CN110857302A - Preparation method of sitagliptin hydrochloride monohydrate crystal form - Google Patents
Preparation method of sitagliptin hydrochloride monohydrate crystal form Download PDFInfo
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- CN110857302A CN110857302A CN201810970325.0A CN201810970325A CN110857302A CN 110857302 A CN110857302 A CN 110857302A CN 201810970325 A CN201810970325 A CN 201810970325A CN 110857302 A CN110857302 A CN 110857302A
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- sitagliptin
- hydrochloride monohydrate
- crystal form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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 invention relates to a preparation method of a sitagliptin hydrochloride monohydrate crystal form, wherein a dissolving solvent is a mixed solvent of an ester solvent and water, and the sitagliptin hydrochloride monohydrate crystal form is prepared by mixing the dissolved sitagliptin, a hydrochloric acid/ester solvent and water, cooling after the reaction is finished, performing suction filtration and drying. The crystal form preparation method can prepare the sitagliptin hydrochloride monohydrate crystal form with high yield and high purity.
Description
Technical Field
The invention relates to a preparation method of a sitagliptin hydrochloride monohydrate crystal form.
Background
Sitagliptin phosphate monohydrate is a marketed form of sitagliptin, developed by Merck, the first DPP-4 inhibitor for the treatment of type 2 diabetes, marketed in the united states at 10 months 2006 under the trade name Januvia.
Characterization information on the crystalline form of sitagliptin phosphate monohydrate appears for the first time in patent US7326708 (patentee: Merck) in the form of XRD, TGA, DSC and nuclear magnetic spectrum. The sitagliptin phosphate monohydrate is prepared by crystallization in the solvent isopropanol and water.
In fact, the Merck company has previously developed a crystalline form of sitagliptin hydrochloride dihydrate, disclosed in its international application WO2003004498, using methanol as the dissolution solvent.
Later in its international application WO2005072530, further crystalline forms of sitagliptin hydrochloride monohydrate are reported. The used dissolving solvent is a mixed solvent of isopropanol and methanol, and the specific process comprises the following steps: after dissolving, reacting with hydrochloric acid/diethyl ester at 55 ℃, cooling, filtering, washing and crystallizing to obtain the product.
Many patent documents on the research of the crystalline form of sitagliptin hydrochloride are also available, and the patent documents include the following: WO2010000469, WO2011123641, WO2012107492, WO2012025944, WO2015170344, WO 2016162877. Polymorphic forms of sitagliptin hydrochloride are studied in the patent literature, and 2010, Ratiopharma GmbH WO2010000469 in Germany disclose Form I and Form II, and U.S. Teva WO2011123641 discloses hydrochloride monohydrate Form III, IV, V in 2011; in 2012, Cadila corporation WO2012147092, india, disclosed hydrochloride salts with a water content of 3.54%; in 2012, USV company WO2012025944, india, disclosed the hydrochloride Form III, IV, V; in 2015, Laurus company WO2015170340 in india disclosed hydrochloride salts Form L1, L2, L3, up to L9; in 2016, Harman corporation of India, WO2016162877, disclosed the hydrochloride monohydrate. In WO2016162877, an ester solvent is used as the dissolution solvent, however, the crystallization solvent system in the example is not a pure ester solvent, and another solvent is used. Thus, such a solvent system is a mixed solvent system.
In view of the defect that the crystalline form of sitagliptin hydrochloride prepared in the patent documents has the characteristic of easy water absorption, research on the crystalline form of sitagliptin hydrochloride is needed, and the crystalline form which is more suitable for medicinal use is developed.
Disclosure of Invention
The sitagliptin hydrochloride monohydrate crystal form prepared by the invention overcomes the problem of water absorption, is closely related to the crystal form preparation process, is a single ester solvent system, and is more suitable for precipitation of the sitagliptin hydrochloride monohydrate crystal form. In addition, the sitagliptin hydrochloride monohydrate prepared by the method is very stable in crystal form.
In order to realize the technical purpose of the invention, the technical scheme adopted by the invention is as follows:
firstly, the invention provides a sitagliptin hydrochloride monohydrate crystal form, and the prepared sitagliptin hydrochloride monohydrate crystal form is detected by adopting X-ray powder diffraction, so that an XRD (X-ray diffraction) pattern shown as an attached figure 1 is obtained.
The X-ray powder diffraction pattern expressed by 2 theta +/-0.2 degrees has characteristic peaks at 27.217,25.653,22.792,19.883,19.792,18.851,18.212,16.127,13.911,8.141 and 6.712.
