Preparation method of promethazine hydrochloride injection

Abstract

The invention provides a preparation method of a promethazine hydrochloride injection. An improved charging sequence of anhydrous sodium sulfite, promethazine hydrochloride and sodium pyrosulfite is adopted. The risk that the liquid medicine is oxidized in the preparation and sterilization process of the promethazine hydrochloride injection is reduced. In addition, the oxidative degradation of promethazine in the processes of encapsulation, sterilization and storage is further reduced by controlling the headspace residual oxygen amount in the encapsulation process, and the stability of the product is improved. The whole preparation process is simple in condition control and easy to realize industrially, the obtained product is consistent with a reference preparation, and the quality is superior to that of the reference preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a method for preparing promethazine hydrochloride injection. Background Art

[0002] Promethazine hydrochloride is a classic antihistamine, and its structural and molecular formulas are as follows:

[0003] C 17 H 20 N2S·HCl

[0004] The molecular weight is 320.88, CAS number 58-33-3.

[0005] Promethazine hydrochloride is a phenothiazine drug that competitively blocks histamine H l It can resist the dilation of capillaries caused by histamine, reduce its permeability, and relieve wheezing caused by contraction of bronchial smooth muscles. It is stronger and more durable than diphenhydramine hydrochloride. Because it can easily enter the brain tissue, it has a significant sedative effect; it can enhance the central inhibitory effect of hypnotics, analgesics and anesthetics; its anticholinergic effect is also strong, and it is better for preventing and treating motion sickness. It is used for skin and mucous membrane allergies, allergic rhinitis, asthma, food allergies, skin scratches, motion sickness, seasickness, airsickness, etc.

[0006] The reference preparation of promethazine hydrochloride injection announced by the State Food and Drug Administration is an original drug licensed by Sanofi and marketed in the European Union, with a specification of 25 mg / ml (calculated as promethazine hydrochloride). The 2009 updated version of the instructions states: Each 1 ml ampoule contains 25 mg of promethazine hydrochloride, 0.5 mg of anhydrous sodium sulfite, and 0.7 mg of sodium metabisulfite.

[0007] From the chemical structure point of view, promethazine hydrochloride is easy to produce oxidation impurity IV (the impurity number in the detection is impurity D: promethazine oxide-sulfoxide), degradation impurity VI (10-methylphenothiazine) and impurity VIII (phenothiazine) in acidic solution under the condition of oxygen. The degradation mechanism is as follows:

[0008]

[0009] Promethazine hydrochloride is easily oxidized to promethazine sulfoxide. However, some of the promethazine hydrochloride injections produced by existing preparation methods have the problem of high levels of oxidized impurities in promethazine hydrochloride injections, and related substances are prone to unqualified during the stability period; some preparation process parameters are too high and are not easy to industrialize; and some preparation processes add new excipients, which increases the safety risk of the injection.

[0010] For example, Chinese patent CN103637980B discloses a method for preparing promethazine hydrochloride injection. The promethazine hydrochloride injection prepared by this method is not resistant to terminal sterilization. After sterilization at 121°C for 15 minutes, the pH value is significantly reduced and the total impurities are increased. When stored under high temperature conditions, the color of the solution changes significantly and the stability is poor.

[0011] For example, Chinese patent CN103637981B discloses a method for preparing promethazine hydrochloride injection. The injection prepared by this method contains a variety of auxiliary materials, and the obtained injection also has the problem of significant color change of the solution and poor stability when stored under high temperature conditions.

[0012] For another example, Chinese patent CN114886847A discloses a method for preparing promethazine hydrochloride injection, which requires that the residual oxygen content of the injection water used must be controlled to no more than 0.2 ppm, which is too high and not easy to industrialize.

[0013] For another example, Chinese patent application CN119235775A discloses a method for preparing promethazine hydrochloride injection. The injection prepared by this method contains more ingredients than the reference preparation of promethazine hydrochloride injection and introduces the auxiliary material thioglycerol, which increases the safety risk.

