Preparation method of tetracaine crystal form

Abstract

The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of a tetracaine crystal form. The preparation method provided by the invention is simple, good in reproducibility and high in yield, an X-ray powder diffraction pattern of the related crystal form has characteristic peaks at 2 theta angles of 4.217 + / -0.2 degrees, 8.560 + / -0.2 degrees, 12.838 + / -0.2 degrees and 17.120 + / -0.2 degrees, and the crystal form has better stability and is of great significance to development of medicinal tetracaine.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a tetracaine crystal form. Background Art

[0002] Tetracaine, CAS No.: 94-24-6, chemical name: 2-(dimethylamino)ethyl 4-(butylamino)benzoate, the structure of Tetracaine is as follows:

[0003] Tetracaine can be used as a long-acting ester local anesthetic, which can block the permeability of sodium ions in nerve cell membranes, slow down the rise of points until it stops, and the conduction and excitability of nerves disappear. It is widely used in spinal anesthesia and surface infiltration anesthesia.

[0004] Patent CN102731333A discloses a method for preparing tetracaine, which relates to a method for purifying a crude tetracaine product, that is, dissolving the crude tetracaine product in 100-200 ml of 5% hydrochloric acid, adding 50-100 ml of an organic solvent (dichloromethane, petroleum ether or isopropyl ether) with a boiling point lower than 80°C, adding 20% ​​sodium hydroxide to adjust the pH to 12-13, separating the liquid to take the organic layer, concentrating the organic layer to dryness under reduced pressure, and drying the obtained solid to obtain a finished tetracaine product.

[0005] Patent CN104557585A discloses a tetracaine hydrochloride crystal and a preparation method thereof. The tetracaine hydrochloride crystal has characteristic peaks at the following 2θ diffraction angles in an X-ray powder diffraction pattern: 6.7°, 11.0°, 13.5°, 14.2°, 14.7°, 17.4°, 18.6°, 19.7°, 20.2°, 21.0°, 21.8°, 23.2°, 23.8°, 24.4°, 24.9°, 26.1°, 27.1°, 28.9°, 30.5°, 32.2°, 33.6°, 34.1°, 34.8°, 35.8°, 38.9°, 39.4° and 40.0°. Specifically, tetracaine hydrochloride powder is weighed, and water at 20-25° C. is added under nitrogen protection to stir and dissolve to prepare a tetracaine hydrochloride solution with a concentration of 5%-20%; a mixed solvent of n-butanol and n-hexane at 2-10° C. is added dropwise under a sound field with a frequency of 25-30 KHz and an output power of 10-70 W and stirring at 50-160 r / min, wherein the volume ratio of n-butanol to n-hexane in the mixed solvent is 2-10:1, and the volume of the mixed solvent is 2-5 times that of the tetracaine hydrochloride solution, and after the addition is completed, the sound field is stopped, and crystal growth is allowed to stand for 3-6 hours; filtering, washing with anhydrous ethanol, and vacuum drying for 5-10 hours to obtain tetracaine hydrochloride crystals.

[0006] Patent CN105646261A discloses a method for preparing tetracaine, specifically: para-aminobenzoic acid and n-butyraldehyde are subjected to a catalytic reduction reaction to prepare N-butyl para-aminobenzoic acid, the reaction solution is filtered and then sodium hydroxide is added to mix, the solution is concentrated under reduced pressure until it becomes viscous, and then toluene is added for fractionation to remove ethanol and water, N,N-dimethylchloroethylamine hydrochloride and sodium carbonate are added after cooling, and then refluxed for 8 hours, cooled, filtered, the organic layer is washed with water, and then evaporated to dryness to obtain a crude tetracaine product.

[0007] Patent CN106518697A discloses a method for preparing tetracaine hydrochloride (1), comprising the following preparation process: p-nitrobenzoyl chloride (2) reacts with dimethylaminoethanol (3) to generate p-nitrobenzoic acid-2-dimethylaminoethyl ester (4), compound (4) is reduced to obtain p-aminobenzoic acid-2-dimethylaminoethyl ester (5), compound (5) reacts with 1-bromobutane (6) under alkaline conditions to generate tetracaine (7), and finally reacts with HCl to generate tetracaine hydrochloride (1).

