Preparation method of small-particle-size terazosin hydrochloride

Abstract

The invention relates to a preparation method of small-particle-size terazosin hydrochloride with low ethanol solvent residue, and belongs to the technical field of medicine crystallization. A terazosin hydrochloride crude product is subjected to heat preservation pulping in ethyl alcohol, then water is added, heat preservation pulping is performed for crystal transformation, and filtering and drying are performed. According to the method, the problems that in the prior art, a small-particle-size terazosin hydrochloride product is high in solvent residue, the particle size is difficult to accurately control, and large-scale production is difficult to carry out are solved, and the technical problems can be effectively solved through the technical scheme.

Description

Technical Field

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

[0002] Terazosin Hydrochloride, chemical name is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydrofuranyl)carbonyl]piperazine hydrochloride, white crystalline solid powder, the structural formula is shown below. Terazosin Hydrochloride is a new type of long-acting selective α- 1- Norepinephrine receptor blockers are FDA-approved drugs for the treatment of hypertension and benign prostatic hyperplasia.

[0003]

[0004] At present, terazosin hydrochloride has been approved for marketing in the form of solid preparations (tablets and capsules). The particle size of the API is often negatively correlated with the dissolution rate and solubility of the solid preparation. Therefore, in order to improve the bioavailability of the solid preparation and reduce the toxic side effects, the particle size of the API can be reduced. Usually, small-particle APIs can be prepared by crushing or crystallization. Among them, the crushing method may cause static electricity to be generated by friction during the crushing process, causing product agglomeration and poor fluidity, resulting in a large amount of API loss affecting the yield, and causing dust pollution that harms human health; in addition, the risk of microbial contamination of the API increases during the crushing process, and the heat generated may cause thermal degradation of the product, thereby affecting the safety and effectiveness of the product. The use of crystallization to prepare small-particle products can effectively avoid the problems caused by the crushing method.

[0005] According to WO9925715A1, terazosin hydrochloride has four polymorphs, among which the original terazosin hydrochloride preparation adopts a dihydrate crystal form. Terazosin hydrochloride is slightly soluble in water. In order to increase the dissolution rate and dissolution of the drug, thereby improving the bioavailability of the drug, terazosin hydrochloride with small particle size is usually prepared to meet the needs of drug preparation production.

[0006] In the patent CN1563001A, the crystallization solvent is 95% ethanol. Terazosin hydrochloride is dissolved by stirring at 60-65°C, and then placed in a refrigerator for rapid cooling and crystallization to obtain terazosin hydrochloride. Although the particle size of the obtained sample is less than 40 microns, the ethanol solvent in the sample remains at about 1%. In addition, the preparation method is only suitable for laboratory test scale, and industrial scale-up is difficult to achieve. The crystallization preparation method used in the patent US20070161791A1 is similar to the above method, with only a slight difference in the amount of ethanol used, and the obtained product still has the above process defects. The patent CN106619548A reports a preparation method for terazosin hydrochloride, which is obtained by acid-base reaction of terazosin free base and hydrochloric acid, adding activated carbon, filtering while hot, cooling and crystallizing the filtrate, and drying to obtain white crystalline terazosin hydrochloride. The obtained sample particle size D90 is greater than 30 microns, and the ethanol solvent in the sample remains at about 1%, which still cannot meet the requirements of ICH Q3C.

[0007] Patent CN114031611A reports a method for preparing terazosin hydrochloride with small particle size and low ethanol residue. This method prepares small-particle products by introducing ultrasonic crystallization, but with batch expansion, the volume of the crystallizer increases, and the problem of uneven sound wave distribution during ultrasonic crystallization becomes more and more significant, which makes it impossible to achieve industrial scale-up. The vibration caused by ultrasonic crystallization poses a huge challenge to the durability of the crystallizer, and a large amount of heat will be generated in this process, which may lead to thermal degradation and affect the purity of the product. In addition, although the ethanol residue of the product prepared by this method is lower than that of the preparation method reported in other literature, the ethanol residue is still about 5000ppm, which is the residual limit specified by ICH Q3C. Therefore, it can be inferred that this method is risky and cannot ensure the continuous and stable production of safe, effective and quality-controlled small-particle products.

[0008] Therefore, it is of great value to develop a new method for preparing terazosin hydrochloride with small particle size to ensure the feasibility of production scale-up and industrialization. Summary of the invention

[0009] Technical problem: In view of the above-mentioned problems such as high solvent residue in small-particle terazosin hydrochloride products, difficulty in precise particle size control, and difficulty in large-scale production, the technical solution of the present invention can effectively solve the above-mentioned technical problems.

[0010] Technical solution: The present invention adopts a method for realizing precise control of product particle size by mutual transformation of different crystal forms, controls the crystal transformation process of terazosin hydrochloride, pulps the crude terazosin hydrochloride in ethanol at low temperature to obtain a crystal monohydrate, then adds an appropriate amount of water to pulp and crystallize at low temperature to obtain the target crystal dihydrate, and then filters, washes, dries, and collects the material to obtain a small-particle product.

[0011] Wherein, preferably, the mass volume ratio of the crude terazosin hydrochloride to ethanol is (w / v) 1:8-1:12; Preferably, the volume ratio of water to ethanol added is (v / v) 1:10-1:12; Preferably, the beating temperature is 0°C-15°C; Preferably, the crude product is kept in ethanol for pulping for 1 h to 2 h; Preferably, the heat preservation and beating time after adding water is 2h-5h; Preferably, the drying temperature is 35°C-50°C.

[0012] Technical effects: 1) By controlling the crystallization process of terazosin hydrochloride, precise control of the particle size of terazosin hydrochloride is achieved. On the one hand, it ensures the process stability and repeatability of small-particle products and large-scale production. On the other hand, the ethanol residue in the product is far less than the limit specified by ICH, thereby ensuring the safety, effectiveness and quality control of the preparation.

