A process for the preparation of a perindopril tert-butylamine salt composition

Abstract

The application discloses a method for preparing perindopril tert-butylamine salt composition, which comprises the following steps: screening perindopril tert-butylamine salt, magnesium stearate, sodium bicarbonate and part of excipients, mixing uniformly, mixing with the rest of the excipients, tabletting, and finally packaging. Through the above process, the related substances of perindopril tert-butylamine tablet can be effectively controlled, the safety and stability of the drug are improved, the operation is convenient, and the method is suitable for commercial production.

Description

Technical Field

[0001] The invention belongs to the pharmaceutical field, specifically relating to a method for preparing a perindopril tert-butylamine salt composition. Background Technology

[0002] Perindopril tert-butylamine salt is an angiotensin-converting enzyme inhibitor used to treat cardiovascular diseases. This drug composition is sensitive to several types of degradation, particularly the formation of two degradation products: side-chain ester hydrolysis (impurity B) and intramolecular cyclization to diketopiperazines (impurity F).

[0003] Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing an improved perindopril tert-butylamine salt composition, the composition comprising the following components:

[0005]

[0006] The method includes the following steps:

[0007] a) Sieve and mix perindopril tert-butylamine salt with magnesium stearate, sodium bicarbonate and some excipients;

[0008] b) The mixture obtained in step a) is then sieved and mixed with the remaining excipients;

[0009] c) Tableting and packaging.

[0010] As a preferred embodiment of the present invention, the excipient in step a) is preferably lactose monohydrate, microcrystalline cellulose, or a mixture thereof, wherein the portion of the excipient accounts for 10%-50% of the composition content, more preferably 15%-50%.

[0011] As a preferred embodiment of the present invention, magnesium stearate accounts for 1.0-3.5% of the composition content.

[0012] As a preferred embodiment of the present invention, sodium bicarbonate accounts for 0.5-3.0% of the composition content, more preferably 1.0-3.0%.

[0013] As a preferred embodiment of the present invention, the microcrystalline cellulose accounts for 20-50% of the composition content, and the monohydrate lactose accounts for 40-70% of the composition content.

[0014] As a preferred embodiment of the present invention, the sodium bicarbonate has a particle size D 90 ≤200μm, further selected as D 90 ≤160μm.

[0015] The particle size described in this invention is determined using a laser particle size analyzer, D 90 This refers to the particle size at which 90% of the particles are cumulatively distributed, meaning that particles smaller than this size account for 90% of the total volume of all particles.

[0016] The applicant discovered that mixing magnesium stearate with perindopril tert-butylamine first is crucial to the stability of the pharmaceutical composition. By changing the order of addition, the obtained product showed improved stability compared to the original drug. Under the premise of consistent in vitro release, the stability of perindopril tert-butylamine salt was significantly improved. This was demonstrated by the fact that after 10 days of forced acceleration (temperature 60±2℃, relative humidity 75%±5%) and 6 months of accelerated conditions (temperature 40±2℃, relative humidity 75%±5%), the total impurity content in the product was ≤0.5%, and the single impurity was ≤0.3%. The impurity growth trend was significantly less than that of the product obtained by adding magnesium stearate and the original product. Therefore, the efficacy and safety of the drug were effectively guaranteed, and the preparation method was simple and could be used for large-scale production. Attached Figure Description

[0017] Figure 1 The in vitro release curve of the sample obtained in Example 9 of this invention under 0.01N HCl conditions;

[0018] Figure 2 The in vitro release curve of the sample obtained in Example 10 of this invention under 0.01N HCl conditions. Detailed Implementation

[0019] The present invention will be further described in detail below with reference to the embodiments, but the implementation methods and protection scope of the present invention are not limited thereto.

[0020] Comparative Example 1: The ingredients were prepared according to the formula in Table 1, in batches of 1 kg. Sodium bicarbonate (particle size D) was added... 90 =157μm), perindopril tert-butylamine and 40% lactose monohydrate were sieved and mixed, then the remaining lactose monohydrate, microcrystalline cellulose and silicon dioxide were sieved and mixed, and then magnesium stearate was sieved and mixed. Finally, the mixture was compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0021] Table 1

[0022]

[0023]

[0024] Comparative Example 2: The ingredients were prepared according to the formula in Table 2, in batches of 1 kg. Magnesium stearate and sodium bicarbonate (particle size D) were added. 90=157μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0025] Table 2

[0026]

[0027] Comparative Example 3: The ingredients were prepared according to the formula in Table 3, in batches of 1 kg. Magnesium stearate and sodium bicarbonate (particle size D) were added. 90 =317μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0028] Table 3

[0029]

[0030] Example 1: Prepare the ingredients according to the formula in Table 1, in batches of 1 kg. Add magnesium stearate and sodium bicarbonate (particle size D) 90 =157μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0031] Example 2: Prepare the ingredients according to the formula in Table 3, in batches of 1 kg. Add magnesium stearate and sodium bicarbonate (particle size D) 90 =157μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0032] Example 3: Prepare the ingredients according to the formula in Table 3, in batches of 1 kg. Add magnesium stearate and sodium bicarbonate (particle size D) 90 =157μm), perindopril tert-butylamine and microcrystalline cellulose are sieved and mixed, then sieved and mixed with monohydrate lactose and silicon dioxide, and finally compressed and packaged to obtain perindopril tert-butylamine tablets.

