NOVEL CRYSTALLINE FORMS OF DESVENLAFAXINE SUCCINATE

FIELD OF THE INVENTION

The present invention relates to novel crystalline forms of the succinate salt of 4-[2- (dimethylamino)-l-(l-hydroxycyclohexyl)ethyl]phenol, a compound of formula I, also known as O -desmethylvenlafaxine or desvenlafaxine.

Formula I

BACKGROUND OF THE INVENTION

US 6,673,838 (the '838 patent) claims the succinate salt of desvenlafaxine and discloses its preparation. The patent discloses and claims several crystalline forms and the amorphous form of desvenlafaxine succinate. Form I of desvenlafaxine succinate reported in the '838 patent is a crystalline monohydrate that is stable up to at least 105 ⁰ C at 5-95% relative humidity, which exhibits an endotherm at 131 ⁰ C according to differential scanning calorimetry (DSC), and which when analyzed by X-Ray Powder Diffractometry (XRPD) exhibits characteristic 2-theta peaks at 10.20, 14.91, 20.56, 22.13, 23.71, 24.60 and 25.79. Form II of the '838 patent is also a crystalline monohydrate, which exhibits a DSC endotherm at 127 ⁰ C and which when analyzed by XRPD has characteristic 2-theta peaks at 13.18, 14.04, 14.35, 14.66, 16.68, 17.67, 19.24, 25.13 and 31.78. Crystalline Form III of the '838 patent is reported to be a hydrate (between a hemihydrate and a monohydrate), which when analyzed by XRPD exhibits characteristic 2-theta peaks at 13.74, 22.55 and 32.42. Crystalline Form IV of the '838 patent is an anhydrous form with a DSC endotherm at 145 ⁰ C, and which when analyzed by XRPD exhibits characteristic 2-theta peaks at 11.29, 17.22, 19.64, 20.91, 21.61, 28.86, 29.80, 30.60, 36.85 and 37.70. The amorphous form of desvenlafaxine succinate reported in the '838 patent exhibits a DSC endotherm at 120 C.

Polymorphism is often characterized as the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Polymorphs and/or solvates of a pharmaceutical solid can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure,, density, sensitivity to conditions such as humidity, light, heat, flowability and compressibility. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of the drug product. The discovery of new polymorphic forms provides an opportunity to improve performance characteristics of a pharmaceutical product. There is need in the art for polymorphic forms of O-desmethylvenlafaxine succinate.

SUMMARY OF THE INVENTION

The present invention provides crystalline Form V of O-desmethylvenlafaxine succinate, wherein the crystalline form exhibits an X-Ray Powder Diffraction pattern having characteristic peaks expressed in degrees 20 (±0.2° 2θ) at 12.15, 13.17, 14.67, 15.8, 19.69, 20.45, 22.27, 24.40, 26.43, 28.44 and 33.69.

The present invention provides a process for preparing crystalline Form V of O- desmethylvenlafaxine succinate comprising the steps of a. combining O-desmethylvenlafaxine, succinic acid and toluene to form a reaction mixture; b. heating the reaction mixture; and c. cooling the reaction mixture of step b to obtain crystalline Form V of O-desmethylvenlafaxine succinate.

The present invention provides a process for preparing crystalline Form VI of O- desmethylvenlafaxine succinate comprising the steps of

a. combining 0-desmethylvenlafaxine, succinic acid, cyclohexane and acetonitrile to form a reaction mixture; b. heating the reaction mixture; and c. cooling the reaction mixture of step b to obtain crystalline Form VI of 6>-desmethylvenlafaxine succinate.

The present invention provides a process for preparing crystalline Form VII of O- desmethylvenlafaxine succinate comprising the steps of a. combining Odesmethylvenlafaxine, succinic acid and toluene to form a reaction mixture; b. heating the reaction mixture; c. adding acetonitrile to the reaction mixture: of step 'b' at elevated temperatures; and d. cooling the reaction mixture of step 'c' to obtain crystalline Form VII of 0-desmethylvenlafaxine succinate.