[0013] 2) Compared with the existing methods of preparing small-particle samples by ultrasonic crystallization, crushing, etc., this method is simple to operate and more suitable for industrial production.

[0014] 3) The D90 of the terazosin hydrochloride raw material prepared by this method can be stably controlled to be less than 13 μm. The use of raw materials with small particle size can improve the dissolution of the drug preparation, thereby improving the bioavailability of the drug preparation and reducing toxic side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 It is the particle size detection spectrum of terazosin hydrochloride prepared in Example 1; Figure 2 It is the particle size detection spectrum of terazosin hydrochloride prepared in Example 2; Figure 3 It is the particle size detection spectrum of terazosin hydrochloride prepared in Example 3; Figure 4 It is the particle size detection spectrum of terazosin hydrochloride prepared in Example 4.

[0016] Specific implementation measures Example 1

[0017] 20g of crude terazosin hydrochloride and 160mL of ethanol were added to a 500mL reaction bottle, and the mixture was slurried at 300 rpm for 1 hour at 15°C-20°C, and then 20mL of water was added, and the mixture was slurried for 2 hours at a temperature of 300 rpm. The mixture was filtered, washed with 40mL of ethanol, and dried at 35°C for 14 hours to obtain 18.2g of white solid powder with a yield of 90.1% and a purity of 99.93%. (Particle size D10 = 1.037μm, D50 = 3.764μm, D90 = 12.311μm). Example 2

[0018] 18g of crude terazosin hydrochloride and 180mL of ethanol were added to a 500mL reaction bottle, and the mixture was slurried at a stirring speed of 400 rpm at a temperature of 10℃-15℃ for 1.5 hours, and then 16.5mL of water was added, and the mixture was kept warm and slurried for 3 hours, filtered, washed with 40mL of ethanol, and dried at 40℃ for 16 hours to obtain 16.5g of white solid powder with a yield of 91.7% and a purity of 99.91%. (Particle size D10 = 0.817μm, D50 = 2.644μm, D90 = 9.094μm). Example 3

[0019] 20g of crude terazosin hydrochloride and 240mL of ethanol were added to a 500mL reaction bottle, and the mixture was slurried at a stirring speed of 500 rpm for 2 hours at a temperature of 5℃-10℃, and then 20mL of water was added, and the mixture was kept warm and slurried for 5 hours, filtered, washed with 40mL of ethanol, and dried at 45℃ for 13 hours to obtain 18.6g of white solid powder with a yield of 93.0% and a purity of 99.94%. (Particle size D10 = 0.804μm, D50 = 2.562μm, D90 = 8.556μm). Example 4

[0020] 24g of crude terazosin hydrochloride and 240mL of ethanol were added to a 500mL reaction bottle, and the mixture was slurried at 600 rpm for 2 hours at 0℃-5℃, then 29mL of water was added, and the mixture was slurried for 4 hours at a temperature of 400 rpm, filtered, washed with 40mL of ethanol, and dried at 50℃ for 8 hours to obtain 22.3g of white solid powder with a yield of 92.9% and a purity of 99.90%. (Particle size D10 = 0.936μm, D50 = 3.665μm, D90 = 7.267μm). Test Example 1 Residual Dissolution Test

[0021] The terazosin hydrochloride bulk drug prepared in Example 1, Example 2, Example 3 and Example 4 were respectively taken, and the ethanol residue in the terazosin hydrochloride bulk drug was detected by headspace gas phase method. The experimental results are shown in Table 1.

[0022]

[0023] According to the experimental results, it can be judged that the smaller the particle size of the terazosin hydrochloride bulk drug, the greater the ethanol residue, but the maximum residual ethanol detected in the terazosin hydrochloride bulk drug prepared in Example 1, Example 2, Example 3 and Example 4 is 1869ppm, which is much smaller than the limit of 5000ppm specified in ICH Q3C, which shows that the preparation process can not only obtain a small particle size product but also effectively remove the ethanol residue, thereby ensuring the safety, effectiveness and quality controllability of the small particle size terazosin hydrochloride bulk drug.

[0024] Test Example 2 Stability Test The small-particle terazosin hydrochloride bulk drug prepared in Example 4 was subjected to an accelerated stability test (40°C ± 2.0°C, 75% RH ± 5% RH). The experimental results are shown in Table 2.

[0025]

[0026] From the above experimental results, it can be seen that the prepared small-particle terazosin hydrochloride bulk drug has good chemical stability during the accelerated stability test, the particles do not agglomerate to increase the particle size, and the powder properties remain loose and non-agglomerated. It shows that the small-particle terazosin hydrochloride bulk drug prepared by the present invention can stably meet the formulation requirements.

Claims

1. A method for preparing a small-particle terazosin hydrochloride with low ethanol solvent residue, characterized in that The crude terazosin hydrochloride product is slurried in ethanol for a period of time, and then water is added to slurry for a period of time, filtered, and finally washed with ethanol and dried.

2. The preparation method according to claim 1, characterized in that The feed mass volume ratio of the crude terazosin hydrochloride product to ethanol is 1:8-1:

12.

3. The preparation method according to claim 1, characterized in that The volume ratio of water to ethanol added is 1:10-1:

12.

4. The preparation method according to claim 1, characterized in that The beating temperature is 0℃-15℃.

5. The preparation method according to claim 1, characterized in that The crude product is kept warm and pulped in ethanol for 1 h to 2 h.

6. The preparation method according to claim 1, characterized in that After adding water, the heat preservation and beating time is 2h-5h.

7. The preparation method according to claim 1, characterized in that The drying temperature is 35℃-50℃.

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