Preparation method of terminal-sterilization-tolerant diphenhydramine hydrochloride injection

Abstract

The invention provides a preparation method of diphenhydramine hydrochloride injection tolerant to terminal sterilization. The preparation method comprises the following steps: (1) weighing a diphenhydramine hydrochloride raw material; (2) taking water for injection, adding a diphenhydramine hydrochloride raw material, and stirring until the diphenhydramine hydrochloride raw material is completely dissolved to obtain a diphenhydramine hydrochloride solution; (3) adjusting the pH value of the diphenhydramine hydrochloride solution to 6.8-8.0 by using sodium hydroxide; (4) filling carbon dioxide gas into the diphenhydramine hydrochloride solution until the pH value of the solution is 5.3-6.5; filtering the solution through a microporous filter; (5) sub-packaging the solution obtained in the step (4) into ampoules, and filling carbon dioxide gas into the headspace of the ampoules; and (6) carrying out terminal sterilization on the filled finished product obtained in the step (5). The diphenhydramine hydrochloride injection has the advantages that the diphenhydramine hydrochloride injection prepared by the method not only meets the pH use requirement, but also can tolerate a terminal sterilization method and improve the sterility assurance level, and meanwhile, the injection is good in quality and high in stability.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparation production, and in particular to a method for preparing diphenhydramine hydrochloride injection resistant to terminal sterilization. Background Art

[0002] Diphenhydramine hydrochloride is an aminoalkyl ether antihistamine. As the first generation H1 receptor blocker developed before the 1980s, it has poor receptor specificity, strong central nervous system activity, and has obvious sedative, local anesthesia, antiemetic and anticholinergic effects, so it is called a sedative antihistamine. In addition, diphenhydramine hydrochloride is also commonly used for skin diseases, motion sickness, rhinitis and urticaria, etc. In recent years, it has also been widely used as a sleep-improving drug.

[0003] However, diphenhydramine hydrochloride has a complex structure, is unstable to heat, acid, and light, and is easily hydrolyzed to produce diphenylmethanol impurities. According to the clinical instructions for use of diphenhydramine hydrochloride and the requirements of domestic and foreign pharmacopoeias, the pH of diphenhydramine hydrochloride injection should be between 4.5 and 6.5. However, if the injection is sterilized by terminal high-temperature sterilization under this condition, it is easy to cause the active substance of diphenhydramine hydrochloride to degrade, and the content of diphenhydramine hydrochloride in the final injection is reduced, the related substance diphenylmethanol is increased, and the quality is reduced. In this regard, the industry currently mainly uses filtration sterilization instead of terminal high-temperature sterilization to sterilize diphenhydramine hydrochloride injection, but the sterility assurance level of this filtration sterilization method is significantly lower than that of terminal sterilization.

[0004] Therefore, how to obtain a diphenhydramine hydrochloride injection that can withstand terminal sterilization remains a top priority. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing diphenhydramine hydrochloride injection that can withstand terminal sterilization.

[0006] The present invention adopts the following technical solutions to solve the above technical problems:

[0007] A method for preparing diphenhydramine hydrochloride injection resistant to terminal sterilization comprises the following steps:

[0008] (1) Weigh the diphenhydramine hydrochloride raw material for standby use;

[0009] (2) taking water for injection into a liquid preparation tank, adding diphenhydramine hydrochloride raw material, and stirring until completely dissolved to obtain diphenhydramine hydrochloride solution;

[0010] (3) adjusting the pH of the diphenhydramine hydrochloride solution to 6.8-8.0 with sodium hydroxide;

[0011] (4) adding carbon dioxide gas to the diphenhydramine hydrochloride solution adjusted with sodium hydroxide until the pH value of the solution is 5.3 to 6.5; then, filtering the solution through a microporous filter;

[0012] (5) dispensing the solution obtained in step (4) into ampoules, and filling the headspace of the ampoules with carbon dioxide gas;

[0013] (6) performing terminal sterilization on the filled finished product obtained in step (5).

