阅读说明：本技术 一种羟丙基倍他环糊***溶液的制备方法 (Preparation method of hydroxypropyl betacyclodextrin aqueous solution ) 是由 陈绪印 梁宁宁 武圆圆 赵大波 盛玉春 于 2020-07-02 设计创作，主要内容包括：本发明提供了一种羟丙基倍他环糊精水溶液的制备方法,包括：S1)将水、氢氧化钠与倍他环糊精混合,加热,得到混合液；所述氢氧化钠与倍他环糊精的摩尔比为(0.2～0.3)：1；S2)在所述混合液中滴加环氧丙烷,滴加结束后,35℃～37℃保温反应,然后升温至55℃～65℃,继续搅拌反应,得到羟丙基倍他环糊精水溶液。与现有技术相比,本发明调整氢氧化钠的添加量,使其大大减少,且无需加入乙醇及盐酸,减少成本,反应过程更加安全,同时使得到的水溶液中盐分含量大大减少,进而增加了产品的持续稳定性。(The invention provides a preparation method of a hydroxypropyl betadex aqueous solution, which comprises the following steps: s1) mixing water, sodium hydroxide and beta-cyclodextrin, and heating to obtain a mixed solution; the molar ratio of the sodium hydroxide to the beta-cyclodextrin is (0.2-0.3): 1; s2) adding propylene oxide dropwise into the mixed solution, keeping the temperature of 35-37 ℃ for reaction after the dropwise addition is finished, then heating to 55-65 ℃, and continuing stirring for reaction to obtain the hydroxypropyl betacyclodextrin aqueous solution. Compared with the prior art, the method has the advantages that the addition amount of the sodium hydroxide is adjusted, the sodium hydroxide is greatly reduced, ethanol and hydrochloric acid are not required to be added, the cost is reduced, the reaction process is safer, the salt content in the obtained aqueous solution is greatly reduced, and the continuous stability of the product is further improved.)

1. A method for preparing a hydroxypropyl betadextrin aqueous solution is characterized by comprising the following steps:

s1) mixing water, sodium hydroxide and beta-cyclodextrin, and heating to obtain a mixed solution; the molar ratio of the sodium hydroxide to the beta-cyclodextrin is (0.2-0.3): 1;

s2) adding propylene oxide dropwise into the mixed solution, keeping the temperature of 35-37 ℃ for reaction after the dropwise addition is finished, then heating to 55-65 ℃, and continuing stirring for reaction to obtain the hydroxypropyl betacyclodextrin aqueous solution.

2. The method according to claim 1, wherein in step S1), the beta-cyclodextrin is added after the water and the sodium hydroxide are mixed and dissolved.

3. The preparation method according to claim 1, wherein the heating in the step S1) is carried out to 55-65 ℃, and the stirring is carried out for 1-2 h under the condition of heat preservation.

4. The preparation method according to claim 1, wherein the heating in the step S1) is carried out to a temperature of 60 ℃, and the stirring is carried out for 1-2 h under heat preservation.

5. The method according to claim 1, wherein propylene oxide is added dropwise when the temperature of the mixed solution in step S2) is 23 to 25 ℃; and the temperature was controlled not to exceed 37 ℃ during the dropwise addition.

6. The method according to claim 1, wherein the dropping rate of the propylene oxide in the step S2) is 200-300 g/h.

7. The method of claim 1, wherein the step S2) is performed by keeping the reaction temperature until the residue of beta-cyclodextrin is less than 2% or no longer significantly reduced.

8. The method according to claim 1, wherein the stirring reaction in step S2) is continued for 1.5-2.5 h.

9. The method according to claim 1, wherein the temperature is raised to 60 ℃ in step S2), and the reaction is continued with stirring.

10. The method according to claim 1, wherein the pH of the aqueous solution of hydroxypropyl betacyclodextrin is 11.5 to 12.4.

Technical Field

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of a hydroxypropyl betacyclodextrin aqueous solution.

