CN109535216B - Preparation method of amorphous obeticholic acid and amorphous obeticholic acid - Google Patents
Preparation method of amorphous obeticholic acid and amorphous obeticholic acid Download PDFInfo
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Abstract
The invention belongs to the field of medicine crystal forms, and particularly relates to a preparation method of amorphous obeticholic acid, the amorphous obeticholic acid prepared by the method and application of the amorphous obeticholic acid in preparation of medicines for preventing or treating farnesol X receptor-mediated related diseases. The preparation method of the amorphous obeticholic acid mainly comprises the following two steps: (a) mixing crystalline obeticholic acid with water in a mass (g): mixing the materials in a volume (ml) of 1: 1-1: 100, and stirring the mixture for 0.5-48 hours at the temperature of 20-80 ℃; (b) filtering and drying to obtain the amorphous obeticholic acid. The method simplifies the operation steps, avoids using a large amount of organic solvent, has the product yield of 98-99 percent, and can prepare the amorphous obeticholic acid with high purity and good stability without further purification steps.
Description
Technical Field
The invention relates to the field of drug crystal forms, and particularly relates to a preparation method of amorphous obeticholic acid and the amorphous obeticholic acid prepared by the method.
Background
Obeticholic acid (OCA), also known as 6-ethyl chenodeoxycholic acid, has a structural formula shown in formula 1, is an analogue of cholic acid, and is based on the molecular structure of natural cholic acid. Obeticholic acid belongs to a potent agonist of farnesoid X receptor, regulates the expression of related genes by first selectively binding and activating Farnesoid X Receptor (FXR), thereby affecting bile acid, blood lipid and sugar metabolism, and thus can be used for treating FXR-mediated regulation disorder, cardiovascular diseases, cholestatic liver diseases, high HDL cholesterol, high triglyceride and fibrotic disorders and the like, including biliary atresia, cholestatic liver diseases, chronic liver diseases, non-alcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver diseases, Primary Biliary Cirrhosis (PBC), liver function damage due to progressive fibrosis, hepatic fibrosis and cardiovascular diseases including arteriosclerosis, hypercholesterolemia and hyperlipidemia, and the like.
As a novel candidate drug for treating primary biliary cirrhosis and non-alcoholic fatty liver disease, the obeticholic acid is developed by American Intercept pharmaceutical companies, and clinical studies show that the levels of alkaline phosphatase and serum bilirubin can be obviously improved by taking obeticholic acid for patients who cannot completely tolerate the ursodeoxycholic acid, which suggests that the clinical effect of obeticholic acid is possibly superior to that of the existing drug ursodeoxycholic acid. The company discloses a preparation method of amorphous form 1 of obeticholic acid and different crystal forms in PCT patent application document WO20131920971A1, and specifically comprises analysis of physicochemical properties of crystal form A, crystal form C, crystal form D, crystal form F and crystal form G, such as different melting points, stability, solubility, dissolution rate, hygroscopicity and the like, so as to evaluate the drug effect and bioavailability, whether the product is easy to separate and carry out large-scale formation, and whether the product is suitable for being used as a pharmaceutical ingredient. Wherein, the crystal forms A, C and D are mixed hydrate/solvent compound crystal forms containing water and a certain range of organic solvents, and solvents such as nitromethane, acetonitrile and the like are used in the preparation processes of the crystal forms F and G, so that the environment is polluted, and the crystal forms F and G are not suitable for being developed and used as pharmaceutical ingredients. In the method for preparing amorphous obeticholic acid in the patent document, obeticholic acid C-type crystal form synthesized and purified through 6 steps is taken as a synthesis intermediate, dissolved in NaOH aqueous solution and added with HCl, so that high-purity obeticholic acid 1 (amorphous form) is prepared. In contrast, in the preparation of crystalline form C intermediates, organic solvents such as crystallization from acetonitrile and recrystallization from nitromethane are required.