[0008] Patent CN109180511A discloses a method for preparing tetracaine hydrochloride, comprising the following steps: ① Preparation of 4-n-butylaminobenzoic acid: adding a solvent, 4-halogenated benzoic acid, n-butylamine and a copper catalyst into a high-pressure reactor, reacting at a certain temperature and time to obtain 4-n-butylaminobenzoic acid; ② Preparation of tetracaine: adding the 4-n-butylaminobenzoic acid obtained in step ①, N,N-dimethylethanolamine, concentrated sulfuric acid and a solvent into a reaction bottle, heating and refluxing to separate water, to obtain tetracaine; ③ Preparation of tetracaine hydrochloride: adding concentrated hydrochloric acid to the tetracaine obtained in step ② in a solvent (isopropanol) at a certain temperature to react to obtain tetracaine hydrochloride.

[0009] Patent CN109761835A discloses a method for preparing tetracaine hydrochloride, which involves a first step reaction of para-aminobenzoic acid with n-butyraldehyde and hydrogen, a second step reaction of the first step reaction product with N,N-dimethylethanolamine, and a third step salt-forming reaction, wherein the third step salt-forming reaction also includes a crystallization step; the crystallization solvent used in the crystallization step is one or more of ethanol, methanol, ethyl acetate, acetone, dichloromethane, and methyl tert-butyl ether; and the temperature of the crystallization step is 0 to 10°C.

[0010] Patent CN115466190A discloses a method for preparing tetracaine, which involves a refining method of mixing tetracaine with n-heptane, methyl tert-butyl ether and purified water, heating and dissolving them, removing the lower aqueous phase, adding activated carbon for adsorption, filtering the activated carbon while hot, cooling the solution to 0-10°C and stirring for 1.5-2.5h, then centrifuging, drying and discharging to obtain a tetracaine product, but the yield of this method is low.

[0011] Patent CN116444387A discloses a method for preparing a high-purity tetracaine bulk drug, which involves suspending a crude tetracaine hydrochloride product with an organic solvent (dichloromethane), neutralizing it with an alkali reagent (triethylamine) to neutrality, washing with water and collecting the organic layer, drying it with anhydrous sodium sulfate, cooling it to crystallize (cooling it to -5 to 0°C for 2 hours), filtering it, and drying the filter cake under reduced pressure to obtain the tetracaine bulk drug.

[0012] CN116924924A discloses a method for synthesizing tetracaine. After the reaction is completed, dichloromethane and water are added for extraction, water is added to the organic phase and the pH is adjusted to 5-6 for phase separation, dichloromethane is added to the aqueous phase and the pH is adjusted to 8-9, the dichlorohexane portion is retained and dried and concentrated, n-hexane is added and heated to reflux, the mixture is stirred at 30-40°C for crystallization for 0.4-0.6h, then kept at 10-15°C for stirring for 1-3h, filtered, and dried at 30-40°C for 5-7h to obtain the product.

[0013] CN116924925A discloses a method for synthesizing tetracaine by reductive amination. After the reaction is completed, 8 mL of water is added, followed by dichloromethane extraction (10 mL×3). The collected organic phase is then washed with saturated brine and dried over anhydrous sodium sulfate. The dichloromethane is removed by filtration and vacuum rotary evaporation to obtain a yellow oily liquid. Finally, column chromatography purification (DCM / MeOH 20:1) is performed to obtain the target product tetracaine (7) (white solid, 112.3 mg, 85% yield). Column chromatography can select 200-300 mesh silica gel or alkaline alumina as the stationary phase, and the eluent is generally a mixed system of petroleum ether and ethyl acetate.

