(R)-ketamine D-tartrate E crystal form and preparation method thereof

Abstract

The invention discloses a (R)-ketamine D-tartrate crystal form E and a preparation method thereof. According to the method, the crystal form E is prepared through recrystallization or direct heating and cooling methods, the process is stable and suitable for large-scale production, and the prepared (R)-ketamine D-tartrate crystal form E is good in crystal form stability and chemical stability.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to a (R)-ketamine D-tartrate E crystal form and a preparation method thereof. Background Art

[0002] Ketamine (a racemic mixture of S- and R-enantiomers) is an NMDA receptor antagonist used primarily for the induction and maintenance of general anesthesia, with other uses including sedation in critical care, analgesia (particularly in emergency care and for the treatment of bronchospasm). Ketamine has also been shown to be effective in the treatment of depression, particularly in patients who have not responded to current antidepressant treatments, and has been shown to produce a rapid antidepressant effect within hours in patients with severe depression.

[0003] (R)-ketamine can antagonize NMDA receptors, enhance excitatory synaptic transmission and synaptic plasticity. Preclinical test results show that (R)-ketamine has antidepressant effects in multiple depression models, including the mouse tail suspension model, the rat forced swimming model, the rat acquired helplessness model, and the rat chronic unpredictable mild stress (CUMS) model, and all of them can take effect quickly. Compared with (S)-ketamine, (R)-ketamine is expected to have milder psychiatric symptoms and addiction potential.

[0004] In 2001, Steiner K. et al. described in patent DE19619665 C2 (US patent No. 6040479) a method for splitting ketamine using L-tartaric acid in water or a mixed solvent of water and alcohol.

[0005] In 2002, Chen Shuhong, Tong Dongwang, Wu Yuexia et al. Resolution of Ketamine Hydrochloride [J]. Chinese Journal of Medicinal Chemistry, 2002, 12(3), 170-171. reported a method of using D-tartaric acid to resolve ketamine.

[0006] Patent WO2023 / 064363A1 reports the preparation of R-ketamine D-tartrate crystal form A, crystal form B, crystal form C and crystal form D and their preparation method by salifying R-ketamine with D-tartaric acid in a solvent, wherein crystal form C is easily converted into crystal form D in a solvent, crystal form B and crystal form C can be converted into each other in a solvent, and crystal form D is relatively stable. Summary of the invention

[0007] The purpose of the present invention is to provide a new (R)-ketamine tartrate crystal form E and a preparation method thereof on the basis of the prior art. The method prepares the E crystal form by a direct recrystallization method, has a stable process, is suitable for scale-up production, and the obtained sample has good crystal stability and chemical stability.

[0008] The present invention provides a (R)-ketamine D-tartrate crystal form E:

[0009]

[0010] The E crystal form uses Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, which shows characteristic peaks at 12.61, 16.64, 21.06, 21.93, 23.44, 27.54 and 29.28, and the error range of the 2θ angle is ±0.2.

[0011] Furthermore, in a preferred embodiment of the present invention, the E crystal form shows characteristic peaks expressed in 2θ at 9.60, 10.86, 12.61, 13.61, 15.99, 16.64, 19.05, 19.36, 19.69, 21.06, 21.93, 23.44, 24.07, 25.48, 26.59, 27.05, 27.54, 29.28, 30.43, 31.59, 32.05, 32.46, 33.18, 36.35 and 38.24, and the error range of the 2θ angle is ±0.2.

[0012] Furthermore, in a more preferred embodiment of the present invention, the DSC melting endothermic peak of the E crystal form is 181-188°C, preferably 185-187°C.

[0013] Further, in a more preferred embodiment of the present invention, the E crystal form meets one or more of the following solid state characteristics:

[0014] (1) Basically in line with Figure 1 Powder X-ray diffraction pattern of

[0015] (2) Basically in line with Figure 2 DSC spectrum of .

[0016] The present invention also provides a method for preparing (R)-ketamine D-tartrate E crystal form, which comprises: heating and dissolving (R)-ketamine D-tartrate with a solvent, filtering, stirring at room temperature for crystallization, filtering, and drying to obtain (R)-ketamine D-tartrate E crystal form solid.

