Preparation method of high-purity polidocanol

Abstract

The present invention discloses a method for preparing high-purity polidocanol, which includes a polymerization reaction of lauryl alcohol and ethylene oxide under the action of a catalyst potassium tert-butoxide or sodium tert-butoxide to obtain polidocanol; by optimizing the type of catalyst, the generation of side reaction products such as polyethylene glycol, ethylene glycol, and diethylene glycol during the polymerization reaction is reduced. The resulting polidocanol has a narrower molecular weight distribution effect than the reference preparation, and the impurity level is significantly lower than that of the reference preparation, meeting the standards of the United States Pharmacopeia.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation method of polidocanol, and particularly relates to a preparation method of high-purity polidocanol. Background Art

[0002] Polidocanol, also known as lauromacrogol and polyoxyethylene lauryl ether, has the molecular formula C 12 H 25 (OCH2CH2) n OH (n≈9), and is a mixture composed of a combination of polymerization degrees n = 1 to n = 24. Its structural formula is as follows. Polidocanol is a surface-active amphiphilic molecular sclerosing agent. The currently marketed dosage form is an injection, which is used for the sclerosis of central veins, reticular veins and small varicose veins of spider-like veins.

[0003]

[0004] The preparation process of polidocanol is mainly the polymerization of starting materials lauryl alcohol and ethylene oxide under the condition of an alkaline catalyst. The reaction formula is as follows. For example, Patent CN1762948A discloses the preparation process of polidocanol: using sodium hydroxide as a catalyst, lauryl alcohol and ethylene oxide polymerize at 140 - 155 °C, cool down, and add acetic acid to adjust the pH to obtain polidocanol. However, subsequent patents such as CN103922901A and others point out that the impurity content of the polidocanol prepared by this method does not meet the quality standards of the European Pharmacopoeia.

[0005]

[0006] Regarding the impurity problem of polidocanol, the prior art mainly reduces the impurity content through the purification of the reactant lauryl alcohol or the product polidocanol. For example, patents such as CN104649863A, CN113200821A, and CN113527060A purify the reactant lauryl alcohol by methods such as vacuum distillation, rectification, and recrystallization to reduce the impurities introduced by the reactants, thereby reducing the impurity content of the product; Patent CN103922901A purifies the product polidocanol by two-stage vacuum distillation to reduce the impurity content of the product. However, increasing the purification process of the reactants or products complicates the preparation process of polidocanol.

[0007] In addition, the prior art has also disclosed a method for reducing the impurity content by optimizing the polymerization reaction conditions of lauryl alcohol and ethylene oxide. For example, Patent CN102276429A reduces the generation of side reaction impurities and thus the impurity content of the product by controlling the water content in the mixture of reactant lauryl alcohol and basic catalyst to be less than 0.1 wt%. However, the requirement of the dehydration step for the water content to be less than 0.1 wt% is too harsh. Especially in the southern regions with high humidity, it is very difficult to reduce the water content below the standard, resulting in a large amount of energy consumption and cost increase.

[0008] The present invention aims to reduce the generation of side reaction impurities and thus the impurity content of the product by optimizing the type of catalyst in the polymerization reaction conditions of lauryl alcohol and ethylene oxide.

[0009] Patent CN115160557A discloses a method for preparing polidocanol, using a solid base catalyst to catalyze the reaction of lauryl alcohol and ethylene oxide. However, its function is to prepare polidocanol mainly composed of nonamer compounds and with a uniform distribution of other polymers, rather than to reduce the impurity content of the product. As far as the inventor knows, no relevant technical inspiration is given by other prior arts either.

[0010] In summary, on the basis of not increasing the refining process, how to optimize the type of catalyst in the polymerization reaction of lauryl alcohol and ethylene oxide to reduce the impurity content of the product is a technical problem that has not been solved in the art. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a method for preparing high-purity polidocanol, which, on the basis of not increasing the refining process, reduces the impurity content of the product by optimizing the type of catalyst in the polymerization reaction of lauryl alcohol and ethylene oxide.

[0012] To solve the above technical problem, the present invention adopts the following technical solutions:

[0013] The present invention provides a method for preparing high-purity polidocanol, and the reaction route is as follows:

[0014]

[0015] The reaction steps include: lauryl alcohol and ethylene oxide undergo a polymerization reaction under the action of a catalyst potassium tert-butoxide or sodium tert-butoxide to obtain polidocanol.

[0016] Preferably, the molar ratio of lauryl alcohol to potassium tert-butoxide or sodium tert-butoxide is 1:(0.06 - 0.2).

