[TITLE OF INVENTION]
METHOD FOR INDUSTRIALLY PRODUCING (2RS)-l-Dimethylamino-3-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride
[TECHNICAL FIELD]
[0001]
This invention concerns to the safe, eco-friendly, economical, scalable & reproducible industrial manufacturing method of sarpogrelate hydrochloride in high chemical purity, high polymorphic purity and high yield by using novel processes of solvent based re-crystallization and Non-solvent based re-crystallization by solid state crystal transition. Sarpogrelate Hydrochloride is a drug substance having various pharmaceutical and medicinal uses.
[BACKGROUND ART]
[0002]
(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 literature [PTL 1]. It is indicated that sarpogrelate hydrochloride has platelet aggregation inhibitory action in the patent literature [PTL 1], and further it is indicated that the above-mentioned compound has serotonine antagonism in the patent literature [PTL 2].
Sarpogrelate hydrochloride has the outstanding 5-HT2 antagonism. It is mostly used 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 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 monograph is provided 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 fine granules.
The manufacturing method of Sarpogrelate hydrochloride is indicated by the patent literature [PTL -1] and specifically, that method is a chemical reaction of a following formula. :
[Chemical formula 2]

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 obtained from acetone (see patent literature [PTL 1]).
The previous patent literature [ PTL 3, 4, 5 ] mentions of two different crystalline forms of sarpogrelate hydrochloride wherein physico-chemical properties of both of the crystal forms have been characterized using Infrared Absorption Spectrum, Differential Scanning Calorimetry, C-NMR spectrum and X-Ray Powder diffraction spectrum. As mentioned in the same, Form-II has an endothermic peak near about 157 deg C in Differential Scanning Calorimetry and in Infrared Absorption spectrum it has an absorption peak in 1593**2.0, 1163**2.0, 1040**2.0, or 792**2.0-cm"1. Whereas Form-I has an endothermic peak near about 152 deg C and it has an absorption peak in 1612**2.0, 1585**2.0, 1434**2.0, 1054**2.0, 932**1.0, 918**2.0, or 780**2.0-cm" in Infrared Absorption spectrum. Further, it is also mentioned that In the medicinal composition which makes the crystal an active principle, although each content ratio in particular of II form crystal and I form crystal is not limited, its medicinal composition manufactured using the bulk drug which contains II form crystal not less than about 75%, for example is preferred, not less than about 85% of II form crystal is more preferred, not less than about 98%) of II form crystal is the most preferred. Also both the crystal forms were evaluated for chemical and physical stability. It was reported that II form crystal concerning this invention has chemical stability higher than compared with crystal mixture. For physical stability, it was reported that, at a temperature lower than 25 deg C, Form-I crystal is a stable form physically, and at temperature higher than 35 deg C, Form-II crystal is a stable form physically.

Patent Literature [PTL 7] describes method for producing crystal form - I.
Patent Literature [PTL 8 and 9] describes method for producing a mixed crystal of Form- II and Form-1 crystal of sarpogrelate hydrochloride comprising of dripping a water-containing ketone solution of crude sarpogrelate hydrochloride into a pre-cooled ketone solution and collecting precipitated crystal by filtration.
Patent Literature [PTL 10] describes re-crystallization and suspension of sarpogrelate hydrochloride using acetonitrile, to form a mixed crystal of Form-1 crystal and Form- II crystal.
Patent Literature [PTL 11] describes various ways of mixing hydrogen chloride with sarpogrelate free base so as to obtain crystal mixture.
[CITATION LIST]
[PATENT LITERATURE]
[0003]
[PTL 1] JP,S58-32847,A [PTL 2] JP,H2-304022,A [PTL 3] JP,2006-160764,A [PTL 4] JP,2006-160765,A [PTL 5] JP,2006-160766,A
[PTL 6] JP, 2010-077155,A
[PTL 7] JP, 2007-217333,A
[PTL 8] JP, 2008-255065,A
[PTL 9] JP, 2008-285445,A
[PTL 10] JP, 2008-285446,A
[PTL 11] JP, 2010-126447,A
[PTL 12] KR, 20100120558,A
[PTL13]KR, 100911720, Bl
[PTL 14] KR, 20080097708,A
[PTL 15] CN, 101239920, A
[PTL 16] US, 5314506, A

