WO2008110338A1

WO2008110338A1 - Polymorph of desvenlafaxine succinate

Info

Publication number: WO2008110338A1
Application number: PCT/EP2008/001920
Authority: WO
Inventors: Walter Wilhelmus Johannus Elffrink
Original assignee: Synthon B.V.
Priority date: 2007-03-09
Filing date: 2008-03-06
Publication date: 2008-09-18

Abstract

The invention relates to a crystalline anhydrous desvenlafaxine succinate of Form V.

Description

POLYMORPH OF DESVENLAFAXINE SUCCINATE

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to new crystalline form of l-[2-(Dimethylamino)-l-(4- hydroxyphenyl)ethyl]-cyclohexanol succinate, a useful pharmaceutically active agent, to compositions and pharmaceuticals containing the same, and to methods of making and using the foregoing.

Description of the Prior Art

Desvenlafaxine, chemically 1 -[2-(Dimethylamino)- 1 -(4-hydroxyphenyl)ethyl]- cyclohexanol of the formula (1):

is an active metabolite of the known pharmaceutical agent venlafaxine, the compound of formula

(2):

The molecule of the formula (1) has one center of optical activity. The term "desvenlafaxine" as used herein refers to racemic desvenlafaxine, unless otherwise noted.

Desvenlafaxine is disclosed in the patent EP 1 12669 / US 4535186, owned by American Home Products, and is also disclosed in the patent application WO 00/59851 of Sepracor. More recently, WO 02/64543 and corresponding US 2003/0045583 Al (hereafter "WO 543") discloses that an advantageous salt form of desvenlafaxine is a (1: 1) succinate salt (hereafter referred to as "desvenlafaxine succinate"), and four crystalline polymorphic/pseudopolymorphic forms of desvenlafaxine succinate, Forms I - IV, are reported.

WO 543 discloses that Form I is a monohydrate that has an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 10.20, 14.91, 20.56, 22.13, 23.71, 24.60, and

25.79 ° 2Θ (± 0.2° 2Θ) and a thermogram having an endotherm at about 131° C. WO 543 further discloses that Form I may be prepared by dissolving desvenlafaxine free base and succinic acid in aqueous acetone, optionally filtering the resulting solution, and slowly cooling the resulting solution (e.g., for 3 hours or longer). WO 543 also discloses that Form II is a monohydrate that has an XRPD pattern having characteristic peaks at 13.18, 14.04, 14.35, 14.66, 16.68, 17.67, 19.24, 25.13, and 31.78° 20 (± 0.2° 20) and a thermogram having an endotherm at about 127° C. WO 543 further discloses that Form II may be prepared by dissolving Form I in acetone, filtering the solution, and vacuum stripping the filtrate on a rotary evaporator at ambient temperature. WO 543 also discloses that Form III has an XRPD pattern having characteristic peaks at

13.74, 22.55, and 32.42° 20 (± 0.2°2O). WO 543 further discloses that Form III is a hydrate with a molar ratio of water of less than 1 but more than 0.5. WO 543 further discloses that Form HI may be prepared by ball milling or cryo-grinding Form I. WO 543 also discloses that Form IV is an anhydrate having an XRPD pattern having characteristic peaks at 11.29, 17.22, 19.64, 20.91, 21.61, 28.86, 29.80, 30.60, 36.85, and 37.70° 2Θ (± 0.2°2θ)and a thermogram having an endotherm at about 145° C. WO 543 further discloses that Form IV may be prepared by slurrying equal amounts of Forms I and II in acetonitrile at about 54 C for several days (e.g., eight days), filtering, and heating the resulting solid for 18 hours at about 120 C.

In addition to disclosing the crystalline polymorphic / pseudopolymorphic Forms I - IV, WO 02/64543 also discloses an amorphous form of desvenlafaxine succinate.

SUMMARY OF THE INVENTION

The present invention relates to a different polymorphic form of desvenlafaxine succinate. Accordingly, an aspect of the present invention provides for a crystalline form of anhydrous desvenlafaxine succinate of Form V.

