JPH01290661A - Production of polymorphically pure terphenazine - Google Patents

Abstract

PURPOSE: To obtain a high-melting point and low-melting point homogeneous polymorph by dissolving terphenazine in a suitable solvent and crystallizing the compound under special conditions.

CONSTITUTION: Terphenazine being a non-sedative antihistaminic, namely 1-(ptert-butylphenyl)-4[4'-(α-hydroxydiphenylmethyl)-1'-piperidinyl] butanol is dissolved in a water-miscible lower alkanol (desirably ethanol), the solution is heated to its reflux temperature, and a sufficient amount of water is added to the concentrated solution under agitation to crystallize terphenazine, and the solution is cooled to collect the crystalline product being a high-melting point homogeneous polymorph having a melting pint of 149-151°C. Terphenazine is dissolved in a suitable solvent (e.g. acetone or toluene) at 0-35°C, the solvent is slowly evaporated, and the crystalline product is collected to obtain a low- melting point homogeneous polymorph having a melting.

COPYRIGHT: (C)1989,JPO

Description

[Detailed description of the invention] [Industrial field of application] Terfenazine, i.e. 1-(p-tert-butylphenyl)
-4-[4'-(α-hydroxydiphenylmethyl)
-1-piperidinyl]butanol is a non-sedating antihistamine.

[Conventional technology]

Previous crystallization procedures for terfenadine, although analytically pure, still produced products with highly variable melting points. I'll go with you. It has recently been discovered that solid terfenazine exists in two distinct forms, crystalline or polymorphic, each form having a different melting point. It has further been discovered that terfenadine crystallized by prior art methods varies widely in polymorphic composition and that this polymorphic diversity is the reason for the observed diversity in the melting points of terfenadine. Ta.

[5 Examples Solved by the Invention] In the present invention, the applicant has discovered a method of producing polymorphically pure terfenazine. These methods facilitate quality integrity capabilities associated with large scale production of terfenadine. Provides a material with controlled silk to physical properties.

[Means to solve problems]

The high melting polymorph of terfenadine is prepared by dissolving terfenadine in a water-miscible lower alkanol, heating the solution to about its reflux temperature, and slowly adding a sufficient amount of water with stirring to dissolve substantially all of the terfenadine. of dissolved terfenadine, cooling to about 25° C. and collecting the crystalline product. A low melting homogeneous variety of terfenadine is prepared by dissolving terfenadine in a suitable solvent at a temperature of about 35°C to about 35°C, and slowly evaporating the solvent.
It is produced by collecting the resulting crystalline product.

The high melting point variegated product of terfenazine has a melting point of 149 to 15
Terfenadine is in substantially pure crystalline form with a temperature of 1°C. The low melting polymorph of terfenadine is a substantially pure crystalline form of terfenadine having a melting point of 146°C.

The term "lower alkanol solvent" means any water-miscible lower alkanol in which terfenazine is soluble, containing 1 to 6 carbon atoms, primary, Contains secondary and tertiary alcohols. Suitable lower alkanol solvents include methanol, ethanol,
Includes n-propanol, isopropanol, isobutanol, amyl alcohol, t-butanol and cyclohexanol. The lower alkanol solvent preferably used for the preparation of the high melting polymorph of terfenazine is methanol, ethanol or propatool. Ethanol is the most preferred solvent. Mixtures of two or more lower alkanols are also included, as are solutions of water and lower alkanols where the water accounts for up to about 10 to 20 times the weight of the solution.

Solutions of terfenazine in lower alkanol solvents are prepared in a conventional manner. Typically the solution of the substance to be recrystallized will be highly concentrated near the point of solute saturation in the solvent. For example, when ethanol is the solvent, the weight-to-volume ratio of terfenadine to ethanol is 0.
1g/read 1~0.31j/rinse 1, preferably 0.15g
#el~0.25g/ml. Typically, the solution to be recrystallized is heated; the temperature of the solution to be recrystallized will be approximately the reflux temperature of the solution, which is about 78° C. when ethanol is the solvent. Preferably, the hot concentrated solution is filtered prior to crystal formation to remove any undissolved particulate material; the filtration is performed directly from the terfenadine high melting point polymorph to impure terfenadine! ! This is especially important when a legacy is to be left behind.

The water is heated and a condensed solution is added to the crystals of terfenazine (
Added to cause a hiatus. Preferably sufficient water will be added so that substantially all of the terfenadine crystallizes. When ethanol is the solvent, the volume to volume ratio of ethanol to water is between 0.75 and 1.5.
ml/ml, preferably about 11/1. Preferably less than 10% of the dissolved terfenadine will remain in solution after complete addition of water; the amount of water required depends on the solvent, the temperature of the heated and concentrated solution, and the temperature of the solution. It depends on various factors including concentration. The amount of water required to recover substantially all of the terfenazine as crystals of the high melting polymorph can be readily determined by one skilled in the art.