Background

Cyclodextrin (CD) is a natural cyclic oligosaccharide product obtained by connecting 6-15 glucose molecules after the starch is subjected to ring cleavage by cyclodextrin glucan transposase, is commonly alpha, beta and gamma-CD, respectively comprises 7 glucose molecules which are connected by glycosidic bonds to form a truncated cone, and has a hollow inner cavity, hydroxyl groups on glucose residues are mainly distributed on the periphery of the cavity, and oxygen atoms of the glycosidic bonds are positioned in the middle of the cavity. Hydrophobic in the cavity and hydrophilic outside the cavity, and due to this specificity, CD has the function of inclusion and solubilization for lipophilic drugs. Because in aqueous solutions the propensity of water molecules in the CD lipophilic cavity to form hydrogen bonds is not satisfied and has a higher heat break than water molecules in solution, the high heat break water molecules, reducing the driving force for system energy, the lipophilic drug whole molecule or lipophilic structure can form an inclusion complex with water molecules in the CD cavity by displacing them. The inclusion complex has a drug that binds to CD non-covalently and is in dynamic equilibrium with the free drug in solution.

Due to the poor solubility and poor inclusion ability of betacyclodextrin, derivatives were produced. Hydroxypropyl-3-cyclodex-trin (HP-beta-CD) is a hydrophilic derivative formed by condensing beta-CD and 1, 2-propylene oxide.

At present, the preparation method of hydroxypropyl betacyclodextrin generally comprises the following steps: dissolving sodium hydroxide in water, adding a proper amount of ethanol, dissolving beta-cyclodextrin, adding epoxy chloropropane (C3H5CLO), reacting for 12 hours under the condition that n (NaOH) to n (beta 2CD) to n (C3H5ClO) is 10: 1: 10, and then carrying out spray drying to obtain hydroxypropyl beta-cyclodextrin powder (research on synthesis process of hydroxypropyl 2 beta 2 cyclodextrin, article number: 10042275X (2006) 0520029203). This method requires adjustment with hydrochloric acid after synthesis of the solution to degrade the pH, but produces a large amount of salts which are not good for professional aqueous solution customers, and contains too many impurities, and if the pH is high, it results in poor solution stability, and the pH of the solution rises continuously with longer standing time.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide a method for preparing an aqueous solution of hydroxypropyl betadextrin, wherein the aqueous solution of hydroxypropyl betadextrin prepared by the method has a high pH and a high stability.

The invention provides a preparation method of a hydroxypropyl betadextrin aqueous solution, which comprises the following steps:

s1) mixing water, sodium hydroxide and beta-cyclodextrin, and heating to obtain a mixed solution; the molar ratio of the sodium hydroxide to the beta-cyclodextrin is (0.2-0.3): 1;

s2) adding propylene oxide dropwise into the mixed solution, keeping the temperature of 35-37 ℃ for reaction after the dropwise addition is finished, then heating to 55-65 ℃, and continuing stirring for reaction to obtain the hydroxypropyl betacyclodextrin aqueous solution.

Preferably, in the step S1), the water and the sodium hydroxide are mixed and dissolved, and then the betacyclodextrin is added.

Preferably, in the step S1), the mixture is heated to 55-65 ℃, and the mixture is stirred for 1-2 hours under the condition of heat preservation.

Preferably, in the step S1), the heating is carried out until the temperature is 60 ℃, and the stirring is carried out for 1-2 hours under the condition of heat preservation.

Preferably, propylene oxide is added dropwise when the temperature of the mixed solution in the step S2) is 23 to 25 ℃; and the temperature was controlled not to exceed 37 ℃ during the dropwise addition.

Preferably, the dropping speed of the propylene oxide in the step S2) is 200-300 g/h.

Preferably, the reaction is kept at step S2) until the residue of beta-cyclodextrin is less than 2% or no longer significantly reduced.

Preferably, the time for continuing the stirring reaction in the step S2) is 1.5-2.5 h.

Preferably, the temperature is raised to 60 ℃ in the step S2), and the reaction is continuously stirred.

Preferably, the pH value of the hydroxypropyl betadex aqueous solution is 11.5-12.4.

The invention provides a preparation method of a hydroxypropyl betadex aqueous solution, which comprises the following steps: s1) mixing water, sodium hydroxide and beta-cyclodextrin, and heating to obtain a mixed solution; the molar ratio of the sodium hydroxide to the beta-cyclodextrin is (0.2-0.3): 1; s2) adding propylene oxide dropwise into the mixed solution, keeping the temperature of 35-37 ℃ for reaction after the dropwise addition is finished, then heating to 55-65 ℃, and continuing stirring for reaction to obtain the hydroxypropyl betacyclodextrin aqueous solution. Compared with the prior art, the method has the advantages that the addition amount of the sodium hydroxide is adjusted, the sodium hydroxide is greatly reduced, ethanol and hydrochloric acid are not required to be added, the cost is reduced, the reaction process is safer, the salt content in the obtained aqueous solution is greatly reduced, and the continuous stability of the product is further improved.

