CN116253699A - New crystal form of tolperisone hydrochloride and preparation method thereof - Google Patents
New crystal form of tolperisone hydrochloride and preparation method thereof Download PDFInfo
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- 229960005334 tolperisone Drugs 0.000 title claims abstract description 81
- FSKFPVLPFLJRQB-UHFFFAOYSA-N 2-methyl-1-(4-methylphenyl)-3-(1-piperidinyl)-1-propanone Chemical compound C=1C=C(C)C=CC=1C(=O)C(C)CN1CCCCC1 FSKFPVLPFLJRQB-UHFFFAOYSA-N 0.000 title claims abstract description 77
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- 238000001228 spectrum Methods 0.000 claims abstract description 3
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- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- 208000019553 vascular disease Diseases 0.000 claims description 4
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- 239000012043 crude product Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention relates to the field of medicine, and relates to a novel crystal form of tolperisone hydrochloride and a preparation method thereof, which uses Cu-K α When the tolperisone hydrochloride is radiated, the characteristic peaks of 2 theta plus or minus 0.2 in the X-ray powder diffraction spectrum of the new crystal form of tolperisone hydrochloride are as follows: 7.36, 14.14, 17.4, 21.5, 22.44, 28.7, 37.34, 44.6. The novel tolperisone hydrochloride crystal form and the preparation method thereof disclosed by the invention have the advantages of high crystallinity and good purity, and particularly the stability and the instantaneous solubility are superior to those of the existing tolperisone hydrochloride, thereby being beneficial to further improving the product quality.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a novel crystal form of tolperisone hydrochloride and a preparation method thereof.
Background
Tolperisone hydrochloride (2-methyl-3-piperidine-1-p-tolylpropane-1-one hydrochloride, shown in the following structural formula), aliases Naomaining, tolperisone, etc., has central muscle relaxing and vasodilating effects. Can directly dilate vascular smooth muscle, inhibit multi-synaptic reflex, and reduce skeletal muscle tension. Relieving muscular tonic clonus caused by brain and spinal cord injury, and increasing peripheral blood flow. Is commonly used for treating ischemic vascular diseases, such as arteriosclerosis, endangiitis and the like; it can also be used for treating apoplexy sequela, cerebral palsy, spinal cord peripheral nerve diseases, etc. Tolperisone hydrochloride has the unique property of mediating muscle relaxation without concomitant sedation and generally does not cause uncoordinated, frailty, confusion or withdrawal phenomena compared to other muscle relaxants.
Patent CN110845443a reviews several common synthetic methods of tolperisone hydrochloride, and although there is a refining process, there is no report on the crystal form of tolperisone hydrochloride, and the white powder is obtained according to the method. Patent CN107868065a discloses a tolperisone hydrochloride crystal detected by XRD, but the refining step has the disadvantages of narrow temperature control range, high operation requirement, wide XRD peak shape and poor crystallinity. In addition, studies in the document Effects of Temperature and Humidity on Stability of Tolperisone Hydrochloride (Nopprat Sae-Lee and Nittaya Sae-Lee, srinakharinwirot Journal of Pharmaceutical Sciences,2005,10 (2): 121-124) have shown that temperature and humidity have a great influence on the stability of hydrochloric acid, and that conditions such as temperature and humidity should be taken into consideration during storage. Therefore, in order to solve the above problems, it is necessary to develop a new crystal form of tolperisone hydrochloride and a stable preparation method thereof.
Disclosure of Invention
The invention aims to provide a novel crystal form of tolperisone hydrochloride and a preparation method thereof, which solve the problems that the stability of the existing amorphous tolperisone hydrochloride is poor, and the crystallinity and the preparation difficulty of the amorphous tolperisone hydrochloride of CN107868065A are poor.
In order to solve the technical problems, the invention adopts the following technical scheme:
new crystal form of tolperisone hydrochloride using Cu-K α When the tolperisone hydrochloride is radiated, the characteristic peaks of 2 theta plus or minus 0.2 in the X-ray powder diffraction spectrum of the new crystal form of tolperisone hydrochloride are as follows: 7.36, 14.14, 17.4, 21.5, 22.44, 28.7, 37.34, 44.6.
Preferably, the novel crystal form of tolperisone hydrochloride is needle-shaped crystal.
The preparation method of the novel crystal form of tolperisone hydrochloride comprises the following steps:
A. dissolving tolperisone hydrochloride compound in the mixed organic solvent under the heating condition;
B. cooling the solution obtained in the step A under a certain condition, crystallizing, wherein the crystallizing process can not be stirred;
C. and (C) filtering, washing and vacuum drying the solid-liquid mixture obtained in the step (B) to obtain the crystal with the novel crystal form of tolperisone hydrochloride.
