Industrial improved process for preparation of cis cevimeline hydrochloride

Abstract

The invention relates to an economical, eco-friendly, and industrially viable process of preparing high-quality product cis-2-methylspiro(1,3-oxathiolane-5,3') quinuclidine hydrochloride known as Cis Cevimeline Hydrochloride prepared by isomerizing racemic cevimeline hydrochloride salt using a metal catalyst to produce Cis cevimeline base in situ, which is further reacted to produce an organic acid salt, preferably, pure p-nitro benzoic acid salt of Cis cevimeline. Cis Cevimeline Hydrochloride so prepared contains i) Not more than 0.5 %, preferably not more than 0.3 % of Trans isomer. ii) Not more than 0.1 % of single largest unspecified impurity; and iii) Not more than 0.15 % of single largest specified impurity, including new Cevimeline impurity-1 and 2. The invention also covers a pure mixture of Cevimeline impurity-1 and 2. Additionally, by subjecting Cis Cevimeline Hydrochloride to a solvent treatment, the desired particle size distribution is achieved.

Description

[0001] Industrial Improved Process for Preparation of Cis Cevimeline Hydrochloride

[0002] Field of the Invention

[0003] The invention relates to an economical, eco-friendly, and industrially viable process of preparing high-quality product cis-2-methylspiro(l,3-oxathiolane-5,3') quinuclidine hydrochloride commonly known as Cis Cevimeline Hydrochloride. High quality product implies a product having purity of at least 98 %, preferably at least 99 %, and more preferably at least 99.50 % of the Cis isomer. High quality also implies not detectable or minute acceptable levels of other impurities. Finally, high-quality product also implies that Cis Cevimeline Hydrochloride of the desired particle size is produced.

[0004] Objects of the Invention

[0005] First object of the present invention is to provide an economical, eco-friendly and industrially viable process of preparing high-quality product cis-2-methylspiro(l,3- oxathiolane-5,3') quinuclidine hydrochloride commonly known as Cis Cevimeline Hydrochloride.

[0006] Under this object, inventors have carefully chosen process conditions to arrive at Cis Cevimeline Hydrochloride through a process that provides better yields and wherein process employs simple, safe and easily available reactants.

[0007] The second object of the present invention is to provide a process of preparing pure ci s-2-methylspiro( 1,3 -oxathiolane-5, 3') quinuclidine hydrochloride commonly known as Cis Cevimeline Hydrochloride wherein cis isomer so produced is at least 98 %, preferably at least 99 % and more preferably, at least 99.50 % pure. Highly pure Cis Cevimeline Hydrochloride is obtained by controlling processes and purity of all intermediates.

[0008] The third object of the present invention is to provide a process of preparing pure ci s-2-methylspiro( 1,3 -oxathiolane-5, 3') quinuclidine hydrochloride commonly known as Cis Cevimeline Hydrochloride wherein cis isomer so produced contains no detectable levels or acceptable levels of all other impurities including two newly identified acid degradation impurities.

[0009] The fourth object of the present invention is to provide a process of preparing pure ci s-2-methylspiro( 1,3 -oxathiolane-5, 3') quinuclidine hydrochloride commonly known as Cis Cevimeline Hydrochloride wherein the particle size of the cis isomer so produced is desirable, consistent and reproducible.

[0010] Background of the Invention

[0011] US Patent: 4,855,290 and CA 1311479C, Fisher et al.

[0012] US pat. No. 4,855,290 / CA 1311479C describes process for 3-Hydroxy-3- mercaptom ethylene quinuclidine using, trimethyl sulfonium iodide, sodium hydride in DMSO form dimethyl sulfoxonium methylide. It is further reacted with 3-Quinuclidinone in DMSO to form epoxide of 3 -methylene quinuclidine. Then reacted with H2S gas in presence of aqueous NaOH in MDC and methanol as solvent produced thiol compound as insitu intermediate. It is insitu reacted with boron trifluoride etherate and acetaldehyde to form racemic cevimeline base, on treatment with dry HC1 gas in chlorofoml produce racemic Cevimeline hydrochloride which on fractional crystallization with ethyl acetate then several times with acetone produce Cis cevimeline hydrochloride with around 33-40% overall yield.

[0013] The drawback of this process was that it provided a low yield of the intermediate due to the formation of the side product, Diol, from the epoxide in-situ intermediate in the presence of a sodium hydroxide solution and the recommended temperature conditions. It also required continuous hydrogen sulfide gas. By passing hydrogen sulfide gas continuously for more than 6.0 hrs., the amount of hydrogen sulfide gas was very high, requiring 6.50 kg of hydrogen sulfide gas for a 13. 9 gm batch size. This poses a significant environmental concern. Hydrogen sulfide is also toxic in nature. Handling it at a commercial scale is difficult due to safety concerns. Additionally, this process lacks scalability due to multiple recrystallization steps and chromatographic purification needed to enrich the cis isomer. This process was not suitable for commercialization.

[0014] USPat.No.5571918 / US4861886 describes A method for condensing 3-hydroxy-3- mercapto methyl quinuclidine with acetaldehyde in presence of organic sulfonic acid, anhydride and tin halide, or oxy acid of phosphorous producing 2- methylspiro(l,3-oxathiolane-5,3') quinuclidine, which comprises isomerizing transform of 2-m ethyl spiro(l ,3 -oxathiolane- 5 ,3 ') quinuclidine or acid addition salts thereof in the presence of a catalyst tin halide, to produce cis-form 2methylspiro (l,3-oxathiolane-5,3') quinuclidine or its salt. Product extraction in n-hexane after basic and acid treatment followed by hydrochlorination with HC1 gas produced Cis Cevimeline hydrochloride.

[0015] The drawback of this process is that the key starting material, 3-hydroxy-3- mercptomethyl quinuclidine, is not stable. Additionally, hazardous materials like p-toluene sulfonic acid and oxy acids of phosphorus are used for the condensation reaction with acetaldehyde.

[0016] No method has been described for the complete conversion of trans isomers to cis isomers by the conventional process mentioned for the preparation of cis Cevimeline hydrochloride.

[0017] US pat No.4981858 and EP0303391 describe the resolution of 2-methylspiro (1 ,3- oxathiolane5,3') quinuclidine with L-tartaric acid or D- tartaric acid to form tartrate salt, further treatment with aqueous sodium hydroxide in water followed by extraction with n-hexane and hydrochlorination with alcoholic HC1 produce Cis Cevimeline hydrochloride.

[0018] The drawback of this process is that the yield is very low (26%), and there was no further discussion on the purification of tartrate salt of cis 2-methylspiro (1 ,3- oxathiolane-5,3') quinuclidine to get desired cis isomers. Therefore, this process was not economically viable.

[0019] US20130060036 / W02011049155 describes a production method for a cis-type 2- alkylspiro( l,3-oxathiolane-5,3 ') quinuclidine hydrochloride, comprising: reacting a cis-trans isomer mixture of 2-alkylspiro(l,3-oxathiolane-5,3') quinuclidine (racemic mixture) with p -nitrobenzoic acid; resolving the resultant product to produce a cis-type 2-alkylspiro (1,3 -oxathiolane-5,3 ') quinuclidine p-nitrobenzoate followed by multiple purification in water to obtained pure p-nitrobenzoate salt, and converting the p-nitrobenzoate into a hydrochloride salt using hydrocarbon solvent such as toluene, hexane, heptane with IPA.HC1 produces Cis Cevimeline Hydrochloride.

[0020] The above process produces a p-nitrobenzoate salt of racemic Cevimeline and such racemic salt is further resolved into Cis Cevimeline p-nitro benzoate salt. In this process, around 35-40% of the trans isomer of Cis Cevimeline p-nitrobenzoate was lost in the mother liquor. To recover this isomer, further isomerization with boron trifluoride ether complex with hydrobromic acid and aldehyde was required, which reduced the overall yield of the Cis isomer.

[0021] US Pat.Nos. US8080663 / US 2008249312 / US8143400 / US20090182146 describe Resolution of racemic cevimeline base with racemic camphor sulfonic acid in toluene to produce cis cevimeline camphor sulfonic acid salt (95:5). Recrystallization in toluene and methanol (or alternate solvent mixture) produce Cis cevimeline camphor sulfonic acid salt as cis isomer. This salt was further treated with aqueous sodium carbonate in water followed by extraction with heptane, solvent recovery and crystallization in diethyl ether / DIPE by adding IPA.HC1 produces Cis Cevimeline hydrochloride.

[0022] None of the prior art provides the impurity profile of the final compound Cis Cevimeline Hydrochloride and is silent about several specified impurities such as diol, thiol, sulfoxide (RRR and RRS), N-oxide etc. The prior arts are also silent about % of trans isomer. There is no mention of stability testing and results of such testing at accelerated and / or long term stability conditions. Summary of the Invention

[0023] Under the first aspect, the invention provides an economical, eco-friendly and industrially viable process of preparing high-quality product cis-2-methylspiro(l,3- oxathiolane-5,3') quinuclidine hydrochloride commonly known as Cis Cevimeline Hydrochloride.

[0024] The process comprises four stages, each providing a pure intermediate / final product.

[0025] High-quality product implies a product having a purity of at least 98 %, preferably at least 99 %, and more preferably at least 99.50 % of the Cis isomer. High quality also implies not detectable or minute acceptable levels of other impurities. Finally, a high-quality product also implies that Cis Cevimeline Hydrochloride of the desired particle size is produced.

[0026] Under another aspect, the invention provides two acid degradants / impurities 1 and 2 newly found and produced due to an acid degradation of Cevimeline. These two impurities are named as 1 and 2 and are a) Cevimeline impurity-1 : 3-(((l-((((lR,4R)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; and b) Cevimeline impurity -2: 3-(((l-((((lS,4S)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol.

[0027] Under yet another aspect, the invention provides Cis Cevimeline Hydrochloride containing not more than 0.15 % of a single specified impurity selected from i) Cevimeline impurity-1 : 3-(((l-((((lR,4R)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; and ii) Cevimeline impurity -2: 3-(((l-((((lS,4S)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol.

[0028] Under a couple of aspects, Cis Cevimeline Hydrochloride of desired particle size is produced.

[0029] One more aspect of the invention provides Cis cevimeline hydrochloride with the following particle size distribution,

[0030] DIO: not more than 5pm;

[0031] D50: not more than 10pm; D90: not more than 25 pm, preferably not more than 20 pm, most preferably not more than 15 pm; wherein Cis cevimeline hydrochloride is slurried in isopropyl alcohol and dried before particle size measurement.

[0032] One more aspect of the invention provides Cis cevimeline hydrochloride with the following particle size distribution,

[0033] DIO: not more than 20pm, preferably not more than 10 pm and more preferably not more than 7.5 pm;

[0034] D50: not more than 50pm; preferably not more than 30 pm and more preferably between 10 pm - 25 pm;

[0035] D90: not more than 100 pm, preferably not more than 80 pm, most preferably not more than 75 pm. wherein Cis cevimeline hydrochloride is dissolved in isopropyl alcohol and precipitated by cyclohexane and dried before particle size measurement.

[0036] Brief description of drawings

[0037] Figure 1 provides a chromatogram of the CVM-I intermediate resulting from stage -I of the process provided under example 1.

[0038] Figure 2 provides a chromatogram of CVM-II intermediate resulting from stage -II of the process provided under example 2.

[0039] Figure 3 provides a chromatogram of CVM-III intermediate resulting from stage- ill of the process provided under example 3. The CVM-III intermediate is Cis Cevimeline para nitro benzoic acid salt. The peak eluted at RT 10 is of p-nitro benzoic acid of this salt.

[0040] Figure 4 provides Cis Cevimeline Hydrochloride prepared in accordance with the present invention having 0.04 % of a trans isomer. Cis Cevimeline Hydrochloride purity is 99.96 %.

[0041] Figure 5 provides Cis Cevimeline Hydrochloride prepared in accordance with the present invention having below detectable levels of any impurity. Cis Cevimeline Hydrochloride purity is 99.97 %. Figures 6A and 6B provide particle size distribution data of Cis Cevimeline Hydrochloride prepared using a solvent treatment wherein Cis Cevimeline Hydrochloride is dissolved in isopropyl alcohol and precipitated by cyclohexane.

[0042] Figures 7A and 7B provide particle size distribution data of Cis Cevimeline Hydrochloride prepared using a solvent treatment wherein Cis Cevimeline Hydrochloride is subject to slurry in isopropyl alcohol.

[0043] Figure 8 provides IR spectra of Cis Cevimeline p-nitro benzoic acid salt.

[0044] Figure 9 provides the Mass spectra of Cis Cevimeline p-nitro benzoic acid salt.

[0045] Figure 10A provides 1H NMR (proton NMR) spectra of Cis Cevimeline p-nitro benzoic acid salt.

[0046] Figure 10B provides 1H NMR (proton NMR) spectra of Cis Cevimeline p-nitro benzoic acid salt enlarged in the 1.2 ppm - 3.6 ppm region.

[0047] Figure IOC provides 1H NMR (proton NMR) spectra of Cis Cevimeline p-nitro benzoic acid salt enlarged in the 5 ppm - 9.5 ppm region.

[0048] Figure 11 A provides 13C NMR spectra of Cis Cevimeline p-nitro benzoic acid salt.

[0049] Figure 11 B provides 13C NMR spectra of Cis Cevimeline p-nitro benzoic acid salt enlarged in the region of 15 ppm -90ppm.

