Venlafaxine base

#The present invention relates to pharmaceutically useful forms of venlafaxine base and methods of making the same.

#Venlafaxine is the common name for the compound 1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl]cyclohexanol, having the structure shown below. 1

#U.S. Pat. No. 4,535,186 describes a class of hydroxycycloalkanephenethyl amines as being useful antidepressants and exemplifies the compound now known as venlafaxine hydrochloride as one of the suitable species. Venlafaxine hydrochloride is approved for sale in various countries including the United States of America. It is available as an immediate release tablet and as an extended release capsule under the brand names EFFEXOR® (Wyeth Ayerst) and EFFEXOR ER® (Wyeth Ayerst), respectively.

#FIG. 1 shows the powder X-ray diffraction pattern for venlafaxine Form I.

#FIG. 2 shows the powder X-ray diffraction pattern for venlafaxine Form II.

#The present invention is based on the surprising discovery that a solid, pharmaceutically useful form of venlafaxine base can be formed. In the above-described prior literature, a solid venlafaxine base was normally formed by evaporating off the solvent to leave a solid residue. The solids produced in this way were generally not in a pharmaceutically useful form as they contained the residue of solvent and impurities as indicated by the yellow color and/or color changes associated therewith. Instead of precipitating a racemic free base directly, the above-described patents usually teach converting the free base to a salt, such as the hydrochloride or tartrate salt, in order to accommodate/facilitate precipitation. The present invention provides a method for precipitating venlafaxine base directly. Via precipitation, alone or with other processing techniques known in the art, a solid pharmaceutically useful venlafaxine base can be obtained.

#Furthermore, the invention is based on the subsequent discovery that venlafaxine base exhibits low water solubility and slow dissolution in water, which combined with its high loading capabilities, makes it an advantageous active for formulating into pharmaceutical dosage forms, especially extended release dosage forms. In addition, venlafaxine base is less aggressive, less irritating, and easier to handle than venlafaxine hydrochloride. Accordingly, venlafaxine base is easier to formulate into a variety of dosage forms, especially extended release dosage forms, than venlafaxine hydrochloride.

#“Venlafaxine base” as used herein means the compound 1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl]cyclohexanol and includes the racemate or mixture of enantiomers of venlafaxine as well as the pure or substantially pure (+) or (−) enantiomer of venlafaxine (hereinafter sometimes referred to as (+)-venlafaxine and (−)-venlafaxine).