FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: "AN IMPROVED PROCESS FOR THE
PREPARATION OF PHARMACEUTICALLY ACCEPTABLE SALTS OF RACEMIC
MILNACIPRAN AND ITS OPTICAL ENANTIOMERS THEREOF".
2. APPLICANT
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: "H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road,
Chandivali, Andheri (East), Mumbai-400072, India.
PREAMBLE TO THE DESCREPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE:
An improved process for the preparation of pharmaceutically acceptable salts of racemic milnacipran and its optical enantiomers thereof.
TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of pharmaceutically acceptable salts of milnacipran by mutual acid radical exchange. Herein the term milnacipran includes racemic milnacipran and its optical enantiomers unless specified. The process comprises the treatment of the racemic milnacipran or mixture of its enantiomers or optical enantiomer with an organic acid which generates the corresponding less soluble acid addition salt that is either purified or is enriched. Recrystallization or pulping using various organic solvents allows either purification or enrichment of the specific enantiomer. The said organic acid salts of the cis-milnacipran or its optical enantiomers prepared according to the present invention could be further converted into the pharmaceutically acceptable salt directly in a single step by exchange of the organic acid salt with mineral acid radical avoiding generally practiced additional process step of the generation of free base which is then converted into the desired pharmaceutically acceptable salt.
Present invention relates to an industrially acceptable improved process for the preparation of milnacipran pharmaceutically acceptable salts of formula I and also for its optical enantiomers namely dextrogyral Z (IS, 2R) of formula III and levogyral Z (1R, 2S) of formula IV from corresponding racemic mixture (50:50 of dextrogyral: levogyral) or mixture of dextrogyral and levogyral enantiomers or dextrogyral and levogyral enantiomers.

wherein A is anionic part of an acid
Formula I

(Racemic form of (cis) milnacipran)

Formula III ((IS, 2R)-(cis)-milnacipran)

((1R, 2S)-(cis)- milnacipran)

BACKGROUND OF THE INVENTION:
Racemic milnacipran chemically named as l-phenyl-2-(aminomethyl)
cyclopropane-N, N-diethyl carboxamide) was first approved for the
treatment of major depressive episodes in France in December 1996. It is
currently marketed (as Ixel) for this indication in over 45 countries
worldwide including several European countries such as Austria,
Bulgaria, Finland, France, Portugal, and Russia. It is also available in
Japan (as Toledomin) and Mexico (as Dalcipran). Cypress Bioscience
bought the exclusive rights for approval and marketing of the drug for
any purpose in the United States and Canada in 2003 from the inventor
Pierre Fabre. It is reported that said drug is also used to treat fatigue,
pain, fibromyalgia, Irritable bowel syndrome and the like. At present, it
is mostly sold in the form of racemic cis milnacipran hydrochloride.
Milnacipran belongs to dual inhibitors of serotonin and norepinephrine
reuptake (SNRI), which is the fourth generation antidepressant and can
inhibit both serotonin and norepinephrine reuptakes, with similar action
strength. It is mainly useful to treat depression. Currently 22 countries
have approved racemic cis milnacipran for treating depression. Cis
milnacipran (Z(±)-2-(amino methyl)-N,N-diethyl-l-phenyl cyclopropane
carboxamide), a molecule synthesized at the PIERRE FABRE
MEDICAMENT Research Centre (Castres, France), also called as TN-
912, dalcipran, minalcipran, midalcipran or midalipran is known to be a
dual inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake.
Dual inhibitors of serotonin (5-HT) and norepinephrine (NE) reuptake
correspond to a well-known class of antidepressant agents which
selectively inhibit reuptake of both serotonin and norepinephrine. By
way of example, venlafaxine and duloxetine are also dual inhibitors of
serotonin and norepinephrine. Studies have shown that the ratio of
norepinephrine reuptake inhibition to serotonin reuptake inhibition by
cis milnacipran is approximately 2:1 (Moret et al., 1985

