Preparation method of small-granularity donepezil hydrochloride crystal

Abstract

The invention belongs to the technical field of medicine crystallization, and relates to a method for preparing small-particle-size donepezil hydrochloride, which comprises the following steps: dissolving a donepezil hydrochloride crude product in methanol, dropwise adding the dissolved feed liquid into methyl tert-butyl ether, cooling, crystallizing, carrying out suction filtration, and drying to obtain the small-particle-size donepezil hydrochloride. The small-particle-size donepezil hydrochloride is directly prepared through a crystallization means, the donepezil hydrochloride bulk drug is accurately controlled within the particle size D90 range of 5-20 microns, stability is good, agglomeration is avoided, fluidity is good, mechanical micronization is not needed, operation is easy, industrial production is convenient, and the method is suitable for industrial production. The granularity of donepezil hydrochloride can be accurately controlled through the crystallization method, so that the safety, effectiveness and controllable quality of a solid preparation of donepezil hydrochloride are ensured.

Description

Technical Field

[0001] The invention relates to a preparation method of small-particle donepezil hydrochloride, belonging to the technical field of drug crystallization. Background Art

[0002] Donepezil Hydrochloride, chemical name is (±)-2-[(1-benzyl-4-piperidinyl)methyl]-5,6-dimethoxy-1-indanone hydrochloride, white crystalline solid powder, the structural formula is shown below. Donepezil Hydrochloride is a highly selective, long-acting, reversible acetylcholinesterase inhibitor developed by Eisai Co., Ltd. of Japan for the treatment of mild to moderate Alzheimer's disease. It inhibits the activity of acetylcholinesterase, reduces the decomposition rate of acetylcholine in the synaptic cleft, increases the acetylcholine content in the synaptic cleft directly involved in neurotransmission, and thus improves the cognitive function of patients with Alzheimer's disease.

[0003]

[0004] At present, the solid preparations of donepezil hydrochloride that have been approved for marketing mainly include common dosage forms such as tablets, capsules and orodisintegrating tablets. In the field of drug research and development, improving the bioavailability of solid preparations and reducing their toxic side effects have always been an important topic of concern. Studies have found that reducing the particle size of donepezil hydrochloride API is one of the effective ways to achieve this goal. There are two main methods for preparing small-particle donepezil hydrochloride APIs: crushing and crystallization. Among them, the crushing method has many disadvantages in the actual operation process. During the crushing process, static electricity is easily generated between drug particles due to friction, which not only causes the product to agglomerate and causes the drug particles to adhere to each other, but also significantly reduces its fluidity, bringing difficulties to subsequent processing. In addition, this agglomeration and decreased fluidity may also lead to the loss of APIs, thereby affecting the yield of the product. At the same time, the dust generated during the crushing process not only pollutes the production environment, but may also be inhaled by operators, causing potential harm to human health. It is worth noting that the pulverization process also increases the risk of microbial contamination of the API, and the heat generated during the pulverization process may trigger a thermal degradation reaction of the product, posing a serious threat to the quality and safety of the drug. The use of a crystallization method to prepare a small-particle size of donepezil hydrochloride API can effectively overcome the above-mentioned series of problems that occur during the pulverization process. By accurately controlling the various parameters in the crystallization process, a small-particle product with uniform particle size and good fluidity can be obtained, while avoiding the generation of problems such as static electricity, agglomeration, dust pollution, microbial contamination, and thermal degradation. However, it is regrettable that through extensive retrieval and in-depth research on existing literature, it is found that there is currently no publicly reported method for preparing a small-particle size of donepezil hydrochloride API.

