WO2006050909A1

WO2006050909A1 - Novel forms of efletirizine dihydrochloride, processes for making them and pharmaceutical compositions including them

Info

Publication number: WO2006050909A1
Application number: PCT/EP2005/011938
Authority: WO
Inventors: Anne-Catherine Burteau; Fritz Blatter; John Surtees
Original assignee: UCB Farchim SA
Current assignee: UCB Farchim SA
Priority date: 2004-11-10
Filing date: 2005-11-08
Publication date: 2006-05-18
Anticipated expiration: 2007-05-10

Abstract

The invention relates to novel forms, specifically an amorphous form and certain solvates, of efletirizine dihydrochloride, processes for making them and pharmaceutical compositions including them.

Description

NOVEL FORMS OF EFLETIRIZINE DIHYDROCHLORIDE, PROCESSES FOR MAKING THEM AND PHARMACEUTICAL COMPOSITIONS INCLUDING THEM.

The present invention relates to novel forms of efletirizine dihydrochloride, processes for preparing them and their use for the preparation of a medicament, more particularly for the preparation of pharmaceutical compositions effective for the treatment of allergic rhinitis and asthma.

The present invention in particular relates to an amorphous form and to solvates of efletirizine dihydrochloride, processes for preparing them and use for the preparation of a medicament, more particularly for the preparation of pharmaceutical compositions effective for the treatment of allergic rhinitis and asthma.

Efletirizine is a substituted benzhydrylpiperazine derivative encompassed within general formula (I) of European patent No. 58146. It belongs to the pharmacological class of histamine Hl -receptor antagonists and shows in vitro high affinity and selectivity for Hl -receptors. It has been demonstrated to have antiallergic and antihistaminic properties and has been suggested for the treatment of seasonal and perennial allergic rhinitis.

Processes for preparing efletirizine or a pharmaceutically acceptable salt thereof have been described in in International patent applications WO 99/28310, WO 97/37982 and WO 03/009849.

International patent application WO 99/28310 and European patent application number EP 0 919 550 Al describe pseudopolymorphic forms of efleterizine dihydrochloride .

It has been reported previously that amorphous forms of certain drugs exhibit enhanced solubility and dissolution characteristics and in some cases distinct bio¬ availability patterns compared to the crystalline forms. The dissolution rate may favor one formulation over another. Further the amorphous and the solvates crystalline forms have different handling properties and stabilities

A particular solid form of an active compound may be more suitable for certain formulations and similarly, a particular formulation may be more suitable for treating certain patient populations.

Therefore it is desirable to have different solid forms of efletirizine dihydrochloride, such as amorphous or solvated, and accordingly the appropriate procedures for the preparation of amorphous or solvated forms of efletirizine dihydrochloride.

The present invention is based on the unexpected finding that efletirizine dihydrochloride can be produced in an amorphous form having advantageous properties. More particularly, contact properties of efletirizine dihydrochloride may be advantageously modified by the amorphous state.

Thus, the present invention relates to an amorphous form of efletirizine dihydrochloride. More particularly, it relates to an amorphous form of efletirizine dihydrochloride which is substantially free of structured or crystalline forms of efletirizine dihydrochloride. Presence or absence of crystalline forms of efletirizine dihydrochloride can be determined by different methods described herein, such as X- Ray Powder Diffraction analysis (XRPD), Raman Spectrometry, Differential Scanning Calorimetry and solid state NMR.

The present invention further relates to pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of an amorphous form of efletirizine dihydrochloride, preferably comprising at least 20% by weight of an amorphous form, more particularly at least 30 % by weight of an amorphous form, even more particularly at least 50% by weight of an amorphous form, most particularly at least 90% by weight of an amorphous form of efletirizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride.

Particular embodiments of the invention relate to pharmaceutical compositions comprising at least 75% by weight, at least 85% by weight, at least 95% by weight of an amorphous form of efletirizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride and particularly comprising a solid form of efletirizine dihydrochloride, which is substantially free of structured or crystalline forms of efletirizine dihydrochloride.

A particular embodiment relates to an amorphous form of efletirizine dihydrochloride present in a prophylactically or therapeutically effective amount in a pharmaceutical composition in admixture with one or more pharmaceutically acceptable excipients.

In a preferred embodiment according to the invention, the amorphous form of efleterizine dihydrochloride is a stable amorphous form.

In a further particular embodiment of the invention, the pharmaceutical composition comprising said amorphous form of efletirizine dihydrochloride is used for the treatment of allergies and asthma, more particularly for the treatment of chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like.

In yet another embodiment of this aspect of the invention, the pharmaceutical composition may be a solid preparation such as metered-dose and/ or drug powder inhalers, medicinal powders or tablets, or a semi-solid preparation such as suspensions, ointments or transdermal patches.

Another aspect of the invention relates to a process for the preparation of an amorphous form of efletirizine dihydrochloride. In one embodiment of the present invention, the process involves suspension or dissolution of efletirizine dihydrochloride in a solvent carrier comprising one or more solvents, and removing the solvent carrier until a solid residue is obtained.

Particular embodiments of the invention relate to methods whereby the solvent carrier is removed by freeze-drying or evaporation using dry nitrogen. Another particular embodiment of the present invention is the use of water as the solvent carrier or as one of the solvents constituting the solvent carrier. This process is simple, eco-friendly and cost effective.

The invention further relates to solvate forms of efietirizine dihydrochloride. Another aspect of the invention relates to a process for the preparation of solvate forms of efietirizine dihydrochloride by crystallising or recrystallising a solid form of efietirizine dihydrochloride from a solvent or solvent mixture containing at least the solvent of which the solvate is formed, and removal of excess of solvent for the isolation of the solid material.

By a preferred method, the solid form may be an amorphous form of efietirizine dihydrochloride. In said preferred method, an amorphous form of efietirizine dihydrochloride is suspended in a solvent or solvent mixture and said suspension is stirred until crystallization of the solvate is complete.

