CN115925584A - Crystallization method of substituted amantadine compound - Google Patents

Abstract

The invention relates to a crystallization method of a substituted amantadine compound, which comprises the following steps: mixing a substituted amantadine compound with ethanol and then heating to obtain a clear solution; cooling the clarified solution, and dropwise adding water while stirring to obtain a solid-liquid mixture; and separating and drying the solid-liquid mixture. The method can stably prepare the compound stable crystal form with the grain diameter D90 of less than 150 mu m, has uniform grain diameter distribution, is suitable for long-acting intramuscular injection formulations, is favorable for smooth ball milling procedure in the preparation process, and can not cause pipeline blockage of a ball mill because of too large grain diameter of the initial material.

Description

Crystallization method of substituted amantadine compound

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a crystallization method of a substituted amantadine compound.

Background

((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate is a substituted amantadine compound, and its structure is as follows. Currently, (((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate is used in long acting intramuscular injection formulations. The dosage form has strict requirements on the particle size of the raw material medicine, and more specifically, the raw material medicine needs smaller particle size to meet the requirements of preparation process equipment.

CN109862887a discloses two crystalline forms of (((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate, i.e. crystalline forms I and II, and in the examples methods of preparation of crystalline forms I and II are disclosed. However, the particle size of forms I and II is not disclosed in all examples. Furthermore, the crystallization process disclosed in CN109862887a requires the use of an isopropanol-water system, an acetone-water system or an acetonitrile-water system. When the isopropanol-water system is used for elution and crystallization, a large amount of isopropanol (10 times of volume) needs to be added, and the economic cost and the solvent recovery cost are high. The yield was low when the crystals were eluted using an acetone-water system (only 75% was recorded in the examples). The acetonitrile-water system is not environment-friendly, wherein acetonitrile is a second solvent, has high toxicity and low solvent residue limit, and is not suitable for the final step of crystallization of medicaments.

Disclosure of Invention

The inventors have found through extensive experimentation that conventional crystallization methods have difficulty in obtaining small particle size ((((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate products suitable for use in long acting intramuscular injection formulations. The (((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate product obtained by these conventional methods generally has a particle diameter D90 of more than 150 μm, which exceeds the particle diameter requirements of the material by an aseptic ball mill, and is liable to cause problems such as clogging of a tube.

The invention aims to overcome the defects of the prior art and provide a crystallization method of a substituted amantadine compound, which can stably prepare a stable crystal form (namely, a crystal form I) of the compound with the particle size D90 of less than 150 mu m, is suitable for a long-acting intramuscular injection formulation, is beneficial to smooth ball milling in a preparation process and can not cause pipeline blockage of a ball mill due to too large particle size of initial materials.

In order to achieve the above object, the present invention provides the following technical solutions.

A method of crystallizing a substituted amantadine compound comprising:

mixing a substituted amantadine compound with ethanol and then heating to obtain a clear solution;

cooling the clarified solution, and dropwise adding water while stirring to obtain a solid-liquid mixture; and

and separating and drying the solid-liquid mixture.

Preferably, the mass ratio of the substituted amantadine compound to the ethanol is 1 (1.6-10), preferably 1: (3.2-8), more preferably 1: (3.2-6.5). Preferably, the mass ratio of the substituted amantadine compound to the water is 1 (1-10); more preferably, the mass ratio is 1 (4-10); more preferably, the mass ratio is 1: (4-8); more preferably, the mass ratio is 1: (5-7). The mass ratio is favorable for dissolving the substituted amantadine compound and is also favorable for high yield and small grain size of the product during recrystallization.

Preferably, the volume ratio of ethanol to water is 1 (0.5-2), preferably 1 (0.7-1.5). In some embodiments, the volume ratio of ethanol to water is 1 (0.5-1); in some embodiments, the volume ratio of ethanol to water is 1 (0.8-1.2). The volume ratio of ethanol and water has obvious influence on the yield of the product, and the volume ratio of the invention can realize the maximization of the yield.

In the present invention, the substituted amantadine-based compound may be ((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate. Preferably, the ethanol used is absolute ethanol; the water is sterile water for injection.

Preferably, the substituted amantadine-like compound is mixed with ethanol and heated under stirring. The substituted amantadine compounds can be promoted to be dissolved in ethanol more quickly by heating under stirring to obtain a clear solution, so that the time cost is saved. Preferably, the heating temperature is 30-70 ℃, more preferably 40-65 ℃; more preferably 45-55 deg.c. In some embodiments, the heating temperature is 50 ℃. Such heating temperatures are beneficial to both the dissolution of the substituted amantadine compounds and the avoidance of degradation of the substituted amantadine compounds due to high temperatures.

