A method for preparing small-particle-size atomoxetine hydrochloride crystals

Abstract

The present invention relates to a method for preparing a small-particle atomoxetine hydrochloride crystal. The HPLC purity of the high-purity atomoxetine hydrochloride of the present invention can reach more than 99.85%, and the small particle size refers to that the main particle size D50 is 10-20 μm. The preparation method is: under room temperature stirring, acyl chloride is slowly added dropwise to an alcohol solvent, and after the addition is completed, the temperature is kept and stirred, and then an ether solvent of atomoxetine crude product is added dropwise to the system, and the filter cake is washed with an alcohol solvent, and dried to obtain a high-purity small-particle atomoxetine hydrochloride crystalline product. The method can obtain a high-purity atomoxetine hydrochloride bulk drug with controllable particle size distribution without pulverizing, and has high yield, is simple and easy to operate, has low cost, and is easy to industrialize.

Description

Technical Field

[0001] The invention belongs to the technical field of crystal medicines, and particularly relates to a method for preparing high-purity, small-particle-size atomoxetine hydrochloride crystals. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Atomoxetine hydrochloride, chemical name: (R)-N-methyl-3-(2-methylphenyloxy)-3-phenyl-1-propylamine hydrochloride, was developed by Eli Lilly and Company and approved by the US FDA in November 2002 for the treatment of attention deficit hyperactivity disorder in children and adolescents. Atomoxetine hydrochloride is a selective inhibitor of presynaptic norepinephrine transporter, which can prolong the activity of norepinephrine released in the synaptic cleft. As the first non-stimulant drug for the specific treatment of attention deficit hyperactivity disorder that has been confirmed to be effective in a large number of trials, it has great market prospects. The chemical structure of atomoxetine hydrochloride is as follows:

[0004]

[0005] Atomoxetine hydrochloride is a chiral drug, and is currently mostly obtained by chiral separation methods, and chiral asymmetric catalytic reactions have recently been developed. The atomoxetine hydrochloride prepared by the above method has many related substances, which is difficult to meet the requirements of preparation production. Therefore, medicinal atomoxetine hydrochloride needs to be refined to its crude product, so as to obtain high-purity atomoxetine hydrochloride raw materials to meet the requirements of preparation production.

[0006] The crystal particle size of the drug will affect its dissolution and release in the pharmaceutical composition, and then affect the bioavailability of the drug in the human body. In the production process of solid pharmaceutical preparations, it is usually necessary to crush the raw materials to meet the needs of uniform dispersion and stable dissolution of solid preparations. The atomoxetine hydrochloride raw material is prone to electrostatic effect during the crushing process, and the particle size of the raw material is difficult to control, resulting in uneven particle size distribution of the raw material after crushing. The crushing process of the atomoxetine hydrochloride raw material generally adopts a jet mill, and the material loss in the process is large, and the generated dust also has certain safety hazards. At present, there is less attention to the particle size control of atomoxetine hydrochloride. Summary of the invention

[0007] Dissolution is an important indicator for quality control of solid preparations. The dissolution of drugs directly affects the absorption and utilization of drugs in the body. If the drug is not easy to dissolve or the dissolution rate is extremely slow, there may be problems with the absorption rate or degree of the drug in the preparation. On the other hand, if the drug dissolves too quickly, it may cause obvious adverse reactions or greatly shorten the time to maintain the efficacy. In the present invention, the inventors found in the process of research and development of atomoxetine hydrochloride pharmaceutical preparations that when the D 50 When the particle size is between 10 and 20 μm, the drug dissolution can be well achieved.

[0008] In view of the above findings, the primary purpose of the present invention is to provide a method for preparing atomoxetine hydrochloride crystals with high purity and small particle size, which can directly obtain a main particle size D 50 The high-purity atomoxetine hydrochloride raw material with a particle size between 10 and 20 μm does not require steps such as crushing and grinding. The method has high molar yield, is simple and easy to operate, has low cost, and is easy to industrialize.

[0009] Based on the above research results, the present invention provides the following technical solutions:

[0010] In a first aspect, a method for preparing small-particle atomoxetine hydrochloride crystals is provided, comprising the following steps: dropwise adding an ether solution of crude atomoxetine to an alcohol solution of acyl chloride for crystallization, and separating the generated solid to obtain the crystals.

[0011] In the alcohol solution of the above acyl chloride, the optimized scheme is as follows:

[0012] The alcohol solvent is a low carbon alcohol such as methanol, ethanol or isopropanol.