[0014] In view of the above-mentioned defects of the prior art, it is urgently necessary to develop a method for preparing promethazine hydrochloride injection which can be consistent with the prescription composition of the reference preparation, can withstand terminal sterilization, and has high stability under high-temperature sterilization conditions, so as to improve the quality of promethazine hydrochloride injection, stability during the shelf life and sterility level. Summary of the invention

[0015] In order to solve one of the above-mentioned technical problems existing in the prior art, the present invention provides a preparation method of promethazine hydrochloride injection.

[0016] According to the present invention, the preparation method of promethazine hydrochloride injection is provided, and the specific preparation steps are as follows:

[0017] Step A: Take 80%-95% of the prepared water for injection, add the prescribed amount of anhydrous sodium sulfite, stir to fully dissolve to obtain solution 1;

[0018] Step B: adding a prescribed amount of promethazine hydrochloride to solution 1, stirring and dissolving, to obtain solution 2;

[0019] Step C: adding a prescribed amount of sodium metabisulfite to solution 2, stirring and dissolving, to obtain solution 3;

[0020] Step D: Add water for injection and make up to the full volume to obtain solution 4;

[0021] Step E: Solution 4 is filtered, sealed, and sterilized to obtain the product.

[0022] The preparation method provided by the present invention has a composition and content of the obtained promethazine hydrochloride injection that are consistent with the reference preparation announced by the State Food and Drug Administration, that is, each 1 mL of injection contains 25 mg of promethazine hydrochloride, 0.5 mg of anhydrous sodium sulfite, and 0.7 mg of sodium pyrosulfite.

[0023] According to one embodiment of the present invention, the nitrogen filling operation is maintained throughout the entire process of steps A to E.

[0024] According to one embodiment of the present invention, the dissolved oxygen content of the water for injection in step A is ≤1.5ppm.

[0025] According to one embodiment of the present invention, during the filling process of step E, the residual oxygen content in the headspace of the ampoule is controlled to be ≤1.5%, preferably ≤1.0%, and more preferably ≤0.7%.

[0026] According to the degradation mechanism of promethazine hydrochloride, the preparation process of promethazine hydrochloride injection provided by the present invention mainly focuses on the pH value change during the product preparation process (the British Pharmacopoeia stipulates that the pH value of the injection of this product is 5.0-6.0).

[0027] The present invention dynamically adjusts the pH range of the solution by adjusting the order of adding materials, thereby preventing the generation of impurities. Specifically, a prescribed amount of anhydrous sodium sulfite is added to the above-mentioned water for injection to keep the solution weakly alkaline. After adding a prescribed amount of promethazine hydrochloride, the pH value of the solution is 6 to 7. This solution environment is conducive to maintaining the stability of the promethazine hydrochloride solution during the preparation process. A prescribed amount of antioxidant sodium pyrosulfite is added to make the pH value of the solution meet the range of 5.0 to 6.0 specified in the European Pharmacopoeia.

[0028] Since the pH value range is controlled, it is not necessary to add nitrogen to the water for injection under such harsh control conditions as disclosed in CN114886847A, which controls the residual oxygen content of the water for injection to "not be higher than 0.2ppm". In the preparation process disclosed in the present invention, the dissolved oxygen content of the water for injection is not higher than 1.5ppm, which is a residual oxygen content index that is very easy to control in industrial operations.

[0029] According to one of the preferred embodiments of the present invention, the temperature is controlled at ≤40°C during the preparation process.

[0030] According to one embodiment of the present invention, the filtration in step E adopts a 0.22 μm filter element filtration method.

[0031] According to one of the preferred embodiments of the present invention, the sterilization in step E is performed by high temperature sterilization. The high temperature sterilization temperature is 121° C., and the sterilization time is not less than 15 minutes. For example, high temperature sterilization at 121° C. can be performed for 15 minutes, 20 minutes, or 30 minutes.

[0032] The beneficial effects of the present invention are:

[0033] 1. The present invention is different from the prior art in that the risk of oxidation of the promethazine hydrochloride injection during preparation and sterilization is reduced by optimizing the order of adding materials and adopting nitrogen protection.

