FIELD OF THE INVENTION
The present invention relates to novel crystalline forms of cinacalcet hydrochloride of formula I
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Formula I
BACKGROUND OF THE INVENTION
Cinacalcet hydrochloride of formula I, is a known calcimimetic agent and is
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Formula I
chemically known as A^-(l-naphthalen-l-ylethyl)-3-[3-(trifluoromethyl)phenyl]-propan-1-amine hydrochloride. It lowers the threshold for CaSR activation by extracellular calcium ions and diminishes parathyroid hormone (PTH) release from parathyroid cells. By targeting the molecular mechanism that modulates PTH secretion on a minute-to-minute basis, calcimimetic compounds offer a novel approach to managing excess PTH secretion in several clinical disorders.
t inacalcct hydrochloride was first disclosed in US Patent 6,211,244. Although the patent is completely silent about the specific process for the preparation of cinacalcet,
general scheme for the preparation of similar products includes the reductive amination of a commercially available aldehyde or ketone with a primary amine in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride and titanium isopropoxide. For cinacalcet, only mass spectral data is provided, otherwise the patent is unable to touch upon the physieochemical characterization data of cinacalcet and its salts thereof. The patent does not disclose any possibility or observation thai the compound exists in different polymorphic forms.
In recent years, solid-state properties of drugs received a great focus in the pharmaceutical industry, as a major contributing factor to both bio-availability and formulation characteristics. The ability of some substances to exist in more than one crystalline form, called polymorphism, was accredited as one of the most important solid-state property of drugs. While polymorphs have the same chemical composition, they differ in the packing and geometrical arrangement thereof, and exhibit different physical properties such as melting point, shape, color, X-ray diffraction pattern, infrared absorption, and solid state NMR spectrum, density, hardness, deformability, stability, dissolution, and the like. Depending on their temperature-stability relationship, one crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermo gravimetric analysis (TGA), and differential scanning calorimetry (DSC), which have been used to distinguish polymorphic forms.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly, so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical
compounds can and reportedly do have different aqueous solubilities or different dissolution rates (release profile) in-vivo. Therefore the discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. However, any failure to predict the bioavailability of a drug may result in administration of either too small or too large undesired doses, which may be dangerous to patients and in extreme cases, lethal.
Other examples are known, where different crystalline forms behave differently during physical processing like milling and pressing. Many process-induced solid-solid transitions of substances are known, that lead to either other crystalline forms or an amorphous form of the substance. The solid-state experts are in a constant search for crystalline forms that can withstand physical stress and still retain their original properties.
Consequently, there is an ongoing search for new polymorphic forms of drugs, which may provide for improved performance thereof.
A single molecule, such as cinacalcet hydrochloride, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties, such as melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
Thus, there is a widely recognized need for, and it would be highly advantageous to have new and distinct crystalline forms of cinacalcet hydrochloride.
The present invention thus provides novel crystalline forms of cinacalcet hydrochloride with consistent grade nature that can be reproduciblv manufactured in order lu snlisly regulalon agencies.
SUMMARY OF THE INVENTION
The present invention relates to novel polymorphic forms of cinacalcet hydrochloride of formula I, (Figure Remove)
Formula-I
thai may exhibit suitable phvsieoehemicul and highly desirable properties for drug development purpose, are non-hygroscopic and which may maintain compound stability during storage, and methods for preparing such crystalline forms.
One aspect of the invention encompasses a crystalline anhydrous cinacalcet hydrochloride Form A characterized by X-ray powder diffraction pattern as depicted in Fig. 1 .
Another aspect of the invention encompasses a cinacalcet hydrochloride Form B characterized by X-ray powder diffraction pattern as depicted in Fig. 2.
Another aspect of the invention encompasses methods for preparing crystalline anhydrous cinacalcet hydrochloride form A and form B and interconverting the two forms.

BRIEF DESCRIPTION OF THE FIGURES
Figure 1 illustrates the powder X-ray diffraction pattern for Form A. Figure 2 illustrates the powder X-ray diffraction pattern for Form B. DETAILED DESCRIPTION OF THE INVENTION
Present invention provides novel polymorphic forms of cinacalcet hydrochloride of formula I,

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. HCI

Formula-I
The cinacalcet hydrochloride crystalline forms encompassed by the invention may be characterized by at least one of Karl Fisher or TGA, X-Ray power diffraction (XRD), or differential scan calorimetry (DSC).
One embodiment of the invention encompasses a crystalline anhydrous cinacalcet hydrochloride form, herein defined as Form A, having about less than 0.7% moisture by weight as measured by Karl Fisher or TGA. Form A may be characterized by X-ray powder diffraction pattern as shown in Fig.l. Form A may furthermore be characterized by a melting point range of about 175°C to about 177°C as measured by differential scanning calorimetry (DSC).
As used herein, the term "anhydrous" refers to cinacalcet hydrochloride crystal form with less than about 0.7% moisture, preferably less than 0.5% moisture.