[0017] Furthermore, in the method for preparing the E crystal form of the present invention, the solvent is a single solvent or a mixed solvent: the single solvent is any one of isopropanol, ethanol, methanol, DMF, n-butanol, NMP, DMSO, tetrahydrofuran, and ethyl acetate; the mixed solvent is any two or more of isopropanol, ethanol, methanol, DMF, n-butanol, NMP, DMSO, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, and acetone, preferably a mixed solvent of any one of isopropanol, ethanol, methanol, DMF, n-butanol, NMP, and DMSO and any one or more of methyl tert-butyl ether, acetone, ethyl acetate, or tetrahydrofuran.

[0018] Furthermore, in the method for preparing the E crystal form of the present invention, the solvent is preferably: isopropanol, ethanol, methanol / methyl tert-butyl ether, methanol / acetone, DMF / isopropanol, n-butanol, NMP / ethyl acetate, DMSO / methyl tert-butyl ether / acetone, tetrahydrofuran / methanol.

[0019] Furthermore, in the method for preparing the E crystal form of the present invention, the heating temperature is 50-150° C., and preferably the heating temperature is the reflux temperature of the solvent used.

[0020] Furthermore, in the method for preparing the E crystal form of the present invention, the drying temperature is 40-80°C, preferably 55-65°C.

[0021] On the other hand, the present invention provides a second method for preparing the E crystal form, which comprises heating (R)-ketamine D-tartrate and cooling to obtain the (R)-ketamine D-tartrate E crystal form solid.

[0022] Furthermore, the heating temperature is 100-150°C, preferably 120-130°C; and the cooling is preferably cooling to room temperature.

[0023] In the specification and claims of the application, unless otherwise stated, the scientific and technological terms used herein have the meanings commonly understood by those skilled in the art. However, in order to better understand the present invention, the definition and explanation of some related terms are provided below. In addition, when the definition and explanation of the terms provided in the application are inconsistent with the meanings commonly understood by those skilled in the art, the definition and explanation of the terms provided in the application shall prevail.

[0024] The "room temperature" mentioned in the present invention refers to the temperature from 10°C to 40°C.

[0025] The "X-ray powder diffraction pattern or XRPD" of the present invention refers to the Bragg formula 2d sinθ=nλ (where λ is the wavelength of the X-ray, The diffraction order n is any positive integer, generally the first-order diffraction peak is taken, n=1). When X-rays are incident on an atomic plane with a lattice plane spacing of d in a crystal or a part of a crystal sample at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle), the Bragg equation is satisfied, thereby measuring this set of X-ray powder diffraction patterns.

[0026] The "2θ or 2θ angle" mentioned in the present invention refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, and more preferably ±0.2.

[0027] The "interplanar spacing or interplanar spacing (d value)" mentioned in the present invention refers to the selection of three non-parallel unit vectors a, b, c connecting two adjacent lattice points by the space lattice, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection lines to obtain a set of straight line grids, called space grids or lattices. The lattice and lattice use geometric points and lines respectively to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is Or Angstrom.

[0028] The "differential scanning calorimetry or DSC" of the present invention measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the same crystal form of the same compound, the error of the thermal transition temperature and melting point can be within about 5°C, usually within about 3°C ​​in consecutive analyses. When a compound is described as having a given DSC peak or melting point, it refers to the DSC peak or melting point ±5°C. "Substantially" also takes this temperature variation into account. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified based on their different transition temperature characteristics. It should be noted that for a mixture, its DSC peak or melting point may vary over a larger range. In addition, since decomposition is accompanied by the melting of the substance, the melting temperature is related to the heating rate.