[NON PATENT LITERATURE]
[0004]
[NPL 1] Journal: Crystal growth and Design, 2006, Vol. 6, No. 6, 1291-1303, Simulation of Mixing effects in anti-solvent crystallization.
[SUMMARY OF INVENTION] [TECHNICAL PROBLEM]
[0005]
However, the prior art has problems as identified in this section and for which solutions shall be provided in this invention.
In patent literature [PTL 1], method described in working example - 2 which uses acetone for the re-crystallization solvent, volume efficiency is bad. Since sarpogrelate hydrochloride is poorly soluble in acetone, huge quantities of acetone, in excess of 300 times that of solute is required to dissolve the product. So it is not efficient manufacturing method on industrial scale.
In patent literature [PTL 8] and [PTL 9], crystallization is achieved by addition of saturated solvent to anti-solvent which is also known as reverse addition. Reverse addition is a variation of anti-solvent re-crystallization whereby the API solution is added to the anti-solvent. The resulting rapid increase in the super-saturation leads to swift nucleation and the precipitation of very fine particles. This practice of reverse addition is widely used in pharmaceutical industry to crystallize small particles. Same is described in Non-Patent literature [NPL 1] and patent literature [PTL 16]. As described in non-patent literature [NPL 1], during a reverse addition, a high anti-solvent composition is achieved, which results in formation of large number of nuclei and slower mean grown rates, consequently the final particle size distribution achieved of crystallized product has more crystals of significantly smaller size. So one of the technical problem of this process is that particle size obtained is very fine which may cause effect in medicinal dosage forms created using this product, such as mixing, handling, flowability etc. Another technical problem is yield loss due to passing out of fine particles into filtrate during filtration of obtained crystals. Also there is high risk of non-reproducibility of particle size distribution during batch to batch or during scale up of operations due to change in conditions of cooling, stirring, addition rate etc.
As per patent literature [PTL 16], in the reverse addition technology concentration gradient cannot be avoided during the initial crystal formation because the introduction of feed solution to anti-solvent in a stirred vessel does not afford a thorough mixing of the two fluids prior to crystal formation. The existence of concentration gradients, and therefore a heterogeneous fluid environment at the point of initial crystal formation impedes optimum crystal structure formation and increases impurity entrainment. Therefore extreme control is required in addition rate, stirring rate, cooling, etc.

As per patent literature [PTL 8] and [PTL 9], the crude crystals are suggested to be dissolved in 1.1 to 3.6 times of acetone or methyl ethyl ketone using 0.08 to 0.25 times water. The limitation here is that if more ratio of water (0.25 times) is used then there would be more yield loss. Further to prevent or reduce such loss, lots of pre-cooled solvent, at least 8 to 10 times would be required. Again if the product solution would be added into so much volume of solvent then there would be a high and sudden under-saturation environment in which crystal quality would be very poor, in addition to yield loss, as described in this section earlier. It is rightly described in paragraph [0026] of Patent literature [PTL 8] that decline in yield by increasing water content is caused and it is not preferable. Based on same, dry crystals of sarpogrelate hydrochloride were tried to dissolve by keeping water content at 0.10 times that of acetone and using acetone (moisture content less than 2%) in varying quantities of 1 x times, 2.5 x times and 3.6x times. It was found that it was not possible to completely dissolve the product in all cases even when reflux temperature and continuous stirring were maintained over three hours. It can be derived from same that if water quantity is to be limited along with limiting total solvent quantity, it will be necessary to maintain high temperatures preferably reflux temperatures to keep the product dissolved. This is the inherent reason as to why the inventor has not described the total quantity of ketone (ketone used for product solution + pre-cooled ketone) in any of the description or working examples or claims of patent literature [PTL 8] or [PTL 9]. Also the inventor has not suggested in any of the description or working example or claims as to what should be the ideal volume or quantity of pre-cooled solvent. Thereby which such process on industrial scale becomes in-efficient and non-workable.
Also it is found that continuous heating is required to keep the product in solution. Also as per description above in this section, to limit the use of water and total solvent quantity, it is essential to heat the reaction mass to near reflux temperatures above 50 deg C and keep the same under continuous heating until entire addition is over. Also Addition is preferred slowly & dropwise, preferably in one hour or more, as described in working example -1, paragraph [0035] of patent literature [PTL 8] and [PTL 9]. This continuous heating of product solution for one hour or more may result into increase in impurity and degradation products.
Another requirement and limitation of this process is that the pre-cooled solvent has to be maintained at temperature (-) 10 to (-) 15 deg C so that overall temperature during entire addition does not excess 5 deg C when heated product solution is added. Same is also described in working example -1, paragraph [0035] of patent literature [PTL 8] and [PTL 9]. This limitation invites attention towards the formation of crystal form-I and the crystal transition temperature as described in patent literature [PTL 3,4,5,6] in the paragraph [0050] which describes that preferable mode of manufacture of Form-I crystals includes process of dissolving a solvent, cooling and carrying out crystallization at a temperature from (-) 10 deg C to the crystal transition temperature which is 20 to 25 deg C. Also in the paragraph [0081] example of experiment 6 wherein investigation for physically stable form is carried out, it is found out that stirring at temperatures below 25 deg C causes transition of Form-II crystals to Form-I crystals.

So crystallization temperatures below 10 deg C are definitely favourable for the growth of Form -I crystals and higher content of Form-I crystals can easily be anticipated in output of process. This is contradictory to the ratio of polymorph mixture claimed in the patent literature [PTL 8] and [PTL 9] wherein Form-II: Form-I is between 7:3 to 9:1 (maximum 10% to 30% form-I). Also there is no description as to whether seeding is essential to achieve such polymorphic ratio consistently or whether such ratios are obtained consistently without seeding. Since the inventor has nowhere disclosed DSC graphs of such mixtures, if achieved. If at all seeding is assumed to be a non-disclosed element, it is of high interest as to by which process such seed would be achieved. Achieving such a high content of Form-II (70% to 90%) is doubtful under controls and conditions described in the patent literature [PTL 8] and [PTL 9].
The limitations of the process described in patent literature [PTL 8] and [PTL 9] due to which it is non-workable and inefficient on industrial scale, includes below technical problems:
(1) Complexity of the entire operation at industrial scale, such as slow addition of large volumes, controlling of addition rates and temperature fluctuations caused due to same, simultaneous addition of product solution while keeping it heated at near reflux temperatures, etc.
(2) Formation of degradation products and impurities due to continuous heating of product solution at temperatures above 45 deg C to keep it soluble in least quantities of water and solvent, for a prolonged time duration exceeding one hour.