Neuropharmacology 24(12): 1211-1219; Palmier et al., 1989, Eur J Clin Pharmacol 37: 235-238).
In January 2009 the U.S. Food and Drug Administration (FDA) approved racemic cis milnacipran (under the brand name Savella for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States. Fibromyalgia, which is estimated to affect from 2-4% of the population in the US, is a complex syndrome associated with chronic widespread musculoskeletal pain and a reduced pain threshold, with hyperalgesia and allodynia (pain-related behavior in response to normally innocuous stimuli). Some associated clinical features include fatigue, depression and other mood disorders, anxiety, sleep disturbances, headache (including migraine), changes in bowel habits (including irritable bowel syndrome), diffuse abdominal pain, and urinary frequency.
The study of racemic cis milnacipran has revealed that the medication containing cis milnacipran does not interact with other medications as it has lower ability of plasma protein-binding, moreover cis milnacipran's half-life is relatively shorter, it has an advantage of no residual effect after treatment, and therefore it has fine tolerance and security, therefore it has acquired a lot of importance in the present scenario".
In 1992, a resolution had been approved by American Food and Drug Administration (FDA) and The European Committee for Proprietary Medicinal Products, which encouraged that drugs with chiral center should be in optically pure form for marketing authorization; in 1996, a project had been proposed by FDA that drugs with chiral center must be in optically pure form when it is applying for marketing authorization. There are two chiral centers in the molecular structure of milnacipran; there should be two groups of enantiomers and therefore four compounds in theory. Due to the molecular configuration, the cis-isomer

is the main synthetic product, that exists in two forms of optical enantiomers: the dextrogyral enantiomer of cis-milnacipran hydrochloride Z-(1S,2R) of formula IV chemically named as Z-(1S,2R)-2-(amino methyl)-N,N-diethyl-l-phenyl cyclopropane carboxamide and the levogyral enantiomer of cis-milnacipran hydrochloride Z-(1R,2S) of formula V chemically named as Z-(1R, 2S)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide. In its hydrochloride form, cis milnacipran (also called F2207) is currently marketed as Iexel in the form of a racemic mixture as a serotoninergic and norepinephrinergic antidepressant agent. F2695 and F2696 represent the dextrogyral and levogyral enantiomers respectively of cis milnacipran hydrochloride (F2207).
Cis milnacipran and its method of preparation are described in US4478836.The said patent also describes the use of cis milnacipran for the treatment of disorders of the central nervous system, in particular depression.
US2004/0162334, US20060014837 and CN1699332A, US7005452 discloses the use of a mixture of enantiomers enriched in the dextrogyral enantiomer of cis milnacipran as well as their pharmaceuticalry-acceptable salts, for the preparation of a drug intended to prevent or to treat disorders that can be managed by double inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake, while limiting the risks of cardiovascular disturbances and/or organ and/or tissue toxicity. The said patent applications also disclose that the dextrogyral enantiomer of cis milnacipran hydrochloride had activity which was significantly higher than racemic cis milnacipran, with less risk of cardiovascular disturbances and tissue and organ organic toxicity. However the said patent or applications do not disclose any information related to pharmacology of levogyral enantiomer of cis milnacipran.

European journal of metabolism and pharmacokinetics, 1998, April-June, 23(2), 166-171 discloses that both dextrogyral referred as F2695 and levogyral referred as F2696 are pharmacologically active, although F2695 carries most of the pharmacology activity.
US7074833 clearly discloses that dextrogyral referred as F2695 is two time superior than the racemic milnacipran and twenty-five times than levogyral referred as F2696. Moreover it also discloses that F2696 is more toxic than F2695. It also discloses the use of dextrogyral F2695 for the preparation of medicine for disorders.
FR2581060B1 discloses an industrial process for the preparation of milnacipran hydrochloride as per scheme-I given herein below:
Scheme I:

EP200638B1 discloses a process comprising reaction of cis-1-phenyl-1-
diethylcarbamoyl-2- phthalimidomethyl-cyclopropane with a primary
alkylamine or hydroxy alkylamine, optionally in a solvent, to get (Z)-l-
phenyl-1 -diethylaminocarbonyl-2-(aminomethyl)cyclopropane base
followed by its reaction with HC1 to give (Z)-1-phenyl-1-diethylaminocarbonyl-2-(aminomethyl)cyclopropane hydrochloride. Schematic representation of the above process is depicted in the scheme II.


