CN112979617A - Irbesartan piperazine salt and preparation method and application thereof - Google Patents
Irbesartan piperazine salt and preparation method and application thereof Download PDFInfo
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- CN112979617A CN112979617A CN201911305147.0A CN201911305147A CN112979617A CN 112979617 A CN112979617 A CN 112979617A CN 201911305147 A CN201911305147 A CN 201911305147A CN 112979617 A CN112979617 A CN 112979617A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
Abstract
The invention relates to an irbesartan piperazine salt and a preparation method and application thereof. The irbesartan piperazine salt related by the invention has good stability and can be stably stored under the condition of high humidity; compared with irbesartan, the irbesartan piperazine salt provided by the invention has the advantages that the dissolution rate and the solubility are both remarkably improved, and the improvement of the dissolution rate and the solubility is facilitated. Meanwhile, the irbesartan piperazine salt is prepared by a solution method or a mechanical grinding method, so that the irbesartan piperazine salt is simple to operate, mild in condition, low in cost and free of solvent residue.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to an irbesartan piperazine salt, and a preparation method and application thereof.
Background
Irbesartan (Irbesartan), the chemical name of which is 2-butyl-3- [4- [2- (1H-tetrazol-5-yl) phenyl ] benzyl ] -1, 3-diazaspiro- [4, 4] non-1-en-4-one, is an oral high-selectivity angiotensin II receptor antagonist and is clinically used for treating essential hypertension and kidney diseases in hypertension and type II diabetes. Irbesartan is a white crystalline powder, readily soluble in chloroform, methanol, ethanol and acetone, and poorly soluble in water, toluene, cyclohexane, n-hexane, and the like. The solubility of irbesartan in water is low, which results in poor bioavailability of irbesartan, and the prior art generally improves the dissolution property and bioavailability of irbesartan by introducing a salt forming reagent and irbesartan to form a salt.
CN101781287A discloses irbesartan hydrobromide and a preparation method thereof, wherein irbesartan is mixed with a solvent to prepare a solution or a suspension, and the mass ratio of the volume of the solvent to the irbesartan is 1-10 mL/g; then mixing with a hydrobromic acid solution, wherein the mass ratio of the hydrobromic acid in the hydrobromic acid solution to the irbesartan is 1 (2.6-5.3); continuously stirring, beginning to dropwise add the elution agent after the solution is clarified, wherein the volume ratio of the elution agent to the solvent is (1-10) to 1; adding seed crystals or growing crystals after crystals are spontaneously generated, and washing and drying crystal mush after the elution agent is dripped to obtain the irbesartan hydrobromide after solid-liquid separation. The irbesartan hydrobromide obtained by the method has the advantages of adjustable particle size, concentrated particle size distribution, smooth surface, good product fluidity, high crystallinity and low static electricity, and is beneficial to industrial operation. And the product has stable property, is not easy to decompose, and is convenient to store, transport and use.
In addition, patent US5629331 discloses irbesartan crystal form a and crystal form B and a preparation method thereof; WO2004/089938A1 discloses an irbesartan crystal form C and a preparation method thereof; patent WO200611859 discloses irbesartan hydrochloride and a preparation method thereof.
However, in the prior art, reports about irbesartan and salts thereof do not relate to the physicochemical properties and applications of products, such as the moisture stability, dissolution rate, solubility and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an irbesartan piperazine salt and a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the present invention provides an irbesartan piperazine salt comprising an irbesartan anion represented by formula (i) and a piperazine cation represented by formula (ii):
the invention creatively provides a new irbesartan salt form, namely irbesartan piperazine salt, which is formed by combining irbesartan anions and piperazine cations through hydrogen bond action, can stably exist under high humidity conditions, has better dissolution performance compared with irbesartan, and is beneficial to improving the bioavailability of irbesartan.
Preferably, the molar ratio of the irbesartan anion to the piperazine cation is 1: 1.