[0050] Figure 11 C provides 13C NMR spectra of Cis Cevimeline p-nitro benzoic acid salt enlarged in the region of 120 ppm - 175ppm.

[0051] Figures 12A and 12B provide HPLC chromatograms of CVM-III by method 1 and method 2 respectively, wherein CVM-III is not prepared in accordance with the present invention.

[0052] Figures 13 A and 13B provide HPLC chromatograms of Cis Cevimeline Hydrochloride by method 1 and method 2 respectively, wherein Cis Cevimeline Hydrochloride is not prepared in accordance with the present invention.

[0053] Figures 14A and 14B provide 1H NMR (proton NMR) spectra of a mixture of CVM impurity 1 and 2 wherein such mixture is at least 90 % pure. Figure 14B provides 1H NMR (proton NMR) spectra of said impurity mixture enlarged in the 1 ppm - 6 ppm region.

[0054] Figure 14C provides 13C NMR spectra of a mixture of CVM impurity 1 and 2 wherein such mixture is at least 90 % pure. Figure 14D provides 13C NMR spectra of a mixture of CVM impurity 1 and 2 enlarged in the region of 10 ppm - 180 ppm.

[0055] Figure 15 provides the Mass spectra of of a mixture of CVM impurity 1 and 2 wherein such mixture is at least 90 % pure.

[0056] Figures 16A and 16B provide IR spectra of a mixture of CVM impurity 1 and 2 wherein such mixture is at least 90 % pure and IR peak details including peak intensity, height, and area.

[0057] Figures 17A and 17B, figures 18Aand 18B, and figures 19Aand 19B provide 3 test results of testing the purity of a mixture of CVM impurity 1 and 2 by HPLC providing that the purity of a mixture of CVM impurity 1 and 2 is always at least 90 %.

[0058] Detailed description of the invention

[0059] The present invention discloses an economical, eco-friendly and industrially viable process of preparing high-quality product cis-2-methylspiro(l,3-oxathiolane-5,3') quinuclidine hydrochloride commonly known as Cis Cevimeline Hydrochloride.

[0060] More particularly, the present invention discloses a process that leads to a high- quality product in terms of isomer purity, chemical purity, and particle size.

[0061] The process of preparing High-quality Cis Cevimeline Hydrochloride of the present invention proceeds through 4 stages as follows,

[0062] 1. Stage-I: Preparation of Thioacetic Acid Salt of 3-hydroxy-3- acetoxymercapto methyl quinuclidine (CVM-I) from 3-Quinuclidinone hydrochloride through in situ formation of Epoxide of 3-methyelene quinuclidine;

[0063] 2. Stage-II: Preparation of Racemic Cevimeline Hydrochloride Hemihydrate (CVM-II) from Thioacetic Acid Salt of 3 -hydroxy-3 -acetoxymercapto methyl quinuclidine (CVM-I);

[0064] 3. Stage-Ill: Preparation of Cis Cevimeline organic acid salt preferably, para nitro benzoic acid salt (CVM-III) from Racemic Cevimeline Hydrochloride Hemihydrate (CVM-II) through in situ formation of Cis Cevimeline base; and

[0065] 4. Stage-IV: Preparation of Cis Cevimeline Hydrochloride (A-012) from Cis Cevimeline organic acid salt.

[0066] More particularly, the process of preparing High-quality Cis Cevimeline Hydrochloride of the present invention involves i) Preparation of Cis Cevimeline organic acid salt preferably, para nitro benzoic acid salt (CVM-III) from Racemic Cevimeline Hydrochloride Hemihydrate (CVM-II) through in situ formation of Cis Cevimeline base; and ii) Preparation of Cis Cevimeline Hydrochloride (A-012) from Cis Cevimeline organic acid salt.

[0067] More particularly, optimized process conditions are chosen in each step coupled with purification of intermediates wherever necessary, to arrive at Cis Cevimeline Hydrochloride through a process which provides better yields and quality at each of the stages I to IV.

[0068] The inventors of the present invention have surprisingly observed that a process to produce Cis Cevimeline Hydrochloride greatly impacts its purity and impurity profile along with levels of impurities. The purity of the final product is very sensitive to various conditions employed during synthesis. The use of solvent, amount of solvent, reactants, and temperature conditions greatly impact the purity of intermediates as well as Cis Cevimeline Hydrochloride.

[0069] Particularly, Trans isomer has to be restricted in the synthesis. United States pharmacopeial limit for the trans isomer in Cis Cevimeline Hydrochloride is only 0.5 %. It has been far more difficult to restrict trans isomer below 0.5 % and further, it is essential to ensure that it does not increase when subjected to various long-term and accelerated stability conditions.

[0070] Most of the prior arts are silent about the impurity profile of Cis Cevimeline Hydrochloride and various intermediates of Cis Cevimeline Hydrochloride.

[0071] Cis Cevimeline Hydrochloride, apart from trans isomer may contain other impurities such as i) Diol impurity; ii) Thiol impurity iii) Cevimeline Sulfoxide (RRS jimpurity; iv) Cevimeline Sulfoxide (RRR jimpurity; v) Cevimeline -N-oxide; vi) Any additional impurity based on the process developed.

[0072] The invention provides Cis Cevimeline Hydrochloride containing i) not more than 0.5 %, preferably not more than 0.3 % of Trans isomer; ii) Not more than 0.1 % of single unspecified impurity; iii) Not more than 0.15 % of single specified impurity selected from a) Cevimeline sulfoxide (RRR); b) Cevimeline sulfoxide (RRS); c) Cevimeline N-Oxide; d) Cevimeline impurity-1 : 3-(((l-((((lR,4R)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; and e) Cevimeline impurity -2: 3-(((l-((((lS,4S)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol. iv) Not more than 0.1 % of diol impurity; v) Not more than 0.1 % of thiol impurity.

[0073] Most of the prior arts fail to provide chromatograms of Cis Cevimeline and its intermediates; and are largely silent about controlling various impurities.

[0074] It is also difficult for a single method to detect all impurities. It is observed that a method employed and known for estimating trans impurity in Cis Cevimeline Hydrochloride, hereinafter method I or Method 1, fails to resolve and estimate all other impurities. It was hence needed to develop one or more further methods for the estimation of other impurities. Accordingly, a second method hereinafter Method II or Method 2 has been developed to ensure that all probable impurities are resolved and can be estimated. A system suitability test ensured the resolution and estimation of other impurities.

[0075] With method II, two newly observed impurities as follows are found in the samples of Cis Cevimeline Hydrochloride, i) Cevimeline impurity-1 : 3-(((l-((((lr,4r)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol.; and ii) Cevimeline impurity-2 : 3-(((l-((((ls,4s)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol.

[0076] Thus, under another aspect the invention provides, i) Cevimeline impurity-1 : 3-(((l-((((lr,4r)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol.; and ii) Cevimeline impurity-2 : 3-(((l-((((ls,4s)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol. Under further aspect, the invention provides Cis Cevimeline Hydrochloride containing not more than 0.15 % of a single specified impurity selected from i) Cevimeline impurity-1 : 3-(((l-((((lR,4R)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; and ii) Cevimeline impurity -2: 3-(((l-((((lS,4S)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol.

[0077] With these two newly found impurities, the task of developing a suitable process that can control impurities became more challenging. The present invention discloses a novel process to prepare high-quality Cis Cevimeline Hydrochloride. The process successfully produced highly pure Cis Cevimeline Hydrochloride with controlled impurities.

[0078] Further, during the development of the process, inventors serendipitously arrived at a process modification to provide Cis Cevimeline Hydrochloride with a controlled particle size. This particle size ensures uniform particles and better processibility of Cis Cevimeline Hydrochloride.

[0079] Under an aspect, the invention provides Cis cevimeline hydrochloride with the following particle size distribution,

[0080] DIO: not more than 5pm;

[0081] D50: not more than 10pm;

[0082] D90: not more than 25 pm, preferably not more than 20 pm, most preferably not more than 15 pm; wherein Cis cevimeline hydrochloride is slurried in isopropyl alcohol and dried before particle size measurement.

[0083] Figures 7A and 7B provide particle size distribution data of Cis Cevimeline Hydrochloride prepared using a solvent treatment wherein Cis Cevimeline Hydrochloride is subject to slurry in isopropyl alcohol.

[0084] Under one more aspect, the invention provides Cis cevimeline hydrochloride with the following particle size distribution, DIO: not more than 20pm, preferably not more than 10 pm and more preferably not more than 7.5 pm;

[0085] D50: not more than 50pm; preferably not more than 30 pm and more preferably between 10 pm - 25 pm;

[0086] D90: not more than 100 pm, preferably not more than 80 pm, most preferably not more than 75 pm; wherein Cis cevimeline hydrochloride is dissolved in isopropyl alcohol and precipitated by cyclohexane and dried before particle size measurement.

[0087] Figures 6A and 6B provide particle size distribution data of Cis Cevimeline Hydrochloride prepared using a solvent treatment wherein Cis Cevimeline Hydrochloride is dissolved in isopropyl alcohol and precipitated by cyclohexane.

[0088] The development of a process that can produce Cis Cevimeline Hydrochloride of high purity with controlled impurities was challenging, and Inventors stumbled upon several unsuccessful experiments before arriving at successful ones as small changes in experiments impacted the purity of products in each reaction requiring consideration of several permutations.

[0089] The inventors conducted a series of experiments followed by optimization at various levels to arrive at Cis Cevimeline Hydrochloride having a purity of at least 98 %, preferably at least 99 %, and more preferably at least 99.50 %.

[0090] The optimum process conditions are achieved by choosing the right process conditions from several alternatives of solvent, reactants, molar ratios, temperatures of reaction, purification processes etc.

[0091] Isomerizing racemic cevimeline hydrochloride (65:35 Cis and Trans ratio) is tried using a metal catalyst (such as stannic chloride) wherein racemic cevimeline hydrochloride is converted into Cis cevimeline base. Such base nevertheless contains around 5.0 % trans isomer. Such high levels are not acceptable. Hence further processing is essential to limit the trans isomer. Cis Cevimeline base having up to 5 % trans isomer is reacted with DL camphor sulfonic acid to form Cis Cevimeline camphor sulfonic acid salt. Surprisingly this escalated instead of reducing impurities and total impurities are found to be 19.71 % including trans isomer of 2.53 %. The following table 1 provides a compilation of impurities generated in the reaction and the corresponding chromatogram is provided in Figure 12A.

[0092] Table 1 The further reactions employed p-nitro benzoic acid instead of DL camphor sulfonic acid to produce Cis Cevimeline para nitrobenzoic acid salt.

[0093] Cis cevimeline para nitrobenzoic acid salt is reacted with sodium hydroxide solution followed by pH adjustment to above 11.5. This was followed by extraction using diisopropyl ether. The diisopropyl ether extract was treated with isopropyl alcohol hydrochloride (IPA.HC1) to produce Cis Cevimeline hydrochloride.

[0094] This process to produce Cis Cevimeline Hydrochloride generated several specified and un specified impurities as mentioned in table 2 below.

[0095] This batch fails to comply miserably with the requirements as per ICH guidelines. The corresponding chromatogram is provided in Fig. 13 A.

[0096] Table 2

[0097] HPLC results: Surprisingly it is found that the generation of impurities in the above reaction was due to the use of Diisopropyl ether for extraction and further reactions. Replacing diisopropyl ether with other solvents was found useful. Hence use of Diisopropyl ether for extraction and further reactions is not part of the present invention.

[0098] Through several failed experiments, it was clear that small changes in the reaction conditions had a significant impact on the purity of the product at each stage as well as on the overall impurity profile.

[0099] In the past, racemic cevimeline hydrochloride had been employed to prepare Cis Cevimeline Hydrochloride (US Patent: 4,855,290 and CA 1311479C, Fisher et al.); however, this reaction had several drawbacks. First, it resulted in a very low yield and also generated Diol impurity.

[0100] In past, various acids have been employed in producing Cis Cevimeline Hydrochloride including L-tartaric acid or D-tartaric acid (US Pat.No.4981858 / EP0303391), Camphor sulfonic acid (US8080663 / US 2008249312 / US8143400 / US20090182146), p-Nitro benzoic acid (US20130060036 W02011049155) etc. But in none of these reactions, Cis Cevimeline Hydrochloride has been prepared from Cis Cevimeline base.

[0101] It was never thought to isomerize Racemic Cevimeline Hydrochloride to Cis Cevimeline base and to further process it into Cis Cevimeline Hydrochloride.

[0102] Inventors have tried following organic and inorganic acids as provided in table 3 below to prepare the corresponding salt. But no acid was found as good as p-nitro benzoic acid.

[0103] Table 3

[0104] Pursuant to selection of p-nitro benzoic acid for preparing Cis Cevimeline Hydrochloride p-nitro benzoic acid salt, few other impurities are also checked and controlled as per ICH M7 guideline. Additional controlled impurities by HPLC include i) 2-Nitro Benzoic Acid ii) 2,4 Dinitro Benzoic Acid iii) 4-Nitro Benzoic Acid i v) 3 -Nitro B enzoi c Aci d v) 3,4 Dinitro Benzoic Acid vi) 4-Niro Toluene.

[0105] Even when the inventors tried isomerizing racemic Cevimeline Hydrochloride salt (65:35 cis-trans ratio) to Cis Cevimeline base, it contained up to 5.0% trans isomer which was not acceptable. Further Cis Cevimeline base having up to 5 % trans isomer is reacted with DL camphor sulfonic acid to form Cis Cevimeline camphor sulfonic acid salt. Surprisingly this escalated instead of reducing impurities and total impurities are found to be 19.71 % including trans isomer of 2.53 %.

