CN106966944B - Vildagliptin crystal form compound and preparation method thereof - Google Patents
Vildagliptin crystal form compound and preparation method thereof Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicines, and discloses a vildagliptin crystal form compound and a preparation method thereof, wherein an X-ray powder diffraction pattern represented by a 2 theta +/-0.2-degree diffraction angle shows characteristic diffraction peaks at 6.02 degrees, 7.53 degrees, 9.62 degrees, 11.41 degrees, 12.60 degrees, 14.03 degrees, 15.13 degrees, 18.64 degrees, 21.22 degrees, 23.01 degrees, 25.06 degrees, 28.62 degrees, 32.03 degrees and 34.42 degrees, and an X-ray powder diffraction pattern obtained by measuring with Cu-K α rays is shown in a figure 1 and is completely different from the prior art.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a vildagliptin crystal form compound and a preparation method thereof.
Background
Vildagliptin (vildagliptin) is a selective, competitive and reversible dipeptidyl peptidase-IV (DPP-IV) inhibitor for oral administration after sitagliptin (sitagliptin), vildagliptin is a primary drug developed by Noval, Switzerland, which is approved by European Union to be on the market in 2007 month 9, the trade name is GA L VUS, the dosage form on the market is a tablet, the specification is 50 mg.2011 month 8, vildagliptin tablets (trade name: Jiaweile) produced by Noval, Switzerland, are obtained as an imported registration batch of vildagliptin tablets, are approved by the State food and drug administration in China, Vildagliptin imported tablets in 2012 are on the market in China, a new choice is provided for the treatment of type 2 diabetes in China, and the application prospect of the vildagliptin (vildagliptin) has great potential.
Chemical name of vildagliptin: (2S) -1- [2- [ (3-Hydroxytricyclo [3.3.1.13,7 ]]Decan-1-yl) amino]Acetyl group]-2-pyrrolidinecarbonitrile; the molecular formula is as follows: c17H25N3O2303.4 as molecular weight; the characteristics are as follows: white to off-white crystalline powders; melting point: 148.0-150.0 ℃; the structural formula is as follows:
dipeptidyl peptidase IV (DPP-IV) inhibitors are novel antidiabetic drugs, play a role in reducing blood sugar by inducing various mechanisms of promoting the biosynthesis and secretion of insulin, inhibiting the apoptosis of β cells, inhibiting the secretion of glucagon, reducing food intake and the like, can reverse the condition of continuous deterioration of the pancreatic islet function of a diabetic patient while controlling blood sugar, and show good application prospects.
Different polymorphs of a drug substance may have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure and density. These properties can directly affect handling and/or production of the drug substance and formulation, and can affect the stability, solubility and bioavailability of the formulation. When a compound exists in polymorphic form, it is important to know the crystal form of the compound applied in each dosage form during the preparation process, because the specific polymorphic form has specific thermodynamic properties and stability, so as to ensure that the same form of the pharmaceutically active compound is applied during the production process. It is therefore essential to maintain the pharmaceutically active compound in a single crystalline form or in a known mixture of crystalline forms.
