), 4.99 (s, 2H), 3.95 (t, J = 4.6 Hz, 2H), 3.79 - 3.52 (m, 12H), 2.42 (del, J = 5.6, 3.6 Hz, 4H)
Example 2: Assessment of thermodynamic stability order of free base forms NF1 vs NF2
Thermodynamic stability of free base forms NF1 vs NF2 was assessed by melting data of both forms as compiled below:
As free base form NF2 exhibits significantly higher melting point onset as well as heat of fusion, this form can be considered the thermodynamically more stable form, with monotropic relationship between both forms.
Example 3: Unsuccessful! up-scale trials for preparation of free base form NF2 a) Crystallisation processes in 2-Propanol :
i) Small scale experiment:
Approx. 50 mg free base (following procedure AD from WO2011058149) were dissolved in approx. 600 μΙ_ of hot 2-Propanol and re-crystallised at RT.
The resulting suspension was filtered to afford a powder representing Free Base form NF2.
ii) Up-scaling experiment:
Approx. 150 mg free base (following procedure AD from WO2011058149) were dispersed in 0.75 mL 2-Propanol and slurried at reflux.
The resulting suspension was filtered to afford a powder representing a mixture of Free Base forms NF1 + NF2.
b) Crystallisation processes in Ethanol:
i) Small scale experiment:
Approx. 30 mg free base (following procedure AD from WO2011058149) were dissolved in approx. 400 μΙ_ of hot Ethanol and re-crystallised at RT.
The resulting suspension was filtered to afford a powder representing Free Base form NF2.
ii) Up-scaling experiment:
Approx. 1.47 g free base (following procedure AD from WO2011058149) were dissolved in 200 mL hot Ethanol solution, and re-crystallised in the hot solution over 18 h.
The resulting suspension was filtered to afford a powder representing Free Base form NF1 with small amounts of Free Base form NF2.
c) Crystallisation processes in Dichloromethane: Ethanol mixtures:
i) Small scale experiment:
Approx. 1 g free base (following procedure AD from WO2011058149) were dissolved in approx. 10 mL Dichloromethane (DCM). After addition of approx. 10 mL Ethanol, DCM was slowly evaporated under vaccum. From the remaining solution crystallisation occurred at RT after several hours.
The resulting suspension was filtered to afford a powder representing Free Base form NF2.
ii) Up-scaling experiment 1 :
Approx. 33 g free base (following procedure AD from WO2011058149) were dissolved in approx. 165 mL Dichloromethane (DCM). After addition of approx. 264 mL Ethanol, DCM was slowly evaporated under at 80 °C. After removal of the heating jacket, crystalllisation occurred from the remaining solution after approx. 4 hours.
The resulting suspension was filtered to afford a powder representing Free Base form NF1.
iii) Up-scaling experiment 2:
Approx. 66 g free base (following procedure AD from WO2011058149) were dissolved in approx. 660 mL Dichloromethane (DCM). After addition of approx. 1320 mL Ethanol, DCM was slowly evaporated under vacuum (water batch temperature 50 °C) until crystallisation.
The resulting suspension was filtered to afford a powder representing a mixture of Free Base form NF1 and a DCM solvate form.
Example 4: Salt formation trials
Approx. 1-5 mg of free base (following procedure AD from WO201 058149) were dispersed at RT with equimolar quantities of respective acids in separate experiments in Ethanol, Acetone, 2-Butanone, Acetonitrile, THF, 1 ,4-Dioxane, Chloroform, Dichloromethane, Acetic Acid, and Isopropylether, respectively. Crystallisation was then attempted via fast evaporation (nitrogen flux), fast cooling (solution put in fridge at 4 °C), and slow evaporation at ambient conditions. Salt formation was assessed by comparison of XRD data with free base and acid patterns.