[0106] Therefore, it was much needed to find a solution to arrive at pure Cis Cevimeline Hydrochloride using alternative processes.

[0107] The process of the present invention involves isomerizing racemic cevimeline hydrochloride salt (65:35 cis trans ratio) using Lewis acid metal catalyst to Cis cevimeline base prepared in situ containing up to 5.0% trans isomer and reacting Cis-Cevimeline base (instead of racemic Cevimeline Hydrochloride) prepared in situ with an organic acid to produce an organic acid salt of Cis-Cevimeline. The said organic acid is inexpensive and easily and abundantly available commercially. The process further provides preparing Cis-Cevimeline Hydrochloride from Cis- Cevimeline organic acid salt.

[0108] More particularly, the present invention provides a process to prepare Cis Cevimeline Hydrochloride hemihydrate through formation of an intermediate Cis- Cevimeline organic acid salt, preferably an intermediate Cis-Cevimeline para nitro benzoic acid salt- (CVM-III) by reacting Cis cevimeline base (having 5.0% trans isomer) prepared in situ with p-nitro benzoic acid. The cis cevimeline base is prepared from racemic Cevimeline hydrochloride hemihydrate (CVM-II).

[0109] The present invention also provides preparation of Racemic Cevimeline Hydrochloride Hemihydrate (CVM-II) from thioacetic acid salt of 3 -hydroxy-3 - acetoxymercapto methyl quinuclidine. The thioacetic acid salt is produced under Stage I by a two-step process wherein in the first step epoxide of 3 -methylene quinuclidine is produced in situ which is subsequently reacted with Thioacetic acid to produce thioacetic acid salt of 3 -hydroxy-3 -acetoxymercapto methyl quinuclidine.

[0110] This thioacetic acid salt of 3 -hydroxy-3 -acetoxy mercapto methyl quinuclidine is reacted with IPA.HC1 and Acetaldehyde diethyl acetal to produce Racemic Cevimeline hydrochloride (65:35). Conversion of racemic cevimeline hydrochloride salt (65:35 cis trans ratio) using Lewis acid metal catalyst with inorganic acid (IPA.HC1) to Cis cevimeline base containing not more than 5 % trans isomer, more particularly, from 0.5-5.0 % trans isomer is extremely crucial before reacting with an organic acid to produce Cis- Cevimeline organic acid salt. Instead, if racemic cevimeline base without isomerization with Lewis acid metal catalyst is directly reacted with an organic acid, it results in loss of trans isomer from 35 - 40 % in mother liquor which can reduce yield by 35 % or more.

[0111] The said process of isomerizing racemic Cevimeline hydrochloride enhances chemical purity of Cis Cevimeline hydrochloride as well as keeps in control several other impurities. .

[0112] Racemic Cevimeline hydrochloride hemihydrate is reacted with Lewis acid / metal catalyst more particularly, stannic chloride and isopropyl alcohol hydrochloride in a dichloromethane solvent. The reaction is then quenched with water and the mixture is basified using a sodium hydroxide solution.

[0113] Dichloromethane layer is separated and treated with an aqueous sulfuric acid solution; the pH of the aqueous layer is adjusted to a basic pH using sodium hydroxide solution. Cis Cevimeline base formed is extracted with toluene and obtained after solvent recovery.

[0114] Further, Cis Cevimeline base is reacted with p -nitrobenzoic acid leading to the formation of Crude Cis Cevimeline para nitrobenzoic acid salt in acetone. This crude salt is then purified in purified water, yielding the final product, Cis Cevimeline para nitrobenzoic acid salt.

[0115] In the final step, Cis Cevimeline para nitrobenzoic acid salt is first basified using a Sodium hydroxide solution in purified water. The basified product is then extracted with Cyclohexane, leading to separation of layers.

[0116] The organic layers are subjected to a carbon treatment followed by filtration. The filtrate is treated with dilute isopropyl alcohol hydrochloride to adjust the pH to acidic levels, resulting in the formation of Cis-Cevimeline Hydrochloride. This Cis-Cevimeline Hydrochloride is further refined through a solvent treatment which comprises slurring in a solvent or recrystallization using a pair of solvent and anti-solvent. The recrystallization process uses a mixture of polar and non-polar solvents such as isopropyl alcohol as solvent for dissolving and cyclohexane as antisolvent for precipitating.

[0117] The result of this final step is the production of the Active Pharmaceutical Ingredient (API), Cis-Cevimeline Hydrochloride having following characteristics i. Cis-Cevimeline Hydrochloride with cis isomer is at least 99 %, preferably at least 99.5 % and more preferably, at least 99.7 % restricting trans isomer to not more than 1 %, preferably not more than 0.5 % and more preferably, not more than 0.3 %. ii. Cis-Cevimeline Hydrochloride of high chemical purity having any single largest unspecified impurity not more than 0.1 % iii. particle size as below,

[0118] DIO: Not more than 20 pm , preferably not more than 10 pm, more preferably not more than 7.5 pm, most preferably Between 1.0 and 7.5 pm

[0119] D50: Not more than 50 pm, preferably not more than 30 pm, more preferably not more than 25 pm, most preferably Between 10.0 and 25.0 pm

[0120] D90: Not more than 100 pm, preferably not more than 80 pm, more preferably not more than 75 pm, most preferably Between 30.0 and 75.0 pm.

[0121] Or particle size as below,

[0122] D10: Not more than 5 pm,

[0123] D50: Not more than 10 pm,

[0124] D90: Not more than 25 pm, preferably not more than 20 pm, more preferably not more than 15 pm.

[0125] Depending on the solvent treatment chosen. iv. Further, in such pure Cis-Cevimeline Hydrochloride, two new acid degradation impurities namely 3-(((l-((((ls,4s)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol (Cevimeline impurity- 1) and 3- (((l-((((lr,4r)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol (Cevimeline impurity -2), are either not detectable or below 0.15 %. v. More particularly, pure Cis-Cevimeline Hydrochloride prepared in accordance with the present invention has following specification as provided in table 4 below:

[0126] Table 4

[0127] Therefore, to summarize, the invention provides a process to prepare Cis- cevimeline base by isomerization of racemic Cevimeline Hydrochloride hemihydrate followed by forming an organic acid salt of Cis-cevimeline base. Cis cevimeline organic acid salt is subjected to a series of treatments such as basification, extraction, carbon treatment, filtration and finally treated with isopropyl alcohol hydrochloride to produce Cis-Cevimeline Hydrochloride of high chemical purity, high isomeric purity, and desired particle size.

[0128] The said process also additionally provides preparation of racemic Cevimeline Hydrochloride hemihydrate from 3-Quinuclidinone hydrochloride.

[0129] Hence, entire process can also be described as follows:

[0130] Stage-I: Preparation of Thioacetic Acid Salt of 3-hydroxy-3-acetoxymercapto methyl quinuclidine (CVM-I) and optimization of process conditions.

[0131] Reaction scheme-I:

[0132] S-[(3-hydroxy-l-azabicyclo[2.2.2]oct-3-yl)methyl] ethanethioate, thioacetic acid salt

[0133] Thiolacetic Acid Salt of 3-hydroxy-3-acetoxymercaptomethyl quinuclidine (CVM-I)

[0134] Detailed process is provided under example 1.

[0135] In stage I, Thioacetic Acid Salt of 3 -hydroxy-3 -acetoxymercaptomethyl quinuclidine is prepared from 3-Quinuclidinone hydrochloride in two steps.

[0136] In a first step 3-Quinuclidinone hydrochloride in a first solvent is reacted with Trimethyl sulfoxonium iodide in presence of a base to produce in situ an intermediate epoxide of 3 -methylene quinuclidine. In the subsequent step, epoxide of 3 -methylene quinuclidine in situ is reacted with Thioacetic acid in a second solvent environment, yielding the Thioacetic Acid Salt of 3 -hydroxy-3 - acetoxymercaptomethyl quinuclidine.

[0137] It has been surprisingly noted that purity of Thioacetic Acid Salt of 3-hydroxy-3- acetoxymercaptomethyl quinuclidine and its yield are impacted by several factors such as type of first and second solvent and amount / volume of a solvent and type of base, mole ratio of a base and the number of portions in which base is added in the reaction, mole ratio of Trimethyl sulfoxonium iodide, mole ratio of Thioacetic acid, reaction temperature, etc.

[0138] After reaction between 3-Quinuclidinone hydrochloride and trimethyl sulfoxonium iodide to produce epoxide of 3-methylene quinuclidine in situ, the reaction is quenched using a saturated sodium chloride solution in water.

[0139] Careful selection of a solvent and a base is necessary to obtain optimum purity and yield. It has been surprisingly found that some solvents do not support the reaction such as Isopropyl alcohol. Also, volume of a solvent is crucial. 4-5 volumes of DMSO for reaction is sufficient to produce desired quality.

[0140] Preferably, a base is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium hydride, potassium hydride, sodium tertiary butoxide, potassium tertiary butoxide and any combination thereof.

[0141] Base can be added at once. But preferably, base is added in portions from 2 - 7. Potassium tert-butoxide provided best results when added in portions from 2 - 7, preferably in portions from 3 - 6.

[0142] For quenching with sodium chloride solution, different amounts of sodium chloride were employed. Best results were obtained when 1- 1.5 % w / w of sodium chloride is used as compared to weight of 3-Quinuclidinone hydrochloride. Once the quantity was fixed, a 30 % solution was employed for quenching.

[0143] A first Solvent is a solvent employed in the first step where 3-Quinuclidinone hydrochloride is reacted with Trimethyl sulfoxonium iodide to produce in situ epoxide of 3-methylene quinuclidine and is selected from dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran and combination of dimethyl sulfoxide and dimethyl formamide. Dimethyl sulfoxide is found to provide best yield and purity when used in amount of from 3 - 6 volumes, preferably 4 - 5 volumes.

[0144] Second solvent is a solvent employed in the second step where epoxide of 3- methylene quinuclidine prepared in situ is reacted with Thioacetic acid and is selected from cyclohexane, Di-isopropyl ether, ethyl acetate and toluene. Best yield and desired purity are obtained in toluene. Best mode employs toluene as a solvent. The purity of product in all solvents is at least 90 %. Use of toluene produced > 90 %, preferably > 95 % pure Thioacetic Acid Salt of 3 -hydroxy-3 - acetoxymercaptomethyl quinuclidine.

[0145] Even when toluene is used, optimum volume such as 15 volume or 20 volume produced purer salt as compare to 10 volumes and 25 volumes. Thus, best mode batch employed from 15 to 20 volumes of toluene.

[0146] To fix mole ratio of Thioacetic acid, 1 mole of epoxide of 3 -methylene quinuclidine prepared in situ is reacted with 1, 1.5, 2, 2.5 moles of Thioacetic acid in separate experiments. All experiments resulted in producing Thioacetic Acid Salt of 3- hydroxy-3-acetoxymercaptom ethyl quinuclidine of at least 90 % purity wherein 1 :2 mole ratio of said epoxide to Thioacetic acid provided the best results in producing Thioacetic Acid Salt of 3 -hydroxy-3 -acetoxymercaptom ethyl quinuclidine of at least 90 %, more preferably at least 95 % purity. Thus, best mode batch employed 1 :2 ratio of epoxide of 3-methylene quinuclidine and Thioacetic acid.

[0147] Further, reaction between epoxide of 3-methylene quinuclidine prepared in situ and Thioacetic acid is carried out at various temperatures such as 0-10°C, 10-20°C, 20- 30°C and 30-40°C. It is observed that a temperature of 0-10°C is most suitable to arrive at most pure Thioacetic acid salt in quantitative yields.

[0148] As temperature goes higher and higher, epoxide of 3-methylene quinuclidine is converted into diol impurity and does not remain available to produce Thioacetic acid salt impacting both yield and purity.

[0149] First two steps are referred as Stage-I reactions and provided under Scheme I.

[0150] At the end of the reaction, reaction mixture is tested for 3-Quinuclidinone hydrochloride. It is preferred that amount of 3-Quinuclidinone hydrochloride remaining unreacted is not more than 10 %, preferably not more than 5 % and more preferably not more than 3 %.

[0151] If reaction mixture shows higher than 10 % of 3-Quinuclidinone hydrochloride, it is stirred further and a sample is withdrawn every hour to test 3-Quinuclidinone hydrochloride till it is not more than 10 %, preferably not more than 5 % and more preferably not more than 3 %. Stage II: Preparation of Racemic Cevimeline Hydrochloride Hemihydrate

[0152] (CVM-H)

[0153] Reaction scheme-II :

[0154] A detailed process is provided under example 2.

[0155] Under stage II, first racemic Cevimeline base is produced which is further treated to produce Racemic Cevimeline Hydrochloride Hemihydrate. The thioacetic acid salt of 3 -hydroxy-3 -acetoxymercapto methyl quinuclidine in a third solvent is reacted with an acid to produce 3 -hydroxy-3 -mercaptomethyl quinuclidine in situ. This reaction is conducted at a temperature not below 75°C, preferably from 75 - 85°C. Subsequent reaction with acetaldehyde diethyl acetal, followed by solvent recovery, addition of dichloromethane, basification with sodium hydroxide solution, layer separation, and treatment of the dichloromethane layer with aqueous sulfuric acid, layer separation, aqueous layer treatment with sodium hydroxide solution, product extraction with toluene and solvent recovery produce racemic Cevimeline base.