Patent CN105777602A discloses a new crystal form of vildagliptin, which has high purity, and the maximum impurity is less than 0.5 per mill; good stability and the like; the preparation method comprises the following steps: adding vildagliptin into a mixed solution of 5-8 times of acetone-acetonitrile-ammonia water, wherein the ratio of acetone to acetonitrile to ammonia water is 3: 1-2: 0.5-1, heating to 60-70 ℃, preserving heat for 30 minutes, and filtering while the solution is hot; the filtrate is kept at 30-35 ℃ for 1-2 hours; and naturally cooling to room temperature, preserving the temperature for 2-3 hours, filtering the precipitated crystals, and naturally drying at room temperature to obtain the high-purity vildagliptin crystals. The X-ray powder diffraction characteristic absorption peaks (2 theta) and D values of the crystal form are as follows:
| staff mark | 28 (degree) | Interplanar spacing (d) | I/ |
| 1 | 6.680 | 16.5034 | 21 |
| 2 | 10.180 | 9.1428 | 3 |
| 3 | 10.950 | 6.5305 | 3 |
| 4 | 13.210 | 6.5184 | 42 |
| 5 | 16.010 | 5.5570 | 13 |
| 6 | 18.920 | 5.1871 | 40 |
| 7 | 19.720 | 5.0947 | 10 |
| 8 | 20.430 | 5.0298 | 10 |
| 9 | 23.620 | 4.9530 | 15 |
| 10 | 24.360 | 4.5514 | 60 |
| 11 | 25.620 | 4.5072 | 10 |
| 12 | 27.200 | 4.7571 | 11 |
| 13 | 29.410 | 4.7452 | 15 |
| 14 | 30.380 | 4.5480 | 10 |
Patent CN101106977A discloses an a-type crystal form of vildagliptin, and its X-ray powder diffraction pattern shows characteristic diffraction peaks at 12.0 °, 13.5 °, 16.13 °, 16.6 °, 17.1 °, 17.2 °, 20.1 °, 22.5 °, 27.4 °, 28.1 ° ± 0.3. The preparation process comprises the following steps: heating a solution of vildagliptin in an organic solvent, wherein the solvent is selected from 2-butanone, 2-propanol/ethyl acetate, 2-propanol, acetone; cooling the solution to about-20 ℃, preferably about-10 ℃ to induce crystallization or adding an anti-solvent to the solution to induce crystallization, and recovering vildagliptin crystals.
When vildagliptin is crystallized, if different solvents and process conditions are adopted, the arrangement number, the position and the lattice form of molecules in crystal unit cells of each crystal form are different, different crystal structures are formed, and the property, the quality and the drug effect of vildagliptin can be changed due to the change of vildagliptin polymorphism. Therefore, the preparation of the stable crystals of vildagliptin has very important significance for further researching the physicochemical properties of the compound and researching the pharmaceutical composition and clinical application of the compound. The vildagliptin crystal form prepared by the method is beneficial to improving the bioavailability, reducing adverse reactions and increasing clinical curative effects in the aspects of crystal form conversion stability, physical stability and chemical stability.
Disclosure of Invention
The invention aims to provide a vildagliptin crystal form compound with good solubility and stability and a preparation method thereof.
In order to realize the purpose of the invention, the technical scheme is as follows:
the invention provides a vildagliptin crystal form compound, wherein an X-ray powder diffraction pattern of the vildagliptin crystal form compound expressed by a 2 theta +/-0.2-degree diffraction angle shows characteristic diffraction peaks at 6.02 degrees, 7.53 degrees, 9.62 degrees, 11.41 degrees, 12.60 degrees, 14.03 degrees, 15.13 degrees, 18.64 degrees, 21.22 degrees, 23.01 degrees, 25.06 degrees, 28.62 degrees, 32.03 degrees and 34.42 degrees.
An X-ray powder diffraction pattern obtained by measuring the vildagliptin crystal form compound by using Cu-K α rays is shown in figure 1.
The invention also provides a preparation method of the vildagliptin crystal form compound, which comprises the following specific steps:
a) dissolving the crude vildagliptin product in methanol, stirring and heating the solution to completely dissolve the crude vildagliptin product until the solution is clear, and filtering while the solution is hot;
b) cooling the obtained solution, adding the pre-cooled mixed solvent into the solution at a flow rate of 1.0-2.0 m L/min when the temperature is reduced to 20-30 ℃ until crystallization occurs, separating out crystals, continuously cooling to-10-5 ℃, preserving heat, stirring and growing the crystals until the crystallization is complete;
c) and (4) carrying out suction filtration, collecting crystals, washing with a small amount of ethanol, and carrying out vacuum drying to obtain vildagliptin crystals.
Preferably, in the step a), the mass-to-volume ratio of vildagliptin to methanol is 1: 5-10 (g/ml).
Preferably, the mixed solvent is a mixed solvent of methanol and dichloromethane, and the volume ratio of the methanol to the dichloromethane in the mixed solvent is 1: 3-5; the volume ratio of the methanol in the step a) to the mixed solvent in the step b) is 1: 2-5.
Preferably, in the step b), the temperature reduction range is 1-5 ℃ per 10 minutes, the crystal growing temperature is-10-5 ℃, and the crystal growing time is 0.5-3 hours.
The invention also provides a pharmaceutical composition containing the vildagliptin crystal form compound, and the pharmaceutical composition is a tablet containing vildagliptin crystals.
