CN107868117B - Stenazole saccharinate and preparation method and application thereof - Google Patents
Stenazole saccharinate and preparation method and application thereof Download PDFInfo
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- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
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Abstract
The invention discloses a brand new stanozolol saccharin salt, which comprises stanozolol cations and saccharin anions with equal material amounts, wherein the stanozolol cations have a structural formula (1), and the saccharin anions have a structural formula (2). The stanozolol saccharin salt can effectively improve the dissolution rate of the stanozolol and solve the problem of poor moisture stability of the stanozolol, and has good thermal stability. Meanwhile, the auxiliary material of the stanozolol saccharin salt is saccharin which is used as a sweetening agent, can improve the taste of the stanozolol medicine, and can be applied to the pharmaceutical industry. The invention also discloses two preparation methods of the stanozolol saccharin salt, which are a solvent volatilization method and a suspension method respectively. The preparation method has the advantages of simple process, easy operation, easily obtained raw materials, low cost and no toxic solvent residue. The invention also discloses the application of the stanozolol saccharin salt in sterol medicaments.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a stanozolol saccharin salt, and a preparation method and application thereof.
Background
The pharmaceutically active ingredient is usually present in a variety of solid forms such as polymorphs, hydrates, solvates, amorphous forms, salts, co-crystals and the like. Different solid existing forms have different physicochemical properties for the same active pharmaceutical ingredient. Therefore, in the pharmaceutical industry, it is of great interest to obtain suitable solid forms of drugs. The medicine exists in the form of salt, and has remarkable effects in improving the stability of active ingredients of the medicine, increasing the solubility, adjusting the dissolution rate, improving the hygroscopicity and the like; therefore, pharmaceutical salts are often the first choice in improving the physicochemical properties of the active ingredient of a drug.
Stanozolol, chemically known as 17 beta-hydroxy-17 alpha-methyl androstaneol [3,2-c ] pyrazole, is the most commonly used class of synthetic steroid drugs. However, stanozolol is almost insoluble in water and readily absorbs moisture to convert to a monohydrate under high humidity conditions; low solubility can lead to poor bioavailability and moisture instability can also pose serious problems for drug storage and quality control. Therefore, there is a need to improve the problems of these physicochemical properties of stanozolol so that the stanozolol can be better applied.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides the stanozolol saccharin salt and the preparation method and the application thereof, and the stanozolol saccharin salt can effectively improve the dissolution rate of the stanozolol and effectively improve the problem of poor stability of the stanozolol in a humid environment.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
a stanozolol saccharin salt, comprising a stanozolol cation and a saccharin anion in equal amounts; wherein the stanozolol cation has the following structural formula (1), and the saccharin anion has the following structural formula (2):
further, the stanozolol saccharin salt belongs to an orthorhombic system, P2 12121A space group; the unit cell parameters of the stanozolol saccharin salt are as follows: axial length
The axial angle α is 90 °, β is 90 °, and γ is 90 °.
Further, the stanozolol saccharin salt has a powder X-ray diffraction pattern obtained with Cu-Kalpha rays, wherein the powder X-ray diffraction pattern at least has characteristic peaks at diffraction angles 2 theta of 6.9 degrees, 10.0 degrees, 10.8 degrees, 11.1 degrees, 13.3 degrees, 13.8 degrees, 14.8 degrees, 15.1 degrees, 15.9 degrees, 17.8 degrees, 18.9 degrees, 19.5 degrees, 19.7 degrees, 20.2 degrees, 20.7 degrees, 20.9 degrees, 22.8 degrees, 22.3 degrees, 23.7 degrees, 23.8 degrees, 24.4 degrees, 25.0 degrees, 25.4 degrees, 27.0 degrees, 28.1 degrees, 31.0 degrees, 33.6 degrees and 35.6 degrees.