Any tolperisone hydrochloride compound, namely 2-methyl-3-piperidine-1-p-tolylpropane-1-one hydrochloride, is taken as a raw material, commercially available tolperisone hydrochloride is generally used, and the tolperisone hydrochloride is prepared by the method, so that crystals with a novel crystal form of tolperisone hydrochloride can be obtained.
Unlike CN107868065A, the raw material used in the crystallization of the present invention is tolperisone hydrochloride, while the raw material in the purification step of CN107868065A is tolperisone that is not salified, the obvious difference is that after salification, the sample changes from liquid to solid, resulting in a great difference in dissolution behavior in organic solvents, in CN107868065A, at 32-35 ℃, acetone: tolperisone (w/w) =3:1, under which conditions the tolperisone hydrochloride solid is never completely dissolved in acetone. It was found experimentally that even at 60 c, 1g of tolperisone hydrochloride requires at least 45ml of acetone to dissolve completely, and that the solubility of tolperisone hydrochloride in acetone can be improved when other benign solvents are added. More importantly, the X-ray powder diffraction detection under the same condition shows that the crystal form of the invention is completely different from CN107868065A and has no comparability-! The novel tolperisone hydrochloride crystal prepared by the invention has better stability and good application prospect.
Preferably, in step a, the mixed organic solvent includes a ketone solvent.
Preferably, the mixed organic solvent further comprises one or more of an ester solvent and an alcohol solvent.
Preferably, the ketone solvent comprises one or more of acetone, methyl ethyl ketone, N-methylpyrrolidone and methyl isobutyl ketone; the ester solvent comprises one or more of ethyl acetate and isopropyl acetate; the alcohol solvent comprises one or more of methanol and ethanol.
Preferably, the mixed organic solvent comprises the ketone solvent, the ester solvent and the alcohol solvent which are mixed according to the volume ratio of 20-60:10-20:1-10.
Preferably, in the step A, the mass volume ratio of the tolperisone hydrochloride compound to the mixed organic solvent is 1 g:35-90 ml.
Preferably, in the step A, the heating condition is 30-80 ℃; in the step B, the crystallization temperature is-10-30 ℃, the crystallization time is 2-24 hours, and in the crystallization process, the temperature is firstly reduced at room temperature and then is further cooled to-10 ℃; in the step C, the vacuum drying temperature is 50-60 ℃ and the drying time is 5-24.
The application of the novel crystal form of tolperisone hydrochloride in preparing medicine for treating ischemic vascular diseases.
The crystal form of the tolperisone hydrochloride can be prepared into medicines together with other necessary substances, such as conventional pharmaceutical excipients, and has better stability when being used for treating ischemic vascular diseases.
The implementation of the invention has the following beneficial effects:
the invention discloses a novel crystal form of tolperisone hydrochloride and a preparation method thereof. The preparation method has the advantages of simple operation and easy industrialization. In addition, the refined novel tolperisone hydrochloride crystal form has the advantages of high purity and good crystallinity, and particularly has better stability and instantaneous solubility than the existing tolperisone hydrochloride product, thereby being beneficial to obtaining better effect and wider application range in the aspect of related preparations.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of tolperisone hydrochloride prepared in example 1;
FIG. 2 (A) is a diagram showing the structure of tolperisone hydrochloride before purification; (B) is a graphic representation of tolperisone hydrochloride prepared in example 1; (C) microscopic image of tolperisone hydrochloride before refining; (D) microscopic image of tolperisone hydrochloride prepared in example 1.
FIG. 3 is a full-wavelength scan of an ultraviolet visible spectrophotometer of tolperisone hydrochloride of effect example 3
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings, for the purpose of making the objects, technical solutions and advantages of the present invention more apparent.
Example 1
Adding 10g of tolperisone hydrochloride crude product into a mixed solvent consisting of 300ml of acetone, 110ml of ethyl acetate and 13ml of ethanol, stirring and dissolving under water bath heating at 60 ℃, stopping stirring after the sample is completely dissolved, standing at room temperature, cooling for 6h, cooling and crystallizing the solution at 5 ℃ for 15h, filtering, washing twice with 50ml of ethyl acetate, and drying in vacuum at 50 ℃ for 8h to obtain 9.3g of needle-like crystals (shown in fig. 2 (B) and fig. 2 (D), wherein floccules are formed before crystallization, shown in fig. 2 (A) and fig. 2 (C), the yield is 93%, the purity is 99.98%, and the XRD is shown in fig. 1.
