Novel solid body forms of mesoprogestin 11-beta-[4E-(hydroxyimino methyl)-phenyl]-17-alpha-methoxy methyl-17 beta-methoxy-estra-4,9-dien-3-one

A technology of hydroxyiminomethyl and methoxymethyl, which is applied in the field of amorphous or highly crystalline compounds) and can solve problems such as poor solubility

Inactive Publication Date: 2008-04-30
合林股份公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Purification by crystallization is hampered by the generally poor solubility in suitable solvents in this respect

Method used

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  • Novel solid body forms of mesoprogestin 11-beta-[4E-(hydroxyimino methyl)-phenyl]-17-alpha-methoxy methyl-17 beta-methoxy-estra-4,9-dien-3-one
  • Novel solid body forms of mesoprogestin 11-beta-[4E-(hydroxyimino methyl)-phenyl]-17-alpha-methoxy methyl-17 beta-methoxy-estra-4,9-dien-3-one
  • Novel solid body forms of mesoprogestin 11-beta-[4E-(hydroxyimino methyl)-phenyl]-17-alpha-methoxy methyl-17 beta-methoxy-estra-4,9-dien-3-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] 2 kg of oxime J867 (MtBE solvate, containing 20-24% MtBE; percentages of solvent contained in the solvate are weight %) were dissolved in 20 L of ethanol at 50° C. with stirring. The above solution was spray dried in a co-current process in a spray dryer operating under an inert atmosphere (nitrogen). The drying chamber in the spray dryer is filled with 60m 3 / h of nitrogen, which is preheated to 175°C. The solution was then sprayed into the drying chamber at a flow rate of 6.4 l / h through a deflector with dual nozzles operating with 3 bar nitrogen as propellant. The outlet temperature of the drying gas is 79-83°C. Oxime J867 dried to fine particles was completely collected in the product filter.

[0072] Oxime J867 has the following quality parameters:

[0073] remaining solvent

Embodiment 2

[0075] 50 ml of toluene was added to 20 g of oxime J867 (MTBE solvate, containing 20%-24% MtBE). The material dissolves very rapidly and completely at 25°C. 2.7 ml of methanol was added to the above solution, and the solution was mixed with 65 ml of MtBE. After about 1 minute, the MtBE solvate started to recrystallize. The whole process is carried out at room temperature. The suspension was stirred at 5°C for 1 hour, then filtered and the filter cake washed with 30 ml of cold MtBE. After drying, the yield was 84% ​​by weight of starting material. The resulting product was an MTBE solvate containing 22.3% MtBE. The purification effect relative to the main pollutants can be seen in the table below:

[0076] Add material

Embodiment 3

[0078] 30 g of MtBE solvate of oxime J867 (MtBE solvate, containing 20-24% MtBE) was suspended in 600 ml of water, then heated to 70° C. and suspended for 30 minutes. The suspension is filtered and then suctioned to dryness in a stream of air. Next, the crystallized material was vacuum-dried at 70° C. and <5 mbar for 3 hours.

[0079] 24 g of highly crystalline oxime J867 were obtained.

[0080] Neither phase inversion in hot water nor drying resulted in a significant increase in the Z-isomer and aldehydes.

[0081] Z-oxime (HPLC)

[0082] Similar data were detected for the highly crystalline form of oxime J867 in XRPD with respect to the intensity and position of the reflections and the heat of fusion in DSC.

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Abstract

The invention relates to novel solid body forms of mesoprogestin 11 beta -[4E-(hydroxyiminomethyl)-phenyl]-17 alpha-methoxymethyl-17 beta-methoxy-estra-4,9-dien-3-one (oxime J867), particularly a highly pure and stable amorphous or highly crystalline form (ansolvate / anhydrate) of compound J867. The invention also relates to methods for producing said novel solid body forms and to the use thereof in pharmaceutical compositions. The novel solid body forms are characterized by exhibiting a high degree of stability. The solid body forms of oxime J 867 can, in particular, be used in the area of fertility control and in hormone replacement therapy.

Description

technical field [0001] The present invention relates to new solid forms of mesoprogestin 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estro-4,9- Dien-3-one (oxime J 867), especially compound J 867 in highly pure and stable amorphous or highly crystalline form (ansolvate / anhydrate (ansolvate / anhydrate)), its preparation method and its use in pharmaceuticals Composition application. Background technique [0002] 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4 is known, for example, from EP-A-0648778 or DE-A-4332283 , 9-dien-3-one. The crystalline form obtained after recrystallization from dichloromethane / isopropanol melted at 113°C. The crystalline form is an isopropanol solvate with an isopropanol content of 14% (see XRPD: Table 2 / Figure 4d). This oxime is characterized by a very strong tendency to crystallize from the solvent in the form of the solvate. However, the solvated form is not very suitable for pharmaceutical appl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J41/00A61K31/565A61P5/36A61K31/569A61P15/08A61P15/12A61P15/18
CPCC07J41/0083C07J41/00A61P15/08A61P15/12A61P15/18A61P5/36
Inventor 德特勒夫·格拉韦彼得·赫斯尔乌韦·穆尔勒加布里埃莱·温特
Owner 合林股份公司
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