A propranolol hydrochloride tablet having a low content of N-nitroso propranolol impurities and a method for preparing the same
By using excipients such as mannitol, glyceryl behenate, and magnesium stearate, along with a combination of crospovidone, alanine, and glycine, the problems of poor tableting effect and impurity formation in propranolol hydrochloride tablets were solved, resulting in better tableting effect and prolonged efficacy.
Patent Information
- Application Number
- CN202311232275.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-22
- Publication Date
- 2026-02-03
- Estimated Expiration
- 2043-09-22
AI Technical Summary
The existing propranolol hydrochloride tablets have poor flowability during the tableting process, resulting in poor tableting effect. In addition, the secondary amine in propranolol hydrochloride is prone to react with nitrosating agents to produce impurities such as N-nitrosoprene propranolol, which affects the efficacy.
Mannitol, glyceryl behenate, and magnesium stearate were used as excipients, and a mixture of crospovidone, alanine, and glycine was added as an inhibitor. By controlling the flowability and uniform dispersion of the excipients, the formation of N-nitrosoprene propranolol was reduced.
It improves the tableting effect and stability of propranolol hydrochloride tablets, reduces the generation of impurity N-nitrosopranolol, prolongs the efficacy, and improves patient compliance.
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Figure BDA0004464323830000061
Abstract
Description
Technical Field
[0001] This application relates to the technical field of pharmaceutical preparations, and in particular to a propranolol hydrochloride tablet with low N-nitrosopropranolol impurity content and its preparation method. Background Technology
[0002] Propranolol hydrochloride is an organic compound and a β-adrenergic receptor blocker. It can block β-receptors in the myocardium, slow the heart rate, inhibit cardiac contractility and conduction, and reduce myocardial oxygen consumption. Clinically, it is mainly used to treat arrhythmias caused by various reasons, and can also be used for angina pectoris, hypertension, pheochromocytoma, etc. The commonly used dosage form of propranolol hydrochloride is tablets. Propranolol hydrochloride tablets are usually made by first mixing propranolol hydrochloride and excipients evenly, and then compressing them. Usually, during tableting, the flowability of the materials is poor, resulting in poor tableting effect. In addition, the secondary amine in propranolol hydrochloride can easily react with the digestive agent to produce the impurity N-nitrosopreprolol, which in turn affects the efficacy of the prepared propranolol hydrochloride tablets. Summary of the Invention
[0003] In order to reduce the generation of impurity N-nitrosoprene propranolol, this application provides propranolol hydrochloride tablets with low N-nitrosoprene impurity content and a method for preparing the same.
[0004] In the first aspect, this application provides a propranolol hydrochloride tablet with low N-nitrosopropranolol impurity content, which adopts the following technical solution:
[0005] A propranolol hydrochloride tablet with low N-nitrosopropranolol impurity content, wherein the propranolol hydrochloride tablet comprises the following components in parts by weight: 0.2-0.3 parts propranolol hydrochloride, 2.0-2.3 parts mannitol, 0.2-0.3 parts behenate glyceryl ester, and 0.05-0.1 parts magnesium stearate.
[0006] By adopting the above technical solution, mannitol, behenicol glyceryl ester, and magnesium stearate are used as excipients. Mannitol, behenicol glyceryl ester, and magnesium stearate all have high fluidity, and behenicol glyceryl ester has lubricating and excipient effects, which is beneficial to the compression of each tablet and reduces the generation of impurity N-nitrosoprene.
[0007] In one specific implementation, the propranolol hydrochloride tablets further include 0.1 to 0.5 parts by weight of a binder, 0.05 to 0.1 parts by weight of a sustained-release agent, 0.05 to 0.1 parts by weight of a retardant, and 0.01 to 0.05 parts by weight of an inhibitor.
[0008] In one specific implementation, the inhibitor comprises a mixture of crospovidone, alanine, and glycine.
[0009] By adopting the above technical solution, cross-linked polyvinylpyrrolidone allows alanine and glycine to be uniformly dispersed in the raw materials. Alanine and glycine can effectively inhibit the formation of N-nitrosoprene propranolol, thereby reducing the side effects of propranolol hydrochloride tablets.
[0010] In one specific implementation, the weight ratio of the cross-linked polyvinylpyrrolidone, the alanine, and the glycine is 1:(3-4):(3-4).
[0011] By adopting the above technical solution, this application further limits the ratio of cross-linked polyvinylpyrrolidone, alanine, and glycine, thereby further reducing the formation of N-nitrosoprene propranolol.
[0012] In one specific embodiment, the adhesive comprises polyvinylpyrrolidone and hydroxypropyl methylcellulose. In another specific embodiment, the slow-release agent comprises one or a mixture of hydroxypropyl cellulose and alginate.
