Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/82—Purification; Separation; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

• This invention relates to a process for the preparation of a polymorph of hydrochloride salt of (I S , 4S) N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine, a compound of formula 1.
• the hydrochloride salt of (l S,4S) N-methyl-4-(3,4- dichlorophenyl)-l,2 , 3,4-tetrahydro-l-naphthalenamine is useful in the treatments of depression , obsessive-compulsive disorder and panic disorder.
• the hvdrochloride salt of (1 S,4S) N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l - naphthalenamine is known to exist in several different crystalline forms.
• United States Patent No . 5 , 248,699 (Sysko et al, issued Sep 28, 1993 - Indian Reference not available) assigned to Pfizer Inc. discloses five polymorphic forms, namely Form I, Form II, Form III, Form IV and Form V.
• the crystal densities of the crystalline forms were 1.354, 1 . 314 , 1 . 313, 1.349, and 1.308 for Form I, Form II, Form III, Form IV and Form V; respectively .
• Form I which has the highest crystal density to be the most thermodynamically stable form. It is suggested that this makes Form I the most suitable crystal form for formulation, however, it has been reported by others - United States Patent No. 5,734,083 (Indian Reference not available) that Form I dissolves too slowly to provide the desired bioavailability from a pharmaceutical formulation.
• the processes for preparation of polymorphic forms I to V of the hydrochloride salt of (1 S,4S) N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine are disclosed in United States Patent No. 5,248,699 (Indian Reference not available).
• Form I is prepared by crystallization over a period of about 3 hours in an acidic solution using solvent such as isopropanol, hexane, ethyl acetate, acetone, methyl isobutyl ketone and glacial acetic acid at crystallization temperature from about 20°C to about 100°C.
• Forms II and IV may be formed by rapid crystallization from an organic solvent.
• Form III is produced by heating Forms I, II or IV to above about 180°C.
• Form V may be prepared by sublimation of the hydrochloride salt of (IS, 4S) N-methyl-4-(3,4- dichlorophenyl)-l, 2,3, 4-tetrahydro- 1 -naphthalenamine at a reduced pressure at a temperature from about 180°C to about 190°C.
• This polymorph Ti is obtained by treating a slurry or solution of free base, (IS, 4S) N-methyl-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine in an organic solvent such as toluene with a polar solvent such as ethyl acetate, diethyl ether or mixtures thereof, so as to form a solution of the free base in the polar solvent; and acidifying the mixture by the addition of a solution of hydrogen chloride (1 - 10% w/w) in an organic solvent such as ethyl acetate.
• Polymorph Form V of (IS, 4S) N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l- naphthalenamine hydrochloride is reportedly prepared by process of sublimation under reduced pressure.
• the objective of the present invention is to prepare polymorphic Form V of the hydrochloride salt of (IS, 4S) N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydro-1 -naphthalenamine by a simple method.
• Form V prepared by the process of the present invention is stable under a variety of conditions that one may encounter during processing and storage of pharmaceutical formulations. For example, it was stable for 3 months at 40°C and 75% relative humidity or when subjected to grinding in a pestle and mortar or when heated upto 140°C for 3 hours
• the objective of the present invention is to develop a simple method to prepare
• Form V of the hydrochloride salt of (1S,4S) N-methyl-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine may be conveniently prepared by adding the hydrochloride salt of (1S,4S) N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydro-1 -naphthalenamine to an alkanol-water solvent system, heating to dissolve, and cooling the solution to allow crystallization to occur so as to obtain Form V
• the present invention relates to a process for the preparation of a polymorph of hydrochloride salt of (1S,4S) N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l- naphthalenamine, comprising adding the hydrochloride salt of (1 S,4S) N-methyl-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine to an alkanol-water solvent system, heating to dissolve and cooling the solution to allow crystallization to occur
• Figure 1 is a characteristic Infrared spectrum (KBr) of Form V of hydrochloride salt of
• the present invention relates to a process for the preparation of a polymorph of hydrochloride salt of (1S,4S) N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l- naphthalenamine, comprising adding the hydrochloride salt of (1S,4S) N-methyl-4-(3,4- dichlorophenyl)-l, 2,3, 4-tetrahydro- 1 -naphthalenamine to an alkanol - water solvent system, heating to dissolve and cooling the solution to allow crystallization to occur so as to obtain Form V
• the volume of alkanol-water solvent system that may be used may range from about 6 to 15 parts per unit weight of the hydrochloride salt of (1S,4S) N-methyl-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine, preferably 8 to 10 parts per unit weight of the hydrochloride salt of (lS,4
• the alkanol-water system may have a relative proportion ranging from 5 1 to 20 1 parts by volume, preferably 5 1 to 10 1 parts by volume and most preferably 8 1 parts by volume
• the alkanol is selected from Ci to C alkanol, more preferably methanol or 2-propanol
• the most preferred alkanol is 2- propanol
• a polyol selected from glycerol, mannitol, sorbitol, inositol, xylitol, 1,3-butanediol, 1,2-propanediol and the like, is added to the alkanol-water solvent system Generally 0 to 25 mole% of the polyol with respect to hydrochloride salt of (1S,4S) N-methyl-4-(3,4-dichlorophenyl)- 1, 2,3, 4-tetrahydro- 1 -naphthalenamine, is added to the solvent system and preferably 10 mole%
• the polyol may be incorporated into the alkanol-water system before, during or after the stage of dissolution of hydrochloride salt of (lS,4S) N-methyl-4-(3,4-dichlorophenyl)- 1,2, 3, 4-tetrahydro- 1 -naphthalenamine with heating
• the polyol may be incorporated preferably as in Example 1 i e dissolved in water and then alkanol added because the dissolution of certain polyol like mannitol is slow in alkanol-water mixture
• the sequence of addition of the polyol should not affect the formation of form V, since the crystallization is occurring from a clear solution
• the dissolution of hydrochloride salt of (1S,4S) N-methyl-4-(3,4-dichloro ⁇ henyl)- 1,2,3, 4-tetrahydro- 1 -naphthalenamine may be achieved by heating the solution Generally the solution is heated to a temperature greater than about 40°C
• the dissolution of hydrochloride salt of (1S,4S) N-methyl-4-(3,4-dichlorophenyl)-l, 2,3,4- tetrahydro-1 -naphthalenamine may be achieved by heating the solution to reflux temperature
• the solution may be cooled to below room temperature to allow crystallization to occur
• the solution is cooled to 20-30°C to allow crystallization to occur
• the solution is allowed to cool for a period of 2 to 8 hours to allow crystallization to occur
• the solution is cooled to 20-30°C over a period of 2 to 8 hours to allow crystallization to occur
• the product may be dried using any conventional drying techniques which may be suitable for the product such as fluidized bed drying, tray drying, rotary drying, drying at reduced pressures, freeze drying or spray drying Driers that have agitational means are preferred.
• Example 3 Method of example 1 was followed except that sorbitol was used in the place of mannitol Form V of the hydrochloride salt of (1S,4S) N-methyl-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-l-naphthalenamine was obtained
• Example 4 The crystal form of hydrochloride salt of (1S,4S) N-methyl-4-(3,4-d ⁇ chlorophenyl)-

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Citations (4)

• 2000
  • 2000-03-29 IN IN979BO1999 patent/IN189886B/en unknown
• 2001
  • 2001-03-27 AU AU55057/01A patent/AU5505701A/en not_active Abandoned
  • 2001-03-27 WO PCT/IN2001/000049 patent/WO2001072684A1/en not_active Ceased
  • 2001-03-27 US US10/239,930 patent/US20030149306A1/en not_active Abandoned

Patent Citations (5)

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