[0014] As one of the preferred embodiments of the present invention, in step (2), stirring is performed for 5 to 10 minutes, more preferably 5 minutes.

[0015] As one of the preferred embodiments of the present invention, in step (3), 1 mol / L sodium hydroxide solution is used to adjust the pH.

[0016] As one of the preferred embodiments of the present invention, in step (4), 0.45 μm and 0.22 μm microporous filters are used for filtration circulation.

[0017] As one of the preferred embodiments of the present invention, in the step (5), the headspace of the ampoule is filled with carbon dioxide gas, and the residual oxygen in the headspace is controlled to be ≤5.0% before sealing.

[0018] As one of the preferred embodiments of the present invention, in step (6), the terminal sterilization method is: sterilization at 121-125° C. for 12-15 min in a water bath sterilizer, more preferably sterilization at 121° C. for 15 min.

[0019] As one of the preferred embodiments of the present invention, when the finished filled product is heated for terminal sterilization, the carbon dioxide gas in the diphenhydramine hydrochloride solution overflows from the solution, and the pH value increases to neutral; after sterilization, the temperature is lowered, and the carbon dioxide gas in the headspace of the ampoule dissolves into the solution, and the pH value of the solution is reduced to 5.3-6.5 again.

[0020] Design principle:

[0021] According to the structure of diphenhydramine hydrochloride, it is easily hydrolyzed under acidic conditions, and the high temperature of terminal sterilization will accelerate the hydrolysis reaction process, so the degradation impurities increase significantly. In this regard, after preparing the diphenhydramine hydrochloride liquid, the pH value is first adjusted to 6.8-8.0 with sodium hydroxide, and then carbon dioxide gas is introduced into the solution to adjust the solution pH to 5.3-6.5 by carbon dioxide gas.

[0022] When the finished product of the diphenhydramine hydrochloride filling of the present invention is heated, carbon dioxide gas will overflow from the solution, and the pH will increase from 5.3 to 6.5 to neutral, so the pH of the solution is neutral when heated, and the solution is more stable; after high-temperature sterilization, when the sample is cooled, the gas in the headspace dissolves into the solution, and the pH is reduced to 5.3 to 6.5 again, meeting the use requirements.

[0023] The advantages of the present invention compared to the prior art are:

[0024] (1) After preparing the diphenhydramine hydrochloride solution, the present invention first uses sodium hydroxide to adjust the pH value to 6.8-8.0, and then introduces carbon dioxide gas into the solution to adjust the pH value of the solution to 5.3-6.5 by means of carbon dioxide gas; when the solution is heated for terminal sterilization, the carbon dioxide gas overflows from the solution and the pH value increases to neutral, so the pH value of the solution is neutral when heated, and the solution is more stable, thereby avoiding the degradation of diphenhydramine hydrochloride in the terminal high-temperature sterilization process; and after high-temperature sterilization, when the sample is cooled, the gas in the headspace dissolves into the solution again, and the pH value is reduced to 5.3-6.5 again, further satisfying the pH requirements of the clinical use instructions and the pharmacopoeias of various countries at home and abroad (the pH value of the present invention is within the pH requirement range of 4.5-6.5);

[0025] (2) The present invention can also significantly prolong the shelf life of diphenhydramine hydrochloride injection;

[0026] In summary, the method of the present invention is used to prepare diphenhydramine hydrochloride injection, which can not only meet the pH requirements of the clinical instructions for use and the pharmacopoeias of various countries at home and abroad, but also can withstand the terminal sterilization method, improve the sterility assurance level of diphenhydramine hydrochloride injection, and at the same time, the injection has good quality and high stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the peak spectrum of related substances detected after the sterilization of the diphenhydramine hydrochloride injection sample in Example 1;

[0028] Figure 2 This is the peak spectrum of related substances detected after the sterilization of the diphenhydramine hydrochloride injection sample in Example 2;

[0029] Figure 3 This is the peak spectrum of related substances detected after the sterilization of the diphenhydramine hydrochloride injection sample in Example 5;

[0030] Figure 4 This is the peak spectrum of related substances detected in the diphenhydramine hydrochloride injection sample of comparative example 1 after sterilization;

[0031] Figure 5 This is the peak spectrum of related substance detection of the diphenhydramine hydrochloride injection sample after sterilization in Comparative Example 4. DETAILED DESCRIPTION

[0032] The embodiments of the present invention are described in detail below. The embodiments are implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operation processes are given, but the protection scope of the present invention is not limited to the following embodiments. At the same time, the reagents, equipment and methods used in the following embodiments are conventional reagents, equipment and methods in the art unless otherwise specified, and will not be repeated.