Form V can be characterized by an XRPD pattern with a peak at an angle of about 27.08° 2Θ (± 0.2° 2Θ), and typically the XRPD pattern includes peaks at angles of about 10.72, 1 1.28, 13.25, 14.64, 17.14, 17.57, 20.07, 22.31, 27.08, and 27.86° 2Θ (± 0.2° 2Θ). In a preferred embodiment, Form V exhibits an XRPD pattern that substantially corresponds to figure 1.

Form V can also be characterized by an IR absorbance peaks (in KBr) at 1719, 1682, and 3253 cm^"1 +/- 5 cm^"1. In a preferred embodiment Form V exhibit an IR absorbance spectrum that substantially corresponds to figure 2.

Another aspect of the present invention provides for processes of forming Form V. The process comprises contacting a dehydrated desveniafaxine with a dehydrated succinic acid in an anhydrous solvent, preferably acetone, and crystallizing the desvenlafaxine succinate Form V from said solvent.

A further aspect of the present invention provides for pharmaceutical compositions comprising crystalline anhydrous desvenlafaxine succinate of Form V and at least one other form of crystalline desvenlafaxine succinate.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows an XRPD pattern corresponding to anhydrous desvenlafaxine succinate of Form V. Figure 2 shows an IR absorbance spectrum corresponding to anhydrous desvenlafaxine succinate of Form V.

DETAILED DESCRIPTION OF THE INVENTION

A new crystalline polymorph of anhydrous desvenlafaxine succinate, herein denoted as Form V, has surprisingly been discovered. In particular, the Form V is a new crystalline polymorph of desvenlafaxine succinate having a different crystal structure from the known Forms I - IV.

The crystalline polymorph Form V is an anhydrate, which means that water is not bound to the salt molecule and is not part of the repeating lattice structure that forms the crystalline lattice. In contrast to Form V, Forms I and II are monohydrates and Form III is a hydrate. The known Form IV of desvenlafaxine succinate is also an anhydrate, as discussed above. Forms IV and V, however, have different crystal structures; i.e., different repeating lattice structure, and thus exhibit different physical properties. Moreover, contrary to the complicated known method to make anhydrated Form IV, the anhydrated Form V of the present invention may be produced by a simpler and/or more reliable process. As a result, the Form V may be technically and economically advantageous over the Form IV.

The Form V of the present invention is a stable crystalline compound. For example, stability tests demonstrated that the heating of Form V at 60⁰C for at least 4.5 months was not associated with changes in the crystalline structure thereof, i.e. no polymorphic transition was observed.

The different crystal structures of Form V and other forms of desvenlafaxine succinate

(such as known Forms I - IV) can typically be identified by XRPD, although other methods such as IR, etc., may also be used.

The Form V can be characterized by an XRPD pattern distinct from any of the known crystalline forms of desvenlafaxine succinate. A particularly clear distinction is seen at an angle of about 27.08° 2Θ (± 0.2° 2Θ), in that desvenlafaxine succinate Form V exhibits a large peak this angle. Thus, the presence of a peak at about 27.08° 2Θ (± 0.2° 2Θ), can be used to characterize or identify the presence of the Form V crystal structure in a venlafaxine succinate sample, and/or to distinguish Form V from known crystalline forms of desvenlafaxine succinate.

Typically the XRPD pattern of Form V contains at least the following peaks at angles of about

10.72, 11.28, 13.25, 14.64, 17.14, 17.57, 20.07, 22.31, 27.08, and 27.86° 2Θ (± 0.2° 2Θ).

Generally, the measured angle values for desvenlafaxine succinate Form V are within +/- 0.2° of the above-recited values, as indicated. Preferably, the measured angle values for desvenlafaxine succinate Form V are identical to the above values after truncating or rounding. A desvenlafaxine succinate that exhibits an XRPD pattern that substantially corresponds to figure 1 is a specific embodiment of the present invention. The IR spectrum of Form V is also different from that of the known crystalline forms of desvenlafaxine succinate. In particular, IR absorbance peaks (in KBr) at 1719 and 1682 cm^"1 +/- 5 cm^"1 and a broad peak at 3253 cm^"1 may serve as characteristic peaks of Form V. A desvenlafaxine succinate that exhibits an IR absorbance spectra that substantially corresponds to figure 2 is a specific embodiment of the present invention.