US20100016636A1 (hereinafter referred as '636) discloses racemic
milnacipran and tartaric acid derivatives or their compositions used as
resolving agents are dissolved in ketone or alcohol solvent.
Crystallization is performed under room temperature and
diastereoisomer salt is precipitated and filtered. The resolved product is
separated and suspended in organic solvent and water. The tartaric acid
salt is treated with an alkali to obtain optically pure (Z)-1-phenyl-1-
diethylaminocarbonyl-2-(aminomethyl)-cyclopropane free base. The free
base is reacted with an acid to obtain its corresponding salt. '636
discloses that to prepare pharmaceutically active HC1 salt of (Z)-l-
phenyl-1 -diethylaminocarbonyl-2-(aminomethyl)-cyclopropane, the
optically pure organic acid salt has to be hydrolysed to generate a free base which in the second process step is converted into the pharmaceutically active salt. There are three process steps to convert the racemic mixture of a compound into the acid addition salt of optically pure compound of the said racemic mixture viz:
i) Preparation of organic acid addition salt of the racemic mixture of with an optically pure tartaric acid derivative;
ii) after the isolation of the optically pure tartaric acid derivative salt the said organic salt is hydrolyzed to obtain free base;
iii) free base is then treated with the mineral acid to obtain inorganic acid addition salt.

'636 neither teaches nor motivates a person skilled in the art to convert the organic acid addition salt which is a tartaric acid derivative salt in this case directly into the mineral acid salt without hydrolysis process step to isolate the free base.
JP04354436B2 discloses a process for preparing milnacipran hydrochloride comprising reaction of (Z)-1-phenyl-1-diethylaminocarbonyl-2-(hydroxymethyl)-cyclopropane with sulphonyl halide to obtain corresponding sulphonate. This sulphonate is then reacted with hexamethylene tetramine, to obtain (Z)-1-phenyl-1-diethylamino carbonyl-2-hexamethylene tetra ammonium methyl cyclopropane salt. The obtained salt is then processed with hydrochloric acid, to obtain milnacipran hydrochloride. Schematic representation of the above process is depicted in the scheme III.
Scheme III

The said patent uses sulphonyl halide followed by its hexamethylenetetramine salt preparation but it neither teaches nor motivates the use of the acid for the corresponding acid salts, which are easy to form due to the presence of free amino group in the milnacipran molecule. Disadvantage of the said prior art is the use of sulphonyl halides which are fumigating.
Therefore there is not any prior art which discloses, teaches or motivates a person skilled in the art about the direct conversion of acid addition

salt of milnacipran into milnacipran hydrochloride without going through the process step of hydrolysis of the organic acid addition salt which is prepared either to purify impure racemic mixture milnacipran base by converting into an organic acid addition salt or for resolution by treating a racemic mixture with an optically active organic salt. The present invention not only reduces a process step and minimizes unit operation but also minimizes yield loss by avoiding isolation of milnacipran base and also improves the purity.
The present invention discloses a process for the preparation of acid addition salt of milnacipran with organic acid and their conversion directly into the pharmaceutically acceptable salts which are formed by mutual exchange of acid radical preferably by mineral acid selected from hydrochloric, hydrobromic, hydrogeniodic, sulphuric acid, phosphoric acid and the like. Hereinabove and herein below the term milnacipran means racemic as well as optical enantiomers. The present invention also relates to a process comprising organic acid salt preparation as a mode of purification of racemic milnacipran or as a mode of enrichment of optically active enantiomer of milnacipran or as a tool for achieving desired impurity profile for optically pure enantiomer. The said process results into milnacipran having an excellent chemical and enantiomeric purity.
In case where organic acid is non chiral, it reacts with racemic milnacipran and acts as a mode of purification as it forms salt with free amino group of the milnacipran moiety , separates out as solid material which can be easily filtered off and further optionally purified by standard crystallization method. Later this purified salt can be directly converted into its pharmaceutically acceptable salts preferably those of mineral acid by mutual exchange of acid radical avoiding the process of hydrolysis to obtain free base as reported in the prior art.

