MX2007000925A - Purification of cinacalcet - Google Patents

Abstract

Isolated cinacalcet carbamate, processes for the preparation thereof, and processes for the use of cinacalcet carbamate as a reference marker and standard are provided. Also provided are cinacalcet salts substantially free of cinacalcet carbamate, and processes for the preparation thereof.

Description

PURIFICATION OF CINACALCET Field of the invention The present invention relates to the impurity of cinacalcet, cinacalcet carbamate.

BACKGROUND OF THE INVENTION (R) -cc-methyl-N- [3- [3- (trifluoromethyl) phenyl] propyl] -1-naphthalenemethane amine (hereinafter "Cinacalcet" or "CNC") has the CAS number of 226256-56-0 , a formula of C22H22F3N, and the following structure: Cinacalcet is the free base form of cinacalcet hydrochloride (n the present "CNC-HCl") that has the CAS number of 364782-34-3 and the following structure: CNC-HC1 is marketed as SENSIPAR®, and was the first drug in the class of compounds called calcimimetics approved by the United States Food and Drug Administration (FDA). Calcimimetics are a class of orally active small molecules that decrease the secretion of parathyroid hormone ("PTH") by activating calcium receptors. The secretion of PTH is normally regulated by the calcium detector receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of the parathyroid hormone, and decreases the levels of the parathyroid hormone within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the excessive secretion of PTH that arises when the calcium receptors of the parathyroid glands can not respond correctly to calcium from the bloodstream. Elevated levels of PTH, an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk of cardiovascular death. The CNC-HC1 as calcimimetic is approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with CNC-HC1 decreases serum PTH levels as well as the calcium ion / phosphorus product, a measure of the amount of calcium and phosphorus in the blood.

Active inorganic ion receptor molecules, especially active calcium receptor molecules, such as those having the general structure of cxnacalcet, are disclosed in U.S. Patent No. 6,011,068. U.S. Patent No. 6,211,244 discloses calcium receptor active compounds related to cinacalcet and methods of making those compounds. Cinacalcet and its enantiomer can be produced by different methods, using the processes disclosed in U.S. Patent No. 6,211,244; DRUGS OF THE FUTURE, 27 (9), 831 (2002); U.S. Patent No. 5,648,541; 4,966,988; and Tetrahedron Letters (2004) 45: 8355, footnote 12.

Like any synthetic compound, cinacalcet salt may contain process impurities, which include untreated starting materials, chemical derivatives of impurities contained in the starting materials, synthetic by-products, and degradation products. It is known in the art that impurities that are present in an active pharmaceutical ingredient ("API") can arise from degradation of the API, for example, during storage or during the manufacturing process, which includes chemical synthesis.

In addition to the stability, which is a factor in the duration of the API, the purity of the API produced in the commercial manufacturing process is a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes should be limited to very small amounts, and preferably are substantially absent. For example, the Q7A guide of the International Conference on Harmonization of the Technical Requirements for the Registration of Pharmaceutical Products for Human Use ("ICH") for API manufacturers requires that process impurities remain below. established limits. The guide specifies the quality of the raw materials, and the parameters of the process, such as temperature, pressure, time, and stoichiometric relationships, which include the steps of purification, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

The product mixture of a chemical reaction is rarely a single compound with a purity sufficient to meet pharmaceutical standards. The collateral products and the by-products of the reaction and the auxiliary reagents used in the reaction, in most cases, are present in the product mixture. At certain stages during the processing of an API, such as cinacalcet salt, its purity should be analyzed, usually by high performance liquid chromatography ("HPLC") or thin layer chromatography ("TLC"), to determine if It is suitable for continuous processing and, finally, for use in a pharmaceutical product. The API does not need to be absolutely pure, since absolute purity is a theoretical ideal that is generally unattainable. In contrast, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and therefore as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.

In general, collateral products, by-products and auxiliary reagents (collectively "impurities") are identified spectroscopically and / or with another physical method, and are then associated with a peak position, such as that of a chromatogram or a spot on a TLC plate. See Strobel,?.?;; Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3rd ed. (Wiley &Sons: New York 1989), p. 953 ("Strobel"). Then, the impurity can be identified, for example, by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between the injection of the sample on the column and the elution of the particular component through the detector. The relative position in the chromatogram is called the "retention time".

