Doxapram hydrochloride monohydrate crystal and preparation method thereof

Abstract

The present invention discloses a doxapram hydrochloride monohydrate crystal and a preparation method thereof. The crystal exhibits characteristic diffraction peaks at 12.18°, 13.82°, 20.38°, 21.00°, 21.94°, 23.70°, and 24.20°, as measured by powder X-ray diffraction at a diffraction angle of 2θ±0.2°. The preparation method of the present invention utilizes a specific proportion of anhydrous ethanol for dissolution, resulting in a refined yield of doxapram hydrochloride monohydrate exceeding 90%. The method also avoids the problem of product precipitation during the filtration process of the solution into a clean area, significantly improving scale-up production operations, product quality, and yield.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a doxapram hydrochloride monohydrate crystal and a preparation method thereof. Background Art

[0002] Doxapram hydrochloride is a central nervous system stimulant. Low doses can stimulate carotid and aortic chemoreceptors, reflexively stimulating the medullary respiratory and cardiovascular centers. Its respiratory stimulant effect is stronger than that of nikethamide. High doses stimulate the spinal cord and brainstem but appear to have no effect on the cerebral cortex. Furthermore, it has a mild stimulant effect on the cardiovascular system, causing a mild increase in pulse rate, cardiac output, and blood pressure. Doxapram hydrochloride has a wide safety margin and can replace picrotoxin, nikethamide, and pentylenetetrazol. It is used to treat respiratory depression caused by central nervous system depressants, acute respiratory failure due to other causes, acute respiratory failure complicated by COPD, and to accelerate recovery after anesthesia and surgery.

[0003] US20130109689A1 and CN201910343598 only report doxapram hydrochloride and its uses, and obtain doxapram hydrochloride through cyano group hydrolysis, bromination rearrangement, condensation reaction, and salt formation. To date, no published literature at home or abroad has reported the crystal form and preparation method of doxapram hydrochloride monohydrate. Summary of the Invention

[0004] The object of the present invention is to overcome at least one deficiency of the prior art and to provide a doxapram hydrochloride monohydrate crystal and a preparation method thereof.

[0005] The technical solution adopted by the present invention is:

[0006] The invention provides a doxapram hydrochloride monohydrate crystal. The powder X-ray diffraction of the crystal, which is expressed by Cu-Ka radiation and a diffraction angle of 2θ±0.2°, shows characteristic diffraction peaks at 12.18°, 13.82°, 20.38°, 21.00°, 21.94°, 23.70° and 24.20°.

[0007] The doxapram hydrochloride monohydrate crystals provided by the present invention lose 3.0% to 4.5% of their weight at 40 to 130° C. during thermogravimetric measurement.

[0008] The method for preparing doxapram hydrochloride monohydrate crystals provided by the present invention comprises the following steps:

[0009] 1) adding crude doxapram hydrochloride to anhydrous ethanol to dissolve the product, and filtering to obtain a filtrate;

[0010] 2) The filtrate obtained in step 1) is heated and stirred, and then water is dropped into the filtrate, cooled and crystallized, filtered, and dried under reduced pressure to obtain doxapram hydrochloride monohydrate.

[0011] In some examples, the amount of anhydrous ethanol used is 5 to 15 times the mass of the crude doxapram hydrochloride, and the amount of water used is 0.5 to 1.5 times the mass of the crude doxapram hydrochloride.

[0012] In some examples, in step 1), medicinal charcoal or diatomaceous earth is added before filtration to remove some insoluble impurities by adsorption.

[0013] In some examples, the amount of anhydrous ethanol used is 5 times the mass of the crude doxapram hydrochloride, and the amount of water used is 0.5 times the mass of the crude doxapram hydrochloride.

[0014] In some examples, the dissolving temperature in step 1) is 75-78°C.

[0015] In some examples, the heating temperature in step 2) is 75-78°C.

[0016] In some examples, the crystallization temperature in step 2) is 2-8° C., and the crystallization time is 6-12 hours.

[0017] In some examples, the endpoint of the reduced-pressure drying is when the drying loss of the doxapram hydrochloride product reaches 3.0-4.5%.

