Preparation method of low-solvent small-particle-size tadalafil

Abstract

The invention relates to a preparation method of low-solvent small-particle-size tadalafil, and belongs to the technical field of medicine crystallization. The method comprises the following steps: adding a tadalafil crude product into a mixed solvent of acetonitrile and water, heating, dissolving, filtering, dropwise adding filtrate into water, carrying out heat preservation, pulping, carrying out suction filtration, drying, and collecting to obtain a small-particle-size sample. The particle size of the tadalafil obtained by the method is controlled to be less than 10 microns, the dissolution behavior of an indissolvable drug solid preparation is improved, and the dissolution rate and dissolution rate of the drug are improved.

Description

Technical Field

[0001] The invention relates to a method for preparing low-solvent small-particle tadalafil, belonging to the technical field of drug crystallization. Background Art

[0002] Tadalafil, chemical name is (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2'-1,6]-pyridino[3,4-b]indole-1,4-dione, white crystalline powder, the structural formula is shown below. Tadalafil is a selective reversible inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase. Its main mechanism of action is that when the human body is sexually stimulated, it releases nitric oxide, which can inhibit specific phosphodiesterase 5, increase the level of cyclic guanosine monophosphate in the corpus cavernosum of the penis, thereby relaxing smooth muscles and dilating blood vessels. After the blood circulation is unobstructed, it flows into the corpus cavernosum of the penis, causing the penis to erect. Clinically, this drug is mainly used for the treatment of male erectile dysfunction and pulmonary hypertension and other diseases, with significant clinical efficacy and very good market application prospects.

[0003]

[0004] Tadalafil is a drug belonging to BCS Class II (low solubility and high permeability). Its dissolution is the rate-limiting step that affects drug absorption, thereby affecting the bioavailability of the drug. In order to improve the dissolution behavior of poorly soluble solid preparations, the dissolution rate and dissolution rate can be increased by using small-particle APIs. At present, there are two methods for preparing small-particle APIs: crushing and crystallization. Among them, the crushing method is easy to cause static electricity in the product during the crushing process, which leads to product agglomeration and poor fluidity, and it is easy to generate a large amount of dust, causing environmental pollution and harming the health of workers; the introduction of microorganisms and the heat generated during the crushing process may cause the product purity to decrease, thereby affecting the quality of the product. Another method is to obtain small-particle products by controlled crystallization. From the operations of the final recrystallization or refining of tadalafil that have been retrieved so far, basically, acid, alkali or multi-component mixed solvents are used. However, there is no report on the preparation method of small-particle tadalafil in the literature.

[0005] WO2004011463A1 discloses a method for refining tadalafil as follows: dissolve tadalafil in 13 times the mass of glacial acetic acid at 80°C, concentrate the solution to one third of the original volume, and then cool it to room temperature. Filter the crystals, wash them with methyl tert-butyl ether (MTBE), and dry them in a vacuum at 80°C. This refining method has the disadvantages of large amount of organic solvent, high drying temperature of acetic acid, easy residue and corrosion to equipment, and high production cost. The crystallization solvent of patent CN102367253A is a binary mixed solvent of C1-C4 alcohol and acetic acid or a ternary mixed solvent of C1-C4 alcohol, acetic acid and water. This method uses acid, which is corrosive to refining and drying equipment. Because it is a mixed organic solvent, solvent recovery is difficult.

[0006] Patent CN105061428A crystallization is to dissolve tadalafil by adjusting the pH of alcohol solution with ammonia water, and then precipitate solid by acidification. It is known that tadalafil will undergo chirality flipping under alkaline conditions to generate isomers, which increases quality risks.

[0007] The crystallization solvents of patent CN104262340A are N,N-dimethylformamide, ethanol and pure water. Multiple mixed organic solvents make solvent recovery difficult. In addition, the boiling point of N,N-dimethylformamide is 153°C and the residual limit specified by ICH Q3C is 88ppm, which is difficult to effectively remove in process engineering and poses a great risk in quality control.

[0008] WO2006049986A1 discloses that the solvents for preparing tadalafil crystal form I include one or more solvents including ketone, C3-C7 ester, N,N-dimethylformamide, dimethyl sulfoxide, ethanol, acetonitrile, chlorocarbon, tert-butyl alcohol, ethyl acetate, DMA, dioxane, and N-methylpyrrole. However, according to the method described therein, dimethyl sulfoxide is used as a solvent, and the residual amount of dimethyl sulfoxide in the obtained product is large, which does not meet the requirements of the pharmacopoeia, and the process cannot be used in production, and the particle size D90 of the obtained product is greater than 100 μm.