Chinese patent application CN105777836A discloses a polymorph of obeticholic acid and a preparation method thereof, including crystal forms I and II. Wherein the crystal form II is obtained by dissolving obeticholic acid in an organic solvent, refluxing, cooling, precipitating crystals, filtering and drying. Wherein the XRPD pattern of form II has no diffraction peaks, is understood to be a polymorphic or amorphous composition.
Chinese patent application CN105085597A discloses a method for preparing amorphous obeticholic acid, which comprises dissolving obeticholic acid in an organic solvent, filtering, and concentrating the filtrate under reduced pressure or spray drying to obtain amorphous obeticholic acid. Wherein the organic solvent is selected from one or more of alcohol solvent, ketone solvent, ester solvent and halogenated hydrocarbon solvent.
The obeticholic acid has multiple crystal forms, and the stability and bioavailability of different crystal forms are greatly different, so that the obeticholic acid has a large influence on a preparation and can seriously influence the biological activity of a medicament. Moreover, the same drug substance may be converted to other crystalline forms under different solvents, temperatures and other processing conditions. Therefore, the research on the properties of the amorphous obeticholic acid, namely the stability, the drug effect and the like of the novel pharmaceutical active ingredient is very significant for the processing technology of the pharmaceutical composition containing obeticholic acid.
However, the prior art including the method for preparing amorphous form disclosed in the above patent application documents has many disadvantages in that the steps are complicated, a large amount of by-products are generated, separation and purification of the product are difficult, or an organic solvent is required, and the method is applied in large scale.
Aiming at the defects or shortcomings of the prior art, the inventor of the application further improves the method for preparing the amorphous obeticholic acid, simplifies the operation steps, avoids using a large amount of organic solvents, and can prepare the amorphous obeticholic acid with high purity without further purification steps.
Disclosure of Invention
The invention aims to provide a preparation method of amorphous obeticholic acid, the amorphous obeticholic acid prepared by the method and application of the amorphous obeticholic acid in preparation of drugs for preventing or treating Farnesoid X Receptor (FXR) mediated related diseases.
In one aspect, the present invention provides a method for preparing amorphous obeticholic acid, comprising the steps of:
(a) mixing obeticholic acid with water;
(b) filtering and drying to obtain the amorphous obeticholic acid.
The obeticholic acid mixed with water in the step (a) may be obeticholic acid in any crystal form. For example, obeticholic acid crystal form a, crystal form B, crystal form C, and optionally other crystal forms or mixed crystal forms formed by different crystal forms.
The mass-volume ratio of obeticholic acid to water in the step (a) is preferably 1: 1-1: 100; more preferably 1:5 to 1: 80; more preferably 1:5 to 1: 40.
After the obeticholic acid and water are mixed in the step (a), preferably stirring is carried out at the temperature of 20-80 ℃; more preferably, the stirring is carried out at 40 to 70 ℃.
After the obeticholic acid and the water are mixed in the step (a), the stirring time is 0.5-24 hours, preferably 1-15 hours, and more preferably 3-10 hours.
One of the drying conditions in the step (b) is 20-100 ℃, and preferably 30-80 ℃; more preferably 40 to 80 ℃.
The invention also provides a preparation method of the amorphous obeticholic acid, which comprises the following steps:
(a) mixing obeticholic acid and water according to the mass-to-volume ratio of 1: 1-1: 100, and stirring for 0.5-24 hours at the temperature of 20-80 ℃;
(b) filtering and drying at 20-100 ℃ to obtain the amorphous obeticholic acid.
The invention further provides a preparation method of amorphous obeticholic acid, which comprises the following steps:
(a) mixing obeticholic acid and water according to the mass-to-volume ratio of 1: 5-1: 40, and stirring for 3-10 hours at the temperature of 40-70 ℃;
(b) filtering, and drying at 40-80 ℃ to obtain the amorphous obeticholic acid.