The irbesartan piperazine salt has a powder X-ray diffraction (XRD) pattern with characteristic peaks at 2 theta diffraction angles of 5.2, 10.3, 12.1, 14.8, 15.9, 17.4, 18.7, 19.4, 20.9, 21.4, 22.1, 22.9, 24.4, 25.9, 26.5, 27.2, 29.3, 30.1, 30.6, 31.9, 32.9, 35.4 and 36.8 (+ -0.2).
The invention relates to irbesartan piperazine salt, which is prepared by the method13The C solid NMR spectrum had characteristic peaks at chemical shifts 14.9ppm, 24.6ppm, 26.4ppm, 29.7ppm, 36.5ppm, 41.8ppm, 77.7ppm, 125.2ppm, 127.4ppm, 129.0ppm, 131.3ppm, 135.6ppm, 140.3ppm, 162.5ppm and 185.1ppm (+ -0.2).
The Differential Scanning Calorimetry (DSC) picture of the irbesartan piperazine salt related by the invention has an endothermic melting peak at 186.4 +/-5 ℃.
The irbesartan piperazine salt crystal structure belongs to an orthorhombic system, the space group is Pna21, and when the test temperature is 293K, the unit cell parameter is
Z＝8、
In another aspect, the present invention provides a method for preparing irbesartan piperazine salt as described above, comprising: and mixing irbesartan and piperazine with a solvent, reacting and drying to obtain the irbesartan piperazine salt.
Preferably, the solvent comprises any one of water, methanol, ethanol, n-propanol, acetone, acetonitrile, ethyl acetate, chloroform, dichloromethane, toluene or n-hexane or a combination of at least two thereof. The combination of the at least two compounds, for example, the combination of water and methanol, the combination of water and ethanol, the combination of ethanol and acetone, the combination of ethyl acetate and chloroform, etc., may be selected from any other combination manners, and thus, the description thereof is not repeated herein.
Preferably, the reaction temperature is 20-30 ℃, such as 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ or 30 ℃.
More specifically, the preparation method of irbesartan piperazine salt provided by the invention comprises a solution method and a mechanical grinding method, and the irbesartan piperazine salt is prepared by the solution method or the mechanical grinding method, so that the preparation method is simple to operate, mild in conditions and low in cost.
For a solution process, the preparation process comprises: adding irbesartan and piperazine into a solvent, mixing, stirring for reaction, filtering the mixed solution, and drying the solid to obtain the irbesartan piperazine salt.
Preferably, the molar ratio of irbesartan to piperazine is 1:2 to 2:1, such as 1:2, 3:5, 3:4, 4:5, 1:1, 5:4, 4:3, 5:3 or 2:1, preferably 1: 1.
Preferably, the addition amount of the solvent is 0.025-0.045mL per mg of irbesartan solvent; for example, 0.025mL, 0.028mL, 0.030mL, 0.032mL, 0.035mL, 0.040mL, or 0.045 mL.
Preferably, the stirring reaction time is 24-72h, such as 24h, 28h, 30h, 32h, 35h, 38h, 40h, 45h, 48h, 55h, 60h, 65h, 70h or 72h, and the like.
For the mechanical milling process, the preparation process comprises: and (3) putting irbesartan and piperazine into a grinding device (such as a ball mill and a grinding bowl), then, dripping a solvent into the irbesartan and piperazine, and carrying out grinding reaction to obtain the irbesartan piperazine salt.
Preferably, the molar ratio of irbesartan to piperazine is 1: 1.
Preferably, the solvent is added in an amount of 0.1-0.25. mu.L, such as 0.1. mu.L, 0.12. mu.L, 0.15. mu.L, 0.16. mu.L, 0.18. mu.L, 0.20. mu.L, 0.22. mu.L or 0.25. mu.L etc., per mg of irbesartan.
Preferably, the stirring reaction time is 20-60min, such as 20min, 25min, 30min, 35min, 40min, 45min, 50min, 55min or 60 min.
In a further aspect, the invention provides the use of irbesartan piperazine salt as described above in the preparation of a medicament for the treatment of hypertension.