[0018] In another aspect, the present invention provides a central nervous system stimulant comprising the doxapram hydrochloride monohydrate crystals described above.

[0019] The beneficial effects of the present invention are:

[0020] Compared with samples without crystal water, the samples containing crystal water prepared by the present invention have a faster dissolution rate and are more suitable for injection applications. In addition, the samples have better thermal stability and are conducive to long-term storage.

[0021] The present invention uses a specific amount of anhydrous ethanol to heat and dissolve the crude product, then adds water to recrystallize the crude doxapram hydrochloride. Scaled-up production has shown that, using the above-described process, the crude product solution does not precipitate solids when filtered into a clean area. The refined yield of doxapram hydrochloride monohydrate of the present invention reaches over 90%, significantly improving the refined yield compared to the yield reported in the preparation literature. Furthermore, the problem of product precipitation during the filtration process of the solution into the clean area is avoided, significantly improving scaled-up production operations, product quality, and yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the TGA diagram of crude doxapram hydrochloride.

[0023] Figure 2 HPLC chart of the product obtained in Example 1.

[0024] Figure 3 This is the TGA diagram of the product obtained in Example 1.

[0025] Figure 4 This is the XRD pattern of the product obtained in Example 1.

[0026] Figure 5 The following are XRD patterns of the products obtained in Examples 2 to 7. DETAILED DESCRIPTION

[0027] The following disclosure provides numerous different embodiments or examples for implementing various aspects of the present invention. Where specific techniques and conditions are not specified in the examples, the experiments were performed in accordance with techniques or conditions described in literature in the art or in accordance with product specifications. All reagents and instruments used, unless the manufacturer is specified, were commercially available.

[0028] The preparation method of crude doxapram hydrochloride in the embodiment of the present invention is as follows: 20.00 kg of doxapram was added to 100.12 kg of anhydrous ethanol, and after complete dissolution, 5.51 kg of hydrochloric acid was added dropwise. After stirring for 0.5 h, the temperature was raised to reflux for 1 h, the temperature was lowered by 2 to 8 ° C for crystallization for 7 h, and the filter cake was filtered and dried under reduced pressure at 25 to 35 ° C to obtain 20.17 kg of crude doxapram hydrochloride with a drying loss of 0.21%. The TGA diagram of the operation process is as follows Figure 1 shown.

[0029] The doxapram hydrochloride monohydrate prepared by the present invention has the structure shown below: , its chemical name is: (±)-1-ethyl-3,3-diphenyl-4-(2-morpholinoethyl)-2-pyrrolidone hydrochloride monohydrate.

[0030] Example 1

[0031] 1) Add 5.03 kg of doxapram hydrochloride to 25.13 kg of anhydrous ethanol, stir and heat at 77°C until fully dissolved, add 0.25 kg of activated carbon, reflux for 0.5 hour, and filter to collect the filtrate;

[0032] 2) Heat and stir the filtrate at 76°C, then drop 2.53 kg of purified water into the filtrate, slowly cool to 7°C to allow crystallization for 8 hours, filter, and dry under reduced pressure to obtain the product.

[0033] Finally, 4.78 kg of doxapram hydrochloride monohydrate was obtained with a yield of 95.03%, a purity of 99.89%, and a loss on drying of 3.89%.

[0034] The HPLC chart of the product obtained in this embodiment is as follows Figure 2 As shown in the TGA diagram Figure 3 shown.

[0035] The XRD pattern was obtained by using a Rigaku MiniFlex 600 X-ray diffractometer (Cu / K-alpha1, 1.54056A, 0°~60°). Figure 4 As shown, from Figure 4 It can be seen that the powder X-ray diffraction of the doxapram hydrochloride monohydrate crystals expressed at a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at 12.18°, 13.82°, 20.38°, 21.00°, 21.94°, 23.70°, and 24.20°.

