CHIN SEIHO (KR)
LEE SUMIN (KR)
| Claims 1. Crystalline l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N- methylazetidin-3-amine mono succinate characterized by one or more XRPD reflections at approximately (°20) 18.0, 24.4 and/or 27.6 (±0.2 degrees). 2. The crystalline compound according to claim 1, characterized by one or more XRPD reflections at approximately (°20) 7.5, 16.8, 18.0, 21.8, 24.4 and/or 27.6 (±0.2 degrees). 3. The crystalline compound according to any one of claims 1-2, characterized by XRPD reflections at approximately (°20) 18.0, 24.4 and 27.6 (±0.2 degrees). 4. The crystalline compound according to claims 1-3, characterized by XRPD reflections at approximately (°20) 7.5, 16.8, 18.0, 21.8, 24.4 and 27.6 (±0.2 degrees). 5. The crystalline compound according to any one of claims 1-4, wherein the crystalline compound has an XRPD pattern essentially similar to the XRPD pattern in Figure 1A or IB. 6. The crystalline compound according to any one of claims 1-4, wherein the crystalline compound has an XRPD pattern according to the XRPD pattern in Figure 1A or IB. 7. The crystalline compound according to any one of claims 1-6, wherein the crystalline compound is characterized by a solid state 13C CP/MAS NMR spectrum with peaks at one or more of 178.0, 177.0, 152.1, 147.7, 146.9, 140.3, 137.8, 129.3, 113.5, 63.3, 57.9, 57.1, 51.2, 35.8, 33.6, 30.9, 27.4 and /or 13.3 ppm ±0.2 ppm. 8. The crystalline compound according to claim 7 characterized by having a 13C CP/MAS NMR spectrum essentially similar to the 13C CP/MAS NMR spectrum in Figure 3. 9. The crystalline compound according to claim 7 characterized by having a 13C CP/MAS NMR spectrum according to the 13C CP/MAS NMR spectrum in Figure 3. 10. The crystalline compound according to any one of claims 7-9, further characterized by one or more XRPD reflections at approximately (°20) (°20) 18.0, 24.4 and 27.6 (±0.2 degrees). 11. The crystalline salt according to any one of claims 1-10 which has a DSC and TGA curve consisting of two not separated endothermic events with an onset at 179.0±2°C and a corresponding weight loss in the TGA curve. 12. The crystalline compound according to any one of claims 1-11 which has a DSC and TGA curve essentially similar to the curves shown in Figure 2. 13. A pharmaceutical composition comprising a crystalline salt according to any of the preceding claims and a pharmaceutically acceptable carrier. 14. A compound or pharmaceutical composition according to any one of the preceding claims for use in the treatment of disease selected from atopic dermatitis, itch, pruritus, and various forms of urticaria. 15. A compound or pharmaceutical composition for use according to claim 14 wherein the disease is atopic dermatitis. |
SUMMARY OF THE INVENTION
The present invention relates to a novel crystalline form of l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate, pharmaceutical compositions comprising the novel crystalline form of l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate and to the use of the novel crystalline form for the treatment of diseases, such as atopic dermatitis (AD), itch, pruritus and various forms of urticaria for example chronic idiopathic urticaria subtypes, such as cholinergic urticaria. Also provided herein is a method of preparing the crystalline form of the invention.
BACKGROUND OF THE INVENTION
US patent no. 9586959 relates, among other compounds, to the compound l-(8- bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-meth ylazetidin-3-amine and pharmaceutically acceptable salts thereof as well as pharmaceutical compositions comprising the same. The patent discloses the preparation of a number of salts of the compound l-(8- bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-meth ylazetidin-3-amine. l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N -methylazetidin-3-amine exhibits a strong histamine 4 receptor inhibitory effect and shows suppressive effects against histamine induced infiltration of inflammatory cells such as mast cells and eosinophils. The compound thus has strong anti-inflammatory and anti-itching effects and may therefore be useful for treating a range of diseases such as those disclosed in US patent No. 9586959, including AD.
Different crystalline solid forms of chemical compounds may have distinct physical properties such as e.g. chemical stability, physical stability, hygroscopicity, melting point, solubility, dissolution rate, morphology and bioavailability which make them more or less suitable as the selected active ingredient in a pharmaceutical product.
