A process for the preparation of hydroxypropyl-beta-cyclodextrin

Abstract

The application belongs to the technical field of medicine preparation, and discloses a preparation method of hydroxypropyl-beta-cyclodextrin, wherein sodium hydroxide solution is prepared according to the substitution degree requirement of a product, beta-cyclodextrin is added into the sodium hydroxide solution and dissolved, the solution is cooled to 15-18 DEG C at a speed of 2-4 DEG C / min and kept at constant temperature for 10-20 min, then propylene oxide is added dropwise, after the dropwise addition is completed, the solution is heated to 20-25 DEG C at a speed of 0.2-1 DEG C / min and maintained for 20-40 min, then the solution is heated to 30 DEG C at a speed of 0.5-2 DEG C / min and kept at constant temperature, then the solution is reacted for 10-47 h according to the substitution degree requirement of the product and the mass concentration of the sodium hydroxide solution selected in step 1, so that the aqueous solution of the target product, hydroxypropyl-beta-cyclodextrin, is obtained. The application has the advantages of simple process, high purity of the prepared hydroxypropyl-beta-cyclodextrin, wide substitution degree, stable average substitution degree of the product, good solubilization effect of the hydroxypropyl-beta-cyclodextrin with the same substitution degree, and good process repeatability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for preparing hydroxypropyl-β-cyclodextrin. Background Technology

[0002] β-Cyclodextrin is a cyclic oligosaccharide composed of 7 glucose molecules linked together. It has a cone-shaped shape, and its cone-shaped structure results in hydrophobicity inside the cavity and hydrophilicity outside the cavity. Encapsulating cyclodextrin as the host molecule with guest molecules can increase the solubility of the guest molecule.

[0003] Because cyclodextrin itself has low solubility, its use as a solubilizer is very limited. By modifying it to introduce new functional groups and increase its hydrophilicity, hydroxypropyl-β-cyclodextrin is one of the cyclodextrin derivatives after modification. Modified hydroxypropyl-β-cyclodextrin has greater water solubility in water and is widely used in pharmaceuticals, food and environmental protection. In particular, as a pharmaceutical excipient, it can improve the water solubility and increase the stability of drugs.

[0004] Currently, the synthesis of hydroxypropyl-β-cyclodextrin can use either propylene oxide or epichlorohydrin as condensing agents. Studies have shown that using propylene oxide as the condensing agent yields a significantly higher product yield than using epichlorohydrin. This is because epichlorohydrin is a crosslinking agent that forms the cyclodextrin polymer. Under alkaline room temperature conditions, besides a small amount of HP-β-CD being formed, most of the product is converted into a water-soluble low-molecular-weight polymer (MW 3000-6000) (China Pharmaceutical Guide, Synthesis and Characterization of Hydroxypropyl-β-Cyclodextrin, 2010, Vol. 36, pp. 30-31+51). Article number: 1673-7210 (2010) 12 (c)-030-03), therefore, propylene oxide is mainly used as a condensing agent in production. However, the boiling point of propylene oxide is 34℃, and the lowest reaction temperature of the existing production process is 35℃~37℃, and the temperature will rise to 55℃~65℃ during the reaction (a method for preparing an aqueous solution of hydroxypropyl-β-cyclodextrin, patent number CN202010633981.9). The temperature required by this process exceeds the required temperature. The boiling point of propylene oxide is not specified, and the lack of a propylene oxide condensation and recovery method greatly contributes to the volatilization of propylene oxide, making it unusable and increasing its usage. This leads to increased raw material costs, and experimental comparisons show that its solubilizing effect on drugs is poor. Furthermore, although the process eliminates the use of acid by adjusting the amount of sodium hydroxide, the adjusted amount of sodium hydroxide is too small, resulting in a high residual amount of betacyclodextrin in the obtained hydroxypropyl betacyclodextrin, which does not meet the content limits stipulated in the pharmacopoeia. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing hydroxypropyl-β-cyclodextrin. This method is simple and maximizes the use of propylene oxide by controlling the reaction temperature, ensuring that the maximum reaction temperature does not exceed the boiling point of propylene oxide (34°C). Compared with existing processes, the process conditions of the present invention are simple, the obtained hydroxypropyl-β-cyclodextrin has a wide range of substitution degrees, the substitution degree of hydroxypropyl-β-cyclodextrin is stable under fixed process conditions, the hydroxypropyl-β-cyclodextrin under the same average substitution degree conditions has a good solubilizing effect on drugs, the residual content of β-cyclodextrin is low, and the obtained hydroxypropyl-β-cyclodextrin has high purity.