[0013] By adopting the above technical solutions, hydroxypropyl cellulose and alginate can delay the absorption, release and distribution of propranolol hydrochloride tablets in the body, improve the efficacy of propranolol hydrochloride tablets, reduce the frequency of medication for patients, and improve compliance.
[0014] In one specific implementation, the retardant includes one or more of monoglycerides, hydrogenated castor oil, and beeswax.
[0015] By adopting the above technical solution, using monoglycerides, hydrogenated castor oil, and beeswax, the release of the drug effect of propranolol hydrochloride tablets can be further delayed.
[0016] Secondly, this application provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, which adopts the following technical solution:
[0017] A method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content includes the following steps:
[0018] First, mix propranolol hydrochloride with glyceryl behenate for 3-5 minutes, then add mannitol and mix for 3-5 minutes. Finally, add magnesium stearate, binder, sustained-release agent, retardant, and inhibitor and mix for 5-7 minutes. Compress the mixture into tablets and dispense them to obtain propranolol hydrochloride tablets.
[0019] By adopting the above technical solution and using the above methods, propranolol hydrochloride tablets with good tableting effect can be obtained.
[0020] In summary, this application includes at least one of the following beneficial technical effects:
[0021] 1. In this application, glyceryl behenate and crospovidone enable alanine and glycine to be uniformly dispersed in the raw materials. Glyceryl behenate, alanine, and glycine can effectively inhibit the formation of N-nitrosoprene impurities, thereby improving the stability and safety of the tablets.
[0022] 2. In this application, mannitol, glyceryl behenate, and magnesium stearate are used as excipients. Mannitol, glyceryl behenate, and magnesium stearate all have high fluidity, and glyceryl behenate has lubricating and excipient effects, which is beneficial to tablet forming, improves compressibility, and makes the tablet surface smooth.
[0023] 3. The method in this application involves first mixing propranolol hydrochloride with glyceryl behenate, then adding mannitol and mixing again, and finally adding magnesium stearate, binder, sustained-release agent, blocker, and inhibitor and mixing again before tableting. This results in tablets with better sustained-release effect, prolonged efficacy, and improved patient compliance. Detailed Implementation
[0024] The present application will be further described in detail below with reference to the embodiments.
[0025] All raw materials used in the examples are commercially available.
[0026] Example
[0027] Example 1
[0028] Example 1 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0029] First, mix 0.2 kg of propranolol hydrochloride with 0.2 kg of behenicol glyceride for 4 min, then add 2 kg of mannitol and mix for 4 min, and finally add 0.05 kg of magnesium stearate and mix for 6 min. Compress the mixture into tablets and dispense them to obtain propranolol hydrochloride tablets.
[0030] Example 2
[0031] Example 2 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0032] First, mix 0.24 kg of propranolol hydrochloride with 0.24 kg of behenicol glyceride for 4 min, then add 2.12 kg of mannitol and mix for 4 min, and finally add 0.078 kg of magnesium stearate and mix for 6 min. Compress the mixture into tablets and package them to obtain propranolol hydrochloride tablets.
[0033] Example 3
[0034] Example 3 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0035] First, mix 0.3 kg of propranolol hydrochloride with 0.3 kg of behenicol glyceride for 4 min, then add 2.3 kg of mannitol and mix for 4 min, and finally add 0.1 kg of magnesium stearate and mix for 6 min. Compress the mixture into tablets and package them to obtain propranolol hydrochloride tablets.
[0036] Example 4
[0037] Example 4 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0038] First, 0.24 kg of propranolol hydrochloride and 0.24 kg of glyceryl behenate were mixed for 4 min. Then, 2.12 kg of mannitol was added and mixed for 4 min. Finally, 0.078 kg of magnesium stearate, 0.3 kg of binder, 0.075 kg of sustained-release agent, and 0.075 kg of inhibitor were added and mixed for 6 min. The mixture was then compressed into tablets and packaged to obtain propranolol hydrochloride tablets. The binder was a mixture of polyvinylpyrrolidone and hydroxypropyl methylcellulose, with a weight ratio of 1:1. The sustained-release agent was a mixture of hydroxypropyl cellulose and alginate, with a weight ratio of 1:1. The inhibitor was hydrogenated castor oil.
[0039] Example 5
[0040] Example 5 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0041] First, 0.24 kg of propranolol hydrochloride and 0.24 kg of glyceryl behenate were mixed for 4 min. Then, 2.12 kg of mannitol was added and mixed for 4 min. Finally, 0.078 kg of magnesium stearate, 0.3 kg of binder, 0.075 kg of sustained-release agent, 0.075 kg of inhibitor, and 0.03 kg of inhibitor were added and mixed for 6 min. The mixture was then compressed into tablets and packaged to obtain propranolol hydrochloride tablets. The binder was a mixture of polyvinylpyrrolidone and hydroxypropyl methylcellulose, with a weight ratio of 1:1. The sustained-release agent was a mixture of hydroxypropyl cellulose and alginate, with a weight ratio of 1:1. The inhibitor was hydrogenated castor oil. The inhibitor was a mixture of crospovidone, alanine, and glycine, with a weight ratio of 1:2.5:2.5.