Further, in the preparation method of the stanozolol saccharinate13The C solid nuclear magnetic resonance spectrum has characteristic peaks at least at chemical shifts of 82.3ppm, 120.1ppm, 121.0ppm, 124.1ppm, 131.9ppm, 133.6ppm, 134.6ppm, 141.5ppm, 144.1ppm and 170.3 ppm.
Another object of the present invention is to provide a process for preparing a salt of stanozolol saccharin as described above, which comprises: mixing stanozolol and saccharin to obtain a mixture; dissolving the mixture in a first organic solvent to obtain a first mixed solution; volatilizing the first organic solvent in the first mixed solution to obtain the stanozolol saccharin salt.
Further, the mass ratio of the stanozolol to the saccharin is 1: 1-1: 2.5.
Further, the first organic solvent is at least one selected from acetone, acetonitrile and ethyl acetate.
Further, dissolving the mixture in the first organic solvent at a temperature of room temperature to 80 ℃; and volatilizing the first organic solvent in the mixed solution at the temperature of room temperature to 80 ℃.
Another object of the present invention is to provide another process for preparing a salt of stanozolol saccharin as described above, which comprises: dissolving saccharin in a second organic solvent to obtain a saccharin solution; adding stanozolol into the saccharin solution to form a suspension; and stirring the turbid liquid to obtain a second mixed solution, carrying out solid-liquid separation on the second mixed solution to obtain filter residue and filtrate, and drying the filter residue to obtain the stanozolol saccharin salt.
Further, the ratio of the amount of the stanozolol to the amount of the saccharin in the saccharin solution is 1: 1-1: 2.5.
Further, the second organic solvent is at least one selected from acetone, acetonitrile and ethyl acetate.
Further, dissolving the saccharin in the second organic solvent at a temperature of from room temperature to 40 ℃; and stirring the suspension for more than 48 hours at the temperature of between room temperature and 40 ℃.
Another object of the present invention is to provide the use of the stanozolol saccharin salt as described in any of the above in sterol drugs.
The invention converts the stanozolol into a brand new stanozolol saccharin salt, and the stanozolol saccharin salt has higher apparent solubility than the stanozolol, thereby being beneficial to improving the bioavailability of the medicaments, and having excellent moisture resistance and good thermal stability. Meanwhile, the auxiliary material of the stanozolol saccharin salt is saccharin which is used as a sweetening agent, can improve the taste of the stanozolol medicine, and can be applied to the pharmaceutical industry. In addition, the two preparation methods of the stanozolol saccharin salt disclosed by the invention have the advantages of simple process, easiness in operation, easiness in obtaining raw materials, low cost and no toxic solvent residue.
Drawings
The above and other aspects, features and advantages of embodiments of the present invention will become more apparent from the following description taken in conjunction with the accompanying drawings, in which:
fig. 1 is a structure diagram of a unit cell of a stanzol alkoxide according to example 1 of the present invention.
Fig. 2 is a powder X-ray diffraction pattern of the stanzol alkoxide of example 1 according to the present invention.
FIG. 3 is a process for preparing a stanzol salt according to example 1 of the present invention13C solid nuclear magnetic resonance spectrum.
Fig. 4 is a differential scanning calorimetry curve of a stanzol alkoxide according to example 1 of the present invention.
Fig. 5 is a graph comparing the solubility of stanozolol with that of the stanozolol alkoxide according to example 1 of the present invention.
Fig. 6 is a graph comparing the powder X-ray diffraction patterns of stanozolol and the stanozolol salt according to example 1 of the present invention after accelerated for 20 days under the conditions of 25 c, 95% relative humidity, respectively.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the specific embodiments set forth herein. Rather, these embodiments are provided to explain the principles of the invention and its practical application to thereby enable others skilled in the art to understand the invention for various embodiments and with various modifications as are suited to the particular use contemplated.
It will be understood that, although the terms "first," "second," etc. may be used herein to describe various substances, these substances should not be limited by these terms. These terms are only used to distinguish one substance from another.