Studies have shown that in X-ray powder diffraction patterns, the diffraction pattern obtained from the new crystalline form tends to be characteristic for the particular crystalline form, where the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the crystal form in question, and when judging whether the diffraction peaks are the same as the known crystal form, the relative positions of the peaks rather than their relative intensities should be noted. The X-ray powder diffraction pattern of the vildagliptin crystal provided by the invention has obviously different peak relative positions with the prior art, so that the vildagliptin crystal is a new crystal form different from the prior art.
The technical scheme of the invention is explained and illustrated by researching the vildagliptin crystal form compound provided by the invention as follows:
1. crystal form detection
The vildagliptin crystal prepared by the invention is taken, and an X-ray powder diffraction pattern obtained by measuring with Cu-K α rays is shown in figure 1, wherein the X-ray powder diffraction pattern expressed by 2 theta +/-0.2 diffraction angles shows characteristic peaks at 6.02 degrees, 7.53 degrees, 9.62 degrees, 11.41 degrees, 12.60 degrees, 14.03 degrees, 15.13 degrees, 18.64 degrees, 21.22 degrees, 23.01 degrees, 25.06 degrees, 28.62 degrees, 32.03 degrees and 34.42 degrees.
2. Differential thermal and thermogravimetric analysis
Differential thermal and thermogravimetric analysis is carried out on the vildagliptin crystal prepared by the invention, and the result is shown in figure 2; the result shows that the product has no absorption peak or transition before 150 ℃, which indicates that no crystal water or crystal solvent exists in the sample; the product has an endothermic peak at about 160 ℃. The product is measured by melting point: 159.0 ℃ -161.0 ℃, melting point of the raw materials of the prior art: 148.0-150.0 ℃, which is laterally proved to be a different crystal form.
3. Moisture analysis
The water content of the vildagliptin crystal is 0.08 percent by adopting a card type moisture tester.
4. Purity detection
Through HP L C purity detection, the purity of the vildagliptin crystal prepared by the method can reach 99.92-99.99%.
Compared with the prior art, the invention has the following advantages:
(1) the vildagliptin crystal form compound provided by the invention is a new crystal form different from the prior art; the preparation method of the vildagliptin crystal form compound provided by the invention is simple and easy to operate, has mild reaction conditions, and is suitable for large-scale production.
(2) The vildagliptin crystal form compound provided by the invention has improved stability, well improves the solubility of vildagliptin in water, improves the bioavailability, is beneficial to the selection and design of a drug administration way and the determination of process parameters of a pharmaceutical preparation, and further improves the production quality of medicines.
Drawings
The invention is further described with reference to the accompanying drawings in which:
fig. 1 is an X-ray powder diffraction pattern of the vildagliptin crystalline form compound prepared in example 1 of the present invention.
Fig. 2 is a TG-DSC diagram of vildagliptin crystalline form compound prepared in example 1 of the present invention.
FIG. 3 shows that the self-made preparation and the original imported preparation of the vildagliptin crystal form of the invention are dissolved in 0.01 mol/L of dissolution medium-1Dissolution profile in hydrochloric acid solution.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following embodiments are provided to explain the technical solution of the present invention in detail, and to help further understand the advantages and effects of the technical solution of the present invention, and the embodiments do not limit the scope of the present invention, which is determined by the claims.
Example 1: preparation of vildagliptin crystal form compound
Putting 100g of vildagliptin into a reaction bottle, adding 1000m L dissolved in methanol, heating, stirring to dissolve the vildagliptin clear, filtering while the vildagliptin clear is hot, cooling to 20 ℃ while stirring (the cooling range is 5 ℃ per 10 minutes), adding 2000ml of pre-cooled mixed solvent B (the volume ratio of methanol to dichloromethane is 1:3) into the solution at the flow rate of 1.0m L/min until crystals appear, continuously cooling to-5 ℃ (the cooling range is 1 ℃ per 10 minutes), stirring for 3 hours, carrying out vacuum filtration, and carrying out vacuum drying on a filter cake at the temperature of 50 ℃ for 6 hours to obtain 90.3g of white solid with the yield of 90.3%.