[0033] Example 1

[0034] The preparation method of the diphenhydramine hydrochloride injection resistant to terminal sterilization in this embodiment is as follows:

[0035] (1) Weigh 50 mg of diphenhydramine hydrochloride raw material and set aside.

[0036] (2) Take 1 ml of water for injection in a liquid preparation tank, add the above-mentioned diphenhydramine hydrochloride raw material, and stir for 5 minutes until it is completely dissolved to obtain a diphenhydramine hydrochloride solution.

[0037] (3) adjusting the pH of the diphenhydramine hydrochloride solution to 6.8 with 1 mol / L sodium hydroxide solution.

[0038] (4) Carbon dioxide gas is introduced into the diphenhydramine hydrochloride solution adjusted with sodium hydroxide until the pH value of the solution is 5.3; then, the solution is filtered and circulated through 0.45 μm and 0.22 μm microporous filters.

[0039] (5) The solution obtained in step (4) is dispensed into ampoules, and the headspace of the ampoules is filled with carbon dioxide gas, and the residual oxygen in the headspace is controlled to be ≤5.0% before sealing.

[0040] (6) The finished filled product obtained in step (5) is terminally sterilized by sterilizing in a water bath sterilizer at 121° C. for 15 min.

[0041] In this embodiment, when the finished filled product is heated for terminal sterilization, the carbon dioxide gas in the diphenhydramine hydrochloride solution overflows from the solution, and the pH rises to neutral; after sterilization, the temperature is lowered, and the carbon dioxide gas in the headspace of the ampoule dissolves into the solution, and the pH of the solution is reduced to the pH before sterilization.

[0042] Example 2

[0043] The preparation method of the terminal sterilization-resistant diphenhydramine hydrochloride injection in this embodiment is basically the same as that in Example 1, except that:

[0044] Step (4): carbon dioxide gas is introduced into the diphenhydramine hydrochloride solution adjusted with sodium hydroxide until the pH value of the solution is 5.7; then, the solution is filtered and circulated through 0.45 μm and 0.22 μm microporous filters.

[0045] Example 3

[0046] The preparation method of the terminal sterilization-resistant diphenhydramine hydrochloride injection in this embodiment is basically the same as that in Example 1, except that:

[0047] Step (3): adjusting the pH of the diphenhydramine hydrochloride solution to 7.2 with 1 mol / L sodium hydroxide solution.

[0048] Step (4): carbon dioxide gas is introduced into the diphenhydramine hydrochloride solution adjusted with sodium hydroxide until the pH value of the solution is 5.7; then, the solution is filtered and circulated through 0.45 μm and 0.22 μm microporous filters.

[0049] Example 4

[0050] The preparation method of the terminal sterilization-resistant diphenhydramine hydrochloride injection in this embodiment is basically the same as that in Example 1, except that:

[0051] Step (3): adjusting the pH of the diphenhydramine hydrochloride solution to 8.0 with 1 mol / L sodium hydroxide solution.

[0052] Step (4): carbon dioxide gas is introduced into the diphenhydramine hydrochloride solution adjusted with sodium hydroxide until the pH value of the solution is 6.3; then, the solution is filtered and circulated through 0.45 μm and 0.22 μm microporous filters.

[0053] Example 5

[0054] The preparation method of the terminal sterilization-resistant diphenhydramine hydrochloride injection in this embodiment is basically the same as that in Example 1, except that:

[0055] Step (3): adjusting the pH of the diphenhydramine hydrochloride solution to 8.0 with 1 mol / L sodium hydroxide solution.

