CN108239055B - THR 1442L-aspartic acid eutectic crystal, preparation method and pharmaceutical composition thereof - Google Patents
THR 1442L-aspartic acid eutectic crystal, preparation method and pharmaceutical composition thereof Download PDFInfo
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- CN108239055B CN108239055B CN201710674102.5A CN201710674102A CN108239055B CN 108239055 B CN108239055 B CN 108239055B CN 201710674102 A CN201710674102 A CN 201710674102A CN 108239055 B CN108239055 B CN 108239055B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to a co-crystal of the SGLT2 inhibitor THR1442 (Bexagliflozin) and L-aspartic acid, the THR 1442L-aspartic acid co-crystal of the invention having one or more improved properties compared to known THR1442 diproline co-crystals. The invention also relates to a method for preparing THR 1442L-aspartic acid eutectic, a pharmaceutical composition thereof and a method for treating diseases or symptoms affected by SGLT or SGLT2 inhibition.
Description
Technical Field
The present application relates to the field of pharmaceutical chemistry crystallization technology. In particular, the present application relates to co-crystals of THR1442 and L-aspartic acid, methods of making and uses thereof, and pharmaceutical compositions comprising the co-crystals.
Background
THR1442 is a sodium-glucose cotransporter 2 (SGLT 2) inhibitor, and can reduce blood glucose concentration and glycosylated hemoglobin in blood of diabetics and reduce body weight.
THR1442 chemical name (2S, 3R,4R,5S, 6R) -2- (4-chloro-3- (- (4- (2-cyclopropyloxyethoxy) benzyl) phenyl-6- (hydroxymethyl) -tetrahydro-2H-pyran-3, 4,5 triol, english name bexagliflozin, molecular formula C 24 H 29 ClO 7 Molecular weight 464.94, CAS number 1118567-05-7, and its chemical structure is shown below:
the crystal forms of THR1442 and the diproline eutectic thereof, the preparation method thereof and the pharmaceutical composition thereof are disclosed in the patents CN102933592B and CN102177147A, and the melting point of the diproline eutectic is 150 ℃ is disclosed in the patent CN 102177147A.
The inventor finds that THR1442 diproline eutectic solid prepared according to the information provided by the prior art CN102933592B patent has the defects of high hygroscopicity, oil formation when meeting water and irregular particle morphology in the research process.
In view of the deficiencies of the prior art, there is a need to develop a solid form of THR1442 with more advantageous properties.
Disclosure of Invention
The invention aims to provide a THR1442 and L-aspartic acid eutectic crystal, a preparation method and application thereof, and a pharmaceutical composition containing the THR 1442L-aspartic acid eutectic crystal. The novel co-crystals of the present invention have one or more improved properties, such as higher crystallinity, better appearance, lower hygroscopicity, better storage stability, better flowability and favorable processing and handling characteristics, as compared to known THR1442 biproline co-crystals. In particular, the solid forms of the present invention have lower hygroscopicity, better storage stability, better particle morphology, better flowability and favorable processing and handling characteristics.
According to an object of the present invention, there is provided a THR 1442L-aspartic acid eutectic.
The THR 1442L-aspartic acid eutectic is an anhydrous substance, and the structural formula is shown in a figure (I):
using Cu-ka radiation, the X-ray powder diffraction pattern of the THR 1442L-aspartic acid co-crystal expressed in terms of 2θ angle has the following characteristic peaks: 6.1.+ -. 0.2 °, 12.1.+ -. 0.2 °, 16.8.+ -. 0.2 °, 17.7.+ -. 0.2 °, 23.7.+ -. 0.2 ° and 24.4.+ -. 0.2 °.
More preferably, the X-ray powder diffraction pattern of the THR 1442L-aspartic acid co-crystal expressed in terms of 2θ has characteristic peaks at the following positions: 6.1.+ -. 0.2 °, 11.9.+ -. 0.2 °, 12.1.+ -. 0.2 °, 16.8.+ -. 0.2 °, 17.7.+ -. 0.2 °, 21.7.+ -. 0.2 °, 22.5.+ -. 0.2 °, 23.7.+ -. 0.2 °, 24.4.+ -. 0.2 °, 25.5.+ -. 0.2 °, 29.7.+ -. 0.2 ° and 35.9.+ -. 0.2 °.