The phrase "substantially corresponds" as used herein encompasses variations caused by different sample preparations, different equipment and/or settings used in measuring, normal experimental error/variation, and small amounts of impurities. Thus, a spectrum may "substantially correspond" to another spectrum even though the two spectra are not identical, superimposable images. Differences in a pattern or spectra that are not attributable to these factors indicate that the pattern or spectra in question does not "substantially correspond" to the reference pattern and, vice versa.

The present invention includes desvenlafaxine succinate Form V as an isolated substance, especially in an essentially pure form and/or essentially morphologically pure form. "Essentially pure" refers to at least 70% pure, preferably at least 80% pure, more preferably at least 90% pure, and still more preferably at least 95%, including at least 98% pure, at least 99% pure, and at least 99.8% pure, with respect to the presence of desvenlafaxine succinate in a sample. "Essentially morphologically pure" refers to at least 70% pure, preferably at least 80% pure, more preferably at least 90% pure, and still more preferably at least 95%, including at least 98% pure, at least 99% pure, and at least 99.8% pure, with respect to the presence of the Form V in a sample. Typically in order for a sample of Form V of desvenlafaxine succinate to have an XRPD pattern or IR spectrum that substantially corresponds to fig. 1 or fig. 2, respectively, the Form V sample must be in essentially pure form and essentially pure morphological form. The present invention also includes mixtures of the Form V with other crystalline forms of desvenlafaxine succinate, and/or with amorphous desvenlafaxine succinate. Thus, a composition that contains a small amount or a large amount of the Form V, regardless of the other materials/substances optionally present therewith is also contemplated to be part of the present invention, but the essentially pure composition is preferred.

The venlafaxine succinate molecule can be made by synthesis techniques known in the art.

The crystalline Form V may be made by a simple process comprising contacting dehydrated venlafaxine base and dehydrated succinic acid in an anhydrous solvent and crystallizing form V desvenlafaxine succinate therefrom. The term "dehydrated" in this context means that the water content is less than 0.5% by weight, but it is not intended to imply or require that water was previously present or that water was necessarily removed. While not required, it is often advantageous to dry the starting materials in order to obtain and/or insure the desired low water content. Thus one embodiment comprises the following steps a - c: a) Drying each of a desvenlafaxine base and a succinic acid to form dehydrated desvenlafaxine base and dehydrated succinic acid, respectively, preferably having a water content of less than 0.2 %; b) Contacting the dehydrated desvenlafaxine base and the dehydrated succinic acid in an anhydrous solvent, preferably acetone; and c) Crystallizing Form V from said anhydrous solvent.

The use of dehydrated starting materials for making desvenlafaxine succinate, i.e., the desvenlafaxine base and the succinic acid, is an important part of the process for crystallizing the anhydrous Form V desvenlafaxine succinate. The presence of small amounts of water apparently plays a role in forming the undesirable hydrated forms, e.g. the Form I. Indeed, Form I can easily be formed instead of the desired anhydrate when higher amounts of water are present in the reaction mixture. Drying the starting materials is a novel and very effective method to at least minimize the formation of hydrated forms of desvenlafaxine succinate, and preferably to ensure that hydrated forms of desvenlafaxine succinate are not formed at all. In any event and however obtained, the dehydrated starting materials have a water content of 0.5% or less, preferably 0.2% or less.

The drying can be performed by any suitable technique, e.g., by heating, by evacuating, or by a combination of both heating and evacuating. The present invention, however, is not limited to these drying techniques. While recited in tandem, it is not required that the starting materials are dried at the same time and/or by the same device. The drying can be sequential and/or by different devices of the same or different modes of operation, e.g. one by heating and the other by vacuum. ^•

Additionally, the contacting of the desvenlafaxine base and succinic acid may be advantageously performed in an anhydrous solvent. An "anhydrous solvent" is a solvent in which the content of water therein is minimized, e.g. to a water content of 0.2 % or less, preferably 0.1% or less (w/v). Suitable anhydrous solvents include acetone, but the invention is not limited thereto.