[0009] CN101128463A discloses that a crude tadalafil product is heated and dissolved in a solvent selected from a mixture of C2-C6 fatty alcohols and ketones or nitrile and a hydroxyl solvent to clarify, and then the remaining half of the solvent is distilled, and then stirred for 13-15 hours under reduced temperature. This operation method is cumbersome and takes a long time, resulting in energy waste, and is not suitable for industrial production.

[0010] CN107880044A discloses using a mixed solvent of acetone and dimethyl sulfoxide as a good solvent to dissolve crude tadalafil, and then dropping the dissolved material into purified water as a poor solvent. However, the boiling point of dimethyl sulfoxide is 189° C., and it is extremely difficult to remove as a residual solvent of the drug.

[0011] CN111072662A discloses that a crude tadalafil product is added to a tetrahydrofuran-acetone mixed solvent, and then 1-6% of water by volume of the mixed solvent is added, and the mixture is heated to reflux until the solution is clear, a portion of the solvent is evaporated in a vacuum, and then the temperature is continuously lowered for crystallization, and the precipitate is filtered and separated to obtain type I crystals. The obtained crystal particle size D90 is between 10-16 μm, and it is difficult to further reduce the crystal particle size by further adjusting the reaction conditions. At the same time, the acetone-tetrahydrofuran mixed solvent used is difficult to recover the solvent, which is not conducive to production.

[0012] WO2016012539A1 discloses a method for recrystallizing tadalafil, which comprises dissolving tadalafil and a mixed solvent under high pressure heating conditions, performing heat filtration, and then cooling and crystallizing. The D90 of the obtained tadalafil is greater than 100 μm. There is a risk of product precipitation during heat filtration, which is not suitable for industrial production, and the particle size is also slightly large.

[0013] Therefore, further research on the final process of tadalafil has great practical application value. Summary of the invention

[0014] Technical problem: The technical solution of the present invention overcomes the above-mentioned technical problems such as the difficulty in recovering the mixed solvents, the disadvantages of hot filtration operation, the residual tadalafil solvent, the difficulty in reducing the particle size control, and the corrosion of equipment.

[0015] Technical solution: The present invention adds crude tadalafil to a mixed solvent of acetonitrile and water, heats to dissolve, filters, drops the filtrate into water, keeps the mixture warm and slurries, vacuum filters, dries, and collects the mixture to obtain a small particle size sample.

[0016] Wherein, preferably, the volume ratio of acetonitrile to water in the mixed solvent for dissolving the crude tadalafil is (v / v) 4:1-5:1; Preferably, the mass volume ratio of the crude tadalafil added to the mixed solvent is (w / v) 1:21-1:24; Preferably, the dissolution temperature of crude tadalafil is 65°C-75°C; Preferably, the mass volume (w / v) of crude tadalafil and water added is 1:38-1:43; Preferably, the dropping time is 0.5 hours to 1.5 hours; Preferably, the temperature of the water is maintained at 0°C-5°C during the dropwise addition process; Preferably, the heat preservation and beating time is 5 to 10 hours; Preferably, the drying temperature is 45°C-55°C.

[0017] Technical effects: 1) By selecting a suitable solvent to completely dissolve tadalafil under heating conditions, the use of mixed organic solvents and high-boiling point organic solvents is limited. On the one hand, the solvent can be recycled, and on the other hand, the risk of solvent residues in the drug is directly reduced.

[0018] 2) This method is simple to operate. Compared with the existing crystallization process such as heat filtration, solvent distillation, and addition of pharmaceutical excipients, this method is simpler and more suitable for industrial production.

[0019] 3) The D90 of tadalafil obtained by this method is controlled to be less than 10 μm, and the dissolution rate and dissolution rate are increased by using a small-particle API, which can improve the dissolution behavior of poorly soluble drug preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the particle size detection spectrum of tadalafil prepared in Example 1 Figure 2 This is the particle size detection spectrum of tadalafil prepared in Example 2 Figure 3 This is the particle size detection spectrum of tadalafil prepared in Example 3 Figure 4 This is the particle size detection spectrum of tadalafil prepared in Example 3

[0021] Specific implementation measures Example 1

[0022] 30g of crude tadalafil, 126mL of water and 504mL of acetonitrile were added to a 500mL reaction bottle, stirred at 65℃-75℃ until dissolved, filtered, and the filtrate was slowly added dropwise to a 2000mL reaction bottle containing 1200mL of purified water over 1.5 hours at a stirring speed of 75 rpm. The temperature was kept at 0℃-5℃ during the addition process. After the addition was completed, the mixture was kept warm and slurried for 5 hours, filtered, and dried at 45℃ for 14 hours to obtain 27.3g of white solid powder with a yield of 90.1% and a purity of 99.95%. (Particle size D10=0.932μm, D50=3.489μm, D90=13.468μm). Example 2