Further preferably, the THR 1442L-aspartic acid eutectic has an X-ray powder diffraction pattern with characteristic peaks and relative intensities at the following diffraction angles 2θ:
without limitation, one typical example of the THR 1442L-aspartic acid co-crystal has an X-ray powder diffraction (XRPD) pattern as shown in FIG. 2.
Without limitation, a typical example of the THR 1442L-aspartic acid eutectic has a DSC pattern as shown in FIG. 5, showing a melting point of 94 ℃.
Fourier infrared spectra of the THR 1442L-aspartic acid eutectic are 1510+ -2, 1236+ -2, 1089+ -2, 1210+ -2, 1054+ -2, 1036+ -2, 1011+ -2, 986+ -2, 967+ -2 and 900+ -2 cm -1 With characteristic peaks.
According to the purpose of the invention, the invention provides a preparation method of THR 1442L-aspartic acid eutectic, which is characterized by adopting any one of the following methods:
(1) THR1442 solid at C 1 -C 3 Forming a solution in alcohol, forming a solution of L-aspartic acid solid in water, mixing an L-aspartic acid aqueous solution and a THR1442 alcohol solution, stirring for crystallization, separating and drying the precipitated crystals to obtain the THR 1442L-aspartic acid eutectic;
preferably, said C 1 -C 3 The alcohol is ethanol;
preferably, the stirring time is 3-7 days;
preferably, the molar ratio of THR1442 solid to L-aspartic acid in the preparation method is 1:1-1:2;
preferably, the operating temperature of the preparation process is 10-40 ℃, more preferably room temperature;
preferably, the mass to volume ratio of THR1442 solid to the alcohol in the preparation method is 100-500 mg:1mL, more preferably 200 to 500mg:1mL;
(2) THR1442 solid at C 1 -C 3 Forming a solution in alcohol, forming a solution of L-aspartic acid solid in water, mixing an L-aspartic acid aqueous solution and a THR1442 alcohol solution, volatilizing and crystallizing to obtain the THR 1442L-aspartic acid eutectic;
preferably, said C 1 -C 3 The alcohol is ethanol;
preferably, the molar ratio of THR1442 solid to L-aspartic acid in the preparation method is 1:1-1:2;
preferably, the volatilization temperature is 20-60 ℃, more preferably 20-40 ℃;
preferably, the concentration of the THR1442 solution is 0.1 to 0.7 times, more preferably 0.1 to 0.5 times the solubility of THR1442 solids in the alcohol.
The THR 1442L-aspartic acid eutectic has the following beneficial effects:
(1) from the results of comparative example 1, it is clear that the co-crystal of the present invention has lower hygroscopicity than the known THR 1442-diproline co-crystal.
(2) The eutectic of the invention is placed in a dryer with a relative humidity of 10% -90% at room temperature for 4 months, and the appearance, XRPD and melting point are unchanged.
(3) Compared with the known THR1442 diproline eutectic, the eutectic of the invention has more regular morphology under PLM, and is beneficial to mixing with auxiliary materials during preparation.
(4) From the results of comparative example 2, it is clear that the co-crystal of the present invention has longer stability in water than the known THR1442 diproline co-crystal.
(5) From the melting point in the DSC diagram, the eutectic melting point of the present invention is about 60 ℃ lower than the known eutectic melting point of THR1442 diproline, which indicates that the eutectic of the present invention is more suitable for the development of formulations such as hot melt extrusion.
The beneficial properties above demonstrate that the co-crystals of the present invention have good stability and flowability, and can better ensure that the pharmaceutical active ingredient itself and the formulation dosage form containing THR1442 avoid and reduce quality, safety and stability problems during pharmaceutical manufacturing and/or storage, etc., such as uneven content of active ingredient, impurities, etc., avoiding special and expensive packaging.
In any of the preparation methods of THR 1442L-aspartic acid eutectic of the invention:
unless otherwise noted, "room temperature" refers to a temperature of 10 to 30 ℃.