[0006] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows:

[0007] A method for preparing hydroxypropyl-β-cyclodextrin includes the following steps:

[0008] 1. Dissolve sodium hydroxide in water to prepare a sodium hydroxide solution with a mass concentration of 2% to 12% according to the product substitution degree requirements. Add β-cyclodextrin to the sodium hydroxide solution and dissolve it, wherein the molar ratio of sodium hydroxide to β-cyclodextrin is 10:1, to obtain a β-cyclodextrin solution.

[0009] 2. Cool the β-cyclodextrin solution obtained in step 1 to 15℃~18℃ at a rate of 2℃~4℃ / min, and maintain the temperature for 10~20min;

[0010] 3. Add propylene oxide dropwise to the β-cyclodextrin solution in step 2, with a molar ratio of cyclodextrin to propylene oxide of 1:14 and a dropping rate of 150–200 g / h. After the dropping is completed, raise the temperature of the solution to 20–25°C at a rate of 0.2–1°C / min and maintain it for 20–40 min. On the one hand, the lower temperature inhibits the volatilization of propylene oxide, and on the other hand, it can fully dissolve propylene oxide in water, which is conducive to the reaction between propylene oxide and β-cyclodextrin.

[0011] 4. The solution obtained in step 3 is heated to 30°C at a rate of 0.5–2°C / min and kept constant. The reaction is carried out for 10–47 h according to the product substitution degree requirements and the mass concentration of sodium hydroxide solution selected in step 1, to obtain an aqueous solution of hydroxypropyl-β-cyclodextrin required for the target product.

[0012] Preferably, the mass concentration of the sodium hydroxide solution in step 1 is selected according to the required degree of substitution of hydroxypropyl-β-cyclodextrin; for low-substituted hydroxypropyl-β-cyclodextrin, a low mass concentration of sodium hydroxide solution is selected.

[0013] Preferably, in step 2, the cooling rate is controlled at 4°C / min; the temperature is reduced to 15°C and maintained for 10 minutes.

[0014] Preferably, in step 3, the propylene oxide droplet addition process is carried out at a constant temperature of 15°C, and after the droplet addition is completed, the temperature is controlled to rise to 20°C at a rate of 0.5°C / min.

[0015] Preferably, the dropping rate of propylene oxide in step 3 is 180 g / h.

[0016] Preferably, in step 4, the solution temperature is increased to 30°C at a rate of 1°C / min.

[0017] Preferably, the reaction time in step 4 is adjusted according to the degree of substitution of the target product; the lower the degree of substitution of β-cyclodextrin, the shorter the reaction time. More preferably, the reaction time for products with a low degree of substitution (3.5–5.0) is controlled between 12 and 24 hours; the reaction time for products with a medium degree of substitution (5.0–6.0) is controlled between 24 and 48 hours; and the reaction time for products with a high degree of substitution (above 6.0) is greater than 48 hours.

[0018] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0019] This invention controls the reaction temperature and corresponding reaction time in multiple stages, keeping the maximum reaction temperature below the boiling point of propylene oxide (34°C), thus reducing the volatilization loss of propylene oxide and achieving cost savings and energy conservation. The resulting hydroxypropyl beta-cyclodextrin has a wide range of substitution degrees, and the substitution degree of hydroxypropyl-β-cyclodextrin is stable under relevant process conditions. Under the same substitution degree conditions, hydroxypropyl-β-cyclodextrin has a good solubilizing effect on drugs, low β-cyclodextrin residual content, and high purity.