The preparation method of the sitagliptin hydrochloride monohydrate crystal form provided by the invention comprises the following steps:
a. mixing the dissolved sitagliptin, hydrochloric acid/ester solvent and water,
wherein the reaction of sitagliptin dissolved in step a with hydrochloric acid in the presence of water is as follows:
b. cooling the solution obtained in the step a to 0-5 ℃;
c. and (5) carrying out suction filtration and drying to obtain the product.
The dissolving solvent may be an ester solvent, and ethyl acetate is more preferable.
The above-mentioned hydrochloric acid/ester solvent is preferably present in the form of an ester solvent of hydrogen chloride;
the molar ratio of the sitagliptin to the ethyl acetate solution of hydrogen chloride is 1: 1.0-1.05;
the dissolving solvent can be heated to dissolve sitagliptin, and the temperature can be from room temperature to 80 ℃, and is preferably 45-60 ℃.
In the step a of the preparation method of the invention, the following steps can be carried out: after dissolving sitagliptin hydrochloride anhydrous hydrate or sitagliptin hydrochloride monohydrate known in the prior art or other hydrates, mixing a hydrochloric acid/ester solvent with water, cooling the solution to 0-5 ℃ after complete reaction, performing suction filtration, and drying to obtain the sitagliptin hydrochloride anhydrous hydrate.
In the step a, the sitagliptin hydrochloride monohydrate crystal form can be prepared with or without adding seed crystals. Therefore, the technical scheme of the invention also comprises the technical scheme of adding the seed crystal.
The crystalline form of sitagliptin hydrochloride monohydrate of the present invention is suitable for use as a formulation. The crystal form and the crystal form prepared by the preparation method have great application in preparing medicines for treating or preventing type 2 diabetes, and are very advantageous crystal form forms.
The sitagliptin hydrochloride monohydrate crystal form prepared by the crystal form preparation method disclosed by the invention still contains a molecule of crystal water after being dried for more than 14 hours at the temperature of 60 ℃ by using a vacuum oven and through TGA and moisture detection, and the experimental conditions are more severe than those of the sitagliptin hydrochloride monohydrate crystal form heated to the temperature higher than 40 ℃ in a dry nitrogen flow, so that the sitagliptin hydrochloride monohydrate crystal form disclosed by the invention is very stable and is not easy to lose the crystal water.
The sitagliptin hydrochloride monohydrate crystal form prepared by the crystal form preparation method provided by the invention has very good stability proved by an accelerated stability experiment. The problem of stability reduction along with the increase of water content in the crystal form in the prior art is solved. The crystallization solvent system is a single ester solvent system, is more suitable for separating out the crystal form of sitagliptin hydrochloride monohydrate, has high purity and overcomes the problem of easy water absorption.
Drawings
Fig. 1 is an XRPD pattern of the crystalline form of sitagliptin hydrochloride monohydrate prepared in example 1.
Fig. 2 is a TGA profile of the crystalline form of sitagliptin hydrochloride monohydrate prepared in example 1.
Fig. 3 is an HPLC chromatogram of the crystalline form of sitagliptin hydrochloride monohydrate prepared in example 1.
Detailed Description
For better understanding of the present invention, the following description is given with reference to specific examples, but the present invention is not limited to the specific embodiments.
Sitagliptin compounds can be prepared with reference to patent WO 03004498.
The detection conditions used in the present invention are:
TGA for thermogravimetric analysis:
the instrument comprises the following steps: TGA/DSC 1 synchronous thermal analyzer;
the instrument parameters are as follows:
protective gas pressure: 20 KPa;
reaction gas pressure: 40 KPa;
initial temperature: 30 ℃;
termination temperature: 300 ℃;
temperature rising procedure: 10.0K/min;
x-ray powder diffraction detection XPRD:
the instrument comprises the following steps: bruker D2Phaser X-ray diffraction powder diffractometer;
x-ray target Cu K α (1.54184A);
pipe pressure: 30 kV;
pipe flow: 10 mA;
2 θ scanning range: 4 to 40 degrees;
scan rate (step time): 0.2 s/step;
step length: 0.02 degree.
Example 1:
100g of sitagliptin and 360g of ethyl acetate are put into a clean and dry 1000ml four-mouth bottle, the temperature is raised to 55-65 ℃ for dissolution and cleaning, after heat filtration and washing, a proper amount of water is added, 51g of a hydrogen chloride ethyl acetate solution is added, the temperature is lowered to 0-5 ℃, the temperature is kept, suction filtration and washing are carried out, the mixture is dried in a 55 ℃ oven and dried for more than 10 hours, and the mixture is collected to obtain 102g of sitagliptin hydrochloride monohydrate crystal form, the HPLC purity is 99.92%, the water content is 3.56%, the XRD (X ray diffraction) spectrum is shown in figure 1, the TGA (gas chromatography) spectrum is shown in figure.