[0014] There are many reports on tetracaine hydrochloride and tetracaine, but they are mainly reports on synthesis, and there are few reports on its crystal form and specific crystal form preparation methods. In order to expand the raw material options available to formulation scientists when designing the drug, it is necessary to study and develop new preparation methods to obtain a tetracaine crystal form with good stability by precisely controlling the reaction conditions and reducing the impurity content. Summary of the invention

[0015] In view of the shortcomings of the prior art, the present invention aims to provide a method for preparing a tetracaine crystal form with good stability, which has a simple preparation process, low cost, high yield and is more suitable for industrial production. The present invention conducts a large number of experimental studies on tetracaine compounds and obtains a tetracaine crystal form with good stability through a simple and easy-to-operate preparation process, which has advantages in industrial production and is conducive to improving the overall performance of the pharmaceutical product (such as easy synthesis or processing, improved stability and shelf life).

[0016] The present invention is achieved through the following technical solutions:

[0017] The invention discloses a method for preparing a tetracaine crystal form, comprising the following steps: dispersing tetracaine in a solvent, and performing recrystallization to obtain the tetracaine crystal form, wherein the X-ray powder diffraction spectrum of the tetracaine crystal form has characteristic peaks at 2θ angles of 4.217±0.2°, 8.560±0.2°, 12.838±0.2°, and 17.120±0.2°; the solvent is a mixed solvent of a first solvent and a second solvent, wherein the first solvent is a mixture of one or more of acetone, methanol, ethanol, isopropanol, methyl tert-butyl ether, ether, tetrahydrofuran, n-hexane, and n-heptane, and the second solvent is water, wherein the mass ratio of the first solvent to the second solvent is 1:0 to 1:10.

[0018] Preferably, in the preparation method, the mass ratio of tetracaine to the first solvent is 1:1 to 1:8.

[0019] In some embodiments, the recrystallization operation in the preparation method is to raise the temperature until the tetracaine is dissolved, lower the temperature to below 25° C. for crystallization, separate and dry.

[0020] In some embodiments, the recrystallization operation in the preparation method is to heat the mixture until the tetracaine is dissolved, optionally add an adsorbent to decolorize and remove impurities, filter while hot, remove the second solvent, cool the obtained organic phase to below 25°C for crystallization, separate and dry; the adsorbent includes activated carbon.

[0021] Preferably, as a specific scheme, the preparation method comprises the following steps: dispersing tetracaine in n-hexane, heating until the tetracaine is dissolved, cooling to below 25°C by cooling by 5°C and stirring for 10 minutes, stirring and crystallizing, filtering and drying to obtain a tetracaine crystal form, wherein the X-ray powder diffraction pattern of the tetracaine crystal form has characteristic peaks at 2θ angles of 4.217±0.2°, 8.560±0.2°, 12.838±0.2°, and 17.120±0.2°; and the mass ratio of tetracaine to n-hexane is 1:1 to 1:8.

[0022] Preferably, as a specific scheme, the preparation method comprises the following steps: dispersing tetracaine in acetone and water, heating until the tetracaine is dissolved, cooling to 0-10°C, stirring and crystallizing, filtering and drying to obtain a tetracaine crystal form, wherein the X-ray powder diffraction pattern of the tetracaine crystal form has characteristic peaks at 2θ angles of 4.217±0.2°, 8.560±0.2°, 12.838±0.2°, and 17.120±0.2°; the mass ratio of acetone to water is 1:0-1:10, and the mass ratio of tetracaine to acetone is 1:1-1:8.

[0023] Preferably, as a specific scheme, the preparation method comprises the following steps: dispersing tetracaine in methyl tert-butyl ether, n-hexane and water, heating until the tetracaine is dissolved, adding an adsorbent to decolorize and remove impurities, filtering while hot, and then removing the second solvent, cooling the obtained organic phase to below 25°C, stirring and crystallizing, filtering and drying to obtain a tetracaine crystal form, wherein the X-ray powder diffraction pattern of the tetracaine crystal form has characteristic peaks at 2θ angles of 4.217±0.2°, 8.560±0.2°, 12.838±0.2°, and 17.120±0.2°; the mass ratio of the methyl tert-butyl ether, n-hexane, and water is 1:1-7:1-4, and the mass ratio of tetracaine to methyl tert-butyl ether and n-hexane is 1:1-3:3-9.

