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Crystalized polyethylene glycol naloxone oxalate and preparation method

A technology of polyethylene glycol naloxone oxalate and polyethylene glycol naloxone, applied in the field of medicine, can solve the problems of large amount of solvent, long time consumption, low yield, etc., and achieve simplified preparation and post-treatment process , Reduce production costs, improve production efficiency and product quality

Inactive Publication Date: 2019-01-04
石家庄蒎格医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The inventor found in the follow-up research process that there are the following problems in the preparation of the above-mentioned patent method: 1) the salt-forming process is relatively cumbersome, and the amount of solvent used is relatively large; 2) a small amount of seed crystals must be added during crystallization; 3) Controlling the low-temperature operation takes a long time and the yield is low; 4) The purity of the product is low, wherein the process impurity G is greater than 0.5%, and there are 4 single impurities exceeding 0.1% (including impurity E)

Method used

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  • Crystalized polyethylene glycol naloxone oxalate and preparation method
  • Crystalized polyethylene glycol naloxone oxalate and preparation method
  • Crystalized polyethylene glycol naloxone oxalate and preparation method

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0029] Example 1, at room temperature (20-35°C), take 30g of polyethylene glycol naloxone free base, add 30mL of methanol and stir to dissolve, then add 5.8g of oxalic acid and stir to dissolve, after 0.5h, dropwise add 300mL of ethyl acetate to crystallize , stirred overnight, filtered with suction, dried under reduced pressure at 40°C for 3h, yield 95%, and obtained material crystal form I, HPLC purity 99.52%, X-ray powder diffraction pattern see figure 1 . The XRPD pattern data for Form I are provided in Table 1.

[0030] Table 1: XRPD values ​​of polyethylene glycol naloxone oxalate crystal form I

[0031]

[0032] That 1 H NMR see image 3 ,That 1 H NMR data are as follows:

[0033] 1 H NMR (400MHz, D 2 O)δ: 6.77-6.72 (m, 1H), 6.69-6.63 (m, 1H), 5.87-5.74 (m, 1H), 5.60-5.49 (m, 2H), 4.88-4.82 (m, 1H), 3.97 -3.90(m, 1H), 3.80-3.74(m, 2H), 3.69-3.37(m, 29H), 3.36-3.25(m, 4H), 3.20-3.12(m, 1H), 3.07-2.96(m, 1H), 2.87-2.75(m, 1H), 2.47-2.35(m, 1H), 1.80-1.46(m, 4...

example 2

[0036]Example 2, at room temperature (20-35°C), take 30g of polyethylene glycol naloxone free base, add 30mL of methanol and stir to dissolve, then add 5.8g of oxalic acid and stir to dissolve, after 0.5h, dropwise add 300mL of methyl tertiary methyl ether, Crystallize, stir overnight, filter with suction, and dry under reduced pressure at 40°C for 3 hours. The yield is 91%, and the crystal form II is obtained. The HPLC purity is 99.67%. The X-ray powder diffraction pattern is shown in figure 2 .

[0037] The XRPD pattern data for Form II are provided in Table 2.

[0038] Table 2: XRPD value of polyethylene glycol naloxone oxalate crystal form II,

[0039]

[0040]

[0041] That 1 H NMR see Figure 5 ,That 1 H NMR data are as follows:

[0042] 1 H NMR (400MHz, D 2 O)δ: 6.80-6.72 (m, 1H), 6.69-6.63 (m, 1H), 5.87-5.74 (m, 1H), 5.60-5.49 (m, 2H), 4.88-4.82 (m, 1H), 3.97 -3.90(m, 1H), 3.80-3.74(m, 2H), 3.69-3.46(m, 29H), 3.36-3.25(m, 4H), 3.20-3.12(m, 1H), 3.07-2.96...

example 3

[0045] Example 3, take the above-mentioned polyethylene glycol-naloxone oxalate I crystal form 28.5g, microcrystalline cellulose 10.4g, mannitol 20.8g, croscarmellose sodium 1.05g, magnesium stearate 0.35g, and 0.035g of propyl gallate, mixed uniformly according to the method of increasing in equal amounts, and directly compressed into tablets.

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Abstract

The invention provides novel crystal forms I and II of polyethylene glycol naloxone oxalate. An X-ray powder diffraction map of the two novel crystal forms include diffraction peaks shown by the angleof 2 theta, wherein the error range of the angle of 2 theta ranges from -0.2 to +0.2, the form I includes the peaks of 6.85 degrees, 13.85 degrees, 20.35 degrees, 22.64 degrees, 23.08 degrees, 24.67degrees and 26.15 degrees, and the form II includes the peaks of 7.01 degrees, 11.46 degrees, 12.89 degrees, 13.71 degrees, 14.95 degrees, 15.83 degrees, 17.55 degrees, 20.45 degrees, 21.96 degrees, 22.73 degrees, 25.78 degrees, 25.62 degrees, 26.21 degrees and 28.60 degrees. The invention further provides a preparation method of the novel crystal forms (I and II). The two crystal forms are simplein technology, easy to prepare, low in production cost and environmentally friendly, and has the good water solubility, purity and stability.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a new crystal form of polyethylene glycol naloxone oxalate and a preparation method thereof. Background technique [0002] Polyethylene glycol naloxone oxalate, English name Naloxegol, chemical name is (5α,6α)-17-allyl-6-(2,5,8,11,14,17,20-heptaoxa Docosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol oxalate, which has the structure [0003] [0004] Molecular formula: C 34 h 53 NO 11 .C 2 h 2 o 4 Molecular weight: 741.83 [0005] The polyethylene glycol naloxone oxalate developed by AstraZeneca and approved for marketing in the United States in 2014 is a pegylated product of naloxone. When given a therapeutic dose, polyethylene glycol naloxone oxalate Salt selectively antagonizes μ-opioid receptors in peripheral tissues, thereby reducing the opioid-induced constipating response. [0006] AstraZeneca's Chinese patent CN103237547B discloses two crystal forms of polyethyle...

Claims

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Application Information

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IPC IPC(8): C07D489/08C07C51/41C07C55/07A61K31/485
CPCC07B2200/13C07D489/08
Inventor 齐艳国解兵亮宋艳杰董文弟曹敏慧王振国任爱国
Owner 石家庄蒎格医药科技有限公司
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