[0156] This racemic Cevimeline base prepared in situ is then treated with IPA.HC1 in fourth solvent isopropyl alcohol. After solvent recovery and product crystallization in cyclohexane, Racemic Cevimeline Hydrochloride Hemihydrate (CVM-II) is produced.

[0157] In stage 3, various acids as well as solvents were tried under different experiments which included p-toluene sulfonic acid monohydrate, cone. Sulfuric acid, methane sulfonic acid and isopropyl alcohol hydrochloride. Surprisingly isolable product was not obtained when methane sulfonic acid and cone. Sulfuric acid are employed and the reactions produced sticky mass, p-toluene sulfonic acid monohydrate and Isopropyl alcohol hydrochloride provided Racemic Cevimeline Hydrochloride Hemihydrate with a purity greater than 90 and 95 % respectively. To the Thio acetic acid salt of 3 -hydroxy-3 -acetoxymercapto methyl quinuclidine in a Isopropyl alcohol is added IPA.HC1 while maintaining temperature below 35°C. Then the temperature is raised to at least 75°C, preferably from 75 - 85°C and maintained for 3 - 3.5 hrs.

[0158] Thioacetic acid salt of 3 -hydroxy-3 -acetoxymercapto methyl quinuclidine and Isopropyl alcohol hydrochloride are used in a mole ratio of from 1 :3 - 1 : 4, more particularly mole ratio of 1:3.5 is found most suitable.

[0159] Suitable solvent is isopropyl alcohol. It has been surprisingly found that very few solvents like ethanol, isopropanol and Dysol (ethanol 90 % + toluene 10 %) support reaction of step 3. Water and methanol produced some sticky mass which could not be processed further. Employing 6 - 12 volumes of Isopropyl alcohol as a third solvent provided purer product in step 4 which is Racemic Cevimeline Hydrochloride Hemihydrate in good yields.

[0160] After, 3 -hydroxy-3 -mercaptomethyl quinuclidine is produced in situ, the reaction mixture is cooled to 25 -35°C and then acetaldehyde diethyl acetal is introduced slowly. Then the temperature of the reaction mixture is raised again to 75 - 85°C and maintained for 3-4 hrs. During stirring, a sample of the reaction mixture is removed every hour and is subjected to HPLC analysis to estimate the content of 3- hydroxy-3 acetoxymercapto methyl quinuclidine (by % area) to ensure completion of reaction.

[0161] Reaction temperature of 75-85°C is crucial. When different lower temperatures were tried, following outcome as provided in table 5 was observed.

[0162] Table 5

[0163] Any unreacted CVM-I intermediate in the reaction mass will be further converted into CVM-II in subsequent operations. This has been verified through multiple batches at a commercial scale.

[0164] In few trial experiments, different mole ratios of acetaldehyde diethyl acetal were employed in stage-3. All mole ratios from 1 :3 to 1 : 6 (1 part of thioacetic acid salt of 3 -hydroxy-3 -acetoxy mercapto methyl quinuclidine and 3 - 6 parts of acetaldehyde diethyl acetal) produced Racemic Cevimeline Hydrochloride Hemihydrate with a purity greater than 90 % with higher yield. Reaction using acetaldehyde diethyl acetal is followed by solvent recovery of isopropyl alcohol by distillation. Further work up process involves addition of dichloromethane from 6 - 12 volumes at a temperature not exceeding 40°C. Adding 10 Volumes of di chloromethane is found most suitable to later produce Racemic Cevimeline Hydrochloride Hemihydrate (CVM-II) of higher purity.

[0165] After adding dichloromethane, re-basification with sodium hydroxide solution is commenced using 25.0% aqueous NaOH solution employed in 6 - 12 volumes. This is followed by layer separation of dichloromethane layer and treatment of the dichloromethane layer with aqueous sulfuric acid employed as 5 % aqueous solution employed in from 6 - 12 volumes and again layer separation and aqueous layer treatment with sodium hydroxide solution. This is followed by product extraction with toluene in 6 - 12 volumes and solvent recovery producing racemic Cevimeline base. pH adjustment is crucial at the time of racemic Cevimeline base extraction in toluene. pH should be adjusted in alkaline pH range from > 7.5 - <13.5 to obtain desired quality and optimum yield of CVM-II. Preferably, pH should be adjusted above 11.5. The most preferred pH range is from 11.5 - 12.5 to give desired purity and optimum yield (best mode pH). Purity in this pH range is > 95 % such as > 98 %. Below, 11.5 and above 13.5, purity is > 90 % - < 95 % and yield is relatively lower.

[0166] In a fourth step, Racemic Cevimeline base is treated with isopropyl alcohol hydrochloride in isopropyl alcohol, followed by another solvent recovery step. The product is finally crystallized in cyclohexane, resulting in the formation of the Racemic Cevimeline Hydrochloride Hemihydrate. Preferably, from 4 - 10 volumes of cyclohexane are employed. Diisopropyl ether is used as an alternative to cyclohexane as both produced Racemic Cevimeline Hydrochloride Hemihydrate of high purity (> 95 %).

[0167] Drying of Racemic Cevimeline Hydrochloride Hemihydrate Racemic Cevimeline hydrochloride is dried at a temperature of from 40 - 65°C, preferably at 50 - 60°C to obtain at least 90 %, preferably at least 95 % pure product.

[0168] Stage-Ill: Preparation of Cis Cevimeline Para nitro benzoic acid salt (CVM-

[0169] Ill)

[0170] Reaction scheme-III:

[0171] Detailed process is provided under example 3.

[0172] Racemic Cevimeline hydrochloride hemihydrate is reacted with stannic chloride and IPA.HCI in di chloromethane as a solvent. After quenching the reaction in water and undergoing a series of layer separations, treatments, and pH adjustments, the Cis Cevimeline base is produced. This base is then reacted with p-nitrobenzoic acid in acetone to yield a crude form of the Cis Cevimeline para-nitrobenzoic acid salt. Further purification in purified water produces the Cis Cevimeline paranitrobenzoic acid salt (CVM-III).

[0173] Few other solvents other than Dichloromethane were tried including di chloroethane and chloroform. The reaction in chloroform produced 2.16 % trans isomer and hence undesirable. Dichlroethane produced lower yield than dichloromethane although levels of trans isomer was acceptable. Dichloromethane used in volumes from around 10 - 12 (i.e. 10 - 12 litres for 1 kg of CVM-II) provided optimum yields.

[0174] Isopropyl alcohol hydrochloride is used from 0.1 volume to 0.4 volumes i.e. from 0.1 - 0.4 kg for 1 kg of CVM-II. All these volumes controlled trans isomer but best yield is obtained for 0.3 volumes of Isopropyl alcohol hydrochloride.

[0175] CVM-II and Stannic chloride are employed in molar ratio of 1 : 1 to 1 :2, preferably, from 1 :>1 to 1 :7. At 1 : 1 molar ratio, trans isomer is found to be higher than 0.5 %. Best ratio is found to be around 1 : 1.5 where trans isomer is controlled below 0.3 and optimum yield is obtained.

[0176] Stannic chloride is added at a lower temperature of not more than 15°C such as 10- 15°C, preferably not more than 5°C such as 0-5°C, more preferably not more than 0°C such as -5 - 0°C and most preferably not more than -5°C such as -5- -10°C. Trans isomer is controlled in all of the above ranges but optimum yield is produced when Stannic chloride is added at a lower temperature of -5- -10°C.

[0177] In stage-III, isomerization reaction is carried out at various temperatures selected between 20-40°C such as 20-25°C, 25-35°C, 35-40°C. Best yield is obtained when reaction temperature is preferably from 25-35°C.

[0178] During work up of the reaction, pH is adjusted between 10 - 14 such as from 10 - 11, from 11.5 - 13.5, above 13.5 etc. Best yield is obtained when pH is adjusted between 11.5 - 13.5.

[0179] During work up of the reaction, 5 % aq. Sulfuric acid solution is used for acidic pH adjustment. Amount of Sulfuric acid solution employed is from 6 volumes to 12 volumes such as 6, 8, 10 and 12 volumes. Best yield is obtained when 10 volumes of 5 % aq. Sulfuric acid solution is employed.

[0180] Toluene which is employed to extract product during work up can be used from 6 volumes to 12 volumes. 10 volumes of Toluene has been found sufficient for product extraction.

[0181] Cis Cevimeline salts with different acids

[0182] Although, p-nitro benzoic acid is a most preferred salt of Cis Cevimeline, inventors have tried following salts, i) Sulfate salt prepared using Cone. Sulfuric acid; ii) Methane sulfonic acid salt using Methane sulfonic acid; iii) Camphor sulfonic acid salt using DL-camphor sulfonic acid; iv) p-toluene sulfonic acid salt using p-toluene sulfonic acid. Following results as shown in table 3 below were obtained emphasizing selection of p-nitro benzoic acid.

[0183] Table 3 - repeated Pursuant to selection of p-nitro benzoic acid for preparing Cis Cevimeline Hydrochloride p-nitro benzoic acid salt, few other impurities are also checked and controlled as per ICH M7 guideline.

[0184] Additional controlled impurities by HPLC include i) 2-Nitro Benzoic Acid ii) 2,4 Dinitro Benzoic Acid iii) 4-Nitro Benzoic Acid i v) 3 -Nitro B enzoi c Aci d v) 3,4 Dinitro Benzoic Acid vi) 4-Niro Toluene.

[0185] Cis Cevimeline p-nitro benzoic acid salt preparation was optimized for i) mole ratio of para nitrobenzoic acid used for Cis cevimeline p-nitro benzoic acid salt preparation

[0186] Many mole ratios of para nitrobenzoic acid to Cis cevimeline base were tried. Four most suitable ones are 0.9, 0.94, 1.0 and 1.05. All these ratios produced Cis cevimeline p-nitro benzoate with acceptable levels of trans isomer. A ratio of 0.94 gave the best yield. ii) Different volume of acetone used for Cis cevimeline p-nitrobenzoic acid salt isolation.

[0187] Different volumes of acetone such as 3, 4, 5 and 6 were tried. Volume 5 gave the best yield. iii) Filtration temperatures for filtering Crude Cis cevimeline p- nitrobenzoic acid salt.

[0188] At least 4 different filtration temperatures were tried including 0-5°C, 5 - 10°C, 15-20°C and 25 - 35°C. While all temperatures controlled trans isomer, best yield is produced when filtration temperature was from 0- 5°C. iv) Purification of Cis cevimeline p-nitrobenzoic acid salt using different solvents. Various solvents such as acetone, methanol, purified water, toluene and cyclohexane were tried. Methanol and Purified water provided best purity. Cyclohexane and toluene produced a product having higher trans isomer. v) Purification using different volumes of purified water; minimum 2.0-5.0 volumes of purified water produced desired quality and optimum yield of CVM-III. 4-volume was recommended for ease of physical operation. vi) Purification by heating at different temperature. Different temperatures from 50 - 90°C were tried including 50-55°C, 60-65°C, 70-80°C and 80-90°C. All conditions favoured high quality product in optimum yields. vii) Different maintaining time before product isolation.

[0189] Different maintaining times before product isolation were employed from 30 mins - 300 mins including 30 mins, 60 mins, 120-180 mins, 240 mins and 300 mins. While maintaining time did not affect the purity, better yield was obtained when maintaining time was from 120 - 180 mins. viii) Different drying temperatures.

[0190] Different drying temperatures from 35-75°C were tried including 35- 40°C, 45-55°C, 60-70°C and 70-75°C. No significant impact was found on the purity or yield but least trans isomer was found when drying was conducted between 45-55°C. ix) Different product isolation temperatures.

[0191] Different product isolation temperatures were tried from 0°C - 35°C such as 0-5°C, 5-10°C, 10-15°C and 25-35°C. Trans isomer was below 0.5 % at all conditions but was minimum when a temperature of 5-10°C was employed during product isolation.

[0192] Structure Elucidation and Characterization of Cis Cevimeline Para nitrobenzoic acid salt The Structure Elucidation and characterization of Cis Cevimeline Para nitrobenzoic acid salt was established by analytical technique such as FT-IR, LC-MS / MS, 'H NMR and13C NMR. The purity of impurity was determined by HPLC.

[0193] Common Name: Cis Cevimeline Para nitrobenzoic acid salt

[0194] Chemical Name: (2R,2'R)-2'-methylspiro [4-azabicyclo [2.2.2] octane-2, 5' [1,3] oxathiolane] 4-nitrobenzoic acid (1 : 1)

[0195] Structure: -

[0196] Molecular Formula = C17H22N2O5S

[0197] Formula Weight = 199.31, 167.11 g / mole Total weight = 366.43 g / mole

[0198] The Chromatographic purity of Cevimeline Para nitrobenzoic acid salt was performed by High Performance Liquid Chromatography (HPLC) using In-house test procedure.

[0199] Cis isomer: 99.89% and HPLC purity: 99.97%

[0200] Characterization by Nuclear Magnetic Resonance Spectrometer The characterization of Cevimeline Para nitrobenzoic acid salt was performed by 400MHz Nuclear magnetic resonance spectrometer (NMR). It was analyzed for proton (1H) and13C NMR experiments by preparing samples in CDC13.