[0036] Example 2

[0037] 1) Add 100.0 g of doxapram hydrochloride to 500.1 g of anhydrous ethanol, stir and heat at 78°C until fully dissolved, add 5.0 g of activated carbon, reflux for 0.5 hour, and filter to collect the filtrate;

[0038] 2) Heat and stir the filtrate at 76°C, then drop 50 g of purified water into the filtrate, slowly cool to 8°C to allow crystallization for 7 h, filter, and dry under reduced pressure to obtain the product.

[0039] Finally, 92.7 g of doxapram hydrochloride monohydrate was obtained with a yield of 92.7%, a purity of 99.72%, and a loss on drying of 4.01%.

[0040] Example 3

[0041] 1) Add 3.86 kg of doxapram hydrochloride to 19.31 kg of anhydrous ethanol and heat at 75°C with stirring until fully dissolved. Add 0.193 kg of activated carbon and reflux for 1 hour. Filter and collect the filtrate.

[0042] 2) Heat and stir the filtrate at 78°C, then drop 1.93 kg of purified water into the filtrate, slowly cool to 2°C to allow crystallization for 8 hours, filter, and dry under reduced pressure to obtain the product.

[0043] Finally, 3.59 kg of doxapram hydrochloride monohydrate was obtained with a yield of 93.11%, a purity of 99.81%, and a loss on drying of 4.12%.

[0044] Example 4

[0045] 1) Add 6 kg of doxapram hydrochloride to 30.03 kg of anhydrous ethanol, stir and heat at 78°C until fully dissolved, add 0.30 kg of activated carbon, reflux for 0.7 hour, and filter to collect the filtrate;

[0046] 2) Heat and stir the filtrate at 75°C, then drop 3.01 kg of purified water into the filtrate, slowly cool to 4°C to allow crystallization for 9 hours, filter, and dry under reduced pressure to obtain the product.

[0047] Finally, 5.56 kg of doxapram hydrochloride monohydrate was obtained with a yield of 92.67%, a purity of 99.80%, and a loss on drying of 4.00%.

[0048] Example 5

[0049] 1) Add 100.0 g of doxapram hydrochloride to 500.0 g of anhydrous ethanol, stir and heat at 75°C until fully dissolved. Add 5.0 g of activated carbon, reflux for 0.7 hour, and filter to collect the filtrate.

[0050] 2) Heat and stir the filtrate at 76°C, then drop 60 g of purified water into the filtrate, slowly cool to 7°C to allow crystallization for 7 h, filter, and dry under reduced pressure to obtain the product.

[0051] Finally, 90.3 g of doxapram hydrochloride monohydrate was obtained with a yield of 90.30%, a purity of 99.81%, and a loss on drying of 3.78%.

[0052] Example 6

[0053] 1) Add 100.0 g of doxapram hydrochloride to 500.1 g of anhydrous ethanol, stir and heat at 78°C until fully dissolved, add 5.0 g of activated carbon, reflux for 0.5 hour, and filter to collect the filtrate;

[0054] 2) Heat and stir the filtrate at 76°C, then drop 70.0 g of purified water into the filtrate, slowly cool to 6°C to allow crystallization for 7 h, filter, and dry under reduced pressure to obtain the product.

[0055] Finally, 87.1 g of doxapram hydrochloride monohydrate was obtained with a yield of 87.10%, a purity of 99.88%, and a loss on drying of 3.86%.

[0056] Example 7

[0057] 1) Add 100.0 g of doxapram hydrochloride to 600.0 g of anhydrous ethanol, stir and heat at 77°C until fully dissolved. Add 5.0 g of activated carbon, reflux for 0.5 hour, and filter to collect the filtrate.

[0058] 2) Heat and stir the filtrate at 75°C, then drop 50.0 g of purified water into the filtrate, slowly cool to 4°C to allow crystallization for 10 h, filter, and dry under reduced pressure to obtain the product.

[0059] Finally, 90.1 g of doxapram hydrochloride monohydrate was obtained with a yield of 90.10%, a purity of 99.90%, and a loss on drying of 4.09%.