Compared with the prior art, the invention has the following beneficial effects:
the irbesartan piperazine salt has good stability, and after the irbesartan piperazine salt is stored for 30 days at the temperature of 25 ℃/RH 95%, the color, the appearance and the crystal phase of a product are not changed, and the irbesartan piperazine salt can be stably stored under the condition of high humidity; compared with irbesartan, the irbesartan piperazine salt provided by the invention has the advantages that the dissolution rate and the solubility are both remarkably improved, the dissolution rate and the solubility are remarkably improved, the bioavailability is improved, and the drug property is further improved. Meanwhile, the irbesartan piperazine salt is prepared by a solution method or a mechanical grinding method, so that the irbesartan piperazine salt is simple to operate, mild in condition, low in cost and free of solvent residue.
Drawings
Figure 1 is a powder XRD pattern of irbesartan piperazine salt obtained in example 1;
figure 2 is a powder XRD pattern of irbesartan piperazine salt obtained in example 3;
FIG. 3 is a diagram of the irbesartan piperazine salt obtained in example 113C, solid nuclear magnetic resonance spectrum;
FIG. 4 is a DSC of piperazine salt of irbesartan obtained in example 1;
FIG. 5 is a comparison of powder XRD patterns before and after humidity acceleration test of irbesartan piperazine salt obtained in example 1;
figure 6 is an intrinsic dissolution diagram of the irbesartan piperazine salt obtained in example 1;
fig. 7 is a powder dissolution diagram of irbesartan piperazine salt obtained in example 1.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
This example provides an irbesartan piperazine salt comprising an equimolar ratio of an irbesartan anion represented by formula (i) and a piperazine cation represented by formula (ii):
the preparation method comprises the following steps:
adding 85.7mg of irbesartan and 17.2mg of piperazine into 3mL of methanol for mixing, stirring at 25 ℃ for reaction for 72 hours, centrifugally filtering the mixed solution, and drying the solid in an oven at 40 ℃ for 24 hours to obtain the irbesartan piperazine salt.
Example 2
This example provides an irbesartan piperazine salt comprising an equimolar ratio of an irbesartan anion represented by formula (i) and a piperazine cation represented by formula (ii):
the preparation method comprises the following steps:
adding 85.7mg of irbesartan and 17.2mg of piperazine into 3mL of acetone, mixing, stirring at 30 ℃ for reaction for 48 hours, centrifugally filtering the mixed solution, and drying the solid in an oven at 40 ℃ for 24 hours to obtain the irbesartan piperazine salt.
Example 3
This example provides an irbesartan piperazine salt comprising an equimolar ratio of an irbesartan anion represented by formula (i) and a piperazine cation represented by formula (ii):
the preparation method comprises the following steps:
putting 42.9mg of irbesartan and 8.6mg of piperazine into a Pulverisette 23 micro ball mill, then dropping 15 mu L of methanol, and grinding for 20min at the frequency of 40Hz and the temperature of 25 ℃ to obtain the piperazine salt of irbesartan.
Example 4
This example provides an irbesartan piperazine salt comprising an equimolar ratio of an irbesartan anion represented by formula (i) and a piperazine cation represented by formula (ii):
the preparation method comprises the following steps:
putting 42.9mg of irbesartan and 8.6mg of piperazine into a Pulverisette 23 micro ball mill, then dropping 15 mu L of dichloromethane, and grinding for 60min at the frequency of 40Hz and the temperature of 20 ℃ to obtain the piperazine salt of irbesartan.
Example 5
Samples of irbesartan piperazine salt obtained in example 1 and example 3 were taken for testing and characterization, and powder XRD patterns were obtained using a Bruker D8 Advance powder X-ray diffractometer, equipped with a LynxEye detector with a Cu ka as the radiation source, a tube current of 40mA, a tube voltage of 40kV, a scanning step of 0.2 °, and a2 θ range of 3 ° to 40 °. The XRD patterns of the obtained powder are shown in figures 1-2, and can be known from figures 1 and 2: the powder XRD patterns prepared by the two methods have characteristic peaks at least at 2 theta diffraction angles of 5.2, 10.3, 12.1, 14.8, 15.9, 17.4, 18.7, 19.4, 20.9, 21.4, 22.1, 22.9, 24.4, 25.9, 26.5, 27.2, 29.3, 30.1, 30.6, 31.9, 32.9, 35.4 and 36.8 (+ -0.2).