[0017] More preferably, the molar ratio of lauryl alcohol to potassium tert-butoxide or sodium tert-butoxide is 1:(0.09 - 0.11).

[0018] Preferably, the mass ratio of lauryl alcohol to ethylene oxide is 1:(1.8 - 2.2).

[0019] More preferably, the mass ratio of lauryl alcohol to ethylene oxide is 1:2.

[0020] Preferably, the polymerization reaction temperature range is 110 - 160 °C.

[0021] More preferably, the polymerization reaction temperature is 120 °C.

[0022] The present invention provides a method for preparing high-purity polidocanol, comprising the following steps:

[0023] (1) Lauryl alcohol and potassium tert-butoxide or sodium tert-butoxide are added to an autoclave in a molar ratio of 1:(0.06 - 0.2), stirred, and evacuated.

[0024] (2) Ethylene oxide is introduced, the temperature of the autoclave is set at 110 - 160 °C, and the pressure is maintained not exceeding 0.5 MPa.

[0025] (3) After completely introducing 1.8 - 2.2 times the mass of lauryl alcohol of ethylene oxide, the temperature is maintained and stirring is continued until the pressure tends to be stable.

[0026] (4) The temperature of the autoclave is lowered to room temperature, acid is added for neutralization, water is removed, and filtration is carried out to obtain polidocanol.

[0027] Preferably, in step (2), the addition method of ethylene oxide is to introduce it in batches, and the mass of each batch introduced is 15 - 35% of the mass of lauryl alcohol.

[0028] More preferably, in step (2), the addition method of ethylene oxide is to first introduce 30 - 35% of the mass of lauryl alcohol of ethylene oxide to initiate the reaction, and then add ethylene oxide in batches, with the mass of each batch introduced being 15 - 23% of the mass of lauryl alcohol.

[0029] Those skilled in the art can know that ethylene oxide can be added by continuous introduction, batch introduction, etc. The choice of the addition method and the addition amount should not cause the pressure in the autoclave to be too high, and generally the pressure is controlled not to exceed 0.5 MPa.

[0030] Preferably, step (2) further includes an initiation reaction, and the initiation reaction temperature is 35 - 60 °C.

[0031] More preferably, step (2) further includes an initiation reaction, the temperature of the autoclave is raised to 35 - 60 °C, and 30 - 35% of the mass of lauryl alcohol of ethylene oxide is introduced to initiate the reaction.

[0032] Those skilled in the art can know that, considering safety and controlling the reaction rate, a low-temperature initiation reaction can be adopted in the early stage of the polymerization reaction.

[0033] Preferably, in step (4), the pH value is adjusted to 5-7 by adding acid for neutralization. There is no special limitation on the type of acid used for pH adjustment, and hydrochloric acid, acetic acid, phosphoric acid, etc. can all be used.

[0034] Preferably, the water removal method in step (4) includes, but is not limited to, one or more of filtration for water removal, vacuum pumping for water removal, and adding desiccants. There is no special limitation on the water removal method for a small amount of water in the product polidocanol. Filtration for water removal includes filtration with diatomaceous earth, ion exchange resin or molecular sieve; vacuum pumping for water removal includes vacuum distillation at a temperature of 60-120°C; adding desiccants includes anhydrous magnesium sulfate, anhydrous sodium sulfate, etc.

[0035] Most preferably, it includes the following steps:

[0036] (1) Add lauryl alcohol and potassium tert-butoxide or sodium tert-butoxide to the autoclave in a molar ratio of 1:(0.09-0.11), stir, and evacuate.

[0037] (2) Heat the autoclave to 35-60°C, introduce ethylene oxide accounting for 30-35% of the mass of lauryl alcohol to initiate the reaction, set the temperature of the autoclave at 110-160°C, add ethylene oxide in batches, with each batch accounting for 15-23% of the mass of lauryl alcohol, and keep the pressure not exceeding 0.5 MPa.

[0038] (3) After completely introducing ethylene oxide twice the mass of lauryl alcohol, keep the temperature and continue stirring until the pressure tends to be stable.

[0039] (4) Cool the temperature of the autoclave to room temperature, add acid for neutralization to adjust the pH value to 5-7, remove water, and filter to obtain polidocanol.

