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1-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone polymorphs®®®

IP.com Disclosure Number: IPCOM000131677D
Publication Date: 2005-Nov-14

Publishing Venue

The IP.com Prior Art Database

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1-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]- 4(S)-(4-hydroxyphenyl)-2-azetidinone polymorphs

    1-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4- hydroxyphenyl)-2-azetidinone (referred to as EZT) belongs to a class of lipid- lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols.

EZT reportedly does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Instead, it appears that 1-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)- hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone localizes and acts at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. The result is a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.

EZT having the following chemical structure

may be obtained, for example,

Novel crystalline forms of EZT were found, and are described herein below.

Form A

Figure 1: The crystalline form, denominated Form A, has main x-ray powder diffraction peaks at about 16.4, 20.2, 22.5, 24.0 and 25.6 degrees two-theta ±0.2 degrees two-theta. Form A can be further characterized by x-ray powder diffraction peaks at about 8.2, 18.6, 19.0, 23.6 and 29.7 degrees two-theta ±0.2 degrees two-theta, as substantially depicted in Figure 1.

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Form A exists either as a solvated or anhydrous form, containing about 0.1 to about
3.5% of water. Form A may also be characterized by a weight loss measured by thermal gravimetric analysis (referred to as TGA) of about 0.2 to about 15% by weight.

The crystalline form, denominated form A, is pure and may contain less than about 5% by weight Form B, and preferably less than about 5% by weight of any other single polymorphic form, as estimated from the XRD diffractogram of a sample.

The crystalline form, denominated form A is also a micronized from of EZT crystal, which is stable upon micronization.

Form B

Figure 2: The crystalline form, denominated Form B, has main x-ray powder diffraction peaks at about 18.7, 19.5, 23.0, 23.5 and 24.6 degrees two-theta ±0.2 degrees two-theta. Form B can be further characterized by x-ray powder diffraction peaks at about 8.0, 15.9, 20.7, 21.9 and 25.5 degrees two-theta ±0.2 degrees two-theta, as substantially depicted in Figure 2.

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Form B exists as a solvated form of solvents selected from the group consisting of: ketone, C1-4 alcohol, ester, aromatic hydrocarbon, halogenated aliphatic hydrocarbon, ether, nitrogen containing hydrocarbon.

Preferably, the ketone is methylisobutyl ketone (referred to as MIBK), methylethlyketone (MEK) or acetone. A preferred C1-4 alcohol is n-propanol, n- butanol, ethanol, propylene glycol or isobutanol. Preferably, the ester is e...