Dimemorfan phosphate crystal form II and preparation method thereof, and pharmaceutical composition

A technology for dimethylorphinyl phosphate and its composition, which is applied in the field of dimethylorphinyl phosphate crystal form II and its preparation and pharmaceutical composition, can solve problems such as the description of recrystallization methods, achieve excellent purity, excellent reproducibility, Effects of good pharmaceutical value

Active Publication Date: 2012-10-24
杭州仟源保灵药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The literature Chem.Pharm.Bull. (1972, 20, 1706-1710) reported that dimethylorphinyl phosphate can be obtained quantitatively from the salt formation of dimethylorphinyl and phosphoric acid, but did not describe its recrystallization method

Method used

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  • Dimemorfan phosphate crystal form II and preparation method thereof, and pharmaceutical composition

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preparation example Construction

[0050] The preferred preparation method of the present invention is: add 20 g of the crude product of dimethylorphinyl phosphate into 200-2000 ml of methanol, heat to reflux to dissolve it, filter, place the filtrate at room temperature for 1-20 h to crystallize, filter, and reduce the temperature below 60 ° C. Dry under pressure to obtain a white solid, dimethylmorphan phosphate crystal form II.

[0051] A dimethylmorphan phosphate crystal form II prepared by the above-mentioned preparation method, which is characterized by the following X-ray diffractometer diagram, and represents the relative relative to the percentage of the strongest line with the interplanar distance d and the Bragg angle 2θ. X-ray powder diffraction pattern expressed by intensity:

[0052] 2θ angle data d-value data Intensity data (%) 5.5 16.1 100.0 11.0 8.0 2.7 12.2 7.3 4.6 12.8 6.9 3.1 13.6 6.5 6.2 14.3 6.2 3.7 ...

Embodiment 1

[0056] Add 20g of dimethylorphinyl phosphate and 80ml of anhydrous methanol into the flask, heat to reflux, dissolve under stirring, cool to room temperature after dissolving, stir at room temperature for 3h, filter, wash with appropriate amount of cold anhydrous methanol, and depressurize at 50°C After drying, 16 g of white solid was obtained, which is a new crystal form of dimethylorphinyl phosphate (form II).

[0057] 1H-NMR (D 2 O, ppm): 2.198~2.223(d,1H), 2.306(s,3H), 2.865(s,3H), 3.530(s,1H), 7.022~7.038(d,1H), 7.095~7.110(d, 1H), 7.159 (s, 1H). ESI-MS: 256.2.

Embodiment 2

[0059] Take 20g of dimethylorphinyl phosphate, add 150ml of ethanol, heat to reflux to dissolve, filter while hot, keep the filtrate at room temperature, and stir at room temperature for 8h. Filter and dry under reduced pressure at 50° C. to obtain 14 g of white solid, which is a new crystal form of dimethylorphane phosphate (crystal form II).

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Abstract

The invention provides a method for preparing dimemorfan phosphate crystal form II, which comprises the following steps: adding a crude dimemorfan phosphate product into methanol, heating under reflux to dissolve the crude dimemorfan phosphate product, cooling to precipitate crystals, filtering, and drying to obtain the solid dimemorfan phosphate crystal form II. The dimemorfan phosphate crystal form has the following X-diffractometer diagram characteristics; and in the X-ray powder diffractogram, interplanar distance d and Bragg angle 2theta represent the relative intensity relative to the percentage of the strongest line. The invention also provides a pharmaceutical composition containing the dimemorfan phosphate crystal form II as an active component and one or more proper auxiliary materials, such as tablets, capsules, granules, oral liquids, syrups, suspensoids and injections. The dimemorfan phosphate crystal form II has favorable pharmaceutical values, and has the characteristics of favorable purity, definite crystal form, excellent reproducibility and the like; and the dimemorfan phosphate crystal form II has valuable physiological activities in the field of preparations, and can be stored for a long time while remaining high stability.

Description

technical field [0001] The present invention relates to a new crystal form of dimethylmorphane phosphate or (9S, 13S, 14S)-3,17-dimethylmorphinan monophosphate of formula (1), i.e. crystal form II and its preparation Methods and pharmaceutical compositions comprising. Background technique [0002] The chemical name of dimethylmorphan phosphate is (9S, 13S, 14S)-3,17-dimethylmorphinan monophosphate, and its structural formula is as follows: [0003] [0004] Formula 1) [0005] This product is a non-addictive central antitussive drug, and its antitussive effect is slightly better than that of dextromethorphan, which is about twice that of codeine. The advantages are low toxicity, good safety, no inhibition of respiration in the therapeutic dose, and no side effect of constipation. It is effective in the antitussive treatment of cough caused by upper respiratory tract infection, acute bronchitis, pneumonia and tuberculosis, lung cancer, chronic bronchitis, etc. Dimethy...

Claims

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Application Information

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IPC IPC(8): C07D221/28A61K31/485A61K9/20A61K9/16A61K9/08A61K9/48A61P11/14
Inventor 虞英民陈丹龙徐承智胡晓岚朱金梁
Owner 杭州仟源保灵药业有限公司
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