[0040] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0041] 1. For the preparation method of polidocanol of the present invention, potassium tert-butoxide or sodium tert-butoxide is used as a catalyst to catalyze the polymerization reaction of lauryl alcohol and ethylene oxide. The present invention avoids the dehydration step which is difficult to achieve and energy-consuming in CN102276429A. Instead, by optimizing the type of catalyst, the generation of side reaction products (such as polyethylene glycol, ethylene glycol, diethylene glycol, etc.) during the polymerization reaction is reduced. The polidocanol obtained has a narrower molecular weight distribution effect than the reference preparation, and the impurity level is significantly lower than that of the reference preparation, meeting the standards of the United States Pharmacopeia.

[0042] 2. On the basis of optimizing the type of catalyst, the present invention further optimizes the polymerization reaction temperature to 110-160°C, especially 120°C. The impurity level of the polidocanol obtained is further reduced: the content of polyethylene glycol is only 0.12%, ethylene glycol and diethylene glycol are not detected, and the total impurity content is only 0.27%.

[0043] 3. The high-purity polidocanol prepared by the preparation method of the present invention has good stability and is not easily degraded at room temperature. By optimizing the preparation method, the problem of poor stability of the polidocanol product prepared by the existing process described in the background art of CN113527060A is solved, so as to reduce the storage difficulty and storage cost and improve the quality of the polidocanol product. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 It is the test result of the molecular weight distribution and impurity content of the polidocanol obtained in Example 1;

[0045] Figure 2 It is the test result of the molecular weight distribution and impurity content of the polidocanol obtained in Example 2;

[0046] Figure 3 It is the test result of the molecular weight distribution and impurity content of the polidocanol obtained in Example 3;

[0047] Figure 4 It is the test result of the molecular weight distribution and impurity content of the polidocanol obtained in Example 4;

[0048] Figure 5 It is the test result of the molecular weight distribution and impurity content of the polidocanol obtained in Example 5;

[0049] Figure 6 It is the test result of the molecular weight distribution and impurity content of the polidocanol obtained in Example 6;

[0050] Figure 7 It is the test result of the molecular weight distribution and impurity content of the polidocanol obtained in Example 7;

[0051] Figure 8 It is the test result of the molecular weight distribution and impurity content of the polidocanol for the 30-day stability investigation at high temperature in Example 9;

[0052] Figure 9 It is the test result of the molecular weight distribution and impurity content of the polidocanol for the 6-month accelerated stability investigation in Example 9;

[0053] Figure 10 It is the test result of the molecular weight distribution and impurity content of the polidocanol of Anshuxi. DETAILED DESCRIPTION OF THE INVENTION

[0054] The technical solutions of the present invention will be further described below with reference to the drawings and embodiments. However, the protection scope of the present invention includes but is not limited to these embodiments, and any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0055] The instruments and reagents used in the embodiments of the present invention are all commercially available products. By way of example, the model and manufacturer information of some reagents are as follows:

[0056] Reagents:

[0057] Lauryl alcohol (model: analytical grade, manufacturer: McLean);

[0058] Potassium tert-butoxide (model: analytical grade, manufacturer: Anaiji);

[0059] Sodium tert-butoxide (model: analytical grade, manufacturer: Aladdin);

[0060] Sodium methoxide (model: analytical grade, manufacturer: Maclean);

[0061] Ansuxi (Specification: 10 mg / vial, manufacturer: Chemische Fabrik Kreussler&Co.GmbH).

[0062] Example 1

[0063] (1) At room temperature, 200 g of lauryl alcohol and 11±1 g of potassium tert-butoxide were added to a 1 L stainless steel autoclave, the speed was set to 400 r / min, and the vacuum was evacuated to below -0.09 MPa.

[0064] (2) Heat the autoclave to 35-60°C, introduce 65±5g of ethylene oxide to initiate the reaction, set the autoclave temperature to 120°C, add ethylene oxide in multiple batches, add 30-45g each batch, and maintain the pressure not exceeding 0.5MPa.

[0065] (3) After 400±3 g of ethylene oxide is completely introduced, the temperature is maintained and stirring is continued for 30 min.

[0066] (4) The temperature of the autoclave was lowered to room temperature, and 15% hydrochloric acid solution was added to adjust the pH to 6. The temperature was controlled at 100°C, and the vacuum degree was lower than -0.9 MPa for 1 h. The mixture was filtered through a 0.22 μm filter membrane to obtain polydocanol.

[0067] The obtained polydocanol was 591.1 g, with a yield of 98.5%.

[0068] Example 2-3 Polymerization Reaction Temperature Investigation

[0069] Based on Example 1, the effects of polymerization reaction temperatures of 110°C (Example 2) and 160°C (Example 3) on the impurity content of the product polydocanol were investigated. The investigation process is as follows:

[0070] Example 2: The difference from Example 1 is that the temperature is maintained at 110°C in step (2).