[0024] Compared with the prior art, the beneficial effects achieved by the present invention are: providing a method for preparing a tetracaine crystal with controllable quality, which is beneficial to improving the quality of drugs, and the preparation method has controllable operation, high yield, low cost, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the X-ray powder diffraction (XRD) pattern of the tetracaine crystalline form obtained in Example 1;

[0026] Figure 2 is the XRD pattern of the tetracaine crystal form obtained in Example 2;

[0027] Figure 3 is the XRD pattern of the tetracaine crystal form obtained in Example 3;

[0028] Figure 4 is the XRD pattern of the tetracaine crystal form obtained in Example 4;

[0029] Figure 5 is the XRD pattern of the tetracaine crystal form obtained in Example 5;

[0030] Figure 6 This is the XRD pattern of the tetracaine crystals obtained in Comparative Example 3. DETAILED DESCRIPTION

[0031] The present invention is further described in detail in conjunction with the following specific examples and drawings, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention does not specifically limit the content.

[0032] The crude tetracaine of the invention is obtained by ester exchange reaction between ethyl p-butylaminobenzoate and N,N-dimethylethanolamine under alkaline conditions, and has a purity of 98%.

[0033] Example 1 Preparation of Tetracaine Crystalline Form

[0034] 100 g of crude tetracaine was added to a 1L three-necked flask, and 200 g of n-hexane was added. The mixture was heated to 60-70°C to dissolve. The temperature was rapidly lowered (directly from the high temperature dissolving state to the 10°C system to cool and stir) to an internal temperature below 25°C. The mixture was stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 78 g of a white solid with a yield of 78% and a purity of 99.9%. The obtained solid was subjected to X-ray powder determination using Cu-ka rays. The XRD spectrum was as follows: Figure 1 As shown, there are diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles: 4.341, 8.599, 12.879, 15.898, 17.179, 19.258, 22.039, 25.299, 25.580, and 25.860.

[0035] Example 2 Preparation of Tetracaine Crystalline Form

[0036] 100 g of crude tetracaine was added to a 1L three-necked flask, and 200 g of n-hexane was added. The mixture was heated to 60-70°C to dissolve. The temperature was gradually reduced (5°C was reduced and the mixture was stirred for 10 min each time) until the internal temperature was below 25°C. The mixture was stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 83 g of a white solid with a yield of 83% and a purity of 99.9%. The obtained solid was subjected to X-ray powder determination using Cu-ka radiation, and its XRD pattern was as follows: Figure 2 As shown, there are diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles: 4.300, 8.560, 12.840, 15.819, 17.139, 19.161, 21.381, 21.941, 23.278, 23.622, 25.222, 25.499, and 25.837.

[0037] Example 3 Preparation of Tetracaine Crystalline Form

[0038] 100 g of tetracaine crude product was added to a 1L three-necked flask, 100 g of acetone was added and stirred to dissolve, 1000 g of purified water was added dropwise to crystallize, the temperature was lowered to 0-10°C, stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 64 g of white solid with a yield of 64% and a purity of 99.8%. The obtained solid was subjected to X-ray powder determination using Cu-ka rays, and its XRD spectrum was as follows: Figure 3As shown, there are diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles: 4.339, 8.598, 12.861, 15.840, 17.160, 19.221, 21.460, 21.980, 25.242, 25.539, and 25.859.

[0039] Example 4 Preparation of Tetracaine Crystalline Form

[0040] 100 g of crude tetracaine was added to a 1L three-necked flask, followed by 50 g of methyl tert-butyl ether and 150 g of n-hexane. The mixture was heated to 60-70°C to dissolve, and the temperature was gradually reduced to below 25°C. The mixture was stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 68 g of a white solid with a yield of 68% and a purity of 99.8%. The obtained solid was subjected to X-ray powder determination using Cu-ka radiation, and its XRD pattern was as follows: Figure 4 As shown, there are diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles: 4.356, 8.618, 12.899, 15.859, 17.199, 19.202, 21.481, 21.720, 22.000, 23.302, 23.680, 25.261, 25.540, and 25.880.