In addition, a chemical entity may exist in several different crystalline solid forms and these include different polymorphic forms that share the same sum formula (e.g. anhydrates) and different solvates (e.g. hemihydrate, monohydrate and dihydrates) of the same chemical entity which do not share the same sum formula. Such crystalline solid forms have distinct crystal structures and vary in physical properties. The different crystalline solid forms can be distinguished from each other by e.g. melting point, XRPD pattern, spectral characteristics (e.g. FT-IR, Raman and SS-NMR), and other physical and chemical properties. Chemical entities can also exist in amorphous form.
The actual crystalline form selected therefore plays an important role in the development and manufacture of an active pharmaceutical ingredient. Should a single crystal form be required, it is important that the crystallization process be robust and reliably produce the desired crystalline form in polymorphically pure form and that the crystalline form does not change (e.g. interconvert to a different crystalline form) during the relevant manufacturing processes, and/or during storage.
A number of different salts of l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N - methylazetidine have been identified. Some of the salts appear as anhydrate, others as monohydrates and dihydrates each in several polymorphic forms that interconvert upon drying or loses water at relatively low temperature and they are therefore not suitable for development as a pharmaceutical.
The novel crystalline form according to the invention is a crystalline form of l-(8- bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-meth ylazetidine monosuccinate. The new crystalline form is herein after called form B.
SUMMARY OF THE INVENTION
The present invention relates to crystalline form B of l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne monosuccinate characterized by one or more XRPD reflections at approximately (20) 7.5, 16.8 and/or 21.8 (±0.2 degrees).
The invention also relates to a pharmaceutical composition comprising the crystalline form mentioned above and a pharmaceutically acceptable carrier.
In one embodiment the invention relates to a compound or pharmaceutical composition as described above for the treatment of disease selected from atopic dermatitis, itch, pruritus, and various forms of urticaria, including chronic idiopathic urticaria subtypes. DETAILED DESCRIPTION OF THE INVENTION
The technical problem underlying the present invention is to circumvent the drawbacks of other crystalline and/or amorphous forms of l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3- a]pyrazin-4-yl)-N-methylazetidin-3-amine such as, ability to form crystals, filtration properties, solubility, thermodynamic properties, stability issues (e.g. due to water uptake), density, and transformation (e.g. interconversion to other polymorphic forms or hydrates/anhydrates) at varying degrees of humidity and during crystallization processes.
Experiments resulted in 14 different polymorphic forms of the l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne monosuccinate. Some were not isolated in pure forms and some converts to other forms upon gentle drying.
Form B have excellent crystallinity, stability and thermal properties.
DEFINITIONS
As used herein the term "rt" or "room temperature" indicates that the applied temperature is not critical and that no exact temperature value have to be kept. Usually, "rt " or "room temperature" is understood to mean temperatures of about 15 °C to about 25 °C [see e.g. EU Pharmacopoeia 7.5, 1 .2 (2012)].
The term "solvate” as used herein describes a crystalline compound in which solvent molecules are incorporated into the crystal lattice of the compound in a stoichiometric or non- stoichiometric manner. If the solvent molecules are water the term "hydrate" is used herein.
The type of hydrate depends on the molar ratio of water molecules to l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne molecules.
The term "monohydrate" implies 0.8 to 1.2 mol water per mol of l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne.
An anhydrate is a crystal form which do not contain any water in the crystal lattice.
The term "non-hygroscopic" as used herein indicates that the increase in mass of a drug substance between about 0% to 80% relative humidity is less than 0.2% by weight.
In the context of the present invention, the term "XRPD reflection peak" denotes a particular 20 position in an XRPD pattern, wherein the signal-to-noise ratio (calculated according to item 2.2.46 of the European Pharmacopoeia) is greater than 3/1. "Absence of a peak" is herein defined as a peak having an intensity of at most 1 %, such as 0.5% or 0.2%, of the highest peak in an XRPD of a sample of the compound of the invention, i.e no detectable XRPD peak above background signals.