a) HCI salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials. b) Sulfate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials. c) Phosphate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials. d) HBr salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials. e) Maleate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials. f) Aspartate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials. g) Fumarate salt:
XRD data suggested potential salt formation from experiments in Chloroforme, Isopropylether, and THF, respectively (all re-crystallised from solutions at 4 °C). TGA data on samples obtained from Isopropylether and THF revealed strong weight loss, strongly indicating solvate forms being formed.
h) Mesylate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials.
i) Esylate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials, j) Edisylate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials, k) Tosylate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials. I) Besylate salt:
XRD data suggested potential salt formation from experiments in 2-Butanone and THF (both from fast solvent evaporation), and from experiment in Acetonitrile (slow solvent evaporation). TGA data on sample obtained from 2-Butanone revealed strong weight loss, strongly indicating a solvate form being formed.
m) Glutatamate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials, n) Malonate salt:
No crystalline salt form was obtained from any of the solvent crystallisation trials, o) L-Tartrate salt:
XRD data suggested potential salt formation from experiments in THF, Acetone, Acetonitrile, Chloroform, Dichloromethane, and Isopropylether (all from crystallisation at 4 °C), from experiments in Acetone, Dichloromethane, and Isopropylether (fast solvent evaporation), and from experiment in Ethanol (slow solvent evaporation). TGA data on sample obtained from Acetonitrile revealed strong weight loss, strongly indicating a solvate form being formed. XRD data further suggested at least two different polymorphic forms being present from potential L-Tartrate salt.
p) Citrate salt:
XRD data suggested potential salt formation from experiment in THF (from crystallisation at 4 °C).
Example 5: Processes for preparation of hemifumarate salt form A1
a) Method 1 : crystallisation from Ethanol:
Approx. 1 g free base (following procedure AD from WO2011058149) and approx. 110 mg fumaric acid were slurried in EtOH (20.00 mL at 80°C for 24h after which it
was filtered to give a white powder, which was dried overnight under vacuum.
1H NMR (DMSO-d6) δ 13.15 (bs, 1H), 7.53-7.60 (m, 3H), 7.43-7.50 (m, 3H), 6.64- 6.67 (d, J = 7.9 Hz, 1 H), 6.62 (s, 1H), 5.01 (s, 2H), 3.95 (m, 2H), 3.59-3.68 (m, 12H), 2.41 (m, 4H)
b) Method 2: crystallisation from Acetone:
To a dry, nitrogen-purged 100-L reactor with a mechanically stirred solution of acetone (75L) was added at a jacket temperature of 25°C, 2.34kg (4.45 mol) free base (following procedure AD from WO2011058149). The jacket temperature was raised to 75°C and stirred for 0.5 hours, which resulted in a clear solution. Fumaric Acid (0.31kg, 2.67mol) was added and stirring continued for 0.5 hours. The heater was shut down and the clear solution was stirred further. After 1 hour (internal temperature 52°C) a precipitation occurred. Stirring was continued over night
(internal temperature 27°C). The suspension was cooled down to 10°C within 1.5 hours and filtered over a 45cm-glass-filter-Nutsche. The remaining cake was washed with acetone (2 x 2L). The solid was dried in a drying oven over night (50°C,
30mbar). The crude product (2.276kg) was grinded in a grater (0.75mm mesh), which afforded 2.240kg (yield = 86%) of a white solid.
1H NMR (DMSO-d6) δ 7.63 - 7.40 (m, 6H), 6.68 - 6.63 (m, 1 H), 6.62 (s, 1 H), 5.00 (s, 2H), 3.95 (t, J = 4.7 Hz, 2H), 3.73 - 3.64 (m, 4H), 3.64 - 3.58 (m, 8H), 2.46 - 2.37 (m, 4H)
Example 6: Processes for preparation of hemifumarate salt form H1
a) Method 1 : crystallisation from Ethanol:
Approx. 320 mg hemifumarate salt A1 (following example 5) was dispersed in 10 mL MeOH and stirred at RT for approx. 45 hours. After adding further 10 mL MeOH, the suspension was further stirred for approx. 27 hours. Small amounts of water (50 pL) was added to the suspension, and further stirred for approx. 90 hours. The suspension was filtered, and dried under vacuum overnight at RT.