The X-ray diffraction pattern characteristic peak data are shown in the following table:
| number of characteristic peaks | d value (Angel) | Angle 2 theta | Strength (%) |
| 1 | 6.712 | 13.15817 | 71.1％ |
| 3 | 8.141 | 10.85126 | 56.1％ |
| 6 | 13.911 | 6.36112 | 88.6％ |
| 8 | 16.127 | 5.49168 | 59.3％ |
| 10 | 18.212 | 4.86718 | 100.1％ |
| 11 | 18.851 | 4.70363 | 40.9％ |
| 12 | 19.792 | 4.48208 | 49.9％ |
| 13 | 19.883 | 4.46189 | 38.0％ |
| 16 | 22.792 | 3.89855 | 57.9％ |
| 20 | 25.653 | 3.46979 | 50.9％ |
| 21 | 27.217 | 3.27383 | 86.5％ |
Example 2:
100g of sitagliptin and 360g of ethyl acetate are put into a clean and dry 1000ml four-mouth bottle, the temperature is raised to 55-65 ℃, after heat filtration and washing, proper amount of water is added, seed crystals are added, 51g of a hydrogen chloride ethyl acetate solution is added, the temperature is reduced to 0-5 ℃, heat preservation, suction filtration and washing are carried out, a wet product is dried in a 55 ℃ oven and dried for more than 10 hours, and the wet product is collected, so that 102g of sitagliptin hydrochloride monohydrate crystal form is obtained, the HPLC purity is 99.89%, and the water content is 3.56%.
Example 3:
100g of sitagliptin and 360g of isopropyl acetate are put into a clean and dry 1000ml four-mouth bottle, the temperature is raised to 45-60 ℃ for dissolution and heat filtration, then a proper amount of water is added, 51g of a hydrochloric acid ethyl acetate solution is added, the temperature is lowered to 0-5 ℃, the temperature is kept, suction filtration and leaching are carried out, a wet product is dried in a drying oven at the temperature of 55 ℃, drying is carried out for more than 10 hours, and the material is collected, so that 98g of sitagliptin hydrochloride monohydrate crystal form is obtained, the HPLC purity is 99.89%, and the water content is 3.56%.
Example 4:
100g of sitagliptin and 360g of isopropyl acetate are put into a clean and dry 1000ml four-mouth bottle, the temperature is raised to 45-60 ℃ for dissolution and heat filtration, then a proper amount of water is added, seed crystals are added, 51g of a hydrochloric acid ethyl acetate solution is added, the temperature is reduced to 0-5 ℃, heat preservation, suction filtration and drip washing are carried out, a wet product is dried in a 55 ℃ oven and dried for more than 10 hours, and the wet product is collected to obtain 97g of sitagliptin hydrochloride monohydrate crystal form, the HPLC purity is 99.89%, and the water content is 3.56%.
Example 5: solubility study
The solubility of the sitagliptin hydrochloride monohydrate obtained by the method in water, isopropanol and methanol is respectively tested.
1. The test conditions are as follows:
ThermoU3000 liquid chromatograph YJS-18
A chromatographic column: waters Symmetry (4.6 x 250mm, 5 μm),
mobile phase: gradient elution was as follows:
the following table: gradient elution conditions
| Time min | 0 | 10 | 12.5 | 15 | 20 |
| A (0.1% perchloric acid solution)% | 75 | 25 | 25 | 75 | 75 |
| B (acetonitrile)% | 25 | 75 | 75 | 25 | 25 |
Flow rate 1ml/min column temperature: 40 ℃, sample introduction: 10 μ L, wavelength: 210nm, sample size: 10 μ L.
Sample preparation: example 1 the resultant sitagliptin hydrochloride monohydrate prepared.
2. Solution preparation:
preparation of a control solution:
accurately weighing 38.13mg of sitagliptin hydrochloride monohydrate, placing the sitagliptin hydrochloride monohydrate in a 25ml measuring flask, adding water to dissolve and dilute the sitagliptin hydrochloride monohydrate to a scale, shaking up, accurately sucking 2ml of sitagliptin hydrochloride, placing the sitagliptin hydrochloride monohydrate in a 50ml measuring flask, adding water to dilute the sitagliptin hydrochloride monohydrate to the scale, and shaking up.
Preparing a test solution:
the sitagliptin hydrochloride monohydrate is respectively put into a 10ml measuring flask filled with water, isopropanol and methanol, and shaken for 30 minutes to form saturated solution.
3. Test results
The following table shows the results of the solubility measurements:
| solvent(s) | Solubility of sitagliptin hydrochloride monohydrate of the invention |
| Methanol | 6.17mg/ml |
| Isopropanol (I-propanol) | 0.177mg/ml |
| Water (W) | 74.3mg/ml |
According to experimental results, the sitagliptin hydrochloride monohydrate prepared by the method is high in solubility.