[0034] 2. By controlling the residual oxygen content in the headspace during the filling process, the oxidative degradation of promethazine hydrochloride injection is further reduced during the filling, sterilization and storage processes. At the same time, the terminal sterilization can withstand excessive sterilization at 121°C / 15 minutes (F0≥12), which greatly improves the sterility assurance level of promethazine hydrochloride injection and thereby improves the safety of promethazine hydrochloride injection during use.

[0035] 3. The prescription of promethazine hydrochloride injection produced by this preparation method is consistent with that of the original reference preparation, and the test results of relevant substances are fully in line with the United States Pharmacopoeia, British Pharmacopoeia and Chinese Pharmacopoeia, and the quality is better than the reference preparation.

[0036] 4. The preparation method provided by the present invention has looser control conditions than the prior art and is easy for industrial production. It not only reduces the risk of oxidation of promethazine hydrochloride injection during the production process, but also avoids the risk of oxidation of the drug solution during storage, thereby increasing stability. DETAILED DESCRIPTION

[0037] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0038] definition

[0039] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural form, and vice versa.

[0040] Unless the context clearly dictates otherwise, the expressions "a", "an" and "an" as used herein include plural references. For example, reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth.

[0041] As used herein, the term "about" refers to a range of ±20% of the value that follows. In some embodiments, the term "about" refers to a range of ±10% of the value that follows. In some embodiments, the term "about" refers to a range of ±5% of the value that follows.

[0042] Examples are provided below to help understand the present invention. However, it should be understood that these examples are only used to illustrate the present invention, but do not constitute any limitation. The actual scope of protection of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention. The reagents and / or kits used in the following examples are all commercially available or can be synthesized by known methods.

[0043] It should be noted that, if the specific conditions are not specified in the examples, the experimental conditions are carried out according to conventional conditions, manufacturer recommendations or publicly reported experimental conditions. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially. If the manufacturer of the reagents used is specified, similar products from other manufacturers are substitutable.

[0044] In the following examples or comparative examples, the reference preparation is selected from:

[0045] The licensee is Sanofi and the product name is Promethazine hydrochloride injection (specification: 1ml: 25mg) marketed in the European Union, batch number: 3J5831.

[0046] Related substance detection methods:

[0047] With reference to the United States Pharmacopoeia (USP2024) promethazine hydrochloride injection, the main focus and comparison during the experiment were on impurity D (oxidation impurity, promethazine oxide-sulfoxide, which is the main degradation impurity in the preparation process of the preparation) and total impurities.

[0048] Embodiment 1:

[0049] In this example, promethazine hydrochloride injection was prepared according to the method provided by the present invention.

[0050]

[0051]

[0052] Preparation method:

[0053] Add 90% of the formulated amount of injection water into the liquid preparation tank, control the temperature of the injection water not to exceed 30°C, fill nitrogen at the bottom, and online monitor the dissolved oxygen content of the injection water. When the dissolved oxygen content ≤ 1.5 ppm, start feeding materials. Add the prescribed amount of anhydrous sodium sulfite and stir for 10 minutes until completely dissolved. Online monitor the dissolved oxygen, add the prescribed amount of promethazine hydrochloride, stir for 5 minutes until completely dissolved, then add the prescribed amount of sodium metabisulfite and stir for 5 minutes until completely dissolved. Make up the volume, filter through a 0.22 μm filter element, and use the method of filling nitrogen before and after filling the liquid medicine, and seal it in a 2 ml colorless medium borosilicate glass ampoule. At this time, the residual oxygen content in the upper part of the liquid medicine in the ampoule is about 0.94%. Seal it by melting, and sterilize it by the method of sterilizing at 121°C for 15 minutes to obtain promethazine hydrochloride injection.