The present invention provides a pharmaceutical composition comprising crystalline Form V of O-desmethylvenlafaxine succinate, and pharmaceutically acceptable, carrier, diluent or excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides new crystalline forms of 0-desmethylvenlafaxine succinate, designated herein as Form V, Form VI and Form VII.

In one embodiment the present invention provides a crystalline Form V wherein the crystalline form exhibits an X-Ray Powder Diffraction pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 12.15, 13.17, 14.67, 15.91, 19.69, 20.45, 22.27, 24.40, 26.43, 28.44 and 33.69.

In one embodiment crystalline Form V has an XRPD pattern substantially identical to that shown in Figure .1. Peak locations and intensities for the XRPD pattern in Figure 1 are provided in Table 1 below.

Table 1

In another embodiment the crystalline Form V of O-desmethylvenlafaxine succinate of the present invention has a moisture content of about 2%.

The crystalline Form V of O-desmethylvenlafaxine succinate of the present invention is a stable crystalline compound. It retains the powder XRPD pattern upto atleast 12 months from the date of its manufacturing, when packed in glass vial and stored below 25 ⁰ C, preferably between 10 to 25 ⁰ C. Further more there was no significant change in the initial chemical purity after storage.

According to another aspect, the present invention provides a process for preparing crystalline form V of O-desmethylvenlafaxine succinate. Crystalline Form V of O- desmethylvenlafaxine succinate may be prepared by a process comprising combining O- desmethylvenlafaxine and succinic acid in a hydrocarbon solvent preferably an aromatic hydrocarbon preferably toluene and isolating the crystalline form V of O- desmethylvenlafaxine succinate from the reaction mixture.

In one specific embodiment, the crystalline Form V of O-desmethylvenlafaxine succinate is prepared by a process comprising the steps of

a. combining 0-desmethylvenlafaxine, succinic acid and toluene to form a reaction mixture; b. heating the reaction mixture; and c. cooling the reaction mixture of step b to obtain crystalline Form V of 0-desmethylvenlafaxine succinate.

The ratio of O-desmethylvenlafaxine to toluene is in the range of 10 to 100. The reaction mixture is heated at or below reflux temperatures, preferably at reflux temperature. Most preferred temperature at which the reaction mixture is heated is in the range of 105 to 110 ⁰ C. The time for which the reflux may be carried is 2 to 6 hours preferably 4 hours.

Typically, after reflux the reaction mixture is cooled to 25 -35 ⁰ C, preferably to about 25-30 ⁰ C and further maintained for a sufficient period of time to obtain crystalline form V of (9-desmethylvenlafaxine succinate. The cooled reaction mixture is maintained preferably for a period of 10 to 30 hours, more preferably for a period of 20 to 22 hours. Preferably the reaction mixture is stirred, vigorously. The formed crystals of Form V may be separated from the liquid medium by any method known in the art such as filtration or centrifugation and the obtained crystals may be optionally dried. Preferably the crystalline Form V is separated by filtration and dried at about 50 ⁰ C, under vacuum-

In another embodiment the present invention provides a crystalline Form VI of O- desmethylvenlafaxine succinate wherein the crystalline form exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 5.73, 11.19, 15.05, 15.58, 17.03, 17.61, 18.00, 19.86, 20.28, 21.20, 22.07, 24.28, 25.59, 26.36, 26.71 and 27.58.

In one embodiment the crystalline Form VI has an XRPD pattern substantially identical to that shown in Figure 2. Peak locations and intensities for the XRPD pattern in Figure 2 are provided in Table 2 below.

Table 2

According to another aspect, the present invention provides a process for preparing crystalline Form VI of O-desmethylvenlafaxine succinate. Crystalline Form VI of O- desmethylvenlafaxine succinate may be prepared by a process comprising combining O- desmethylvenlafaxine, a hydrocarbon solvent preferably cyclohexane, a nitrile preferably acetonitrile and succinic acid and isolating the crystalline Form VI of O- desmethylvenlafaxine succinate from the reaction mixture.