[0013] The acyl chloride includes but is not limited to one or more of acetyl chloride, chloroacetyl chloride, propionyl chloride, butyryl chloride or benzoyl chloride.

[0014] The alcohol solution of the acyl chloride can be prepared at room temperature, by dropping the acyl chloride into the alcohol solvent, stirring and keeping warm after the dropping is complete, and the volume ratio of the acyl chloride to the alcohol solvent is 1:0.9-1.1. The above stirring time can be adjusted routinely by the technicians, based on whether the two components can be fully mixed. For example, at room temperature, continue stirring for 8-15 minutes after the dropping is complete to mix.

[0015] The optimized solution of the above crude atomoxetine in ether is as follows:

[0016] The crude atomoxetine refers to unpurified atomoxetine prepared by a synthetic reaction or atomoxetine after simple purification. According to the general knowledge in the art, in addition to the atomoxetine compound entity, this crude product may also include a small amount of impurities remaining in the synthesis process; for example, in some embodiments of the present invention, the HPLC purity of the crude atomoxetine is 96.0% to 98.0%. The preparation method provided in the first aspect of the present invention has certain requirements for the content of atomoxetine in the crude atomoxetine, and has no strict requirements on the source of the crude atomoxetine, such as the synthesis method, impurity types, etc.

[0017] It should be noted that the arrangement of each step in the present invention and the selection of the organic solvent for dissolving the crude atomoxetine product are extremely critical, because they directly affect the purity of the product and the particle size of the product, and even whether crystals can be obtained. Further, the selection of the organic solvent for dissolving the crude atomoxetine product is an important factor in obtaining the expected high purity and corresponding particle size. The inventors found in the research process that when other solvents such as tetrahydrofuran or acetone are used to dissolve the crude atomoxetine product, it is not only difficult to obtain a higher yield and purity of the product, but it is even impossible to obtain atomoxetine hydrochloride crystals.

[0018] According to the present invention, in the scheme with better effect, the ether solvent for dissolving the crude atomoxetine is ethyl ether, isopropyl ether or methyl tert-butyl ether. By adopting the above solvent combination, the present invention can not only obtain the expected particle size of atomoxetine hydrochloride, but also make its main particle size D 50 The particle size is maintained at 10-20 μm, and the product yield and purity are improved. The product yield can be maintained at more than 92%, and the yield of some combinations can be maintained at more than 96%. The HPLC purity of the product can be maintained at more than 99.80%, and can reach up to 99.85% and above.

[0019] Furthermore, in the above embodiment, the weight-to-volume ratio of the crude atomoxetine to the ether solvent is 1:2-20 (g / mL), and further, the weight-to-volume ratio is 1:3-8 (g / mL), and as a selection of some technical solutions, the weight-to-volume ratio can be 1:4, 1:5, 1:6 or 1:8, etc.

[0020] Furthermore, the molar ratio of the crude atomoxetine to the acyl chloride is 1:1-5, and further, the molar ratio is 1:1-1.5.

[0021] In some preferred embodiments of the above preparation method, the crystallization time is 1-10 hours; further, the crystallization time is 3-5 hours.

[0022] In some other preferred embodiments, the drying method is vacuum drying, the drying temperature is 30-80°C, and further, the drying temperature is 50-60°C.

[0023] In some further embodiments, the drying time is 2-8 hours; further, the drying time is 3-6 hours.

[0024] In a second aspect, the present invention also provides small-particle atomoxetine hydrochloride crystals prepared by the above method.

[0025] In a third aspect, there is provided a use of the small particle size crystals described in the second aspect in the preparation of atomoxetine solid preparations.

[0026] The above-mentioned solid preparations include but are not limited to powders, granules, tablets, capsules, pills, films, etc.; the present invention uses hydrochloric acid to simulate the acidic environment of gastric fluid and measures the dissolution performance of the above-mentioned small-particle atomoxetine hydrochloride crystals. The results show that the crystal product provided by the present invention has a dissolution rate that exceeds the existing capsule drugs. Based on the verification results, technical researchers in this field can infer that in a preferred embodiment, the small-particle size crystals are more suitable for the preparation of granules, tablets or capsules.