[0005] Therefore, in view of the current lack of small-particle donepezil hydrochloride API preparation methods and the many drawbacks of the pulverization method, the development of a new and effective small-particle donepezil hydrochloride preparation method can not only provide reliable technical support for the smooth expansion of its production scale, effectively solve the key problems in the process of transformation from laboratory research and development to industrial production, but also effectively promote the industrialization process of the API and meet the market demand for high-quality donepezil hydrochloride solid preparations. From a commercial perspective, the successful development of this innovative preparation method will significantly enhance the core competitiveness of enterprises in this field, create huge economic benefits, and have important commercial value that cannot be ignored. Summary of the invention

[0006] The technical problem solved by the present invention is as follows: In order to improve bioavailability and reduce toxic side effects, the present invention provides a method for preparing a small-particle donepezil hydrochloride raw material with high stability and convenient for industrial production.

[0007] Technical solution: Dissolve the crude donepezil hydrochloride in methanol, then drip the dissolved liquid into methyl tert-butyl ether, cool and crystallize, filter and dry to obtain small-particle donepezil hydrochloride. Specifically, the following steps are included: Step 1: Add crude donepezil hydrochloride to methanol, heat to 50-60° C., and stir to dissolve; Step 2: slowly drop the solution of step 1 into methyl tert-butyl ether at a certain temperature, keep warm and stir for 2-3 hours, then cool to 0-10°C, and keep warm and stir for another 2-2.5 hours; Step 3: Filter the precipitated solid and dry it to obtain the small-particle-sized donepezil hydrochloride raw material.

[0008] Wherein, preferably, the solid-liquid ratio of the crude donepezil hydrochloride to methanol is (w / v) 1:7-1:10; Preferably, the liquid-to-liquid ratio of methanol to methyl tert-butyl ether is (v / v) 1:2-1:5; Preferably, the temperature range of methyl tert-butyl ether is 0-35°C; Preferably, the time for adding the methanol solution of donepezil hydrochloride to methyl tert-butyl ether is 2-4 hours; Preferably, the drying temperature is 55-65°C.

[0009] Technical effects: (1) Small-particle donepezil hydrochloride is directly prepared from the crude product by crystallization, without the need for mechanical micronization. The operation is simple and convenient for industrial production. The yield is greater than 90% and the purity is greater than 99.9%.

[0010] (2) The crystallization method can achieve precise control of the particle size of donepezil hydrochloride raw material within the range of D90 5-20μm, with good stability, no agglomeration and good fluidity. The precise control of the particle size of donepezil hydrochloride ensures the safety, effectiveness and quality control of its solid preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 is a particle size detection spectrum of donepezil hydrochloride prepared in Example 1; Figure 2 is a particle size detection spectrum of donepezil hydrochloride prepared in Example 2; Figure 3 is the particle size detection spectrum of donepezil hydrochloride prepared in Example 3; Figure 4 This is the particle size detection spectrum of donepezil hydrochloride prepared in Example 4.

[0012] Specific implementation measures The relevant substances used in the experiment were detected by high performance liquid chromatography, and the chromatographic conditions were as follows: chromatographic column: Thermo Hypersil GOLD C18 (150 mm×4.6 mm, 5μm); mobile phase: weigh 2.5 g of sodium 1-decane sulfonate and dissolve it in 650 ml of water, add 350 ml of acetonitrile and 1 ml of perchloric acid and mix evenly (pH is about 1.8), flow rate: 1.0 ml / min; detection wavelength: 271 nm; column temperature: 35℃; injection volume: 20μl.

[0013] As used herein, the term "D10" refers to the particle size corresponding to the cumulative particle size distribution number of a sample when it reaches 10%. Its physical meaning is that the particles with a particle size smaller than it account for 10%. Similarly, the term "D50" refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample when it reaches 50%; its physical meaning is that the particles with a particle size larger than it account for 50%, and the particles with a particle size smaller than it also account for 50%. D50 is also called the median diameter or median particle size. The term "D90" refers to the particle size corresponding to the cumulative particle size distribution number of a sample when it reaches 90%. Its physical meaning is that the particles with a particle size smaller than it account for 90%. The particle size distribution is measured by Malvern MS3000 particle size analyzer. Example 1