[0020] In summary, compared with current production processes, the present invention is simpler, produces hydroxypropyl-β-cyclodextrin with high purity, and can be used to produce hydroxypropyl beta-cyclodextrin with different degrees of substitution (wide range of substitution). Hydroxypropyl-β-cyclodextrin with the same degree of substitution has good solubilizing effect and good process repeatability. Attached Figure Description

[0021] Figure 1 The substitution degree curves of hydroxypropyl-β-cyclodextrin under different alkali concentrations in Examples 1-6 of this invention are shown. Detailed Implementation

[0022] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0023] Example 1

[0024] Dissolve 46.5g of sodium hydroxide in 2279.3g of water to prepare a 2% sodium hydroxide solution. Dissolve 150g of β-cyclodextrin in the alkaline solution. Place the alkaline solution of β-cyclodextrin in a low-temperature constant-temperature circulator and set a cooling program at a cooling rate of 2℃ / min until the temperature drops to 18℃, then maintain this temperature for 10min. Then, add 94.6g of propylene oxide dropwise at a rate of 200g / h. After the propylene oxide is added, set the temperature program to increase the temperature to 25℃ at a rate of 1℃ / min and maintain this temperature for 20min. Finally, set the temperature program to increase the temperature to 30℃ at a rate of 2℃ / min and react for 10h. Hydroxypropyl-β-cyclodextrin is obtained with an average degree of substitution of 3.64, a yield of 87.5% (based on total dry matter), and a β-cyclodextrin content of 0.25%.

[0025] Example 2

[0026] Dissolve 18.6 g of sodium hydroxide in 446.6 g of water to prepare a 4% sodium hydroxide solution. Dissolve 60 g of β-cyclodextrin in the alkaline solution. Place the alkaline solution of β-cyclodextrin in a low-temperature constant-temperature circulator, set the cooling program to a cooling rate of 3 °C / min, reduce the temperature to 17 °C, and maintain the temperature for 15 min. Then, add 37.8 g of propylene oxide dropwise at a rate of 190 g / h. After the propylene oxide is added, set the temperature program to increase the temperature to 23 °C at a rate of 0.8 °C / min and maintain the temperature for 30 min. Finally, set the temperature program to increase the temperature to 30 °C at a rate of 1.5 °C / min and react for 10 h to obtain hydroxypropyl-β-cyclodextrin. The average degree of substitution is 4.04, the yield is 87.3% (based on total dry matter), and the β-cyclodextrin content is 0.20%.

[0027] Example 3

[0028] Dissolve 27.9 g of sodium hydroxide in 437.2 g of water to prepare a 6% sodium hydroxide solution. Dissolve 90 g of β-cyclodextrin in the alkaline solution. Place the alkaline solution of β-cyclodextrin in a low-temperature constant-temperature circulator, set the cooling program to a cooling rate of 4 °C / min, reduce the temperature to 16 °C, and maintain the temperature for 20 min. Then, add 57.6 g of propylene oxide dropwise at a rate of 180 g / h. After the propylene oxide is added, set the temperature program to increase the temperature to 20 °C at a rate of 0.6 °C / min and maintain the temperature for 25 min. Finally, set the temperature program to increase the temperature to 30 °C at a rate of 1 °C / min and react for 24 h. Hydroxypropyl-β-cyclodextrin is obtained. The average degree of substitution is 5.02, the yield is 87.4% (based on total dry matter), and the β-cyclodextrin content is 0.30%.

[0029] Example 4

[0030] Dissolve 37.2 g of sodium hydroxide in 427.9 g of water to prepare an 8% sodium hydroxide solution. Dissolve 120 g of β-cyclodextrin in the alkaline solution. Place the alkaline solution of β-cyclodextrin in a low-temperature constant-temperature circulator, set the cooling program to a cooling rate of 3 °C / min, reduce the temperature to 15 °C, and maintain the temperature for 13 min. Then, add 75.7 g of propylene oxide dropwise at a rate of 170 g / h. After the propylene oxide is added, set the temperature program to increase the temperature to 22 °C at a rate of 0.4 °C / min and maintain the temperature for 30 min. Finally, set the temperature program to increase the temperature to 30 °C at a rate of 0.5 °C / min and react for 36 h. Hydroxypropyl-β-cyclodextrin is obtained. The average degree of substitution is 5.48, the yield is 87.5% (based on total dry matter), and the β-cyclodextrin content is 0.35%.