Example 1
This example discloses a completely new substance, which is a stanozolol saccharin salt composed of equal amounts of the stanozolol cation and saccharin anion; wherein, the stanozolol cation and the saccharin anion respectively have the following structural formulas (1) and (2):
the stanozolol saccharin salt of the embodiment is prepared by taking stanozolol and saccharin as raw materials and adopting a solvent volatilization method or a suspension method.
The structure, the property and the like of the stanozolol saccharin salt of the embodiment are analyzed and detected respectively, and the method comprises the following aspects:
(1) determination of Crystal Structure
In particular, Bruker Ape is usedx II CCD diffractometers, diffraction points were collected in an omega scan with Mo K α rays monochromatized with graphite (λ ═ 0.71073nm) at 273(2) K (i.e. 273K ± 0.2K), the collected data were reduced by SAINT program and corrected for semi-empirical absorption by the SADABS method. Finally, the structure of the stanozolol saccharin salt is obtained by direct solution, and F is subjected to full-matrix least square method2And correcting to obtain the coordinates and anisotropic parameters of all non-hydrogen atoms. The hydrogen atoms on carbon are theoretically fixed on parent atoms in the structure refining process, and the hydrogen atoms connected with nitrogen atoms or oxygen atoms are determined by a difference Fourier map; the cell structure diagram shown in fig. 1 was obtained. The crystal structure of the stanozolol saccharin salt is measured to know that the stanozolol saccharin salt belongs to an orthorhombic system, P2 12121A space group; and the unit cell parameters of the stanozolol saccharin salt are as follows: axial length
The axial angle α is 90 °, β is 90 °, γ is 90 °; wherein the bracketed numbers in the axial lengths a, b, c indicate errors in the last digit, e.g.
To represent
To represent
To represent
It is to be noted that, in fig. 1, one unit cell of the stanozolol saccharin salt is represented in a box; meanwhile, a and b in the coordinate system in fig. 1 represent the directions of the axial lengths a and b, and the direction of the axial length c is perpendicular to the paper surface and thus is not shown.
(2) Powder X-ray diffraction measurement
Specifically, the measurement conditions were as follows, using a Bruker D8Advance diffractometer: the radiation source is Cu Kalpha, the tube voltage is 40kV, the tube current is 40mA, the step length is 0.01 degrees, and the scanning range is 3-40 degrees; a powder X-ray diffraction pattern as shown in figure 2 was obtained. Through the determination of the powder X-ray diffraction pattern of the stanozolol saccharin salt, the stanozolol saccharin salt has characteristic peaks at least at diffraction angles 2 theta of 6.9 degrees, 10.0 degrees, 10.8 degrees, 11.1 degrees, 13.3 degrees, 13.8 degrees, 14.8 degrees, 15.1 degrees, 15.9 degrees, 17.8 degrees, 18.9 degrees, 19.5 degrees, 19.7 degrees, 20.2 degrees, 20.7 degrees, 20.9 degrees, 22.8 degrees, 22.3 degrees, 23.7 degrees, 23.8 degrees, 24.4 degrees, 25.0 degrees, 25.4 degrees, 27.0 degrees, 28.1 degrees, 31.0 degrees, 33.6 degrees and 35.6 degrees; the measurement error was ± 0.1 °.
(3)13C solid NMR measurement
Specifically, the measurement conditions are as follows by adopting a Bruker AVANCE III-500 nuclear magnetic resonance spectrometer: a 4mm double resonance magic angle rotating probe, the magnetic field intensity is 11.7T, the magic angle spinning speed is 8kHz, and tetramethylsilane is used for calibration (0 ppm); obtain as shown in FIG. 313C solid nuclear magnetic resonance spectrum. By the preparation of stanozolol saccharinate13C solid nuclear magnetic resonance measurement shows that the stanozolol saccharin salt has characteristic peaks at least at chemical shifts of 82.3ppm, 120.1ppm, 121.0ppm, 124.1ppm, 131.9ppm, 133.6ppm, 134.6ppm, 141.5ppm, 144.1ppm and 170.3 ppm; the measurement error was. + -. 0.1 ppm.