In case where racemic milnacipran is pure but does not qualify the criteria of impurity profile, the said invention works well by forming the organic acid addition salt of milnacipran leaving behind the impurities in mother liquor.
In case of preparing optical enatiomers of milnacipran and their pharmaceutically acceptable salts, the present invention works in three ways depending upon the choice of acid for the purpose.
If the organic acid under the invention is optically pure, it serves three purposes as salt formation along with resolution providing salts of optical enantiomers, purification by the salt formation as it forms salt with free amino group of the resolved optical enantiomers of milnacipran and enrichment of the specific optical enantiomer by choosing (+) or (-) chiral acid. The said salt can be directly converted into its pharmaceutically acceptable salts preferably those of mineral acid by mutual radical exchange of acid in a single step.
In case where optically active milnacipran is pure but does not qualify the criteria of impurity profile, the said invention works well by forming the organic acid addition salt of milnacipran leaving behind the impurities in mother liquor.
Disclosed herein is also a process for the preparation of optically pure enantiomer of milnacipran wherein the organic acid addition salt of racemic optically enriched or optically pure enantiomer is directly converted into the corresponding pharmaceutically active mineral acid salt by mutual exchange of organic acid radical with the desired mineral acid radical in a single step.

OBJECT OF THE NVENTION:
First aspect of the invention is to provide a novel process for the preparation of pharmaceutically acceptable salts of racemic milnacipran and its optical enantiomers.
Second aspect of the invention is to provide a novel process for the preparation of pharmaceutically acceptable salts of milnacipran using milnacipran acid addition salts as an intermediate.
Third aspect of the invention is to provide a process comprising direct conversion of acid addition salt of milnacipran into its pharmaceutically acceptable salt by mutual acid exchange without the hydrolysis of acid addition salt to isolate free base.
Forth aspect of the present invention is the purification of racemic milnacipran having less chemical purity by its acid addition salts.
Fifth aspect of the invention is to provide an improved process for the preparation of pharmaceutically acceptable salts of optical enantiomers of milnacipran using water as solvent.
Sixth aspect of the invention is to skip and avoid the hydrolysis of intermediate acid addition salt to obtain free base which is then by an additional process step is converted into the desired pharmaceutically active salt.
Seventh aspect of the invention is to avoid the loss of yield by the additional step of hydrolysis of the intermediate acid addition salt to obtain free base.

Eighth aspect of the invention is to qualify the criteria of impurity profile by the salt preparation of organic acid addition salt which in turn in a single step is converted into pharmaceutically acceptable salt of milnacipran meeting with criteria of impurity profile.
ADVANTAGES OF THE PRESENT INVENTION:
1. The process eliminates the hydrolysis step of the intermediate acid addition salt to isolate the milnacipran base.
2. One unit operation of hydrolysis to obtain free base is reduced.
3. Acid addition salt formation acts as a mode of purification for making racemic milnacipran and its optical enantiomers.
4. Use of simple commercially available acids thereby reducing overall costing of the product.
5. Higher yield and higher purity.
6. Use of water as solvent.
7. Purification of organic acid addition salt as an intermediate is much easier for the purification of the milnacipran base.
8. Since acid addition salts are solids and therefore are easy and safe to handle.
9. Avoiding chromatographic separations.
lO.The process is low cost, easy to operate, suitable for industrial scale production.
SUMMARY OF THE INVENTION:
The present invention relates to an improved process for the preparation of pharmaceutically acceptable salts of milnacipran by mutual acid radical exchange. Herein the term milnacipran includes racemic milnacipran and its optical enantiomers. The process comprises the treatment of the racemic milnacipran or mixture of its enantiomers with an organic acid which generates a less soluble acid addition salt that is

either purified or is enriched. Recrystallization or pulping by standard crystallization process allows either purification or enrichment of the specific enantiomer. The organic acid salts of the racemic cis-milnacipran or its optical enantiomers prepared according to the present invention could be further converted into the mineral acid salt by exchange of the organic acid salt with mineral acid in a single step directly without hydrolysis process step to isolate free base.
DETAILED DESCREPTION OF THE INVENTION:
Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of the skill in the art, the invention may be embodied as a method, system or process.
Efficient, industrially viable and economical process for the preparation of pharmaceutically acceptable salts of milnacipran and its optical enantiomers by the mutual acid radical exchange method is illustrated in the following reaction schemes.
Compound of formula I and its hydrochloride is known in the art. Present invention relates to an efficient process for the preparation of pharmaceutically acceptable salts over the processes known in the art to overcome the shortcomings therein in the processes disclosed in the prior art.
Racemic milnacipran required for the purpose of the present invention is prepared by the process as disclosed in EP0200638Bl.The schematic representation for the same is as given below:


In first embodiment of the invention, racemic milnacipran is reacted with an organic acid to form the corresponding organic acid addition salt in a solvent to purify the milnacipran. The said organic acid addition salt of milnacipran so obtained is then converted into pharmaceutically acceptable salts by mutual acid radical exchange by the addition of corresponding acid. The invention is represented by scheme IV given herein below. Acid addition salt formed in this embodiment contains milnacipran with an improved chemical purity than the original milnacipran base used for the purpose. Therefore salt formation works as one mode of purification of milnacipran. Secondly purified salt is directly converted into pharmaceutically acceptable salt in a single step avoiding hydrolysis and isolation of purified milnacipran base by the addition of corresponding acid. Schematic representation for the said embodiment is as given in scheme IV.
Scheme IV:


Racemic milnacipran defined in the first embodiment includes impure, pure milnacipran having a particular impurity profile not meeting desired specifications of the pharmaceutically acceptable milnacipran.
Organic acid used for the purpose of the first embodiment is selected from the group of organic acids which are capable of forming acid addition salts with milnacipran. Preferably organic acid for the present invention is selected from citric acid, succinic acid, malic acid, mandelic acid, oxalic acid, tartaric acid or derivatives thereof and the like.
Solvent used for the purpose of first embodiment is chosen from the group of esters, aromatic hydrocarbon and ketones.
Acids used for the preparation of pharmaceutically acceptable salts are selected from the group of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid and the like.
In a preferred embodiment racemic milnacipran having the less chemical purity is reacted with oxalic acid using ethyl acetate as a solvent to prepare racemic milnacipran oxalate containing milnacipran with enhanced chemical purity. This optionally purified salt is then reacted with hydrochloric acid using isopropyl alcohol as a solvent to prepare milnacipran hydrochloride in a single step avoiding isolation of the free base. Schematic representation for the said embodiment is as given in scheme V.


In another preferred embodiment wherein racemic milnacipran having higher chemical purity but not meeting the impurity profile as per the requirement in the market or industries is reacted with organic acid to prepare the corresponding milnacipran organic acid addition salt. The said salt is then optionally purified and reacted with hydrochloric acid to prepare the milnacipran hydrochloride with improved impurity profile in a single step without isolating the free base.
Inventors of the present invention found that racemic milnacipran obtained by the route of synthesis that is followed remains associated with N,N'-dimethylphthalimide as an impurity upto the extent of about 5%, which is formed during deprotection of phthalimide group using monomethyl amine.
The present invention has been proved to be successful tool for the removal of the said impurity by employing the efficient process disclosed herein in the present invention.
In another preferred embodiment wherein racemic milnacipran acid addition salt having higher chemical purity is converted in a single step into milnacipran hydrochloride with the same chemical purity.
In second embodiment of the invention racemic milnacipran is reacted with chiral organic acid in a solvent to prepare diastereomeric salts of milnacipran with enhanced optical purity. The optionally purified salt is then directly converted into pharmaceutically acceptable salts in a single step by the addition of corresponding mineral acid eliminating the process steps of hydrolysis to isolate milnacipran base. The preparation of chiral acid addition salt of milnacipran is represented in scheme VI.


Scheme VI:

Chiral organic acid for the second embodiment of the present invention is selected from the group of tartaric acid, di-p-toluyl tartaric acid, di-p-benzoyl tartaric acid, di-p-methoxybenzoyl tartaric acid, camphor sulphonic acid, mandelic acid and derivatives thereof and the like.
Solvent is selected from water, aromatic hydrocarbon, aliphatic alcohol, aliphatic ketone, ether, ester, acyclic and cyclic aliphatic hydrocarbon or mixture thereof. Preferably solvent is selected from toluene, isoprpoanol alcohol, acetone, methyl tert butyl ether, cyclohexane, hexane and the like. More preferably solvent is water.
In a preferred embodiment crude racemic milncipran having inferior purity is dissolved in water, till a clear solution is obtained followed by the addition of aqueous solution of D-(-)-mandalic acid under stirring, heat optionally, continue stirring till (IS, 2R)-cis-milnacipran D-(-)-mandelate is precipitated completely. The optically pure (IS, 2R)-cis-milnacipran D-(-) - mandelate so obtained is filtered off and washed with water. This isolated (IS, 2R)-cis-milnacipran D-(-)- mandelete contained about 99% optically pure (IS, 2R)-cis-milnacipran with yield of about 89%.Only single crystallization from ethyl acetate enhanced optical

purity to about 99% with yield of about 77%.The said salt is then directly converted in a single step into (IS, 2R)-cis-milnacipran hydrochloride with required purity without hydrolysis to prepare and isolate (IS, 2R)-cis-milnacipran base. Schematic representation for the said embodiment is as given in scheme VII.

