Technical Field of Invention:
This invention relates to the industrial manufacturing method of (2RS)-1-Dimethylamino-3-{2-[2-(3- methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride also known as Sarpogrelate Hydrochloride.
(2RS)-1-Dimethylamino-3-{2-[2-(3- methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride is also known as Sarpogrelate Hydrochloride which is a known pharmaceutical drug.
More specifically it relates to a novel process for dissolution, filtration, purification and re-crystallization of (2RS)-1-Dimethylamino-3-{2-[2-(3- methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride.

BACKGROUND OF THE INVENTION:
(2RS)-1-Dimethylamino-3-{2-[2-(3- methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride or Sarpogrelate hydrochloride is a publicly known compound which can be manufactured based on the description of the working example 2 of the patent documents (1). It is indicated that the above-mentioned compound has platelet aggregation inhibitory action in the patent documents 1, and further it is indicated that the above-mentioned compound has serotonine antagonism in the patent documents 2.
[Patent documents 1] JP,S58-32847,A [Patent documents 2] JP,H2-304022,A [Patent documents 3] JP,2006-160764,A [Patent documents 4] JP,2006-160765,A [Patent documents 5] JP,2006-160766,A
[Patent documents 6] JP,2007-217333
[Patent documents 7] JP,2008-255065 [Patent documents 8] JP,2008-285445
(2RS)-1-Dimethylamino-3-{2-[2-(3- methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride or Sarpogrelate hydrochloride has the outstanding 5-HT2 antagonism, It is mostly used by clinical as medicine effective in an improvement of ischemic various symptoms, such as an ulcer accompanying a chronic arterial occlusive disease, a pain, and a cold sense. Sarpogrelate hydrochloride can be manufactured based on the description of the working example 2 of the patent documents 1. it can be described by the following formula [Chemical formula 1]


Above shown in Formula (I) is sarpogrelate hydrochloride (JAN) which is (2RS)-1-Dimethylamino-3-{2-[2-(3- methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride. It has CAS # 135159-51-2. Its molecular weight is 465.97. The pharmaceutical drug substance specifications are also described in Japanese Pharmacopoeia XVI. Original product of Sarpogrelate Hydrochloride is marketed with brand name ANPLAG and it is widely sold in the forms of tablets and granules.

OBJECTS AND SUMMARY OF INVENTION
The manufacturing method of (2RS)-1-Dimethylamino-3-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride or Sarpogrelate hydrochloride is indicated by the patent documents 1, and specifically, that method is a chemical reaction of a following formula. :

The compound of formula (IV) is produced by making the succinic anhydride of formula (III)
react to the amino compound of formula (II) and was made into the hydrochloride, and the
crude crystal of this hydrochloride has been recrystallized and obtained from acetone so that it
may be shown (patent documents 1).
However, recrystallization given in these patent documents 1 is the recrystallization under thin
conditions. Industrially, only unreal recrystallization conditions are indicated.
Patent document (6) describes recrystallization using hydrous solvent preferably hydrous
acetone or hydrous acetonitrile.
Whereas in patent documents (7) and (8) describes the method of precipitating pure crystal of Sarpogrelate Hydrochloride using a hydrous ketone solution.
The person tried to manufacture sarpogrelate hydrochloride Using the process described in (6) ,(7) , (8) and found that the yield obtained is poor. Due to presence of water yield decreases (same also mentioned in patent doc. 8). Alternatively Lots of solvent is to be used in case the use of water needs to be limited. Also the major impurity and degradation product BP984 (patent doc. 1) having retention time 0.82 and limit of 0.2% (as described in Japanese Pharmacopoeia 16 ) cannot be successfully reduced or controlled using hydrous system. Also water based systems produce higher proportion of Form-I crystal form of sarpogrelate hydrochloride. But since Form- II is a more preferable form [as decribed in patent docs – (3), (4) and (5) ] it is not desirable to have water based (hydrous) systems for obtaining final crystal of product. Another disadvantage of Water based (hydrous) systems is that they require more