Preferably, after obtaining the clarified solution and before cooling the clarified solution, the clarified solution is hydrociltrated through a two stage 0.22 μm filter cartridge for sterilization.

Preferably, the clarified solution is cooled to 10-30 ℃, preferably 20-30 ℃, most preferably 25 ℃. The cooling end point is beneficial to the growth of crystals, and is convenient for practical production operation and control, and economic energy consumption is also considered.

Preferably, the stirring speed is 50-300rpm, preferably 50-200rpm, more preferably 50-100rpm, when water is added dropwise under stirring; the dropping time is 30-90min, preferably 30-60min. Preferably, stirring is continued after the dripping is finished, and the continuous stirring time can be 0.1-3h; preferably 0.5-3h; more preferably 1.5-2.5h; . In some embodiments, the continued stirring time is 2h. The continuous stirring can ensure that the crystallization is more complete, which is beneficial to improving the yield.

The cooling end point, the stirring speed and the dripping time of the invention are more conducive to obtaining a recrystallized product with smaller particle size, and are particularly suitable for preparing downstream sterile preparations.

In the present invention, the separation is performed by filtration or centrifugation. In the invention, the drying mode is vacuum drying, the drying temperature is 40-60 ℃, and the drying time is 3-5h.

Compared with the prior art, the invention has the following beneficial effects:

1. the invention provides a crystallization method of a substituted amantadine compound, which can stably prepare a stable crystal form (namely a crystal form I) of the compound with the particle size D90 of less than 150 mu m, has uniform particle size distribution, is suitable for long-acting intramuscular injection formulations, is favorable for smoothly carrying out a ball milling process in a preparation process, and cannot cause the blockage of a ball mill pipeline because the particle size of an initial material is too large.

2. The method uses ethanol and water as solvents, is green and environment-friendly, and has low economic cost. In addition, the method has the advantages of simple process operation, high yield, low water content, low solvent residue and high purity of the obtained product, is particularly suitable for industrial production of sterile raw material medicines, and can ensure the safety of the sterile raw material medicines to a higher degree.

Drawings

FIG. 1 is a typical particle size distribution plot for the crystalline form I of (((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate made by the process of the present invention (where D90 is 83.43 μm, D50 is 30.16 μm, and D10 is 6.89 μm).

FIG. 2 is a typical X-ray powder diffraction (XRPD) pattern of crystalline form I of (((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate prepared in example 1 of this invention.

FIG. 3X-ray powder diffraction pattern of the mixed crystal product of ((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate crystalline form I + II obtained in comparative example 3 of the present invention.

Detailed Description

In order to facilitate understanding of the present invention, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention. Unless otherwise indicated, the starting materials and reagents used in the examples are all commercially available products. Reagents, equipment, or procedures not described herein are routinely determinable by one of ordinary skill in the art.

Example 1

25.00kg of ((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate was weighed into a 500L dissolution tank, 160kg of absolute ethanol ((((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate and absolute ethanol in a mass ratio of 1.4) were added, mechanical stirring and heating were started, and heating was carried out to 50 ℃ for dissolution. Then, the obtained clarified solution is hydraulically filtered through a two-stage 0.22 mu m filter core (used for sterilization) to a 500L crystallization kettle, and the temperature of the crystallization kettle is controlled to be 25 ℃ to realize temperature reduction. Subsequently, the mechanical stirring was turned on, and 150kg of sterile water for injection (volume ratio of absolute ethanol to water: 1: 0.74) was added dropwise at a stirring rate of 80rpm for 30min. Continuously stirring for 2h after water is dripped, filtering, and vacuumizing and drying at 50 ℃ for 4h to obtain the crystal form I sterile bulk drug with qualified water content, wherein the yield is 95.6%; the contents are as follows: 99.9 percent; HPLC purity 100%; the water content is 0.08%; 974ppm of ethanol residues; particle size D90=83 μm.