[0027] The beneficial effects of one or more of the above technical solutions are:

[0028] The method of the present invention can obtain atomoxetine hydrochloride raw material with high purity (more than 99.80%) and controllable particle size distribution (main particle size can be between 10-20 μm) suitable for preparation without crushing, and the method has high molar yield (more than 90%), is simple and easy to operate, the conditions are easy to control, the cost is low, and it is easy to industrialize production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0030] Figure 1 This is the particle size distribution diagram of atomoxetine hydrochloride prepared in Example 1;

[0031] Figure 2 This is the HPLC spectrum of atomoxetine hydrochloride prepared in Example 1;

[0032] Figure 3 This is the particle size distribution diagram of atomoxetine hydrochloride prepared in Example 2;

[0033] Figure 4 This is the HPLC spectrum of atomoxetine hydrochloride prepared in Example 2;

[0034] Figure 5 This is the particle size distribution diagram of atomoxetine hydrochloride prepared in Comparative Example 1;

[0035] Figure 6 This is the HPLC spectrum of atomoxetine hydrochloride prepared in Comparative Example 1;

[0036] Figure 7 This is the particle size distribution diagram of atomoxetine hydrochloride prepared in Comparative Example 2;

[0037] Figure 8 The HPLC spectrum of atomoxetine hydrochloride prepared in Comparative Example 2 is shown.

[0038] Fig. 9 It is a comparison chart of the dissolution curves of Example 1, Comparative Example 1 and the reference preparation (Zesta) in 0.1 mol / L hydrochloric acid. DETAILED DESCRIPTION

[0039] It should be noted that the following detailed descriptions are all illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0040] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0041] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0042] In the following examples, the initial atomoxetine (i.e. the crude atomoxetine described in the present application) has an HPLC purity of 97.0%-98.5%. Unless otherwise specified, the particle size described in the present invention is determined by laser scattering method, and the determination is in accordance with the provisions of the pharmacopoeia or current standards.

[0043] Example 1

[0044] Add 150ml of anhydrous ethanol to a 1000ml reaction bottle, add 15ml of acetyl chloride dropwise under stirring at room temperature, and continue stirring for 10min after the addition is complete. Slowly add 250ml of isopropyl ether solution of 33.1g of atomoxetine to the reaction system. After the addition is complete, keep warm and crystallize for 3h. Filter, wash the filter cake with ethanol, and dry it at 50℃ for 4 hours. The final product yield is 94.5%, and the main particle size D50 is 16.33μm ( Figure 1 ), HPLC purity 99.85% ( Figure 2 ).

[0045] Example 2

[0046] Add 150ml of anhydrous methanol to a 1000ml reaction bottle, add 14ml of chloroacetyl chloride dropwise under stirring at room temperature, and continue stirring for 10min after the addition is complete. Slowly add 33.1g of atomoxetine in 300ml of isopropyl ether solution to the reaction system. After the addition is complete, keep warm and crystallize for 4h. Filter, wash the filter cake with methanol, and dry it at 60℃ for 3 hours. The final product yield is 92.8%, and the main particle size D50 is 19.70μm ( Figure 3 ), HPLC purity 99.84% ( Figure 4 ).

[0047] Example 3

[0048] Add 150ml of isopropanol to a 1000ml reaction bottle, add 14ml of acetyl chloride dropwise under stirring at room temperature, and continue stirring for 10min after the addition is complete. Slowly add 280ml of methyl tert-butyl ether solution of 33.1g of atomoxetine to the reaction system. After the addition is complete, keep warm and crystallize for 4h. Filter, wash the filter cake with isopropanol, and dry it at 40℃ for 6 hours. The final product yield is 91.5%, the main particle size D50 is 18.51μm, and the HPLC purity is 99.78%.

[0049] Example 4

[0050] Add 150ml of anhydrous methanol to a 1000ml reaction bottle, add 14ml of propionyl chloride dropwise under stirring at room temperature, and continue stirring for 10min after the addition is complete. Slowly add 33.1g of atomoxetine in 300ml of isopropyl ether solution to the reaction system. After the addition is complete, keep warm and crystallize for 3h. Filter, wash the filter cake with methanol, and dry it at 60℃ for 3 hours. The final product yield is 93.5%, the main particle size D50 is 20.98μm, and the HPLC purity is 99.83%.

[0051] Example 5

[0052] Add 150ml of anhydrous ethanol to a 1000ml reaction bottle, add 15ml of acetyl chloride dropwise under stirring at room temperature, and continue stirring for 10min after the addition is complete. Slowly add 33.1g of atomoxetine in 300ml of ether solution to the reaction system. After the addition is complete, keep warm and crystallize for 4h. Filter, wash the filter cake with ethanol, and dry it at 60℃ for 2 hours. The final product yield is 92.4%, the main particle size D50 is 18.71μm, and the HPLC purity is 99.84%.

