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Butorinol tartrate crystal form I as well as preparation method and application of butorinol tartrate crystal form I

A technology of butorphanol and tartaric acid, which is applied in the field of drug crystal forms, can solve problems such as undiscovered butorphanol tartrate new crystal forms, changes in product crystal forms or purity, and reduced crystallization yields, and achieve product quality risks Low concentration, good crystal stability, and high product purity

Pending Publication Date: 2022-07-01
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And the amount of solvent used is small. In this case, butorphanol free base is in a supersaturated state. During the production scale-up stage, the feed liquid is easily cooled and precipitated during the process of entering the clean area through press filtration, resulting in blockage of pipelines and increased crystallization. The solvent volume may lead to a decrease in the crystallization yield or a change in the crystal form or purity of the product
[0007] And except above-mentioned master's thesis, so far, have not yet found the report of other new crystal forms of butorphanol tartrate, also do not have other more economical, the production technology suitable for industrialization is disclosed, so butorphanol tartrate polymorph and its The preparation method is worthy of in-depth study

Method used

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  • Butorinol tartrate crystal form I as well as preparation method and application of butorinol tartrate crystal form I
  • Butorinol tartrate crystal form I as well as preparation method and application of butorinol tartrate crystal form I
  • Butorinol tartrate crystal form I as well as preparation method and application of butorinol tartrate crystal form I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Add 0.79Kg (1.0L) of ethanol and butorphanol free base (100g, 0.306mol) to the reaction kettle A, stir, and heat up to reflux to dissolve. Add 0.21Kg of purified water in the reactor B, add D-tartaric acid 68.8g (1.5eq.), add the D-tartaric acid solution in the reactor B to the clear butorphanol solution, add, and slowly cool down to 30 Below ℃, continue to stir for 4-6 h, filter, and dry the filter cake under reduced pressure to constant weight to obtain 121 g of crystalline solid, yield: 83%, HPLC purity 99.98%, total impurities 0.02%.

[0047] The powder diffraction pattern of the crystalline sample is shown in figure 1 , the data are shown in Table 1, DSC has a characteristic absorption peak at 223.38 ° C, TGA shows that the crystalline sample begins to decompose and lose weight when heated to 223.38 ° C, the water content of the crystal form is measured by KF method, and the water content is 0.16%.

[0048]Table 1:

[0049]

[0050]

Embodiment 2、 Embodiment 3

[0052] Add butorphanol free base (0.5 g) into the reaction flask, add an appropriate amount of solvent according to Table 2 below, heat up to reflux and stir to dissolve. Quantitatively weigh 0.25 g of D-tartaric acid, add 0.75 ml of purified water and stir to dissolve, slowly add the tartaric acid aqueous solution to the butorphanol free base solution, and slowly cool down to 0 °C after the dropwise addition is completed, stir and crystallize for 4-6 hours, There is solid precipitation, centrifuge, the obtained solid is dried to constant weight at 40°C, yield: 84%, HPLC purity 99.98%, total impurities 0.02%, the obtained sample is measured by XRD, see Figure 5 .

[0053] Table 2:

[0054] solvent Solvent dosage Crystal form Example 2 methanol 2.5mL Form I Example 3 isopropyl alcohol 5.0mL Form I

Embodiment 4、5、6

[0056] The butorphanol free base (0.5 g) was added to the reaction flask, an appropriate amount of ethanol was added according to Table 3 below, and the temperature was raised and refluxed and stirred until it was dissolved. Quantitatively weigh 0.25 g of D-tartaric acid, add 0.75 ml of purified water and stir to dissolve it, slowly add the tartaric acid aqueous solution to the ethanol solution of butorphanol free base, slowly cool down to 0 °C after the dropwise addition, stir and crystallize 4- 6h, a large amount of solid was precipitated, centrifuged, and the obtained solid was dried at 40°C to constant weight, yield: 84%, HPLC purity 99.97%, total impurities 0.03%, the obtained sample was measured by XRD, see attached Image 6 .

[0057] table 3:

[0058] Solvent dosage Crystal form Example 4 2.5ml Form I Example 5 5.0ml Form I Example 6 7.5ml Form I

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Abstract

The invention discloses a novel crystal form I of butorphinol tartrate. An X-ray powder diffraction pattern represented by a diffraction angle of 2 theta + / -0.2 degrees has characteristic peaks at the positions of 10.42 degrees, 12.66 degrees, 14.72 degrees, 16.08 degrees, 20.18 degrees, 21.70 degrees, 23.42 degrees, 24.46 degrees, 25.28 degrees, 27.30 degrees and the like. According to the crystal form I disclosed by the invention, a water-containing crystallization solvent system is adopted, an excessive alcohol solvent is adopted to dissolve butorphinol free alkali, tartaric acid is dissolved by water, feed liquid is not easy to separate out in a filter pressing operation process of entering a clean area, and industrial amplification operation is utilized, so that the purity of the crystal form I is greatly improved. Meanwhile, the obtained crystal form has the advantages of being high in crystallinity, good in crystal form stability and beneficial to production and storage, in addition, water and ethanol of three solvents are used as a crystallization solvent, and the crystal form has the advantages that the quality of a finished product is easy to control, and the risk is low.

Description

technical field [0001] The invention belongs to the field of pharmaceutical crystal forms, and in particular relates to butorphanol tartrate crude drug crystal form I and a preparation method and application thereof. Background technique [0002] Butorphanol is a central analgesic first developed by Bristol-Myers Squibb Co. It is a mixed opioid receptor agonist-antagonist. Its tartrate is clinically used, mainly as a preoperative drug. Or premedication, adjunctive anesthesia for labor analgesia and severe pain that requires opioid analgesia or other treatment ineffective. [0003] The chemical name of butorphanol is L-(-)-17-cyclobutylmethyl-3,14-dihydroxymorphinan, which has a typical morphinan structure core. Butorphanol is a white crystalline solid with formula C 12 H 29 NO 2 , molecular weight 327.47, CAS number 42408-82-2. It was first approved by the FDA in 1978. The trade name is Stadol. It has two dosage forms: injection and nasal spray. The specifications are i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/28C07C59/255C07C51/43A61P25/04
CPCC07D221/28C07C59/255C07C51/43A61P25/04C07B2200/13
Inventor 汪永强丁刚申茂昌乔智涛王颖
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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