[0029] Beneficial Effects

[0030] The technical solution of the present invention has the following advantages:

[0031] 1. The (R)-ketamine D-tartrate E crystal form obtained by the present invention has good crystal stability and chemical stability, and is more advantageous as an intermediate material in terms of storage, transportation, and preparation of the final product (R)-ketamine hydrochloride;

[0032] 2. The present invention provides an R-ketamine D-tartrate E crystal form and a preparation method thereof. The method prepares the E crystal form by a direct recrystallization method, has a stable process, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 : X-ray powder diffraction pattern of R-ketamine D-tartrate E crystal form.

[0034] Figure 2 : DSC spectrum of R-ketamine D-tartrate E crystal form.

[0035] Figure 3 : X-ray powder diffraction pattern of R-ketamine D-tartrate D crystal form.

[0036] Figure 4 : DSC spectrum of R-ketamine D-tartrate D crystal form. DETAILED DESCRIPTION

[0037] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technical schemes that are reasonably modified based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0038] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0039] Test conditions of the instruments used in the experiment:

[0040] 1. X-ray Powder Diffraction (XRPD)

[0041] Instrument model: Bruker D8 Focus powder X-ray diffractometer.

[0042] X-ray parameters: Cu / Kα

[0043] Voltage: 40 kilovolts (kV)

[0044] Current: 40 milliamperes (mA)

[0045] Scanning range: 3°~60°

[0046] Scanning step: 0.02°

[0047] Scanning speed: 0.5 seconds / step

[0048] 2. DSC thermal analysis method (Differential Scanning Calorimeter, DSC)

[0049] Instrument model: German Netzsch DSC 200F3 differential scanning calorimeter

[0050] Purge gas: Nitrogen

[0051] Heating rate: 10.0K / min

[0052] Temperature range: 30-300℃

[0053] 3. High Performance Liquid Chromatograph (HPLC)

[0054] Instrument model: LC-20AD Shimadzu liquid chromatograph

[0055] Chromatographic column: SHIMADZU Shim-pack GIST C18 (4.6*150mm, 5μm) column

[0056] Mobile Phase:

[0057] A: 0.01 mol / L diammonium hydrogen phosphate solution (adjust pH to 7.5 with phosphoric acid) - acetonitrile (80:20)

[0058] B: 0.01 mol / L diammonium hydrogen phosphate solution (adjust pH to 7.5 with phosphoric acid)-acetonitrile (20:80)

[0059] Flow rate: 1.0 ml / min Column temperature: 30°C

[0060] Wavelength: 215nm Injection volume: 20μL

[0061] Gradient conditions:

[0062]

[0063] Example 1: Preparation of (R)-ketamine D-tartrate E crystal form

[0064] 1.00 g (R)-ketamine D-tartrate was added to the reaction bottle, 40 ml isopropanol was added, heated to reflux, completely dissolved, hot filtered, the filtrate was stirred at room temperature for 2 hours, suction filtered, and the filter cake was dried at 55-65°C for 2 hours to obtain 0.80 g of white solid. Its X-ray powder diffraction pattern is shown in Figure 1 , DSC spectrum see Figure 2 , X-ray powder diffraction characteristic peaks are shown in Table 1.

[0065] Table 1E Crystalline characteristic peaks

[0066]

[0067]

[0068] Embodiment 2:

[0069] 1.00 g (R)-ketamine D-tartrate and 18 ml anhydrous ethanol were added to a reaction bottle, heated to reflux, completely dissolved, hot filtered, the filtrate was stirred at room temperature for 3 hours, filtered with suction, and the filter cake was dried at 55-65°C for 2 hours to obtain 0.72 g of a white solid. The product was determined to be E crystal form by X-ray powder diffraction.

[0070] Embodiment 3:

[0071] 1.00 g (R)-ketamine D-tartrate and 20 ml n-butanol were added to a reaction flask, heated to reflux, completely dissolved, hot filtered, the filtrate was stirred at room temperature for 3 hours, filtered with suction, and the filter cake was dried at 55-65°C for 2 hours to obtain 0.79 g of a white solid. The product was determined to be E crystal form by X-ray powder diffraction.