(3) Crystals achieved are of impure nature, have fine particle size distribution, and are small enough to pass out during filtration thereby causing yield loss.
(4) Conditions are well suited for the growth of Form-I crystals, as well as transition of Form-II crystals into Form-I, since crystallization begins at temperatures below 10 deg C. Thereby inherent inability to produce or maintain higher content of Form-II crystals.

(5) It has no description regarding how consistently polymorphic ratio claimed between 7:3 to 9:1 is maintained, despite of unfavourable conditions. No controls such as seeding are shown.
(6) Process output is non-reproducible due to batch to batch variation in addition rate, temperature fluctuations and concentration gradients created due to addition of hot solution (more than 45 deg C) into extremely cold solvent (less than (-) 10 deg C), changes caused in temperature controls of product solution (heating) and in temperature controls of pre-cooled solvent (cooling), which will all effect nature, size and impurity entrapped in the crystals formed.

Patent Literature [PTL 3,4,5,] describes of methods to achieve both the crystal form - I and form-II.
It reports the crystal transition temperature of both crystal forms when suspended in a solvent. In patent literature [PTL 3,4,5] in paragraph [0049] and in working examples from [0056 to 0062], the manufacturing method of crystal form-II is described giving several examples. In all such examples, high content of Form-II is obtained either by suspending the product in solvent and heating at elevated temperatures or by adding a crystal seed at elevated temperature prior to cooling crystallization. A technical problem is that there are no examples or description to derive form-II without using solvent mediated crystal transition at elevated temperature or without adding seed crystal. And any such seed crystal is again obtained only by suspending in solvent and heating at elevated temperature. Another problem is regarding the investigation and the criteria set for determining the physical stability amongst both crystal forms (I and II). Such an investigation is described in paragraph [0081] wherein suspension and stirring of crystal mixture is carried out in a solvent at various temperatures to determine physical stability. It is reported that crystal form-I is physically more stable at temperatures below 25 deg C whereas crystal form-II is physically more stable at temperatures above 35 deg C. The technical problem is that there is no further study reported as to what is the solid-state transition or physical stability of crystal form or crystal mixture when it is subjected to physical impact caused by mechanical means or fluid energy means such as milling, compaction, attrition or such similar operations which are common during the manufacturing of the drug substance as well as during conversion of same to a dosage form. Since if under such stress conditions one of the particular crystal form is preferred, then polymorphic form or ratio of drug substance may be changed unintentionally. More often a crystal form which is preferred and which itself does not change during physical stress or impact is regarded as a more stable form physically. Also it is well known that after the manufacture of bulk drug substance, it may be required to attain a particular particle size distribution as a part of dosage form requirement or specifications. To attain such a particular particle size distribution, most commonly used industrial techniques are milling such as pulverising, air jet milling etc,. And during dosage form manufacture it may be passing thru physical stress during the operations such as compaction, wet granulation, pelletisation until it is packed. So in present invention effect of physical stress conditions such as grinding and milling are studied and preferred method for manufacturing a more physically stable crystal form is reported.
In patent literature [PTL 10] paragraph [0003] the inventor himself acknowledges that when a solvent is used to obtain product having medicinal use, the toxicity of the solvent is important quality point, since the residual solvent shall be ingested in the body along with medicine, and therefore it is a prime requirement that solvent used for crystallization is easy to remove at operation of drying and the toxicity of solvent itself should be low. But contradictory to this, the

inventor himself has claimed for the use of one of the most toxic solvent acetonitrile for re-crystallization of sarpogrelate hydrochloride whose maximum allowable limits are only upto 410 ppm in the final product. The inventor mentions in working example 1, paragraph [0017] use of almost 15 times of toxic solvent acetonitrile used for re-crystallization process. It is also described that after drying the sample under reduced pressure, the residual solvent is measured using headspace gas chromatography which is around 200 ppm. Also, all the claims made in the patent literature [PTL 10] include the use of acetonitrile for the purpose of re-crystallization and suspension of sarpogrelate hydrochloride. Therefore technical problems of this invention are:
(1) It uses toxic solvent acetonitrile for the purpose of re-crystallization and suspension of sarpogrelate hydrochloride. The limits of acetonitrile in final product as set by ICH guidelines for residual solvents is 410 ppm and categorised under class-2 solvent. The ICH guidelines describe class-2 solvents as the solvents suspected of other significant but reversible toxicities. The Japanese Pharmacopoeia XVI has specified in monograph of sarpogrelate the test of residual solvent as test for purity of drug substance. So compared to class-3 solvents which have limit upto 5000 ppm, acetonitrile remains one of the most lesser used due to same reasons. So, acetonitrile having such an high toxicity is not preferred as a solvent for re-crystallization which is essentially a final step of drug substance.
(2) Drying of sarpogrelate hydrochloride re-crystallized by acetonitrile will be very critical, since drying at temperatures higher than 60 deg C for longer durations can cause increase in impurity and degradation products.
(3) Re-crystallization using acetonitrile has bad volume efficiency, as described in working example 1, paragraph [0017] use of almost 15 times of acetonitrile is made, yet dissolution is achieved at reflux temperature around 80 deg C. Same is also confirmed by referring to paragraph [0010] wherein, amount of solvent used is from 1 to 20 times. Also acetonitrile being expensive solvent, it would not be economical to use in such quantities.
(4) Due to dissolution at high temperatures, the impurities and degradation products shall be formed.
(5) The inventor relies on solvent mediated crystal transition using elevated temperatures to increase content of form-II in the crystal mixture, thereby which suspension of sarpogrelate hydrochloride is carried out in acetonitrile at elevated temperatures, as described in claim (2) and as also described in working example 2 [0018], and in description [0014]. As per working example 1 [0017], even after adding of seed crystal at elevated temperatures, the polymorph ratio obtained was 36:64 (form I: form II). In working example 2, when crystal mixture is suspended in acetonitrile, therefore form-II content increased and polymorph ratio obtained was 20:80. Also there has been no description as to how seed crystal was achieved, and of what ratio seed crystal is preferable.