[0041] Example 5 Preparation of Tetracaine Crystalline Form

[0042] 2290g of crude tetracaine, 2290g of methyl tert-butyl ether, 14198g of n-hexane, and 4122g of water were added to a 100L reactor, heated until dissolved, 115g of activated carbon was added, and the mixture was heated to 50-55°C, filtered while hot, and the filtrate was separated. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was cooled to an internal temperature below 25°C, stirred for 0.5-1 hour, filtered, and dried to obtain 1877g of white solid with a yield of 82% and a purity of 99.9%. The obtained solid was subjected to X-ray powder determination using Cu-ka rays, and its XRD spectrum was as follows: Figure 5 As shown, there are diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles: 4.320, 8.578, 12.857, 17.140, 19.219, 21.959, 25.192, and 25.501.

[0043] Example 6 Preparation of Tetracaine Crystalline Form

[0044] 100 g of tetracaine crude product was added to a 1L three-necked flask, 100 g of ether was added and stirred to dissolve, 600 g of purified water was added dropwise to crystallize, the temperature was lowered to 0-10°C, stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 80 g of white solid with a yield of 80% and a purity of 99.2%. The obtained solid was subjected to X-ray powder determination using Cu-ka rays, and its XRD spectrum was consistent with that in Example 1.

[0045] Example 7 Preparation of Tetracaine Crystalline Form

[0046] 100 g of tetracaine crude product was added to a 1L three-necked flask, 100 g of tetrahydrofuran was added and stirred to dissolve, 500 g of purified water was added dropwise to crystallize, the temperature was lowered to 0-10°C, stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 81 g of a white solid with a yield of 81% and a purity of 99.5%. The obtained solid was subjected to X-ray powder determination using Cu-ka rays, and its XRD spectrum was consistent with that in Example 1.

[0047] Comparative Example 1: Refining of tetracaine

[0048] 100 g of crude tetracaine was added to a 3L three-necked flask, 1500 g of n-hexane was added, and the mixture was heated to 60-70 ° C to dissolve. The temperature was gradually reduced to below 25 ° C, stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 34 g of a white solid with a yield of 34% and a purity of 99.1%. The obtained solid was subjected to X-ray powder determination using Cu-ka rays, and its XRD spectrum was consistent with that in Example 1.

[0049] Comparative Example 2: Refining of Tetracaine

[0050] 100 g of tetracaine crude product was added to a 2L three-necked flask, 500 g of methyl tert-butyl ether and 500 g of n-hexane were added, and the mixture was heated to 60-70°C to dissolve, and the temperature was gradually reduced to below 25°C, and the mixture was stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 42 g of a white solid with a yield of 42% and a purity of 100%. The obtained solid was subjected to X-ray powder determination using Cu-ka rays, and its XRD pattern was consistent with that in Example 1.

[0051] Comparative Example 3 Preparation of Tetracaine Crystalline Form

[0052] 100 g of tetracaine crude product was added to a 3L three-necked flask, 100 g of acetone was added and stirred to dissolve, 2000 g of purified water was added dropwise to crystallize, the temperature was lowered to 0-10°C, stirred for 0.5-1 hour, filtered, and the filter cake was dried to obtain 90 g of white solid with a yield of 90% and a purity of 99.3%. The obtained solid was subjected to X-ray powder determination using Cu-ka ray, and its XRD pattern was as follows: Figure 6As shown, it has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angles: 4.301, 8.576, 12.856, 14.320, 15.819, 16.139, 17.120, 18.780, 19.179, 20.919, 21.681, 21.959, 23.278, 23.620, 25.499, 25.960.