In one embodiment, crystalline Form VI of Odesmethylvenlafaxine succinate is prepared by a process comprising the steps of a. combining O-desmethylvenlafaxine, succinic acid, cyclohexane and acetonitrile to form a reaction mixture; b. heating the reaction mixture; and c. cooling the reaction mixture of step b to obtain crystalline Form VI of O-desmethylvenlafaxine succinate.

The ratio of cyclohexane to acetonitrile is in the range of (1 : 1) to about (10:1) preferably about 6:1. The reaction mixture is heated at or below reflux temperatures, preferably to at about reflux temperature. The time for which the reflux may be carried is 2 to 8 hours preferably 4 hours. In one embodiment the reaction mixture is partially concentrated before cooling

Typically, after reflux the reaction mixture or the reaction mixture obtained after partial concentration is cooled to 20 -35 ⁰ C, preferably to about 25-30 ⁰ C and further maintained for a sufficient period of time to obtain crystalline Form VI of O- desmethylvenlafaxine succinate. The cooled reaction mixture is maintained preferably for a period of 30 to 60 hours, more preferably for a period of 40 to 48 hours. Preferably the reaction mixture is stirred. The obtained crystalline form may be recovered by any method known in the art. Preferably the crystalline form is filtered and dried at about 40 o ¹ ,C.

In one embodiment the present invention provides a crystalline Form VII of O- desmethylvenlafaxine succinate wherein the crystalline Form exhibits an X-Ray Powder Diffraction pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 10.78, 14.37, 14.72, 16.69, 17.21, 17.67, 20.11, 25.16, 25.88, 27.61and 30.33.

In one embodiment the crystalline Form VII has an XRPD pattern substantially identical to that shown in Figure 3. Peak locations and intensities for the XRPD pattern in Figure 3 are provided in Table 3 below.

Table 3

The crystalline Form VII of O-desmethylvenlafaxine succinate of the present invention is a stable crystalline compound. It retains the powder XRPD pattern upto atleast 12 months from the date of its manufacturing, when packed in glass vial and stored below 25 ⁰ C, preferably between 10 to 25 ⁰ C. Further more there was no significant change in the initial chemical purity after storage.

According to another aspect, the present invention provides a process for preparing crystalline Form VII of O-desmethylvenlafaxine succinate. Crystalline Form VII of O- desmethylvenlafaxine succinate may be prepared by a process comprising combining desvenlafaxine, a hydrocarbon solvent preferably toluene and succinic acid and heating followed by addition of nitrile solvent preferably acetonitrile and isolating the crystalline Form VII of O-desmethylvenlafaxine succinate from the reaction mixture.

In one embodiment, crystalline Form VII of O-desmethylvenlafaxine succinate is prepared by a process comprising the steps of a. combining O-desmethylvenlafaxine, succinic acid and toluene to form a reaction mixture; b heating the reaction mixture; c. adding acetonitrile to the reaction mixture of step 'b' at elevated temperatures; and d. cooling the reaction mixture of step 'c' to obtain crystalline Form VII of O-desmethylvenlafaxine succinate.

In one embodiment O-desmethylvenlafaxine, toluene and succinic acid are heated at or below reflux temperatures, preferably to at about reflux temperature. The time for which the reflux may be carried is 1 to 4 hours preferably 2 hours. The acetonitrile may be added to the reaction mixture at elevated temperature in the range of 85-95 C.

