New crystal form of lorazepam, preparation method and pharmaceutical applications thereof

A technology of lorazepam and medicinal charcoal, which is applied in the field of medicine and can solve the problems of affecting the long-term storage and transportation of preparations, low oral bioavailability of medicines, and unstable when exposed to light.

Active Publication Date: 2020-01-14
HUNAN DONGTING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is known that the melting point of lorazepam is almost insoluble in water. It is reported that the solubility in water is only 0.08 mg / ml, and the melting point of the crystals is 166-168 ° C. It is unstable when exposed to light. These properties bring challenges to the formulation of drugs, such as Low solubility usually leads to problems such as low oral bioavailability of the drug, and the stability of the API will not only affect the preparation of pharmaceutical preparations, but also affect the long-term storage and transportation of the preparations

Method used

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  • New crystal form of lorazepam, preparation method and pharmaceutical applications thereof
  • New crystal form of lorazepam, preparation method and pharmaceutical applications thereof
  • New crystal form of lorazepam, preparation method and pharmaceutical applications thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0096] Embodiment 1: Preparation of lorazepam

[0097] Step 1, acetoxylation reaction prepares the acetoxy compound of formula II

[0098] Add 1 mol (305 g) of the ketone base of formula I, 14 mol of glacial acetic acid, 2.5 mol of potassium acetate, 1.8 mol of potassium persulfate, and 2.5 mol of iodine into the reaction flask, stir at 80°C to react for 7 hours, then distill under reduced pressure at 65°C Remove the acid solution; then add ethyl acetate (4 times the amount of the ketone base), 5% sodium thiosulfate solution (6 times the amount of the ketone base) in the reaction flask, stir for 25 minutes, let stand layer; collect the organic layer, extract the aqueous layer twice with ethyl acetate, combine the organic layers, add 1.25 times the volume of saturated sodium chloride solution therein, stir for 25 minutes, let stand to separate the layers, and separate the organic layer; the organic layer Add medicinal charcoal (0.75%), stir and decolorize at 65°C for 25 minu...

Embodiment 2

[0103] Embodiment 2: Preparation of lorazepam

[0104] Step 1, acetoxylation reaction prepares the acetoxy compound of formula II

[0105] Add 1 mol (305 g) of ketones of formula I, 15 mol of glacial acetic acid, 2 mol of potassium acetate, 2 mol of potassium persulfate, and 2 mol of iodine into the reaction bottle, stir at 70°C to react for 8 hours, then distill off the acid solution at 70°C under reduced pressure Then add ethyl acetate (3 times of the ketone-based charging capacity), 5% sodium thiosulfate solution (7 times of the ketone-based charging capacity) in the reaction flask, stir for 20 minutes, leave standstill and make layering; collect Extract the organic layer and the aqueous layer twice with ethyl acetate, combine the organic layers, add 1 times the volume of saturated sodium chloride solution to it, stir for 20 minutes, let stand to separate the layers, and separate the organic layer; the organic layer is used for medicinal purposes Charcoal (0.5%), stirred...

Embodiment 3

[0110] Embodiment 3: Preparation of lorazepam

[0111] Step 1, acetoxylation reaction prepares the acetoxy compound of formula II

[0112]Add 1 mol (305 g) of ketones of formula I to the reaction flask, 12 mol of glacial acetic acid, 3 mol of potassium acetate, 1.5 mol of potassium persulfate, and 3 mol of iodine, stir at 90°C to react for 6 hours, then distill off the acid at 60°C under reduced pressure solution; then add ethyl acetate (5 times of the ketone-based feeding amount), 5% sodium thiosulfate solution (5 times of the ketone-based feeding amount) in the reaction flask, stir for 30 minutes, and let stand to make stratification; Collect the organic layer, extract the aqueous layer twice with ethyl acetate, combine the organic layers, add 1.5 times the volume of saturated sodium chloride solution to it, stir for 30 minutes, let stand to separate the layers, and separate the organic layer; add medicine to the organic layer Use charcoal (1%), stir and decolorize at 60°...

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Abstract

The invention relates to a new crystal form for preparing lorazepam, a preparation method and pharmaceutical applications thereof, wherein specifically the lorazepam crystal has diffraction peaks at about 12.17 DEG, about 14.15 DEG, about 15.27 DEG, about 16.84 DEG, about 17.91 DEG and about 20.81 DEG in a powder X-ray diffraction pattern represented by a 2[theta] angle by using Cu-Kalpha radiation, for example, the crystal has diffraction peaks at about 7.93 DEG, about 9.04 DEG, about 12.17 DEG, about 14.15 DEG, about 15.27 DEG, about 16.84 DEG, about 17.91 DEG, about 20.81 DEG, about 21.44 DEG and about 26.38 DEG. The invention further provides a preparation method of the new crystal of larazepam, and pharmaceutical applications of the new crystal form. According to the invention, the prepared new crystal form for preparing lorazepam shows excellent properties defined in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of benzodiazepine drug lorazepam. It also relates to lorazepam prepared by the method, and its use in drugs with anxiolytic, antiepileptic, anticonvulsant and sedative hypnotic effects. The present invention also relates to the new crystal form of lorazepam prepared by the method of the present invention, and the pharmaceutical use of the new crystal form. Background technique [0002] Loarzepam, molecular formula C15H10Cl2N2O2, molecular weight 321.16, chemical name: 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzo Diazepin-2-one, its chemical structural formula is: [0003] [0004] Lorazepam is white or off-white crystalline powder; odorless; lorazepam is slightly soluble in ethanol and almost insoluble in water. [0005] Lorazepam, also known as lorazepam, lorazepam and lorazepam, belongs to benzodiazepine (BZD) drugs. It acts on the G...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/24C07D243/26A61K31/5513A61P25/22A61P25/08A61P25/20A61P29/00
CPCC07D243/24C07D243/26A61P25/22A61P25/08A61P25/20A61P29/00C07B2200/13
Inventor 侯奇伟王波冯建辉
Owner HUNAN DONGTING PHARMA
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