[0201] Assignment

[0202] 'II NMR (In CDCh)- 400 MHz

[0203]

[0204] Total Hydrogen = 22

[0205] Total carbon = 17

[0206] Infrared Spectrum:

[0207] The Infrared spectra of Cevimeline Para nitrobenzoic acid salt was performed using Shimadzu IR Affinity- 1 S using inhouse ATR method at Kalintis Healthcare Pvt.Ltd. The IR spectra graphs are attached below.

[0208] FT-IR Frequency for Cevimeline Para nitrobenzoic acid salt. Approx. Frequency cm-1 Assignment 3471.87 -O-H Stretching, 2931.80 -C-H Stretching, 1641.42 - C=O stretching, 1510.26 -N-0 stretching nitro compound, 1454.33 -C-H bending (methyl group) 1365.60-1469.76, -O-H bending 1099.43-1153.43, -C-0 stretching 1006.84-1028.06, -O-H bending 819.75-877.61, -C-H bending 1,4 substitutions, 709.80-796.60 -C-H bending.

[0209] Characterization by Mass Spectrometry

[0210] The characterization of Cevimeline Para nitrobenzoic acid salt was performed by Mass. It was analyzed for the Mass in +ve mode.

[0211] Mass Results,

[0212] Molecular weight of Cevimeline base: 199.31 g / mole, Molecular weight of Para nitrobenzoic acid: 166.11 g / mole, m / z value of Cevimeline base: 200.05 [M+H]+and m / z value of para nitro benzoic acid, 165.92 (M-H)'

[0213] Note: During mass analysis, Cevimeline para nitro benzoic acid salt split down into Cevimeline base and para nitrobenzoic acid, hence individual m / z value obtained in positive and negative region. Conclusion: - On the basis of above spectral data (FT-IR, LC-MS / MS, 1H NMR and 13C NMR) analysis, the structure of Cevimeline Para nitrobenzoic acid salt, (2R,2'R)-2'- methylspiro [4-azabicyclo [2.2.2] octane-2, 5' [1,3] oxathiolane] 4- nitrobenzoic acid (1 :1) was confirmed.

[0214] Figures 8 - 11 provide data on the characterization of Cis Cevimeline p-nitro benzoic acid salt. Figure 8 provides an IR spectra, figure 9 provides a LC-MS / MS Mass Spectra, figure 10A - IOC provide 1H NMR / proton NMR spectra, figures 11 A - 11C provide 13C NMR spectra of Cis Cevimeline p-nitro benzoic acid salt.

[0215] Stage-IV: Preparation of Cis Cevimeline Hydrochloride Reaction scheme:

[0216] Detailed process is provided under example 4.

[0217] In stage-IV, Cis-cevimeline organic acid salt is subjected to a series of treatments such as basification, extraction, carbon treatment, filtration and finally treated with isopropyl alcohol hydrochloride to produce Cis-Cevimeline Hydrochloride of high chemical purity, high isomeric purity, and desired particle size.

[0218] Process for manufacturing of Cis Cevimeline Hydrochloride by breaking of Cis cevimeline para nitrobenzoic acid salt with sodium hydroxide solution and extraction with cyclohexane followed by isolating Cis Cevimeline Hydrochloride by adding IPA.HC1 followed by recrystallization with Cyclohexane and isopropyl alcohol produce crystalline material with desired particle size

[0219] Following optimizations were applied in the above process. i) Different volume of purified water for salt breaking. Different volumes of water including from 2 volumes to 4 volumes were tried for salt breaking. 3 volumes was found the best in providing desired quality and optimum yield of Cis Cevimeline Hydrochloride. ii) Different pH conditions for salt breaking.

[0220] Different pH conditions were tried for salt breaking including from pH 10 - > 13.5. pH had no impact on trans isomer and other impurities, however, pH from 11.5 - 13.5 was found sufficient to break down Cevimeline para nitrobenzoate salt to produce desired quality and optimum yield of Cis Cevimeline Hydrochloride. iii) Different solvents for Cevimeline base extraction.

[0221] Different solvents were employed for extraction of Cevimeline base such as diisopropyl ether, cyclohexane, toluene, dichloromethane and ethyl acetate. Product could not be isolated when Dichloromethane is used for extraction. Lower yield was obtained with ethyl acetate. Best solvents were diisopropyl ether and cyclohexane. However, DIPE has a tendency to generate peroxide upon storage which could potentially lead to the formation of the Cevimeline sulfoxide impurity, making it a less advisable choice. Hence cyclohexane was the best solvent. iv) Different volume of cyclohexane for Cevimeline base extraction and product isolation. v) Different quantity of Activated carbon.

[0222] Different quantities of activated carbon from 3 - 10 % such as 3 %, 5 %, 7% and 10% were employed. Quantity of activated carbon did not have any impact on purity and yield of the product. A minimum of 5.0% w / w carbon is preferred to get the desired decription of Cevimeline hydrochloride. vi) Different mole ratio of IPA.HCL used for product isolation.

[0223] Different mole ratios of IPA.HCL including from 0.9 to 1.10 were tried such as 0.9, 0.95, 0.98, 1.0 and 1.1. All mole ratios produced desired quality product with controlled trans isomer and no other impurities were found. A mole ratio of 0.98 was chosen. vii) Different addition time of IPA.HC1 for product isolation.

[0224] Different addition time of IPA.HC1 were tried from fast addition (dumping), addition over 30 mins, addition over 60 mins. etc. Since this is an exothermic reaction, addition over an extended period of more than 60 min. is preferred. viii) Different maintaining time at 5-10°C.

[0225] Different maintaining times at 5-10°C after IPA.HC1 addition in Cevimeline base solution were tried from 30 mins to 300 mins. Maintaining time of from 90-120 min is found sufficient to produce the desired results. ix) Different Drying temperatures for drying API under vacuum.

[0226] Various temperatures were employed for drying from 40-80°C such as 40-50°C, 50-60°C, 60-70°C and 70-80°C. Drying temperature did not affect purity or levels of trans isomer. However, to avoid overdrying, a drying temperature was selected as 50-60°C. x) Different temperatures of addition of IPA.HCL.

[0227] Different temperatures were tried from 0-15°C such as 0-5°C, 5-10°C and 10-15°C. It is surprisingly found that as temperature increases trans isomer increases and when temperature is above 10°C, trans isomer increases beyond acceptable levels. Therefore, 0-5°C is chosen as a safe temperature at which addition of IPA.HC1 xi) Solvent treatment of Cevimeline Hydrochloride to get desired particle size.

[0228] It is an aspect of the invention to produce Cis Cevimeline Hydrochloride of desired particle size. It is surprisingly noted that solvent treatment such as slurring and crystallization significantly impact particle size of Cis Cevimeline Hydrochloride.

[0229] Different solvents are used for crystallization such as polar solvents and a combination of polar and non-polar solvents. It is possible to obtain particle size from D90 = 25 pm (90 % particles have size below or up to 25 pm, preferably up to 20 pm and more preferably up to 15 pm ) to D90 = 100 pm (90 % particles have size below or up to 100 pm, preferably up to 80 pm and more preferably up to 75 pm) merely by slurring or choosing certain solvent(s) of crystallization (refer figures 7A and 7B). Similarly, it is possible to obtain following particle size distribution Using dissolving Cis Cevimeline Hydrochloride in isopropyl alcohol and precipitating using cyclohexane.

[0230] D10: not more than 20pm, preferably not more than 10 pm and more preferably not more than 7.5 pm;

[0231] D50: not more than 50pm; preferably not more than 30 pm and more preferably between 10 pm - 25 pm;

[0232] D90: not more than 100 pm, preferably not more than 80 pm, most preferably not more than 75 pm.

[0233] Table 6 provides results of particle size according to selection of different solvents.

[0234] Table 6

[0235] Stability Studies

[0236] Three large scale validation batches were manufactured as per process described under examples 1 - 4 and Cis Cevimeline Hydrochloride is so produced was subj ected to long term stability testing (at 25°C / 60 % RH) and accelerated stability testing (at 40°C / 75% RH). Samples were removed from respective conditions at the initial (beginning), 1 month, 2 months, 3 months and 6 months and were tested for the following i) Description. ii) Identification by a) IR and b) HPLC. iii) Water content by KF iv) Content of chloride. v) Assay by HPLC. vi) Organic impurities by HPLC wherein trans isomer impurity is estimated by method 1 and other impurities are estimated using method 2.

[0237] The details of all results on one batch are as follows: Table 7 - Condition - 40°C / 75 % RH

[0238] Table 7 - Condition - 40°C / 75 % RH

[0239] Table 7 - Condition - 40°C / 75 % RH

[0240] Table 7 - Condition - 40°C / 75 % RH

[0241] Table 7 -Condition - 40°C / 75 % RH

[0242] Table 8 - Condition - 25°C / 60 % RH

[0243] Table 8 - Condition - 25°C / 60 % RH

[0244] Table 8 - Condition - 25°C / 60 % RH

[0245] Table 8 - Condition - 25°C / 60 % RH

[0246] Table 8 - Condition - 25°C / 60 % RH

[0247] Advantages of Current process:

[0248] Stage-I: Preparation of Thio acetic Acid Salt of 3-hydroxy-3-acetoxymercapto methyl quinuclidine.

[0249] Process for manufacturing of Thio acetic Acid Salt of 3 -hydroxy-3 - acetoxymercapto methyl quinuclidine according to the present invention involves reaction using Quinuclidinone hydrochloride and trimethyl sulfoxonium iodide at preferably 0-10°C in dimethyl sulfoxide as solvent. Potassium tert-butoxide is added in this reaction. It is most preferably divided into a few equal parts from 2 - 6 depending on the weight to be added and added in 2 - 6 equal portions parts / lots, preferably, 4 - 5 equal portions at 0-10°C. The mixture was stirred for an additional 2-3 hours at 0-10°C followed by workup. The , epoxide intermediate formed insitu is extracted in 20 volume toluene and then reacted with thio acetic acid to produce Thio acetic Acid Salt of 3 -hydroxy-3 -acetoxymercapto methyl quinuclidine. The product filtration is done at 0-10°C.

[0250] Advantage:

[0251] (1) In the earlier reported process, after carrying out the reaction at 0-5°C, the reaction mixture was maintained at room temperature for 16 hrs followed by work up process. The epoxide intermediate which was prepared insitu was extracted in 10 volume toluene, and then reacted with thio acetic acid. The product filtration was also conducted at room temperature. Exposing reaction mixture to room temperature for a longer time as well as carrying out product filtration at room temperature together with using low volumes of solvent toluene for extraction impacted yield of the product, Thio acetic Acid Salt of 3 -hydroxy-3 - acetoxymercapto methyl quinuclidine which is produced in overall 36.72% molar yield.

[0252] In the current process according to the present invention, reaction temperature as well as work-up temperature were controlled and product filtration is also conducted at 0-10°C. Also, a higher volume of toluene was used (20 volumes as against 10 volumes of prior art), to produce Thio acetic Acid Salt of 3 -hydroxy-3 - acetoxymercapto methyl quinuclidine with overall 61-67% molar yield.

[0253] Controlling reaction temperature and increasing the volume of toluene for extraction did not impact the cost of production as yield obtained is almost doubled which reduced the overall cost of production of Cevimeline hydrochloride.

[0254] Stage-II: Preparation of Racemic Cevimeline Hydrochloride Hemihydrate (CVM-H).

[0255] Process for manufacturing of racemic cevimeline hydrochloride according to the present invention comprises i) reacting Thio acetic acid salt with IPA.HC1 and acetaldehyde diethyl acetal in Isopropyl alcohol followed by ii) workup in acidic and basic conditions; iii) extracting racemic cevimeline base with toluene (10- volume) and finally iv) hydrochlorination using IPA.HC1, and isolation in cyclohexane. This process produced racemic cevimeline hydrochloride with an 80% yield.

[0256] Advantage:

[0257] (1) In an earlier reported process, racemic cevimeline hydrochloride was produced by reacting Thio acetic acid salt with p-toluene sulfonic acid monohydrate as organic acid and acetaldehyde diethyl acetal in Isopropyl alcohol followed by workup in acidic and basic condition. The racemic cevimeline base was extracted with heptane (50 volume) and solvent was distilled to produce crude racemic cevimeline base.

[0258] By modification and optimisation of the reported process, it is possible to avoid use of p-toluene sulfonic acid monohydrate which is expensive that IPA.HC1 and hazardous in nature and a potential genotoxic compound. Hence, current process employs safer and more economical reactant that the reported process. Stage-Ill: Cis Cevimeline Para nitro benzoic acid salt

[0259] Advantage of current process using organic acid (p-Nitrobenzoic acid).

[0260] The process for manufacturing of Cis cevimeline Para nitrobenzoic acid salt comprises i) first isomerising racemic cevimeline hydrochloride (65:35 cis and trans ratio) using metal catalyst (stannic chloride) into Cis cevimeline base that contains up to 5 % , more preferably from 0.5-5.0 % trans isomer. Then this base is further converted into Cis cevimeline Para nitro benzoic acid salt using para nitro benzoic acid in acetone. Further process involves recrystallisation of Cis Cevimeline para nitrobenzoic acid salt in purified water to produce high quality of Cis Cevimeline para nitrobenzoic acid salt having a) no Trans isomer or Trans isomer in an amount of less than 0.30% and b) all specified organic impurities below 0.15%; and c) unspecified impurities below 0.10%.

