WO2005084674A1 - Amorphous form of desloratadine and a process for the preparation thereof - Google Patents

Abstract

An amorphous form of desloratadine and processes for making the amorphous form as well as compositions, pharmaceutical compositions, and methods utilizing the crystalline form are provided.

Description

Amorphous form of desloratadine and a process for the preparation thereof CROSS-REFERENCE TO RELATED APPLICATION This application claims priority of Indian Patent Application No. 148/CHE/2004, filed March 3, 2004, of which entire content is incorporated herein by reference, and U.S. Provisional Patent Application No. 60/591,800, filed July 28, 2004, of which entire content is incorporated herein by reference.

BACKGROUND OF THE INVENTION Desloratadine is an active metabolite of loratadine, which is orally active, long- acting histamine Hi receptor antagonist. It belongs to a second generation of Hi histamine receptor antagonists that are thought to offer advantages over the first generation compounds. The advantages are believed to include less sedation, low anticholinergic activity, and longer acting duration with the resulting improved patient compliance. For description of desloratadine and related compounds, and their uses, see, e.g., U.S. Patent Nos. 6,506,767 and 4,659,716. SUMMARY OF INVENTION The invention relates to an amorphous form of desloratadine. The invention also relates to a composition that includes desloratadine in a solid form, wherein at least 80 % by weight of the solid desloratadine is an amorphous form of desloratadine. The invention also relates to a process for preparation of amorphous form of desloratadme. The invention also relates to a pharmaceutical composition that contains an amoφhous form of desloratadine and one or more pharmaceutically acceptable carriers or diluents. Preferably, the pharmaceutical composition is a solid dosage form for oral administration. DESCRIPTION OF THE ACCOMPANYING DRAWINGS Figure 1 is an X-ray powder diffractogram of an amorphous form of desloratadine.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. For purposes of the present invention, the following terms are defined below. A "compound" is a chemical substance that includes molecules of the same chemical structure. "Pharmaceutically acceptable" means 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. The term "composition" includes, but is not limited to, a powder, a suspension, an emulsion and/or mixtures thereof. The term composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. A "composition" may contain a single compound or a mixture of compounds. The term "pharmaceutical composition" is intended to encompass a product comprising the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s), and pharmaceutically acceptable excipients. The term "excipient" means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluent, carrier, and so on. The excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient. The term "isolating" is used to indicate separation of the compound being isolated regardless of the purity of the isolated compound from any unwanted substance which presents with the compound as a mixture. Thus, degree of the purity of the isolated or separated compound does not affect the status of "isolating". The term "substantially free of in reference to a composition, as used herein, means that said substance cannot be detected in the composition by methods known to those skilled in the art at the time of the filing of this application. Desloratadine (8-chloro-6, ll-dihydro-11-4 (4- piperidinylidene)-5H- benzo [5,6] cyclohepta [1,2-b] pyridine) has the structure

