Preparation of cinacalcet salt free from nitrosamine by using inert gas during particle size reduction

Abstract

The present invention relates to a particle size reduction process using inert gas for preparation of nitrosamine free Cinacalcet salt. Wherein, Cinacalcet salt is substantially free of nitrosamine impurities.

Description

[0001] TITLE OF THE INVENTION:

[0002] PREPARATION OF CINACALCET SALT FREE FROM NITROSAMINE BY USING INERT GAS DURING PARTICLE SIZE REDUCTION

[0003] FIELD OF THE INVENTION:

[0004] The present invention relates to a particle size reduction process using inert gas for preparation of nitrosamine free Cinacalcet salt. Wherein, Cinacalcet salt is substantially free of nitrosamine impurities.

[0005] BACKGROUND OF THE INVENTION:

[0006] N-[l(R)-(l-naphthyl)ethyl]-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-amine hydrochloride (herein “Cinacalcet HQ") structurally represented by formula (1), has a CAS number of 364782-34-3, a molecular formula of C22H23CIF3N and the following structure:

[0007] Cinacalcet Hydrochloride is marketed as SENSIP AR™ and acts as a cal cimimetic (i.e., it mimics the action of calcium on tissues) by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues.

[0008] SENSIPAR™ is a calcium-sensing receptor agonist approved for the treatment of Secondary Hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis, Hypercalcemia in patients with Parathyroid Carcinoma (PC), Severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy.

[0009] US 6,011,068 discloses inorganic ion receptor activity, especially calcium receptoractive molecules, such as those having the general structure of Cinacalcet. US 6,211,244 discloses calcium receptor-active compounds related to Cinacalcet and methods of making such compounds. As per US’ 144, Cinacalcet may be produced by reacting 1 -acetyl naphthalene with 3-[3-(trifluoromethyI)phenyl|propyiamine in the presence of titanium isopropoxide to produce an imine corresponding to Cinacalcet, followed by treatment with methanolic sodium cyanoborohydride and resolution of the racemic Cinacalcet base by chiral liquid chromatography.

[0010] Similarly, using the process disclosed in US’244, as well as drugs of the future (2002) 27 (9): 831 the desired Cinacalcet enantiomer may be produced by reacting (R)-l-(l-naphthyl) ethylamine with 3-| 3-(trifluoromethyl)phenyl] propionaldehyde in the presence of titanium isopropoxide to produce the imine that corresponds to Cinacalcet, followed by treatment with ethanolic sodium cyanoborohydride.

[0011] US’244 discloses an additional process for the synthesis of Cinacalcet. This process involves use of 3-trifluoromethylcinnamonitrile.

[0012] In recent years, Nitrosamine contamination of drug products has been admitted as a major regulatory issue for the pharmaceutical industry.

[0013] Drug developers are searching for solutions that will help overcome their formulation challenges in mitigating nitrosamine formation.

[0014] Manufacturers are looking to optimize the formulation process of drug products to limit nitrosamine formation. However, optimization of formulation processes may not prevent nitrosamine contamination entirely. For these reasons, manufacturers are looking to block nitrosamine formation in drug products / substances.

[0015] One possible strategy is that the formation of nitrosamines typically occurs under acidic conditions in presence of nitrosating agents and the risk of contamination is much lower in neutral or basic environments. But this strategy is not always suitable because some of the drug substances are not stable at higher pH levels.

[0016] Nitrosamines are substances produced essentially unintentionally during chemical synthesis. They feature a nitroso group (NO+) bonded to a deprotonated amine. Nitrosamines are a group of carcinogens that are formed by the reaction of a nitrosatable substrate precursor (amine source) with a nitrosating agent (e.g. nitrous acid, nitrites, or nitrogen oxides, etc.).

[0017] Moreover, the nitrosating agent NOx (like NO+, NCT” and N2O3), are present as environmental pollutants (nitrous acid, nitrogen oxides) in the air in variable proportion.

[0018] Due to the wide range of potential routes of formation for nitrosamines, many active pharmaceutical ingredients and impurities are themselves responsible to be nitrosated, either during same or subsequent stages of the synthetic process of the active pharmaceutical ingredient, during drug product manufacturing, or in the finished and packaged drug product.

[0019] The environmental pollutants containing nitrosating agents (NOx) present in air has impact on the secondary amine group that can be converted into N-nitrosamine impurities.

[0020] Hence, there remains a need for developing new process which can block the nitrosamine formation in Active drug substance.

[0021] There is continuous evolution in the manufacturing operations viz. particle size reduction process etc. in the preparation of Cinacalcet HC1 and numerous controls as per different guidelines of worldwide drug authorities has been applied to make the drugs suitable for human consumption and subsequently for treatment. In recent years in pharmaceutical industry API manufacturing to have efficient in-process controls in the preparation of active pharmaceutical ingredients mainly free of nitrosamine impurities.