[0072] Embodiment 4:

[0073] 1.00 g (R)-ketamine D-tartrate and 3 ml DMF were added to a reaction bottle, heated to 100°C, completely dissolved, hot filtered, 20 ml isopropanol was added dropwise to the filtrate, stirred at room temperature for 3 hours, filtered, and the filter cake was dried at 55-65°C for 2 hours to obtain 0.70 g of a white solid. The product was determined to be E crystal form by X-ray powder diffraction.

[0074] Embodiment 5:

[0075] 1.00 g (R)-ketamine D-tartrate was added to the reaction bottle, heated in an oil bath at 130°C for 2 hours, cooled to room temperature, and sealed in a brown bottle. The product was determined to be E crystal form by X-ray powder diffraction.

[0076] Example 6: Preparation of (R)-ketamine D-tartrate crystal form D

[0077] 1.00 g (R)-ketamine D-tartrate and 27.00 g acetone / water (93:7) were added to a reaction flask, heated to reflux, completely dissolved, hot filtered, the filtrate was stirred at room temperature for 1.5 hours, filtered, and the filter cake was dried at 55-65°C for 1.5 hours to obtain 0.71 g of a white solid. Its X-ray powder diffraction pattern is shown in Figure 3 , DSC spectrum see Figure 4 The characteristic peaks of X-ray powder diffraction are shown in Table 2.

[0078] Table 2D Crystalline characteristic peaks

[0079] 2θ° d value Intensity Intensity% 7.509 11.76371 30557 96.7 8.340 10.59381 1742 5.5 12.650 6.99194 2585 8.2 14.250 6.21023 5071 16.0 14.744 6.0033 2426 7.7 15.122 5.85418 27704 87.7 16.919 5.23608 31599 100.0 18.234 4.86136 1851 5.9 18.864 4.70051 2340 7.4 19.431 4.56465 3075 9.7 19.703 4.50226 4831 15.3 20.434 4.34276 2380 7.5 20.848 4.25739 2339 7.4 21.408 4.14731 7519 23.8 22.576 3.93525 6342 20.1 22.842 3.89006 6152 19.5 23.858 3.72674 4191 13.3 24.311 3.65827 1912 6.1 24.670 3.60589 2662 8.4 27.447 3.24695 13719 43.4 27.784 3.20836 1833 5.8 28.229 3.15875 1408 4.5 30.114 2.9652 2376 7.5 30.641 2.91542 4386 13.9 31.328 2.853 2393 7.6 32.397 2.7613 5228 16.5 33.202 2.6961 4915 15.6 33.935 2.63955 1822 5.8 35.457 2.52968 1654 5.2 37.065 2.42353 1457 4.6 37.509 2.39583 1382 4.4 40.363 2.23277 1610 5.1

[0080] Embodiment 7:

[0081] 1.00 g (R)-ketamine D-tartrate and 15 ml dioxane were added to a reaction bottle, heated to reflux under stirring, and the mixture could not be completely dissolved. 1 ml of deionized water was added dropwise, and the solid was completely dissolved. The mixture was filtered hot, and the filtrate was stirred at room temperature for 3.5 hours, filtered with suction, and the filter cake was dried at 55-65° C. for 2 hours to obtain 0.76 g of an off-white solid. The product was determined to be a D-type crystal by X-ray powder diffraction.

[0082] Embodiment 8:

[0083] 1.00 g of (R)-ketamine D-tartrate was added to a ball mill mortar at a grinding speed of 600 rpm for 2 hours. After grinding, the solid was taken out to obtain 0.88 g of an off-white solid. The product was determined to be a D crystal form by X-ray powder diffraction.

[0084] Example 9: Crystal stability study

[0085] The stability test was conducted in accordance with the Chinese Pharmacopoeia 2015 edition Part IV General Rules 9001 Guidelines for Stability Tests of Drug Substances and Preparations (see Chinese Pharmacopoeia Part 4, page 354). Specifically, the E crystal form (prepared according to Examples 1, 2, and 3) and the D crystal form (prepared according to Examples 4, 5, and 6) were tested for stability factors under high humidity (RH92.5%), high temperature (60°C) and light (4500±500lx) conditions, and samples were taken for PXRD (X-ray powder diffraction) detection on 30 days, and HPLC content (w / w, %) was determined at the same time, and compared with the results of 0 days.