Meanwhile, combining the results of the above fig. 2 and fig. 3, it can be seen that the crystalline form of the stanozolol saccharin salt of this example has high purity without significant raw material impurities.
(4) Differential scanning calorimetry test
Specifically, the measurement conditions are as follows by using a TA Q2000 differential scanning calorimeter: taking about 3mg of stanozolol saccharin salt as a sample, packaging the sample by using an aluminum tray, wherein the heating temperature range is not 25-200 ℃, the heating rate is 10.0 ℃/min, and the purging gas is 50mL/min N2Temperature calibration was performed using NIST indium metal; a differential scanning calorimetry test curve as shown in fig. 4 was obtained. The melting point of the stanozolol saccharin salt is 216.1 ℃ through the differential scanning calorimetry test of the stanozolol saccharin salt.
(5) Solubility test
To better illustrate the apparent solubility of the salt of stanozolol saccharin in this example, the solubility of the prior art stanozolol was also determined under the same conditions, and the solubility comparison between the two is shown in fig. 5.
In fig. 5, 1 line represents the change in solubility of stanozolol over time, and 2 lines represent the change in solubility of stanozolol saccharin salt over time. As can be seen from fig. 5, the salt of stanozolol saccharin according to this example has a greatly improved apparent solubility compared to stanozolol.
(6) Moisture resistance test
Specifically, an acceleration test was performed under the conditions of 25 ℃ and 95% relative humidity for 20d, and the powder X-ray diffraction patterns of the stanozolol saccharin salt before and after acceleration were measured after 20 d. Meanwhile, in order to better explain the moisture resistance of the saccharinate salt of stanozolol of the present example, the moisture resistance of the prior art is also measured under the same conditions, and the change in moisture resistance of the two is shown in fig. 6.
In fig. 6, 1 line represents a powder X-ray diffraction pattern of stanozolol before acceleration, 2 lines represents a powder X-ray diffraction pattern of stanozolol after acceleration, 3 lines represents a powder X-ray diffraction pattern of stanozolol saccharin salt before acceleration, and 4 lines represents a powder X-ray diffraction pattern of stanozolol saccharin salt after acceleration. As can be seen from fig. 6, the result of the accelerated test of the stanozolol saccharin salt of this embodiment under the above-mentioned severer conditions is that the structure is not changed, but the structure of the prior art stanozolol is changed; it is demonstrated that the stanozolol saccharin salts of this example have excellent moisture resistance.
The stanozolol saccharin salt according to the embodiment can be applied to the field of sterol drugs as conversion drugs of different forms of stanozolol. For example, in clinic, it can be used for the prevention and treatment of hereditary angioneurotic edema, and the treatment of severe trauma, chronic infection, malnutrition and other consumptive diseases.
Meanwhile, as can be seen from the results of the solubility test (5) and the moisture resistance test (6), the salt of stanozolol saccharin of the present embodiment can overcome the disadvantage of low solubility of the stanozolol drug, thereby facilitating the improvement of the bioavailability of the stanozolol drug, and also overcomes the disadvantage of the moisture instability of the stanozolol drug, thereby being better applied to medical treatment.
The invention also discloses two preparation methods of the stanozolol saccharin salt in the above embodiment 1, which are respectively introduced in the following different embodiments.
Example 2
This example discloses one of the preparation methods of stanozolol saccharin salts as in example 1, which is a solvent evaporation method, and specifically includes the following steps:
s1: 0.1mmol of stanozolol and 0.1mmol of saccharin were mixed to obtain a mixture.
Generally, the ratio of the amounts of the stanozolol and the saccharin is controlled within the range of 1:1 to 1: 2.5.
S2: and dissolving the mixture in a first organic solvent at a temperature of between room temperature and 80 ℃ to obtain a first mixed solution.