[0033] Example 4: Prepare the ingredients according to the formula in Table 4, in batches of 1 kg. Add magnesium stearate and sodium bicarbonate (particle size D) 90 =157μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0034] Table 4

[0035]

[0036] Example 5: Prepare the ingredients according to the formula in Table 5, in batches of 1 kg. Add magnesium stearate and sodium bicarbonate (particle size D) 90 =157μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0037] Table 5

[0038]

[0039] Example 6: Prepare the ingredients according to the formula in Table 6, in batches of 1 kg. Add magnesium stearate and sodium bicarbonate (particle size D) 90 =157μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0040] Table 6

[0041]

[0042] Example 7: Prepare the ingredients according to the formula in Table 7, in batches of 1 kg. Add magnesium stearate and sodium bicarbonate (particle size D) 90 =157μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0043] Table 7

[0044]

[0045] Example 8: Prepare the ingredients according to the formula in Table 3, in batches of 1 kg. Add magnesium stearate and sodium bicarbonate (particle size D) 90 =198μm), perindopril tert-butylamine and 40% monohydrate lactose were sieved and mixed, then mixed with the remaining monohydrate lactose, microcrystalline cellulose and silica, and finally compressed and packaged to obtain the finished perindopril tert-butylamine tablets.

[0046] Example 9: Experiment investigating the effect of different mixing processes of magnesium stearate on dissolution curves

[0047] The drug dissolution of the finished products obtained in Comparative Example 1 and Example 1 was tested in 0.01N HCl medium. The results are shown in the accompanying drawings. Figure 1 The results showed that the change in the magnesium stearate mixing process did not have a significant effect on the dissolution of perindopril tert-butylamine, and was consistent with... The dissolution curves are similar.

[0048] Dissolution test conditions: Dissolution test apparatus II, rotation speed 50 rpm, temperature 37℃, release medium 900 ml, 0.01 N HCl hydrochloric acid buffer, detection method: high performance liquid chromatography.

[0049] Example 10: An experiment investigating the effect of different proportions of magnesium stearate on dissolution curves.

[0050] The drug dissolution of the finished products obtained in Comparative Example 2 and Example 2 / 4 was tested in 0.01N HCl medium. The results are shown in the accompanying drawings. Figure 2 The results showed that a magnesium stearate content of 3.5% significantly affected the dissolution rate at 5 min and 10 min, but the drug was ultimately completely dissolved within 60 min, without any lubrication effect, and it was compatible with... The dissolution curves are similar.

[0051] The dissolution test conditions were the same as in Example 9.

[0052] Example 11: Experiments on the stability of related substances

[0053] The finished products obtained from Comparative Examples 1-3 and Examples 1-8 and After being placed in a constant temperature and humidity chamber under forced accelerated conditions (temperature 60±2℃, relative humidity 75%±5%) for 10 days or in a constant temperature and humidity chamber under accelerated conditions (temperature 40±2℃, relative humidity 75%±5%, the same accelerated conditions specified in the Guidelines for Stability Testing of Raw Materials and Preparations in Chapter 9001 of the 2015 edition of the Chinese Pharmacopoeia) for 6 months, the percentage of impurities in the drug composition was determined by the area normalization method. The results are shown in Tables 5 and 6, respectively.

[0054] Table 5

[0055]

[0056] Table 6

[0057]

[0058]

[0059] The results above show that the perindopril tert-butylamine tablets prepared in Examples 1, 2, 3, 4, 5, 6, 7, and 8 by modifying the magnesium stearate mixing process had a total impurity content ≤0.5% and a maximum single impurity content ≤0.3% after 10 days of accelerated testing and 6 months of accelerated testing. Furthermore, the related substances in both stability tests were better than those of the original product. The finished product exhibits good stability. Therefore, the perindopril tert-butylamine tablet formulation prepared by this invention has high stability and better meets the requirements of relevant regulations for clinical drug use.

Claims

1. A method for preparing a perindopril tert-butylamine salt composition, said composition comprising the following components: The method includes the following steps: a) Sieve and mix perindopril tert-butylamine salt with magnesium stearate, sodium bicarbonate and some excipients; b) The mixture obtained in step a) is then sieved and mixed with the remaining excipients; c) Tableting and packaging Sodium bicarbonate particle size D 90 ≤200μm, The excipient in step a) is selected from monohydrate lactose, microcrystalline cellulose, or mixtures thereof, and the portion of the excipient accounts for 10%-50% of the composition formulation content.

2. The method according to claim 1, characterized in that, The excipients described in step a) constitute 15%-50% of the composition formulation.

3. The method according to claim 1, characterized in that, Magnesium stearate accounts for 1.0-3.5% of the composition formulation.

4. The method according to claim 1, characterized in that, Sodium bicarbonate accounts for 0.5-3.0% of the composition formulation.

5. The method according to claim 1, characterized in that, Sodium bicarbonate accounts for 1.0-3.0% of the composition formulation.

6. The method according to claim 1, characterized in that, Microcrystalline cellulose accounts for 20-50% of the composition formulation, and monohydrate lactose accounts for 40-70% of the composition formulation.

7. The method according to claim 1, characterized in that, Sodium bicarbonate particle size D 90 ≤160μm.

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