Example 2
Adding 10g of tolperisone hydrochloride crude product into a mixed solvent consisting of 400ml of acetone, 100ml of ethyl acetate and 15ml of ethanol, stirring and dissolving under heating in a water bath at 50 ℃, stopping stirring after the sample is completely dissolved, cooling for 6 hours at room temperature, cooling and crystallizing the solution for 15 hours at 5 ℃, filtering and washing twice with 50ml of ethyl acetate, and vacuum drying for 8 hours at 50 ℃ to finally obtain 9.1g of needle-like crystals, wherein the yield is 91%, the purity is 99.94%, and XRD is consistent with that of figure 1.
Example 3
15g of tolperisone hydrochloride crude product is added into a mixture composed of 400ml of acetone, 200ml of ethyl acetate and 17ml of ethanol, stirring and dissolving are carried out under the condition of heating in a water bath at 55 ℃, after the sample is completely dissolved, stirring is stopped, cooling is carried out for 6 hours at room temperature, cooling and crystallizing are carried out for 15 hours under the condition of 0 ℃ after the solution is put into the solution, suction filtration is carried out, the solution is washed twice by 10ml of acetone, vacuum drying is carried out for 8 hours at 50 ℃, and finally 13.95g of needle-like crystals are obtained, the yield is 93%, the purity is 99.96%, and XRD is consistent with that of figure 1.
Example 4
15g of tolperisone hydrochloride crude product is added into a mixture composed of 400ml of methyl ethyl ketone, 200ml of ethyl acetate and 10ml of methanol, stirring and dissolving are carried out under the condition of heating in a water bath at 55 ℃, after the sample is completely dissolved, stirring is stopped, cooling is carried out for 6 hours at room temperature, the solution is placed into the condition of cooling and crystallizing for 15 hours at 0 ℃, then suction filtration and washing twice with 10ml of methyl ethyl ketone are carried out, vacuum drying is carried out for 8 hours at 50 ℃, 14.13g of needle-like crystals are finally obtained, the yield is 94.2%, the purity is 99.98%, and XRD is consistent with that of figure 1.
Example 5
Adding 15g of tolperisone hydrochloride crude product into a mixture composed of 450ml of N-methylpyrrolidone, 150ml of isopropyl acetate and 15ml of methanol, stirring and dissolving under water bath heating at 60 ℃, stopping stirring after the sample is completely dissolved, cooling for 8 hours at room temperature, cooling and crystallizing the solution for 15 hours at 5 ℃, filtering, washing twice with 10ml of N-methylpyrrolidone, and drying in vacuum for 8 hours at 50 ℃, thus obtaining 14.4g of needle-like crystals with 96% yield and 99.97% purity, and XRD is consistent with that of figure 1.
Effect example 1
1g of tolperisone hydrochloride was dissolved in various solvents, and after heating and dissolution at 55 ℃, the solution was cooled and crystallized, and the specific results are shown in Table 1.
TABLE 1 comparison of different crystallization conditions
As can be seen from Table 1, the combination of acetone, ethyl acetate, ethanol, ketone, ester, alcohol, as represented by the ratio of 20-60:10-20:1-10 by volume, as a mixed solvent, was crystallized without stirring, and tolperisone hydrochloride needle crystals were obtained. Wherein acetone may be replaced with other similar ketones such as methyl ethyl ketone, N-methylpyrrolidone, methyl isobutyl ketone, ethyl acetate may be replaced with other similar esters such as isopropyl acetate, and ethanol may be replaced with other similar alcohols such as methanol, similar results may be obtained, and tolperisone hydrochloride needle crystals may also be obtained (see examples 1 to 5).
Effect example 2
Accelerated stability experiments were performed on three different sources of tolperisone hydrochloride (40 ℃ ± 2 ℃ C., 75% ± 5% RH), wherein sample A was prepared as in example 1, sample B was prepared as in the complex procedure of patent CN107868065A, and sample C was a commercially available sample. The results are shown in Table 2.
TABLE 2 accelerated stability test results
As can be seen from Table 2, sample A and sample B are both superior to sample C in the market, but from comparison of sample A and sample B, sample A can maintain a purity of 99.9% or higher over the first 3 months, while sample B starts to drop to a level of 99.9% or lower at month 3, and drops to a level of 99.8% or lower at month 6, and is not at a level of high grade purity. Namely, the stability of the tolperisone hydrochloride crystal prepared by the invention is better than that of the product in the prior art. The same test was performed on tolperisone hydrochloride compounds prepared in other examples of the present invention, and similar results were obtained. The results show that the novel crystal form of tolperisone hydrochloride has better stability, the preparation process is simpler and more convenient, the industrialization is easy, and the preparation method is favorable for carrying out other related experiments of tolperisone hydrochloride and manufacturing, storing and preparation production of related medicines.