In an XRPD pattern, the main characteristics of diffraction line profiles are 20 position, peak height, peak area and shape (characterized by, for example, peak width or asymmetry, analytical function, empirical representation). The 20 position is the most important factor as for example the intensity will be affected by sample preparation, and the width of the peaks by particle size. In addition to the diffraction peaks, an X-ray diffraction experiment also generates a more-or-less uniform background in an XRPD pattern, upon which the peaks are superimposed. Besides specimen preparation, other factors contribute to the background, for instance the sample holder, diffuse scattering from air and equipment, other instrumental parameters such as detector noise, general radiation from the X-ray tube, etc. The peak-to- background ratio can be increased by minimizing background and/or by choosing prolonged exposure times.
Abbreviations
DSC: Differential Scanning Calorimetry
DVS: Dynamic Vapor Sorption
TGA: Thermogravimetric Analysis
XRPD: X-ray Powder Diffraction
13 C CP/MAS NMR: 13 C cross polarization magic angle spinning nuclear magnetic resonance
SXRD: Single crystal X-ray Diffraction
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1A: XRPD pattern for l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N - methylazetidin-3-amine mono succinate, form B (3-45° 2theta)
Figure IB: XRPD pattern for l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N - methylazetidin-3-amine mono succinate, form B (3-30° 2theta)
Figure 2: DSC and TGA curve of l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N - methylazetidin-3-amine mono succinate, form B.
Figure 3: 13 C CP/MAS NMR (14.1 T) spectrum of l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3- a]pyrazin-4-yl)-N-methylazetidin-3-amine mono succinate, form B. Thus, in one embodiment the invention relates to the l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne monosuccinate.
In another embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate characterized by one or more XRPD reflections at approximately (°20) 18.0, 24.4 and/or 27.6 (±0.2 degrees).
In a further embodiment the invention relates to a crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate characterized by one or more XRPD reflections at approximately (°20) 7.5, 16.8, 18.0, 21.8, 24.4 and/or 27.6 (±0.2 degrees).
In a further embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate characterized by XRPD reflections at approximately (°20) 18.0, 24.4 and 27.6 (±0.2 degrees).
In a further embodiment the invention relates to a crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate, characterized by XRPD reflections at approximately (°20) 7.5, 16.8, 18.0, 21.8, 24.4 and 27.6 (±0.2 degrees).
In a further embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate, wherein the crystalline compound has an XRPD pattern essentially similar to the XRPD pattern in Figure 1A or IB.
In a further embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate, wherein the crystalline compound has an XRPD pattern according to the XRPD pattern in Figure 1A or IB.
In a further embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate, wherein the crystalline compound is characterized by a solid state 13 C CP/MAS NMR spectrum with peaks at one or more of 178.0, 177.0, 152.1, 147.7, 146.9, 140.3, 137.8, 129.3, 113.5, 63.3, 57.9, 57.1, 51.2, 35.8, 33.6, 30.9, 27.4 and /or 13.3 ppm (±0.2 ppm).
In a further embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono solvate characterized by having a 13 C CP/MAS NMR spectrum essentially similar to the 13 C CP/MAS NMR spectrum in Figure 3. In a further embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono solvate characterized by having a 13 C CP/MAS NMR spectrum according to the 13 C CP/MAS NMR spectrum in Figure 3.
In a further embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate which has a DSC and TGA curve consisting of two not separated endothermic events with an onset at 179.0±2°C and a corresponding weight loss in the TGA curve
In a further embodiment the invention relates to crystalline l-(8-bromopyrido[2,3- e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ami ne mono succinate which has a DSC and TGA curve essentially similar to the curves shown in Figure 2.
In some embodiments form B is a propanol solvate, suitably a 1-propanol solvate.
In additional embodiments the invention relates to pharmaceutical composition comprising a crystalline compound as described above and a pharmaceutically acceptable carrier.
In an additional embodiment the invention relates to a pharmaceutical composition as above for use in the treatment of disease selected from atopic dermatitis, itch, pruritus, and various forms of urticaria.
In a particular embodiment the invention relates to a pharmaceutical composition as above wherein the forms of urticaria include chronic idiopathic urticaria subtypes, such as cholinergic urticaria.