Example 6: stability study
The sitagliptin hydrochloride monohydrate prepared by the method still contains a molecule of crystal water after being dried for more than 14 hours at the temperature of 60 ℃ by using a hot air oven and through TGA and moisture detection.
After 3-6 months of accelerated stability experiments, the water content, the single impurity content and the total impurity content of the sitagliptin hydrochloride monohydrate prepared by the method are basically unchanged, and the sitagliptin phosphate monohydrate crystal form is very stable and is not easy to absorb water and is unstable.
Claims (10)
1. The sitagliptin hydrochloride monohydrate crystal form is characterized in that an X-ray powder diffraction pattern expressed by 2 theta +/-0.2 degrees has characteristic peaks at 27.217,25.653,22.792,19.883,19.792,18.851,18.212,16.127,13.911,8.141 and 6.712.
2. A preparation method of a sitagliptin hydrochloride monohydrate crystal form is characterized by comprising the following steps:
a. mixing the dissolved sitagliptin, a hydrochloric acid/ester solvent and water, wherein the reaction of the sitagliptin dissolved in the step a and hydrochloric acid existing in the water is as follows:
b. cooling the solution obtained in the step a to 0-5 ℃;
c. and (5) carrying out suction filtration and drying to obtain the product.
3. The process for the preparation of the crystalline form of sitagliptin hydrochloride monohydrate according to claim 2, characterized by comprising the following steps: a. dissolving sitagliptin hydrochloride anhydrous hydrate or sitagliptin hydrochloride monohydrate known in the prior art or other hydrates, mixing the dissolved sitagliptin hydrochloride monohydrate or other hydrates with a hydrochloric acid/ester solvent and water, and b, cooling the solution obtained in the step a to 0-5 ℃; c. and (5) carrying out suction filtration and drying to obtain the product.
4. The production method according to claim 2 or 3, wherein the dissolution solvent is an ester solvent.
5. The method according to claim 4, wherein the solvent is ethyl acetate.
6. The method according to claim 2 or 3, wherein the step a comprises a step of seeding.
7. The production method according to claim 2 or 3, wherein the dissolution temperature is from room temperature to 80 ℃.
8. The method according to claim 2 or 3, wherein the molar ratio of sitagliptin to the ethyl acetate solution of hydrogen chloride is 1: 1.0-1.05.
9. Use of the crystalline form according to claim 1, characterized in that it is used as active ingredient for further formulations.
10. The crystal form of claim 1 and the application of the crystal form obtained by the preparation method of claim 2 or 3, and is characterized in that the crystal form is used as an active ingredient for further preparing a 2-type diabetes mellitus pharmaceutical preparation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023139276A1 (en) * | 2022-01-24 | 2023-07-27 | Zaklady Farmaceutyczne Polpharma S.A. | Process for preparing crystalline sitagliptin hydrochloride monohydrate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005072530A1 (en) * | 2004-01-16 | 2005-08-11 | Merck & Co., Inc. | Novel crystalline salts of a dipeptidyl peptidase-iv inhibitor |
| WO2012025944A2 (en) * | 2010-08-27 | 2012-03-01 | Usv Limited | Sitagliptin, salts and polymorphs thereof |
| CN105175422A (en) * | 2015-09-18 | 2015-12-23 | 深圳市海滨制药有限公司 | Sitagliptin phosphate crystal and preparation method and application thereof |
| WO2016162877A1 (en) * | 2015-04-09 | 2016-10-13 | Finochem Limited Harman | "a process for preparing 7-[(3r)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyi]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate and its crystalline form" |
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- 2018-08-24 CN CN201810970325.0A patent/CN110857302A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005072530A1 (en) * | 2004-01-16 | 2005-08-11 | Merck & Co., Inc. | Novel crystalline salts of a dipeptidyl peptidase-iv inhibitor |
| WO2012025944A2 (en) * | 2010-08-27 | 2012-03-01 | Usv Limited | Sitagliptin, salts and polymorphs thereof |
| WO2016162877A1 (en) * | 2015-04-09 | 2016-10-13 | Finochem Limited Harman | "a process for preparing 7-[(3r)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyi]- 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine hydrochloride monohydrate and its crystalline form" |
| CN105175422A (en) * | 2015-09-18 | 2015-12-23 | 深圳市海滨制药有限公司 | Sitagliptin phosphate crystal and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| NARAYAN VARIANKAVAL等: "From Form to Function: Crystallization of Active Pharmaceutical Ingredients", 《AICHE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023139276A1 (en) * | 2022-01-24 | 2023-07-27 | Zaklady Farmaceutyczne Polpharma S.A. | Process for preparing crystalline sitagliptin hydrochloride monohydrate |
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Application publication date: 20200303 |