Example 2: preparation of vildagliptin crystal form compound
Putting 100g of vildagliptin into a reaction bottle, adding 500ml of vildagliptin dissolved in methanol, heating, stirring to dissolve the vildagliptin clear solution, filtering while the vildagliptin clear solution is hot, cooling to 25 ℃ while stirring (the cooling range is 5 ℃ per 10 minutes), adding 1500ml of pre-cooled mixed solvent B (the volume ratio of methanol to dichloromethane is 1:5) into the solution at the flow rate of 1.5m L/min until crystals are formed, continuously cooling to-10 ℃ while the cooling range is 1 ℃ per 10 minutes, stirring for 2 hours, carrying out vacuum filtration, and drying a filter cake in vacuum at 50 ℃ for 4 hours to obtain 88.6g of white solid with the yield of 88.6%, wherein the X-ray powder diffraction spectrum of the prepared crystals obtained by using Cu-K α ray measurement is similar to that of example 1.
Example 3: preparation of vildagliptin crystal form compound
Putting 150g of vildagliptin into a reaction bottle, adding 1200m L dissolved in methanol, heating and stirring to dissolve the vildagliptin clear, filtering while the vildagliptin clear is hot, cooling to 30 ℃ while stirring (the cooling range is 5 ℃ per 10 minutes), adding 2400ml of pre-cooled mixed solvent B (the volume ratio of methanol to dichloromethane is 1:4) into the solution at the flow rate of 2m L/min until crystals appear, continuously cooling to-5 ℃ (the cooling range is 1 ℃ per 10 minutes), stirring for 2 hours, performing vacuum filtration, and drying a filter cake in vacuum at 50 ℃ for 5 hours to obtain 137.3g of white solid, wherein the yield is 91.5%.
Example 4: preparation of vildagliptin crystal form compound
Putting 80g of vildagliptin into a reaction bottle, adding 800m L dissolved in methanol, heating and stirring to dissolve the vildagliptin clear, filtering while the vildagliptin clear is hot, cooling to 30 ℃ while stirring (the cooling range is 5 ℃ per 10 minutes), adding 3000ml of pre-cooled mixed solvent B (the volume ratio of methanol to dichloromethane is 1:3) into the solution at the flow rate of 2m L/min until crystals are formed, continuously cooling to-5 ℃ (the cooling range is 1 ℃ per 10 minutes), stirring for 2 hours, carrying out vacuum filtration, and drying a filter cake in vacuum at 50 ℃ for 5 hours to obtain 74g of white solid with the yield of 92.4%.
Example 5: preparation of vildagliptin crystal form compound
Putting 80g of vildagliptin into a reaction bottle, adding 800ml of m L dissolved in methanol, heating and stirring for dissolving, filtering while hot, cooling to 30 ℃ while stirring (the cooling range is 5 ℃ per 10 minutes), adding 4000ml of pre-cooled mixed solvent B (the volume ratio of methanol to dichloromethane is 1:4) into the solution at the flow rate of 2m L/min until crystals appear, continuously cooling to-5 ℃ (the cooling range is 1 ℃ per 10 minutes), stirring for 2 hours, performing vacuum filtration, and drying a filter cake in vacuum at 50 ℃ for 5 hours to obtain 72.6g of white solid, wherein the yield is 90.8%.
The invention is further illustrated by the following experimental examples:
experimental example 1: solubility determination
Test products: samples prepared according to examples 1-3 of the present invention;
the reference 2 is a vildagliptin crystal form prepared according to patent CN101106977A (the crude vildagliptin product of the same example 1 is used as a raw material, added into 5 times of acetone, heated to dissolve, cooled to about-10 ℃ to 0 ℃ for crystallization, filtered, and dried to obtain the vildagliptin crystal form).
The reference 3 is a vildagliptin crystal form prepared according to patent CN105777602A (the crude vildagliptin product of the same example 1 is used as a raw material, added into a mixed solution of 8 times of acetone-acetonitrile-ammonia water in a ratio of 3: 2: 1, heated to 60-70 ℃, kept for 30 minutes, filtered while hot, filtered at 30-35 ℃, kept for 1-2 hours, naturally cooled to room temperature, kept for 2-3 hours, crystallized, filtered, and dried to obtain the vildagliptin crystal form).