The retention time can vary an average value based on the condition of the instrumentation, as well as many other factors. To mitigate the effects of these variations by accurately identifying an impurity, practitioners use the relative retention time ("RRT") to identify impurities. See Strobel p. 922. The RRT of an impurity is the retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added or is present in the mixture in an amount large enough to be detectable and sufficiently low so as not to saturate the column, and to use the compound as the reference marker for the determination of the RRT.

Those skilled in the art of drug manufacturing, research and development understand that a compound in a relatively pure state can be used as a "reference standard". A reference standard is similar to a reference marker, but can be used for quantitative analysis, rather than simply qualitative analysis, as with a reference standard. A reference standard is an "external standard" when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. See Strobel p. 924; Snyder, L.R .; Kirkland, J.J. Introduction to Modern Liquid Chromatography, 2d ed. (John Wiley &Sons: New York 1979), p. 549 ("Snyder"). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response. See U.S. Patent No. 6,333,198, incorporated herein by reference.

The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor" has been predetermined, which compensates for differences in detector sensitivity to the two compounds. See Strobel p. 894. For this purpose, the reference standard is added directly to the mixture, and it is called the "internal standard". See Strobel p. 825; Snyder p. 552 The reference standard can serve as an internal standard when, without the deliberate addition of the reference standard, an unknown mixture contains a detectable amount of the standard reference compound using the so-called "standard aggregate" techniques.

In the "standard aggregate technique", at least two samples are prepared by adding known and different quantities of the internal standard. See Strobel, pp. 391-393; Snyder pp. 5171-572. The proportion of the detector response to the reference standard present in the mixture without the aggregate can be determined by plotting the detector response against the amount of the reference standard added to each of the samples, and extrapolating the graph to the zero concentration of the standard reference. See, for example, Strobel, Fig. 11.4, p. 392. The response of a detector on HPLC (for example, ultraviolet ("UV") detectors or refractive index detectors) can and is generally different for each compound eluting from the HPLC column. The response factors, as is known, explain this difference in the response signal of the detector to different compounds eluting from the column.

As art experts know, the management of impurities in the process is greatly improved by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product. i Cinacalcet impurities that include, but are not limited to, the initial materials that did not react, the byproducts of the reaction, the products of the side reactions, or the degradation products are undesirable and, in extreme cases, may still be harmful to a patient who is treated with a dosage form that contains the API. Therefore, there is a need in the art for a method to determine the level of impurities in cinacalcet samples and to remove impurities. 0 Extract of the invention In one embodiment, the present invention provides an impurity of cinacalcet, cinacalcet carbamate, 3- (3- (trifluoromethyl) phenyl) propyl (R) -1 (naphthalene-1-yl) ethyl. carbamate CNC-carbamate "), which has the following structure: In another embodiment, the present invention provides the salt of 0 cinacalcet having cinacalcet carbamate in an amount of 0.03 percent area at 0.15 percent area as measured by HPLC.

In another embodiment, the present invention provides a method for preparing a cinacalcet salt, cinacalcet hydrochloride, containing cinacalcet carbamate in an amount of 0.03 percent area at 0.15 percent area measured by a chromatographic method , preferably HPLC or TLC, comprising the steps of (a) dissolving cinacalcet base, containing cinacalcet carbamate in an amount of 3 percent area at 6 percent area determined by a chromatographic method, in acetone, an ether C2-8 linear or branched chain, mixtures thereof or with water; (b) adding hydrogen chloride to obtain a precipitate; and (c) recovering the cinacalcet hydrochloride.

In another embodiment, the present invention provides a process for using cinacalcet carbamate as a reference marker or a reference standard. The cinacalcet carbamate can be used as a reference marker to determine the presence of cinacalcet carbamate in a sample of cinacalcet hydrochloride. In addition, cinacalcet carbamate can be used as a reference standard to determine the relative amount of CNC carbamate.