[0053] Test Example 1 Evaluation of the stability of tetracaine crystals

[0054] The stability of the tetracaine obtained in each embodiment and comparative example was studied. The samples were placed under different conditions for sampling, and the stability of the impurity content and the crystal state was detected. The results are shown in Table 1. The preparation method provided by the present invention is simple, and the obtained tetracaine crystal has good stability, is not easy to crystallize or produce impurities under high humidity and high temperature conditions, is convenient for long-term storage of drugs, can well avoid crystallization and degradation impurities in the process of drug development, thereby avoiding changes in bioavailability and efficacy, and has strong economic value.

[0055] Table 1 Stability test results

[0056]

[0057]

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the technical principles of the present invention, and these improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing a tetracaine crystal form, characterized in that: The preparation method comprises the following steps: dispersing tetracaine in a solvent, and performing recrystallization to obtain a tetracaine crystal form, wherein the X-ray powder diffraction spectrum of the tetracaine crystal form has characteristic peaks at 2θ angles of 4.217±0.2°, 8.560±0.2°, 12.838±0.2°, and 17.120±0.2°; the solvent is a mixed solvent of a first solvent and a second solvent, wherein the first solvent is a mixture of one or more of acetone, methanol, ethanol, isopropanol, methyl tert-butyl ether, ether, tetrahydrofuran, n-hexane, and n-heptane, and the second solvent is water, wherein the mass ratio of the first solvent to the second solvent is 1:0 to 1:

10.

2. The preparation method according to claim 1, characterized in that: In the preparation method, the mass ratio of tetracaine to the first solvent is 1:1 to 1:

8.

3. The preparation method according to claim 1, characterized in that: The recrystallization operation in the preparation method is to raise the temperature until the tetracaine is dissolved, lower the temperature to below 25° C. for crystallization, separate and dry.

4. The preparation method according to claim 1, characterized in that: The recrystallization operation in the preparation method is to heat up until the tetracaine is dissolved, optionally add an adsorbent to decolorize and remove impurities, filter while hot, then remove the second solvent, cool the obtained organic phase to below 25°C for crystallization, separate and dry; the adsorbent includes activated carbon.

5. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: dispersing tetracaine in normal hexane, heating until the tetracaine is dissolved, cooling to below 25°C by cooling by 5°C and stirring for 10 minutes, stirring and crystallizing, filtering and drying to obtain a tetracaine crystal form, wherein the X-ray powder diffraction spectrum of the tetracaine crystal form has characteristic peaks at 2θ angles of 4.217±0.2°, 8.560±0.2°, 12.838±0.2° and 17.120±0.2°; and the mass ratio of tetracaine to normal hexane is 1:1 to 1:

8.

6. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: dispersing tetracaine in acetone and water, heating until the tetracaine is dissolved, cooling to 0-10°C, stirring and crystallizing, filtering and drying to obtain a tetracaine crystal form, wherein an X-ray powder diffraction spectrum of the tetracaine crystal form has characteristic peaks at 2θ angles of 4.217±0.2°, 8.560±0.2°, 12.838±0.2° and 17.120±0.2°; the mass ratio of acetone to water is 1:0-1:10, and the mass ratio of tetracaine to acetone is 1:1-1:

8.

7. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: dispersing tetracaine in methyl tert-butyl ether, n-hexane and water, heating until the tetracaine is dissolved, adding an adsorbent for decolorization and impurity removal, filtering while hot, removing the second solvent, cooling the obtained organic phase to below 25°C, stirring and crystallizing, filtering and drying to obtain a tetracaine crystal form, wherein the X-ray powder diffraction spectrum of the tetracaine crystal form has characteristic peaks at 2θ angles of 4.217±0.2°, 8.560±0.2°, 12.838±0.2° and 17.120±0.2°; The mass ratio of methyl tert-butyl ether, n-hexane and water is 1:1-7:1-4, and the mass ratio of tetracaine to methyl tert-butyl ether and n-hexane is 1:1-3:3-9.

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