Another embodiment of the invention encompasses a cinacalcet hydrochloride Form B characterized by X-ray powder diffraction pattern as depicted in Fig.2.
However, it is to be understood that the X-ray diffraction (XRD) patterns reported as absolute positions in the figures are intended to include the normal amount of positional variation due to experimental error, operator error, differences in equipment, technique, packing, contamination, and the like. However, based on this technique, particularly in conjugation with other techniques like infra red spectra and endotherms, one of ordinary skill in this art will be able to identify whether or not a compound is cinacalcet hydrochloride in accordance with the present invention. It should be kept in mind that slight variations in the observed 20 angles values are expected, based on the specific diffractometer employed, the analyst, and the sample preparation techniques. More variation is expected for the relative peaks intensities, which is largely affected by particle size of the sample. Thus, identification of exact crystalline form of a compound should be based primarily on observed 28 angles with lesser importance attributed to relative peak intensities.
Another embodiment of the invention encompasses methods of preparing crystalline anhydrous cinacalcet hydrochloride Form A by recrystallizing cinacalcet hydrochloride from a suitable solvent arid isolating the highly pure Form A. Cinacalcet hydrochloride used can be prepared by the prior art processes or it can be form B or any other form as to be claimed herein.
In more detailed embodiment, the invention encompasses methods for preparing crystalline anhydrous cinacalcet hydrochloride form A comprising dissolving cinacalcet hydrochloride in a solvent to form a mixture, heating the mixture from about 60°C to about 140°C, cooling the mixture to form a cinacalcet hydrochloride precipitate, and collecting the precipitate. The solvent used can be selected from, but not limited to protic or aprotic solvents preferably alcohols, kelones, ethers,

halogenated solvent, hydrocarbons, acid derivatives including anhydrides, esters, halides, amides, nitriles, the like and mixtures thereof.
Another embodiment of the invention encompasses a method of preparing crystalline anhydrous cinacalcet hydrochloride form A comprising dissolving cinacalcet hydrochloride in a solvent to form a mixture, heating the mixture to below solvent's boiling point until cinacalcet hydrochloride dissolves, cooling the mixture to about room temperature to about 4°C, adding an anti-solvent to precipitate cinacalcet hydrochloride form A, and collecting the precipitate.
The anti-solvent can be selected from, but not limited to water, protic or aprotic solvents preferably alcohols, ketones, ethers, halogenated solvent, hydrocarbons, acid derivatives including anhydrides, esters, halides, amides, nitriles, the like and mixtures thereof. As used herein, the term "antisolvent" refers to a poor solvent for the substance in question which when added to a solution of the substance, causes the substance to precipitate.
According to another embodiment of the present invention cinacalcet hydrochloride Form B can be prepared directly from cinacalcet, prepared by the methods reported in prior art or as reported in our co-pending application no.2104/DEL/2006 by reacting it with hydrochloric acid in the presence of water.
According to yet another embodiment of the present invention cinacalcet hydrochloride Form A can be prepared directly from cinacalcet by reacting it with hydrochloric acid in the presence of organic solvent.
Another embodiment of the invention encompasses methods of preparing anhydrous form A comprising subjecting the corresponding hydrated form B, to a water minimizing recrystallization or by subjecting the hydrated form B to an azeotropic distillation. As used herein, the term "water-minimizing recrystallization" refers to a

recrystallization wherein the ratio of anhydrous solvent to substrate hydrate is such that the percentage of water present is minimized, thereby inducing precipitation of the anhydrous form of the substrate.
As used herein, the term "azeotropic distillation" refers to a type of distillation in which a substance is added to the mixture to be separated in order to form an azeotropic mixture with one or more of the constituents of the original mixture. The azeotrope or azeotropes thus formed will have boiling points different from the boiling points of the original mixture. As used herein, the term "azeotropic distillation" also refers to co-distillation.
In addition, form B may be prepared from the corresponding anhydrous form A, by subjecting the corresponding anhydrous form to an aqueous recrystallization. As used herein, the term "aqueous recrystallization" refers to those processes wherein either 1) a solid material is dissolved in a volume of water or a water/organic solvent mixture sufficient to cause dissolution and the solid material recovered by evaporation of the solvent; 2) a solid material is treated with a minimal amount of water or a water/organic solvent mixture which is not sufficient to cause dissolution, heated to obtain dissolution and cooled to induce crystallization or 3) a solid material is dissolved in a volume of water or a water/organic solvent mixture sufficient to cause dissolution and then the solvent is partially evaporated to form a saturated solution which induces crystallization.
Although, the following examples illustrate the present invention in more detail, but should not be construed as limiting the scope of the invention.
Example 1
Cinacalcet hydrochloride (12 g) in acetonitrile was heated at 80°C for a period of about 10 minutes. 1'he solution was stirred at room temperature for about 2 hours and

the solid was filtered under reduced pressure to give cinacalcet hydrochloride form A having XRD patterns as shown in Fig. 1.
Example 2
Cinacalcet hydrochloride (10 g) was dissolved in dioxane (30 ml) by warming to 40°C and cooled to room temperature followed by the addition of n-hexane (30 ml). The solution stirred for about 1 hour and filtered to give cinacalcet hydrochloride form A.
Example 3
Cinacalcet (10 g) was treated with dilute hydrochloric acid (40 ml, 6N) and stirred for 1 hour at ambient temperature. After completion of reaction, the precipitated product was filtered, washed with water and dried to give cinacalcet hydrochloride form B.
It is against this and other backgrounds, which shall be set in a detailed manner in complete specifications, which will be filed in due course, the present invention is brought out. The present invention provides new forms of cinacalcet hydrochloride and processes for the preparation thereof.