A suitable solvent for the preparation of the solvate forms of efietirizine dihydrochloride can be an organic solvent selected from the group consisting essentially of acids, esters, ethers, carbonyl compounds, nitriles, amides, sulfur containing solvents, halogenated hydrocarbons and aromatic hydrocarbons. In a particular embodiment of the invention a solvent is selected from the group consisting essentially of ethyl acetate, diethyl ether, N-methyl pyrrolidone, acetonitrile, dimethylformamide, acetone, dimethyl sulfoxide, dichloromethane, chloroform and toluene. In a preferred embodiment of the invention a solvent is selected from the group consisting of acetonitrile, ethyl acetate, N-methyl pyrrolidone (NMP) and dimethyl sulfoxide (DMSO).

The invention also relates to a pharmaceutical composition comprising at least

20% by weight of a solvate form of efietirizine dihydrochloride, or at least 30% by weight, or at least 50% by weight, or at least 90% by weight of a solvate form of efietirizine dihydrochloride with respect to the total weight of efietirizine dihydrochloride.

In a preferred embodiment of the invention, the amount of a particular efietirizine solvate can be quantified in a sample by X-Ray Powder diffraction (XRPD), Raman spectrometry, TG-FTIR or solid state NMR.

A particular embodiment relates to a solvate form of efietirizine dihydrochloride present in a prophylactically or therapeutically effective amount in a pharmaceutical composition in admixture with one or more pharmaceutically acceptable excipients. In a particular embodiment of the invention, the pharmaceutical composition comprising said solvate form of efletirizine dihydrochloride is used for the treatment of allergies and asthma, more particularly for the treatment of chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like. In another embodiment of this aspect of the invention, the pharmaceutical composition may be a solid preparation such as metered-dose and/or drug powder inhalers, medicinal powders or tablets, or a semi-solid preparation such as suspensions, ointments or transdermal patches.

The term "efletirizine " (INN: International Non-proprietary Name) as used herein refers to 2-[2-[4-[bis(4-fluorophenyl)methyl]-l-piperazinyl]ethoxy] acetic acid, i.e. the compound of the following formula:

The term "efletirizine dihydrochloride" as used herein refers to a salt of efleterizine wherein two molecules of HCl are combined with one molecule of efleterizine.

The term "structured form" as used herein refers to any form of efletirizine dihydrochloride which is non-amorphous, i.e. in which at least one X-Ray Powder Diffraction pattern can be recognized, more particularly any kind of "crystalline form" in which this molecule can occur.

The term " crystalline form " as used herein refers to any pseudo-polymorphic or polymorphic form of efletirizine dihydrochloride and, in particular, to the two polymorphic crystalline forms of efletirizine dihydrochloride, namely anhydrous efletirizine dihydrochloride and efletirizine dihydrochloride monohydrate which are described in International patent application WO 99/28310 and in European patent application EP 0 919 550 Al, as well as to another polymorphic form of efletirizine dihydrochloride which is described in the International patent application WO 03/009849, and also to solvate forms of efletirizine dihydrochloride such as disclosed by the present invention. The term "amorphous form" as used herein relates a form of efletirizine dihydrochloride which is substantially free of any structured form, particularly substantially free of any crystalline form of efletirizine dihydrochloride.

The expression "substantially free" as used herein means less than 5% by weight, preferably less than 3% by weight, more preferably less than 1% by weight, most preferably less than 0.5 % by weight with respect to the total weight of efletirizine dihydrochloride .

The expression "stable amorphous form" as used herein when referring to efleterizine dihydrochloride means that the amorphous form of efleterizine dihydrochloride has a glass transition (Tg) measured by Differential Scanning

Calorimetry greater than 50°C, preferably greater than 80⁰C, most preferably greater than 95°C.

The term "solvate form" as used herein relates to a solid form of efletirizine dihydrochloride associated or bound with an organic solvent molecule in an amount corresponding substantially with the amount able to remain within the crystalline network of the material under drying conditions.

The term "efletirizine dihydrochloride product" as used herein relates to a product comprising at least 90% by weight, preferably at least 95% by weight, most preferably at least 99% by weight of one or more solid forms of efletirizine dihydrochloride with respect to the total weight of the product.

The presence of a crystalline form of efletirizine dihydrochloride can be distinguished from the presence of an amorphous form of efletirizine dihydrochloride, using a number of different techniques including X-Ray Powder diffraction (XRPD),

Raman spectroscopy, solution calorimetry, differential scanning calorimetry (DSC), solid state nuclear magnetic resonance (solid state NMR) or (near) infrared spectroscopy, thermogravimetiy coupled with infrared spectroscopy (TG-FTTR), all of these techniques being well-established in the art. An amorphous form of efletirizine dihydrochloride can also be distinguished from structured forms of efletirizine dihydrochloride based on the morphology of the particles as may be observed via electron microscopy.