[0022] The prior art processes for preparation of Cinacalcet HC1 are not suitable to control unwanted nitrosamine impurities.

[0023] Hence, there remains a need for providing efficient, safe, industrially feasible and economically viable process for manufacturing of Cinacalcet salt to substantially eliminate the problems associated with the prior art processes and provide Cinacalcet salt which is free from nitrosamine impurities with good yield and purity.

[0024] The increase in level of N-nitrosamine impurity during particle size reduction operation may be due to high possibility of nitrosamine impurity formation because of air oxidation (oxidation of nitrogen to produce nitric oxide / nitrosonium ion) during the milling / micronization operation. The air used during particle size reduction operation may contain nitrogen oxide or nitrox species (NOx) as nitrating agent and during the particle size reduction operation collision of molecules happen, which generates heat that leads to oxidation of nitrogen in Cinacalcet salt and resulted into the formation of nitrox (NOx) which is conducive factor for the formation of N-nitroso cinacalcet impurity during particle size reduction operation.

[0025] The particle size reduction process is used for crushing feed stock materials with relatively large particle sizes into powders with relatively small particle sizes. Often, particle size reduction processes are operated with compressed air obtained from the ambient atmosphere wherein the compressed air is used as a carrier to suspend the particles in a fluid flow within the particle size reducer. However, the compressed air may include some environmental pollutants such as NOx (like NO+, NOi” and N2O3). Such NOx content may be introduced into the compressed air from a variety of sources. For example, the moving compressor component may have NOx located thereon and the NOx may blend with the air being compressed. When the compressed air is used as a feed gas, milling gas, or both, to operate the milling / micronization process, the NOx included in the compressed air is often imparted to the final product of the particle size reduction operation. Impurities such as NOx can contaminate the final product such as a milled Cinacalcet salt that is extracted from the particle size reducer. As a result, the particle size reduced Cinacalcet salt may be either unusable, or may have to undergo further processing to remove the N-nitrosamine impurities. Thus, there is a need for improvements in the current particle size reduction process of Cinacalcet salt.

[0026] OBJECTS OF THE PRESENT INVENTION:

[0027] The primary object of the present invention is to provide an efficient, economically and an industrially viable particle size reduction process for preparation of Cinacalcet salt essentially free of nitrosamines impurities.

[0028] Yet, another object of the present invention is to provide particle size reduction process involving the use of inert gas for preparation of Cinacalcet salt essentially free of nitrosamines impurities.

[0029] SUMMITRY OF THE INVENTION:

[0030] The present invention discloses a particle size reduction process using inert gas for the preparation of nitrosamine free Cinacalcet salt.

[0031] The present invention surprisingly observed nitrosamine free Cinacalcet salt by using an inert gas in the particle size reduction process for preparation of Cinacalcet salt.

[0032] The present invention discloses the particle size reduction process using inert gas for preparation of nitrosamine free Cinacalcet salt.

[0033] BRIEF DESCRIPTION OF THE FIGURES AND DRAWINGS:

[0034] Figure- 1: Illustrates operation flow chart for particle size reduction of Cinacalcet salt.

[0035] DETAILED DESCRIPTION OF THE INVENTION:

[0036] Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only and is not intended to limit the scope of the present invention.

[0037] Before the present invention is described, it is to be understood that 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. Further, it is to be understood that the present invention is not limited to the methodologies 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, as these may vary within the specification indicated. 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. Further the terms disclosed in the embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

[0038] The term "substantially free of' means that a contaminant substance can be controlled or cannot be detected as per respective guidelines in the compound and / or composition by methods known to those skilled in the art at the time of the filing of this application.

[0039] The term “Nitrosamine free” means that a nitrosamine impurity can be controlled or cannot be detected as per respective guidelines in the compound and / or composition by methods known to those skilled in the art at the time of the filing of this application.

[0040] The term “inert atmosphere” means an environment in which operation can take place without the risk of contamination from reactive gases that exist in the air, such as oxygen and carbon dioxide; generally, inert gases are used to create inert atmosphere.

[0041] One of the embodiments of the present invention provides a particle size reduction process for preparation of nitrosamine free Cinacalcet salt, the said process comprising: a. Feeding the Cinacalcet salt into particle size reducing chamber through a feeding chamber for reducing the particle size; b. introducing a stream of inert gas in feeding chamber and / or particle size reducing chamber containing Cinacalcet salt; c. treating the inert gas and the Cinacalcet salt within the particle size reducing chamber, during particle size reduction operation for reduction of Cinacalcet salt particle size; and d. Collecting nitrosamine free Cinacalcet salt with reduced particle size from the receiver.

[0042] The Cinacalcet salt can be prepared as per Indian patent / patent application IN202321075864 family or IN202421042824 family or IN259898 family or any prior art process known to person skilled in art or any novel, improved process. Wherein, optionally all unit process and unit operation are performed under inert atmosphere. The Cinacalcet salt is selected from the group comprising of Cinacalcet HC1, any pharmaceutically acceptable salt.