As for the drying in the step (b) of the preparation method of the amorphous obeticholic acid provided by the invention, the vacuum degree can be reduced by conventional means according to requirements, such as a water pump and an oil pump for vacuumizing, wherein the vacuum degree is-0.06 MPa to-0.095 MPa.
One of the drying conditions in the step (b) is preferably a vacuum degree of-0.08 MPa to-0.09 MPa.
In another aspect, the invention also provides an amorphous obeticholic acid prepared by any one of the methods of the invention.
The purity of the amorphous obeticholic acid prepared by the method reaches over 99.8 percent, and the yield reaches 98 to 99 percent.
In addition, the amorphous obeticholic acid can be applied to preparation of medicaments for preventing or treating Farnesoid X Receptor (FXR) mediated related diseases. In particular to the preparation of medicaments for preventing or treating cardiovascular diseases, cholestatic liver diseases, high HDL cholesterol, high triglyceride and fibrotic diseases. More particularly, the method can be applied to the preparation of medicines for preventing or treating bile duct atresia, cholestatic liver disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, Primary Biliary Cirrhosis (PBC), liver function damage caused by progressive fibrosis, hepatic fibrosis and cardiovascular diseases (such as atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia and the like), and the like.
The preparation method of the amorphous obeticholic acid greatly simplifies the preparation method of the amorphous obeticholic acid in the prior art, and avoids the defects of preparation by adopting an organic solvent or preparation by using acid and alkali. The preparation method of the amorphous obeticholic acid does not need any organic solvent, does not need acid-base reagent, has less working procedures, simple operation and high yield, and the prepared amorphous obeticholic acid has good stability and high purity.
Drawings
Figure 1 is an X-ray diffraction (XRD) pattern of amorphous obeticholic acid.
Detailed Description
The technical solutions of the present invention are further explained with reference to the specific embodiments, but the present invention is not limited in any way, and any modifications, alterations or equivalent replacement methods that can be realized by those skilled in the art to which the present invention belongs will fall within the scope of the claims of the present invention without departing from the inventive concept and technical solutions of the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are all commercially available unless otherwise specified, and obeticholic acid used in the examples can be prepared by a method reported in the literature.
Example 1
Selecting obeticholic acid obtained by recrystallization from dichloromethane, wherein 0.4% of dichloromethane remains, weighing 5g of obeticholic acid, adding 50ml of purified water, stirring for 5 hours at 50 ℃, filtering, drying the solid obtained by filtering for more than 8 hours at 50 ℃ under the vacuum degree of-0.06 MPa to-0.095 MPa, and obtaining amorphous obeticholic acid 4.95g, wherein the solid of obeticholic acid is identified to be amorphous by XRD, the yield is 99.0%, the HPLC purity is 99.91%, and the water content is 0.1%.
Example 2
Selecting obeticholic acid obtained by recrystallization from ethyl acetate, wherein the ethyl acetate residue is 0.55%, weighing 5g of obeticholic acid, adding 200ml of purified water, stirring at 40 ℃ for 10 hours to form a uniform suspension, filtering, drying the solid at 40 ℃ under the vacuum degree of about-0.06 MPa to-0.095 MPa to obtain powdery obeticholic acid solid 4.92g, and identifying the obeticholic acid solid to be amorphous by XRD, wherein the yield is 98.4%, the HPLC purity is 99.90%, and the moisture content is 0.09%.
Example 3
Selecting obeticholic acid disclosed in the prior art as a raw material, weighing 5g of obeticholic acid, adding 60ml of purified water, stirring for 3 hours at 60 ℃, filtering, drying the solid at 55 ℃ under vacuum at a vacuum degree of-0.08 MPa to-0.09 MPa to obtain 4.93g of powdery obeticholic acid solid, and identifying the obeticholic acid solid to be amorphous by XRD, wherein the yield is 98.6%, the HPLC purity is 99.89%, and the water content is 0.1%.