The most appropriate method of analysis may be dependent on the formulation of the efletirizine dihydrochloride compound. Thus, in many cases, the presence or absence, as well as the relative concentration of structured forms can be identified by X-Ray Powder Diffraction analysis (using a sample of 100% crystalline efletirizine dihydrochloride as a reference) alone. In view of the analysis of tablets comprising efletirizine dihydrochloride admixed, e.g. in a low drug loading, with a number of excipients, infrared spectroscopy (TG-FTIR) or Raman spectroscopy or solid state NMR may be more suitable. More particularly, according to the present invention an amorphous form of efletirizine dihydrochloride can be characterized using X-Ray Powder Diffraction (XRPD) analysis. In general, the identification of a structured form of a compound in its X-Ray powder diffraction pattern is based upon the position of discrete peaks corresponding to a diffraction angle (usually expressed as 2 theta). This diffraction angle 2 theta (position [°2Θ]) is linked to the spacing between a particular set of planes distanced (d-value, e.g. expressed in nm). The Bragg equation calculates the distance d from the wavelength of the source used and the measured angle. Structured forms of efletirizine dihydrochloride in a sample will result in sharp well-defined peaks. By measuring the intensity of the diffraction lines and comparing them with the above- mentioned standard it is possible to make a quantitative analysis of mixtures comprising one or more structured forms. Quantitative data can be obtained by measuring the peak heights using the Internal Standard Method (being more appropriate for powdered mixtures) or the External Standard Method (being appropriate for solid systems when the mass absorption coefficient is known). Slight but not significant variations in observed 2 theta values or d-spacing values can occur based on the sample preparation, the diffractometer, and the analyst. According to a particular embodiment of the present invention, the X-ray diffraction pattern was determined on a Philips 1710 X-ray powder diffractometer using CuK radiation (the wavelength of CuK radiation is 0.15406 nm). The ratio of CuKαl to CuKα2 radiation is 2:1. The X-ray tube was operated at a voltage of 45kV, and a current of 45 mA. A step size of 0.02°, and a counting time of 2.4 second per step was applied. Either silicon or quartz sample holders of 0.5 mm depth and 12 diameter were used. An amorphous form of efletirizine dihydrochloride according to the present invention displays no significant X-Ray Powder Diffraction peaks (as illustrated herein in Example 1 - Figure 1). Thus, in a particular embodiment the present invention relates to an amorphous form of efletirizine dihydrochloride being characterized by a X-Ray Powder Diffraction pattern substantially in accordance with Figure 1.

The amorphous form of efleterizine dihydrochloride may be characterized using differential scanning calorimetry (DSC). In a particular embodiment according to the present invention, the stable amorphous form of efleterizine dihydrochloride is substantially free of residual solvent or water and has a glass transition at 98°C with a heat capacity of 0.62 J/g. Upon further heating, said form undergoes crystallization near 173 ⁰C, and then the produced crystal form melts near 211 ⁰C. Typically, differential scanning calorimetry is carried out with a Perkin Elmer DSC7 (closed gold sample pan or gold-plated steel sample pan, with a heating rate 10° K/minute or 20° K/minute). In some cases the sample pans can be closed under nitrogen atmosphere. Additionally or alternatively, an amorphous form of efleterizine dihydrochloride can be characterized by Raman spectroscopy, for example using a Bruker RFS 100 FT- Raman system with a near infrared Nd:YAG laser operating at 1064 nm and a liquid nitrogen-cooled germanium detector. An amorphous form of efletirizine dihydrochloride will result in a spectrum as described herein in Example 2 and Figure 2.

In preferred embodiments according to the present invention contact of the amorphous form of efleterizine dihydrochloride with water or residual solvent is avoided as crystallisation may occur.

In a further embodiment according to the present invention, kinetic stability of the amorphous form or the stable amorphous form of efletirizine dihydrochloride may be improved by mixing said form with suitable polymers, for example to form a solid solution. Preferably, said solid solution may exhibit an increased glass transition temperature.

According to a particular embodiment, the present invention, relates to an efletirizine dihydrochloride product which comprises at least 20 % by weight, more particularly at least 30 % by weight, even more particularly at least 50 % by weight and most particularly at least 90 % by weight of an amorphous form of efleterizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride. According to a particular embodiment of the invention, said product is substantially free of any structured form of efletirizine dihydrochloride, more particularly substantially free of crystalline forms of efletirizine dihydrochloride.

Most of the above-described analytical methods allow both a qualitative and a quantitative determination of the relative amount of an amorphous form of efletirizine dihydrochloride in a composition based on efletirizine dihydrochloride. More particularly, X-Ray Powder Diffraction provides a convenient and practical means for quantitative determination of the relative amounts of crystalline and amorphous forms, since the intensities of the diffraction peaks in a mixture are proportional to the fraction of the material in the mixture. The percentage of a structured form can be determined in an unknown composition by comparing the X-ray powder diffraction patterns measured with those of a known standard containing efletirizine dihydrochloride in a substantially pure structured form, and by comparing the relative intensities of the peaks with a calibration curve obtained from the known standard. Such a calibration curve can be obtained by the skilled person using reference mixtures of amorphous and structured forms of efletirizine dihydrochloride in different (e.g. incremental) ratios from which X-Ray Powder diffraction patterns are taken and/or solid state NMR spectra are recorded. The intensities of the diffraction peaks can then be plotted against the known percentage of the structured form of efletirizine dihydrochloride in the mixture. For an unknown composition of structured and amorphous forms, the intensities of the peak in the mixture, relative to the intensity of the peak in the calibration mixture can be used to determine the percentage of a structured form in the composition, with the remainder being an amorphous form.

Thus, according to a particular embodiment, the invention relates to an efletirizine dihydrochloride product which comprises less than 80 % by weight, more particularly less than 70 % by weight, more particularly less than 50 % by weight, and still more particularly less than 10 % by weight of any structured form of efletirizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride present in said composition as may be determined by X-Ray Powder Diffraction analysis. According to a further particular embodiment, the present invention relates to an efleterizine dihydrochloride product comprising one or more structured forms of efletirizine dihydrochloride in combination with an amorphous form of efletirizine dihydrochloride. Said product comprising an amorphous form of efletirizine dihydrochloride can be prepared by mixing an amorphous form of efletirizine dihydrochloride with other solid forms of efletirizine dihydrochloride. Examples of other solid forms of efletirizine dihydrochloride include, but are not limited to, known crystalline forms of efletirizine dihydrochloride as well as solvate forms of efletirizine dihydrochloride such as the ones disclosed hereinafter. A specific embodiment of the present invention relates to said product comprising at least 20 % by weight of an amorphous form of efletirizine dihydrochloride, more particularly 30 % by weight of an amorphous form of efletirizine dihydrochloride, even more particularly 50 % by weight of an amorphous efletirizine dihydrochloride, most particularly at least 90 % by weight of an amorphous form of efletirizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride. The amorphous form of efletirizine dihydrochloride according to the present invention can be prepared by a number of different methods such as, but not limited to, precipitation, spray drying, freeze drying, precipitation from the melt, vapor condensation, crash cooling, and co-precipitation with suitable solvents.