(6) It is essential for crude crystal of sarpogrelate hydrochloride to have more than 99.8% purity by liquid chromatography. Same limitation is described by inventor himself in best mode of carrying invention [0008] and in working example -1 [0017] wherein crude crystal of 99.8% purity is used. Though it is not usual to have such high purity of crude crystal, it has been made as a pre-requirement for quality of crude crystals of sarpogrelate hydrochloride and detailed explanation for same is not provided. Also process to obtain such high purity of crude crystal is not provided. And if at all such process exists which can achieve more then 99.8% purity of crystal, than the requirement of re-crystallization or purification is not justified.
In patent literature [PTL 11] it is claimed that hydrogen chloride is added to the solution of sarpogrelate free base in variety of ways such as addition in form of gaseous state, solution state etc. so as to obtain mixed crystal of sarpogrelate hydrochloride. This literature describes at various places in paragraph [0010], in working example 25, paragraph [0050], working example 26, paragraph [0051], comparative example 4, paragraph [0055] a method consisting of free basing the preceding intermediate of sarpogrelate and thereafter extracting the same using organic solvent, further which is made to react with succinic anhydride to form sarpogrelate free base. To this sarpogrelate free base the hydrogen chloride is added in variety of ways to derive crystal mixture. Also described in this literature are working examples 1 to 24, paragraphs [0026 to 0049] wherein hydrogen chloride is added to the sarpogrelate free base in variety of ways so as to form crystal mixture.
But significant technical problems of this patent literature comes from the fact that there is no provision or ways shown to purify the entrapped impurities from crystals of sarpogrelate hydrochloride which are formed by various described means. The significant technical problems in this invention are below:
(1) It is essentially not a re-crystallization process. It is only a precipitation or salting out process of sarpogrelate free base, and similar to methods described specifically for sarpogrelate free base in the prior art patent literature [PTL 1]. It is a very common practice to form pharmaceutically acceptable hydrochloride salt of a free base and wide used industrial practice. But it is very rare that any pharmaceutical salt form is used directly thereafter for dosage form preparation without purification by re-crystallization process, since re-crystallization has many functions essential and inevitable to achieve pharmaceutical form of high purity such as achieving pure white crystals (not off-white or brownish), achieving crystals free from impurities trapped during precipitation of crude product, etc.
(2) Addition of hydrogen chloride explained in descriptions [0017] [0018] [0019] of patent [PTL 11] is shown to be preferred at temperatures of 30 to 60 deg C, 40 deg C and 30 to 60 deg C respectively. Which is quite abnormal considering the fact that addition of hydrogen chloride is an exothermic reaction and if during such additions are done at temperatures above 10 deg C then there are very high chances of volatilization of hydrogen chloride gas. It shall also cause

temperature fluctuations within the reaction mass which are not favourable for developing good quality of crystals. Reasons for adopting such higher temperatures for addition are also not justified or explained due to the fact that elevated temperatures cause increase in degradation products.
(3) Un-realistic achievement of 99.7% to 99.9% of liquid chromatographic purity of the crude
crystals obtained in such manner, shown using more than 25 examples.
(4) Process does not have ability to improve colour of crystals so obtained, by dissolution of crystals and treating them with activated carbon to improve colour of product. Such a product may not be suitable for pharmaceutical use, since Japanese pharmacopoeia XVI specifies color to be 'White' for sarpogrelate hydrochloride.
(5) Due to slow addition of hydrogen chloride, especially at elevated temperatures, impurity and degradation products are generated.
It is evident that the inventor has neglected this facts even in the presence of prior arts present concerning this invention. Therefore working of this invention on industrial scale is doubtful.
Therefore a process is required to manufacture sarpogrelate hydrochloride in high polymorphic purity and chemical purity, especially by re-crystallization means. Thereby which Sarpogrelate hydrochloride which has medical uses is obtained by a process which is safe, economical, industrially viable and scalable, reproducible, least toxic and having least environmental impact.
[SOLUTION TO PROBLEM]
[0006]
For Solving the above problems, the inventors studied extensively so as to provide a more efficient process of achieving sarpogrelate hydrochloride in high polymorphic purity, chemical purity, high yield, using re-crystallization means, and therefore they came to complete the present invention.
That is, the present invention is solved by the following means:
1. Re-crystallization of sarpogrelate hydrochloride by using a solvent mixture consisting of any
less toxic solvent or solvent mixture, wherein dissolution is achieved by addition of less toxic
aliphatic monocarboxylic acid(s) or their mixtures selected from formic acid (methanoic acid),
acetic acid (ethanoic acid), propionic acid (propanoic acid), so as to obtain polymorphic mixture
(form-I and form-II) of sarpogrelate hydrochloride.
2. Re-crystallization of sarpogrelate hydrochloride using a solvent mixture consisting of any less
toxic aliphatic ketone(s) or their mixtures, preferably acetone (propanone), methyl ethyl ketone
(butanone), methyl isobutyl ketone (4-Methylpentan-2-one), wherein dissolution is achieved by
addition of less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid

(methanoic acid), acetic acid (ethanoic acid) propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.
3. Re-crystallization of sarpogrelate hydrochloride using a solvent mixture consisting of any less toxic alcohol(s) or their mixtures, preferably methanol, ethanol, 1-Butanol, 2-Butanol, 1-Propanol, 2-Propanol, 1-Pentanol, 3-Methyl-1-butanol, 2-methyl-l-propanol, ethyleneglycol by using less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid (methanoic acid), acetic acid (ethanoic acid), propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.
4. Re-crystallization of sarpogrelate hydrochloride using a solvent mixture consisting of any less toxic ester(s) or their mixtures , preferably ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate, Isopropyl aceate, Propyl acetate by using less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid (methanoic acid), acetic acid (ethanoic acid) propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.
5. Re-crystallization of sarpogrelate hydrochloride is carried out using solvent mixtures consisting of less toxic esters and/or alcohols and/or aliphatic ketones along with less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid (methanoic acid), acetic acid (ethanoic acid) propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.
6. Re-crystallization of sarpogrelate hydrochloride using minimum of solvents, therefore using maximum 8 times (w/w of solute) of aliphatic ketones or alcohols or esters or their mixtures along with maximum 2 times (w/w of solute) of aliphatic monocarboxylic acid, and thereby limiting the total solvent volume up to maximum 10 times (w/w of solute).
7. Re-crystallization of sarpogrelate hydrochloride using the solvent mixtures mentioned above (1) to (6) and adding water so as to aid dissolution of solute or to reduce total solvent volume or to control acidity of solvent mixture or to increase content of form-I crystal in the product. Alternatively limiting the water content from any of solvent mixtures described from (1) to (6) by passing it over drying agent, so as to achieve higher yield or to minimize impurity by hydrolysis or to achieve higher content of form-II crystal in the product.
8. Following non-limiting set of steps may be conducted so as to achieve refining or re-crystallization of sarpogrelate hydrochloride, so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride, using solvent mixtures described above from (1) to (7) :
(a) Suspending and stirring of crude crystals in solvent or solvent mixture consisting of esters and/or alcohols and/or aliphatic ketones.
(b) By gradually adding a specific or mixture of aliphatic monocarboxylic acid(s) under stirring.

(c) Heating the reaction mass gradually so as to cause dissolution.
(d) Achieving dissolution of reaction mass below 40 deg C by using higher proportion of solvent in comparison to anti-solvent, and later in the process compensating the same by adding anti-solvent.
(e) Adding activated carbon in slurry form to aid purification.
(f) Filtering the solution from filter(s) which retain carbon and other suspended matter whereas allow the filtrate to pass.
(g) Adding seed crystal or suspension at a particular temperature or at defined stage.
(h) Controlling cooling rate of reaction mass and thereafter chilling below 10 deg C, so as to obtain crystals in high yield, by a cooling crystallization technique.
(i) Controlling saturation and crystallization rate of reaction mass by controlled addition of anti-solvent into the reaction mass at a given temperature or temperature range under stirring, so as to obtain higher content of form-II crystal. Such crystals are obtained using anti-solvent crystallization.
(j) A three component solvent mixture in which any two amongst ester/alcohol/aliphatic ketone achieve dissolution using aliphatic monocarboxylic acid. And further during re-crystallization, one of the solvent amongst ester/alcohol/aliphatic ketone is distilled with or without vacuum, so as to achieve saturation and crystallization. Optimising of such a process which is known as evaporative crystallization.
(k) Allowing aging of the crystals, preferably below 10 deg C.
(1) Filtration of reaction mass so as to isolate the crystals.
(m) Washing of crystals obtained using least toxic solvent or solvent mixture.
(n) Drying of crystals obtained, preferably under reduced pressure and preferably at temperature below 60 deg C.
(o) Milling of the product, preferably using pulveriser or air jet mill.
9. Adding hydrogen chloride to sarpogrelate free base using Any of solvent mixtures described from above (1) to (7) and by using manufacturing process described above in (8) and (9). Such addition of hydrogen chloride may be caused by any means such as purging of anhydrous hydrochloric gas, by charging solvent enriched with hydrogen chloride, so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.