[0031] Example 5

[0032] Dissolve 46.5 g of sodium hydroxide in 418.6 g of water to prepare a 10% sodium hydroxide solution. Dissolve 150 g of β-cyclodextrin in the alkaline solution. Place the alkaline solution of β-cyclodextrin in a low-temperature constant-temperature circulator, set the cooling program to a cooling rate of 4 °C / min, reduce the temperature to 16 °C, and maintain the temperature for 18 min. Then, add 94.6 g of propylene oxide dropwise at a rate of 160 g / h. After the propylene oxide is added, set the temperature program to increase the temperature to 24 °C at a rate of 0.2 °C / min and maintain the temperature for 35 min. Finally, set the temperature program to increase the temperature to 30 °C at a rate of 0.8 °C / min and react for 47 h. Hydroxypropyl-β-cyclodextrin is obtained. The average degree of substitution is 6.00, the yield is 87.4% (based on total dry matter), and the β-cyclodextrin content is 0.28%.

[0033] Example 6

[0034] Dissolve 36.2 g of sodium hydroxide in 265.6 g of water to prepare a 12% sodium hydroxide solution. Dissolve 120 g of β-cyclodextrin in the alkaline solution. Place the alkaline solution of β-cyclodextrin in a low-temperature constant-temperature circulator, set the cooling program to a cooling rate of 2 °C / min, reduce the temperature to 17 °C, and maintain the temperature for 12 min. Then, add 75.7 g of propylene oxide dropwise at a rate of 150 g / h. After the addition of propylene oxide, set the temperature program to increase the temperature to 21 °C at a rate of 0.5 °C / min and maintain the temperature for 40 min. Finally, set the temperature program to increase the temperature to 30 °C at a rate of 1.7 °C / min and react for 47 h. Hydroxypropyl-β-cyclodextrin is obtained. The average degree of substitution is 6.55, the yield is 87.2% (based on total dry matter), and the β-cyclodextrin content is 0.25%.

[0035] Results and Analysis:

[0036] The experimental parameters for the synthesis of hydroxypropyl-β-cyclodextrin in Examples 1-6 are shown in Table 1.

[0037] Table 1 Experimental parameters of hydroxypropyl-β-cyclodextrin in Examples 1-6

[0038]

[0039] The hydroxypropyl-β-cyclodextrins of Examples 1-6 were analyzed according to the method for determining the average degree of substitution as specified in the United States Pharmacopeia—1H NMR spectroscopy. The results are shown in Table 2 (the curves obtained from these results are shown in Table 2). Figure 1 ):

[0040] Table 2. Degree of substitution of hydroxypropyl-β-cyclodextrin in Examples 1-6

[0041]

[0042] Comparative example:

[0043] A comparative experiment was conducted using the method described in Patent No. CN202010633981.9, "A method for preparing an aqueous solution of hydroxypropyl-β-cyclodextrin" (Example 2). 288g of purified water and 4.4g of sodium hydroxide were added to a 500mL three-necked flask. After stirring and dissolving, 150.5g of weighed β-cyclodextrin was added. The temperature was raised to 60℃ at a rate of 0.1℃ / min using a low-temperature constant-temperature circulator, and stirred for 30min (the β-cyclodextrin was not completely dissolved, and the solution became a white turbid liquid; obvious stratification occurred after stirring was stopped). The cooling program was set to cool down to 24°C at a rate of 1°C / min. 50.2g of propylene oxide was slowly added dropwise using a constant pressure funnel. The propylene oxide was added in 13 minutes (based on the actual dropping rate in Example 2, it takes 0.12 minutes to add 50.2g. The inventors believed that the dropping rate was too fast, so they controlled it according to the most preferred dropping rate of 250g / h in the patent. The theoretical dropping time is 12 minutes, and the actual dropping time is 13 minutes. The highest temperature during the dropping process is 27°C, which meets the patent requirement of a maximum temperature below 37°C). After the addition was completed, a heating program was set to raise the temperature to 36.4°C at a rate of 1°C / min, and the reaction was allowed to proceed for 47 hours. (In Example 2, only the temperature of 36.4°C was mentioned after the addition was completed, without detailed explanation of the operation. It is speculated that the addition rate in Example 2 was too fast, and the exothermic reaction directly raised the temperature of the liquid to 36.4°C. However, the highest temperature during the inventor's experiment was below 36.4°C. Therefore, the inventor used the same heating rate as the present invention. Since it was not possible to take samples for testing at any time during the experiment, the longest reaction time of 47 hours was chosen for comparison with the present invention.) After the reaction was completed, the temperature was rapidly raised to 60°C and stirred for 2 hours. Then, a cooling program was set to lower the temperature to room temperature, resulting in an aqueous solution of hydroxypropyl-β-cyclodextrin. (After stirring was stopped and the solution was allowed to stand, the solution still showed stratification, with undissolved beta-cyclodextrin precipitating. In order not to affect the detection of related substances, the inventor passed the solution through a 0.22 μm aqueous membrane to remove the obviously insoluble β-cyclodextrin.)