[0071] Example 3: The difference from Example 1 is that the temperature is maintained at 160°C in step (2).

[0072] Example 4-7 Investigation of the Types of Polymerization Reaction Catalysts

[0073] On the basis of Examples 2-3, the effects of the types of polymerization reaction catalysts, sodium tert-butoxide (Examples 4-5) and sodium methoxide (Examples 6-7), on the impurity content of the product polidocanol were investigated. The investigation process is as follows:

[0074] Example 4: The difference from Example 2 is that in step (1), 200 g of lauryl alcohol and 9.5 g of sodium tert-butoxide were added to a 1 L stainless steel autoclave.

[0075] Example 5: The difference from Example 3 is that in step (1), 200 g of lauryl alcohol and 9.5 g of sodium tert-butoxide were added to a 1 L stainless steel autoclave.

[0076] Example 6: The difference from Example 2 is that in step (1), 200 g of lauryl alcohol and 6 g of sodium methoxide were added to a 1 L stainless steel autoclave.

[0077] Example 7: The difference from Example 3 is that in step (1), 200 g of lauryl alcohol and 6 g of sodium methoxide were added to a 1 L stainless steel autoclave.

[0078] Example 8 Detection Results of the Molecular Weight Distribution and Impurity Content of Polidocanol

[0079] The polidocanol obtained from the above Examples 1-7 and the lyophilized reference preparation Anshuxi were subjected to detection of molecular weight distribution and impurity content. The detection method referred to the detection method of the United States Pharmacopoeia and the gas phase detection method of Patent CN114740103A.

[0080] The detection results are as Figure 1-7 shown in Figures 8 and 9 and Tables 1-2:

[0081] Table 1 Detection Results of the Molecular Weight Distribution of Polidocanol (%)

[0082]

[0083] Note: En represents the polymerization of n ethylene oxides with lauryl alcohol.

[0084] Table 2 Detection Results of the Impurity Content of Polidocanol (%)

[0085] Category Lauryl alcohol Polyethylene glycol Ethylene glycol Diethylene glycol Total impurities USP standard 0.95～2.70％ ≤0.6％ ≤0.15％ ≤0.15％ ≤1.0％ EP standard ≤2.0％ ≤3.0％ / / / Example 1 1.81 0.12 ND ND 0.27 Example 2 1.78 0.26 ND 0.06 0.49 Example 3 1.72 0.34 0.03 0.06 0.63 Example 4 1.68 0.26 ND 0.05 0.47 Example 5 1.77 0.34 ND 0.05 0.65 Example 6 12.11 2.36 0.17 0.14 5.62 Example 7 1.99 9.05 0.19 0.15 10.81 Anshuxi 1.88 1.07 ND 0.06 1.95

[0086] Note: Total impurities do not include lauryl alcohol.

[0087] The test results show that: ① The preferred catalyst types are potassium tert-butoxide or sodium tert-butoxide (Examples 1-5). Compared with other metal alkoxide catalysts such as sodium methoxide (Examples 6-7), they have the technical effect of significantly reducing the content of single impurities (polyethylene glycol, ethylene glycol, diethylene glycol, etc.) and total impurities in the product. The impurity level is significantly lower than that of the reference preparation Anshuxi and meets the standards of the United States Pharmacopeia.

[0088] ② Further optimize the polymerization reaction temperature to 120 °C (Example 1), and the technical effect of the content of single impurities (polyethylene glycol, ethylene glycol, diethylene glycol, etc.) and total impurities in the obtained product is the best.

[0089] Results of stability study of Example 9

[0090] The polidocanol obtained in Example 1 was sealed in a soda-lime glass bottle without inert gas protection and subjected to stability studies under high-temperature conditions (60 °C) and accelerated conditions (40 °C ± 2 °C, 75% RH ± 5% RH). Molecular weight distribution and impurity content were detected, and the detection methods referred to the detection methods of the United States Pharmacopeia and the gas-phase detection method of Patent CN114740103A.