The water to be added to the heated and concentrated terfenadine solution is preferably heated, preferably between 60°C and 100°C.
heated to a temperature of °C. Preheating the water facilitates maintaining a constant temperature of the heated and concentrated terfenadine solution.

? Water is preferably added to the heated and concentrated terfenadine solution at a rate such that the temperature of liquid a can be maintained at approximately its reflux temperature, preferably slowly and dropwise with agitation, e.g. by stirring. Typically water addition takes 10 minutes to 2 hours. After all the water has been added to the lower vulcanol solution of terfenadine, it is preferred to age the crystals before filtration to collect the product; This can be achieved by continuing to heat the alkanol solution. Preferably the temperature during ripening is the reflux temperature of the solution, but can be any temperature at about ambient temperature. Aging can proceed for any amount of time from about 1 day, preferably from about 0 to 6 hours.

After the addition of water to the heated concentrated terfenadine solution in lower alkanol is complete and after ripening of the crystals, the resulting mixture is optionally allowed to cool to an ambient temperature of about 25°C. Preferably this cooling is achieved simply by removing the heating source and is not facilitated by any cooling means.

- Once cooled to ambient temperature, the mixture is then cooled to about 0-5°C, for example by using a simple ice-water bath. Salts such as sodium chloride or calcium chloride can be used to lower the temperature of the cooling bath, further lowering the temperature if desired. The cooled mixture is then filtered from the slurry to collect the solid product.

The solid product can be washed with additional water, preferably a small amount of cold water or a mixture of water and alkanol, such as 50x aqueous ethanol. The product can then be dried by conventional means, such as under vacuum, and heated preferably to about 50-75°C, most preferably about 60°C, to facilitate the disappearance of residual water and lower alkanol. I can do it.

The term "suitable solvent" as used in the present invention during the preparation of the low melting point polymorph of terfenadine refers to any solvent in which terfenadine is soluble, such as a hydrocarbon solvent, i.e. a source of carbon and hydrogen. Solvents containing only elements such as pentane, hexane, benzene, toluene and xylene, or ketones or aldehydes having 1-10 carbon atoms, such as methyl ethyl ketone, 2-butanone, cyclopentanone, isopropyl Methyl ketones and acetophenones can be used. Also included are mixtures of two or more lower ketones. Ketone solvents and toluene are preferred. Acetone is the most preferred solvent.

Solutions of terfenadine are prepared in a conventional manner by simply adding the solvent to a polymorphic mixture of terfenadine or, for high melting polymorphs of terfenadine, with stirring. When preparing a solution for the purpose of producing a pure, low-melting polymorph of terfenadine, substantially pure terfenadine, i.e., substantially free of contaminants other than the polymorph of terfenadine, is used. Terfenadine is often used.

Heating to increase the rate of dissolution is undesirable, and unlike the solution to be used to recrystallize the solute, the solution used here of terfenazine in a lower ketone solvent is saturated or substantially It doesn't have to be close to saturation.

For example, a solution of 50 mg of terfenazine in acetone of about 121 mg is satisfactory. It is preferred to filter the solution to remove any undissolved terfenadine or other impurities.

The lower ketone solvent is then evaporated. Slow evaporation is preferred, for example by leaving the solution in an open container at room temperature for several hours to several days.

For example, a solution of 50 mg of terfenadine in acetone in 121 is evaporated over two days. Heating to increase the rate of evaporation is not recommended; evaporation at room temperature is preferred; the use of X-chemistry is also not preferred; however, good air circulation should be provided to prevent accumulation of excessively evaporated solvent. That is recommended. The resulting crystalline product is a substantially pure low melting polymorph of terfenazine.

Example 1 - Preparation of a low-resolution polymorph of terfenazine from an acetone solution. The acetone was then slowly evaporated over two days.The dried product terfenazine was
It was a low melting point polymorph of 0X.

Example 2 Terfenadine - Layer - Usitoda - Ho - Yup - Comparison - 72.6 g of wet impure terfenadine ( about 51%
water) was prepared. The flask was then charged with 2501 aqueous ethanol and the slurry was heated to reflux, forming a cloudy solution. The solution was heated to 11 liters with a mechanical stirrer, a reflux condenser equipped with a nitrogen bubbler, and a pressure equalization addition funnel.
The solution was filtered hot into a three-barrel flask. The ethanol solution was slowly added to reflux (V2001) in deionized water over 30 minutes, resulting in crystallization of terfenadine. The resulting slurry was then heated at reflux for 5 hours to achieve crystallization of the product. The slurry was then slowly cooled to room temperature. The slurry was then cooled in a water bath for 30 minutes. The solids were filtered from the slurry and
(v/v) ethanol/water, washed twice with 501 parts water, air dried, and vacuum dried at 60°C;
37.0 g of terfenazine was obtained as pure high melting polymorph. Melting point 149.5-151'C.