10. Performing Non-solvent based Re-crystallization process of sarpogrelate hydrochloride,
causing solid-state crystal transition by mechanical impact or fluid impact whereby the
polymorphic ratio of both the forms - I and II is modified using such techniques. Carrying out
such a crystal transition by pharmaceutically preferable forms of mechanical impaction and fluid
impaction at low temperature such as pulveriser and fluid jet mill using air or nitrogen. And
combining this method alongwith classification system so as to derive desired particle size
distribution. And application of such a process to sarpogrelate hydrochloride achieved using
means described in (1) to (10) or by any other means or process. Also application of such a
process where sarpogrelate hydrochloride is milled along with other pharmaceutical excipients as
a part of pharmaceutical dosage form preparation.
11. By Non-solvent based Re-crystallization process of sarpogrelate hydrochloride, causing solid-state crystal transition by mechanical impact or fluid impact wherein the content of crystal Form-II is increased due to such a process so as to achieve preferably more than 75%, more preferably greater than 85% and most preferably greater than 98% of Form-II content in the final product. Such a crystal transition process being carried out by pharmaceutically preferable forms of mechanical impaction and fluid impaction at low temperature such as pulveriser and fluid jet mill using air or nitrogen. And combining this method alongwith classification system so as to derive desired particle size distribution. And application of such a process to sarpogrelate hydrochloride achieved using means described in (1) to (10) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled along with other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.
12. By Non-solvent Re-crystallization process of sarpogrelate hydrochloride, causing solid state crystal transition by mechanical impact or fluid impact so as to increase the crystal content of Form-II to more than 70% and to simultaneously achieve a particle size distribution having D(0.1) < 5 um, D(0.5) < 25 um and D(0.9) < 50 um or still a finer particle size distribution such as D(0.1) < 2 um, D(0.5) < 5um and D(0.9) < 10 um . Such a crystal transition process being carried out by pharmaceutically preferable forms of mechanical impaction and fluid impaction at low temperature such as pulveriser and fluid jet mill using air or nitrogen. And combining this method alongwith classification system so as to derive desired particle size distribution. And application of such a process to sarpogrelate hydrochloride achieved using means described in (1) to (11) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled along with other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.
13. By Non-solvent Re-crystallization process of sarpogrelate hydrochloride, using solid state
crystal transition by mechanical impact or fluid impact so as to cause more than 5% increase in
Form-II content of final product (with respect to content of Form-II in product before milling),
thereby which a final product so achieved is more stable than the initial product due to more than
5% increase in Form-II. Such a crystal transition process being carried out by pharmaceutically

preferable forms of mechanical impaction and fluid impaction at low temperature such as pulveriser and fluid jet mill using air or nitrogen. And combining this method along with classification system so as to derive desired particle size distribution. And application of such a process to sarpogrelate hydrochloride achieved using described means (1) to (12) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled along with other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.
14. By using process of solvent based solid state crystal transition wherein slurry of sarpogrelate hydrochloride is grinded using a wet grinding mill, thereby to achieve higher content of form-II (with respect to content of Form-II in product before milling). And application of such a process to sarpogrelate hydrochloride achieved using means (1) to (13) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled alongwith other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.
15. By re-crystallization process of sarpogrelate hydrochloride wherein process controls or process equipments as described from means (1) to (14) are enhanced to achieve higher efficiency for the claimed results, For example:

(a) Enhanced Process Controls such as : Rate of cooling, heating, stirring, addition, saturation, dissolution, seeding, nitrogen blanketing, temperature of milling, degree of chilling etc.
(b) Enhanced Process equipments such as : high vacuum drying, spray drying, milling or grinding under nitrogen etc.

16. By obtaining crystal seed or crystal seed mixture or suspensions or solutions from any specific or combination of the process as described from means (1) to (15). And making use of same in sarpogrelate hydrochloride manufacturing method(s) described from means (1) to (15) so as to achieve desired results such as by seeding so as to achieve desired polymorphic form or ratio of polymorphic forms or desired particle size distribution or achieving higher yield or achieving higher purity.
17. By using a specific or combination of sarpogrelate hydrochloride manufacturing method described in means (1) to (16) so that the major impurity and degradation product BP984 (described as decomposed substance A, having impurity limit of 1/5 peak area of standard solution and hplc retention time 0.82 as per Japanese Pharmacopoeia XVI) in the final product is reduced and controlled below 1/15 peak area of standard solution, which is much less than the limits (1/5 of area) of related substances test by hplc as described in sarpogrelate hydrochloride monograph of Japanese Pharmacopoeia XVI.

18. By using a specific or combination of sarpogrelate hydrochloride manufacturing method
described in means (1) to (17) whereby the total related substance impurity of final product is
reduced and controlled below 1/5 the area of standard solution, which is much less than the
limits (1/2 of area) of related substances test by hplc as described in sarpogrelate hydrochloride
monograph of Japanese Pharmacopoeia XVI.
19. By using a specific or combination of sarpogrelate hydrochloride manufacturing method described in means (1) to (18) whereby the highest content of Form-II (DSC endotherm between 155 to 157 deg C and IR absorption peaks at least two amongst 792, 1163, 1040, 1464, 1406, 1742, 1497, 1603) is achieved consistently in the final product, preferably greater than 75%, more preferably greater than 85% and most preferably greater than 98%.
20. By using a specific or combination of sarpogrelate hydrochloride manufacturing method described in means (1) to (19) whereby which only class-3 solvents (as defined by ICH guidelines) are used and so their presence in the final product are controlled below 500 ppm which is much less than limits of 5000 ppm (set by ICH guidelines - Residual solvent).
21. By using a specific or combination of sarpogrelate hydrochloride manufacturing method described in means (1) to (20) whereby water content in final product achieved is consistently below 0.2%) which is much less than limits 0.5% (described in sarpogrelate hydrochloride monograph of Japanese Pharmacopoeia XVI).
22. By using a specific or combination of sarpogrelate hydrochloride manufacturing method described in means (1) to (21) thereby which polymorphic mixture of Form-I and Form-II is obtained, and the polymorphic ratio of in final product is consistently achieved between 7:3 to 9:1 (Form-II: Form-I).
23. By using a specific or combination of sarpogrelate hydrochloride manufacturing method described in claim (1) to (22) whereby dissolution and/or re-crystallization is carried out at temperature below 60 deg C to avoid product degradation.