Preferably, the first organic solvent is any one or a mixture of at least two of acetone, acetonitrile and ethyl acetate; in this example, 5mL of acetone was used as the first organic solvent.
S3: volatilizing the first organic solvent in the first mixed solution at the temperature of room temperature to 80 ℃ to obtain the stanozolol saccharin salt.
Preferably, before volatilizing the first organic solvent in the first mixed solution, the first mixed solution may be subjected to a filtering operation, preferably using a sieve with a pore size of 0.22 μm, to remove impurities in the first mixed solution and purify the first mixed solution, thereby obtaining a higher crystalline and higher purity salt of stanzol saccharin.
It is to be noted that, when the mixture is dissolved in step S2, the concentration of the obtained first mixed solution may be arbitrary, but in order to reduce the volatilization time of the first organic solvent in the subsequent first mixed solution, it is preferable that the first mixed solution is a saturated solution.
In view of the preparation method of this example, the obtained stanozolol saccharin salt was crystalline salt with a yield of 90%.
Example 3
This example provides another preparation method of the stanozolol saccharin salt as in example 1, which is a suspension method and specifically includes the following steps:
q1: dissolving 0.5mmol of saccharin in a second organic solvent at a temperature of between room temperature and 40 ℃ to obtain a saccharin solution.
Preferably, the second organic solvent is any one or a mixture of at least two of acetone, acetonitrile and ethyl acetate; in this example, 5mL of ethyl acetate was used as the second organic solvent.
It is noted that the concentration of the saccharin solution when formulated herein can be any concentration, but in order to reduce the waste of the second organic solvent during subsequent solid-liquid separation, it is preferred that the saccharin solution be a saturated solution.
Q2: 0.5mmol of stanozolol was added to the saccharin solution to form a suspension.
Generally, the ratio of the amount of the stanozolol to the amount of the saccharin in the saccharin solution can be controlled to be 1:1 to 1: 2.5.
Q3: and stirring the suspension for more than 48 hours at the temperature of between room temperature and 40 ℃ to obtain a second mixed solution.
In this example, the suspension was stirred for 3 d.
Q4: and carrying out solid-liquid separation on the second mixed solution to obtain filter residue and filtrate, and drying the filter residue to obtain the stanozolol saccharin salt.
In the step, solid-liquid separation is preferably performed by adopting a suction filtration mode, and the obtained filter cake is vacuum-dried to obtain the stanozolol saccharin salt.
In view of the preparation method of this example, the obtained stanozolol saccharin salt was a powdered salt with a yield of 84%.
While the invention has been shown and described with reference to certain embodiments, those skilled in the art will understand that: various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents.
Claims (8)
1. A stanozolol saccharin salt, which is characterized by comprising a stanozolol cation and a saccharin anion in equal amounts; wherein the stanozolol cation has the following structural formula (1), and the saccharin anion has the following structural formula (2):
the stanozolol saccharin salt belongs to an orthorhombic system, P212121A space group; the unit cell parameters of the stanozolol saccharin salt are as follows: axial length
The axial angle α is 90 °, β is 90 °, γ is 90 °;
wherein the stanozolol saccharin salt has a powder X-ray diffraction pattern obtained with Cu-Kalpha rays, and the powder X-ray diffraction pattern at least has characteristic peaks at diffraction angles 2 theta of 6.9 degrees, 10.0 degrees, 10.8 degrees, 11.1 degrees, 13.3 degrees, 13.8 degrees, 14.8 degrees, 15.1 degrees, 15.9 degrees, 17.8 degrees, 18.9 degrees, 19.5 degrees, 19.7 degrees, 20.2 degrees, 20.7 degrees, 20.9 degrees, 22.8 degrees, 22.3 degrees, 23.7 degrees, 23.8 degrees, 24.4 degrees, 25.0 degrees, 25.4 degrees, 27.0 degrees, 28.1 degrees, 31.0 degrees, 33.6 degrees and 35.6 degrees;
wherein, inThe preparation method of the stanozolol saccharin salt13The C solid nuclear magnetic resonance spectrum has characteristic peaks at least at chemical shifts of 82.3ppm, 120.1ppm, 121.0ppm, 124.1ppm, 131.9ppm, 133.6ppm, 134.6ppm, 141.5ppm, 144.1ppm and 170.3 ppm.