Effect example 3
The instantaneous solubility of three different samples was determined. Sample a was prepared as in example 1, sample B was prepared as in the complex procedure of patent CN107868065a, and sample C was a commercially available sample. The commercial sample was scanned with an ultraviolet-visible spectrophotometer at full wavelength (the result is shown in fig. 3), the maximum absorption wavelength was 261nm, the absorbance at different concentrations was measured at this wavelength to obtain a standard curve of tolperisone hydrochloride, three samples were taken out of 0.5g each, 5ml of purified water was added, and the absorbance was measured after sampling and dilution at 0.5min, 1min, 1.5min and 2min, respectively, the concentration in the effluent was calculated from the standard curve, and the results are shown in table 3.
TABLE 3 instantaneous solubility of samples
As can be seen from table 3, although the total solubility of the three samples is substantially the same, compared with the sample B and the sample C, the tolperisone hydrochloride crystal sample a prepared by the present invention can reach a saturated concentration within 1 minute, and has a good instantaneous solubility, which indicates that the tolperisone hydrochloride crystal sample a has a higher efficiency in human absorption, so that the tolperisone hydrochloride crystal sample a has a good advantage in preparation.
The foregoing disclosure is merely illustrative of the preferred embodiments of the present invention and is not intended to limit the scope of the claims herein, as equivalent changes may be made in the claims herein without departing from the scope of the invention.
Claims (10)
1. A novel crystal form of tolperisone hydrochloride is characterized in that Cu-K is used α When the tolperisone hydrochloride is radiated, the characteristic peaks of 2 theta plus or minus 0.2 in the X-ray powder diffraction spectrum of the new crystal form of tolperisone hydrochloride are as follows: 7.36, 14.14, 17.4, 21.5, 22.44, 28.7, 37.34, 44.6.
2. The novel crystalline form of tolperisone hydrochloride of claim 1, wherein the novel crystalline form of tolperisone hydrochloride is a needle-like crystal.
3. A process for the preparation of a new crystalline form of tolperisone hydrochloride according to claim 1, comprising the steps of:
A. dissolving tolperisone hydrochloride compound in the mixed organic solvent under the heating condition;
B. cooling the solution obtained in the step A under a certain condition, crystallizing, wherein the crystallizing process can not be stirred;
C. and (C) filtering, washing and vacuum drying the solid-liquid mixture obtained in the step (B) to obtain the crystal with the novel crystal form of tolperisone hydrochloride.
4. The process for preparing a new crystalline form of tolperisone hydrochloride according to claim 1, wherein in step a, the mixed organic solvent comprises a ketone solvent.
5. The process for preparing a new crystalline form of tolperisone hydrochloride according to claim 4, wherein the mixed organic solvent further comprises one or more of an ester solvent and an alcohol solvent.
6. The process for preparing a new crystalline form of tolperisone hydrochloride according to claim 5, wherein the ketone solvent comprises one or more of acetone, methyl ethyl ketone, N-methylpyrrolidone, methyl isobutyl ketone; the ester solvent comprises one or more of ethyl acetate and isopropyl acetate; the alcohol solvent comprises one or more of methanol and ethanol.
7. The method for preparing a novel crystal form of tolperisone hydrochloride according to claim 5, wherein the mixed organic solvent comprises the ketone solvent, the ester solvent and the alcohol solvent which are mixed according to a volume ratio of 20-60:10-20:1-10.
8. The process for preparing a novel crystalline form of tolperisone hydrochloride according to claim 1, wherein in step a, the mass to volume ratio of tolperisone hydrochloride compound to the mixed organic solvent is 1 g:35-90 ml.
9. The method for preparing a new crystal form of tolperisone hydrochloride according to claim 1, wherein in step a, the heating condition is 30-80 ℃; in the step B, the crystallization temperature is-10-30 ℃, the crystallization time is 2-24 hours, and in the crystallization process, the temperature is firstly reduced at room temperature and then is further cooled to-10 ℃; in the step C, the vacuum drying temperature is 50-60 ℃ and the drying time is 5-24 h.
10. The use of a new crystalline form of tolperisone hydrochloride according to claim 1, for the preparation of a medicament for the treatment of ischemic vascular diseases.
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