[0043] The inert gas used in steps (b) and (c) is selected from the group comprising of nitrogen, helium, argon, neon, xenon, krypton. Preferably, nitrogen.

[0044] The inert gas used in steps (b) and (c) is introduced at optimum pressure.

[0045] According to another embodiment of the present invention, the particle size reduction process can be carried out at optimum temperature if required.

[0046] According to another embodiment of the present invention, the particle size reduction process can be carried out until required particle size of Cinacalcet salt is achieved.

[0047] According to another embodiment of the present invention, the treating of step (b) can be carried out until required particle size of Cinacalcet salt is achieved.

[0048] According to another embodiment of the present invention, sieving, sifting and blending operations are optionally performed under inert atmosphere.

[0049] According to another embodiment of the present invention, unit process, unit operations, packaging system and transportation are optionally performed under inert atmosphere.

[0050] According to another embodiment of the present invention, the supply of inert gas may be done by any suitable device that supplies inert gas. [For example, the supply may include a container of liquid nitrogen with a vaporizer to gasify the liquid nitrogen or a container of compressed nitrogen gas].

[0051] According to another embodiment of the present invention, the particle size reduction technique used is selected from milling, cutting, grinding, trituration. Preferably, milling.

[0052] According to another embodiment of the present invention, the particle size reduction equipment used is selected from but not limited to air jet mill, fluidized bed jet mill, disc / flat jet mill, ball mill, hammer mill, Comil-Cone mill, roller mill, fluid energy mill, edge runner mill, end runner mill, attrition mill, tumbling mill. Preferably, air jet mill.

[0053] Cinacalcet salt obtained from the process of the present invention are substantially free of Nitrosamine impurities, N-nitroso cinacalcet impurity, process related impurities, by products, carry over impurities and degradation impurities. Cinacalcet salt obtained from the process of the present invention has a purity of at least 99.5% by HPLC.

[0054] BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION:

[0055] The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.

[0056] Example-01:

[0057] The samples of Cinacalcet HC1 obtained after powder processing operation i.e. milling / micronization with compressed air are tested for N-nitroso cinacalcet content. The level of said impurity is significantly increased during micronization operations and results for the same are captured in table 1. Table 1: Content of nitroso Cinacalcet before and after micronization operation with compressed air.

[0058] Example-02:

[0059] The samples of Cinacalcet HC1 obtained after powder processing operation i.e. milling / micronization with inert gas (Nitrogen) are tested for nitroso cinacalcet content. The level of said impurity is significantly controlled during micronization operations and results for the same are captured in table 2.

[0060] Table 2: Content of nitroso Cinacalcet before and after micronization operation with inert gas (Nitrogen).

Claims

We claim,1. A particle size reduction process for preparation of nitrosamine free Cinacalcet salt, the said process comprising: a. Feeding the Cinacalcet salt into particle size reducing chamber through a feeding chamber for reducing the particle size; b. introducing a stream of inert gas in feeding chamber and / or particle size reducing chamber containing Cinacalcet salt; c. treating the inert gas and the Cinacalcet salt within the particle size reducing chamber, during particle size reduction operation for reduction of Cinacalcet salt particle size; and d. Collecting nitrosamine free Cinacalcet salt with reduced particle size from the receiver.Wherein the particle size reduction process can be carried out until required particle size of Cinacalcet salt is achieved.

2. The process as claimed in claim 1, wherein the inert gas used in steps (b) and (c) is selected from the group comprising of nitrogen, helium, argon, neon, xenon, krypton.

3. The process as claimed in claim 1, wherein the inert gas used in steps (b) and (c) is introduced at optimum pressure.

4. The process as claimed in claim 1 , wherein the particle size reduction process can be carried out at optimum temperature if required.

5. The process as claimed in claim 1, wherein sieving, sifting and blending operations are optionally performed under inert atmosphere.

6. The process as claimed in claim 1, wherein unit process, unit operations, packaging system and transportation are optionally performed under inert atmosphere.

7. The process as claimed in claim 1, wherein the supply of inert gas may be done by any suitable device that supplies inert gas; the supply includes acontainer of liquid nitrogen with a vaporizer to gasify the liquid nitrogen or a container of compressed nitrogen gas.

8. The process as claimed in claim 1, wherein the particle size reduction technique used is selected from milling, cutting, grinding, trituration.

9. The process as claimed in claim 1, wherein the particle size reduction equipment used is selected from but not limited to air jet mill, fluidized bed jet mill, disc / flat jet mill, ball mill, hammer mill, Comil-Cone mill, roller mill, fluid energy mill, edge runner mill, end runner mill, attrition mill, tumbling mill.

10. The process as claimed in claim 1, wherein Cinacalcet salt obtained from the process of the present invention are substantially free of Nitrosamine impurities, N-nitroso cinacalcet impurity, process related impurities, by products, carry over impurities and degradation impurities.

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