1H NMR (DMSO-d6) δ 7.62 - 7.40 (m, 6H), 6.66 (d, J = 8.0 Hz, 1 H), 6.62 (s, 1 H), 5.00 (s, 2H), 4.01 - 3.89 (m, 2H), 3.72 - 3.64 (m, 4H), 3.64 - 3.57 (m, 8H), 2.45 - 2.38 (m, 4H)
b) Method 2: aqueous suspension conversion from hemifumarate salt form A1 :
Approx. 37 mg hemifumarate salt A1 (following example 5) was dispersed in 0.6 ml_ USP Gastric Juice (pH 1.2) and stirred at RT for approx. 7 days. The suspension was centrifuged, and dried at ambient conditions overnight.
1H NMR (DMSO-d6) δ 7.63 - 7.40 (m, 6H), 6.68 - 6.64 (m, 1 H), 6.62 (s, 1 H), 4.99 (s, 2H), 4.01 - 3.90 (m, 2H), 3.74 - 3.52 (m, 12H), 2.46 - 2.37 (m, 4H)
Approx. 15 mg hemifumarate salt A1 (following example 5) was dispersed in 0.4 ml_ Dl Water and stirred at RT for approx. 5 weeks. The suspension was centrifuged, and dried at ambient conditions overnight.
Example 7: Solubility determinations of hemifumarate salt forms (A1 and H1)
Approximately 2-5 mg of [6-Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5- dihydro-1 H-5l6-thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone
hemifumarate salt (form A1 , form H1) were dispersed in 1-2 ml_ FaSSIF medium (pH 6.5) or FeSSIF medium (pH 5.0), respectively, in Whatman Uniprep Syringless Filter vials.
All dispersions were agitated at 37 °C for 24 hours. Dispersions were then filtered via the internal filter of the Uniprep vials, and clear filtrates were analysed by HPLC for dissolved quantities of N-((S)-2,3-Dihydroxy-propyl)-3-(2-fluoro-4-iodo-phenylamino)- isonicotinamide.
Results from solubility determinations are summarised below.
Both hemifumarate salt forms exhibit comparable and high solubility levels in biorelevant intestinal media.
Example 8: Processes for preparation of besylate salt form Besylate-NF1
a) Method 1 :
Approx. 10 g free base (following procedure AD from WO2011058149) was dissolved in approx. 90 mL anhydrous acetonitrile under reflux. Approx. 3.3 g Benzensulfonic Acid which was pre-dissolved in approx. 10 mL anhydrous acetonitrile was added to the refluxing solution of free base. After starting crystallisation under reflux, the heating bath was removed and the mixture was stirred at RT for 1 hour, and then at 0°C for 30 minutes.. The suspension was filtered off and dried under vacuum to give an off-white powder. After concentration of the mother liquors under vacuum, the resulting precipitate was also filtered off and washed with acetonitrile and acetone. Both separated powder fractions were re-combined in water (200 mL), and heated to 70 °C. After addition of further 30 mL water, the resulting fine suspension was removed by filtration as hot solution. The hot clear filtrate was concentrated down to approx. 80 mL at 70 °C, and then cooled down to RT. Resulting suspension was filtered off, washed with water, and dried under vacuum.