Drawings

FIG. 1 is a color analysis chart of HPBCD 50C exposure of an aqueous solution of hydroxypropyl betacyclodextrin obtained in example 1;

FIG. 2 is a schematic view of the structure of a reaction vessel used in example 2.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The invention provides a preparation method of a hydroxypropyl betadextrin aqueous solution, which comprises the following steps: s1) mixing water, sodium hydroxide and beta-cyclodextrin, and heating to obtain a mixed solution; the molar ratio of the sodium hydroxide to the beta-cyclodextrin is (0.2-0.3): 1; s2) adding propylene oxide dropwise into the mixed solution, keeping the temperature of 35-37 ℃ for reaction after the dropwise addition is finished, then heating to 55-65 ℃, and continuing stirring for reaction to obtain the hydroxypropyl betacyclodextrin aqueous solution.

In the present invention, the sources of all raw materials are not particularly limited and may be commercially available.

Mixing water, sodium hydroxide and betacyclodextrin; in the invention, preferably, water and sodium hydroxide are mixed and dissolved firstly, and then the beta-cyclodextrin is added for mixing; the water is preferably purified water; the molar ratio of the sodium hydroxide to the beta-cyclodextrin is (0.2-0.3): 1, preferably (0.2 to 0.28): 1, more preferably (0.2 to 0.26): 1, more preferably (0.2 to 0.24): 1; the concentration of sodium hydroxide in the mixed and dissolved system is preferably 0.2-0.6 mol/L, more preferably 0.3-0.5 mol/L, still more preferably 0.4-0.45 mol/L, and most preferably 0.42-0.43 mol/L.

Adding beta-cyclodextrin, mixing, and heating to obtain mixed solution; the heating is preferably carried out until the temperature is 55-65 ℃, preferably slowly heated to 58-62 ℃, more preferably slowly heated to 60 ℃, and stirred for 0.5-2 h, more preferably 0.5-1 h under heat preservation; the speed of the slow heating temperature rise is preferably 0.05-0.2 ℃/min, and more preferably 0.1 ℃/min; the cyclodextrin is dissolved repeatedly by heating, keeping warm and stirring.

Preferably, the mixed solution is cooled to 23-25 ℃ and then the epoxypropane is dripped, and more preferably, the mixed solution is cooled to 24 ℃ and then the epoxypropane is dripped; and the temperature is controlled not to exceed 37 ℃ during the dripping; the cooling rate is preferably 0.5-2 ℃/min, and more preferably 1 ℃/min; the dripping speed of the propylene oxide is preferably 200-300 g/h, more preferably 220-280 g/h, still more preferably 240-260 g/h, and most preferably 250 g/h.

After the dropwise addition is finished, carrying out heat preservation reaction at 35-37 ℃, preferably carrying out heat preservation reaction at 36-37 ℃, and more preferably carrying out heat preservation reaction at 36.5 ℃; the incubation is preferably carried out until the residue of beta-cyclodextrin is less than 2% or no longer significantly reduced.

After the heat preservation reaction is finished, heating to 55-65 ℃, preferably to 58-62 ℃, more preferably to 60 ℃, and continuing stirring for reaction; the stirring reaction time is preferably 1.5-2.5 h, more preferably 1.8-2.2 h, and still more preferably 2 h. By heating reaction, the color of the reaction solution can be lightened, the residue of beta-cyclodextrin and the residue of propylene oxide can be further reduced, and the substitution degree can be improved.

After the reaction is finished, preferably cooling to room temperature to obtain a hydroxypropyl betacyclodextrin aqueous solution; the pH value of the hydroxypropyl betadex aqueous solution is preferably 11.5-12.4.

The invention adjusts the addition amount of the sodium hydroxide, greatly reduces the addition amount of the sodium hydroxide, does not need to add ethanol and hydrochloric acid, reduces the cost, has safer reaction process, greatly reduces the salt content in the obtained aqueous solution, and further increases the continuous stability of the product.

In order to further illustrate the present invention, the following examples are provided to describe the preparation method of an aqueous solution of hydroxypropyl betacyclodextrin.

The reagents used in the following examples are all commercially available.