The "stirring" may be carried out by a method conventional in the art, for example, stirring means including magnetic stirring, mechanical stirring, and stirring speed of 50 to 1800 rpm, preferably 300 to 900 rpm.
The "separation" may be by methods conventional in the art, such as centrifugation or filtration. Preferably, the filtration is carried out under reduced pressure, generally at room temperature at a pressure of less than atmospheric pressure, preferably at a pressure of less than 0.09MPa.
The "drying" may be accomplished using techniques conventional in the art, such as normal temperature drying, forced air drying, or reduced pressure drying; the pressure may be reduced or normal, preferably less than 0.09MPa. The drying apparatus and method are not limited and may be a fume hood, a forced air oven, a spray dryer, fluidized bed drying or a vacuum oven; the process may be carried out under reduced or no pressure, preferably at a pressure of less than 0.09Mpa.
The starting material THR1442 can be prepared by the method described in example 2-example 10 of patent document CN102933592B, which is incorporated herein by reference in its entirety, and is also commercially available.
Further, the invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more THR 1442L-aspartic acid co-crystals of the invention or THR 1442L-aspartic acid co-crystals prepared by the methods of the invention, and at least one pharmaceutically acceptable carrier.
The excipients in the pharmaceutical composition are well known to those skilled in the art, and the choice of type, use, and amount thereof is well known to those skilled in the art. Examples include sugars, cellulose and its derivatives, starch or modified starch, solid inorganics such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulphate, calcium carbonate, semisolids such as lipids or paraffins, binders such as microcrystalline cellulose, ethylcellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, glidants such as colloidal silicon dioxide, light anhydrous silicic acid, crystalline cellulose, talc or magnesium stearate, disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, dry corn starch, lubricants such as stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol.
The administration route of the pharmaceutical composition includes oral administration, intravenous injection, tissue injection, transdermal administration, rectal administration, nasal drip administration, and the like. The pharmaceutical composition can be prepared into a certain dosage form according to the administration route or the requirement, and can be solid or liquid. Solid oral dosage forms, including, for example, tablets, granules, powders, pills, and capsules; liquid oral dosage forms, including, for example, solutions, syrups, suspensions, dispersions and emulsions; injectable formulations include, for example, solutions, dispersions and lyophilisates. The formulation may be adapted for immediate release, sustained release or controlled release of the pharmaceutically active ingredient. May be conventional, dispersible, chewable, orally dissolving or fast-melting formulations.
The pharmaceutical composition may be prepared using methods well known to those skilled in the art. In preparing pharmaceutical compositions, the THR 1442L-aspartic acid co-crystals of the invention are admixed with one or more pharmaceutically acceptable excipients, optionally with other crystalline forms, amorphous forms, co-crystals of pharmaceutically acceptable THR1442, optionally with one or more other pharmaceutically active ingredients. The solid preparation can be prepared by direct mixing, granulating and the like.
Further, the present invention provides the use of one or more THR 1442L-aspartic acid co-crystals of the invention or THR 1442L-aspartic acid co-crystals obtained by the process of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of one or more disorders or conditions in which it is medically desirable to select a compound having an inhibitory effect on sodium-dependent glucose co-transporter SGLT, wherein the disorders or conditions include type I and type II diabetes, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, oedema, dyslipidemia, chronic heart failure, atherosclerosis and cancer.
Further, the present invention provides a method of treating and/or preventing one or more disorders or conditions comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the THR1442 co-crystals of the invention or a combination thereof or a pharmaceutical composition thereof, the disorder or condition being a medical need to select a compound having an inhibitory effect on sodium-dependent glucose co-transporter SGLT, wherein the disorder or condition comprises type I and type II diabetes, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, oedema, dyslipidemia, chronic heart failure, atherosclerosis, cancer, and the like. The patient includes, but is not limited to, a mammal.
Drawings
Fig. 1 is an X-ray powder diffraction pattern of a known THR1442 diproline co-crystal prepared by the method described in example 1F of reference CN 102933592B.
Fig. 2 is a PLM profile of a known THR1442 diproline co-crystal prepared by the method described in example 1F of reference CN 102933592B.