Preferably the acetonitrile is added to the reaction mixture at 90 ⁰ C. Prior to adding acetonitrile the refluxing reaction mixture is cooled gradually to, 90 ⁰ C. Preferably the amount of acetonitrile used is in the range of 5 to 20 volumes. Typically following the addition of acetonitrile the reaction mixture is maintained in the temperature range of 80-90 ⁰ C for a period of 0.5 to 1 hour. The reaction mixture is cooled to 25 -35 ⁰ C, preferably to about 25-30 ⁰ C and further maintained for a sufficient period of time to obtain crystalline form VII of desvenlafaxine succinate. The cooled reaction mixture is maintained preferably for a period of 20 to 35 hours, more preferably for a period of 24 to 30 hours. Preferably the reaction mixture is stirred while cooling. The formed crystals of Form VII may be separated from the liquid medium by any method known in the art such as filtration or centrifugation and the obtained crystals may be optionally dried. Preferably the crystalline Form VII is separated by filtration and dried at about 40 ⁰ C.

In another embodiment the present invention provides pharmaceutical compositions comprising the above crystalline forms of O-desmethylvenlafaxine succinate and pharmaceutically acceptable, carrier, diluent or excipient.

In one specific embodiment present invention provides pharmaceutical compositions comprising the crystalline Form V of O-desmethylvenlafaxine succinate and pharmaceutically acceptable, carrier, diluent or excipient.

The novel crystalline forms of O-desmethylvenlafaxine succinate of the present invention may be formulated into conventional dosage forms such as, for example, conventional release tablets, sustained release preparations, pills, suspensions, emulsions, granules, capsules, suppositories, injection preparations, and the like. The dosage forms may be obtained by using pharmaceutically acceptable excipients, in amounts and manner conventional to the pharmaceutical art.

The novel crystalline forms of 0-desmethylvenlafaxine succinate of the present invention may be used alone or in combination with one or more other therapeutically active agents.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention.

Examples Experimental Methods

General description of the equipment.

X-ray diffraction data were acquired using a PANalyticalX'pert PRO X-ray diffractometer model.

System description: K ₀₁ =I.54060 A ⁰ , voltage 45 kV, current 40 mA, Xray source : Cu.. Experiment parameters: pattern measured between 2θ=4° and 29=40° with 0.05° increments; count time was 0.5 second per increment.

The water content measurements were carried out using a METTLER TOLEDO Model: DL31Karl Fischer Titrator according to standard procedures.

Purity by HPLC was performed by Waters 2690 Seperations module.system.

Example 1

O-desmethylvenlafaxine (free base) and succinic acid were mixed in a 1 :1 molar concentration in 600 ml of toluene, and the reaction mixture was heated to reflux temperature for 4 hours. The reaction mixture was then cooled gradualy to about 25 to 3O ⁰ C, and maintained at that temperature for about 20 to 22 hours. The solid thus obtained was filtered and dried at about 5O ⁰ C to obtain crystalline form V of O-desmethylvenlafaxine succinate. The moisture content of the crystalline form V was found to be about 2%. . HPLC purity; > 98%.

Example 2

O-desmethylvenlafaxine (free base) and succinic acid were dissolved in a 1 :1 molar concentration in a mixture of 60 parts cyclohexane and 10 parts acetonitrile. The reaction mixture was heated to reflux temperature and maintained for about 4 hours at reflux conditions with partial concentration. The reaction mixture was then cooled gradually to about 25 to 3O ⁰ C under stirring for about 48 hours. The solid thus obtained was filtered and dried at about 4O ⁰ C to obtain crystalline form VI of O-desmethylvenlafaxine succinate. HPLC purity; > 98%.

Example 3

Odesmethylvenlafaxine (free base) and succinic acid were dissolved in a 1:1 molar concentration in 60 parts of toluene. The reaction mixture was heated to reflux temperature and maintained for about 2 hours at reflux conditions. The reaction mixture was then cooled gradually to about 85 ⁰ C, and 10 parts of acetonitrile was added to the reaction mixture. The reaction mixture was maintained at about 85°C for about 45 minutes. The reaction mixture was then cooled gradually to about 25 to 30 ⁰ C under stirring for about 30 hours. The solid thus obtained was filtered and dried at about 40 ⁰ C to obtain crystalline form VII of 0-desmethylvenlafaxine succinate. HPLC purity; > 98%.