[0053] Comparative Example 1

[0054] In a 500ml glass reaction bottle, 30.4g of atomoxetine was dissolved in a mixed solvent of 30ml of acetonitrile and 70ml of isopropyl ether. Stirring was started and the temperature was controlled below 35°C. 51.0g of 33% hydrochloric acid ethanol solution was added dropwise for about 0.5h. The mixture was stirred at 15-25°C for 1.0h, and then the temperature was lowered. After about 1.0h, the mixture was cooled to 0-10°C, stirred at this temperature for 3h, and then filtered. The filter cake was washed with an acetonitrile-isopropyl ether mixed solution, and the filter cake was vacuum dried at 45-55°C for 3h, with a yield of 75.9%. Its main particle size D50 is 225.55μm ( Figure 5 ), HPLC purity 99.78% ( Figure 6 ).

[0055] Comparative Example 2

[0056] Add 150ml of anhydrous ethanol to a 1000ml reaction bottle, add 15ml of acetyl chloride dropwise under stirring at room temperature, and continue stirring for 10min after the addition is complete. Slowly add 33.1g of atomoxetine in 300ml of ethyl acetate solution to the reaction system. After the addition is complete, keep warm and crystallize for 4h. Filter, wash the filter cake with ethyl acetate, and dry it at 50℃ for 3 hours. The final product yield is 72.4%, and the main particle size D50 is 20.98μm ( Figure 7 ), HPLC purity: 95.40% ( Figure 8 ).

[0057] Comparative Example 3

[0058] Add 150 ml of anhydrous ethanol to a 1000 ml reaction bottle, add 15 ml of acetyl chloride dropwise under stirring at room temperature, and continue stirring for 10 min after the addition is complete. Slowly add 33.1 g of atomoxetine in 300 ml of tetrahydrofuran solution to the reaction system. No crystals are precipitated, and the system is an emulsion!

[0059] Dissolution curve comparison

[0060] The dissolution curves of Example 1, Comparative Example 1 and the reference preparation (Zesta) in 0.1 mol / L hydrochloric acid were compared (see Fig. 9 ). The results show that the dissolution curves of Example 1 of the present invention and the reference preparation in 0.1 mol / L hydrochloric acid are basically consistent.

[0061] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing small-particle atomoxetine hydrochloride crystals, characterized in that: The method comprises the following steps: adding an ether solution of a crude atomoxetine product dropwise to an alcohol solution of an acyl chloride to perform crystallization, and separating the generated solid to obtain the product; In the alcohol solution of the acyl chloride, the low-carbon alcohol solvent is a low-carbon alcohol, including methanol, ethanol or isopropanol; The acyl chloride is one or more of acetyl chloride, chloroacetyl chloride, propionyl chloride, butyryl chloride or benzoyl chloride; The alcohol solution of the acyl chloride is prepared at room temperature, and the acyl chloride is added dropwise to the alcohol solvent. After the addition is completed, the mixture is stirred and kept warm. The volume ratio of the acyl chloride to the alcohol solvent is 1:0.9-1.

1. In the ether solution of the crude atomoxetine, the ether solvent is diethyl ether, isopropyl ether or methyl tert-butyl ether.

2. The method for preparing small-particle atomoxetine hydrochloride crystals according to claim 1, characterized in that: The stirring time is carried out at room temperature and the stirring time is 8 to 15 minutes.

3. The method for preparing small-particle atomoxetine hydrochloride crystals according to claim 1, characterized in that: The HPLC purity of the crude atomoxetine is 96.0% to 98.0%.

4. The method for preparing small-particle atomoxetine hydrochloride crystals according to claim 1, characterized in that: The weight-to-volume ratio of the crude atomoxetine to the ether solvent is 1 g: 2-20 mL.

5. The method for preparing small-particle-size atomoxetine hydrochloride crystals according to claim 1, characterized in that: The molar ratio of the crude atomoxetine to the acyl chloride is 1:1-5.

6. The method for preparing small-particle-size atomoxetine hydrochloride crystals according to claim 1, characterized in that: The crystallization time is 1-10h.

7. The method for preparing small-particle-size atomoxetine hydrochloride crystals according to claim 1, characterized in that: The drying method is vacuum drying, and the drying temperature is 30-80°C; Or, the drying time is 2-8h.

Images