chilling under prolonged time of stirring, for example : stirring has to be maintained for more then 12 hours below 5 deg C temperatures so as to achieve moderate or below moderate yields. Another solid state aspect of pure crystal form is flowability, which again is very poor in the hydrous systems. Flowability is an important solid state characteristic of this particular pharmaceutical compound since it is also formulated and marketed as granules apart from tablets.
Therefore there is a need to provide industrial scale method of recrystallization, purification, filtration and dissolution of Sarpogrelate Hydrochloride which uses least solvent, is simple in operation, but provides high purity, high yield, high reproducibility, free flowing crystals, desired crystal form and polymorphic mixtures, lesser degradation products etc.

DETAILED DESCRIPTION OF INVENTION
The present invention relates to the process involving dissolution, filtration, purification and recrystallization of Sarpogrelate Hydrochloride crude crystal using a solvent mixture comprising of ketone(s) and carboxylic acid(s) or mixtures thereof.
The present invention also relates to preparing a solution of sarpogrelate hydrochloride crude crystal in a solvent mixture consisting of ketone(s) and carboxylic acid(s) or mixtures thereof; heating the solution to achieve complete dissolution; providing charcoal treatment; filtering the solution; cooling and crystallizing so as to achieve the pure crystal form of sarpogrelate hydrochloride.
The present invention also relates to preparing a solution of sarpogrelate hydrochloride crude crystal in a solvent mixture consisting of ketone(s) and carboxylic acid(s) or mixtures thereof; heating the solution to achieve complete dissolution; providing charcoal treatment; filtering the solution; controlling the cooling rate and seeding the solution with crystal seed or seed mixture so as to achieve the desired crystal form or crystal mixture of sarpogrelate hydrochloride.
The present invention describes use of acetone, methyl ethyl ketone and methyl isobutyl ketone as a ketone solvent, whereas it describes use of formic acid and acetic acid as a carboxylic acid.
Although acetone, methyl ethyl ketone and methyl isobutyl ketone are mentioned as amongst ketones, methyl ethyl ketone is preferred especially.
Although formic acid and acetic acid is mentioned as amongst carboxylic acids, formic acid is preferred especially.
Preferred solvent mixture described in this invention means a solvent mixture of ketone(s) and a carboxylic acid(s) and or mixtures thereof, where ketone is preferably acetone, methyl ethyl ketone, methyl isobutyl ketone, and the carboxylic acid is preferably formic acid or acetic acid.
According to the present invention the addition of water has been avoided consciously in the solvent mixture used for dissolving, purifying, filtering & re-crystallizing the final crystal form of sarpogrelate hydrochloride. Solvents selected in this invention are of least toxic potential.
According to one embodiment of the present invention, crude crystal of sarpogrelate hydrochloride are dispersed or dissolved in solvent mixture consisting of methyl ethyl ketone (MEK) and formic acid. Further they are heated under stirring to dissolve completely the crude crystals. The solution is provided with activated charcoal treatment and then filtered. The filtrate is cooled to achieve pure crystals of sarpogrelate hydrochloride. The crystals obtained