[0261] Advantage:

[0262] (1) No process reported earlier, mentions isomerising racemic cevimeline hydrochloride into Cis Cevimeline base and converting the said base to Cis Cevimeline para nitrobenzoic acid salt.

[0263] (2) In an earlier reported process, Racemic Cevimeline base (having 65:35 Cis and Trans ratio) was directly converted into Cis Cevimeline Para nitro benzoic acid salt using Para nitrobenzoic acid without isomerisation of racemic cevimeline. Hence, around 50% or more is lost in mother liquor.

[0264] While in the process according to the present invention, first isomerisation is performed to produce Cis cevimeline base (97:3 Cis and Tans ratio) in situ which is converted into Cis cevimeline Para nitrobenzoic acid salt and further process involved removing 3.0% trans isomer so that Trans isomer is either absent or is in amount of up to 0.3%. Further advantage of this salt preparation is restricting a) all specified organic impurities below 0.15% and b) unspecified impurities below 0.10%. This process enables production of a highly pure intermediate before producing a high quality drug substance.

[0265] Conducting a first isomerisation of Racemic Cevimeline base (having 65:35 Cis and Trans ratio) before salt preparation enables conversion of unwanted 35% trans Cevimeline isomer into Cis Cevimeline Base with up to 3-5% trans Cevimeline isomer. Cis Cevimeline Base is converted in situ into Cis cevimeline para nitrobenzoic acids salt with almost qualitative yield which reduced overall cost too.

[0266] By modification and optimisation of the reported process, current process achieves high yield of 65-70% as against the reported yield of 28.72 % and no or low amount of trans isomer impurity which is not more than 0.30% as against 1.70 % of trans isomer impurity reported previously.

[0267] The current process has several advantages such as economic viability, and it is easy to scale up and to reduce huge amounts of industrial waste.

[0268] Stage-IV : Cis Cevimeline Hydrochloride

[0269] Advantage using Cyclohexane and Isopropyl to get the desired particle size.

[0270] The current process for manufacturing of Cis Cevimeline Hydrochloride by breaking cis cevimeline para nitrobenzoic acid salt with sodium hydroxide solution and extraction with cyclohexane followed by isolating Cis Cevimeline Hydrochloride by adding IPA.HC1 which is recrystallised using Cyclohexane and isopropyl alcohol to produce crystalline material with desired particle size. Alternatively, isopropyl alcohol slurry is used to achieve finer particle size.

[0271] Advantage:

[0272] (1) In earlier reported processes, n-hexane, DIPE are used as solvents to extract the Cis cevimeline base, which is converted into Cis Cevimeline hydrochloride using IPA.HC1 while in the current process cyclohexane is used as a solvent to extract Cis cevimeline base, which is converted into Cevimeline hydrochloride using IPA.HC1. N-hexane is highly flammable, while DIPE tends to generate peroxide on holding. This peroxide might generate Cevimeline sulfoxide impurity whenever peroxide comes in contact with the solvent itself. It is difficult to eliminate the Cevimeline sulfoxide impurity once it is generated. Compared with N-hexane and DIPE as solvents, cyclohexane is less flammable, does not facilitate formation of peroxide and sulfoxide and is easy to handle at a commercial scale.

[0273] Additionally, the current process of recrystallisation of Cevimeline Hydrochloride employs different solvents to generate Cis Cevimeline Hydrochloride of different desired particle sizes. Preferably, it is dissolved in Isopropyl alcohol followed by the addition of Cyclohexane, which produces Cis Cevimeline hydrochloride having the desired particle size mentioned in the tables 9A and 9B below.

[0274] Table 9A: Desired particle size using solvent / antisolvent

[0275] Additionally, if a lower particle size distribution is desired, isopropyl alcohol slurry can be used, which provides the following particle size distribution.

[0276] Table 9B: Desired particle size using slurrying

[0277] The Cis Cevimeline Hydrochloride prepared in accordance with the present invention is a high-quality product with trans isomer of less than 0.30%, any specified impurity in an amount of not more than 0.15 % and any unspecified impurity in an amount of not more than 0.1%. Cis Cevimeline Hydrochloride produced by this improved and scalable process is stable in accelerated and longterm storage conditions.

[0278] Other advantage:

[0279] It is also difficult for a single method to detect all impurities. It is observed that a method employed and known for estimating trans impurity in Cis Cevimeline Hydrochloride, referred to as method I or Method 1, fails to resolve and estimate all other impurities.

[0280] Accordingly, a second method referred as Method II or Method 2 has been developed to ensure that all probable impurities are resolved and can be estimated. A system suitability test ensured the resolution and estimation of other impurities.

[0281] Method II or 2 by HPLC

[0282] Reagents:

[0283] Water HPLC grade or equivalent Di potassium hydrogen phosphate Sodium Hydroxide Acetonitrile

[0284] Methanol

[0285] 1 N Sodium hydroxide solution:

[0286] 4 gm of sodium hydroxide is weighed and transferred in 100 mL of water. It is sonicated to dissolve and mixed well.

[0287] Sodium hydroxide Another 2.5 g sodium hydroxide is weighed and dissolved in 25 mL of water or alternate volumes can be prepared if required.

[0288] Diluent:

[0289] 900 mL of water and 100 mL of methanol are mixed, sonicated to degas, and mixed well.

[0290] Preparation of Buffer solution:

[0291] Weighed and transferred 5.4 g of Dipotassium hydrogen phosphate in water and mixed to dissolve solids. The pH of the solution is adjusted to 10.0 ± 0.2 with a controlled addition of sodium hydroxide (2.5 g in 25 ml) and mixed well.

[0292] Preparation of Mobile Phase- A:

[0293] To prepare mobile phase A, 1000 mL of buffer and 5mL of acetonitrile are mixed, sonicated to degas, and mixed well, or alternate volumes can be prepared if required.

[0294] Preparation of Mobile Phase-B:

[0295] To prepare 1000 ml of mobile phase B, 300 mL of buffer and 700 ml of acetonitrile are mixed, sonicated to degas, and mixed well or alternate volumes can be prepared if required.

[0296] HPLC Chromatographic Parameters:

[0297] » Column: C 18

[0298] » Detection: UV at 210 nm

[0299] ® Run time: 70 minutes

[0300] ® Gradient program - A suitable gradient program can be applied, for example, from 0 - 12 minutes and from 60 - 70 mins - 100 % mobile phase A and from 12thminute to 60 min, mobile phase A is gradually reduced from 100 - 20 % and mobile phase B is increased from 0 - 80%.

[0301] * Following RTs of the impurities 1 and 2 were observed. Table 10:

[0302] New impurities

[0303] The inventors, by using Method 2, identified two isomeric impurities never reported before at the final stage of Cis Cevimeline Hydrochloride, namely 3-(((l- ((((ls,4s)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol (Cevimeline impurity-1) and 3-(((l-((((lr,4r)-3- Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol (Cevimeline impurity-2). These impurities are generated in an acidic environment due to acid degradation; hence, their estimation is essential while producing acceptable pharmaceutical salt. It is further essential to incorporate limits of these two newly identified impurities in the final release specification of API with a limit of not more than 0.15%. Due to their isomeric nature, their retention times are very close. They have been found always together. These impurities have the following structure.

[0304] Structure:

[0305] (Cevimeline impurity-1) (Cevimeline impurity-2)

[0306] (ss isomer) (rr isomer) Molecular weight: 372.59 g / mole

[0307] The impurities were characterized and confirmed by spectral techniques like NMR, Mass, and IR.

[0308] These two impurities elute out very closely and are found together. Generally, their weight ratio is from 1 :20 to 20: 1, preferably from 1 : 10 to 10:1, and more preferably from 1 :7.5 to 7.5: 1, and most preferably from 1 :5 to 5: 1 in most samples including those that are degraded beyond acceptable levels.

[0309] The inventors were able to separate at least 75 %, preferably at least 80 %, more preferably at least 85 %, and most preferably, at least 90 % pure mixture of CVM impurity 1 and CVM impurity 2 as reported in Table 11 below.

[0310] Table 11: Successful separation of pure mixture of CVM impurity 1 and CVM impurity 2

[0311] Following tables 12 - 15 provideXH and13C NMR, characteristic peaks in FTIR and Mass results

[0312] Table 12

[0313] Table 13

[0314]

[0315] Table 15:

[0316] Cis cevimeline Hydrochloride is hydrochloride salt with hemihydrate form, hence on storage, it may release traces of HC1 and water already present in the hemihydrate form; these two impurities are forms in acetic condition, hence to control these two impurities as per ICH guideline, identification and characterisation of these impurities are necessary with specified limit. These two impurities are not reported in the prior art.

[0317] Experimental Details

[0318] The following examples illustrate the invention without limiting the scope of the invention in any way.

[0319] Example 1

[0320] Stage-I: Preparation of Thioacetic Acid Salt of 3-hydroxy-3-acetoxymercapto methyl quinuclidine (CVM-I). Dimethyl sulfoxide (950.0 ml) is charged into a Round bottom flask, and 3- Quinuclidinone hydrochloride (200.0 gm) and Trimethyl sulfoxonium iodide (326.79 gm) are added while ensuring the temperature remains below 35°C. An additional Dimethyl sulfoxide (50.0 ml) is flushed to ensure complete transfer. The reaction mixture is cooled to 10 to 15°C. Potassium tert-butoxide (Part-1) (69.43 gm) is slowly introduced in reaction mass to maintain the temperature at 10 to 15°C, all under a nitrogen atmosphere. After this addition, the reaction mass is chilled to 0 to 10°C and stirred for 15-20 minutes at this temperature. The subsequent additions of Potassium tert-butoxide are continued (in equal portions / parts from 2 to 6, preferably 4 - 5, most preferably 5), adding 69.43 gm each time, ensuring the temperature is maintained between 0 to 10°C. The reaction mass is stirred for 15- 20 minutes at the same temperature range under a nitrogen atmosphere after each addition. After the final Part addition of Potassium tert-butoxide, the reaction mass is stirred for an additional 1-3 hours at 0 to 10°C.

[0321] Confirmed the completion of reaction by GC analysis with following limit. Determination of 3-Quinuclidinone hydrochloride content by GC (by % area) is not more than 10.0 %, preferably not more than 5.0 % and most preferably not more than 3.0 %

[0322] 30% solution of Sodium Chloride (2000 ml) is slowly added to the reaction mass through the addition pot, ensuring the temperature remains below 15°C. Then, sodium chloride (200.0 gm) is added to the mixture, maintaining the temperature below 15°C. The reaction mass is stirred for 10-15 minutes, Subsequently, toluene (1600 ml) is added to the reaction mass, The mixture is stirred for an additional 20- 30 minutes, maintaining the temperature below 15°C.

[0323] Salt Filtration:

[0324] The inorganic salt is removed by filtration and washed with Toluene (400 ml).

[0325] Layer separation and Product extraction: The filtrate is charged into RBF, the mixture is cooled below 15°C if necessary and allowed to settle for 20 to 30 minutes. The bottom aqueous layer is separated from the upper organic layer. The organic layer is transferred to a separate flask.

[0326] Next, the aqueous layer is charged in RBF. Charge Toluene (1000 ml) is added and stirred for 20 to 30 minutes. The mixture is allowed to settle for another 20 to 30 minutes at the same temperature range. The bottom aqueous layer is separated from the upper organic layer and the organic layer is transferred to the separate flask.

[0327] Repetition of the process: The aqueous layer is charged in RBF, toluene (1000 ml) is added and stirred for 20 to 30 minutes, it is allowed to settle for 20 to 30 minutes, the layers are separated, and the organic layer is transferred to the above mentioned separate flask.

[0328] After these steps, all the organic layers are combined in the RBF, and stirred for 10 to 15 minutes. The mixture is allowed to settle for another 10 to 15 minutes, and then aqueous layer if any is separated. Finally, the reaction mass is chilled to a temperature range of 0 to 5°C.

[0329] Product Isolation:

[0330] Thioacetic acid (188.38 gm) is added slowly while maintaining the temperature between 0-5°C. The reaction mass is stirred until the precipitation occurs, keeping the temperature within the 0-5°C range. The reaction mass is maintained at this temperature for 3 to 4 hours.

[0331] Product Filtration & Washing:

[0332] The product is filtered and washed with chilled toluene (400 ml). Then, the material is unloaded.

[0333] Product drying

[0334] The material is dried under vacuum for 4 hours at a temperature of 40°C to 50°C in vacuum dryer. Unload the material CVM-I, yield obtained in the range of range 200-250 gm (44.37-69.33% molar) based on input KSM. After drying, a sample of the dried material (CVM-I) is sent for "HPLC analysis." HPLC Purity Specification: Not Less than 90.0 % (Area) (mixture of Cis and Trans) Note: After meeting the above specifications, the next steps are initiated (Stage-II).

[0335] Example 2

[0336] Stage-II: Preparation of Racemic Cevimeline Hydrochloride Hemihydrate (CVM-II).

[0337] In the RBF (4-neck, round bottom flask), isopropyl alcohol (1950 ml) is charged. Thioacetic acid salt of 3 -hydroxy-3 -acetoxymercapto methyl quinuclidine (CVM- I) (200.0 gm) is added followed by the addition of 20-25% IPA. HCL (455.0 gm) and flushed with isopropyl alcohol (50 ml).

[0338] The reaction mass is heated to a temperature of 75 to 85°C and maintained in this range for 3 to 3.5 hours. Then the reaction mass is cooled to 25 to 35°C. Acetaldehyde diethyl acetal (405.47 gm) is slowly introduced. The reaction mass is heated again to 75 to 85°C and stirred for 3 to 4 hours in this temperature range.