[0044] The hydroxypropyl-β-cyclodextrin obtained in the comparative example was analyzed by 1H NMR spectroscopy, and its average degree of substitution was 5.4627. Liquid chromatography analysis showed that the β-cyclodextrin content was 1.57%. In contrast, the hydroxypropyl-β-cyclodextrin with a similar degree of substitution (degree of substitution 5.4833) in this invention contained only 0.35% β-cyclodextrin. Solubility experiments were conducted on Examples 2, 3, 4, and 5 with the comparative example. Taking the poorly soluble drug ibuprofen as an example, the solubility effects are shown in Table 3.

[0045] Table 3 Comparison of solubilization effects between Examples 2-5 and the comparative examples

[0046]

[0047] * Ibuprofen is a product of Shanghai Maclean Biochemical Technology Co., Ltd., CAS No.: 15687-27-1, Product No.: I821809-25g

[0048] As shown in Table 3, the solubilization of the embodiments in this invention is higher than that of the comparative examples. The average degree of substitution in the embodiments is close to that of the comparative example 4. The solubilization factor is 2.84 times higher than that of the comparative example when the HP-β-CD concentration is 0.002 mol / L, and 11.56 times higher when the HP-β-CD concentration is 0.01 mol / L.

[0049] This invention uses a programmed temperature control method to regulate the reaction of β-cyclodextrin with propylene oxide under different alkali concentrations, and performs linear fitting on the degree of substitution of the resulting hydroxypropyl-β-cyclodextrin, R0. 2 The value is 0.9871, and the linear relationship between the alkali concentration and the average degree of substitution is good. Compared with the existing process, the process of the present invention is simple to operate, and the hydroxypropyl-β-cyclodextrin prepared has high purity. It can be used to produce different kinds of hydroxypropyl beta-cyclodextrin (with a wide degree of substitution). The hydroxypropyl-β-cyclodextrin at the same degree of substitution has good solubilizing effect and good process repeatability.

[0050] It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing hydroxypropyl-β-cyclodextrin, characterized in that, Includes the following steps: (1) Dissolve sodium hydroxide in water and prepare a sodium hydroxide solution with a mass concentration of 2% to 12% according to the product substitution degree requirements. Add β-cyclodextrin to the sodium hydroxide solution and dissolve it. The molar ratio of sodium hydroxide to β-cyclodextrin is 10:1 to obtain a β-cyclodextrin solution. (2). The β-cyclodextrin solution obtained in step (1) is cooled to 15°C at a rate of 4°C / min and kept at a constant temperature for 10 min; (3). In step (2), propylene oxide is added dropwise to the β-cyclodextrin solution at a constant temperature of 15°C. The molar ratio of cyclodextrin to propylene oxide is 1:14, and the dropping rate is 180 g / h. After the dropping is completed, the solution is heated to 20°C at a rate of 0.5°C / min and maintained for 20 to 40 min. (4). The solution obtained in step (3) is heated to 30°C at a rate of 1°C / min and kept constant for 10 to 47 h to obtain an aqueous solution of hydroxypropyl-β-cyclodextrin required for the target product.

2. The method for preparing hydroxypropyl-β-cyclodextrin as described in claim 1, characterized in that: In step (1), the mass concentration of the sodium hydroxide solution is selected according to the required degree of substitution of hydroxypropyl-β-cyclodextrin. For low-substituted hydroxypropyl-β-cyclodextrin, a low mass concentration of sodium hydroxide solution is selected.

3. The method for preparing hydroxypropyl-β-cyclodextrin as described in claim 1, characterized in that: In step (4), the reaction time is adjusted according to the degree of substitution of the target product. The lower the degree of substitution of β-cyclodextrin, the shorter the reaction time.

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