[0042] Example 6
[0043] Example 6 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0044] First, 0.24 kg of propranolol hydrochloride and 0.24 kg of glyceryl behenate were mixed for 4 min. Then, 2.12 kg of mannitol was added and mixed for 4 min. Finally, 0.078 kg of magnesium stearate, 0.3 kg of binder, 0.075 kg of sustained-release agent, 0.075 kg of inhibitor, and 0.03 kg of inhibitor were added and mixed for 6 min. The mixture was then compressed into tablets and packaged to obtain propranolol hydrochloride tablets. The binder was a mixture of polyvinylpyrrolidone and hydroxypropyl methylcellulose, with a weight ratio of 1:1. The sustained-release agent was a mixture of hydroxypropyl cellulose and alginate, with a weight ratio of 1:1. The inhibitor was hydrogenated castor oil. The inhibitor was a mixture of crospovidone, alanine, and glycine, with a weight ratio of 1:3:3.
[0045] Example 7
[0046] Example 7 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0047] First, 0.24 kg of propranolol hydrochloride and 0.24 kg of glyceryl behenate were mixed for 4 min. Then, 2.12 kg of mannitol was added and mixed for 4 min. Finally, 0.078 kg of magnesium stearate, 0.3 kg of binder, 0.075 kg of sustained-release agent, 0.075 kg of inhibitor, and 0.03 kg of inhibitor were added and mixed for 6 min. The mixture was then compressed into tablets and packaged to obtain propranolol hydrochloride tablets. The binder was a mixture of polyvinylpyrrolidone and hydroxypropyl methylcellulose, with a weight ratio of 1:1. The sustained-release agent was a mixture of hydroxypropyl cellulose and alginate, with a weight ratio of 1:1. The inhibitor was hydrogenated castor oil. The inhibitor was a mixture of crospovidone, alanine, and glycine, with a weight ratio of 1:3.5:3.5.
[0048] Example 8
[0049] Example 8 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0050] First, 0.24 kg of propranolol hydrochloride and 0.24 kg of glyceryl behenate were mixed for 4 min. Then, 2.12 kg of mannitol was added and mixed for 4 min. Finally, 0.078 kg of magnesium stearate, 0.3 kg of binder, 0.075 kg of sustained-release agent, 0.075 kg of inhibitor, and 0.03 kg of inhibitor were added and mixed for 6 min. The mixture was then compressed into tablets and packaged to obtain propranolol hydrochloride tablets. The binder was a mixture of polyvinylpyrrolidone and hydroxypropyl methylcellulose, with a weight ratio of 1:1. The sustained-release agent was a mixture of hydroxypropyl cellulose and alginate, with a weight ratio of 1:1. The inhibitor was hydrogenated castor oil. The inhibitor was a mixture of crospovidone, alanine, and glycine, with a weight ratio of 1:4:4.
[0051] Example 9
[0052] Example 9 provides a method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content, comprising the following steps:
[0053] First, 0.24 kg of propranolol hydrochloride and 0.24 kg of glyceryl behenate were mixed for 4 min. Then, 2.12 kg of mannitol was added and mixed for 4 min. Finally, 0.078 kg of magnesium stearate, 0.3 kg of binder, 0.075 kg of sustained-release agent, 0.075 kg of inhibitor, and 0.03 kg of inhibitor were added and mixed for 6 min. The mixture was then compressed into tablets and packaged to obtain propranolol hydrochloride tablets. The binder was a mixture of polyvinylpyrrolidone and hydroxypropyl methylcellulose, with a weight ratio of 1:1. The sustained-release agent was a mixture of hydroxypropyl cellulose and alginate, with a weight ratio of 1:1. The inhibitor was hydrogenated castor oil. The inhibitor was a mixture of crospovidone, alanine, and glycine, with a weight ratio of 1:4.5:4.5.
[0054] Comparative Example
[0055] Comparative Example 1
[0056] Comparative Example 1 provides a method for preparing propranolol hydrochloride tablets, comprising the following steps:
[0057] First, mix 0.2 kg of propranolol hydrochloride with 2.2 kg of mannitol for 4 min, then add 0.05 kg of magnesium stearate and mix for 6 min. Compress the mixture into tablets and dispense them to obtain propranolol hydrochloride tablets.