Fig. 3 is an isothermal adsorption pattern of a known THR1442 diproline co-crystal prepared by the method described in example 1F of reference CN 102933592B.
FIG. 4 is an X-ray powder diffraction pattern of the THR 1442L-aspartic acid co-crystal prepared in example 1 of the present invention.
FIG. 5 is a DSC chart of the THR 1442L-aspartic acid co-crystal prepared in example 1 of the present invention.
FIG. 6 is an IR spectrum of the THR 1442L-aspartic acid co-crystal prepared in example 1 of the present invention.
FIG. 7 is an isothermal adsorption pattern of THR 1442L-aspartic acid eutectic prepared in example 1 of the present invention.
FIG. 8 is a PLM spectrum of the THR 1442L-aspartic acid co-crystal prepared in example 1 of the present invention.
Detailed description of the preferred embodiments
The invention will be further understood by the following examples, which are not intended to limit the scope of the invention.
The detection instrument and the method are as follows:
x-ray powder diffraction (XRPD): the instrument was Bruker D8Advance diffractometer. Samples were tested at room temperature. The detection conditions are as follows, the angle range: 3-40 degrees 2 theta, step length: 0.02 ° 2θ, speed: 0.2 seconds/step.
Polarized Light Microscopy (PLM) spectra were taken from XP-500E polarized light microscope (Shanghai rectangular optics instruments Co., ltd.). The objective lens magnification is 4 times, the eyepiece lens magnification is 10 times, and the appearance of the sample is observed and photographed.
Differential thermal analysis Data (DSC) were obtained from TA Instruments Q200MDSC. The detection method comprises the following steps: 1-10mg of sample is placed in a small-hole aluminum crucible, and dried at a heating rate of 10 ℃/min and 40mL/min 2 The sample was warmed from room temperature to 200-250 c under the protection of (c).
Thermogravimetric analysis data (TGA) were obtained from TA Instruments Q500TGA. The detection method comprises the following steps: placing 5-15 mg of sample into platinum crucible, adopting sectional high-resolution detection mode, drying N at 40mL/min at heating rate of 10 deg.C/min 2 The sample was warmed from room temperature to 300 ℃ under the protection of (c).
Dynamic moisture adsorption analysis data and isothermal adsorption analysis data were taken from TA Instruments Q5000TGA. The detection method comprises the following steps: a sample of 1-10mg is typically taken and placed in a platinum crucible and dried N at 10mL/min 2 The weight change of the sample during the change of relative humidity from 0% to 80% to 0% was examined under the protection of (a) and the isothermal adsorption profile was obtained using a software process.
Infrared spectroscopic analysis (IR) data were obtained from Bruker Tensor 27 using an ATR apparatus at 600-4000cm -1 Within the range, infrared absorption spectra were collected.
Nuclear magnetic hydrogen spectrum data [ ] 1 HNMR) was obtained from Bruker Avance II DMX 500.500 MHz nuclear magnetic resonance spectrometer. 1-5 mg of the sample is weighed and dissolved in the nuclear magnetic sample tube with about 0.5mL of deuterated reagent for detection.
Unless otherwise noted, the examples were run at room temperature and the solvent ratios were all volume ratios.
The various reagents used in the examples were commercially available unless otherwise specified.
Preparation example 1
THR1442 was prepared according to the method described in example [0110-0123] of CN 102933592B.
1 HNMR(500MHz，Methanol-d4):δ7.38-7.27(m，3H)，7.13(d，J＝8.3Hz，2H)，6.85(d，J＝8.4Hz，2H)，4.13-4.03(m，5H)，3.91-3.87(m，1H)，3.87-3.83(m，2H)，3.71(dd，J＝11.9，5.0hz, 1H), 3.50-3.40 (m, 4H), 3.30 (d, j=9.1 hz, 1H), 0.59 (d, j=3.4 hz, 2H), 0.53-0.48 (m, 2H).
Preparation example 2
THR1442 diproline cocrystal was prepared as described in example 1F of reference CN 102933592B.
The X-ray powder diffraction pattern is shown in figure 1.
The PLM pattern is shown in FIG. 2.
The isothermal adsorption pattern is shown in figure 3.