The solubility is measured according to the general example of Chinese pharmacopoeia 2015 year edition, and the method comprises the following steps: taking a proper amount of the product, adding water respectively, strongly shaking for 30 seconds every 5 minutes, and observing the dissolution condition within 30 minutes to obtain the product, wherein the results are shown in Table 1.
Table 1 solubility test results in water for inventive forms and controls
The above dissolved aqueous solution sample was stirred at a constant temperature of 25 ℃ for 72 hours, and 5ml was sampled. Filtering the sample with 0.45 μm microporous membrane, discarding the primary filtrate, diluting the subsequent filtrate to a certain multiple, and determining the drug content as water solubility (mg/ml). The results are shown in Table 2:
table 2 comparison of the solubility in water of the crystalline forms of the invention with the crystalline forms of the prior art
As can be seen from the above table, at 25 ℃, the solubility of the vildagliptin crystal compound in water is significantly improved compared with the prior art, and the water solubility is improved by about 4 times.
Experimental example 3: detection of related substances
The related substance impurities in the vildagliptin crystals prepared in examples 1-5 are detected and analyzed by reference documents (myrica rubra, old red, vildagliptin related substance inspection, Guangzhou chemical industry 2016,44(16): 149-: the structural formulas of the vildagliptin and impurities I, II and III are shown as follows, wherein the impurity II is an intermediate for synthesizing the vildagliptin, the impurity I is a reaction product of the vildagliptin and the impurity II, and the impurity III is obtained by incomplete amide dehydration or hydrolysis conversion of cyano groups in molecules in the vildagliptin synthesis process; the results are shown in Table 3.
Vildagliptin and impurities I, II and III
Table 3: results of impurity detection analysis of samples of each example
The invention surprisingly finds that the crystal form compound prepared by the preparation method does not contain impurities I, II and III, other contents are obviously reduced, and the content change is small along with the prolonging of the storage time.
Experimental example 4 stability test
Experimental example the stability of vildagliptin crystals provided by the invention was investigated by accelerated tests and long-term tests.
1. Accelerated test
The samples prepared in examples 1 to 3 were stored at 40. + -. 2 ℃ and 75. + -. 5% relative humidity for 6 months, and sampled at the end of 0, 1, 2, 3 and 6 months to determine the properties, related substances and contents, and the results are shown in Table 4.
Table 4: accelerated test results (temperature 40. + -. 2 ℃ C., relative humidity 75. + -. 5%)
As shown in Table 5, the vildagliptin crystal of the invention is placed for 6 months under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5%, the content of related substances is not obviously increased, all indexes are not obviously changed, and the stability of the product is good.
2. Long term test
The samples prepared in examples 1 to 3 were stored at 25. + -. 2 ℃ and 60. + -. 5% relative humidity for 6 months, and sampled at the end of 0, 3, 6, 9, 12, 18 and 24 months to determine the properties, related substances and contents, and the results are shown in Table 5.
Table 5: long-term test results (temperature 25 + -2 deg.C, relative humidity 60 + -5%)
As shown in Table 5, the vildagliptin crystal of the invention is stable after being placed for 24 months under the conditions of the temperature of 25 +/-2 ℃ and the relative humidity of 60 +/-5%, and all indexes have no obvious change. The chemical stability is good, and the method is suitable for the preparation and long-term storage of the pharmaceutical preparation.
Experimental example 5 dissolution measurement
The solubility of the vildagliptin tablets in different dissolution media is examined, and the result shows that the vildagliptin tablets are dissolved in water, phosphate buffer solution with pH6.8, phosphate buffer solution with pH4.5, and 0.1 mol/L-1Hydrochloric acid solution, 0.01mo L & L-1The vildagliptin tablet is a pH-independent preparation, and according to the requirements of vildagliptin tablet import drug registration standard dissolution rate, the original ground reference drug and self-made sample are respectively taken, and the slurry method is adopted for 50 revolutions, and the concentration is 0.01 mol/L-1Hydrochloric acid solution 1000m L as dissolution mediumThe elution amounts were calculated by sampling and measuring at elution times of 5, 10, 15, 20 and 30min (an equal amount of elution medium was added after each sampling).