[0014] 32g crude donepezil hydrochloride and 320mL methanol were added to a 500mL reaction bottle, heated to 50-60℃, stirred to dissolve, filtered, and slowly added the filtrate to a 1000mL reaction bottle containing 640mL methyl tert-butyl ether at a stirring speed of 100 rpm within 2 hours. During the dropping process, the temperature was kept at 30-35℃, then slowly cooled to 0-5℃, stirred at this temperature for 2-3 hours, filtered, and dried at 55℃ for 10 hours to obtain 30.2g white solid powder with a yield of 94.38% and a purity of 99.94%. (Particle size D10=0.57μm, D50=1.88μm, D90=5.56μm). Example 2

[0015] 20g crude donepezil hydrochloride and 180mL methanol were added to a 500mL reaction bottle, the temperature was raised to 50℃-60℃, the solution was stirred and filtered, and the filtrate was slowly added dropwise to a 1000mL reaction bottle containing 540mL methyl tert-butyl ether at a stirring speed of 150 rpm within 2.5 hours. During the addition, the temperature was kept at 20℃-25℃, then slowly cooled to 0-5℃, stirred at this temperature for 2-3 hours, filtered, and dried at 60℃ for 7 hours to obtain 18.5g white solid powder with a yield of 92.50% and a purity of 99.91%. (Particle size D10=1.01μm, D50=3.98μm, D90=9.85μm). Example 3

[0016] 30 g of crude donepezil hydrochloride and 240 mL of methanol were added to a 500 mL reaction bottle, the temperature was raised to 50°C-60°C, the solution was stirred and filtered, and the filtrate was slowly added dropwise to a 2000 mL reaction bottle containing 960 mL of methyl tert-butyl ether at a stirring speed of 250 rpm within 2.5 hours. During the addition, the temperature was kept at 10°C-15°C, and then the temperature was slowly lowered to 0-5°C, the mixture was stirred at this temperature for 2-3 hours, filtered, and dried at 65°C for 8 hours to obtain 28.6 g of white solid powder with a yield of 95.33% and a purity of 99.95%. (Particle size D10=1.09μm, D50=5.93μm, D90=12.01μm). Example 4

[0017] 15 g of crude donepezil hydrochloride and 150 mL of methanol were added to a 500 mL reaction bottle, the temperature was raised to 50°C-60°C, the solution was stirred and filtered, and the filtrate was slowly added dropwise to a 2000 mL reaction bottle containing 750 mL of methyl tert-butyl ether at a stirring speed of 500 rpm within 3 hours. During the addition, the temperature was kept at 0°C-5°C, and then the mixture was stirred and insulated for 2-3 hours, filtered, and dried at 65°C for 10 hours to obtain 13.9 g of white solid powder with a yield of 92.67% and a purity of 99.93%. (Particle size D10=2.66μm, D50=7.74μm, D90=17.0μm). Test Example 1 Dissolution Test

[0018] The donepezil hydrochloride raw materials prepared in Example 1, Example 2, Example 3 and Example 4 were respectively prepared into tablets according to patent CN114272219A, and the dissolution was investigated by the second method (paddle method) of Appendix XD of Part II of the 2020 edition of the Chinese Pharmacopoeia, wherein the dissolution medium was pH 6.8 phosphate buffer, the rotation speed was 50 rpm, the temperature was 37±0.5°C, and the dissolution medium was 900 mL. The experimental results are shown in Table 1.