Example 1
40mg of THR1442 solid sample obtained in preparation example 1 is taken, 0.2mL of ethanol is added to form a solution, 11.4 mgL-aspartic acid is taken, 4mL of water is added to ultrasonically form a solution, the L-aspartic acid aqueous solution is added to the THR1442 ethanol solution, white turbidity is separated out, the solution is stirred for 5 days at room temperature, then the solution is filtered under reduced pressure, and the solid is dried for 10 hours at 40 ℃ in vacuum, thus obtaining 47.3mg of THR 1442L-aspartic acid eutectic with the yield of 92%.
The X-ray powder diffraction pattern is shown in FIG. 4.
The DSC chart is shown in FIG. 5.
The IR spectrum is shown in fig. 6.
The isothermal adsorption pattern is shown in FIG. 7.
The PLM pattern is shown in FIG. 8.
The nuclear magnetic hydrogen spectrum data are as follows: 1 HNMR (500 mhz, dmso-d 6): delta 7.33-7.22 (m, 2H), 7.16 (dd, j=8.2, 2.1hz, 1H), 7.02 (d, j=8.5 hz, 2H), 6.77 (d, j=8.6 hz, 2H), 4.88 (dd, j=5.0, 1.8hz, 2H), 4.76 (d, j=5.8 hz, 1H), 4.38 (t, j=5.8 hz, 1H), 3.98-3.85 (m, 5H), 3.68-3.59 (m, 3H), 3.36 (dt, j=11.9, 6.0hz, 2H), 3.21-3.00 (m, 5H), 1.16 (s, 1H), 0.40 (q, j=2.9 hz, 2H), 0.35 (dt, j=8.4, 5.5.hz, 2H), and th2H.
Example 2
40mg of THR1442 solid sample obtained in preparation example 1 is taken, 0.4mL of isopropanol is added for dissolving, 11.5mg of L-aspartic acid is taken, 4mL of water is added for ultrasonic treatment to form a solution, the L-aspartic acid water solution is added into the isopropanol solution of THR1442, white turbidity is separated out, stirring is carried out for 3 days at 10 ℃, then decompression filtration is carried out, and the solid is dried for 48 hours at 10 ℃ under vacuum, thus 44.0mg of THR 1442L-aspartic acid eutectic is obtained, and the yield is 85%.
Example 3
50mg of THR1442 solid sample obtained in preparation example 1 is taken, 0.1mL of methanol is added for dissolving, 14.3 mgL-aspartic acid is taken, 4mL of water is added for ultrasonic heating to form a solution, the L-aspartic acid aqueous solution is added into the THR1442 methanol solution, white turbidity is separated out, the solution is stirred for 7 days at 40 ℃, then the solution is filtered under reduced pressure, and the solid is dried for 24 hours at 40 ℃ in vacuum, thus 55.9mg of THR 1442L-aspartic acid eutectic is obtained, and the yield is 87%.
Example 4
50mg of THR1442 solid sample obtained in preparation example 1 is taken, 0.1mL of ethanol is added for dissolving, 28.6 mgL-aspartic acid is taken, 5mL of water is added for ultrasonic heating to form a solution, the L-aspartic acid aqueous solution is added into the THR1442 ethanol solution, white turbidity is separated out, the solution is stirred for 5 days at room temperature, then the solution is filtered under reduced pressure, and the solid is dried for 24 hours at 40 ℃ in vacuum, thus 55.5mg of THR 1442L-aspartic acid eutectic is obtained, and the yield is 86%.
Example 5
46.5mg of THR1442 solid sample obtained in preparation example 1 is taken, 2.0mL of methanol solution is added, 13.3 mgL-aspartic acid is taken, 3mL of water is added to ultrasonically form solution, L-aspartic acid water solution is added to the methanol solution of THR1442, the obtained solution is placed at 10 ℃ to volatilize, 57.0mg of THR 1442L-aspartic acid eutectic is obtained, and the yield is 95%.