[0054] Comparative Example 1

[0055] Refer to Chinese Patent CN114886847A (referred to as the ’847 patent) to carry out process reproduction

[0056] Name of raw materials Dosage Promethazine Hydrochloride 25g Anhydrous sodium sulfite 0.5g Sodium metabisulfite 0.7g Water for injection Add to 1000ml

[0057] Preparation method:

[0058] Add 80% of the formulated amount of injection water into the liquid preparation tank, control the temperature of the injection water at 30°C, fill nitrogen at the bottom, and online monitor the dissolved oxygen content of the injection water. When the dissolved oxygen content ≤ 0.2 ppm, start feeding materials. Add the prescribed amount of anhydrous sodium sulfite and sodium metabisulfite, stir for 5 minutes until completely dissolved, then add the prescribed amount of promethazine hydrochloride, stir for 5 minutes until completely dissolved. Make up the volume, filter through a 0.45 μm + 0.22 μm polyethersulfone filter element, and use the method of filling nitrogen before and after sealing to seal it in a 2 ml colorless medium borosilicate glass ampoule. Control the residual oxygen content in the upper part of the liquid medicine ≤ 2.0%, seal it by melting, and sterilize it by the method of sterilizing at 121°C for 15 minutes to obtain the promethazine hydrochloride injection disclosed in the ’847 patent.

[0059] Respectively test the "related substances" of the promethazine hydrochloride injection obtained in Example 1 of the present invention, the reference preparation and the ’847 patent. The results are shown in Table 1:

[0060] Table 1 Detection results of "related substances" by changing the feeding order

[0061]

[0062] The results show that for the promethazine hydrochloride injection obtained in the comparative example, the detected amount of oxidation impurity D is significantly greater than that of the reference preparation, and the total impurities are equivalent to those of the reference preparation. After adjusting the order of adding materials, both the detected amount of impurity D and the total impurity amount are significantly better than those in the comparative example; compared with the reference preparation, the detected amount of impurity D is basically the same as that of the reference preparation, but the total impurity content is significantly less than that of the reference preparation.

[0063] Further referring to the records in Table 5 of the specification of Chinese Patent '847, the related substance tests of Example 2 of this patent and its marketed products 1 and 2 showed that the total impurity contents (%) were 0.5, 0.7, and 0.6 respectively. This further confirmed that by changing the addition sequence of the materials according to the present invention, the total impurity content in the prior art can be significantly reduced.

[0064] Comparative Example 2

[0065] On the basis of Example 1, the dissolved oxygen content of the injection water during liquid preparation was investigated to examine the influence of the dissolved oxygen content of the injection water on the impurity content.

[0066] Name of raw materials Dosage Promethazine Hydrochloride 25g Anhydrous sodium sulfite 0.5g Sodium metabisulfite 0.7g Water for injection Add to 1000ml

[0067] Preparation method:

[0068] The preparation method was carried out with reference to Example 1 for formulation, and the dissolved oxygen content of the injection water was controlled to be greater than 1.5 ppm to obtain the injection of Comparative Example 2.

[0069] The "related substances" of the promethazine hydrochloride injection obtained in Example 1 of the present invention, the reference preparation, and Comparative Example 2 were respectively tested, and the results are shown in Table 2:

[0070] Table 2 Detection results of "related substances" by changing the injection water

[0071]

[0072] The results showed that:

[0073] When the dissolved oxygen content of the injection water during liquid preparation is higher than 1.5 ppm, the impurity D has an obvious increasing trend, far exceeding the reference preparation. After controlling the dissolved oxygen content ≤ 1.5 ppm, the content of impurity D is significantly reduced, approaching the reference preparation, and at the same time, the total impurity content is also significantly lower than the reference preparation.

[0074] Comparative Example 3

[0075] On the basis of Example 1, during the filling and sealing process, the headspace residual oxygen in the ampoule was investigated to examine the influence of different headspace residual oxygen on the product stability.