[0019]

[0020] Based on the above experimental results, it can be clearly found that the particle size of donepezil hydrochloride raw material shows a clear rule, that is, the smaller the particle size, the faster the dissolution rate and the higher the solubility of the tablets prepared with this raw material in the dissolution process. It can be reasonably inferred that there is a significant negative correlation between the particle size of donepezil hydrochloride raw material and its dissolution in the body. From the perspective of drug preparation development, it has significant advantages to choose to use small-particle-sized donepezil hydrochloride raw material for preparation research and development. The preparation developed based on the small-particle-sized donepezil hydrochloride raw material can achieve a faster dissolution rate and a higher dissolution rate, which enables the drug to be absorbed and utilized by the human body more quickly and fully. In this way, it can not only effectively improve the bioavailability of the drug, so that the drug can exert a more ideal therapeutic effect in the body, but also reduce the toxic and side effects of the drug to a certain extent, reduce the additional burden on patients due to adverse drug reactions, and provide a stronger guarantee for the safety and effectiveness of clinical medication. Test Example 2 Accelerated stability test

[0021] The small-particle donepezil hydrochloride bulk drug substance prepared in Example 4 was subjected to an accelerated stability test (40°C ± 2°C, 75% RH ± 5% RH). The purity of donepezil hydrochloride bulk drug substance was tested using the liquid phase method reported in "HPLC Method for Testing Related Substances in Donepezil Hydrochloride Preparations" by Zhao Zhe et al. The experimental results are shown in Table 2.

[0022]

[0023] According to the above experimental results, under the conditions of accelerated stability test, the small-particle donepezil hydrochloride API not only exhibits good chemical stability, but also the particles do not agglomerate, the particle size remains stable, and the powder properties remain loose and do not agglomerate. This shows that the small-particle donepezil hydrochloride API prepared by the present invention can stably meet the requirements of the preparation. Test Example 3 Residual Dissolution Test

[0024] The donepezil hydrochloride bulk drugs prepared in Example 1, Example 2, Example 3 and Example 4 were respectively taken, and the residual amounts of methanol and methyl tert-butyl ether in the donepezil hydrochloride bulk drug were detected by headspace gas phase method. The experimental results are shown in Table 3.

[0025]

[0026] According to the experimental results, it can be judged that the smaller the particle size of the donepezil hydrochloride raw material, the greater the residual amount of methanol and methyl tert-butyl ether. However, in the donepezil hydrochloride raw materials prepared in Example 1, Example 2, Example 3 and Example 4, the maximum residual detection amounts of methanol and methyl tert-butyl ether were 1124 ppm and 709 ppm, respectively, which are far lower than the limits of 3000 ppm and 5000 ppm specified in ICH Q3C. This shows that the preparation process can not only obtain small-particle products, but also effectively remove the residues of methanol and methyl tert-butyl ether, thereby ensuring the safety, effectiveness and quality controllability of small-particle donepezil hydrochloride raw materials.

Claims

1. A method for preparing small-particle size donepezil hydrochloride, characterized in that The crude product of donepezil hydrochloride was dissolved in methanol, and then the dissolved liquid was dropped into methyl tert-butyl ether, cooled for crystallization, filtered and dried.

2. The preparation method according to claim 1, characterized in that The specific preparation method comprises the following steps: Step 1: Add crude donepezil hydrochloride to methanol, heat to 50-60°C and stir to dissolve; Step 2: slowly drop the solution of step 1 into methyl tert-butyl ether at a certain temperature, keep warm and stir for 2-3 hours, then cool to 0-10°C, and keep warm and stir for another 2-2.5 hours; Step 3: Filter the precipitated solid and dry it to obtain the small-particle-sized donepezil hydrochloride raw material.

3. The preparation method according to any one of claims 1 or 2, characterized in that The solid-liquid mass volume ratio of the crude donepezil hydrochloride and methanol added is 1:7-1:

10.

4. The preparation method according to any one of claims 1 or 2, characterized in that The liquid-liquid volume ratio of methanol to methyl tert-butyl ether is 1:2-1:

5.

5. The preparation method according to any one of claims 1 or 2, characterized in that The temperature range of methyl tert-butyl ether is 0-35°C.

6. The preparation method according to any one of claims 1 or 2, characterized in that The time for adding the methanol solution of donepezil hydrochloride to methyl tert-butyl ether dropwise is 2-4 hours.

7. The preparation method according to any one of claims 1 or 2, characterized in that The drying temperature is 55-65℃.

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