) In another embodiment, the present invention provides a process for preparing a cinacalcet salt containing CNC carbamate comprising the steps of (a) obtaining one or more samples from one or more other batches of cinacalcet base; (b) measuring the CNC carbamate level in each of the samples obtained in step (a); (c) selecting the batch of the cinacalcet base based on the sample comprising a CNC carbamate level in an amount of 3 percent area to 6 percent area determined by 10 HPLC, based on the measurement or measurements made in step (b); and (d) using the batch selected in step (c) to prepare the cinacalcet salt.

When the cinacalcet base sample of step (a) contains more than 3 percent area by CNC carbamate HPLC, according to the measurement of step (b), the sample can be purified before performing the step ( c) In another embodiment, the present invention provides a pharmaceutical composition comprising a cinacalcet base or salts thereof having 0.03 percent area to 0.15 percent area determined by HPLC of cinacalcet carbamate and therefore minus one pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a process for preparing a pharmaceutical composition comprising combining the cinacalcet salt having from 0.03 percent area to 0.15 percent area determined by HPLC or CNC carbamate with at minus one pharmaceutically acceptable excipient.

Brief Description of the Drawings Figure 1 illustrates a typical HPLC chromatogram of a Cinacalcet HC1 sample substantially free of carbamate.

Detailed description of the invention As used herein, the term "room temperature" means a temperature of 18 ° C to 25 ° C, preferably 20 ° C to 22 ° C.

As used herein, "CNC" refers to cinacalcet.

As used herein, "cinacalcet salt" can be any salt having a pKa lower than the pKa of the cinacalcet base. Suitable acids that can be used to form these salts can include HC1, HBr, H2SO4, oxalic acid, tartaric acid, succinic acid and citric acid. More preferably, the cinacalcet salt is HC1 from cinacalcet.

As used herein, the term "reference marker" is used in the qualitative analysis to identify components of a mixture based on their position, for example, in a chromatogram or on a Thin Layer Chromatography (TLC) plate. See Strobel pp. 921, 922, 953. For this purpose, the compound does not necessarily have to be added to the mixture if it is present in the mixture, a "reference marker" is used only for the qualitative analysis, while a reference standard can be used for quantitative or qualitative analysis, or both. Therefore, a reference marker is a subgroup of a reference standard, and is included within the definition of a reference standard.

As used herein, the term "reference standard" refers to a compound that can be used both for quantitative analyzes and for qualitative analyzes of a pharmaceutical ingredient. For example, the HPLC retention time of the compound makes it possible to determine a relative retention time, making possible the qualitative analysis. The concentration of the compound in the solution before injection into the HPLC column allows the areas below the peaks to be compared. HPLC, making quantitative analysis possible.

The reference standards are described in general terms above. However, as will be understood by those skilled in the art, a detector response may be, for example, peak heights or integrated peak areas of a chromatogram obtained, for example, by detecting ultraviolet radiation or refractory index, from the eluent of an HPLC system or, for example, the detection of flame ionization (WFID) or the detection of thermal conductivity, from the eluent of a gas chromatograph, or other detector response, for example The absorbance of ultraviolet radiation points on a fluorescent TLC plate The position of the reference standard can be used to calculate the relative retention time for the cinacalcet salts and the impurities of the cinacalcet salts.

In one embodiment, the present invention provides an impurity of cinacalcet, cinacalcet carbamate ("CNC carbamate"), having a molecular weight of 401 g / mol as measured by mass spectroscopy ("MS") analysis and having the formula: The CNC caxbamate of the present invention can be characterized by data selected from a spectrum of 1H NMR having chemical shifts of hydrogen at 1.67, 1.95, 2.75, 4.12, 5.11, 5.68 and 7.35-8.15 ppm; a 15CNMR spectrum having chemical carbon shifts at 21.59, 30.42, 31.96, 46.58, 63.99, 122.16-142.23 and 155.63 ppm; and by a retention time ("RT") of 22-23 minutes in an HPLC analysis or a relative retention time ("RRT") of 2.6, such as that described hereinbelow.