[0056] Step (4): carbon dioxide gas is introduced into the diphenhydramine hydrochloride solution adjusted with sodium hydroxide until the pH value of the solution is 6.5; then, the solution is filtered and circulated through 0.45 μm and 0.22 μm microporous filters.

[0057] Comparative Example 1

[0058] The preparation method of the diphenhydramine hydrochloride injection in this comparative example is basically the same as that in Example 1, except that:

[0059] Step (3): adjusting the pH of the diphenhydramine hydrochloride solution to 6.5 with 1 mol / L sodium hydroxide solution.

[0060] Comparative Example 2

[0061] The preparation method of the diphenhydramine hydrochloride injection in this comparative example is basically the same as that in Example 1, except that:

[0062] Step (3): adjusting the pH of the diphenhydramine hydrochloride solution to 8.5 with 1 mol / L sodium hydroxide solution.

[0063] Comparative Example 3

[0064] The preparation method of the diphenhydramine hydrochloride injection in this comparative example is basically the same as that in Example 1, except that:

[0065] Step (3): adjusting the pH of the diphenhydramine hydrochloride solution to 6.5 with 1 mol / L sodium hydroxide solution.

[0066] Step (4): After nitrogen (instead of carbon dioxide, the same amount) is filled into the diphenhydramine hydrochloride solution adjusted with sodium hydroxide, the solution is filtered and circulated through 0.45 μm and 0.22 μm microporous filters.

[0067] Comparative Example 4

[0068] The preparation method of the diphenhydramine hydrochloride injection in this comparative example is basically the same as that in Example 1, except that:

[0069] Step (3): adjusting the pH of the diphenhydramine hydrochloride solution to 5.3 with 1 mol / L sodium hydroxide solution.

[0070] Step (4): The diphenhydramine hydrochloride solution adjusted with sodium hydroxide is not filled with any gas, but is directly filtered and circulated through 0.45 μm and 0.22 μm microporous filters.

[0071] Experimental example

[0072] This experimental example is used to test the stability of the diphenhydramine hydrochloride injection of the above embodiments and comparative examples.

[0073] 1. Terminal sterilization tolerance stability

[0074] The diphenhydramine hydrochloride injection samples prepared in each embodiment and comparative example were taken for testing the content of related substances before and after terminal sterilization. The results are shown in Table 1. Figures 1 to 5 shown.

[0075] Table 1 Test results of injection solutions in various embodiments and comparative examples before and after terminal sterilization

[0076]

[0077]

[0078] Combined with Table 1 Figures 1 to 5 The results show that:

[0079] (1) In the test results of Examples 1 to 5, the contents of the related substances are significantly lower than those of Comparative Examples 1, 3 and 4;

[0080] (2) The various test indicators of the diphenhydramine hydrochloride injections of Examples 1 to 5 did not show significant differences before and after high-temperature sterilization; however, the diphenhydramine hydrochloride injections prepared according to Comparative Examples 1, 3 and 4 showed significantly higher contents of related substances in the injections after high-temperature sterilization than the test data before high-temperature sterilization;

[0081] (3) Combined with the data of Example 1, Comparative Example 1 and Comparative Example 2, even if the solution is adjusted to a consistent pH with carbon dioxide before sterilization and is within the required range of the present invention, if the pH during sodium hydroxide adjustment is less than 6.8, the impurities in the final product are still very large; however, if the pH during sodium hydroxide adjustment is no longer greater than 8.0, the product properties will change and a white flocculent precipitate will be produced.

[0082] (4) Based on the data of Example 1, Comparative Example 3 and Comparative Example 4, only by using carbon dioxide to perform final pH adjustment on the diphenhydramine hydrochloride solution can the terminal sterilization tolerance stability of the injection be improved.