Example 2

23.00kg ((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate was weighed into a 500L dissolution vessel, 148kg of absolute ethanol ((((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate and absolute ethanol mass ratio of 1: 6.4) were added, mechanical stirring and heating were started, and heating was carried out to 50 ℃ for clearing. The resulting clarified solution was then filtered hydraulically through a two-stage 0.22 μm filter (for sterilization) into a 500L crystallization kettle, and the temperature of the crystallization kettle was controlled at 25 ℃ to effect cooling. Subsequently, mechanical stirring was started and 138kg of sterile water for injection was added dropwise at a stirring rate of 80rpm, the addition time being controlled to 35min. Continuously stirring for 2h after water is dripped, filtering, and vacuumizing and drying at 50 ℃ for 4h to obtain the crystal form I sterile bulk drug with qualified water content, wherein the yield is 92.8%; the content is as follows: 99.9 percent; HPLC purity 100%; the water content is 0.07%; 886ppm of ethanol residues; particle size D90=76 μm.

Example 3

120g of ((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate was weighed into a 2L dissolution vessel, 384g of absolute ethanol (((((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate and absolute ethanol mass ratio of 1. The resulting clarified solution was then filtered hydraulically through a two-stage 0.22 μm filter (for sterilization) into a 2L crystallization kettle, and the temperature of the crystallization kettle was controlled at 25 ℃ to effect cooling. Subsequently, the mechanical stirring was switched on and 720g of sterile water for injection were added dropwise at a stirring rate of 80rpm, the dropwise addition time being controlled at 30min. Continuously stirring for 2h after water is dripped, filtering, and vacuumizing and drying at 50 ℃ for 4h to obtain the crystal form I sterile bulk drug with qualified water content, wherein the yield is 96.3%; the contents are as follows: 99.9 percent; HPLC purity 100%; the water content is 0.07%; residual ethanol content 796ppm; particle size D90=85 μm.

Example 4

The procedure of example 1 was followed except that 112.5kg of sterile water for injection (volume ratio of absolute ethanol to water 1. The yield of the obtained crystal form I sterile raw material medicine is 93.0 percent, and the HPLC purity is 99.81 percent.

Comparative example 1 (((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate and anhydrous ethanol mass ratio was not good)

100g of ((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate was weighed into a 2L dissolution vessel, 1200g of absolute ethanol (((((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate and absolute ethanol mass ratio of 1. Then, the obtained clarified solution is hydraulically filtered through a two-stage 0.22 μm filter core (for sterilization) into a 2L crystallization kettle, and the temperature of the crystallization kettle is controlled at 25 ℃ to realize temperature reduction. Subsequently, the mechanical stirring was started and 600g of sterile water for injection was added dropwise at a stirring rate of 80rpm, the addition time being controlled to 30min. Continuously stirring for 2h after water is dripped, filtering, and vacuumizing and drying at 50 ℃ for 4h to obtain the crystal form I sterile bulk drug with qualified water content, wherein the yield is 75.3%; residual ethanol content 796ppm; particle size D90=235 μm.

As can be seen by comparing example 3 with comparative example 1, the mass ratio of (((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate to absolute ethanol of example 3 was 1; while comparative example 1, in which the mass ratio of ((((1r, 3r,5s, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate to absolute ethanol was 1.

Comparative example 2 (poor temperature of drop crystallization)

100g of ((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate was weighed into a 2L dissolution tank, 640g of absolute ethanol (((((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate and absolute ethanol in a mass ratio of 1. The resulting clarified solution was then filtered hydraulically through a two-stage 0.22 μm filter (for sterilization) into a 2L crystallization kettle, with the kettle temperature controlled at 50 ℃. Subsequently, the mechanical stirring was started and 600g of sterile water for injection was added dropwise at a stirring rate of 80rpm, the addition time being controlled to 30min. Continuously stirring for 2h after water is dripped, filtering, and vacuumizing and drying at 50 ℃ for 4h to obtain the crystal form I sterile bulk drug with qualified water content, wherein the yield is 76.0%; HPLC purity 99.85%; the particle size D90=335 μm, the particle size is large and the distribution is uneven; the crystallization process has the phenomenon of agglomeration and gelatinization.

Comparative example 3 (poor crystallization temperature drop by drop)

100g of ((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate was weighed into a 2L dissolution vessel, 640g of absolute ethanol (((((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate and absolute ethanol mass ratio of 1.4) were added, mechanical stirring and heating were started, and heating was carried out to 50 ℃ for clearing. Then, the obtained clarified solution is hydraulically filtered through two stages of 0.22 mu m filter elements (for sterilization) into a 2L crystallization kettle, the temperature of the crystallization kettle is controlled to be 0 ℃, and the temperature is reduced. Subsequently, the mechanical stirring was started and 600g of sterile water for injection was added dropwise at a stirring rate of 80rpm, the addition time being controlled to 30min. After water is dripped, stirring is continuously carried out for 2 hours, then filtering is carried out, vacuumizing and drying are carried out for 4 hours at 50 ℃, thus obtaining a product with qualified water, XRD detection shows that the product is a mixed crystal product of crystal form I + II, and the yield is 89.6%; HPLC purity 99.79%; the crystallization process has explosive crystallization and uneven particle size distribution, and most importantly, the crystal form II is easy to generate.