The determination method comprises taking vildagliptin tablet, and determining according to dissolution rate with concentration of 0.01 mol/L-1The hydrochloric acid solution 1000m L is used as dissolution medium, and the rotation speed is 50r min-1Sampling at 5, 10, 15, 20 and 30min according to the method, measuring (supplementing equivalent dissolution medium after each sampling), filtering to obtain sample solution, adding vildagliptin control 10mg into 100m L flask, and adding 0.01mol L-1Dissolving the hydrochloric acid solution, diluting to scale, shaking, precisely measuring 5m L, placing in 10m L measuring flask, adding 0.01mol L-1The hydrochloric acid solution is diluted to the scale and shaken up to be used as a reference solution. Performing high performance liquid chromatography with Agilent extended-C column18(4.6mm × 100mm, 5 μm), using phosphate buffer (1.15 g of anhydrous dipotassium hydrogen phosphate is dissolved in 1000m L water, the pH value is adjusted to 5.50 +/-0.05 by 10% of phosphoric acid) -acetonitrile (80: 20) as a mobile phase, the detection wavelength is 210nm, the flow rate is 1.0m L, the column temperature is 35 ℃, 10 μ L of the two solutions are respectively taken and injected into a liquid chromatograph, a chromatogram is recorded, the dissolution amount of the vildagliptin is calculated by the peak area according to an external standard method, the cumulative dissolution amount and the dissolution curve are calculated, and the result is shown in figure 3.
Claims (3)
1. A preparation method of a vildagliptin crystal form compound is characterized by comprising the following steps:
a) dissolving the crude vildagliptin product in methanol, stirring and heating the solution to clarify the solution, and filtering the solution while the solution is hot;
b) and (3) cooling the obtained solution, adding a pre-cooled mixed solvent into the solution at a flow rate of 1.0-2.0 m L/min when the temperature is reduced to 20-30 ℃ until crystallization occurs, separating out crystals, continuously cooling to-10-5 ℃, keeping the temperature, stirring and growing the crystals until the crystallization is complete, wherein the mixed solvent is a mixed solvent of methanol and dichloromethane, the volume ratio of the methanol to the dichloromethane in the mixed solvent is 1: 3-5, and the volume ratio of the methanol in the step a) to the mixed solvent in the step b) is 1: 2-5.
c) And (4) carrying out suction filtration, collecting crystals, washing with a small amount of ethanol, and carrying out vacuum drying to obtain vildagliptin crystals.
2. The preparation method of the vildagliptin crystal form compound according to claim 1, characterized in that: in the step a), the mass-to-volume ratio of the vildagliptin to the methanol is 1: 5-10 g/ml.
3. The preparation method of the vildagliptin crystal form compound according to claim 1, characterized in that: in the step b), the temperature reduction range is 1-5 ℃ per 10 minutes, the crystal growing temperature is-10-5 ℃, and the crystal growing time is 0.5-3 h.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104326961A (en) * | 2014-11-20 | 2015-02-04 | 海南中和药业有限公司 | Synthetic process of vildagliptin |
| CN104744334A (en) * | 2015-03-25 | 2015-07-01 | 合肥创新医药技术有限公司 | Preparation method for vildagliptin |
| CN104817482A (en) * | 2015-03-17 | 2015-08-05 | 宁波百思佳医药科技有限公司 | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin |
| CN104945299A (en) * | 2015-05-28 | 2015-09-30 | 烟台万润药业有限公司 | Efficient synthesis method of vildagliptin |
| CN105712920A (en) * | 2014-12-04 | 2016-06-29 | 南京优科生物医药研究有限公司 | Preparation method of vildagliptin |
-
2017
- 2017-03-01 CN CN201710116341.9A patent/CN106966944B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104326961A (en) * | 2014-11-20 | 2015-02-04 | 海南中和药业有限公司 | Synthetic process of vildagliptin |
| CN105712920A (en) * | 2014-12-04 | 2016-06-29 | 南京优科生物医药研究有限公司 | Preparation method of vildagliptin |
| CN104817482A (en) * | 2015-03-17 | 2015-08-05 | 宁波百思佳医药科技有限公司 | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin |
| CN104744334A (en) * | 2015-03-25 | 2015-07-01 | 合肥创新医药技术有限公司 | Preparation method for vildagliptin |
| CN104945299A (en) * | 2015-05-28 | 2015-09-30 | 烟台万润药业有限公司 | Efficient synthesis method of vildagliptin |
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| CN106966944A (en) | 2017-07-21 |
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