Thus, another aspect of the invention relates to a process for the preparation of an amorphous form of efletirizine dihydrochloride. The process of the invention involves dissolution or suspension of any structured form of efletirizine dihydrochloride in a suitable solvent carrier, comprising one or more solvents, and then removing said solvent carrier until a solid residue is obtained. A suitable solvent carrier according to the present invention is one that comprises water as one of the solvents. According to a particular embodiment of the invention, said suitable solvent carrier is water, preferably deionized water, or is a water-tetrahydrofuran mixture, preferably a 1 : 1 volume ratio mixture of water and tetrahydrofuran. Removal of said solvent can be effected in different ways, such as those described above. A particular embodiment of the invention relates to a process wherein the solvent is removed by freeze-drying or evaporation e.g. using dry nitrogen. Most particularly, the solid residue is obtained as a white powder, which powder comprises an amorphous form of efletirizine dihydrochloride. According to a particular embodiment of the present invention, the amorphous form of efletirizine dihydrochloride is prepared by freeze-drying as described in the examples herein and said process for preparing amorphous efletirizine dihydrochloride comprises the steps of (a) suspending or dissolving a structured form of efletirizine dihydrochloride in a suitable solvent, preferably deionized water, and then (b) freeze- drying said solution until a white solid powder is obtained.

An amorphous form of efletirizine dihydrochloride according to the present invention has specific physicochemical properties which are of particular interest for use as a solid form of efletirizine dihydrochloride for pharmaceutical processing or formulation, as well as for the therapeutic administration of efletirizine dihydrochloride .

Said amorphous form of efletirizine dihydrochloride is stable in the presence of those apolar solvents in which efletirizine dihydrochloride is poorly soluble, but does not form a solvated crystalline form. Such apolar solvents are for example alkanes, such as heptane, or pharmaceutically acceptable oils. Thus, where solvated crystalline forms are not desired, the amorphous form of efletirizine dihydrochloride may preferably be used in the preparation of pharmaceutical compositions, e.g. patches, oily solutions or suspensions, suppositories and the like.

When the amorphous form of efletirizine dihydrochloride is stored or maintained in a suitable solvent, the corresponding solvate of efletirizine dihydrochloride can be obtained. The invention thus further relates to solvate forms of efletirizine dihydrochloride. In a particular and more preferred embodiment of the present invention, the amorphous form of efletirizine dihydrochloride is used as the starting material in the process for the preparation of solvate forms of efletirizine dihydrochloride. Several techniques allow characterization and therefore identification and/or demonstration of the presence of a solvate form of efletirizine dihydrochloride in a sample. These techniques include X-Ray Powder Diffraction, Raman spectrometry, differential scanning calorimetry, thermogravimetry coupled with infrared spectroscopy, solid phase NMR and the like. Application of these techniques for the characterization of the solvate forms of efletirizine dihydrochloride according to the present invention is illustrated in examples 3 to 7 of the present application. In many cases the presence as well as the relative concentration of a solvate form of efletirizine dihydrochloride can be identified by X-Ray Powder Diffraction analysis, using a substantially pure sample of the solvate form of efletirizine dihydrochloride as a reference. For the analysis of tablets comprising efletirizine dihydrochloride admixed, e.g. in a low drug loading, with a number of excipients, infrared spectroscopy or Raman spectrometry or solid state NMR may be more suitable. The most appropriate method of analysis may be dependent on the formulation of the efletirizine dihydrochloride compound and on the type of solvate form of efletirizine dihydrochloride.

The solvate forms of efletirizine dihydrochloride can be characterized using X- ray powder diffraction analysis, for instance using a Philips 1710 X-Ray powder diffractometer using CuKa radiation (the wavelength of CuKαl radiation is 1.54060 A), with the X-ray tube operated at a Voltage of 45kV and a current of 45 mA, a step size of 0.02°, and a counting time of 2.4 s per step is typically applied. The identification of a particular form of a compound in its diffraction pattern is based upon the position of discrete peaks corresponding to a diffraction angle 2 theta. The diffraction angle 2 theta (position [°2»]) is linked to the spacing between a particular set of planes distanced (d-value [A]). The Bragg equation calculates the distance d from the wavelength of the source used and the measured angle. A solvate form of efletirizine dihydrochloride in a sample will result in sharp well-defined peaks. By measuring the intensity of the diffraction lines and comparing them with standards it is possible to make a quantitative analysis of mixtures. Quantitative data can be obtained by measuring the peak heights using the Internal Standard Method (more appropriate for powdered mixtures) or the External Standard Method (for solid systems when the mass absorption coefficient is known). As a non-limiting reference, X-Ray Powder Diffraction pattern of solvate forms of efletirizine dihydrochloride are provided in Figures 3A to 7A of the present application.

Additionally or alternatively, solvate forms of efletirizine dihydrochloride can be characterized by Raman spectroscopy, for instance using a Bruker RFS 100 FT- Raman system with a near infrared Nd:YAG laser operating at 1064 nm and a liquid nitrogen-cooled germanium detector. Solvate forms of efletirizine dihydrochloride will result in a typical spectrum as described in Examples 3 to 7 of the present application, which examples refer also to TG-FTIR analysis. Such analysis can be carried out for example with a Netzsch Thermo-Microbalance TG 209 coupled to a Bruker FTTR Spectrometer Vector 22 (sample pans with a pinhole, N2 atmosphere, heating rate 10 K/min). Most of the above described methods allow both a qualitative and a quantitative determination of the relative amount of one or more solvate forms of efletirizine dihydrochloride in a sample or composition. More particularly, X-Ray Powder Diffraction provides a convenient and practical means for quantitative determination of the relative amounts of solvate forms, as the intensities of the peaks in a mixture are proportional to the fraction of the material in the mixture. The percentage of a solvate form of efleterizine dihydrochloride can be determined in an unknown composition by comparing the X-Ray Powder Diffraction patterns measured with those of a known standard containing a pure solvate form of efletirizine dihydrochloride, by comparing the relative intensities of the peaks with a calibration curve obtained from a pure sample. Such a calibration curve can be obtained by the skilled person using artificial mixtures of different solid forms of efletirizine dihydrochloride in different (e.g. incremental) ratios of which X-Ray diffraction patterns are taken or on which solid NMR is achieved. The intensities of the peaks can then be plotted against the known percentage of the solvate form of efletirizine dihydrochloride in the sample. For an unknown composition comprising solvate forms of efletirizine dihydrochloride, the intensities of the peak in the mixture, relative to the intensity of the peak in the calibration mixture can be used to determine the percentage of solvate form in the composition