1H NMR (DMSO-d6) δ 9.85 (s, 1 H), 7.85 - 7.44 (m, 8H), 7.38 - 7.22 (m, 3H), 6.70 (d, J = 7.9 Hz, 1 H), 5.01 (s, 2H), 4.48 (s, 2H), 4.13 - 3.86 (m, 4H), 3.77 - 3.53 (m, 8H), 3.30 - 3.05 (m, 4H)
Example 9: Processes for preparation of citrate salt form Citrate-NF1
a) Method 1 :
Approx. 1 g free base (following procedure AD from WO201 1058149) and approx. 401.3 mg Citric Acid were dispersed in approx. 20 mL water and heated at 100 °C. Further quantities of water were added portion-wise (~10 mL) until a clear solution was obtained. The solution was concentrated under vacuum (water batch
temperature 70 °C) down to a volume of approx. 15 mL, and further stirred overnight at RT. The resulting suspension was filtered off, washed with water, and dried under vacuum.
1H NMR (DMSO) δ 7.64 - 7.52 (m, 3H), 7.52 - 7.42 (m, 3H), 6.66 (dd, J = 8.0, 1.0 Hz, 1 H), 5.01 (s, 2H), 3.99 - 3.90 (m, 2H), 3.73 - 3.56 (m, 12H), 2.74 (d, J = 15.4 Hz, 2H), 2.63 (d, J = 15.4 Hz, 2H), 2.52 - 2.44 (m, 4H).
Claims
1. [6-Fluoro-1 -(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1 H-5I6- thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone hemifumarate salt Form A1 , having a molar ratio of fumarate:base of 0.5:1 and being
characterized by the following data: a) Powder X-Ray Diffraction pattern
Powder X-ray peak list of hemifumarate salt Form A1 :
No. °2Θ (Cu-Κα! radiation) +
0.2°
1 6.9
2 7.6
3 13.4
4 13.9
5 15.2
6 17.3
7 17.7
8 18.3
9 18.6
10 19.1
11 19.5
12 19.8
13 20.1
14 20.9
15 23.1
16 23.7
17 24.3
18 24.8
19 25.2
20 25.6
21 27.9
b) Single crystal X-Ray Structure data
Hemifumarate salt Form A1 crystallises In the trlclinlc space group P-1 with the lattice parameters a = 7.4±0.1 A, b = 13.8±0.1 A, c = 14.5±0.1 A, and a = 1 11.5±0.5°, ? = 101.0±0.5°, and γ = 91.0±0.5° ±0.5. c) Infrared spectroscopy data
Form A1 IR band positions +2 cm"1 (relative intensity*)
3432 cm-1 (w), 3074 cm'1 (w), 3039 cm'1 (w), 2968 cm"1 (w), 2908 cm"1 (w), 2857 cm'1 (w), 1683 cm'1 (w), 1629 cm"1 (m), 1545 cm"1 (w), 1519 cm"1 (w), 1508 cm'1 (w), 1454 cm'1 (m), 1418 cm'1 (w), 1333 cm'1 (m), 1248 cm'1 (w), 1224 cm"1 (w), 1 161 cm'1 (m), 1112 cm'1 (m), 1024 cm'1 (w), 884 cm'1 (w), 810 cm"1 (w), 726 cm"1 (w), 575 cm"1 (w), 534 cm"1 (w)
*"s" = strong (transmittance < 50 %), "m" = medium (50 % < transmittance < 70 %), "w" = weak (transmittance > 70 %) d) Raman-spectroscopy data
Hemifumarate salt Form A1 Raman band positions +2 cm'1 (relative
intensity*):
3069 cm"1 (w), 3040 cm'1 (w), 2999 cm"1 (m), 2981 cm"1 (w), 2970 cm"1 (m), 2909 cm"1 (m), 1612 cm"1 (m), 1597 cm"1 (s), 1545 cm'1 (s), 1478 cm'1 (s), 1369 cm"1 (s)
*"s" = strong (relative Raman intensity > 0.2), "m" = medium (0.2 > relative Raman intensity > 0.1 ), "w" = weak (relative Raman intensity < 0.1)
2. [6-Fluoro-1 -(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1 H-5I6- thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone hemifumarate salt Form H1 , having a molar ratio of fumarate:base of 0.5: 1 and being