Analysis: Calculated value of C3゜Ha+NO□: C,81,4
8: H, 8,76; N, 2.97° actual measurement (a: C, 81, 5: H, 8,70; N,
2.94° Residue on ignition: $0.02 Example 3 Preparation of Terfenadine Machine Eleven three-barrel flasks equipped with a stirrer, pressure equalization addition funnel, and reflux condenser with nitrogen bubbler to 7
2.8 g (0,149 mol) of terfenadone l water
Fresh food and 3201 steam, water and ethanol were added.

Heat the mixture to reflux to form a clear solution.8372
A solution of 12.0 g (0.317 mol) of sodium borohydride in 50 g of 50% sodium hydroxide and 25.6 ml of water was added dropwise with stirring over a period of 1 hour. After the addition was complete the reaction mixture was stirred at reflux for 2 hours.

Terfenadine began to crystallize. slurry then 32
01 water was added at a rate that the reaction remained at reflux. The slurry was then slowly cooled to room temperature. Filter the solids from the slurry and 50150 of 1001
Washed with (v/v) was produced as a mixture of polymorphs. Melting point 149.5~
150℃.

Example 4 Preparation of a high-melting variegated product of terfenadine Terfenadine obtained in Example 3 was charged into 12 Ellenmeyer flasks and mixed with 2501 absolute ethanol. The mixture was heated to reflux resulting in a cloudy packet solution. The solution was filtered into an H three-barrel flask equipped with a reflux condenser fitted with a mechanical stirrer, a pressure equalizing addition funnel, and a nitrogen bubbler.

The flask and filter were washed with refluxing 701 ethanol. The filtrate was kept at reflux and 3201 deionized water was added at a rate that the mixture remained at reflux. After the addition is complete,
The resulting slurry was brought to reflux for 10 minutes and then slowly cooled to room temperature. Filter the solids from the slurry and
1 of 50150 (v/v) ethanol/water;
Wash twice with 250 ml of deionized water, air dry, and
Vacuum drying at 0° C. yielded 66.2 g (97% recovery) of terfenadine. '@ point 148.5 ~! 50'
C.

This represents a 94% yield of terfenadine from terfenadine through reduction, crystallization and recrystallization.

Analysis: Calculated value of C32H4+N02: C,81,
48; H, 8,76; N, 2.97゜Real 11111i: C, 81,7; )l, 8.8
9; N, 2.87° Residue when ignited: 0.0
Not detected at the limit of 4%.

Example 5 Preparation of a low melting polymorph of terfenadine from a toluene solution Approximately 50 mg of terfenadine (19X high melting polymorph, 81% low melting polymorph) was dissolved in 12 ml of toluene at room temperature. The toluene was then slowly evaporated over a period of two days. The dry product was a low melting polymorph of terfenadine with a purity of 100%.

Applicant: Merrell Dow Pharmaceuticals, Inc.

Claims (1)

[Claims] 1. Terfenazine is dissolved in a water-miscible lower alkanol, the solution is heated to approximately its reflux temperature, and a sufficient amount of water is slowly added with stirring to dissolve substantially all of the terfenazine. A method for producing a high melting homogeneous polymorph of terfenazine comprising carrying out crystallization, cooling, and collecting the crystalline product. 2. Claim 1, wherein the water-miscible lower alkanol is methanol, ethanol or isopropanol.
The method described in section. 3. The method according to claim 1, wherein the water-miscible lower alkanol is ethanol. 4. The method according to claim 1, wherein the weight-to-volume ratio of terfenadine to ethanol in the solution is between 0.1 g/ml and 0.3 g/ml. 5. The volume-to-volume ratio of ethanol to water is approximately 0.75.
4. The method according to claim 3, wherein the amount is ml/ml to 1.5 ml/ml. 6. The volume to volume ratio of ethanol to water is approximately 1.0 m
3. The method according to claim 3, wherein the amount of 1/ml is 1/ml. 7. The temperature of the solution of terfenadine in ethanol is about 7.
The method according to claim 3, wherein the temperature is 8°C. 8. A solution of terfenadine in ethanol with a weight-to-volume ratio of terfenadine to ethanol of about 0.15-0.25 is heated to 78°C, resulting in a volume-to-volume ratio of ethanol to water of about 1 ml/ml. Add enough water over about 30 minutes to bring the resulting slurry to reflux temperature.
Heat for an hour, cool slowly to room temperature, then 0°C to 5°C
2. A method according to claim 1, wherein the recovered terfenadine is cooled to a temperature of 100 ml, filtered and dried. 9. A method for producing a low melting polymorph of terfenadine comprising dissolving terfenadine in a suitable solvent at 0°C to about 35°C, slowly evaporating the solvent and collecting the crystalline product. 10. The method according to claim 9, wherein the solvent is acetone. 11. The method according to claim 9, wherein the solvent is toluene.