[0076] Name of raw materials Dosage Promethazine Hydrochloride 25g Anhydrous sodium sulfite 0.5g Sodium metabisulfite 0.7g Water for injection Add to 1000ml

[0077] Preparation method:

[0078] The preparation method was carried out with reference to Example 1. During filling, by adjusting the nitrogen filling method and nitrogen pressure of the equipment, the headspace residual oxygen ranges in the ampoules were made to be below 0.7% (3-1), 0.7% - 1.0% (i.e., Example 1), 1.0 - 1.5% (3-2), and 1.5 - 2.0% (3-3) respectively. After sealing, sterilization was carried out by the method of sterilizing at 121°C for 15 minutes to obtain the promethazine hydrochloride injection solutions of each group.

[0079] The "related substances" of the promethazine hydrochloride injection solutions of 3-1, 3-2, 3-3, Example 1, and the reference preparation were tested respectively, and the results are shown in Table 3:

[0080] Table 3 Detection results of "related substances" with changed headspace residual oxygen amounts

[0081]

[0082] The results showed that:

[0083] When filling the injection solution, when the headspace residual oxygen amount was not more than 1.5%, the detected amount of impurity D was close to that of the reference preparation, and the total impurities were less than those of the reference preparation. When the headspace residual oxygen amount ≤ 1.0%, the data results were better, especially when the headspace residual oxygen amount ≤ 0.7%, the total impurities were significantly less than those of the reference preparation.

[0084] Comparative Example 4

[0085] On the basis of Example 1, the temperature of the injection water during solution preparation was investigated, and the influence when the temperature of the injection water was 30 - 40°C was investigated.

[0086] Name of raw materials Dosage Promethazine Hydrochloride 25g Anhydrous sodium sulfite 0.5g Sodium metabisulfite 0.7g Water for injection Add to 1000ml

[0087] Preparation method:

[0088] The preparation method was carried out with reference to Example 1, and the temperature of the injection water was controlled to be greater than 30°C and not exceeding 40°C to obtain the injection of Comparative Example 4.

[0089] The "related substances" of the promethazine hydrochloride injection solutions obtained in Example 1 of the present invention, the reference preparation, and Comparative Example 4 were tested respectively, and the results are shown in Table 4:

[0090] Table 4 Detection results of "related substances" with changed water temperature

[0091]

[0092] The results showed that:

[0093] When the temperature of the injection water during solution preparation was relaxed to 30 - 40°C, the detected amount of impurity D was basically the same as that of the reference preparation, but the total impurities were significantly less than those of the reference preparation, and the quality was better than that of the reference preparation and the comparative experiment.

[0094] Comparative Example 5

[0095] On the basis of Example 1, the influence of prolonging the sterilization time on the product quality was investigated.

[0096] Name of raw materials Dosage Promethazine Hydrochloride 25g Anhydrous sodium sulfite 0.5g Sodium metabisulfite 0.7g Water for injection Add to 1000ml

[0097] Preparation method:

[0098] The preparation method was carried out with reference to Example 1 for formulation, and the parameters during sterilization were adjusted to 121 °C and sterilization for 30 minutes to obtain the injection of Comparative Example 5.

[0099] The "related substances" of the promethazine hydrochloride injection obtained in Example 1 of the present invention, the reference preparation and Comparative Example 5 were respectively tested, and the results are shown in Table 5:

[0100] Table 5 Detection results of "related substances" with prolonged sterilization time

[0101]

[0102]

[0103] The results showed that:

[0104] After the sterilization time was extended from 15 minutes to 30 minutes, the impurities did not increase significantly, and the total impurities were significantly less than those of the reference preparation. It shows that the preparation method provided by the present invention has good tolerance to high-temperature sterilization, and the stability is significantly higher than that of the reference preparation.

[0105] Example 2

[0106] According to the process parameters provided by the present invention, three batches were continuously prepared to investigate the process stability.

[0107] Name of raw materials Dosage Promethazine Hydrochloride 75g Anhydrous sodium sulfite 1.5g Sodium metabisulfite 2.1g Water for injection Add to 3000ml

[0108] Preparation method: The formulation was carried out with reference to Comparative Example 3-1.