[0339] The completion of reaction is confirmed by HPLC analysis with following limit.

[0340] Determination of 3 -hydroxy-3 acetoxymercapto methyl quinuclidine (CVM-I) to ensure completion of the reaction

[0341] Content of 3-hydroxy-3 acetoxymercapto methyl quinuclidine (CVM-I) is determined (by HPLC % area) with a limit of not more than 10.0 %, preferably not more than 5.0 % and most preferably not more than 3.0 %.

[0342] Note: If the result is compliant, the next steps in the process are initiated.

[0343] Solvent distillation:

[0344] The reaction mass is cooled below 45°C. The isopropyl alcohol is completely distilled from the reaction mass, using vacuum to ensure the temperature is below 60°C. The reaction mass is degassed for 10 to 15 minutes to remove as much isopropyl alcohol (IPA) as possible, ensuring the vacuum is not less than (NLT) 650 mmHg at 50 to 60°C. After degassing, the reaction mass is cooled to below 40°C. Work up:

[0345] Dichloromethane (2000 ml) is charged into the RBF, ensuring the temperature below 40°C. The reaction mass is cooled to 0 to 5°C. The appropriate amount of the 25% sodium hydroxide solution (approx. 2000 ml) is gradually added in RBF at a temperature of 0 to 15°C, aiming to adjust the pH above 11.5.

[0346] Layer separation:

[0347] Purified water (1000 ml) is charged into the RBF, Then the temperature is raised between 25 and 35°C. the mixture is stirred for 15 to 30 minutes within this temperature range. The mixture is allowed to settle for 15 to 30 minutes. Afterward, the organic layer is kept in a separate RBF.

[0348] Dichloromethane (400 ml) is added to the aqueous layer, the combination is stirred for 15 to 30 minutes at the same temperature. Then, it is allowed to settle for another 15 to 30 minutes.

[0349] Both collected organic layers are combined at 25-35°C. The prepared 5.0% sulfuric acid solution (1400 ml) is slowly added through the addition funnel to the reaction, maintaining a temperature of 25 to 35°C. The reaction mass is stirred for 15 to 30 minutes within this temperature range. The mixture is allowed to settle for another 15 to 30 minutes. Afterwards, the bottom organic layer is separated.

[0350] The organic layer is charged into RBF. The prepared 5.0% sulfuric acid aqueous solution (600 ml) is introduced slowly through the addition funnel in the organic layer, keeping the temperature between 25 to 35°C. The reaction mass is stirred for 15 to 30 minutes at this temperature range. The mixture is allowed to settle for another 15 to 30 minutes. Afterward, the bottom organic layer is separated and discarded.

[0351] For the aqueous layers, di chloromethane (400 ml) is charged. The reaction mass is stirred for 15 to 30 minutes within this temperature range and allowed to settle for another 15 to 30 minutes. Then, the bottom organic layer is separated and discarded. The aqueous layer reaction mass is cooled to 0 to 5°C.

[0352] At a temperature of 0 to 15°C, the 25% sodium hydroxide solution (328 ml) is slowly added to adjust the pH greater than 11.5.

[0353] Then the temperature is raised to 25 to 35°C and the reaction mass is maintained for 15 to 30 minutes within this range. Toluene (1400 ml) is charged in RBF. Stirring is continued for an additional 15 to 30 minutes at the same temperature. After this, the mixture is allowed to settle for another 15 to 30 minutes. Once settled, the bottom aqueous layer is separated. The organic layer is transferred to a separate RBF.

[0354] To this aqueous layer, toluene (600 ml) is charged and the temperature between 25 to 35°C is maintained. The mixture is stirred for 15 to 30 minutes within this temperature range, then it was allowed to settle for another 15 to 30 minutes. After settling, the bottom aqueous layer is separated and discarded. The organic layer is transferred to separate RBF.

[0355] Solvent distillation:

[0356] Combine both toluene layers and the maximum possible amount of toluene is distilled out from the reaction mass using vacuum, ensuring that the temperature remains below 60°C. . The reaction mass is degassed for 15 to 30 minutes at a temperature between 50 to 60°C, ensuring that the vacuum is no less than 650 mmHg.

[0357] The isopropyl alcohol (100 ml) is charged while maintaining the temperature at 50 to 60°C. After this, the reaction mass is cooled to a temperature range of 25 to 35°C.

[0358] Hydrochlorination:

[0359] 20-25% IPA.HC1 (125.20 gm) is slowly added at 25 to 45°C to the above reaction mass and it is maintained at 25 to 45°C for 15 to 30 min.

[0360] Solvent distillation: The maximum possible amount of toluene and isopropyl alcohol together from the reaction mass is distilled using vacuum ensuring that the temperature remains below 60°C. . The reaction mass is degassed for 15 to 30 minutes at a temperature between 50 to 60°C, ensuring the vacuum is no less than 650 mmHg.

[0361] Product isolation:

[0362] Cyclohexane (1600 ml) is charged at 50 to 60°C. The reaction mass is cooled to 25 to 35°C. The reaction mass is maintained at 25 to 35°C for 90 to 120 min.

[0363] Product Filtration & Washing:

[0364] The product is filtered and washed with Cyclohexane (400 ml) and the material is unloaded.

[0365] Drying:

[0366] Wet cake is charged in dryer and dried under vacuum NLT 650 mmHg for an initial 4 hours at 50°C to 60°C. Ensure Water content by KF is not more than 4.6 % after drying.

[0367] After complying with water content and completion of drying, unload the material. CVM-II is obtained in the range of 0.55-0.80w / w (65.47-95.23%) based on CVM- I input.

[0368] Analyse the dry sample for “Purity by HPLC”. It should be Sum of Cis and trans isomer of Cevimeline HC1, not Less than 90.0 % (Area)

[0369] Example 3

[0370] Stage-Ill: Preparation of Cis Cevimeline Para nitro benzoic acid salt (CVM- III)

[0371] In the 4-neck round bottom flask charge di chloromethane (1900 ml) and Racemic Cevimeline Hydrochloride Hemihydrate (CVM-II) (200.0 gm) are charged at temperatures below 35°C. The mixture is flushed with dichloromethane (50 ml) and the reaction mass is maintained at temperatures below 35°C for 15 to 30 minutes. In the next step, the reaction mass is cooled to a temperature range of -5 to -10°C. 20-25% IPA.HC1 (60 ml) is added at this temperature. Gradually stannic chloride (319.20 gm) is added while maintaining the temperature between -5 to -10°C, and then flushed with an additional dichloromethane (50 ml). The reaction mass temperature is raised to 25 to 35°C and stirred within this temperature range for up to 24 hours.

[0372] Determination of Trans isomers of cevimeline content by HPLC - Trans isomers should not be more than 5.0%.

[0373] Work up:

[0374] Purified water (2000 ml) is charged below 35°C in RBF. The purified water is chilled to 5-8°C. The reaction mass in transferred to chilled purified water in the RBF, maintaining a temperature of 5-8°C. Then the reaction mass is maintained at 0 to 5°C for 15 to 30 minutes.

[0375] An appropriate amount of the 25% Sodium Hydroxide solution (2000 ml) is slowly added through the addition funnel in RBF, maintaining a temperature of 0 to 15°C to adjust the pH above 11.5

[0376] Layer separation:

[0377] Temperature of the reaction mass is increased between 25 and 35°C. The mass is stirred for 15 to 30 minutes, ensuring the temperature remains below 35°C. It is allowed to settle for another 15 to 30 minutes within the same temperature range. Then, the bottom organic layer is separated and kept in separate RBF. Next, Dichloromethane is added (400 ml) to the RBF containing aqueous layer ensuring the temperature remains below 35°C. The solution is stirred for 15 to 30 minutes at a temperature below 35°C. It is allowed to settle for the same duration. The bottom organic layer is separated and kept in separate RBF, once more and the aqueous layer is discarded.

[0378] The 5.0% sulfuric acid aqueous solution (1400 ml) is added to the RBF via the addition funnel, maintaining a temperature of 25 to 35°C. The mixture is stirred for 15 to 30 minutes within this temperature range. Then the mixture is allowed to settle for another 15 to 30 minutes. Finally, the layers are separated. The aqueous layer is kept in a separate RBF.

[0379] The Organic Layer is charged in RBF at 25-35°C. 5% Sulfuric acid aqueous solution (600 ml) is added slowly at 25 to 35°C through an addition funnel in the reactor. It is stirred for 15 to 30 minutes. It is allowed to settle for 15 to 30 minutes. The bottom Organic layer is separated from the aqueous layer and the organic layer is discarded. Dichloromethane (400 ml) is charged into the combined aqueous layers at 25 to 35°C and stirred for 15 to 30 minutes. It is allowed to settle for 15 to 30 minutes. The bottom organic layer is separated from the aqueous layer and the organic layer is discarded. The aqueous reaction mass is cooled to 0 to 5°C.

[0380] 25% Sodium Hydroxide solution (375 ml) is slowly added in sufficient amount through the addition funnel in RBF at 0 to 15°C to adjust pH above 11.5.

[0381] Layer separation:

[0382] The above reaction mass is heated to 25-35°C and stirred for 15-30 minutes. Toluene (1400 ml) is added while maintaining the temperature between 25 to 35°C and stirred for an additional 15-30 minutes. The mixture is allowed to settle for 15- 30 minutes within the same temperature range. The bottom aqueous layer is separated and retained. Toluene layer is stored separately.

[0383] The temperature of the retained aqueous layer is maintained between 25-35°C. Then toluene (600 ml) is added ensuring the temperature remains between 25 to 35°C, and stirred for 15-30 minutes. After stirring, the mixture is allowed to settle for 15-30 minutes at 25-35°C.. Separate toluene and aqueous layers. Toluene layer is stored aqueous layer is discarded.

[0384] Solvent Distillation:

[0385] Combine the toluene layers and the reaction mass is heated to distilled out toluene under a vacuum, maintaining a temperature below 60°C. The reaction mass is degassed for 15-30 minutes at 50-60°C, ensuring a vacuum of no less than 650 mmHg. The degassed reaction mass is cooled to 32-38°C. The cevimeline base is stored in RBF.

[0386] Cis Cevimeline base solution preparation:

[0387] Acetone (310 ml) is charged in RBF containing Cis Cevimeline Base (155 gm obtained above) and stirred until a clear solution is observed. Product isolation:

[0388] Acetone (400 ml) followed by para nitro benzoic acid (122 gm) are charged in the RBF at below 35°C. Slowly Cis Cevimeline Base Solution is added at below 55°C through an addition funnel into the reaction mass. The addition funnel is flushed with Acetone (65 ml) and charged in the RBF below 55°C. The reaction mass is heated to reflux at 50 to 60°C and maintained for 45 to 60 min at 50 to 60°C. It is slowly cooled to 25 to 35°C and chilled to 0 to 5°C maintaining at 0 to 5°C for 120 to 180 minutes.

[0389] Product Filtration & Washing:

[0390] The product is filtered through the Buchner funnel and washed with chilled Acetone (155 ml). The crude Cis cevimeline para nitrobenzoic acid salt is unloaded.

[0391] LOD of Cis cevimeline para nitrobenzoic acid salt is checked before purification (for dry weight calculation) and the dry weight based on LOD is calculated.

[0392] Purification

[0393] Purified water (850 ml) is charged in RBF followed by crude Cis Cevimeline para nitrobenzoic acid salt (on a dry basis) (225.0 gm) below 35°C and flushed with purified water (50 ml) and heating to 70-80°C and stirring for 30 to 60 minutes to get a clear solution. The solution is slowly cooled to 25 to 35°C. and slowly chilled to 5 to 10°C and maintained for 120 to 180 minutes.

[0394] Product Filtration & Washing:

[0395] The product is filtered through the Buchner funnel and washed with chilled Purified water (225 ml). The Cis cevimeline para nitrobenzoic acid salt is unloaded. The purification process is repeated in water till impurities are controlled as provided in table 16 below Table 16

[0396] Drying:

[0397] The drying of the material is carried out under vacuum at NLT 650 mmHg at 45°C to 55°C for an initial 4 hours till water content by KF is not more than 3.0%. Yield is obtained in the range of 120-220 gm, 40.08-73.48% molar. Example 4

[0398] Stage-IV: Preparation of Cevimeline Hydrochloride (A-012)

[0399] Purified water (500 ml) and Cis Cevimeline para nitro benzoic salt (175) are charged in the 4-neck round bottom flask (RBF) and flushed with purified water (25 ml) at below 35°C and the mass is cooled to 10°C to 20°C. Slowly, 25% Sodium Hydroxide solution is added through the addition funnel in RBF to adjust pH above 11.5.

[0400] Product extraction and layer separation:

[0401] The temperature is raised and maintained at 25-35°C for 30 to 45 minutes. Cyclohexane (1400 ml) is charged in the RBF and stirred for 30 to 45 minutes and allowed to settle for 15 to 30 minutes and then the layers are separated.

[0402] The aqueous layer is charged in the RBF. Cyclohexane (350 ml) is added. Then it is stirred for 30-45 minutes. Further it to allowed to settle for 15 to 30 minutes. The layers are separated and the bottom aqueous layer is collected and discarded.

[0403] Both organic layers are combined at 25-35°C. Purified water (87 ml) is charged and stirred for 30-45 minutes and allowed to settle for 15 to 30 minutes. The bottom aqueous layer is separated and discarded.