Example 6
46.5mg of THR1442 solid sample obtained in preparation example 1 is taken, 10.0mL of ethanol is added for dissolving, 20 mgL-aspartic acid is taken, 4mL of water is added for ultrasonic treatment to form a solution, the L-aspartic acid aqueous solution is added into the THR1442 ethanol solution, the obtained solution is placed at 60 ℃ for volatilization, 56.2mg of THR 1442L-aspartic acid eutectic is obtained, and the yield is 94%.
Example 7
46.5mg of THR1442 solid sample obtained in preparation example 1 is taken, 14mL of isopropanol is added for dissolving, 26.6 mgL-aspartic acid is taken, 5mL of water is added for ultrasonic heating to form a solution, the L-aspartic acid water solution is added into the isopropanol solution of THR1442, the obtained solution is placed at 40 ℃ for volatilization, 55.6mg of THR 1442L-aspartic acid eutectic is obtained, and the yield is 93%.
Examples 2-7 produced samples having the same or similar XRPD pattern, DSC pattern, TGA pattern, IR pattern as the example 1 samples, indicating that examples 2-7 were the same eutectic compound as the example 1 samples.
Example 8
Typical tablets that may be prepared by conventional tabletting techniques may comprise:
example 9
A typical capsule for oral administration contains 25.7mg of the co-crystal of THR1442 and L-aspartic acid of the invention, 122.8mg of dextrates and 1.5mg of magnesium stearate. The mixture was passed through a 30 mesh screen and filled into size 2 gelatin capsules.
Comparative example 1
The known THR1442 and diproline eutectic prepared in preparation example 1 and the THR 1442L-aspartic acid eutectic solid prepared in example 1 are taken for crystal form hygroscopicity comparison experiments, and the specific operation is as follows: 2-5 mg of sample is respectively taken for DVS characterization, and the hygroscopicity of the crystal forms in the environment with 0-80% of relative humidity is examined.
Table 1: comparative example 1 comparative experimental data statistics
As shown in Table 1, compared with the THR1442 diproline eutectic prepared by the prior art, the THR 1442L-aspartic acid eutectic has lower hygroscopicity in the 0-80% RH environment, and can effectively avoid the problems of non-processing of the preparation and the like caused by external factors such as environmental moisture and the like in the preparation, storage and the like. Is favorable for accurate quantification in unit preparation and later transportation and storage, and is more suitable for the application of the preparation.
Comparative example 2
The comparison test of the stability in water was carried out by taking the known THR1442 diproline cocrystal prepared in preparation example 1 and the THR 1442L-aspartic acid cocrystal solid prepared in example 1, and the specific operation is as follows: at room temperature, 5mg of the sample was placed in a 5mL glass bottle, 0.5mL of water was added at room temperature, the stirring speed was 100 rpm, and the dispersion of the sample system was observed.
Table 2: comparative example 2 comparative experimental data statistics
As shown in Table 2, compared with the THR1442 diproline eutectic prepared by the prior art, the THR 1442L-aspartic acid eutectic can form a better dispersion system in water, so that the conditions of sample morphology and crystal form change caused by water use in the preparation process can be avoided, and the preparation product can be ensured to have better uniformity and stability.
All patents, patent application publications, patent applications, and non-patent publications cited in this specification are herein incorporated by reference in their entirety.
The foregoing is merely illustrative of the embodiments of the present invention, and the scope of the present invention is not limited thereto, and any changes or substitutions that may be made by those skilled in the art without departing from the inventive concept are intended to be included within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope defined by the claims.
Claims (11)
1. A eutectic crystal of THR1442 and L-aspartic acid with structural formula shown in figure (I),
wherein the X-ray powder diffraction pattern of the co-crystal expressed in terms of 2θ has the following characteristic peaks: 6.1.+ -. 0.2 °, 11.9.+ -. 0.2 °, 12.1.+ -. 0.2 °, 16.8.+ -. 0.2 °, 17.7.+ -. 0.2 °, 21.7.+ -. 0.2 °, 22.5.+ -. 0.2 °, 23.7.+ -. 0.2 °, 24.4.+ -. 0.2 °, 25.5.+ -. 0.2 °, 29.7.+ -. 0.2 ° and 35.9.+ -. 0.2 °.