It can be seen by comparing example 1, comparative example 2 and comparative example 3 that comparative example 2 has no temperature reduction process, and the dropwise crystallization temperature (i.e., crystallization kettle temperature) is higher, resulting in lower yield and larger particle size, which is not suitable for the aseptic ball milling process in the downstream preparation process. The drop crystallization temperature of comparative example 3 was lower, resulting in the production of a mixed crystal product of crystalline form I + II. Therefore, from the viewpoint of energy consumption and yield, it is more preferable to select room temperature (25. + -. 5 ℃ C.) as the temperature for the dropwise crystallization.

Comparative example 4 (poor stirring speed)

100g of ((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate was weighed into a 2L dissolution tank, 640g of absolute ethanol ((((((1r, 3R,5S, 7r) -3,5-dimethyladamantan-1-yl) carbamoyl) oxy) methylbenzoate and absolute ethanol in a mass ratio of 1. The resulting clarified solution was then filtered hydraulically through a two-stage 0.22 μm filter (for sterilization) into a 2L crystallization kettle, and the temperature of the crystallization kettle was controlled at 25 ℃ to effect cooling. Subsequently, the mechanical stirring was started and 600g of sterile water for injection was added dropwise at a stirring rate of 25rpm, the addition time being controlled to 30min. Continuously stirring for 2h after water is dripped, filtering, and vacuumizing and drying at 50 ℃ for 4h to obtain a crystal form I product with qualified water content, wherein the yield is 93.0%; the particle size D90=355 μm, the particle size is large and the distribution is not uniform, and the method is not suitable for a sterile ball milling process in a downstream preparation process.

As can be seen by comparing example 1 with comparative example 4, comparative example 4 has an inferior stirring rate, resulting in a larger particle size, which is not suitable for the aseptic ball milling process in the downstream formulation process.

Comparative example 5 (volume ratio of absolute ethanol to water is not good)

The procedure of example 1 was followed except that 75kg of sterile water for injection (anhydrous ethanol and water in a volume ratio of 1. The obtained crystal form I sterile raw material medicine has the yield of 82.6 percent; HPLC purity 99.88%.

As can be seen by comparing example 1, example 4 and comparative example 5, the volume ratio of anhydrous ethanol and water has a significant effect on the yield of the product, and the yield gradually decreases as the volume ratio of ethanol and water becomes larger. The volume ratio of the ethanol to the water is preferably 1 (0.5-2), and the product yield can be maximized.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. A method of crystallizing a substituted amantadine compound, comprising:

mixing a substituted amantadine compound with ethanol and then heating to obtain a clear solution;

cooling the clarified solution, and dropwise adding water while stirring to obtain a solid-liquid mixture; and

and separating and drying the solid-liquid mixture.

2. The crystallization method according to claim 1, wherein the mass ratio of the substituted amantadine-based compound to ethanol is 1 (1.6-10); the mass ratio of the substituted amantadine compounds to the water is 1 (1-10).

3. The crystallization method according to claim 2, wherein the mass ratio of the substituted amantadine-based compound to the ethanol is 1: (3.2-8); the mass ratio of the substituted amantadine compounds to water is 1: (4-10).

4. The crystallization method according to claim 1 or 2, wherein the volume ratio of ethanol to water is 1 (0.5-2).

5. The crystallization method according to claim 1 or 2, characterized in that the clear solution is cooled to 10-30 ℃.

6. The crystallization method according to claim 5, characterized in that the clear solution is cooled to 20-30 ℃.

7. The crystallization method according to claim 1 or 2, characterized in that, when water is added dropwise under stirring, the stirring rate is 50 to 300rpm; the dripping time is 30-90min.

8. The crystallization method according to claim 1 or 2, characterized in that the heating temperature is 30-70 ℃.

9. The crystallization method according to claim 1 or 2, characterized in that stirring is continued after the completion of the dropwise addition; the stirring is continued for 0.1 to 3 hours.

10. The crystallization method according to claim 1 or 2, characterized in that the substituted amantadine-based compound is mixed with ethanol and heated under stirring.

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