2. A method for preparing a salt of stanozolol saccharin according to claim 1, comprising:
mixing stanozolol and saccharin to obtain a mixture; the mass ratio of the stanozolol to the saccharin is 1: 1-1: 2.5;
dissolving the mixture in a first organic solvent to obtain a first mixed solution;
volatilizing the first organic solvent in the first mixed solution to obtain the stanozolol saccharin salt.
3. The method according to claim 2, wherein the first organic solvent is at least one selected from acetone, acetonitrile, and ethyl acetate.
4. The production method according to any one of claims 2 to 3, wherein the mixture is dissolved in the first organic solvent at a temperature of room temperature to 80 ℃; and volatilizing the first organic solvent in the first mixed solution at the temperature of room temperature to 80 ℃.
5. A method for preparing a salt of stanozolol saccharin according to claim 1, comprising:
dissolving saccharin in a second organic solvent to obtain a saccharin solution;
adding stanozolol into the saccharin solution to form a suspension; the mass ratio of the stanozolol to the saccharin in the saccharin solution is 1: 1-1: 2.5;
and stirring the turbid liquid to obtain a second mixed solution, carrying out solid-liquid separation on the second mixed solution to obtain filter residue and filtrate, and drying the filter residue to obtain the stanozolol saccharin salt.
6. The method according to claim 5, wherein the second organic solvent is at least one selected from acetone, acetonitrile, and ethyl acetate.
7. The process according to any one of claims 5 to 6, wherein the saccharin is dissolved in the second organic solvent at a temperature of from room temperature to 40 ℃; and stirring the suspension for more than 48 hours at the temperature of between room temperature and 40 ℃.
8. Use of a salt of stanozolol saccharin as described in claim 1 in the preparation of a sterol drug.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3030358A (en) * | 1961-05-11 | 1962-04-17 | Sterling Drug Inc | Process for reduction of delta4 androstene [3.2-c] pyrazole compounds |
| CN1092429A (en) * | 1992-08-05 | 1994-09-21 | 荷兰加甜剂公司 | Aspartame (asccharin) crystalline processing method |
| EP1102590A1 (en) * | 1998-08-04 | 2001-05-30 | MERCK SHARP & DOHME LTD. | Use of a nk-1 receptor antagonist for treating or preventing abnormal bone resorption |
| CN1348363A (en) * | 1998-08-27 | 2002-05-08 | 布里斯托尔-米尔斯·斯奎布公司 | Novel pharmaceutical salt form |
| CN103169714A (en) * | 2005-07-12 | 2013-06-26 | Dmi生物科学公司 | Methods and products for treatment of diseases |
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2016
- 2016-09-28 CN CN201610855584.XA patent/CN107868117B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3030358A (en) * | 1961-05-11 | 1962-04-17 | Sterling Drug Inc | Process for reduction of delta4 androstene [3.2-c] pyrazole compounds |
| CN1092429A (en) * | 1992-08-05 | 1994-09-21 | 荷兰加甜剂公司 | Aspartame (asccharin) crystalline processing method |
| EP1102590A1 (en) * | 1998-08-04 | 2001-05-30 | MERCK SHARP & DOHME LTD. | Use of a nk-1 receptor antagonist for treating or preventing abnormal bone resorption |
| CN1348363A (en) * | 1998-08-27 | 2002-05-08 | 布里斯托尔-米尔斯·斯奎布公司 | Novel pharmaceutical salt form |
| CN103169714A (en) * | 2005-07-12 | 2013-06-26 | Dmi生物科学公司 | Methods and products for treatment of diseases |
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