The CNC carbamate can be formed in the synthesis of the cinacalcet base for example, by the processes disclosed in the provisional applications of US Pat. Nos. 60 / 681.1671 and 60 / 702.1918. This process comprises combining mesylate (FTOMs) of formula II: with the (R) -Natylethyl amine ("R-NEA") of the formula III: (neither) in the presence of a base with a solvent at elevated temperature, to give the CNC base of the formula (IV): The CNC base can react again with an acid to form the cinacalcet salt. The selected cinacalcet salt can be any salt having a pKa less than the pKa of the cinacalcet base. Suitable acids that can be used to form these salts can be HC1, HBr, H2S0, oxalic acid, tartaric acid, succinic acid and citric acid. More preferably, the cinacalcet salt is HC1 from cinacalcet.

The CNC carbamate can be formed in different amounts while using different solvents during the synthesis of 1 cinacalcet base as shown in Table 1.

Table 1 In another embodiment of the present invention, the isolated CNC carbamate is provided. The CNC carbamate formed during the synthesis of the cinacalcet base can be isolated by subjecting the cinacalcet base containing the CNC carbamate to column chromatography. Column chromatography involves using a silica gel, as a stationary phase, and a gradient of eluents that remove the CNC carbamate from the column on which it is adsorbed, starting from 100 percent n-hexane to 20 percent ethyl acetate / 80 percent n-hexane over a period of 10 minutes.

In the column chromatography described above, the stationary phase, a solid adsorbent, is placed on a vertical glass column (usually) and the mobile phase, a liquid is added upstream and flows down through the column (by gravity) or by external pressure). Column chromatography is generally used as a purification technique; isolates the desired compounds from a mixture. The mixture to be analyzed by column chromatography is applied on top of the column. The liquid solvent (the eluent) is passed through the column by gravity or by applying air pressure. The equilibrium is established between the solute adsorbed on the adsorbent and the mobile phase that flows down through the column. As the different compounds of the mixture have different interactions with the stationary and mobile phases, they are transported together with the mobile phase to varying levels and a separation is achieved. Individual components or eluents are collected as solvent droplets from the bottom of the column.

In another embodiment, the present invention provides a cinacalcet salt having CNC carbamate in a significant amount of 0.03 percent area to 0.15 area percent as determined by a chromatographic method. Preferably the cinacalcet salt is HC1 from cinacalcet.

In yet another embodiment, the present invention provides a method for preparing cinacalcet HCl containing cinacalcet carbamate in an amount of 0.03 percent at 0.15 percent area measured by a chromatographic method, preferably HPLC or TLC comprising the steps of (a) dissolving the cinacalcet base, which contains cinacalcet carbamate in an amount of 3 percent area at 6 percent area that is determined by a chromatographic method, in acetone, a linear C2-8 ether or reamidated chain, mixtures thereof or with water; (b) mixing hydrogen chloride to obtain a precipitate; and (c) recovering the cinacalcet hydrochloride.

The preferred solvent is acetone or methyl tere-butyl ether ("MTBE"). The added HCl may be in the form of a gas or an aqueous solution. Preferably, the HCl is added as a gas. More preferably, the gaseous HCl is added in an amount of 1 to 2 equivalents relative to the base of cinacalcet. When the HCl is aqueous, it is preferably added at a concentration of 1 N in an amount of 1.5 equivalents. Preferably, the reaction is at room temperature. The obtained cinacalcet HCl may be in the crystalline form.

In another aspect of the present invention, the use of CNC carbamate is provided as a reference marker or reference standard.

The use of cinacalcet carbamate as a reference marker to determine the presence of cinacalcet carbamate in the base or cinacalcet salt is by the process comprising (a) determining the retention time by a chromatographic method, such as HPLC or TLC, corresponding to the cinacalcet carbamate in a reference marker comprising CNC carbamate; (b) passing a base or cinacalcet salt sample in a column chromatography method; and (c) using the retention time in step (a) to identify the presence of cinacalcet carbamate in the sample.

In another embodiment, a method is provided for determining the amount of CNC carbamate in the cinacalcet salt or base comprising (a) using a chromatographic method such as HPLC or TLC to measure the area below the peak corresponding to the CNC carbamate. in a standard of reference comprising a known amount of cinacalcet carbamate; and (b) determining the level of CNC carbamate in the sample by comparing the area of step (a) with the area below the peak in a sample comprising a salt or base of cinacalcet contaminated with CNC carbamate.