[ ADVANTAGEOUS EFFECTS OF THE INVENTION]
Sarpogrelate hydrochloride is having medicinal uses and has been now used for medical purposes for more than 15 years.
In the present invention manufacturing method of sarpogrelate hydrochloride involving re-crystallization and purification of crude crystals is described whereby the polymorphic mixture of Form-I and Form-II of sarpogrelate hydrochloride is obtained.
The present invention and manufacturing methods claimed are superior to the prior acts as per below:
(1) Simplicity of the entire re-crystallization operation which is efficient on industrial scale.
(2) Higher yield using lesser total solvent volume, since dissolution in re-crystallization is achieved using solvent consisting from aliphatic monocarboxylic acid.
(3) Process uses lowest total solvent volume required for re-crystallization.
(4) Minimum process time for entire re-crystallization operation.
(5) Provides Crystals which are of superior whiteness in colour than those obtained by a process which involves only precipitation of free base by addition of hydrogen chloride. And also provides crystals of more white colour than the process which does not have any provision for re-dissolution, filtration by means of re-crystallization once crystals are formed.
(6) Provides a scope of re-dissolution by the means of re-crystallization if due to accidental means some impurity or extraneous matter is detected in final product. Therefore a more advantageous process than a process in which there is no provision for re-dissolution and filtration of crystals.
(7) Provides Crystals which are free flowing in nature.
(8) Provides Crystals having higher content of Form-II polymorph, with a scope of adding seed crystals at temperatures lower than 50 deg C. Thereby the need of seeding at elevated temperatures, in excess of 60 deg C is avoided.
(9) Provides a novel and simple approach to obtain more than 75% of Form-II polymorph of
sarpogrelate hydrochloride, by means of Non-solvent re-crystallization causing solid state crystal
transition by impacts caused by mechanical and fluid energy source. The preferred means of
such solid state transition are milling or grinding using pulveriser or fluid jet mill.

(10) Provides a novel and simpler approach to modify or derive a required polymorphic ratio of
Form - I and II of sarpogrelate hydrochloride, using solid state crystal transition process.
(11) Provides sarpogrelate hydrochloride having higher content of Form-II polymorph, without the need of suspending the crystals and heating at higher temperatures so as to cause solvent mediated crystal transition, as described in prior arts.
(12) Such a Process for obtaining higher content of Form-II polymorph using solid state transition has several advantages over the prior art processes described in patent literature [PTL 3,4,5,6] which are solvent mediated crystal transition process. Advantages are as below:

- It does not require product to be suspended into a solvent, thereby a solvent free process.
- Particle size distribution can be obtained simultaneously while causing polymorphic change.
- It has higher yield compared to a solvent process and is a faster process.

- Feasibility to treat entire batch without the need of suspending in solvent and drying thereafter.
- It does not harm impurity profile of existing product, which can be caused due to solvent mediated transition above 50 deg C.
- It does not spoil the colour of crystals due to heating at elevated temperatures above 40 deg C, rather it improves the colour of crystals in terms of whiteness.
(13) Provides Crystals of coarser particle size distribution and having higher bulk density, then
by processes describing anti-solvent crystallization.
(14) Provides Lowest toxicity content in the sarpogrelate hydrochloride drug substance and in
the dosage form using sarpogrelate hydrochloride manufactured by present invention. The
toxicity content is minimum in terms of residual solvents carried forward to dosage form. Since
the present invention uses of only class-3 solvents (described by ICH guidelines, having limit
upto 5000 ppm). Whereby it Avoids use of more toxic solvents such as class-2 solvents. Residual
Solvent is a test prescribed in monograph for sarpogrelate hydrochloride in Japanese
pharmacopoeia.
(15) Process does not require prolonged drying time or special drying techniques so as to achieve minimum residual solvent and water content specifications, since process does not use any toxic solvents and does not use any water. Thereby scope of increase in degradation product due to prolonged drying at higher temperatures is avoided.
(16) Typical batches produced using present invention were tested for Residual solvent by headspace gas chromatography, wherein presence of only class-3 solvent was detected at levels below 500 ppm, which are much less than internationally acceptable limits of 5000 ppm levels as prescribed by ICH guidelines.

(17) Process prevents formation of degradation product, described as Impurity-A (relative retention time 0.82) in related substance test of Japanese Pharmacopoeia monograph of sarpogrelate hydrochloride.
(18) Process output has minimum content of water in dried crystals, which is a test prescribed in monograph for sarpogrelate hydrochloride in Japanese pharmacopoeia.
(19) Process which does not have any prolonged cooling or heating times in re-crystallization step, thereby achieving pure product by maintaining yield, economy and efficiency of process on industrial scale.
(20) Avoids use of water in process which is responsible for formation of degradation products and impurities by hydrolysis. Also water is a significant source of microbiological contamination which is of pharmaceutical concern.
(21) Re-crystallization Process does not have a pre-requirement to have a very highly pure crude crystals (liquid chromatographic purity) or highly pure sarpogrelate free base (achieved by purification of previous process steps), so as to derive highly pure final product. Since such steps to achieve high purity crude crystals will also result in yield loss which is critical during final process stages.
(22) Provides the novel use of aliphatic monocarboxylic acids as suitable and superior solvent for the purpose of re-crystallization of sarpogrelate hydrochloride crude crystals. Aliphatic monocarboxylic acids are least toxic, have anti-bacterial properties and are widely used in the food industry as an preservative.
(23) Provides the novel use of aliphatic monocarboxylic acids to aid dissolution, re-crystallization and purification of sarpogrelate hydrochloride by using least toxic and most preferred pharmaceutical solvents such as aliphatic ketones, alcohols and esters.
(24) Establishes that Form-II is the preferred form under physical stress, which may be caused un-intentionally during pharmaceutical manufacturing processes such as milling or grinding.