characterized by the following data: a) Powder X-Ray Diffraction pattern
Powder X-ray peak list of hemifumarate salt Form H1
No. °2Θ (Cu-Kcti radiation) ±
0.2°
1 6.6
2 7.6
3 8.3
4 10.2
5 1 1.6
6 14.4
7 15.6
8 16.5
9 16.7
10 18.8
1 1 19.1
12 19.6
13 20.5
14 20.8
15 21.6
16 21.8
17 22.2
18 22.6
19 23.0
20 24.1
21 25.9
b) Single crystal X-Ray Structure data
Hemifumarate salt Form H1 crystallises in the triclinic space group P-1 with the lattice parameters a = 9.4±0.1 A, b = 13.1 ±0.1 A, c = 14.6±0.1 A, and a = 102.0±0.5°, β- 103.6±0.5°, and y = 110.9±0.5° ±0.5
c) Infrared spectroscopy data
Hemifumarate salt Form H1 IR band positions +2 cm"1 (relative intensity*)
3440 cm-1 (m), 3062 cm"1 (w), 2958 cm'1 (m), 2909 cm"1 (w), 2865 cm'1 (m), 1639 cm'1 (w), 1626 cm'1 (s), 1547 cm'1 (m), 1515 cm'1 (m), 1503 cm'1 (w), 1459 cm'1 (m), 1432 cm'1 (m), 1371 cm'1 (m), 1326 cm'1 (m), 1265 cm'1 (m), 1252 cm'1 (m), 1159 cm'1 (m), 1110 cm'1 (m), 1025 cm'1 (w), 879 cm'1 (w), 812 cm"1 (m), 670 cm"1 (w), 521 cm"1 (w),
*"s" = strong (transmittance < 50 %), "m" = medium (50 % < transmittance < 70 %), "w" = weak (transmittance > 70 %) d) Raman-spectroscopy data
Hemifumarate salt Form H1 Raman band positions +2 cm"1 (relative intensity*):
3078 cm'1 (w), 3064 cm-1 (w), 3039 cm'1 (w), 3010 cm'1 (w), 3001 cm'1 (w), 2960 cm'1 (w), 2910 cm'1 (w), 2865 cm'1 (w), 1612 cm'1 (m), 1597 cm'1 (m), 1546 cm'1 (m), 1486 cm'1 (m), 1371 cm'1 (m)
*"s" = strong (relative Raman intensity > 0.2), "m" = medium (0.2 > relative Raman intensity > 0.1), "w" = weak (relative Raman intensity < 0.1)
3. [6-Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1 H-5l6- thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone besylate salt Form NF1, having a molar ratio besylate:base of 1 :1 and being characterized by the following data:
a) Powder X-Ray Diffraction pattern
Powder X-ray peak list of besylate salt Form Besylate-NF1
No. °2Θ (Cu-Και radiation) ±
0.2°
1 6.5
2 8.1
3 9.7
4 11.6
5 13.0
6 13.8
7 14.8
8 15.4
9 17.4
10 17.6
11 17.9
12 18.3
13 18.6
14 18.8
15 19.7
16 20.0
17 22.2
18 22.3
19 23.5
20 24.1
21 26.0
22 27.5
b) Raman-spectroscopy data
Besylate salt Form Besylate-NF1 Raman band positions +2 cm"1 (relative intensity*):
3076 cm"1 (w), 3058 cm"1 (w), 3023 cm"1 (w), 3002 cm"1 (w), 2990 cm"1 (w), 2955 cm'1 (m), 2901 cm"1 (w), 2870 cm"1 (w), 1611 cm"1 (m), 1604 cm'1 (m), 1590 cm'1 (w), 1544 cm"1 (w), 1481 cm"1 (m), 1368 cm"1 (w), 999 cm"1 (m)
*"s" = strong (relative Raman intensity > 0.2), "m" = medium (0.2 > relative Raman intensity > 0.1), "w" = weak (relative Raman intensity < 0.1)
4. [6-Fluoro-1-(4-morpholin-4-ylmethyl-phenyl)-5,5-dioxo-4,5-dihydro-1 H-5l6- thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-yl-methanone citrate salt Form NF1 , having a molar ratio citrate:base of 1 :1 and being characterized by the following data:
Powder X-ray peak list of citrate salt Form Citrate-NF1
No. °2Θ (Cu-Κα radiation) ± 0.2°
1 4.9
2 7.5
3 9.7
4 10.4
5 13.3
6 13.9
7 14.8
8 15.1
9 15.8
10 17.7
11 18.6
12 19.1
13 19.4
14 20.2
15 20.8
16 21.9
17 22.9
18 24.0
19 24.4
20 24.6
21 28.0
5. Salt forms according to claims 1 , 2, 3 or 4 for use as a medicament.
6. Pharmaceutical composition comprising a salt form according to claims 1 , 2, 3 or 4, and one or more excipients.
7. Solid oral dosage form comprising a salt form according to claims 1 , 2, 3 or 4.
8. Dry compression tablet comprising a salt form according to claims 1 , 2, 3 or 4.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113754685A (en) * | 2020-06-02 | 2021-12-07 | 江苏恒瑞医药股份有限公司 | Dihydrothiochromene pyrazole derivative, preparation method and medical application thereof |
| CN113754678A (en) * | 2020-06-02 | 2021-12-07 | 江苏恒瑞医药股份有限公司 | Dihydrothiochromene pyrazole derivative, preparation method and medical application thereof |
| WO2022007924A1 (en) * | 2020-07-09 | 2022-01-13 | 江苏恒瑞医药股份有限公司 | Oxa-azabicyclic derivative, preparation method therefor and medical use thereof |
| WO2022022630A1 (en) | 2020-07-29 | 2022-02-03 | 江苏恒瑞医药股份有限公司 | Oxa-azaspiro derivative, and preparation method therefor and pharmaceutical use thereof |
| WO2022207648A1 (en) | 2021-03-29 | 2022-10-06 | Ionctura Sa | A pi3k-delta inhibitor for the treatment of pancreatic cancer |
| WO2022207646A1 (en) | 2021-03-29 | 2022-10-06 | Ionctura Sa | A pi3k-delta inhibitor for use in treatment regimens |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113754685A (en) * | 2020-06-02 | 2021-12-07 | 江苏恒瑞医药股份有限公司 | Dihydrothiochromene pyrazole derivative, preparation method and medical application thereof |
| CN113754678A (en) * | 2020-06-02 | 2021-12-07 | 江苏恒瑞医药股份有限公司 | Dihydrothiochromene pyrazole derivative, preparation method and medical application thereof |
| CN113754678B (en) * | 2020-06-02 | 2023-03-10 | 江苏恒瑞医药股份有限公司 | Dihydrothiochromene pyrazole derivative, preparation method and medical application thereof |
| WO2022007924A1 (en) * | 2020-07-09 | 2022-01-13 | 江苏恒瑞医药股份有限公司 | Oxa-azabicyclic derivative, preparation method therefor and medical use thereof |
| WO2022022630A1 (en) | 2020-07-29 | 2022-02-03 | 江苏恒瑞医药股份有限公司 | Oxa-azaspiro derivative, and preparation method therefor and pharmaceutical use thereof |
| CN115836077A (en) * | 2020-07-29 | 2023-03-21 | 江苏恒瑞医药股份有限公司 | Oxaazaspiro derivatives, preparation method and medical application thereof |
| WO2022207648A1 (en) | 2021-03-29 | 2022-10-06 | Ionctura Sa | A pi3k-delta inhibitor for the treatment of pancreatic cancer |
| WO2022207646A1 (en) | 2021-03-29 | 2022-10-06 | Ionctura Sa | A pi3k-delta inhibitor for use in treatment regimens |
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