The contacting of the dehydrated starting materials (i.e., the dehydrated desvenlafaxine base and the anhydrated succinic acid) in the anhydrous solvent proceeds, at least partly, upon dissolution, followed by the crystallization of the formed salt as the desired Form V. The contact temperature may be from ambient temperature to the boiling point temperature of the solvent. The time of the contact is not specifically limited. The precipitation of the Form V is preferably spontaneous, and it may be achieved by simply cooling the reaction mixture. Advantageously, seed crystals of the Form V may be added to facilitate or enhance crystallization.

The formed crystals of the Form V may be separated from the liquid medium by conventional techniques, e.g., by filtration or centrifugation, and the Form V crystals are optionally dried to remove at least a portion of residual solvent. In particular, the dried product should contain less than 0.3 molar equivalents of the residual liquid solvent. Furthermore, the product may be milled and/or sieved.

Desvenlafaxine succinate Form V can be formulated into various pharmaceutical compositions with one or more pharmaceutically acceptable excipients, e.g., as described for the other forms of desvenlafaxine succinate in WO '543. The pharmaceutical composition can be a unit dosage form, such as a solid oral dosage form (e.g., tablet or capsule), a solution or suspension (especially for an aqueous sterile solution or suspension for parenteral administration), or bulk precursor thereof, such as a pre-blended mixture ready for further blending/addition of ingredients, or a blend ready for tabletting or filling into capsules.

Usually, the excipient is a pharmaceutically acceptable carrier or diluent, such as one or more calcium phosphates, microcrystalline cellulose, hydroxypropyl methylcellulose, lactose, and starches, but is not limited thereto. Other suitable excipients include, but are not limited to, fillers, binders, lubricants, disintegrants, preservatives, pH-adjustors, colorants, etc. The desvenlafaxine succinate Form V pharmaceutical compositions are preferably formulated into tablets. The tablets may be monolithic tablets, i.e. tablets that upon ingestion do not disintegrate into a plurality of smaller units from which the active ingredient is finally released. Alternatively, the tablets may be disintegrable tablets. The tablets may be produced by any suitable tabletting technique, e.g., by wet granulation, dry granulation, or direct compression. Tabletting methods that do not employ a solvent ("dry processes") are preferable. The tablets containing the compositions may be coated by a film coat. The film coat may protect the tablet against the environment (light, air, moisture) during storage and handling. Any conventional film coat may be used.

Alternatively, desvenlafaxine succinate Form V pharmaceutical compositions can be filled into capsules. Generally, the process of filing the compositions into tablets comprises blending the active substance and excipient(s) in one or more mixing or blending steps and then filling the blend into capsules. The pharmaceutical compositions of the present invention may contain desvenlafaxine succinate Form V as the only desvenlafaxine succinate form, or may contain desvenlafaxine succinate Form V as one of two or more desvenlafaxine succinate forms. For example, the pharmaceutical composition may contain desvenlafaxine succinate Form V and at least one other form, wherein the composition is substantially free of a hydrate form of desvenlafaxine succinate, particularly of Form I. In a particular embodiment, the pharmaceutical composition is substantially free of each of the desvenlafaxine succinate Forms I - IV, i.e. the composition contains less than 2%, preferably less than 1 % and more preferably less than 0.2% and/or an undetectable amount via XRPD, of the sum of all of Forms I - IV with respect to the total amount of desvenlafaxine succinate (including the Form V) in the composition. In another embodiment, the pharmaceutical composition contains a mixture of forms of desvenlafaxine succinate including Form V. For example, the desvenlafaxine succinate contained in the composition may include at least 0.1 %, such as I % to 100 %, of desvenlafaxine succinate Form V. Typically at least 10 %, and preferably at least 90%, of the desvenlafaxine succinate in the composition is the Form V.

The pharmaceutical composition of the present invention is generally formulated into a unit dosage form, such as the above-described tablets or capsules. In a unit dosage form, the total amount of desvenlafaxine succinate present, regardless of form, is effective for providing a therapeutic effect to a mammal. The unit dose may be a single tablet, one half of a tablet, or two or more tablets taken at essentially the same time or in the same administration. Unit dose in capsule form may comprise one or more capsules.