[0023] 18g of crude tadalafil, 83mL of water and 374mL of acetonitrile were added to a 500mL reaction bottle, stirred at 65℃-75℃ until dissolved, filtered, and the filtrate was slowly added dropwise to a 2000mL reaction bottle containing 684mL of purified water over 1.5 hours at a stirring speed of 200 rpm. The temperature was kept at 0℃-5℃ during the addition process. After the addition was completed, the mixture was kept warm and slurried for 7 hours, filtered, and dried at 50℃ for 10 hours to obtain 17.1g of white solid powder with a yield of 95.0% and a purity of 99.96%. (Particle size D10=0.904μm, D50=2.971μm, D90=9.083μm). Example 3

[0024] 10.5 g of crude tadalafil, 50 mL of water and 200 mL of acetonitrile were added to a 250 mL reaction bottle, stirred at 65°C-75°C until dissolved, filtered, and the filtrate was added dropwise to a 1000 mL reaction bottle containing 450 mL of purified water within 1 hour at a stirring speed of 300 rpm. The temperature was kept at 0°C-5°C during the addition process. After the addition was completed, the mixture was kept warm and slurried for 10 hours, filtered, and dried at 55°C for 8 hours to obtain 8.2 g of white solid powder with a yield of 91.1% and a purity of 99.94%. (Particle size D10 = 0.770 μm, D50 = 2.371 μm, D90 = 6.435 μm). Example 4

[0025] 40.5 g of crude tadalafil, 160 mL of water and 800 mL of acetonitrile were added to a 1000 mL reaction bottle, stirred at 65°C-75°C until dissolved, filtered, and the filtrate was added dropwise to a 2000 mL reaction bottle containing 1620 mL of purified water within 0.5 hours at a stirring speed of 500 rpm. The temperature was kept at 0°C-5°C during the addition process. After the addition was completed, the mixture was kept warm and slurried for 5 hours, filtered, and dried at 45°C for 12 hours to obtain 34.1 g of white solid powder with a yield of 94.7% and a purity of 99.95%. (Particle size D10 = 0.488 μm, D50 = 1.760 μm, D90 = 4.234 μm). Test Example 1

[0026] The tadalafil raw materials prepared in Example 1, Example 2, Example 3 and Example 4 were respectively prepared into tablets according to patent CN117503716A, 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 1.2 + 0.2% SDS, the rotation speed was 50 rpm, the temperature was 37 ± 0.5 ° C, and the dissolution medium was 1000 mL. The experimental results are shown in Table 1.

[0027]

[0028] From the above experimental results, it can be seen that the smaller the particle size of tadalafil API, the greater the tablet dissolution rate and dissolution degree. It can be judged that the particle size is negatively correlated with the in vivo dissolution. The preparations developed by selecting tadalafil API with small particle size have faster dissolution rate and greater dissolution degree, which can effectively improve its bioavailability and reduce its toxic side effects. Test Example 2

[0029] The tadalafil bulk drug prepared in Example 1, Example 2, Example 3 and Example 4 were respectively taken, and the acetonitrile residue was detected by the headspace gas chromatography method reported in "Detection of 4 Residual Solvents in Tadalafil Bulk Drug by Headspace Gas Chromatography" by Zhang Jidong et al. The experimental results are shown in Table 2.

[0030]

[0031] According to the above experimental results, the smaller the particle size of the tadalafil API, the greater the residual acetonitrile, but the residual acetonitrile detected in the tadalafil API prepared in Example 1, Example 2, Example 3 and Example 4 is much less than the ICH Q3C limit of 410ppm, which shows that the preparation process can not only obtain a small particle size product but also effectively remove the acetonitrile residue, thereby ensuring the safety, effectiveness and quality controllability of the small particle size tadalafil API.

Claims

1. A method for preparing low-solvent small-particle tadalafil, characterized in that The crude tadalafil is added to a mixed solvent of acetonitrile and water, heated to dissolve, filtered, the filtrate is added dropwise to water, the mixture is slurried by heat preservation, filtered, dried, and the material is collected to obtain a small particle size sample.

2. The preparation method according to claim 1, characterized in that The volume ratio of acetonitrile to water in the mixed solvent is 4:1-5:

1.

3. The preparation method according to claim 1, characterized in that The mass volume ratio of the crude tadalafil to the mixed solvent is 1:21-1:

24.

4. The preparation method according to claim 1, characterized in that The filtrate is added dropwise into water, wherein the mass volume ratio of the crude tadalafil to water is 1:38-1:

43.

5. The preparation method according to claim 1, characterized in that The filtrate is added dropwise into water, wherein the adding time is 0.5h-1.5h.

6. The preparation method according to claim 1, characterized in that The filtrate is added dropwise into water, wherein the temperature of the water is maintained at 0°C-5°C during the adding process.

7. The preparation method according to claim 1, characterized in that The heat preservation and beating time is 5h to 10h.

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