Example 6
The irbesartan piperazine salt sample obtained in example 1 is tested and characterized by using a BrukeraVANCE III-500 nuclear magnetic resonance spectrometer under the following test conditions: 4mm double resonance magic angle rotating probe with magic angle rotation speed of 8kHz, using cross polarization pulse sequence while suppressing the rotating sidebands, with tetramethylsilane as chemical shift reference (0ppm), obtained as shown in FIG. 313C solid nuclear magnetic resonance spectrum. As can be seen from fig. 2: it has characteristic peaks at least at chemical shifts 172.3ppm, 149.0ppm, 144.2ppm, 137.7ppm, 130.3ppm, 125.4ppm, 118.1ppm, 116.0ppm, 110.0ppm, 82.1ppm, 80.4ppm, 50.2ppm, 46.0ppm, 40.3ppm, 36.1ppm, 27.4ppm, 15.6ppm, 10.9ppm (± 0.2).
Example 7
In this example, a single crystal sample of irbesartan piperazine salt according to the present invention was tested using an Xcalibur Gemini single crystal X-ray diffractometer manufactured by Agilent corporation, usa, and the X-ray source was Mo K α target
The test temperature was 293K. The crystal structure is solved by a direct method, Olex 2-1.2 software is used, the structure is refined by a full matrix least square method, non-hydrogen atoms are all anisotropically refined, hydrogen atoms directly connected with carbon are connected and fixed in position by geometry, and hydrogen atoms connected with nitrogen and oxygen atoms are positioned by a difference Fourier map. The salt belongs to the orthorhombic system, the space group is Pna21, the test temperature is 293K, and the unit cell parameters are
Z＝8、
Example 8
The irbesartan piperazine salt sample obtained in example 1 is taken for testing and characterization, Differential Scanning Calorimetry (DSC) is performed by using DSC D250 of TA company, about 4mg of the sample is weighed and placed in a crucible, covered tightly, and heated at a speed of 10 ℃/min under the protection of nitrogen, the temperature is increased from 30 ℃ to 200 ℃, a DSC diagram as shown in fig. 4 is obtained, and it can be known that: an endothermic peak appeared at 186.4. + -. 5 ℃.
Example 9
By using a CTHI-150B1 constant temperature and humidity chamber of Shanghai Schurbackae instruments and equipments Limited, after the sample prepared in example 1 is stored for 30 days at 25 ℃/RH 95%, the color, morphology and crystal phase of the product are not changed, and the powder XRD contrast pattern before and after the accelerated experiment is shown in FIG. 5, which shows that the product can be stably stored under high humidity.
Example 10
The intrinsic dissolution test was performed on the sample prepared in example 1 using an RC-6 dissolution apparatus manufactured by tianjin celestial optics ltd. The temperature was set at 37. + -. 0.2 ℃ and the stirring speed was 100 rpm. Weighing 300mg equivalent of irbesartan raw material and irbesartan piperazine salt, respectively, pressing the two groups of samples into tablets with the diameter of 10mm by using a tablet press, wrapping the tablets to expose one surface, placing the tablets in 500mL of phosphate buffer solution with the pH value of 6.8, sampling once every 5min, taking 6 times in total, performing concentration determination by using Waters 2535 high performance liquid chromatography, and performing three groups of experiments in parallel. Fig. 6 shows a straight line of the intrinsic dissolution of irbesartan raw material and irbesartan piperazine salt as a function of time, from which it can be seen that: the intrinsic dissolution rates of irbesartan and irbesartan piperazine salt are respectively 4.82 multiplied by 10-5And 1.79X 10-2mg/mL/cm2/min。
Example 11
The powder dissolution test was performed on the sample prepared in example 1, and 50mL of phosphate buffer solution having a pH of 6.8 was placed in a 100mL beaker, the temperature was controlled to 37 ± 0.2 ℃, and the magnetic stirring speed was 350 rpm. And respectively weighing 500mg equivalent of irbesartan raw material and irbesartan piperazine salt two groups of samples, placing the samples in the solvent, sampling at regular intervals to determine the concentration, simultaneously supplementing the medium with the same amount, and carrying out the experiment for 24 hours. The irbesartan concentration is measured by using high performance liquid chromatography, and three groups of experiments are carried out in parallel. Fig. 7 shows the time-dependent dissolution profiles of irbesartan raw material and irbesartan piperazine salt, from which: the maximum concentrations of irbesartan and irbesartan piperazine salt are 0.53 and 8.69mg/mL respectively, and the equilibrium concentrations are 0.15 and 0.72mg/mL respectively.