In another preferred embodiment of the invention optically pure milnacipran but not meeting impurity profile criteria is reacted with organic acid resulting into the formation of organic acid addition salt of optically pure milnacipran, which is filtered off. The said organic acid addition salt is then optionally purified and is converted directly in a single step into milnacipran hydrochloride by addition of hydrochloric acid meeting the required criteria of impurity profile.
In another preferred embodiment wherein optically active milnacipran acid addition salt having higher optical purity is converted in a single step into milnacipran hydrochloride with the same optical purity.
The following non limiting examples are provided to illustrate further the present invention, It will be apparent to those skilled in the art that

many modifications, variations and alterations to the present disclosure, both to materials, methods and reaction conditions, may be practiced. All such modifications, variations and alterations are intended to be within the spirit and scope of the present inventions.
Example 1: Process for preparation of racemic milnacipran hydrochloride from racemic milnacipran oxalate salt without isolating milnacipran base:
A. Racemic milnacipran (20.0 g 0.081 moles) having chemical purity of
64% was taken in 150 ml ethyl acetate and mixture was stirred to get
clear solution; oxalic acid (8g, 0.089 moles) was added to the above
contents in one lot. Initial clear solution turned into precipitate after
stirring for 1/2 hr. Contents were heated to 60-65 °C for 30 minutes and it
was gradually cooled to room temperature and maintained under stirring
for 4-5 hrs followed by chilling to 10-15 °C for one hour. Precipitated
solid i.e. racemic milnacipran oxalate salt was filtered off. Yield was
about 60% of theory and chemical purity was more than 95%.
B. Racemic milnacipran oxalate salt (10.0 g 0.029moles) obtained from
example 1 was taken in 20 ml of isopropyl alcohol and 20ml methyl tert
butyl ether followed by passing of dry HC1 gas till pH less than 1. The
contents were stirred for an hour to get clear solution. The mixture was
slowly brought to room temperature and then at 0-5°C for next 6hr. The
solid was filtered off and washed with precooled mixture of IPA (15ml)
and methyl tert butyl ether (150ml), to 5°C.
Dry wt of racemic milnacipran hydrochloride was 5.4g. Yield is 73% of the theory.

Example 2: Process for preparation of pure racemic milnacipran hydrochloride from impure racemic milnacipran oxalate salt without isolating milnacipran free base:
A. Racemic milnacipran (20.0 g 0.081 moles chemical purity of 97% but
having 2.7% impurity of N, N'-dimethylphthalimide was taken in 150
ml ethyl acetate and mixture was stirred to get clear solution; oxalic acid
(8g, 0.089 moles) was added to the above contents in one lot. Initial
clear solution turned into precipitate after stirring for Vz hr. Contents
were heated to 60-65°C for 30 minutes and it was gradually cooled to
room temperature and maintained under stirring for 4-5 hrs followed by
chilling to 10-15 °C for one hour. Precipitated solid i.e. racemic
milnacipran oxalate salt was filtered off. Yield was about 61% of theory
and chemical purity was found to be 99.6% with the said impurity as
0.09 %.
B. Racemic milnacipran oxalate salt (10.0 g 0.029moles with 0.09% N,
N'-dimethylphthalimide ) obtained from example 2was taken in 20 ml of
isopropyl alcohol and 20ml methyl tert butyl ether followed by passing
of dry HC1 gas till pH less than 1. The contents were stirred for an hour
to get clear solution. The mixture was slowly brought to room
temperature and then at 0-5°C for next 6hrs. The solid was filtered off
and washed with precooled mixture of IPA (15ml) and methyl tert butyl
ether (150ml), to 5°C.
Dry wt of racemic milnacipran hydrochloride was 5.4g. Yield is 71% of the theory with N,N'-dimethyl phthalimide impurity less than 0.05%
Example 3: Process for preparation of chiral milnacipran D (-) hydrochloride from chiral milnacipran D (-) mandelate salt without isolating optical milnacipran free base.