According to another aspect, the present invention relates to an efletirizine dihydrochloride product which comprises at least 20% by weight, more particularly at least 30% by weight, more particularly at least 50% by weight, even more particularly at least 90% by weight of a solvate form of efleterizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride. The amount of a solvate form of efletirizine dihydrochloride can be determined by any of the methods as described above, but in particular by X-Ray Powder Diffraction or Raman spectrometry.

Another aspect of the invention relates to a process for preparing solvate forms of efletirizine dihydrochloride comprising a step of crystallization and optionally re- crystallization of a solid form of efletirizine dihydrochloride in one or more suitable solvents. The crystallization or re-crystallization step of the process involves suspending or dissolving a solid form of efletirizine dihydrochloride in one or more suitable solvents and stirring the suspension or solution obtained until crystallization of the solvate form is completed. Excess solvent may be removed by filtration and/or drying of the material using conventional techniques. A particular and preferred embodiment of this aspect of the invention relates to a process wherein said solid form of efletirizine dihydrochloride is the amorphous form of efletirizine dihydrochloride according to the present invention.

The solvate forms of efletirizine dihydrochloride according to the present invention can be prepared by other methods as well. One alternative method is to suspend or dissolve the free base of efletirizine in a suitable solvent system, for example a mixture of an organic solvent with a co-solvent such as, but not limited to, acetone, and then bubble anhydrous HCl gas through the organic suspension or solution under suitable time and temperature conditions.

Suitable solvents for use in the preparation of solvate forms of efletirizine dihydrochloride according to the invention may be selected from the group consisting essentially of carboxylic acid esters, for example ethyl acetate, ethers, for example diethyl ether, nitriles, for example acetonitrile, amides for example dimethylformamide (DMF) or N-methyl pyrrolidone (NMP), carbonyl compounds,for example acetone, sulfur-containing solvents for example dimethylsulfoxide (DMSO), halogenated hydrocarbons for example dichloromethane or chloroform, and aromatic hydrocarbons for example toluene, and mixtures thereof in suitable proportions. Thus, another aspect of the present invention relates to an amorphous form of efletirizine dihydrochloride being present in a prophylactically or therapeutically active amount in a composition. The term composition includes, but is not limited to, a solid dosage form such as metered-dose and/or drug powder inhalers, medicinal powders and tablets or semi-solid preparations such as a suspension, a gel, an ointment, and/ or mixtures thereof.

The present invention particularly relates to a pharmaceutical composition comprising at least 20% by weight of an amorphous form of efletirizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride, more particularly at least 30 % by weight of an amorphous form of efletirizine dihydrochloride, even more particularly at least 50 % by weight of an amorphous form of efletirizine dihydrochloride and most particularly at least 90 % by weight of an amorphous form of efletirizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride. The invention further relates to one or more solvate forms of efletirizine dihydrochloride present in a prophylactically or therapeutically active amount in a pharmaceutical composition.

The invention particularly relates to a pharmaceutical composition comprising at least 20% by weight of a solvate form of efletirizine dihydrochloride, or at least 30% by weight, or at least 50% by weight, or at least 90% by weight of a solvate form of efletirizine dihydrochloride with respect to the total weight of efletirizine dihydrochloride.

The term "pharmaceutically acceptable" refers to that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use. According to a further aspect of the invention a pharmaceutical composition comprising an amorphous form of efletirizine dihydrochloride or a pharmaceutical composition comprising a solvate form of efleterizine dihydrochloride may be provided for the treatment or alleviation of the effects of allergies, including chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like. More particularly, the formulation of the pharmaceutical composition is adjusted so that at least 20 % by weight of the total efletirizine dihydrochloride dosage is present in amorphous form. The dosage depends essentially on the specific method of administration and on the purpose of the treatment and on the severity of the disease. The size of the individual doses and the administration program can best be determined based on an individual assessment of the relevant case. Methods required to determine the relevant factors are familiar to the person skilled in the art.

A preferred daily dosage of efletirizine dihydrochloride is from about 0.01 mg to about 5.0 mg of such a form per kg of body weight of the patient. A particularly preferred daily dosage is from about 0.1 to about 3.0 mg per kg of body weight of the patient. The best results have been obtained with a daily dosage from about 0.1 to 2.0 mg per kg of body weight of the patient. The dosage may be administered once per day of treatment, or divided into smaller dosages, for example 1 to 4 times a day, and preferably 1 to 3 times a day, and administered over about a 24 hours time period to reach a total given dosage. The exact dosages in which the compositions are administered can vary according to the type of use, the mode of use, the requirements of the patient, as determined by a skilled practitioner. The exact dosage for a patient may be specifically adapted by a skilled person in view of the severity of the condition, the specific formulation used, and other drugs which may be involved.

Pharmaceutical compositions used according to the present invention may be administered by any conventional means. There is no restriction on routes of administration for the compounds of the present invention as medicines. The preferred route of administration however is oral administration. Any other convenient route of administration can be used, for example absorption through epithelial or mucocutaneous linings.