The applicant states that the invention is illustrated by the above examples as one of the irbesartan piperazine salts and the preparation method and application thereof, but the invention is not limited to the above examples, i.e. it is not meant to imply that the invention must be implemented by means of the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (10)
1. An irbesartan piperazine salt, comprising an irbesartan anion represented by formula (i) and a piperazine cation represented by formula (ii):
2. irbesartan piperazine salt according to claim 1, wherein the molar ratio of irbesartan anion to piperazine cation is 1: 1.
3. The process for the preparation of irbesartan piperazine salt according to claim 1 or 2, comprising: and mixing irbesartan and piperazine with a solvent, reacting and drying to obtain the irbesartan piperazine salt.
4. The method for preparing irbesartan piperazine salt according to claim 3, wherein the solvent comprises any one or a combination of at least two of water, methanol, ethanol, n-propanol, acetone, acetonitrile, ethyl acetate, chloroform, dichloromethane, toluene or n-hexane.
5. The process for the preparation of irbesartan piperazine salt according to claim 3 or 4, wherein the temperature of the reaction is 20-30 ℃.
6. A process for the preparation of irbesartan piperazine salt according to claim 3, comprising: adding irbesartan and piperazine into a solvent, mixing, stirring for reaction, filtering the mixed solution, and drying the solid to obtain the irbesartan piperazine salt.
7. Process for the preparation of irbesartan piperazine salt according to claim 6, wherein the molar ratio of irbesartan to piperazine is 1:2 to 2:1, preferably 1: 1;
preferably, the addition amount of the solvent is 0.025-0.045mL per mg of irbesartan solvent;
preferably, the stirring reaction time is 24-72 h.
8. A process for the preparation of irbesartan piperazine salt according to claim 3, comprising: and (3) putting irbesartan and piperazine into a grinding device, then dripping a solvent, and carrying out grinding reaction to obtain the irbesartan piperazine salt.
9. The method for preparing irbesartan piperazine salt according to claim 8, wherein the molar ratio of irbesartan to piperazine is 1: 1;
preferably, the addition amount of the solvent is 0.1-0.25 μ L per mg of irbesartan added solvent;
preferably, the stirring reaction time is 20-60 min.
10. Use of irbesartan piperazine salt according to claim 1 or 2 for the preparation of a medicament for the treatment of hypertension.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040198788A1 (en) * | 2001-08-28 | 2004-10-07 | Sankyo Company, Limited | Medicinal compositions containing angiotensin II receptor antagonist |
| CN101433536A (en) * | 2007-11-12 | 2009-05-20 | 北京瑞康医药技术有限公司 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
| CN101468002A (en) * | 2007-12-29 | 2009-07-01 | 北京瑞康医药技术有限公司 | Therapeutic composition containing amlodipine salt and losartan medicine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040198788A1 (en) * | 2001-08-28 | 2004-10-07 | Sankyo Company, Limited | Medicinal compositions containing angiotensin II receptor antagonist |
| CN101433536A (en) * | 2007-11-12 | 2009-05-20 | 北京瑞康医药技术有限公司 | Therapeutic compositions containing amlodipine niacin and losartan medicament |
| CN101468002A (en) * | 2007-12-29 | 2009-07-01 | 北京瑞康医药技术有限公司 | Therapeutic composition containing amlodipine salt and losartan medicine |
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Application publication date: 20210618 |