The preparation of desloratadine generally is known in the art. For example, the processes for preparation of desloratadine are disclosed in U.S. Patent Nos. 4,659,716 and 4,282,233, both of which are incorporated by reference herein in their entirety and for the stated purpose of showing the preparations. The process disclosed in the '716 patent involves esterification of 8-chloro-6,l 1-dihydro-l l-(4-piperidylidene)-5H- benzo[5,6]cyclohepta[l,2-b] pyridine, which is then hydrolyzed and de-carboxylized by 70% ethanolic solution of KOH at reflux temperature. It is known that different solid forms of the same drug may have substantial differences in certain pharmaceutically important properties such as dissolution characteristics and bioavailability, as well as stability of the drug. Furthermore, different physical forms may have different particle size, hardness and glass transition temperatures. Amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random. Amorphous solids do not give a definitive x-ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide rapid bioavailability. Furthermore, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in solid dosage form manufacture process such as compressibility, economically or environmentally suitable solvents or process, or higher purity or yield of the desired product. According to one aspect of the invention, there is provided desloratadine in an amorphous form. An XRD spectrum of a sample of desloratadine obtained by the inventors is shown in Fig. 1. As seen therefrom, the XRD pattern is highly characteristic of an amorphous solid. The X-ray diffractogram was measured on Bruker Axe, DS Advance Powder X-ray Diffractometer with Cu K alpha- 1 Radiation source. It has been found that obtaining an amorphous solid of desloratadine is not a simple matter. Thus, a particular process for preparation of the amorphous form of desloratadme is also provided and includes: a) providing a solution of desloratidine in an organic solvent; and b) removing the solvent by spray drying or agitated thin film drying to obtain a solid residue which is the amorphous form of desloratidine. The step of providing a solution of desloratadine may include dissolving any form of desloratadine in a suitable organic solvent or obtaining an existing solution from a previous processing step. Examples of solvents that can be used for the process of preparing an amorphous form of desloratadine include alcoholic solvents having from 1 to 5 carbon atoms, and aromatic and non-aromatic carbocycles. The preferred solvents are methanol, toluene, and cyclohexane. To dissolve desloratadine in the solvent, the dissolution temperature may range from about 10 to about 45 °C; the preferred temperature is from about 20 to about 40 °C. The concentration of solution of desloratadine before solvent removal may range from about 1% to about 20% by w/v, preferably from about 5% to about 12%, more preferably, from about 8% to about 11% by w/v. Removal of the solvent is accomplished by using spray drying or agitated thin film evaporation. One of the preferred methodologies involves vertical agitated thin-film drying (or evaporation). Agitated thin film evaporation technology involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled condition. In vertical agitated thin-film drying (or evaporation) (ATFD-V), the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside- flowing solution while the heating jacket heats it. Another preferred method is spray-drying, in which a solution of desloratadine is sprayed into the spray drier at the flow rate ranging from 10 to 300 ml/hr, preferably flow rate is 40 to 210 ml/hr. The air inlet temperature to the spray drier used may range from 70 °C to 150 °C, preferably from 85 °C to 110 °C and the outlet air temperature used may range from 30 °C to 80 °C. The solid residue obtained after the solvent removal is isolated and, if desired, may be dried further using conventional methods. The advantages of the process include simplicity, eco-friendliness and suitability for commercial use. The amorphous form of desloratadine shown in Fig. 1 is produced by the described process. The invention also relates to a composition of solid desloratadine wherein at least 80% of the total weight of desloratadine is in the amorphous form. In a preferred form of this composition, the solid desloratadine is suitable for use as a bulk active ingredient in formulating pharmaceutical products. The remainder of the solid desloratadine in the composition, i.e., 20% or less of the total weight of desloratadine, may be other forms of desloratadine, e.g., crystalline forms. In an embodiment of the invention, the composition may include at least 95% of the amorphous form of desloratadine with respect to total weight of the solid desloratadine in the composition. In another embodiment of the invention, the composition may include at least 99% of the amorphous form of i desloratadine with respect to total weight of the solid desloratadine in the composition. In yet another embodiment of the invention, the composition is substantially free of any forms of desloratadine other than its amorphous form. A crystalline form of desloratadine is disclosed in U.S. Patent No. 4,659,716, which is incorporated by reference above. Amorphous desloratadine may be differentiated from other solid forms of desloratadine by using X-ray powder diffraction (XPD). The XPD pattern of amorphous desloratadine, as illustrated in Fig. 1, lacks discernible acute peaks. Thus, amorphous desloratadine according to the present invention is characterized in providing an X-ray powder diffraction pattern containing one or more broad diffuse halos having very low counts in contrast to the sharp diffraction peaks characteristic of crystalline materials. Of course it will be appreciated that a mixture of detectable amounts of crystalline and amorphous desloratadine will exhibit both the characteristic sharp peaks and the diffuse halo(s) on XPD. This will be evident by an increase in the baseline and also a reduction in crystalline peak intensities. X-ray diffraction also provides a convenient and practical means for quantitative determination of the relative amounts of crystalline and/or amorphous forms in a solid mixture. X-ray diffraction is adaptable to quantitative applications because the intensities of the diffraction peaks of a given compound in a mixture are proportional to the fraction of the corresponding powder in the mixture. The percent composition of amorphous or crystalline forms of desloratadine in an unknown composition can be determined. Preferably, the measurements are made on solid powder desloratadme. The X-ray powder diffraction patterns of an unknown composition can be compared to known quantitative standards containing pure crystalline forms of desloratadine to identify the percent ratio of a particular crystalline form. This is done by comparing the relative intensities of the peaks from the diffraction pattern of the unknown solid powder composition with a calibration curve derived from the X-ray diffraction patterns of pure known