[0091] The test results are as Figure 1 、 8 shown in Table 3-9 and Table 3-4:

[0092] Table 3 Detection results of polidocanol molecular weight distribution (%)

[0093]

[0094] Table 4 Detection results of polidocanol impurity content (%)

[0095] Category Lauryl alcohol Polyethylene glycol Ethylene glycol Diethylene glycol Total impurities Example 1 - 0 days 1.81 0.12 ND ND 0.27 Example 1 - 30 days at high temperature 1.80 0.51 0.02 0.06 0.81 Example 1 - 6 months of acceleration 1.82 0.58 N / A 0.05 0.80

[0096] The investigation results show that the polidocanol obtained in Example 1 has good stability. During the 30-day stability study under high-temperature conditions and the 6-month stability study under accelerated conditions, the content of single impurities (polyethylene glycol, ethylene glycol, diethylene glycol, etc.) and total impurities did not increase significantly, and the impurity level is still significantly lower than that of the reference preparation Anshuxi and meets the standards of the United States Pharmacopeia.

Claims

1. A method for preparing polydocanol, the reaction steps comprising: Lauryl alcohol and ethylene oxide undergo a polymerization reaction under the action of a catalyst, potassium tert-butoxide or sodium tert-butoxide, to produce polydocanol; the molar ratio of lauryl alcohol: potassium tert-butoxide or sodium tert-butoxide is 1: (0.06 ~ 0.2).

2. The method for preparing polydocanol according to claim 1, characterized in that: The molar ratio of lauryl alcohol to potassium tert-butoxide or sodium tert-butoxide is 1: (0.09-0.11).

3. The method for preparing polydocanol according to claim 1 or 2, characterized in that: In the polymerization reaction, the mass ratio of lauryl alcohol:ethylene oxide is 1:(1.8 ~ 2.2).

4. The method for preparing polydocanol according to claim 3, characterized in that: The mass ratio of lauryl alcohol to ethylene oxide is 1:

2.

5. The method for preparing polydocanol according to claim 1 or 2, characterized in that: In the polymerization reaction, the polymerization reaction temperature ranges from 110 to 160°C.

6. The method for preparing polydocanol according to claim 5, characterized in that: The polymerization reaction temperature is 120°C.

7. The method for preparing polydocanol according to claim 1 or 2, characterized in that: In the polymerization reaction, the mass ratio of lauryl alcohol to ethylene oxide is 1:(1.8-2.2), and the polymerization reaction temperature ranges from 110-160°C.

8. The method for preparing polydocanol according to claim 7, characterized in that: The mass ratio of lauryl alcohol to ethylene oxide is 1:2, and the polymerization reaction temperature range is 120°C.

9. A method for preparing polydocanol, comprising the following steps: (1) Add lauryl alcohol and potassium tert-butoxide or sodium tert-butoxide in a molar ratio of 1: (0.06 to 0.2) into an autoclave, stir, and evacuate; (2) Add ethylene oxide, set the autoclave temperature to 110-160°C, and maintain the pressure at no more than 0.5 MPa; (3) After completely introducing ethylene oxide in an amount of 1.8 to 2.2 times the mass of lauryl alcohol, maintain the temperature and continue stirring until the pressure tends to stabilize; (4) Lower the temperature of the autoclave to room temperature, add acid for neutralization, remove water, and filter to obtain polydocanol.

10. The method for preparing polydocanol according to claim 9, characterized in that: In the step (2), the ethylene oxide is added in batches, and the mass of each batch is 15-35% of the mass of lauryl alcohol.

11. The method for preparing polydocanol according to claim 9, characterized in that: The step (2) further comprises initiating a reaction, wherein the initiating reaction temperature is 35-60°C.

12. The method for preparing polydocanol according to claim 9, characterized in that: In step (4), acid is added for neutralization to adjust the pH value to a range of 5 to 7.

13. The method for preparing polydocanol according to claim 9, characterized in that: The dehydration method in step (4) is selected from one or more of filtration dehydration, vacuum dehydration, and adding a desiccant.

14. A method for preparing polydocanol, comprising the following steps: (1) Add lauryl alcohol and potassium tert-butoxide or sodium tert-butoxide in a molar ratio of 1: (0.09 to 0.11) into an autoclave, stir, and evacuate; (2) Heat the autoclave to 35-60°C, introduce ethylene oxide at a mass ratio of 30-35% of the mass of lauryl alcohol to initiate the reaction, set the autoclave temperature at 110-160°C, add ethylene oxide in batches, with each batch introducing 15-23% of the mass of lauryl alcohol, and maintain the pressure at no more than 0.5 MPa; (3) After completely introducing ethylene oxide in an amount twice the mass of lauryl alcohol, maintain the temperature and continue stirring until the pressure tends to stabilize; (4) Lower the temperature of the autoclave to room temperature, add acid to neutralize and adjust the pH to 5-7, remove water, and filter to obtain polydocanol.

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