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Crystal form A of Bictegravir sodium salt, and preparation method and use of crystal form A of Bictegravir sodium salt

A crystal form and sodium salt technology, applied in organic chemical methods, medical preparations containing active ingredients, pharmaceutical formulations, etc., can solve the problems of reducing tablet and filling production efficiency, poor physical properties of crystal form powder, and bioavailability Reduce problems such as improving product appearance, excellent compressibility, and reducing adsorption

Active Publication Date: 2020-11-24
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Form I has very low solubility, poor solubility will lead to reduced bioavailability
In addition, the physical properties of the crystalline powder are poor, and these unfavorable properties may reduce the production efficiency of tablet compression and filling in the preparation, and at the same time bring great difficulties to the quality control of the drug

Method used

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  • Crystal form A of Bictegravir sodium salt, and preparation method and use of crystal form A of Bictegravir sodium salt
  • Crystal form A of Bictegravir sodium salt, and preparation method and use of crystal form A of Bictegravir sodium salt
  • Crystal form A of Bictegravir sodium salt, and preparation method and use of crystal form A of Bictegravir sodium salt

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The preparation of embodiment 1 Bictegravir sodium salt

[0034] Add 10g of Bictegravir into 100mL of dichloromethane, stir to dissolve, cool down to 0-10°C; add 1.26g of sodium methoxide to 12mL of methanol, stir to dissolve, cool down to 0-10°C, slowly add the above methylene chloride solution dropwise After 20 minutes of dripping, the dripping was completed, stirring and crystallizing at 0-10°C for 3h, suction filtration, rinsing the filter cake with an appropriate amount of dichloromethane, and drying at 50°C for 16h to obtain 9.8g of off-white solid, which is the crystal form of Bictegravir sodium salt a.

[0035] The XRPD peak data of the crystal form A of Bictegravir sodium salt are shown in Table 1:

[0036] Table 1

[0037]

[0038]

[0039] Embodiment 2 fluidity test

[0040] According to the "United States Pharmacopoeia", the fluidity of the crystal form A prepared by the present invention is studied through the compressibility coefficient, and the b...

Embodiment 3

[0045] Embodiment 3 compressibility test

[0046] Adopt manual tablet press to carry out tabletting, when tabletting, select to be able to be pressed into the circular parallel punching of cylindrical tablet (guarantee the isotropy of tablet). Take a certain amount of original research crystal form and crystal form A respectively, use a certain pressure to press into round tablets, place them in a desiccator for 24 hours, and use a tablet hardness tester to test their radial crushing force (hardness , N). Measure the diameter (D) and thickness (L) of the tablet with a vernier caliper, and use the formula T=2N / πDL to calculate the tensile strength of the powder at different hardnesses. Under a certain pressure, the greater the tensile strength, the better its compressibility. When the amount of sample in the screening stage is small, the recommended parameters in the table below can be used for testing. The recommended parameters for the tensile strength test are as follows:...

Embodiment 4

[0051] Embodiment 4 adhesion test

[0052] Add an appropriate amount of crystal form A and the original research crystal form into a suitable mold, press a certain pressure for tableting, stay for about half a minute after tableting, and weigh the amount of powder absorbed by the punch. After using this method for several times of continuous pressing, record the cumulative final adsorption amount of the punch, the highest adsorption amount and the average adsorption amount during the pressing process. The experimental data are shown in Table 4:

[0053] Table 4

[0054] crystal form Cumulative final adsorption amount (mg) Maximum adsorption capacity (mg) Average adsorption capacity (mg) Form A 0.14 0.10 0.028 Original crystal form 0.21 0.17 0.042

[0055] The results show that compared with the original crystal form, the average adsorption amount of the crystal form A of the present invention is only 0.028 mg, which is far lower than that ...

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Abstract

The invention relates to the technical field of biomedicine, in particular to a crystal form A of Bictegravir sodium salt, and a preparation method and use of the crystal form A of Bictegravir sodiumsalt. Compared with existing crystal forms, the crystal form A of Bictegravir sodium salt provided by the invention has lower hygroscopicity; has good solubility in simulated biological media and purewater; has better fluidity; has better compressibility; and has less adhesion.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to crystal form A of Bictegravir sodium salt, a preparation method and application. Background technique [0002] Bictegravir is a new type of integrase inhibitor developed by Gilead. Unlike the previously developed integrase inhibitors, Bictegravir only needs to be used once a day and does not require the synergist cobicistat. [0003] [0004] In current treatment guidelines in Europe and the United States, Bictegravir is recommended as the first-line treatment for AIDS. Bictegravir is another blockbuster drug that Gilead will launch in the HIV drug field after TAF, and it is expected to stabilize Gilead's monopoly position in the HIV drug market share. [0005] Patent CN106459085A discloses a crystal form I of Bictegravir sodium salt. The solubility of Form I is very low, and poor solubility will lead to reduced bioavailability. In addition, the physical properties of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18A61K31/537A61P31/18
CPCA61P31/18C07B2200/13C07D498/18
Inventor 于立国孙光祥顾斌张云然王兵孙海江邵梁都瑜峰金生华
Owner CHANGZHOU PHARMA FACTORY
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