A further aspect of the present invention is directed to a pharmaceutical composition comprising the crystalline compound of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition may be an oral dosage form, preferably a tablet and/or capsule.
In addition, the present invention relates to the use of the crystalline compound of the present invention for the preparation of a solid medicament.
In another embodiment the present invention relates to solid pharmaceutical compositions comprising an effective amount of the crystalline compound of the present invention and a pharmaceutically acceptable carrier as well as to processes of preparing the same. Moreover, the present invention is directed to the pharmaceutical composition of the present invention and/or the crystalline compound of the present invention for use in the treatment of any of the disease or disorders mentioned in US patent No. 9586959, including diseases and disorders such as atopic dermatitis (AD), itch, pruritus and any of the various types of urticaria.
The pharmaceutical compositions of the present invention comprising the crystalline compound of the present invention may further comprise one or more pharmaceutically acceptable excipients. Such excipients are preferably selected from the group consisting of diluents, sweeteners, buffering agents, glidants, flowing agents, flavouring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickeners. Other excipients known in the field of pharmaceutical compositions may also be used. Furthermore, the pharmaceutical composition may comprise a combination of two or more excipients also within one of the members of the above-mentioned group.
Suitable binders which can be used for the pharmaceutical compositions of the present invention comprising the crystalline compound of the present invention, further comprise e.g. alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluoses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkylcellulose esters, starches such as starch 1551, modified starches such as sodium carboxymethyl starch, pectins, chitin derivatives such as chitosan, heparin and heparinoids, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar- agar, gum arabic, guar gum and xanthan gum, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, e.g. poloxamers and poloxamines, copovidone.
Suitable diluents which can be used for the pharmaceutical compositions of the present invention comprising the crystalline compound of the present invention further comprise e.g. calcium carbonate, dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lactose anhydrous, lactose monohydrate, mannitol, sorbitol, starch, modified starch, sodium chloride, sucrose, compressible sugar, confectioner's sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), commercially available as Microcelac®, a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2), commercially available as Prosolv®.
Suitable glidants which can be used for the pharmaceutical compositions of the present invention comprising the crystalline compound of the present invention further comprise e.g. talc, colloidal silicon dioxide, starch and magnesium stearate.
Suitable disintegrants which can be used for the pharmaceutical compositions of the present invention comprising the crystalline compound of the present invention further comprise e.g. starch, ion exchange resins, e.g. Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gum, e.g croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulphate, modified corn starch, microcrystalline cellulose, magnesium aluminium silicate, alginic acid, alginate and powdered cellulose.
Suitable lubricants which can also be used for the pharmaceutical compositions of the present invention comprising the crystalline compound of the present invention further comprise e.g. magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulphate and magnesium lauryl sulphate.
Some formulations, e.g. tablets may contain ingredients that have XRPD reflection peaks in the same position or area as the crystalline compound of the invention or have broad peaks. These may hide some of the XRPD pattern or peaks of the crystalline compound of the invention when the XRPD experiment is performed on a formulation comprising the crystalline compound of the invention as opposed to the pure crystalline salt alone. This means that one cannot always see all XRPD reflection peaks of the crystalline compound of the invention when an XRPD experiment is performed on a formulation of the crystalline compound
Thus, according to one embodiment, the invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein together with pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein said pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) comprises one or more ingredients which exhibit XRPD reflection peaks including one or more XRPD reflection peaks that overlap with and hide one or more XRPD reflection peaks of the crystalline compound of the invention.
The same issues may arise with solid state NMR where for example intense signals from a cellulose component should be expected in the spectral region 60-110 ppm and the peaks from stearate will be seen in the spectral region 15-40 ppm - along with a carbonyl peak around 172 ppm. Thus, according to one embodiment, the invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein together with pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein said pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) comprises one or more ingredients which are characterized by a 13 C CP/MAS NMR spectrum that may include one or more peaks that overlap with and hide one or more 13 C CP/MAS NMR peaks of the crystalline compound of the invention.