[0086] Table 3 Factors affecting the stability of E and D crystal forms

[0087]

[0088] From the data in Table 3, we can see that the E crystal form not only can maintain a stable crystal morphology under the conditions of high humidity for 10 days, high temperature for 10 days and light for 10 days, but also has stable chemical properties, and the content has hardly changed compared with that at 0 days, and the content can reach more than 99.8%. However, the D crystal form is unstable and is easily converted to the E crystal form.

[0089] The above is a description of the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for illustrating the concept of the present invention.

[0090] Various non-substantial changes and improvements of the present invention can be made by those skilled in the art without departing from the concept of the present invention, and all of these fall within the scope of protection claimed by the present invention.

Claims

1. A (R)-ketamine D-tartrate crystal form E: It is characterized in that The E crystal form uses Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, which shows characteristic peaks at 12.61, 16.64, 21.06, 21.93, 23.44, 27.54 and 29.28, and the error range of the 2θ angle is ±0.

2.

2. The E crystal form according to claim 1, characterized in that: Its X-ray powder diffraction pattern shows characteristic peaks expressed in 2θ degrees at 9.60, 10.86, 12.61, 13.61, 15.99, 16.64, 19.05, 19.36, 19.69, 21.06, 21.93, 23.44, 24.07, 25.48, 26.59, 27.05, 27.54, 29.28, 30.43, 31.59, 32.05, 32.46, 33.18, 36.35 and 38.24, and the error range of the 2θ angle is ±0.

2.

3. The E crystal form according to claim 1, characterized in that: The DSC melting endothermic peak of the E crystal form is 181-188°C, preferably 185-187°C; Further preferably, the E crystal form meets one or more of the following characteristics: (1) having a powder X-ray diffraction pattern substantially consistent with that of FIG1 ; (2) It is basically consistent with the DSC spectrum of Figure 2.

4. A method for preparing the (R)-ketamine D-tartrate E crystalline form as described in any one of claims 1 to 3, characterized in that: (R)-ketamine D-tartrate is dissolved by heating with a solvent, filtered, stirred at room temperature for crystallization, filtered, and dried to obtain (R)-ketamine D-tartrate E crystalline solid.

5. The preparation method according to claim 4, characterized in that: The solvent is a single solvent or a mixed solvent: the single solvent is any one of isopropanol, ethanol, methanol, DMF, n-butanol, NMP, DMSO, tetrahydrofuran, and ethyl acetate; the mixed solvent is any two or more of isopropanol, ethanol, methanol, DMF, n-butanol, NMP, DMSO, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, and acetone, preferably a mixed solvent of any one of isopropanol, ethanol, methanol, DMF, n-butanol, NMP, and DMSO and any one or more of methyl tert-butyl ether, acetone, ethyl acetate, or tetrahydrofuran.

6. The preparation method according to any one of claims 4 to 5, characterized in that: The solvents are: isopropanol, ethanol, methanol / methyl tert-butyl ether, methanol / acetone, DMF / isopropanol, n-butanol, NMP / ethyl acetate, DMSO / methyl tert-butyl ether / acetone, and tetrahydrofuran / methanol.

7. The preparation method according to any one of claims 4 to 6, characterized in that: The heating temperature is 50-150° C., and preferably the heating temperature is the reflux temperature of the solvent used.

8. The preparation method according to any one of claims 4 to 7, characterized in that: The drying temperature is 40-80°C, preferably 55-65°C.

9. A method for preparing the (R)-ketamine D-tartrate E crystalline form as claimed in any one of claims 1 to 3, characterized in that: (R)-ketamine D-tartrate is heated and cooled to obtain (R)-ketamine D-tartrate E crystalline solid.

10. The preparation method according to claim 9, characterized in that: The heating temperature is 100-150° C., preferably 120-130° C.; the cooling is preferably cooling to room temperature.

Images