The desvenlafaxine succinate containing at least a portion of desvenlafaxine succinate Form V (i.e., at least 0.1 %) can be used to treat a mammal in need thereof by administering an effective amount of the desvenlafaxine succinate.

The present invention is further described with reference to the following non-limiting examples.

EXAMPLES

Example 1

1.5 g of desvenlafaxine free base and 0.48 g of succinic acid was dried over-weekend at 40°C in vacuo. The solid material was dissolved in 60 ml of refluxing dry acetone. The solution was cooled to room temperature. Seeds of the Form V (90%) from the Example 2 (described below) were added.

After filtration and drying, 1.12 g of solid material was obtained. The solid material contained crystalline anhydrous desvenlafaxine succinate Form V.

Example 2

1.79 g of desvenlafaxine free base and 0.88 g of succinic acid were suspended in 80 ml dry acetone in a flask. The flask was heated to reflux and a suspension was formed. The flask was placed in an ice bath for 2 h at RT. After filtration and drying, 1.34 g of a solid was obtained.

A product comprising approximately 90% of the Form V was obtained by storing the obtained solid for 11 days at 60⁰C.

Each of the patents and patent applications mentioned above are incorporated herein by reference in their entirety. The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.

Claims

1. A crystalline anhydrous desvenlafaxine succinate of Form V.

2. The desvenlafaxine succinate according to claim 1, having an XRPD pattern with a peak at an angle of about 27.08° 2Θ (± 0.2° 2Θ).

3. The desvenlafaxine succinate according to claim 1 or 2, having an XRPD pattern with peaks at angles of about 10.72, 11.28, 13.25, 14.64, 17.14, 17.57, 20.07, 22.31, 27.08, and 27.86° 2Θ (± 0.2° 2Θ).

4. The desvenlafaxine succinate according to claim 1-3, wherein said desvenlafaxine succinate exhibits an XRPD pattern that substantially corresponds to figure 1.

5. The desvenlafaxine succinate according to claim 1-4, having IR absorbance peaks (in KBr) at 1719, 1682, and 3253 cm^"1 +/- 5 cm^"1.

6. The desvenlafaxine succinate according to claim 1-5, wherein said desvenlafaxine succinate exhibits an IR absorbance spectrum that substantially corresponds to figure 2.

7. The desvenlafaxine succinate according to claim 1-6, wherein said desvenlafaxine succinate is at least 90% pure Form V.

8. The desvenlafaxine succinate according to claim 1-7, comprising less than 0.3 molar equivalents of a residual solvent.

9. A pharmaceutical composition, comprising the desvenlafaxine succinate of Form V according to claim 1-8 and a pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9, wherein said composition is a unit dose and said desvenlafaxine succinate of Form V is contained in an effective amount to provide a therapeutic effect to a mammal.

11. The pharmaceutical composition according to claim 9 or 10, wherein said composition is substantially free of a hydrate form of desvenlafaxine succinate, particularly of Form I.

12. The pharmaceutical composition according to claim 9-11, wherein said pharmaceutically acceptable excipient is a carrier or diluent.

13. The pharmaceutical composition according to claim 9-12, wherein said composition is a solid oral dosage form.

14. A process, which comprises contacting a dehydrated desvenlafaxine with a dehydrated succinic acid in an anhydrous solvent, preferably acetone, and crystallizing the desvenlafaxine succinate Form V from said solvent.

15. The process according to claim 14, which further comprises, prior to said contacting step, drying each of a desvenlafaxine base and a succinic acid to a water content of less than 0.2 % to form said dehydrated desvenlafaxine base and dehydrated succinic acid, respectively.

16. The process according to claim 14 or 15, wherein the contacting step is performed at a temperature of from ambient temperature to the boiling point of the solvent.

17. A composition according to claim 9-13, comprising crystalline anhydrous desvenlafaxine succinate of Form V and at least one other form of crystalline desvenlafaxine succinate.

18. Crystalline anhydrous desvenlafaxine succinate Form V according to claim 1-8, and/or pharmaceutical composition according to claim 9-13, or 17 for use in medicine.