Pharmaceutical compositions used according to the present invention may be immediate release dosage form, slow or modified release dosage form or a combination thereof. The pharmaceutical forms according to the present invention may be prepared according to conventional methods used by pharmacists. The forms can be administered together with other components or biologically active agents, or pharmaceutically acceptable excipients, such as surfactants, carriers, disintegrants, lubricants, binders, flavors, colorants, diluents, vehicles and the like. The pharmaceutical compositions according to the invention include any conventional therapeutically inert carrier. They can contain inert as well as pharmacodynamically active additives. Furthermore, substances conventionally used as preserving, stabilizing, moisture retaining, and emulsifying agents as well as substances such as salts for varying the osmotic pressure, substances for varying pH such as buffers, and other additives can also be present. If desired an antioxidant can also be included in the pharmaceutical compositions of this invention. Compositions may also comprise specific stabilizing agents such as sugars, including mannose and mannitol. Carrier substances or diluents can be organic or inorganic substances, for example gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycol and the like. A prerequisite is that all adjuvants and substances used in the manufacture of the pharmaceutical compositions are non-toxic.

Pharmaceutical compositions can be administered by spray inhalation. Any conventional pharmaceutical composition for spray inhalation administration may be used. Another mode of administration is by aerosol.

The pharmaceutical composition of the invention can also be formulated for topical application. The composition for topical application can be in the form of an aqueous solution, lotion or jelly, an oily solution or suspension or a fatty emulsion or ointment.

The pharmaceutical composition of the invention can also be used for modified or slow prolonged release with a transdermal or intramuscular therapeutic system or with an appropriate formulation for oral modified or slow release.

The pharmaceutical compositions according to the present invention may also be administered rectally or by nasal instillation or aerosols, or in the form of unguents or creams. The pharmaceutical compositions which can be used for oral administration are preferably solid, for example, in the form of uncoated or coated tablets, pills, dragees, gelatine capsules, and the like. For administration by the rectal route, the compositions containing the compounds of the present invention are generally used in the form of suppositories.

The preferred pharmaceutical forms, for example tablets, capsules, pellets, suppositories and the like, may be prepared by conventional pharmaceutical methods, wherein the forms of efletirizine dihydrochloride according to the present invention are mixed with one or more solid or liquid, non-toxic and pharmaceutically acceptable carriers, including a dispersing agent, a disintegrating agent, a stabilizing agent and the like. If appropriate, it is also possible to add preservatives, sweeteners, coloring agents and the like. The selection of the optimal excipients and their proportion within the pharmaceutical composition of the present invention depends on the specific therapeutic indication and of the required drug release characteristics and is well known to the skilled person.

According to one embodiment, the pharmaceutical composition of the invention is administered in traditional solid form for oral administration, for example film- coated tablets, capsules, dragees, and the like. The pharmaceutical compositions according to the present invention may be a coated or non-coated tablet comprising in addition to the forms of efletirizine dihydrochloride described herein the following compounds: efletirizine dihydrochloride, diluents such as lactose, binders such as cellulose, lubricants such as magnesium stearate and colloidal silica. Optionally, disintegrants such as croscarmellose may be added. In particular embodiments, the tablet may be coated with coating agents such as cellulose derivatives.

Pharmaceutical compositions of the invention are useful to treat or prevent allergies, more particularly persistent allergic rhinitis. These compositions are able to alleviate the effects of persistent allergic rhinitis.

The following examples are merely illustrative and are not intended to limit the scope of the invention to the specific embodiments described herein.

Brief description of the drawings Figure 1 shows a X-Ray powder diffraction pattern of the amorphous form of efletirizine dihydrochloride according to the present invention.

Figure 2 shows the Raman spectrum of the amorphous form of efletirizine dihydrochloride according to the present invention.

Figure 3 shows, for an efletirizine dihydrochloride ethyl acetate solvate according to an embodiment of the invention: (A) the X-ray powder diffraction pattern, (B) the Raman spectrum.

Figure 4 shows, for an efletirizine dihydrochloride acetonitrile solvate according to an embodiment of the invention: (A) the X-ray powder diffraction Pattern, (B) the Raman spectrum. Figure 5 shows, for an efletirizine dihydrochloride N-methylpyrrolidone solvate according to an embodiment of the invention: (A) the powder X-ray diffraction pattern, (B) the Raman spectrum.

Figure 6 shows, for an efletirizine dihydrochloride dimethylsulfoxide solvate A according to an embodiment of the invention: (A) the X-ray powder diffraction pattern, (B) the Raman spectrum.

Figure 7 shows, for an efletirizine dihydrochloride dimethylsulfoxide solvate B according to an embodiment of the invention: (A) the X-ray powder diffraction pattern, (B) the Raman spectrum.

Example 1 - production of an amorphous form of efletirizine dihydrochloride by freeze-drying - characterization using X-Ray Powder Diffraction (XRPD) analysis and differential scanning calorimetric analysis Two portions of 1.5 g of crystalline efletirizine dihydrochloride were placed in two different 100 ml round glass flasks and into each flask 15.0 ml of deionized water (Fluka no. 95306) were added at 23.2°C. The slightly turbid solutions were filtrated through a 0.45 μm Millipore filtration unit, and the clear solutions were again transferred into two different 100 ml round glass flasks. The clear solutions were frozen in a bed of dry ice (solid CO₂) at -78°C, and subsequently the glass flasks with the frozen solutions were connected to a lyophilisator (type: CHRIST, BETA 2-8 LD-2). The initial pressure was 0.10 mbar, and the cold trap temperature was -80⁰C. After about 15 hours, lyophilization was complete and the flasks were disconnected. The obtained white solid powder, yield 2.95 g, was characterized by XRPD, Raman spectroscopy, differential scanning calorimetry, and the water content was determined by Karl Fischer titration.

