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A process for the crystallisation of a tetrahydrobenzazepine compound in anhydrous form

IP.com Disclosure Number: IPCOM000234784D
Publication Date: 2014-Feb-05
Document File: 4 page(s) / 60K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present invention relates to a new process for the crystallisation of Lorcaserin to obtain the hydrochloride salt of Lorcaserin in an anhydrous form.

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A PROCESS FOR THE CRYSTALLIZATION OF A TETRAHYDROBENZAZEPINE COMPOUND IN ANHYDROUS FORM


[0001] Lorcaserin is an active pharmaceutical substance with an empirical formula of C11H14NCl and a molecular weight of 195.69. Lorcaserin is the international commonly accepted non-proprietary name for (R)-8-chloro-1-methyl- 2,3,4,5-tetrahydro-1H-3-benzazepine, which is represented by Formula (I):

NH Cl

[0002] The present document discloses a process for the crystallization of the hydrochloride salt of Lorcaserin in anhydrous form, said process comprising:


a) providing a solution of Lorcaserin base in a solvent comprising n-butanol;


b) if water is present, removing water from the reaction mixture;


c) optionally, combining the reaction mixture with a suitable antisolvent; and


d) adding hydrogen chloride to the reaction mixture,

wherein the antisolvent is a liquid compound which, once combined with the reaction mixture, reduces the solubility of the hydrochloride salt of Lorcaserin in the resulting reaction mixture with respect to its solubility in n-butanol. Preferably, the antisolvent is selected from the group comprising n-butyl acetate, tert-butyl methyl ether, ethyl acetate, heptane, isopropyl acetate, methyl ethyl ketone, methyl isopropyl ketone, and mixtures thereof.


[0003] The process of removing water from the reaction mixture preferably comprises azeotropic distillation.


[0004] The above process for the crystallization of the hydrochloride salt of Lorcaserin in anhydrous form can optionally comprise a seeding step with the desired anhydrous form of Lorcaserin hydrochloride.

(I)


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[0005] The L-(+)-tartaric acid salt of Lorcaserin which is used as starting material in the below experimental examples can be prepared for example by the procedure disclosed in Example 13 of patent application WO 2005/019179 A2.

Example 1: Crystallization of anhydrous Lorcaserin hydrochloride


16.0 g of the L-(+)-tartaric acid salt of Lorcaserin were suspended in a mixture of 150 mL of n-butanol and 50 mL of water, at 20-25 ºC. The mixture was basified to pH 11 by the addition of sodium hydroxide. Phases were separated and the organic layer was washed with water. Water was azeotropically removed from the reaction mixture, together with 130 mL of n-butanol. The solution was cooled to 0-10 ºC, and hydrogen chloride was bubbled into the reaction mixture. The resulting suspension was filtered, and the wet solid was dried at 80 ºC under vacuum until constant weight to yield anhydrous Lorcaserin hydrochloride as a white solid. XRPD: See Figure 1.

Example 2: Crystallization of anhydrous Lorcaserin hydrochloride


16.0 g of the L-(+)-tartaric acid salt of Lorcaserin were suspended in a mixture of 150 mL of n-butanol and 50 mL of water, at 20-25 ºC. The mixture was basified to pH 11 by the addition of sodium hydroxide. Phases were separated and the organic layer was washed with water. Water was azeotropically removed from the reaction mixture, togeth...