[0060] The characterization of the crystal structure of doxapram hydrochloride monohydrate obtained in Examples 2 to 7 is as follows:

[0061] Take equal amounts of doxapram hydrochloride monohydrate obtained in Examples 2 to 7 and mix them evenly. The crystal structures thereof are determined under the conditions of Example 1. The XRD patterns are shown in FIG. Figure 5 As shown, from Figure 5 It can be seen that the powder X-ray diffraction of the doxapram hydrochloride monohydrate crystals, expressed at a diffraction angle of 2θ ± 0.2°, shows characteristic diffraction peaks at 12.08°, 13.68°, 20.84°, 20.84°, 21.80°, 23.58°, and 24.08°. The monohydrate prepared in Examples 2 to 7 also has the same crystal structure as that of Example 1.

[0062] Comparative Example 1

[0063] 1) Add 100.0 g of doxapram hydrochloride to 400.0 g of anhydrous ethanol and heat at 77°C with stirring until fully dissolved. Add 5.0 g of activated carbon and reflux for 0.5 hour. Filter and collect the filtrate.

[0064] 2) Heat and stir the filtrate at 76°C, then drop 50.0 g of purified water into the filtrate, slowly cool to 5°C to allow crystallization for 7 h, filter, and dry under reduced pressure to obtain the product.

[0065] Finally, 94.5 g of doxapram hydrochloride monohydrate was obtained with a yield of 94.50%, a purity of 99.62%, and a loss on drying of 4.15%. Due to the small amount of ethanol solvent, stirring was difficult during crystallization, making it unsuitable for large-scale industrial production.

[0066] Comparative Example 2

[0067] 1) Add 100.0 g of doxapram hydrochloride to 500.1 g of anhydrous ethanol, stir and heat at 76°C until fully dissolved, add 5.0 g of activated carbon, reflux for 0.5 hour, and filter to collect the filtrate;

[0068] 2) Heat the filtrate at 75°C with stirring, then slowly cool it to 6°C for crystallization for 7 h. Filter and dry under reduced pressure to obtain the product.

[0069] Finally, 94.5 g of doxapram hydrochloride monohydrate was obtained with a yield of 94.50%, a purity of 99.62%, and a loss on drying of 4.15%. Due to the low amount of ethanol solvent, stirring was difficult during crystallization, making it unsuitable for scale-up industrial production.

[0070] Comparative Example 3

[0071] 1) Add 100.0 g of doxapram hydrochloride to 500.0 g of isopropyl alcohol, stir and heat at 76°C until fully dissolved. Add 5.0 g of activated carbon, reflux for 0.5 hour, and filter to collect the filtrate.

[0072] 2) Heat and stir the filtrate at 77°C, then drop 50.0 g of purified water into the filtrate, slowly cool to 5°C to allow crystallization for 11 h, filter, and dry under reduced pressure to obtain the product.

[0073] Finally, 85.3 g of doxapram hydrochloride monohydrate was obtained with a yield of 85.30%, a purity of 99.61%, and a loss on drying of 4.23%.

[0074] Characterization of crystal structure:

[0075] The XRD pattern was obtained by using a Rigaku MiniFlex 600 X-ray diffractometer (Cu / K-alpha1, 1.54056A, 0°~60°). Figure 4 and Figure 5 As shown in the figure, it can be seen that the powder X-ray diffraction of the doxapram hydrochloride monohydrate crystals prepared in Examples 1 to 7 expressed by a diffraction angle of 2θ ± 0.2° shows characteristic diffraction peaks at 12.18°, 13.82°, 20.38°, 21.00°, 21.94°, 23.70°, and 24.20°, and has the same crystal structure.

[0076] The present invention has studied the dissolution rate of the samples in the above examples in water, and the results are shown in Table 1.

[0077] Table 1 Comparison of dissolution rates of various examples in water

[0078] Examples Sample addition amount (g) Water volume (ml) Dissolution time Example 1 10 100 2min Example 2 10 100 2min Example 3 10 100 2min Example 4 10 100 2min Example 5 10 100 2min Example 6 10 100 2min Example 7 10 100 2min Comparative Example 1 10 100 2min Comparative Example 2 10 100 5min10s

[0079] As shown in Table 1, the samples containing crystalline water have a faster dissolution rate than the samples without crystalline water and are more suitable for injection applications.

