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Crystal polymorph of potassium n-[8-(2-hydroxybenzoyl)amino]octanoate and its preparation method and use

A technology of hydroxybenzoyl and polymorphs, applied in the field of crystal polymorphs of N-[8-amino]octanoate potassium and its preparation, can solve the problems of gastric acid instability, low fat solubility, large molecular weight, etc. Achieve the effects of improving bioavailability, enhancing blood sugar reduction, and increasing permeability

Active Publication Date: 2021-09-17
杭州先为达生物科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Macromolecular drugs such as peptides and protein drugs are often characterized by large molecular weight, low fat solubility, instability to gastric acid, and can be destroyed by various digestive enzymes in the gastrointestinal tract. Oral administration cannot smoothly enter the intestinal tract for absorption
In response to the above problems, people try to overcome drug absorption barriers in many ways. In addition to some attempts in dosage forms, gastrointestinal absorption enhancers are often used to improve the biofilm permeability of drugs. Although the absorption of drugs is increased, but It also increases the absorption of intestinal toxins, and long-term use lacks safety

Method used

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  • Crystal polymorph of potassium n-[8-(2-hydroxybenzoyl)amino]octanoate and its preparation method and use
  • Crystal polymorph of potassium n-[8-(2-hydroxybenzoyl)amino]octanoate and its preparation method and use
  • Crystal polymorph of potassium n-[8-(2-hydroxybenzoyl)amino]octanoate and its preparation method and use

Examples

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preparation example Construction

[0207] The application provides a method for preparing a crystal form I of potassium N-[8-(2-hydroxybenzoyl)amino]octanoate, comprising the following steps:

[0208] Step 1: add an organic solvent to the reaction vessel and stir, then add N-[8-(2-hydroxybenzoyl)amino]octanoic acid, stir evenly, dropwise add potassium hydroxide solution, after the dropwise addition, concentrate to obtain the crude product ;

[0209] Step 2: adding an organic solvent to the crude product to obtain a filter cake after beating and suction filtration, rinsing the filter cake and placing it in a drying oven for drying, the drying temperature is 60°C to 100°C, and the drying time is 30 to 40h. The crystal form I of the potassium N-[8-(2-hydroxybenzoyl)amino]octanoate is obtained.

[0210] The drying temperature may be 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C. The drying time may be 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h.

[0211] Preferably, the drying is divided into t...

Embodiment 1

[0334] Prepare N-[8-(2-hydroxybenzoyl)amino]octanoic acid NAC with reference to the method in Example 1 of International Patent Application WO2008 / 028859

[0335] Preparation of PNAC Form I

[0336]Isopropanol (22070.0ml, 4.0vol) was added to the 50L reaction kettle, stirring was started, and NAC (5518g, 1.0eq) was added. The system was heated to 50° C., and the prepared 50% potassium hydroxide solution (1304.0 g, 1.0 eq) was added dropwise to the system. After dripping, the system turned into a clear and transparent yellow solution, and the reaction was kept at 50 °C for 1 h. The reaction solution was concentrated in batches at 40°C to obtain a crude product with a pale orange color.

[0337] The crude product was added in batches of isopropanol (19310.0 ml, 3.5 vol) for beating, and beating for 1 h. The system was subjected to suction filtration, and the filter cake was rinsed with isopropanol (2760.0 ml, 0.5 vol). The filter cake was transferred to a vacuum drying oven,...

Embodiment 2

[0344] Preparation of PNAC Form II

[0345] The PNAC crystal form I prepared in Example 1 is exposed to an environment of 60% relative humidity at room temperature, and the storage time is longer than 24 hours to obtain a product.

[0346] After determination, the product is crystal form II, and the XRPD, TGA / DSC of the product are as follows Figure 3-4b As shown, wherein the characteristic XRPD peaks of Form II (characterized by °2θ) are as follows in Table 2:

[0347] Table 2 shows the characteristic XRPD peaks of Form II (characterized by °2θ)

[0348]

[0349] DSC spectrum ( Figure 4a ) showed that the melting endothermic peak of Form II began to appear at 157.1 °C, and the peak was 162.5 °C; DSC ( Figure 4a ) and TGA ( Figure 4b ), it can be seen that the crystal form II is a 1 / 3 hydrate.

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Abstract

The application discloses a crystal polymorph of potassium N-[8-(2-hydroxybenzoyl) amino] octanoate, and the crystal polymorph of potassium N-[8-(2-hydroxybenzoyl) amino] octanoate is polymorphic The crystalline form is crystalline form I, and the crystalline form I has at least an X-ray powder diffraction pattern with characteristic peaks represented by 2θ°: 7.83±0.2, 26.64±0.2, and 18.89±0.2. The N-[8-(2-hydroxybenzoyl)amino] octanoic acid potassium crystal polymorph provided by the application has four crystal forms, which have high solubility and strong stability, can deliver drugs more effectively, and increase the The permeability of the drug in the gastrointestinal tract is conducive to making oral preparations, so that the preventive and / or therapeutic drugs can be better delivered to the body to achieve the effect of improving bioavailability.

Description

technical field [0001] The present application relates to the field of chemical medicine, in particular to a potassium N-[8-(2-hydroxybenzoyl)amino]octanoate crystal polymorph and a preparation method and application thereof. Background technique [0002] Macromolecular drugs such as peptides and protein drugs are often characterized by large molecular weight, low fat solubility, unstable to gastric acid, and can be destroyed by various digestive enzymes in the gastrointestinal tract. Oral administration cannot smoothly enter the intestinal tract for absorption. In response to the above problems, people have tried to overcome the barriers to drug absorption from various aspects. In addition to some attempts in dosage forms, gastrointestinal absorption enhancers are often used to improve the biofilm permeability of drugs. Although the absorption of drugs is increased, but It also increases the absorption of intestinal endotoxins, and it lacks safety for long-term use. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C235/52C07C231/12C07C231/24A61K47/18A61K38/28A61K38/26A61K38/22A61P3/10A61P3/04A61P37/02A61P19/10
CPCC07C231/12C07C231/24C07C235/52A61K47/183A61K38/28A61K38/26A61K38/22A61P3/10A61P3/04A61P37/02A61P19/10C07B2200/13A61K45/00C07C235/60
Inventor 王宏阳江师月李尧潘海
Owner 杭州先为达生物科技股份有限公司
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