as per this method are having higher proportion of Form-II and are free flowing in nature. This method uses lesser solvents and produces higher yield. This method is energy efficient and less time consuming since prolonged chilling is not required. This method is simple in operation and can be performed easily on industrial scale.
Wherever described in the present invention, purification experiments relates to the process of dissolution, filtration, purification & re-crystallization of sarpogrelate hydrochloride crude crystals so as to obtain pure crystals of sarpogrelate hydrochloride.
In various purification experiments performed it was found that with the use of solvent mixture consisting of ketone and carboxylic acid , especially methyl ethyl ketone and formic acid, the major impurity BP984 (patent doc. 1) having retention time 0.82 and limit of 0.2% (as described in Japanese Pharmacopoeia 16 ) is successfully reduced and controlled well within the limits. This shall ensure a better stability of drug substance during its storage and life cycle. Since the impurity BP984 is a major degradation product, The tablets, granules or formulations using the drug substance having impurity BP984 at low levels is highly desired. Using present invention BP984 can be consistently kept limited upto 0.05% impurity levels in final product.
In various purification experiments performed using water based systems, as described in patent documents 1 to 8, it was found that crystals obtained of the pure product were not free flowing in nature. Whereas in the experiments performed using preferred solvent mixture it was observed that freely flowing pure crystals were repeatedly obtained. Considering that Sarpogrelate hydrochloride is marketed as granules and tablets, the feature of flowability is very important for the manufacture as well as administration of the final dosage form.
In various purification experiments performed using water based (hydrous) solvent mixtures, it was observed that yields obtained of pure crystals is significantly poor. Considering that sarpogrelate hydrochloride is an expensive product, such an yield loss during final stages of production can have significant impact on the overall product economics and can cause a unjustified economic burden on the patient due to increased final dosage form costs. This disadvantage is overcome using the preferred solvent mixture, since yields obtained by this invention are significantly higher. Thereby a lesser expensive end product can be provided to the end user.
In the various purification experiments performed using water based (hydrous) solvent mixtures including the processes as described in patent documents 1 to 8, it was observed that dissolution of crude crystals required significant amount of solvents, in excess of 10 times to that of solute, so as to limit the proportion of water in the final solvent mixture. Since if lesser solvent is used and water is higher in the final solvent mixture then it will ensure lesser yield, poor crystal nature, more proportion of undesired crystal form etc. So while performing water

based experiments water proportion had to be kept at minimum in final solvent mixture so as to achieve results, but in doing so the solvents had to be used in excess of 10 times, in some cases even 30 times. This disadvantage is overcome using the present invention, which describes use of preferred solvent mixture. Present invention uses minimum of solvent, preferably in the range of 3 to 6 times of the solute. Therefore present invention generates lesser solvent waste and is a more eco friendly process.
In the various purification experiments performed using water based (hydrous) solvent mixtures including the processes as described in patent documents 1 to 8, it was observed that in order to crystallize the final product prolonged stirring under chilled conditions is required. As suggested in some patent documents overnight stirring i.e. in excess of 15 hours is required to achieve results. This results in lesser productivity due to more occupancy of the equipments. Also it is time consuming as well as energy consuming. This disadvantage is overcome by the present invention, by which the process time is significantly reduced and prolonged stirring under chilled conditions are not essential.
In the various purification experiments performed it was observed that even without addition of crystal seed or mixture, the process could easily achieve higher ratio of crystal form II with respect to crystal form I. Ratio of 7:3 (form II: form I) and above was easily achieved by present invention without the need of seeding. With the addition of crystal seed or seed mixture, any of the desired ratio could be easily reproduced, for example 75:25, 80:20, 90:10 etc. Under controlled conditions of temperature and under controlled seeding, crystal seed mixture having more then 98% form II is achieved. By this means selective crystallization and thereby obtaining selective crystal seed mixtures is possible using this process.
According to this invention crystal form I corresponds to the crystal form having melting range between 150 to 152 deg C, Whereas crystal form II corresponds to the crystal form having melting range between 154 to 156 deg C.
Best Mode of Carrying Out the Invention: it became clear that re-crystallization and purification could be performed by dissolving the crude crystal of sarpogrelate hydrochloride in solvent mixture of methyl ethyl ketone and formic acid, filtering, crystallizing, washing and drying the pure crystals. Methyl ethyl ketone is preferably 4 to 6 times, whereas formic acid is preferably 0.6 to 1.3 times that of solute. The results of melting point of pure product obtained by following this procedure typically are in excess of 153 deg C. Further by controlling the cooling rate and or by adding seed or seed mixture higher proportion of Form II crystal is achieved. Following this method crystals of sarpgrelate hydrochloride containing more then 95% of crystal form II are achieved, of which melting range is in between 154 to 157 deg C. Typically the Related substances and Purity tests by HPLC method (following procedure