Example 4
Selecting obeticholic acid disclosed in the prior art as a raw material, weighing 5g of obeticholic acid, adding 100ml of purified water, stirring for 6.5h at 70 ℃, filtering, drying the solid at 60 ℃ under the vacuum degree of-0.06 MPa to-0.095 MPa to obtain 4.90g of powdery obeticholic acid solid, and identifying the obeticholic acid solid to be amorphous by XRD, wherein the yield is 98.0%, the HPLC purity is 99.92% and the water content is 0.08%.
High purity amorphous obeticholic acid can also be prepared in the same yields as in examples 1-4 by mixing the starting material obeticholic acid with purified water in the same manner as in the above examples, wherein the ratio of the mass of obeticholic acid to the volume of purified water is 1:5, 1:80, and 1: 100.
Comparative example 1
Referring to the examples disclosed in chinese patent application CN105085597A, 10g of obeticholic acid C crystal form was dissolved in 500ml of absolute ethanol, and after filtration, a clear obeticholic acid solution was obtained; and (3) removing the solvent by spray drying to obtain 9.25g of white obeticholic acid solid, wherein the yield is 92.5%, and the obeticholic acid solid is amorphous and has the HPLC purity of 99.8% through XRD identification.
Comparative example 2
Dissolving 10g of obeticholic acid C crystal form in 50ml of acetone, and filtering to obtain a clear obeticholic acid solution; and (3) removing the solvent by reduced evaporation on a rotary evaporator, and drying at 50 ℃ in vacuum to obtain 9.70g of white obeticholic acid solid with the yield of 97.0%, wherein the obeticholic acid solid is amorphous by XRD identification.
Comparative example 3
Dissolving 10g of obeticholic acid C crystal form in 100ml of butyl acetate, filtering, removing the solvent by reduced evaporation on a rotary evaporator, drying at 60 ℃ in vacuum to obtain 9.53g of white obeticholic acid solid, wherein the yield is 95.3%, and the obeticholic acid solid is amorphous by XRD identification.
Solvent residue determination
Next, the obeticholic acid samples prepared in the above examples and comparative examples were subjected to solvent residue measurement. The specific solvent residue determination method is as follows:
a chromatographic column: a commercially available capillary column (30 m. times.0.32 mm. times.1.8 μm) using 6% cyanopropylphenyl-94% dimethylchlorosilane as the stationary liquid or a capillary column of similar polarity was used.
Temperature programming: the initial temperature is 45 ℃, the temperature is kept for 6min, the temperature is increased to 80 ℃ at the rate of 5 ℃ per minute and is kept for 2 min, and the temperature is increased to 220 ℃ at the rate of 30 ℃ per minute and is kept for 2 min;
sample inlet temperature: 160 deg.C
Detector temperature: 260 deg.C
Linear velocity: 19.6cm/s
The split ratio is as follows: 10:1
Headspace conditions: equilibrating at 90 ℃ for 30 minutes
The measurement results are shown in table 1.
| Solvent residue (%) | |
| Examples 1 to 4 | Solvent free over limit |
| Comparative example 1 | Ethanol: 0.65 |
| Comparative example 2 | Acetone: 0.57 |
| Comparative example 3 | Butyl acetate: 0.55 |
TABLE 1
As shown in table 1, the solvent residues of the amorphous obeticholic acid prepared by the method of the present invention did not exceed the limit of 0.1%, while the solvent residues in the amorphous obeticholic acid of the comparative example were 0.65%, 0.57%, and 0.55%, respectively. As shown in the determination results in Table 1, the amorphous obeticholic acid provided by the invention has very low solvent residue, is favorable for being used as a pharmaceutical active ingredient for preparing medicaments, has simple steps, can meet the requirements of being used as the pharmaceutical active ingredient without the step of removing the solvent by distillation and the like, and can be prepared into different dosage forms of pharmaceutical compositions for preventing or treating Farnesoid X Receptor (FXR) mediated related diseases.
