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Crystal form of azilsartan medoxomil and preparation method thereof

A technology of azilsartan medoxomil and crystal form, applied in the crystal form of azilsartan medoxomil and the field of preparation thereof, can solve the problems of low dehydration temperature, high melting point, unfavorable tablet compressibility and the like

Active Publication Date: 2016-09-28
SOLIPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The known crystal form J2 mentioned in the patent document WO2012 / 090043A1 has low solubility in water, which affects the dissolution of the drug, thereby affecting the bioavailability, and the melting point is too high, so it is not suitable for the preparation obtained by the hot-melt extrusion method, and The crystalline form has small particles, which is not conducive to the compressibility of the tablet; the known crystalline form J4 mentioned is a hydrate, which has a low dehydration temperature and poor thermal stability

Method used

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  • Crystal form of azilsartan medoxomil and preparation method thereof
  • Crystal form of azilsartan medoxomil and preparation method thereof
  • Crystal form of azilsartan medoxomil and preparation method thereof

Examples

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Effect test

Embodiment 1

[0249] The known crystal form J2 of azilsartan medoxomil can be prepared according to the method described in Example 1 of patent document WO2012 / 090043A1.

[0250] Specifically, the preparation method of known crystal form J2 of azilsartan medoxomil is as follows: at 15-20°C, dissolve 0.5g of known crystal form I of azilsartan medoxomil in 50mL of methanol, and volatilize the solution after filtering to obtain Form J2 is known.

[0251] The XRPD pattern of the known crystal form J2 is shown in Figure 37 .

[0252] DSC diagram see Figure 38 , showing a melting point of 170 °C.

[0253] See TGA diagram Figure 39 , showing as anhydrous substance, the decomposition temperature is 229°C.

[0254] PLM diagram see Figure 40 , showing extremely small particles.

Embodiment 2

[0256]The known crystal form J4 of azilsartan medoxomil can be prepared according to the method described in Example 4 of the patent document WO2012 / 090043A1.

[0257] Specifically, the preparation method of the known crystal form J4 of azilsartan medoxomil is as follows: 0.5 g of azilsartan medoxomil crystal form I is dissolved in acetone (7.5 mL) and ethyl acetate (7.5 mL) at 40-50° C. ) in the mixed solution, lower the temperature to 0-5°C and stir, and filter to obtain the known crystal form J4.

[0258] The XRPD pattern of the known crystal form J4 is shown in Figure 41 .

[0259] See DSC diagram Figure 42 , showing that it transformed at 146°C after desolvation to form anhydrous known crystal form J2 with a melting point of about 170°C.

[0260] See TGA diagram Figure 43 , showing that there is a 6.4% weight loss at 95°C, which is about 2 water molecules, which is a dihydrate, and the decomposition temperature is 222°C.

Embodiment 3

[0262] Weigh 100mg of known crystal form J2 and add it to a 30mL single-necked flask, then add 10mL of acetone, spin dry quickly, and obtain a foamy solid amorphous.

[0263] The XRPD pattern of the amorphous substance is shown in Figure 4 , no XRPD diffraction peak, it is amorphous.

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Abstract

The invention relates to a crystal form of azilsartan medoxomil and a preparation method thereof. In particular, the present invention relates to the compound 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl ]‑4‑yl]methyl]‑2‑ethoxy‑1H‑benzimidazole‑7‑carboxylic acid (5‑methyl‑2‑oxo‑1,3‑dioxol‑4‑yl)methanol Various new crystal forms of esters and their preparation methods. The new crystal form of the present invention has higher solubility in water than the prior art and has a lower melting point, so it has better dissolution rate and bioavailability than the existing crystal form and is more conducive to obtaining by hot-melt extrusion method Pharmaceutical preparations.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical crystals. Specifically, it relates to a crystal form of azilsartan medoxomil and a preparation method thereof. Background technique [0002] Azilsartan medoxomil is a novel angiotensin II receptor blocker developed by Japan's Takeda Pharmaceutical Company, which was approved by the U.S. FDA in February 2011 under the trade name Edabi. The drug is also a prodrug of the new angiotensin II receptor blocker azilsartan, which is used for the treatment of hypertension and related complications. The drug is taken orally and can be used alone or in combination with other antihypertensive drugs for the treatment of hypertension and related complications. In the phase III clinical trial of once-daily administration of 20-80 mg azilsartan medoxomil, its safety and efficacy were confirmed, and in the comparative experiments with losartan and olmesartan medoxomil, it had higher hypotensive effect. T...

Claims

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Application Information

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IPC IPC(8): C07D413/14A61K31/4245A61P9/12
CPCC07B2200/13C07D413/14A61P9/12
Inventor 沈涛盛晓霞盛晓红
Owner SOLIPHARMA
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