samples. The curve can be calibrated based on the X-ray powder diffraction pattern for the strongest peak from a pure sample of crystalline forms of desloratadine. The calibration curve may be created in a manner known to those of skill in the art. For example, five or more artificial mixtures of crystalline forms of desloratadine, at different amounts, maybe prepared, hi a non-limiting example, such mixtures may contain, 2%, 5%, 7%, 8%, and 10%) of desloratadine for each crystalline form. Then, X-ray diffraction patterns are obtained for each artificial mixture using standard X-ray diffraction techniques. Slight variations in peak positions, if any, may be accounted for by adjusting the location of the peak to be measured. The intensities of the selected characteristic peak(s) for each of the artificial mixtures are then plotted against the known weight percentages of the crystalline form. The resulting plot is a calibration curve that allows determination of the amount of the crystalline forms of desloratadine in an unknown sample. For the unknown mixture of crystalline and amorphous forms of desloratadine, the intensities of the selected characteristic peak(s) in the mixture, relative to an intensity of this peak in a calibration mixture, may be used to determine the percentage of the given crystalline form in the composition, with the remainder determined to be the amorphous material. In addition to X-ray powder diffraction, amorphous desloratadine, or the presence of some amorphous desloratadine, can be distinguished from crystalline desloratadine, using Raman spectroscopy, solution calorimetry, differential scanning calorimetry, solid state nuclear magnetic resonance spectra (ssNMR) or infra-red spectroscopy. Each of these techniques is well established in the art. Amorphous desloratadine can also be identified based on the morphology of the particles seen under an electron microscope. Furthermore, amorphous desloratadine is likely to be much more soluble than crystalline desloratadine because the former is lack of lattice energy, providing another means of discriminating between the crystalline and amorphous desloratadine forms, or detecting an amount of amorphous form within a desloratadine preparation. As noted above, numerous techniques can be employed to detect a particular form of a compound within a mixture. The limits of detection of a particular form in admixture with another form, i.e. crystalline in amorphous or vice versa, are as follows: by XPD it is reported to be approximately 5% according to Hancock and Zografi (J. Pharm. Sci., 86:1- 12, 1997) and approximately 2.0% according to Surana and Suryanarayanan (Powder Diffraction, 15:2-6, 2000). The limit of detection by solution calorimetry is reported to be approximately 1% according Hogan and Buckton (International Journal of Pharmaceutics, 207:57-64, 2000). The limit of detection by solid state NMR is reported to be approximately 5-10% according to Saindonet al., (Pharmaceutical Research, 10:197-203, 1993). The limit of detection by near infra red spectroscopy is reported to be approximately 2-5% according to Blanco and Villar (Analyst, 125:2311-2314, 2000). The limit of detection by Modulated Differential Scanning Calorimetry (MDSC) is reported to be approximately 6% according to Saklatvala et al., (International Journal of Pharmaceutics, 192: 55-62, 1999). The limit of detection by FTRaman spectroscopy is reported to be approximately 2% according to Taylor and Zografi (Pharm. Res. 15:755- 761, 1998). All of the above detection limits are general guidelines and apply to crystalline forms. As noted above, the amount of the amorphous form can be determined by determining the total amount of the sample and the percentage of the crystalline fraction. In another embodiment, the invention provides pharmaceutical compositions containing the amorphous form of desloratadine, which can be formulated with a one or more pharmaceutically acceptable carriers, also known as excipients, which ordinarily lack pharmaceutical activity, but have various useful properties which may, for example, enhance the stability, sterility, bioavailability, and ease of formulation of a pharmaceutical composition. These carriers are pharmaceutically acceptable, meaning that they are not harmful to humans or animals when taken appropriately and are compatible with the other ingredients in a given formulation. The carriers may be solid, semi-solid, or liquid, and may be formulated with the compound in bulk. The resulting mixture may be manufactured in the form of a unit-dose formulation (i.e., a physically discrete unit containing a specific amount of active ingredient) such as a tablet or capsule. Generally, the pharmaceutical compositions of the invention may be prepared by uniformly admixing the active ingredient with liquid or solid carriers and then shaping the product into the desired form. The pharmaceutical compositions may be in the form of suspensions, solutions, elixirs, aerosols, or solid dosage forms. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. A tablet may be prepared by direct compression, wet granulation, or molding, of the active ingredient(s) with a carrier and other excipients in a manner known to those skilled in the art. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets may be made on a suitable machine. A mixture of the powdered compound moistened with an inert liquid diluent is suitable in the case of oral solid dosage forms (e.g., powders, capsules, and tablets). If desired, tablets may be coated by standard techniques. The compounds of this invention may be formulated into typical disintegrating tablets, or into controlled or extended release dosage forms. The amount of active ingredient included in a unit dosage form depends on the type of formulation that is formulated. A pharmaceutical composition of the invention will generally include about 0.1 % by weight to about 99% by weight of active ingredient, preferably about 1% by weight to 50% by weight. Suitable carriers include but are not limited to fillers, binders, lubricants, inert diluents, surface active/dispersing agents, flavorants, antioxidants, bulking and granulating agents, adsorbants, preservatives, emulsifiers, suspending and wetting agents, glidants, I disintegrants, buffers and pH-adjusting agents, and colorants. Examples of carriers include celluloses, modified celluloses, cyclodextrins, starches, oils, polyols, sugar alcohols and sugars, and others. For liquid formulations sugar, sugar alcohols, ethanol, water, glycerol, and polyalkylene glycols are particularly suitable, and may also be used in solid formulations. Cyclodextrins may be particularly useful for increasing bioavailability. Formulations for oral administration may optionally include enteric coatings known in the art to prevent degradation of the formulation in the stomach and provide release of the drug in the small intestine. One example of pharmaceutical tablet of the amorphous desloratadine may include, as inactive ingredients, hypromellose 2910, i lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol

3000, sodium starch glycolate, titanium dioxide, triacetin and 1 or more of synthetic red and yellow iron oxides and talc. The invention is further described by reference to the following examples which set forth in detail the preparation of compounds and compositions of the present invention, as well as their utility. It will be apparent to those skilled in the art, that many modifications, both to materials, and methods, may be practiced without departing from the purpose and interest of this invention. The examples that follow are not intended to limit the scope of the invention as described hereinabove or as claimed below. EXAMPLE 1. 9.4 grams of desloratadine were dissolved in 100 ml methanol with stirring at about 25-35 °C for 5-10 minutes. The resulting solution was filtered through hyflowbed. The filtered solution was spray-dried to remove the solvent under the following condition: flow rate 58-195 ml/hr, air inlet temperature between 90-100 °C and air outlet temperature between 40-46 °C, hot air flow rate 12.5-17.5 m³/hr and N₂ pressure for atomizer 1.8-2.0 kg/cm² to afford amorphous desloratadine.

EXAMPLE 2. 15 grams of desloratadine were dissolved in 100 ml methanol under stirring at about 25-35 °C for 5-10 minutes. The resulting solution was filtered through hyflowbed. The filtered solution was spray-dried to remove the solvent under the following condition: flow rate 58-195 ml/hr, air inlet temperature about 105 °C and air outlet temperature about 70 °C, hot air flow rate 12.5-17.5 m /hr and N₂ pressure for atomizer 1.8-2.0 kg/cm to afford amorphous desloratadine.

EXAMPLE 3. Soluble granules containing an amorphous desloratadine: Soluble granules containing an amorphous desloratadine may have the following content:

Aroma 20

EXAMPLE 4. Dispersible tablet containing an amoφhous desloratadine. Dispersible tablet containing an amoφhous Desloratadine may have the following content:

Claims

We claim:

1. A compound which is desloratadine in an amoφhous form.

2. The compound of claim 1 having substantially the same X-ray diffraction pattern as shown in Figure 1.

3. A composition comprising desloratadine as a solid, wherein at least 80 % by weight of said solid desloratadine is in an amoφhous form.

4. The composition of claim 3, wherein at least 95 % of said solid desloratadine is in said amoφhous form.

5. The composition of claim 3, wherein at least 99 % of said solid desloratadine is in said amoφhous form.

6. The composition of claim 3, which is substantially free of crystalline forms of desloratadine.

7. A pharmaceutical composition comprising an amoφhous form of desloratadine and one or more pharmaceutically acceptable carriers.

8. The pharmaceutical composition of claim 7, which is a solid dosage form for oral administration.

9. A process for making an amoφhous form of desloratidine, said process comprising: a) providing a solution of desloratidine in an organic solvent; b) removing said solvent by spray drying or agitated thin film drying to obtain a solid residue which is said amoφhous form of desloratidine.

10. The process of claim 9, wherein said organic solvent is a C1-C5 alcohol.

11. The process of claim 10, wherein said C 1 -C5 alcohol is methanol.