The person skilled in the art will not have difficulty performing the chromatographic method. In a sample, an HPLC method includes the steps of (a) combining a CNC sample with a mixture of acetonitrile and water at a ratio of 1: 1 to obtain a solution; (b) injecting the solution into a column of BDS Hypersil C-18 (or similar) of 100 x 4.6 mm, which is maintained at room temperature; (c) gradually eluting the sample from the column using a buffer mixture: acetonitrile at a ratio of 3: 2 by volume and acetonitrile and a buffer mixture: acetonitrile: ethanol at a ratio of 2: 9: 9 as eluent; and (d) measuring the amount of CNC carbamate in the relevant sample with an ultraviolet radiation detector, preferably at a wavelength of 243 nm.

In yet another aspect of the present invention, there is provided a process for preparing a cinacalcet salt comprising CNC carbamate in an amount of 0.03 percent area to 0.15 percent area determined by a chromatographic method comprising the steps of (a) providing one or more samples of one or more lots of cinacalcet base; (b) measure the CNC carbamate level in each of the samples in an amount of 3 percent area to 6 percent area that is determined by HPLC, based on the measurement or measurements made in step (b); and (d) using the batch selected in step (c) to prepare said cinacalcet salt.

Preferably, the cinacalcet salt of step (d) is in an amount of 0.03 area percent at 0.15 area percent which is determined by HPLC.

When the cinacalcet base sample of step (a) contains more than 3 percent CNC carbamate area, according to the measurement of step (d), the sample can be purified, before performing step (c).

In still another aspect, the present invention provides a pharmaceutical composition comprising cinacalcet base or salts having 0.03 percent deletion at 0.15 area percent by HPLC of cinacalcet carbamate, optionally prepared by any of the aforementioned methods above, and at least one pharmaceutically acceptable excipient.

In one aspect the present invention provides a process for preparing a pharmaceutical composition comprising combining the cinacalcet salt having from 0.03 percent to 0.15 percent area by CNC carbamate HPLC with at least one excipient pharmaceutically acceptable Examples HPLC method HPLC method to analyze CNC carbamate Column and packaging Hypersil GOLD 250 mm 4.6 mm 3μ CN 25003-254630 Eluent 40% - 0.02 M KH2P04 adjusted to pH = 6.0 with 60% KOH - Acetonitrile Downtime 35 minutes Flow 1.0 mi / minute Detector 210 nm Injection volume 10 μ] 1 Diluent 50% water: 50% ACN Column temperature Ambient The cinacalcet HCl samples are prepared by accurately weighing 10 mg of cinacalcet HCl in a 50 ml volumetric flask, dissolving and diluting to volume with a diluent. The samples are then injected into the HPLC column, combining the chromatogram until the end of the gradient. The area of each impurity is determined using a suitable integrator.

All impurities in a sample are calculated as follows:% impurity in sample = impurity area in sample x 100 ? Areas of all peaks A sample of CNC was combined with a mixture of CNC was combined with a mixture of acetonitrile and water at a ratio of 1: 1 to obtain a solution. The solution was injected onto a BDS Hypersil C-18 (or similar) column of 100 x 4.6 rom, at room temperature. The sample was eluted gradually from the column using a buffer mixture: acetonitrile at a ratio of 3: 2 by volume, and acetonitrile and a buffer mixture: acetonitrile: ethanol at a ratio of 2: 9: 9 as an eluent; and measuring the amount of CNC carbamate, in the relevant sample with an ultraviolet radiation detector, preferably at a wavelength of 243 mm.

Preparation of Cinacalcet Base substantially contaminated with CNC Carmbamato Example 1 .5 g of mesylate (FTOMs) were dissolved in acetonitrile (204 ml). (R) -1-naphthylethyl amine (14.5 ml) and anhydrous K2CO3 (24.9 g) were added and the reaction mixture was heated to reflux temperature and refluxed for 16 hours. Then the salts were filtered and the solvent was removed under reduced pressure. The residue was dissolved in DCM (75 ml). The solution obtained was washed with 5 percent aqueous solution of HC1 (pH = 1), followed by a saturated solution of NaHCO3 (pH = 8-9), and finally with water. The organic phase was separated and dried over dried to obtain 33.4 g of cinacalcet base containing 3 percent area by CNC carbamate HPLC.