described in Japanese Pharmacopoeia XVI) showed more then 99.80% purity, which had the specific degradation product and major impurity BP984 (retention time 0.82, limit 0.2%) in the range of 0.01% to 0.06%, whereas all other individual impurities were well within limit of 0.1%. It became clear that highly pure final product is achievable alongwith obtaining high yield and desired crystal forms and mixtures. Also the final dried crystals of products were highly free flowing in nature and were easier to handle during further physical operations such as milling, sifting. It was noticed that desired particle size distribution and bulk density could be easily achieved using the crystals obtained from present invention.
Typical experiments conducted using present invention have proven the ability to repeatedly reproduce the results as described above.
The results of various experiments conducted during this invention were monitored using specifications and method of analysis of sarpogrelate hydrochloride as described in the Japanese Pharmacopoeia XVI.
The invention will now be exemplified by the following non-limiting examples. Hereafter, although an example and the example of an experiment explain this invention concretely, this invention is not limited to these statements. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.
EXAMPLES
Example 1
adding 10g crude crystal of sarpogrelate hydrochloride to a solvent mixture consisting of 50 ML acetone and 28 mL acetic acid, the solution is warmed to achieve dissolution and then it was cooled to obtain the crystals. The crystals were filtered and washed with acetone, after drying finally 9.2 gm of pure crystals were obtained. Purity by HPLC was not less then 99.5%. Melting Range of the final product was in the range of 152 to 155 deg C.
Example 2
adding 10g crude crystal of sarpogrelate hydrochloride to a solvent mixture consisting of 50 ML Methyl Ethyl Ketone (MEK) and 10 ML formic acid, the solution is warmed to achieve dissolution and then it was cooled to obtain the crystals. The crystals were filtered and washed with MEK, after drying finally 9.4 gm of pure crystals were obtained. Purity by HPLC was not less then 99.5%. Melting range of the final product was in range of 153.5 to 156 deg C.

WE CLAIM
1. The process for producing sarpogrelate hydrochloride comprising the steps of :
(a) Dispersing and/or dissolving crude crystals of sarpogrelate hydrochloride in a solvent mixture consisting of ketone(s) and carboxylic acid(s) and or mixtures thereof.
(b) Treating with purification aid, preferably active charcoal and filtering the solution.
(c) Heating and or Cooling the filtrate, with or without adding crystal seed or seed mixture.
(d) Isolating the crystals, preferably using filtration.
(e) Washing the crystals with solvent or solvent mixture, preferably a ketone.
(f) Drying the crystals, preferably under reduced pressure.

2. A way according to process as claimed in claim 1, wherein the solvent mixture is selected from the group of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and from group of carboxylic acids such as acetic acid, formic acid and/or mixtures thereof.
3. The process involving re-crystallization and/or dissolution and/or filtration and/or purification and/or washing of sarpogrelate hydrochloride using solvent mixtures and/or procedure selected from claim 1 to 2 and/or from claim 4 to 20.
4. The process involving recrystallization and/or dissolution and/or filtration and/or purification of sarpogrelate base using solvent mixtures and/or procedure selected from claim 1 to 3 and/or from claim 5 to 20 and/or further forming hydrochloride salt to achieve sarpogrelate hydrochloride using solvent mixtures and/or procedure selected from claim 1 to 3 and/or from claim 5 to 20.
5. The process for manufacture of sarpogrelate hydrochloride using solvent mixture consisting of ketone(s) and carboxylic acid(s) and or mixtures thereof.
6. The process involving recrystallization and/or dissolution and/or filtration and/or purification and/or washing of sarpogrelate hydrochloride using solvent mixture consisting of methyl ethyl ketone and carboxylic acid, prefereably formic acid.
7. The process invovling recrystallization and/or dissolution and/or filtration and/or purification and/or washing of sarpogrelate hydrochloride using solvent mixture consisting of acetone and carboxylic acid preferably formic acid.