[0080] The present invention studied the thermal stability of the samples in the above examples, and the results are shown in Table 2.

[0081] Table 2 Statistics of thermal stability of samples

[0082] Examples Thermal stability Examples Thermal stability Example 1 Stablize Example 6 Stablize Example 2 Stablize Example 7 Stablize Example 3 Stablize Comparative Example 1 Stablize Example 4 Stablize Comparative Example 2 Unstable Example 5 Stablize

[0083] As shown in Table 2, the samples containing crystalline water have better thermal stability at 40°C than those without crystalline water, which is conducive to long-term storage.

[0084] Next, the types of solvents were investigated, and various solvents such as methanol, ethanol, isopropanol, acetone, acetonitrile, and DMF were investigated. The specific operation was the same as that in Comparative Example 3, except that the solvent was added to the crude doxapram hydrochloride product in step 1. The results are shown in Table 3.

[0085] Table 3 Statistics of crystallization results in different solvents

[0086] Solvent type Methanol ethanol Isopropyl alcohol acetone Acetonitrile DMF Crude doxapram hydrochloride: solvent (g / g) 1：5 1：5 1：5 1：5 1：5 1：5 Crude doxapram hydrochloride: water (g / g) 1:0.5 1:0.5 1:0.5 1:0.5 1:0.5 1:0.5 Yield (%) 76.43 95.65 85.30 91.43 / / purity(%) 99.83 99.89 99.61 99.12 / / Loss on drying (%) 3.91 3.89 4.23 4.12 / / Remark: / / / The crystallization solution is too thick and not conducive to operation No precipitation No precipitation

[0087] The data comparison in Table 3 shows that the yield is relatively higher when ethanol crystallization is used, which is more conducive to scale-up production and cost control.

[0088] In summary, the doxapram hydrochloride monohydrate prepared by the present invention has the advantages of good thermal stability, fast dissolution in water, and high purity, and the preparation process is simple, high yield, and strong reproducibility, and is suitable for industrial production.

[0089] The above is a further detailed description of the present invention and should not be considered as a limitation on the specific implementation of the present invention. For those skilled in the art, simple deductions or substitutions that do not depart from the concept of the present invention are within the scope of protection of the present invention.

Claims

1. A method for preparing doxapram hydrochloride monohydrate crystals, characterized in that: The monohydrate crystals use Cu-Ka radiation, and powder X-ray diffraction expressed as a diffraction angle of 2θ±0.2° shows characteristic diffraction peaks at 12.18°, 13.82°, 20.38°, 21.00°, 21.94°, 23.70°, and 24.20°; The following steps are involved: 1) adding crude doxapram hydrochloride to anhydrous ethanol and dissolving it at a dissolution temperature of 75-78° C., wherein the amount of anhydrous ethanol used is 5-15 times the mass of the crude doxapram hydrochloride, and filtering to obtain a filtrate; 2) The filtrate obtained in step 1) was heated and stirred at a temperature of 75 to 78° C., and then water was added dropwise to the filtrate, wherein the amount of water was 0.5 to 1.5 times the mass of the crude doxapram hydrochloride. The mixture was cooled and crystallized at a temperature of 2 to 8° C. for 6 to 12 hours. The mixture was filtered and dried under reduced pressure to obtain doxapram hydrochloride monohydrate.

2. The preparation method according to claim 1, characterized in that The doxapram hydrochloride monohydrate loses 3.0% to 4.5% of its weight at 40 to 130° C. during thermogravimetric measurement.

3. The preparation method according to claim 1, characterized in that The amount of the anhydrous ethanol used is 5 times the mass of the crude doxapram hydrochloride, and the amount of the water used is 0.5 times the mass of the crude doxapram hydrochloride.

4. The preparation method according to claim 1, characterized in that The endpoint of the reduced-pressure drying is when the drying loss of the doxapram hydrochloride product reaches 3.0-4.5%.

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