Stability determination
Obeticholic acid prepared in examples 1-4 of the present application (measured at 40 ℃) was determined according to the guidelines of the stability tests of the raw drug and the formulation (chinese pharmacopoeia 2015 edition, 9001). The results of the stability measurements are shown in Table 2.
TABLE 2
Therefore, the amorphous obeticholic acid obtained by the preparation method has excellent stability.
As described in the above examples, when the ratio of the mass of obeticholic acid to the volume of purified water is 1:5, 1:80, and 1:100, and the mixture is mixed, amorphous obeticholic acid with little solvent residue and excellent stability can be prepared.
Claims (10)
1. A method for preparing amorphous obeticholic acid, comprising the steps of:
(a) mixing obeticholic acid and water according to the mass-to-volume ratio of 1: 1-1: 100, and stirring for 0.5-24 hours at the temperature of 20-80 ℃;
(b) filtering and drying at 20-100 ℃ to obtain the amorphous obeticholic acid.
2. The method according to claim 1, wherein the mass-to-volume ratio of obeticholic acid to water in step (a) is 1: 5-1: 80.
3. The method according to claim 1, wherein the mass-to-volume ratio of obeticholic acid to water in step (a) is 1: 5-1: 40.
4. The method for preparing amorphous obeticholic acid according to claim 1, wherein obeticholic acid is mixed with water in step (a) and then stirred at 40-70 ℃.
5. The method for preparing amorphous obeticholic acid according to claim 1, wherein the obeticholic acid is mixed with water in step (a) and stirred for 1-15 hours.
6. The method for preparing amorphous obeticholic acid according to claim 1, wherein the obeticholic acid is mixed with water in step (a) and then stirred for 3-10 hours.
7. The method for preparing amorphous obeticholic acid according to claim 1, wherein the drying temperature in step (b) is 30-80 ℃.
8. The method for preparing amorphous obeticholic acid according to claim 1, wherein the drying temperature in step (b) is 40-80 ℃.
9. The method for preparing amorphous obeticholic acid according to claim 1, wherein the obeticholic acid mixed with water in step (a) is crystalline obeticholic acid.
10. The method for preparing amorphous obeticholic acid according to claim 1, characterized in that it comprises the following steps:
(a) mixing obeticholic acid and water according to the mass-to-volume ratio of 1: 5-1: 40, and stirring for 3-10 hours at the temperature of 40-70 ℃;
(b) filtering and drying at 40-80 ℃ to obtain the amorphous obeticholic acid.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105085597A (en) * | 2015-08-28 | 2015-11-25 | 成都百裕科技制药有限公司 | Preparation method of non-shaped obeticholic acid |
| WO2017008773A1 (en) * | 2015-07-16 | 2017-01-19 | Zentiva, K.S. | Crystalline forms of obeticholic acid |
| CN106632564A (en) * | 2015-10-30 | 2017-05-10 | 苏州泽璟生物制药有限公司 | Obeticholic acid salt and amorphous material thereof, and pharmaceutical composition |
| CN106810587A (en) * | 2015-12-01 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | The method for preparing unformed shellfish cholic acid difficult to understand |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017008773A1 (en) * | 2015-07-16 | 2017-01-19 | Zentiva, K.S. | Crystalline forms of obeticholic acid |
| CN105085597A (en) * | 2015-08-28 | 2015-11-25 | 成都百裕科技制药有限公司 | Preparation method of non-shaped obeticholic acid |
| CN106632564A (en) * | 2015-10-30 | 2017-05-10 | 苏州泽璟生物制药有限公司 | Obeticholic acid salt and amorphous material thereof, and pharmaceutical composition |
| CN106810587A (en) * | 2015-12-01 | 2017-06-09 | 中美华世通生物医药科技（武汉）有限公司 | The method for preparing unformed shellfish cholic acid difficult to understand |
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