XRPD was performed on a Philips 1710 X-ray powder diffractometer using CuK radiation (the wavelength of CuK (1 radiation is 0.15406 nm). The ratio of CuK (1 to CuK (2 radiation was 2: 1. The X-ray tube was operated at a voltage of 45kV, and a current of 45 mA. A step size of 0.02°, and a counting time of 2.4 second per step were applied.

The X-ray powder diffraction pattern is shown in figure 1. The absence of diffraction peaks in the X-ray powder diffraction diagram of figure 1 shows that the sample corresponds to an amorphous form of efletirizine dihydrochloride. Furthermore, analysis of the same sample in its dry state by differential scanning calorimetry (DSC) reveals a transition at 98°C with a heat capacity of 0.62 J/g. The water content of the white powder according to the Karl Fischer titration method is 2.3 %.

Example 2: Production of an amorphous form of efletirizine dihydrochloride by evaporation — characterization using Raman spectroscopy.

2.0 g of crystalline efletirizine dihydrochloride were placed in a 22 ml glass vial to which 12 ml of deionized water (Fluka no. 95306) was added at 23.2 ⁰C. The resulting suspension was heated to 60 ⁰C in a laboratory thermostate (LAUDA RM6) for about 10 minutes. The resulting opalescent solution was filtrated through a 0.45 μm Millipore filtration unit and 5.0 ml of the obtained clear solution was transferred into a 15 ml glass vial. A flow of dry nitrogen, at a flow rate of about 130 ml/minute was directed over the solution by a small glass pipette. Within about 96 hours the solution evaporates completely and the obtained white solid powder was investigated by Raman spectroscopy on a Bruker RFS 100 FT-Raman system with a near infrared Nd:YAG laser operating at 1064 nm and a liquid nitrogen-cooled germanium detector. For each sample, 64 scans with a resolution of 2 cm-1 were accumulated, using 100 mW laser power. A Raman spectrum identical the one shown in figure 2 was obtained. The Raman spectrum of the obtained amorphous form of efletirizine dihydrochloride shows characteristic Raman peaks at the following wavenumbers in [cm- 1]: 3072 (s), 3007 (m), 2965 (s), 1606 (s), 1437 (m), 1304 (m), 1231 (m), 1187 (s), 1166 (m), 1048 (m), 861 (w), 842 (m), 830 (m), 784 (m), 723 (m), 651 (w), 632 (s), 578 (w), 485 (w), 445 (m), 376 (m), 219 (w), 92 (vs), wherein (vs) stands for very strong intensity, (s) for strong intensity, (m) for medium intensity, and (w) stands for weak intensity.

Example 3: Preparation and characterization of an efletirizine dihydrochloride ethyl acetate solvate 174 mg of amorphous efletirizine dihydrochloride was suspended in 4.0 ml ethyl acetate (Fluka analytical grade no.45767) at 23±2 ⁰C. The resulting suspension was stirred at 25±2 °C for about 15 hours, before the solid is separated by filtration. The obtained white crystalline material was dried in air at ambient temperature and investigated by XRPD, Raman spectroscopy, TG-FTIR and DSC. Yield: 136 mg. TG- FTIR analysis revealed that the obtained crystals contain 15 % by weight of residual ethyl acetate, the most part of it being released near 150 ⁰C. The DSC melting point was close to 135 °C and an enthalpy of fusion shows of about 70 J/g, if taken in a closed sample pan. Furthermore, the obtained crystals are characterized by a specific X-ray powder diffraction pattern as shown in figure 3A of which the most characteristic parameters (wherein (vs) stands for very strong intensity, and (s) for strong intensity) are listed in table 1 below, and a Raman spectrum as shown in figure 3B which shows characteristic strong (s) to very strong (vs) Raman peaks at the following wavenumbers in [cm ¹]: 3077 (s), 2975 (s), 1190 (s), 856 (s), 632 (s) and 99 (vs). -

Example 4 - preparation and characterization of an efletlrizine dihydrochloride acetonitrile solvate

141 mg of amorphous efletirizine dihydrochloride is suspended in 3.0 ml acetonitrile (Fluka analytical grade no. 00700) at 23±2 ⁰C. The resulting suspension was stirred at 23+2 ⁰C for about 17 hours before the solid is separated by filtration. The obtained white crystalline material (yield: 87 mg) was dried in air at ambient temperature and investigated by X-ray powder diffraction, Raman spectroscopy, and TG-FTIR. TG-FTIR analysis reveals that the obtained crystals contain about 14 % of residual acetonitrile, wherein the most part of it is released between 50 ^CC and 150 °C. Furthermore, the obtained crystals were characterized by a specific X-ray powder diffraction pattern as shown in figure 4A of which the most characteristic parameters (wherein (s) stands for strong intensity) are listed in table 2 below, and a Raman spectrum as shown in figure 4B which shows characteristic strong (s) to very strong (vs) Raman peaks at the following wavenumbers in [cm^"1]: 3072(s), 2974 (s), 2938 (s), 1607 (s), 1187 (s), 857 (s), 97 (vs).

Table 2: characteristic 2Θ values and d-soacings of the acetonitrile solvate

Example 5 - preparation and characterization of an efletirizine dihydrochloride N- methylpyrrolidone (NMP) solvate

300 mg of crystalline efletirizine dihydrochloride was suspended in 1.0 ml NMP (Fluka analytical grade no. 69118) at 23+2 ⁰C. The resulting suspension was stirred at 25±2 ⁰C for about 14 hours, before the solid was separated by filtration. The obtained white crystalline material (yield: 150 mg) was dried in air at ambient temperature and investigated by X-ray powder diffraction, Raman spectroscopy, and TG-FTIR. TG-FTIR analysis revealed that the obtained crystals contain about 35 % by weight of residual NMP and a small amount of water, both of them being continuously released between 50 ⁰C and 250 ⁰C. Furthermore, the obtained crystals were characterized by a specific XRPD pattern as shown in figure 5A, the most characteristic parameters (wherein (vs) stands for very strong intensity, and (s) for strong intensity) being listed in table 3 below, and a Raman spectrum as shown in figure 5B which shows characteristic strong (s) to very strong (vs) Raman peaks at the following wavenumbers in [cm^'1]: 1607 (s), 1189 (s), 855 (s), 106 (vs).