[0083] It can be seen that the present invention can control the residual oxygen content and adjust the pH of the product by changing the solution system environment of diphenhydramine, controlling the pH of sodium hydroxide, and controlling the carbon dioxide filling during the preparation process, so that diphenhydramine hydrochloride can withstand the terminal sterilization process, significantly improve the quality of diphenhydramine hydrochloride injection, and improve the sterility assurance level of diphenhydramine hydrochloride.

[0084] 2. Storage stability

[0085] The diphenhydramine hydrochloride injection samples prepared in Examples 1 to 5 and Comparative Examples 1, 3, and 4 were stored in a high temperature (60° C.) environment for 30 days, and then the contents of related substances were detected. The results are shown in Table 2.

[0086] Table 2 Terminal sterilization storage stability results of injection solutions in various embodiments and comparative examples

[0087]

[0088] Combining the results in Table 1 and Table 2, we can see that:

[0089] (1) The diphenhydramine hydrochloride injection prepared in Examples 1 to 5 was placed at a high temperature of 60° C. for 30 days, and the various indicators did not change significantly, and the content of the related substances was significantly lower than that of the related substances in Comparative Examples 1, 3, and 4;

[0090] (2) In Comparative Examples 1, 3 and 4, the contents of related substances all increased significantly; among them, in Comparative Example 4, no indegradable gas was used for protection, and the increase of related substances was more obvious;

[0091] (3) The shelf life of the diphenhydramine hydrochloride injection prepared in each example is significantly longer than that of the diphenhydramine hydrochloride injection prepared in Comparative Example 1, Comparative Example 3 and Comparative Example 4.

[0092] It can be seen that the diphenhydramine hydrochloride injection prepared by the preparation method of the present invention has a longer shelf life.

[0093] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing diphenhydramine hydrochloride injection resistant to terminal sterilization, characterized in that: The steps include: (1) Weigh the diphenhydramine hydrochloride raw material for standby use; (2) taking water for injection into a liquid preparation tank, adding diphenhydramine hydrochloride raw material, and stirring until completely dissolved to obtain diphenhydramine hydrochloride solution; (3) adjusting the pH of the diphenhydramine hydrochloride solution to 6.8-8.0 with sodium hydroxide; (4) adding carbon dioxide gas to the diphenhydramine hydrochloride solution adjusted with sodium hydroxide until the pH value of the solution is 5.3 to 6.5; then, filtering the solution through a microporous filter; (5) dispensing the solution obtained in step (4) into ampoules, and filling the headspace of the ampoules with carbon dioxide gas; (6) performing terminal sterilization on the filled finished product obtained in step (5).

2. The method for preparing diphenhydramine hydrochloride injection resistant to terminal sterilization according to claim 1, characterized in that: In the step (2), stirring is performed for 5 to 10 minutes.

3. The method for preparing diphenhydramine hydrochloride injection resistant to terminal sterilization according to claim 1, characterized in that: In the step (3), the pH is adjusted using a 1 mol / L sodium hydroxide solution.

4. The method for preparing diphenhydramine hydrochloride injection resistant to terminal sterilization according to claim 1, characterized in that: In the step (4), 0.45 μm and 0.22 μm microporous filters are used for filtration circulation.

5. The method for preparing diphenhydramine hydrochloride injection resistant to terminal sterilization according to claim 1, characterized in that: In the step (5), the headspace of the ampoule is filled with carbon dioxide gas, and the residual oxygen in the headspace is controlled to be ≤5.0% before sealing.

6. The method for preparing diphenhydramine hydrochloride injection resistant to terminal sterilization according to claim 1, characterized in that: In the step (6), the terminal sterilization method is: sterilization in a water bath sterilizer at 121-125° C. for 12-15 minutes.

7. The method for preparing the terminal sterilization-resistant diphenhydramine hydrochloride injection according to any one of claims 1 to 6, characterized in that: When the finished filled product is heated for terminal sterilization, the carbon dioxide gas in the diphenhydramine hydrochloride solution overflows from the solution, and the pH rises to neutral; after sterilization, the temperature is lowered, and the carbon dioxide gas in the headspace of the ampoule dissolves into the solution, and the pH of the solution drops again to 5.3-6.5.

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