8. The process involving recrystallization and/or dissolution and/or filtration and/or purification and/or washing of sarpogrelate hydrochloride using solvent mixture consisting of ethyl acetate and carboxylic acid preferably formic acid.
9. The process involving recrystallization and/or dissolution and/or filtration and/or purification and/or washing of sarpogrelate hydrochloride using solvent mixture of hydrous ketone and carboxylic acid or by using solvent mixture of ketone and hydrous carboxylic acid or by using solvent mixture consisting of hydrous ketone and hydrous carboxylic acid.

10. The process by which crystal seed or seed mixture is added in any of process described from claim 1 to 9 and/or from claim 11 to 20 so as to achieve desired crystal form and/or crystal seed mixture and/or polymorphic forms and/or polymorphic ratio of sarpogrelate hydrochloride.
11. The process involving dispersion and/or dissolution of sarpogrelate hydrochloride in solvent mixture consisting of ketone(s) and carboxylic acid(s) and or their mixtures thereof using solvent mixtures and/or procedure described in claims 1 to 10 and/or from claims 12 to 20,and then dropping this solution in a solvent. Alternatively, dropping a solvent or solvent mixture in a solution prepared by dispersing and/or dissolving sarpogrelate hydrochloride in solvent mixture consisting of ketone(s) and carboxylic acid(s) and or mixtures thereof using solvent mixtures and/or procedure described in claims 1 to 10 and/or from claims 12 to 20.
12. The process involving use of water especially by addition and/or removal of water so as to improve and/or modify any of solvent mixture and/or process described from claims 1 to11 and/or from claim 13 to claim 20.

13. The process following procedure described in claims 1 to 12 and/or from claims 14 to 20 for successful removal and/or control of major impurity and degradation product BP984 (patent document 1, having impurity limit of 0.2% and hplc retention time 0.82 as per Japanese Pharmacopoeia 16 ), Thereby consistently achieving sarpogrelate hydrochloride having impurity levels of BP984 upto maximum 0.06% which is well within the limits established.
14. The process which involves improvement in final crystal nature or physical state such as flowability, solubility, color, bulk density, particle size distribution, polymorphism and other physical and/or solid state characteristics using any of the process described from claim 1 to claim 13 and/or from claim 15 to 20 in addition to unit operations such as spray drying, air jet milling, pulverizing, size reduction process, air classification etc.

15. The process which achieves consistently pure crystal forms I and/or crystal form II, or a process achieving consistent crystal polymorphic mixtures of sarpogrelate hydrochloride in desired ratios, for example 7:3, 8:2, 9:1 (of form II: form I ) using any of the process as described from Claim 1 to claim 14 and/or from claim 16 to 20.
16. The process involving process improvisations such as techniques of cooling , crystallization, precipitation, evaporative crystallization and/or by modifying cooling rates and/or durations and/or by modifying reaction parameters using any of the process as described from claims 1 to claim 15 and/or from claim 17 to claim 20.
17. The process of obtaining crystal seed and/or crystal seed mixture and/or crystal polymorph and/or crystal polymorphic mixture and/or suspensions using any of the process as described from claim 1 to claim 16 and/or claim 18 to 20.
18. The process of achieving improved powder form suitable for formulation such as free flowing crystals or granules or fine granules or pellets or directly compressible grade granules or directly compressible powder of sarpogrelate hydrochloride using any of the process described from claim 1 to claim 17 and/or from claims 19 to 20.
19. The process to achieve sarpogrelate hydrochloride having higher proportion of stable crystal form II especially more than 98% pure crystal form II of sarpogrelate hydrochloride using any of the process described from claim 1 to claim 18 and/or from claim 19 to 20, and thereby achieving a more stable end product.
20. The process to achieve sarpogrelate hydrochloride having melting point and/or DSC (differential scanning calorimetry) endotherm more then 152 deg C or preferably more then 154 deg C, using any of process described from claim 1 to claim 19.