The absence of other crystalline forms of l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3- a]pyrazin-4-yl)-N-methylazetidin-3-amine can be tested by comparing an XRPD pattern taken of any crystalline form of l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N - methylazetidin-3-amine or a salt thereof with an XRPD pattern of form B as obtained e.g. from example 1 and shown in figure 1A or IB. For such a comparison, the XRPD pattern shown in figure 1A or IB can be taken as an XRPD pattern of 100% pure crystalline compound of form B of the present invention.
Description of the test methods used to characterize the polymorphic forms disclosed herein
X-Ray Powder Diffraction (XRPD)
XRPD patterns were collected with a PANalytical X'pert PRO MPD diffractometer using an incident Cu Ko radiation and operating at 45 kV and 40 mA. The XRPD patterns were collected in the 2 theta range from 3 to 45 degrees with a stepsize of 0.0066°, counting time of 148.93 s and in transmission geometry. In the incident beam path, an elliptically graded multilayer mirror together with a 4 mm fixed mask, fixed anti-scatter slit 1° and fixed divergence slits of 1 /2° were placed to line focus the Cu Ko X-rays through the sample and onto the detector. At the diffracted beam path, a long antiscatter extension and antiscatter slits of 2 mm were placed to minimize the background generated by air. Furthermore, Soller slits of 0.02 rad were placed on both the incident and diffracted beam paths to minimize broadening from axial divergence.
The sample was placed on a 3 pm thick foil on a 96 high throughput well plate stage and oscillated in the X direction for better particle statistics. The diffraction patterns were collected using a PIXel RTMS detector with an active length of 3.347° and located 240 mm from the sample.
Thermo gravimetric analysis (TGA): TGA experiments were conducted using a TGA550 instrument from TA Instruments. About 1- 10 mg of sample was loaded into a ceramic pan for the measurements. The sample temperature was ramped from 25 to 500°C at 10°C/min. Nitrogen was used as the purge gas at a flow rate of 50 mL/min.
Differential Scanning Calorimetry (DSC)
DSC: Heating rate of 10°C/ min under a nitrogen atmosphere. About 1-2 mg of sample was loaded into an open aluminum pan for the measurements. Instrument Q20 from TA Instruments.
Single-crystal X-ray diffraction
Data were collected using a SuperNova, Dual diffractometer with an Atlas CCD area detector (Temperature: 120(2) K; Cu Ka Radiation A = 1.5418 A; data collection method: co scans). Further details can be found in Table 1. Program(s) used to solve structure: CrysAlisPro, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlisl71 .NET), ShelXL (Sheldrick, 2008) used to refine structure and Olex2 (Dolomanov et al., 2009) for ORTEP drawings.
Solid-state NMR spectroscopy
13 C CP/MAS NMR spectra were recorded at 298 K on a Bruker Avance III HD 600 NMR spectrometer (14.1 T) equipped with a 4 mm double-tuned CH-^C) CMP probe using a contact time of 6 ms, a recycle delay of 64 s, spin-rate of 14.1 kHz, 128 scans and high-power X H decoupling during the acquisition time of 45.9 ms. Prior to Fourier Transformation the time domain data (Free Induction Decay) was apodized by Lorentzian linebroadening of 5 Hz. All spectra are referenced to the chemical shift of the carbonyl group in o-glycine at 176.5 ppm (external sample).
The given error ranges in this application for the spectroscopic characteristics, including those in the claims, may be more or less depending on factors well known to a person skilled in the art of spectroscopy and may for example depend on sample preparation, such as particle size distribution, or if the crystal form is part of a formulation, on the composition of the formulation, as well as instrumental fluctuations, and other factors.
EXAMPLES
Example 1
60 mg of l-(8-bromopyrido[2,3-e][l,2,4]triazolo[4,3-a]pyrazin-4-yl)-N -methylazetidin-3- amine mono succinate was dissolved in 4 mL EtOH:H2O (99: 1) mixture. The sample solution was filtered through a 0.45pm filter and 5 drops of EtOH:H2O [99: 1] were added.
The solution was added carefully into a 5mm NMR tube that was filled with an equivolume of the heptane with a lower density. The tube was sealed with a polyethylene cap and left undisturbed in the fume cupboard. The XRPD is show in figures 1A and IB.