Example 2 10.0 g of mesylate (FTOMs) (1 equivalent) were dissolved in toluene (60 ml). (R) -1-naphthylethyl amine (0.98 equivalent) and anhydrous K 2 CO 3 (2 equivalents) were added and the reaction mixture was heated to reflux temperature and refluxed for 14 hours. Then the salts were filtered and the solvent was removed under reduced pressure. The residue was dissolved in DCM (75 ml). The solution obtained was washed with 5 percent aqueous solution of HC1 (pH = 1), followed by a saturated solution of NaHCO 3 (pH = 8-9) and finally with water. The organic phase was separated and dried over Na2SO4 and filtered. The solvent was evaporated until dried to obtain 11.0 g of Cinacalcet base containing 12 percent area by CNC carbamate HPLC.

Example 3 5.0 g of mesylate (FTOMs) (1 equivalent) was dissolved in Toluene (80 ml). (R) -1-naphthylethyl amine (0.98 equivalent) and K2CO3 (2 equivalents) were added and the reaction mixture was heated at 80 ° C for 12 hours. Then tetrabutyl ammonium bromide ("TBAB") was added (5 percent per mole of FTOMs). The mixture was heated for another hour at 80 ° C. The salts were filtered and the solvent was removed under reduced pressure. The residue was dissolved in DCM (75 ml). The solution obtained was washed with 5 percent aqueous solution of HC1 (pH = 1), followed by a saturated solution of NaHCO 3 (pH = 8-9) and finally with water. The organic phase was separated and dried over a2SO4 and filtered. The solvent was separated to dry to obtain cinacalcet base containing 40.5 area percent by CNC carbamate HPLC. The carbamate from CNC was isolated by column chromatography on silica gel, eluent gradient: 100 percent n-hexane-20 percent ethyl acetate / 80 percent n-hexane for 10 minutes.

Purification process: Preparation of substantially pure Cinacalcet Hydrochloride of CNC Carbamate from the base of contaminated cinacalcet Example 4 The cinacalcet base (2.0 kg) prepared according to Example 1 was dissolved in acetone (4 ml) at room temperature. Then 1N HCl (1.5 equivalent) and water (40 ml) were added. The mixture was stirred at room temperature for 4 hours to obtain a precipitate. The product was isolated by filtration, washed with water (10 ml) and dried at 50 ° C in a vacuum oven for 24 hours to obtain 1.75 g of cinacalcet hydrochloride containing less than 0.15 percent of CNC carbamate area measured by HPLC. (purity by HPLC 99.9 percent).

The CNC base (3.15g) was dissolved in MTBE (15 volumes) at room temperature. The HCl gas bubbled into the obtained solution until no further crystallization of cinacalcet hydrochloride was observed. The suspension was stirred at room temperature for another hour. The product was then isolated by filtration, washed with MTBE (2 x 2 mL) and dried in a vacuum oven at 50 ° C for 16 hours to obtain 1.93 g of CNC HCl containing less than 0.1 per cent. cent area of CNC carbamate by HPLC.

Example 6 The CNC base (3.0 g) was dissolved in MTBE (20 volumes) at room temperature. The HCl gas bubbled in the solution obtained until no further crystallization of cincalcet hydrochloride was observed. - The suspension was stirred at room temperature for another hour. The product was then isolated by filtration, washed with MTBE (2 x 2 ml) and dried in a vacuum oven at 50 ° C for 15 hours to obtain 12.08 g of CNC HCl containing less than 0.1 percent of CNC carbamate area by HPLC.

While it is evident that the invention disclosed herein is well calculated to meet the objectives expressed above, those skilled in the art will appreciate that numerous modifications and embodiments can be envisioned. Accordingly, it is desired that the appended claims cover all those modifications and embodiments that are within the true spirit and scope of the present invention.

Claims (18)

1. An impurity of cinacalcet, cinacalcet carbamate, which has the formula:

2. An isolated cinacalcet carbamate impurity of claim 1.

3. A cinacalcet salt, comprising the cinacalcet impurity according to claim 1, in an amount of 0.03 percent area to 0.15 area percent.