[0404] Carbon treatment:

[0405] Both organic layers are charged at 25-35°C in a RBF, Further, activated charcoal (8.75 gm) is charged and maintained for 45 to 60 min.

[0406] Carbon Filtration & washing:

[0407] The charcoal is filtered through celite bed and washed with cyclohexane (175 ml). The filtrate is collected in a RBF. Hydrochlorination:

[0408] The reaction mass is chilled to 5 to 10°C and slowly IPA (85.4 gm) and 20- 25%IPA.HC1 (85.4 gm) (net basis 0.98 mole equivalent) are added and maintained for 90 to 120 min.

[0409] Product Filtration & Washing:

[0410] The product is filtered through the Buchner funnel and washed with cyclohexane (350 ml). The wet cake of Cis cevimeline hydrochloride is unloaded. The wet cake is charged in the dryer and the material is dried under vacuum with NLT 650 mmHg at 50°C to 60°C for 2.0 hours. The dry material is unloaded for the crystallisation process. Yield is obtained in the range of 43.75-105.0 gm, 0.25-0.60 w / w (37.42- 89.82%) on CVM-III input.

[0411] Crystallisation to get the desired particle size:

[0412] Isopropyl alcohol (175 ml) and the previously dried Cevimeline hydrochloride (50 gm) are charged in the 4-neck round bottom flask (RBF) at temperatures below 35°C and flushed with isopropyl alcohol (25 ml) and subjected to stirring. The reaction mass is heated to 60°C to 65°C. Once a clear solution is observed, stirring speed is slowed down and slowly cyclohexane (500 ml) is added while maintaining the temperature at 60°C to 65°C. The mixture is gradually cooled to 25°C to 35°C and then further chilled to 0°C to 5°C and maintained for 90 to 120 minutes.

[0413] Product Filtration & Washing:

[0414] The product is filtered and washed with cyclohexane (25 ml). The wet cake of Cis cevimeline hydrochloride is unloaded.

[0415] Drying:

[0416] Wet cake is charged in to dryer and Vacuum drying of the material is done at 50°C to 60°C for 4 Hours then till Water content by KF is achieved Between 3.50 - 4.50. Unload the material and yield is measured. It is obtained in the range of 0.88-0.96 w / w (88.0-96.0% molar) based on input Cevimeline hydrochloride. Sifting:

[0417] The dried material is sifted using the desired mesh sieve in Sifter and sifted material is collected.

[0418] The samples are taken for analysis and are analysed for i) Description; ii) Organic impurities by HPLC.; and ii) Particle Size Distribution analysis and comply with the specification of table 17. Table 17

[0419] Alternatively, by employing isopropyl alcohol slurry, the following particle size distribution can be achieved.

[0420] Additionally, if a lower particle size distribution is desired, isopropyl alcohol slurry can be used which provides the following particle size distribution (table 18).

[0421] Table 18

[0422] Over all yield is obtained in the range of 43.75-105.0 gm, 0.25-0.60 w / w (37.42-

[0423] 89.82%) on CVM-III input.

Claims

ClaimsWe claim1. A process for preparing Cis Cevimeline Hydrochloride comprising i) Isomerization of racemic Cevimeline hydrochloride hemihydrate using a metal catalyst to produce in situ Cis-Cevimeline base; ii) Reacting in a solvent Cis-Cevimeline base in situ with an organic acid to produce organic acid salt of Cis cevimeline and optionally recrystallizing the same; iii) Salt breaking by treating the organic acid salt of Cis cevimeline of step ii with a base; iv) Adding cyclohexane in the reaction mixture of step iii and extracting; v) Optionally repeating extraction with cyclohexane; vi) Treating cyclohexane solution with charcoal; vii) Filtering and cooling the filtrate to 5 - 10°C; viii) Adding isopropyl alcohol and isopropyl alcohol hydrochloride at 5- 10°C to filtrate / reaction mass of step vii and maintaining at the same temperature for 30 - 300 minutes, preferably from 90-120 mins to produce Cis cevimeline hydrochloride; ix) Filtering and subjecting wet cake of Cis cevimeline hydrochloride to drying; x) Optionally treating dried Cis cevimeline hydrochloride with a solvent and drying.

2. The process as claimed in claim 1 wherein the metal catalyst is stannic chloride.

3. The organic acid is p -nitro benzoic acid.

4. The process as claimed in claim 1 wherein in the salt breaking step, the base for treating organic acid salt of Cis cevimeline is a solution of sodiumhydroxide and the amount of sodium hydroxide solution added provides a pH in the range of 11.5 -13.5.

5. The process as claimed in claim 1 wherein a) Cis-Cevimeline base prepared in situ contains not more than 5 % of trans isomer; b) The organic acid is p-nitro benzoic acid and organic acid salt is p-nitro benzoic acid salt of Cis Cevimeline. c) The solvent for reacting Cis-Cevimeline base with p-nitro benzoic acid is acetone; and d) p-nitro benzoic acid salt of Cis Cevimeline is recrystallized in water by dissolving it in water at 70-80°C to obtain a clear solution followed by cooling and isolation.

6. The process as claimed in claim 1 treating dried Cis cevimeline hydrochloride with a solvent comprises either slurring the dried Cis cevimeline hydrochloride in isopropyl alcohol or recrystallizing Cis cevimeline hydrochloride in isopropyl alcohol and cyclohexane wherein Cis cevimeline hydrochloride is first dissolved in isopropyl alcohol and precipitated using cyclohexane.

7. The process as claimed in claim 6 wherein dried Cis cevimeline hydrochloride is slurry in isopropyl alcohol.

8. The process as claimed in claim 7 wherein the ratio of amounts of Cis cevimeline hydrochloride and isopropyl alcohol is from 1 :2 to 1 :5 wherein Cis cevimeline hydrochloride amount is expressed in weight and amounts of isopropyl alcohol is expressed in volume.

9. The process as claimed in claim 6 wherein dried Cis cevimeline hydrochloride is dissolved in isopropyl alcohol and precipitated using cyclohexane.

10. The process as claimed in claim 9 wherein the ratio of amounts of Cis cevimeline hydrochloride, isopropyl alcohol and cyclohexane is from 1 :4: 10 to 1 :4:20 wherein Cis cevimeline hydrochloride amount is expressed in weight and amounts of isopropyl alcohol and cyclohexane are expressed in volume.

11. The process as claimed in claim 7 wherein Cis cevimeline hydrochloride after slurring in isopropyl alcohol has the following particle size distribution,DIO: not more than 5pm;D50: not more than 10pm;D90: not more than 25 pm, preferably not more than 20 pm, most preferably not more than 15 pm.

12. The process as claimed in claim 9 wherein Cis cevimeline hydrochloride after dissolving in isopropyl alcohol and precipitating by cyclohexane has the following particle size distribution,DIO: not more than 20pm, preferably not more than 10 pm and more preferably not more than 7.5 pm;D50: not more than 50pm; preferably not more than 30 pm and more preferably between 10 pm - 25 pm;D90: not more than 100 pm, preferably not more than 80 pm, most preferably not more than 75 pm.

13. The process as claimed in claim 1 wherein the Cis cevimeline hydrochloride after the solvent treatment is dried till water content is from 3.5 - 4.5 %.

14. The process for preparing Cis Cevimeline Hydrochloride as claimed in claim 5 and 6 wherein the Cis cevimeline hydrochloride contains i) not more than 0.5 %, preferably not more than 0.3 % of Trans isomer. ii) Not more than 0.1 % of single unspecified impurity; iii) Not more than 0.15 % of single specified impurity selected from a) Cevimeline sulfoxide (RRR); b) Cevimeline sulfoxide (RRS);c) Cevimeline N-Oxide; d) Cevimeline impurity-1 : 3-(((l-((((lR,4R)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; e) Cevimeline impurity -2: 3-(((l-((((lS,4S)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; iv) Not more than 0.1 % of diol impurity; v) Not more than 0.1 % of thiol impurity.

15. The process for preparing Cis Cevimeline Hydrochloride as claimed in claims 5, 6, and 14 wherein the Cis cevimeline hydrochloride contains not more than 0.15 % of acid degradant impurity selected from a) Cevimeline impurity-1 : 3-(((l-((((lR,4R)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; b) Cevimeline impurity -2: 3-(((l-((((lS,4S)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol.

16. The process as claimed in claim 1 wherein Cevimeline hydrochloride hemihydrate (CVM-II) is prepared by reacting racemic cevimeline base prepared in situ and isopropyl hydrochloride in isopropyl alcohol and followed by isolation / crystallization using cyclohexane.

17. The process as claimed in claim 16 wherein racemic cevimeline base is obtained in a two steps reaction wherein in the first step, thioacetic acid salt of 3 -hydroxy-3 -acetoxymercapto methyl quinuclidine (CVM-I) is reacted with isopropyl alcohol hydrochloride in isopropyl alcohol at 75 - 85°C to produce in situ 3 -hydroxy-3 -mercaptomethyl quiniclidine which is reacted with acetaldehyde diethyl acetal followed by one or more work up processes.

18. The process as claimed in claim 17 wherein thioacetic acid salt of 3- hydroxy-3-acetoxymercapto methyl quinuclidine (CVM-I) is reacted withisopropyl alcohol hydrochloride in isopropyl alcohol in a mole ratio of from 1 :3 - 1 :

4. at a temperature of from 75-85°C.

19. The process as claimed in claim 18 wherein thioacetic acid salt of 3- hydroxy-3-acetoxymercapto methyl quinuclidine is obtained from 3- Quinuclidinone hydrochloride in two steps wherein in a first step 3- Quinuclidinone hydrochloride in a first solvent is reacted with Trimethyl sulfoxonium iodide at 0-10°C in presence of a base to produce in situ an intermediate epoxide of 3-methylene quinuclidine and in the subsequent step, epoxide of 3-methylene quinuclidine in situ is reacted with Thioacetic acid in a second solvent environment, yielding the Thioacetic Acid Salt of 3 -hydroxy-3 -acetoxymercaptom ethyl quinuclidine.

20. The process as claimed in claim 19 wherein the first solvent is selected from dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran; a combination of dimethyl sulfoxide and dimethyl formamide; and a second solvent is selected from cyclohexane, Di-isopropyl ether, ethyl acetate and toluene.

21. The process as claimed in claim 19 wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium hydride, potassium hydride, sodium tertiary butoxide, potassium tertiary butoxide and any combination thereof.

22. The process as claimed in claim 19 wherein the base is added in 2 - 6 portions.

23. The process as claimed in claim 21 wherein the base is potassium tertiary butoxide.

24. The process as claimed in claim 23 wherein the base is potassium tertiary butoxide and it is added in five equal portions / lots / parts at 0-10°C.

25. Cis Cevimeline Hydrochloride containing not more than 0.15 % of a single specified impurity selected from i) Cevimeline impurity-1 : 3-(((l-((((lR,4R)-3-Hydroxyquinuclidin-3- yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; andii) Cevimeline impurity -2: 3-(((l-((((lS,4S)-3-Hydroxyquinuclidin-3- yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol.

26. Cis Cevimeline Hydrochloride containing i) not more than 0.5 %, preferably not more than 0.3 % of Trans isomer; ii) Not more than 0.1 % of single unspecified impurity; iii) Not more than 0.15 % of single specified impurity selected from a) Cevimeline sulfoxide (RRR); b) Cevimeline sulfoxide (RRS); c) Cevimeline N-Oxide; d) Cevimeline impurity-1: 3-(((l-((((lR,4R)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol; and e) Cevimeline impurity -2: 3-(((l-((((lS,4S)-3-Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3-ol. iv) Not more than 0.1 % of diol impurity; v) Not more than 0.1 % of thiol impurity.

27. Cis cevimeline para nitrobenzoic acid salt having following specification28. Mixture of i) Cevimeline impurity-1 which is 3-(((l-((((lR,4R)-3- Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3- ol and ii) Cevimeline impurity -2 which is 3-(((l-((((lS,4S)-3- Hydroxyquinuclidin-3-yl) methyl) thio) ethyl) thio) methyl) quinuclidin-3- ol.

29. Mixture of claim 27 wherein the said mixture has a purity of at least 75 %, preferably at least 80 %, more preferably at least 85 % and most preferably at least 90 % considering a total of two impurities.

30. Mixture of claim 27 or 28 wherein weight ratio of Cevimeline impurity-1 and Cevimeline impurity-2 is from 1 :20 to 20:1, preferably from 1 : 10 to 10: 1, more preferably from 1 :7.5 to 7.5: 1, and most preferably from 1 :5 to 5: 1.

31. Cis cevimeline hydrochloride with the following particle size distribution, D10: not more than 5pm;D50: not more than 10pm;D90: not more than 25 pm, preferably not more than 20 pm, most preferably not more than 15 pm; wherein Cis cevimeline hydrochloride is slurried in isopropyl alcohol and dried before particle size measurement.

32. Cis cevimeline hydrochloride with the following particle size distribution, DIO: not more than 20pm, preferably not more than 10 pm and more preferably not more than 7.5 pm;D50: not more than 50pm; preferably not more than 30 pm and more preferably between 10 pm - 25 pm;D90: not more than 100 pm, preferably not more than 80 pm, most preferably not more than 75 pm. wherein Cis cevimeline hydrochloride is dissolved in isopropyl alcohol and precipitated by cyclohexane and dried before particle size measurement.

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