A. Racemic cis-milnacipran (20.0 g 0.081 moles) is taken in 70 ml water
, the mixture is stirred to get clear solution followed by the addition of
D (-) mandelic acid (14.0 g, 0.092 moles) solution made in 70 ml water.
The mixture is stirred, solid formation is observed, stirring is continued
for 1.0 hour. Contents are heated to 60-65°C to get clear solution and
further maintained for 30 min to 60 min. The mixture is gradually
brought to room temperature and maintained under stirring for 8-10hrs.
The crystallized solid i.e.(lS,2R)-cis- milnacipran-(D)- mandelate salt is
filtered off.
B. Chiral milnacipran D(-) mandelate salt (25.Og ,0.063 moles) was
suspended in the mixture of 20 ml of isopropyl alcohol and 65 ml of
methyl tertbutyl ether. The mass was slowly heated to 40°C. At this
temperature 11-13ml of 18%IPA.HC1 was added drop wise to get clear
solution. The contents were stirred for 1/2 hr and then cooled to 0-5°C and
maintained for 4hr. Obtained solid was filtered and washed with
precooled mixture of IPA (15ml) and methyl tert butyl ether (150ml),.
Suck dry. Dry wt 13g. Yield is about 74% of theory and optical purity of
required (+) Milnacipran contained in which 95-96% e. e.

We claim:
1. A process for the preparation of pharmaceutically acceptable salts of racemic milnacipran comprising:
a) reaction of racemic milnacipran with an organic acid in a solvent to obtain organic acid addition salt of racemic milnacipran;
b) optionally purifying the organic acid addition salt obtained in step a;
c) reacting the organic acid addition acid salt from the step a or b with mineral acid to prepare the mineral acid addition salt of racemic milnacipran without isolating milnacipran base.

2. Process of claim la wherein organic acid is selected from citric acid, succinic acid, malic acid, mandelic acid, oxalic acid, tartaric acid or derivatives thereof.
3. Process of claim la wherein solvent is selected from the group of C1-C4 esters, ketones and aromatic hydrocarbons, ethers or mixture thereof preferably C1-C4 ester.
4. Process of claim 3 wherein solvent is selected from methyl acetate, ethyl acetate, propyl acetate preferably ethyl acetate or mixture thereof preferably ethyl acetate.
5. Process of claim lc wherein mineral acid is selected from HC1, HBr, HI,, sulphuric acid, phosphoric acid ,nitric acid.
6. Process of claim 5 wherein mineral acid is HC1.

7. A process for the preparation of pharmaceutically acceptable salts
of optically active milnacipran comprising:
a) reacting racemic milnacipran with an chiral organic acid to obtain organic acid addition salt of optically active milnacipran in a solvent;
b) optionally purifying the salt formed in step a;
c) reacting the optically active organic acid addition salt from the steps a or b with mineral acid to prepare the mineral acid addition salt of optically active milnacipran. Without isolating free base of optically active milnacipran.

8. Chiral organic acid as claimed in claim 7a is selected from the group of tartaric acid, camphor sulphonic acid, mandelic acid or derivatives thereof, preferably mandelic acid.
9. Process of claim 7 wherein solvent is selected from water, aromatic hydrocarbon, aliphatic alcohol, aliphatic ketone, ether, ester, acyclic and cyclic aliphatic hydrocarbon or mixture thereof.
10. Process of claim 9 wherein solvent is selected from water, toluene, isoprpoanol alcohol, acetone, methyl tert butyl ether, cyclohexane, hexane or mixtures thereof.
11.Process of claim 10 wherein solvent is water.
12. Process of claim 7c wherein mineral acid is selected from HC1, HBr, HI,, sulphuric acid, phosphoric acid ,nitric acid.
13.Process of claim 12 wherein mineral acid is HC1.
14.A process for the preparation of substantially pure (IS, 2R)-cis-milnacipran HC1 in a single step comprising:

d) reacting (lS,2R)-cis-milnacipran chiral organic acid addition salt with mineral acid to obtain directly (lS,2R)-cis-milnacipran hydrochloride without isolating free optically active (IS, 2R)-cis-milnacipran base