4. The cinacalcet salt according to claim 3, wherein the salt is cinacalcet hydrochloride.

5. A method for preparing cinacalcet hydrochloride according to claim 4, comprising the steps of: a. dissolve the cinacalcet base, which contains cinacalcet carbamate in an amount of 3 percent to 6 percent, in a solvent selected from the group consisting of acetone, a linear or branched-chain C2-8 ether, mixtures of them and water; b. mix hydrogen chloride to obtain a precipitate; and c. recover the hydrochloride from. cinacalcet

6. The method according to claim 5, wherein the solvent is acetone or methyl tere-butyl ether.

7. The method according to claim 5 or 6, wherein the hydrogen chloride is gaseous or an aqueous solution.

8. The method according to claim 7, wherein the hydrogen chloride is gaseous.

9. A process for using cinacalcet carbamate as a reference marker for determining the presence of cinacalcet carbamate in a cinacalcet base or salt comprising: a) determining a retention time, which corresponds to the cinacalcet carbamate, by a chromatographic method in a reference marker, comprising the cinacalcet carbamate according to claim 1; b) pass a sample of base or salt of cinacalcet with the chromatography method; and c). use the retention time of step (a) to identify the presence of cinacalcet carbamate in the sample.

10. The process according to claim 9, wherein the chromatographic method is HPLC or TLC.

11. A process for using cinacalcet carbamate as a reference standard for determining the amount of the cinacalcet carbamate in a cinacalcet salt or base, comprising using a chromatographic method to measure the area below a peak corresponding to the cinacalcet carbamate in a reference standard, the reference standard comprises a known quantity of the cinacalcet carbamate according to claim 1; and determining the level of cinacalcet carbamate in the sample by comparing the measured area of the peak to the area below the measured peak in a sample comprising a cinacalcet salt or base contaminated with cinacalcet carbamate.

12. The process according to claim 11, wherein the chromatographic method is HPLC or TLC.

13. A process for preparing a cinacalcet salt, comprising cinacalcet carbamate according to claim 1 in an amount of 0.03 to 0.15 percent area, determined by HPLC, the process comprises the steps of: (a) provide one or more samples of one or more of the cinacalcet base batches; (b) measuring the level of carbamate of cinacalcet in each of the samples of (a); (c) selecting the batch of cinacalcet base based on the sample comprising a level of carbamate of cinacalcet in an amount of 3 percent to 6 percent area determined by HPLC, based on the measurement or measurements made in step (b); (d) using the batch selected in step (c) to prepare the cinacalcet salt; (e) dissolving the batch in a solvent selected from the group consisting of acetone, straight or branched C2-8 ether, mixtures thereof and water; (f) mixing an acid to obtain a precipitate; and (g) recover the salt of cinacalcet.

14. The process according to claim 13, wherein the cinacalcet salt of step (d) is in an amount of 0.03 percent to 0.15 percent determined by HPLC.

15. A process for preparing a cinacalcet salt, comprising the cinacalcet carbamate according to claim 1 in an amount of 0.03 to 0.15 percent area, determined by HPLC, the process comprises the steps of: (a) ) provide one or more samples of one or more of the lots of the cinacalcet base; (b) measuring the level of carbamate of cinacalcet in each of the samples of (a); (c) selecting the batch of the cinacalcet base based on the sample comprising a level of carbamate of cinacalcet in an amount greater than 0.15 percent determined by HPLC, based on the measurement or measurements made in step (b); (d) using the batch selected in step (c) to prepare the cinacalcet salt; (e) dissolving the batch in a solvent selected from the group consisting of acetone, straight or branched C2-8 ether, mixtures thereof and water; (f) mixing an acid to obtain a precipitate; and (g) recover the salt of cinacalcet.

16. A pharmaceutical composition, comprising a cinacalcet salt according to claim 3 or 4, having from 0.03 percent to 0.15 percent area by HPLC of cinacalcet carbamate, and at least one pharmaceutically excipient 'ceptable.

17. A process for preparing a pharmaceutical composition comprising combining a cinacalcet salt, containing 0.03 percent to 0.15 percent by HPLC of cinacalcet carbamate according to claim 1, with at least one pharmaceutically acceptable excipient .

18. The use of the cinacalcet carbamate according to claim 1 as a reference marker or reference standard.