[0058] Performance testing and release effect: According to the dissolution test method in Appendix C, Method II of the 2010 edition of the Chinese Pharmacopoeia, 900 mL of HCl solution was used as the dissolution medium. The paddle method was used at a speed of 50 rpm. The operation was carried out according to the method. The solution was taken at the specified time point and filtered through a 0.45 μm microporous membrane. At the same time, the same volume of medium was added. The filtrate was used as the test solution. The drug concentration was determined by ultraviolet spectrophotometry and the time required for 100% complete drug release was calculated.
[0059] Impurity detection: The content of N-nitrosoprene in propranolol hydrochloride tablets was tested after 30 days of storage. The lower the content of N-nitrosoprene, the fewer side effects the propranolol hydrochloride tablets would have.
[0060] Table 1 Performance test results of propranolol hydrochloride tablets
[0061]
[0062] Combining Example 1 and Comparative Example 1, the release time of propranolol hydrochloride tablets in Example 1 was prolonged, and the content of N-nitrosopranolol impurities in the propranolol hydrochloride tablets was also reduced. It can be seen that when preparing propranolol hydrochloride tablets, adding behenicol glyceryl to the formulation can improve the tableting effect of propranolol hydrochloride tablets due to the lubricating and excipient effects of behenicol glyceryl. This results in a prolonged release time of the prepared propranolol hydrochloride tablets with fewer side effects.
[0063] In conjunction with Examples 1-3, the release time of propranolol hydrochloride tablets in Examples 1-3 was not significantly different from the content of N-nitrosopranolol. This indicates that increasing the amount of raw materials used in the preparation of propranolol hydrochloride tablets has little impact on the effect of the prepared tablets.
[0064] Combining Examples 2 and 4, the release time of propranolol hydrochloride tablets in Example 4 is longer. However, the content of N-nitrosopranolol in Examples 2 and 4 is not significantly different. It can be seen that when preparing propranolol hydrochloride tablets, adding a binder composed of polyvinylpyrrolidone and hydroxypropyl methylcellulose, a sustained-release agent composed of hydroxypropyl cellulose and alginate, and a retardant hydrogenated castor oil to the raw materials can prolong the release time of propranolol hydrochloride tablets.
[0065] Combining Examples 4 and 5, the content of N-nitrosoprene in Example 5 was lower, but the release time of propranolol hydrochloride tablets in Example 5 was shorter. This shows that when preparing propranolol hydrochloride tablets, an inhibitor composed of cross-linked povidone, alanine, and glycine was added to the raw materials. Cross-linked povidone allowed alanine and glycine to be evenly dispersed in the raw materials. By utilizing the combination of alanine and glycine, the formation of N-nitrosoprene could be effectively inhibited, thereby reducing the side effects of propranolol hydrochloride tablets, but it would accelerate the release time of propranolol hydrochloride tablets.
[0066] In conjunction with Examples 5-9, the release time of propranolol hydrochloride tablets in Examples 5-9 did not change significantly, but the content of N-nitrosopranolol in Examples 6-8 was low. It can be seen that when an inhibitor composed of cross-linked povidone, alanine and glycine is added, the preferred weight ratio of cross-linked povidone, alanine and glycine in the inhibitor is 1:(3-4):(3-4), and the prepared propranolol hydrochloride tablets have fewer side effects.
[0067] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.
Claims
1. A propranolol hydrochloride tablet with low N-nitrosopropranolol impurity content, characterized in that: The propranolol hydrochloride tablets comprise the following components in parts by weight: 0.2-0.3 parts propranolol hydrochloride, 2.0-2.3 parts mannitol, 0.2-0.3 parts glyceryl behenate, 0.05-0.1 parts magnesium stearate, 0.1-0.5 parts binder, 0.05-0.1 parts sustained-release agent, 0.05-0.1 parts blocker, and 0.01-0.05 parts inhibitor; the inhibitor comprises a mixture of crospovidone, alanine, and glycine; the blocker comprises one or more of monoglycerides, hydrogenated castor oil, and beeswax.
2. The propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content according to claim 1, characterized in that: The weight ratio of the cross-linked polyvinylpyrrolidone, the alanine, and the glycine is 1:(3-4):(3-4).
3. The propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content according to claim 2, characterized in that: The adhesive comprises one or a mixture of both of polyvinylpyrrolidone and hydroxypropyl methylcellulose.
4. The propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content according to claim 1, characterized in that: The sustained-release agent includes one or a mixture of both of hydroxypropyl cellulose and alginate.
5. A method for preparing propranolol hydrochloride tablets with low N-nitrosopropranolol impurity content as described in any one of claims 1-4, characterized in that: Includes the following steps: First, mix propranolol hydrochloride with glyceryl behenate for 3-5 minutes, then add mannitol and mix for 3-5 minutes. Finally, add magnesium stearate, binder, sustained-release agent, retardant, and inhibitor and mix for 5-7 minutes. Compress the mixture into tablets and dispense them to obtain propranolol hydrochloride tablets.
Citation Information
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