A racemic liquid of opposite enantiomers usually crystallizes as a racemic compound (racemate), rarely as a conglomerate, and even more rarely as a solid solution. We discovered a Type II solid solution (mixed crystal) of the enantiomers of the chiral drug tazofelone (TZF) by seeding its racemic liquid with enantiomerically pure crystals (enantiomorphs). Without seeding, the racemic liquid crystallized as a racemic compound. The crystal structure of this solid solution resembles that of the enantiomorph but has static disorder arising from the random substitution of enantiomers. This solid solution is a kinetic product of crystallization made possible by its faster growth rate compared to that of the competing racemate (by 4- to 40-fold between 80 and 146 degrees C). The free energy of the solid solution continuously varies with the enantiomeric composition between those of the conglomerate and the racemates. The existence of the TZF solid solution explains the absence of eutectic melting between crystals of different enantiomeric compositions. The ability of TZF to simultaneously form racemate and solid solution originates from its conformational flexibility. Similar solid solutions of enantiomers may exist in other systems and may be discovered in similar ways. The study demonstrates the use of cross-nucleation for discovering and engineering crystalline materials to optimize physical properties.

2005-10-01·The Journal of Physical Chemistry B3区 · 化学

Measuring Free-Energy Difference between Crystal Polymorphs through Eutectic Melting

3区 · 化学

Article

作者: Jones, Karen J. ; Huang, Jun ; Yu, Lian

We describe a method to measure the free-energy difference, DeltaG, between crystal polymorphs from their calorimetric data of eutectic melting with a common additive. The use of different additives yields DeltaG as a function of temperature. The method is suitable for crystals that chemically decompose or physically transform before melting. It applies to not only true polymorphs but also pairs of racemate and conglomerate of resolvable enantiomers. We illustrate the method with the polymorphs of glycine, d-mannitol, and tazofelone and report a new value (123 degrees C) for the enantiotropic transition temperature of alpha and gamma glycine. We show how different additives (including a liquid additive, water) can be used for different compounds. The DeltaG data thus obtained are important for structure-stability studies and controlling crystallization in polymorphic systems.

1999-01-01·Chirality4区 · 化学

Stereoselective metabolism of tazofelone, an anti-inflammatory bowel disease agent, in rats and dogs and in human liver microsomes

4区 · 化学

Article

作者: Terry D. Lindstrom ; Brenda R. Hanssen ; Sekhar S. Surapaneni ; Michael P. Clay

Incubation of (R)-tazofelone and (S)-tazofelone in rat, dog, and human liver microsomes demonstrated that the (R)-tazofelone enantiomer was more rapidly metabolized, with two diastereomeric sulfoxides as the major metabolites formed in all three species. The two diasteresomers epimerized at physiological pH, therefore total sulfoxide formation rates were measured. The formation of the total sulfoxide metabolites followed Michaelis-Menten kinetics. The K(m), Vmax, and intrinsic formation clearance (Vmax/K(m)) values were determined in rat, dog, and human liver microsomes. The intrinsic formation clearance of sulfoxide from (R)-tazofelone exceeded that of (S)-tazofelone in all three species. In vivo studies in rats and dogs dosed orally and intravenously confirmed the stereoselective metabolism of tazofelone observed in vitro. Plasma concentrations of (S)-tazofelone exceeded (R)-tazofelone in rats and dogs by a factor of 3 to 4. In rat portal plasma, both enantiomers were of approximately equal concentration after oral dosing, indicating similar absorption. The half-lives of tazofelone and total sulfoxides in rats were 3.5 and 2.8 h, respectively. In dogs, the half-lives of tazofelone and total sulfoxides were 2.2 and 5.5 h, respectively. Plasma clearance was 2.3 l/h in rats and 1.4 l/h in dogs, and the volumes of distribution were 12 and 4.5 l, respectively, in rats and dogs. Both enantiomers were highly bound to plasma proteins to a similar extent in both species.

100 项与 Tazofelone 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
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适应症	最高研发状态	国家/地区	公司	日期
炎症性肠病	临床2期	美国	Eli Lilly & Co.	1999-01-01
溃疡性结肠炎	临床2期	美国	Shire Pharmaceuticals Group	-
克罗恩病	临床2期	美国	Shire Pharmaceuticals Group	-
肠易激综合征	临床2期	美国	Shire Pharmaceuticals Group	-