Table 3: characteristic 2Θ values and d-spacings of the NMP solvate

Example 6 - preparation and characterization of efletirizine dihydrochloride DMSO Solvate A

100 mg of crystalline efletirizine dihydrochloride were dissolved in 1.0 ml of dimethylsulfoxide (DMSO, Fluka no. 34943). 100 ml of this solution were placed into a well of a 96 quartz microliter well plate. Then the solution was evaporated under a flow of dry nitrogen at a flow rate of 400 ml per minute. Evaporation was effected through a specially designed sealing system with flow channels as described in WO 03/026797. After 48 hours evaporation was complete and the obtained solid residue was characterized by Raman spectroscopy and X-ray powder diffraction. The X-ray powder diffraction pattern is shown in figure 6A and the most characteristic parameters (wherein (vs) stands for very strong intensity, and (s) for strong intensity) are listed in table 4 below. The Raman spectrum is depicted in figure 6B and shows characteristic strong (s) to very strong (vs) Raman peaks at the following wavenumbers in [cm ¹]: 1187 (s), 854 (s), 684 (s), 316 (s).

Table 4: Characteristic 29 values and d-spacings of the DMSO solvate A

Example 7 - preparation and characterization of efletirizine dihvdrochloride DMSO Solvate B

1,000 mg of crystalline efletirizine dihydrochloride were dissolved in 3.0 ml of DMSO (Fluka no. 34943). 600 ml of this solution were injected into 7.0 ml of tetrahydrofuran (Fluka no. 87368) at 10 ⁰C. The resulting solution was then stirred at room temperature for about 2 hours, after which time a white precipitate was formed. The obtained suspension of said precipitate was filtered, and the crystalline solid was dried in air at ambient temperature and investigated by Raman spectroscopy and XRPD. The X-ray powder diffraction pattern is depicted in figure 7A and the most characteristic parameters (wherein (vs) stands for very strong intensity, and (s) for strong intensity) are listed in table 5 below. The Raman spectrum is depicted in figure 7B and shows characteristic strong (s) to very strong (vs) Raman peaks at the following wavenumbers in [cm^"1]: 1607 (s), 1189 (s), 855 (s), 104 (vs).

Table 5: Characteristic 2Θ values and d-spacings of the DMSO solvate B

Claims

1. An amorphous form of efietirizine dihydrochloride.

2. An amorphous form of efietirizine dihydrochloride according to Claim 1 characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 1.

3. An efietirizine dihydrochloride product which comprises at least 20 % by weight of an amorphous form of efleterizine dihydrochloride according to claim 1 or claim 2 with respect to the total weight of efietirizine dihydrochloride.

4. The efleterizine product according to claim 3 which is substantially free of any structured form of efietirizine dihydrochloride.

5. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the amorphous form of efietirizine dihydrochloride according to claim 1 or to claim 2 in admixture with one or more pharmaceutically acceptable salts.

6. A pharmaceutical composition according to claim 5 comprising at least 20% by weight of the amorphous form of efietirizine dihydrochloride with respect to the total weight of efietirizine dihydrochloride.

7. A process for the preparation of the amorphous form of efietirizine dihydrochloride according to claim 1 or claim 2, comprising the (a) suspension or dissolution of a structured form of efietirizine dihydrochloride in a suitable solvent carrier and (b) removal of said solvent carrier until a solid residue is obtained.

8. A process for the preparation of the amorphous form of efleterizine dihydrochloride according to claim 7 wherein the solvent carrier is removed by freeze-drying.

9. A solvate form of efietirizine dihydrochloride characterized in that the solvent in the solvate form is an organic solvent selected from the group consisting essentially of carboxylic acids esters, ethers, carbonyl compounds, nitriles, amides, sulfur-containing solvents, halogenated hydrocarbons and aromatic hydrocarbons.

10. The solvate form according to claim 9, wherein the solvent present in said solvate form is ethyl acetate and wherein said solvate form is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 3A.

11. The solvate form according to claim 9, wherein the solvent present in said solvate form is acetonitrile and wherein said solvate form is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 4A.

12. The solvate form according to claim 9, in which the solvent present in said solvate form is N-methylpyrrolidone and wherein said solvate form is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 5A.

13. The solvate form according to claim 9, in which the solvent present in said solvate form is dimethylsulfoxide and wherein said solvate form is characterized by an X- ray powder diffraction pattern substantially in accordance with Figure 6A.

14. The solvate form according to claim 9, in which the solvent present in said solvate form is dimethylsulfoxide and wherein said solvate form is characterized by an X- ray powder diffraction pattern substantially in accordance with Figure 7A.

15. A pharmaceutical composition comprising the solvate form of efletirizine dihydrochloride according to any one of claims 9 to 14 in a prophylactically or therapeutically effective amount in admixture with one or more pharmaceutically acceptable excipients.

16. A pharmaceutical composition according to claim 15 comprising at least 20% by weight of the solvate form of efletirizine dihydrochloride according to any one of claims 9 to 14 with respect to the total weight of efletirizine dihydrochloride.

17. A process for the preparation of the efletirizine dihydrochloride solvate form according to any one of claims 9 to 14, comprising the steps of crystallization and optionally recrystallization of a solid form of efletirizine dihydrochloride in one or more suitable solvent.

18. The process according to claim 17, wherein said solvent is selected from the group consisting essentially of carboxylic acid esters, ethers, carbonyl compounds, nitriles, amides, sulfur containing solvents, halogenated hydrocarbons and aromatic hydrocarbons.

19. The process according to claim 17 or claim 18 wherein the solid form of efletirizine dihydrochloride is the amorphous form of efletirizine dihydrochloride according to claim 1 or claim 2.