2. The co-crystal of THR1442 and L-aspartic acid according to claim 1, wherein the X-ray powder diffraction pattern expressed in terms of 2Θ has characteristic peaks and their relative intensities at:
3. the co-crystal of THR1442 and L-aspartic acid according to claim 1 or 2, wherein the co-crystal has a fourier infrared spectrum at wavenumbers 1510±2, 1236±2,
1089.+ -.2, 1210.+ -.2, 1054.+ -.2, 1036.+ -.2, 1011.+ -.2, 986.+ -.2, 967.+ -.2 and 900.+ -.2 cm -1 With characteristic peaks.
4. A method of preparing a co-crystal of THR1442 and L-aspartic acid according to any one of claims 1 to 3, wherein the method is any one of the following methods:
(1) THR1442 solid at C 1 -C 3 Forming a solution in alcohol, forming a solution of L-aspartic acid solid in water,mixing an L-aspartic acid aqueous solution and a THR1442 alcohol solution, stirring for crystallization, and separating and drying the precipitated crystals to obtain the eutectic of the THR1442 and the L-aspartic acid;
the stirring time is 3-7 days;
in the preparation method, the molar ratio of THR1442 solid to L-aspartic acid is 1:1-1:2;
the operation temperature of the preparation method is 10-40 ℃;
in the preparation method, the mass volume ratio of THR1442 solid to the alcohol is 100-500 mg:1mL;
(2) Forming a solution of THR1442 solid in C1-C3 alcohol, forming a solution of L-aspartic acid solid in water, mixing an aqueous solution of L-aspartic acid and a THR1442 alcohol solution, volatilizing and crystallizing to obtain the eutectic of THR1442 and L-aspartic acid;
in the preparation method, the molar ratio of THR1442 solid to L-aspartic acid is 1:1-1:2;
the volatilization temperature is 10-60 ℃;
the concentration of the THR1442 solution is 0.1-0.7 times of the solubility of THR1442 solid in the alcohol.
5. The process according to claim 4, wherein C in the process (1) and the process (2) 1 -C 3 The alcohol is ethanol.
6. The process according to claim 4, wherein the operating temperature in the process (1) is room temperature.
7. The preparation method according to claim 4, wherein the mass-to-volume ratio of THR1442 solid to the alcohol in the method (1) is 200 to 500mg:1mL.
8. The process according to claim 4, wherein the volatilization temperature in the process (2) is 10 to 40 ℃.
9. The production method according to claim 4, wherein the concentration of the THR1442 solution in the method (2) is 0.1 to 0.5 times the solubility of the THR1442 solid in the alcohol.
10. A pharmaceutical composition comprising a disease-treating and/or preventing effective amount of one or more co-crystals selected from THR1442 and L-aspartic acid as claimed in any one of claims 1 to 3 and at least one pharmaceutically acceptable carrier.
11. Use of a co-crystal of THR1442 and L-aspartic acid as claimed in any one of claims 1 to 3 or a pharmaceutical composition as claimed in claim 10 in the manufacture of a medicament for the treatment and/or prophylaxis of one or more disorders or conditions selected from type I and type II diabetes, hyperglycemia.
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| GB202213849D0 (en) | 2022-09-22 | 2022-11-09 | Macfarlan Smith Ltd | Crystalline forms of bexagliflozin, processes for the preparation and use thereof |
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| CN102177147A (en) * | 2008-08-22 | 2011-09-07 | 泰拉科斯有限公司 | Processes for the preparation of SGLT2 inhibitors |
| CN102933592A (en) * | 2010-06-12 | 2013-02-13 | 泰拉科斯有限公司 | Crystalline form for diphenylmethane sglt2 inhibitor |
| CN104619713A (en) * | 2013-05-24 | 2015-05-13 | 四川海思科制药有限公司 | Oxabicyclo derivatives, preparation method and use thereof |
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| CN102177147A (en) * | 2008-08-22 | 2011-09-07 | 泰拉科斯有限公司 | Processes for the preparation of SGLT2 inhibitors |
| CN102933592A (en) * | 2010-06-12 | 2013-02-13 | 泰拉科斯有限公司 | Crystalline form for diphenylmethane sglt2 inhibitor |
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