[0109] Pretreatment of water for injection: Take an appropriate amount of water for injection, fill it with nitrogen until the dissolved oxygen content ≤ 1.5 ppm, and then set it aside. The water temperature was controlled below 40 °C;

[0110] Concentrated formulation: Weigh about 90% of the prescription amount of oxygen-depleted water for injection into the liquid preparation tank, and start stirring; then weigh the prescription amount of anhydrous sodium sulfite and add it to the above liquid preparation tank under stirring until it is dissolved and clear; then weigh the prescription amount of promethazine hydrochloride and add it to the above liquid preparation tank under stirring, and continue stirring until it is dissolved and clear; finally weigh the prescription amount of sodium metabisulfite and add it to the above liquid preparation tank under stirring, and continue stirring until it is dissolved and clear.

[0111] Dilute formulation: Weigh the remaining amount of water for injection and add it to the above liquid preparation tank under stirring, and continue stirring evenly.

[0112] Filtration: Filter the above solution (using a polyethersulfone filter element with a pore size of 0.22 μm).

[0113] Sealing: Take the above liquid medicine for filling and heat sealing, and protect it with nitrogen before and after filling (the residual oxygen in the headspace < 0.7%).

[0114] Sterilization: Sterilize by moist heat at 121 °C for 15 minutes.

[0115] Note: The whole process above is protected with nitrogen.

[0116] Continuously prepare three batches, and test the "related substances" of the obtained promethazine hydrochloride injection respectively. The results are shown in Table 6.

[0117] Conduct retention stability studies on the third batch of samples and the reference preparation simultaneously. Place the samples at a high temperature of 60 °C for 10 days and 30 days, and the test results are shown in Table 7.

[0118] Table 6 Detection results of "related substances" for three batches

[0119]

[0120] Table 7 Detection results of "related substances" for high-temperature stability test

[0121]

[0122] The results show that: for the preparation method provided by the present invention, three batches of samples are continuously prepared, and the quality of the obtained products is better than that of the reference preparation. The injection produced according to this patent not only has better quality than the reference preparation, but also has good stability. When placed at 60 °C for 10 days and 30 days, the test results are significantly better than those of the reference preparation.

[0123] The technical solution of the present invention is not limited to the limitations of the above specific embodiments. Any technical deformation made according to the technical solution of the present invention falls within the protection scope of the present invention.

Claims

1. A method for preparing promethazine hydrochloride injection, the specific preparation steps are as follows: Step A: Take 80%-95% of the prepared water for injection, add the prescribed amount of anhydrous sodium sulfite, stir to fully dissolve to obtain solution 1; Step B: adding a prescribed amount of promethazine hydrochloride to solution 1, stirring and dissolving, to obtain solution 2; Step C: adding a prescribed amount of sodium metabisulfite to solution 2, stirring and dissolving, to obtain solution 3; Step D: Add water for injection and make up to the full volume to obtain solution 4; Step E: Solution 4 is filtered, sealed, and sterilized to obtain: Each 1 mL of the promethazine hydrochloride injection contains 25 mg of promethazine hydrochloride, 0.5 mg of anhydrous sodium sulfite, and 0.7 mg of sodium metabisulfite.

2. The preparation method according to claim 1, characterized in that: The nitrogen filling operation is maintained throughout steps A to E.

3. The preparation method according to claim 1, characterized in that: The dissolved oxygen content of the water for injection described in step A is ≤1.5ppm.

4. The preparation method according to claim 1, characterized in that: During the filling process of step E, the residual oxygen content in the headspace of the ampoule is controlled to be ≤1.5%, preferably ≤1.0%, and more preferably ≤0.7%.

5. The preparation method according to claim 1, characterized in that: The temperature was controlled at ≤40°C during the preparation process.

6. The preparation method according to claim 1, characterized in that: The filtration in step E is carried out using a 0.22 μm filter element.

7. The preparation method according to claim 1, characterized in that: The sterilization in step E is carried out at a high temperature of 121° C. for not less than 15 minutes.

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