[DESCRIPTION OF EMBODIMENTS]
Detailed description is given concerning the mode of carrying out the invention as follows;
In this invention the crude crystals of sarpogrelate hydrochloride are obtained by conventional means and those described in prior art such as patent literature [PTL 1 and 2]. Such crude crystals are preferably dried using vacuum. Although there is no pre-requirement of such crude crystals to be of highly pure (liquid chromatography) it would be always advantageous to optimise the process of preparing crude crystals to achieve higher quality.
Desired solvent mixture to be used for re-crystallization may be selected from below:
Solvent mixture consisting of aliphatic monocarboxylic acid and aliphatic ketone is selected from group of aliphatic monocarboxylic acid preferred from least toxic and widely used such as acetic acid, formic acid and propanoic acid, whereas aliphatic ketone is selected from amongst least toxic and widely used such as acetone, methyl ethyl ketone and methyl iso-butyl ketone. Though it is not limited, the solvent mixture should ideally have maximum 8 times (w/w of solute) of aliphatic ketones and it should have maximum 2 times (w/w of solute) of aliphatic monocarboxylic acid, based on inventors experience.
Solvent mixture consisting of aliphatic monocarboxylic acid and esters is selected from group of aliphatic monocarboxylic acid preferred from least toxic and widely used such as acetic acid, formic acid and propanoic acid, whereas esters may be selected amongst least toxic and widely used such as ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate, Isopropyl acetate and propyl acetate. Though it is not limited, the solvent mixture should ideally have maximum 8 times (w/w of solute) of esters and it should have maximum 2 times (w/w of solute) of aliphatic monocarboxylic acid, based on inventors experience.
Solvent mixture consisting of aliphatic monocarboxylic acid and alcohols is selected from group of aliphatic monocarboxylic acid preferred from least toxic and widely used such as acetic acid, formic acid and propanoic acid, whereas alcohols may be selected amongst least toxic and widely used such as methanol, ethanol, 1-Butanol, 2-Butanol, 1-Propanol, 2-Propanol, 1-Pentanol, 3-Methyl-1-butanol, 2-methyl-l-propanol and ethylene glycol. Though it is not limited, the solvent mixture should ideally have maximum 8 times (w/w of solute) of alcohols and it should have maximum 2 times (w/w of solute) of aliphatic monocarboxylic acid, based on inventors experience.

Further, to such mixtures prepared above, any less toxic polar solvent or mixture of polar solvents such as water, alcohol, ester, ketone, ether, etc. may be added so as to aid dissolution or to minimise the total solvent volume required for re-crystallization purpose.
Also in the present invention, though water is not a desired component of solvent mixture, any process benefits which seem to be arising out of process experience, by which minimal water is added initially and thereafter yield loss is compensated by addition of anti-solvent, then water may be incorporated into the solvent mixture selected, as an additional component.
Also, any non-polar solvent or mixture of non-polar solvents such as halocarbons, aromatic halocarbons or alkanes may be added, so as to limit the dissolution by acting as anti-solvent.
While selecting the grade of formic acid, two commercially available grades are available as 98% and 85%. Though using of any grade or mixtures of grade is not limited, the grade which is used for the working examples of this invention is of 98%.
When selecting for solvent mixtures, toxicity, wide usage, solubility, volatility, flash points, boiling points, commercial availability, worker safety etc. should be regarded as important criteria.
Though it is not limited to below steps, the process of re-crystallization using crude crystals of sarpogrelate hydrochloride may be carried out using any specific or combination of below steps.
From the selected solvent mixtures, ketones / esters / alcohols, or their mixtures should be first charged into the reaction vessel. Ideally to achieve economy and volume efficiency of the process, they should be maximum 8 times w/w of the solute and ideally between 3 to 5 times w/w of solute.
Thereafter the crude crystals must be suspended in the solvent and stirring should resume.
The selected aliphatic monocarboxylic acid should be added gradually, preferably at temperature below room temperature, thereafter which product dissolution is achieved by heating and stirring. Though it is not limited, the proportion of aliphatic monocarboxylic acid should be maximum 2 times and ideally between 0.6 to 1.4 times w/w of solute.
Though it is not limited, a temperature below 60 deg C is preferable so as to achieve dissolution. Such a temperature should be optimised using experience of the process and solvent mixture selected.

Purification aid such as activated carbon, preferably prepared in the slurry form is added to the reaction mass and stirring is continued.
The reaction mass solution is then filtered using a filter or set of filters which is capable to permit product solution to pass whereas it retains the carbon and other unwanted suspended matter. Ideally a jacketed pressure filter or a sparkler filter, followed by terminal micron filter is preferred.
The filtrate is then collected in a clean reaction vessel for final crystallization.
Cooling of filtrate is preferably carried out gradually to achieve better quality of crystals and to minimise the entrapment of impurities in the crystals. Such a cooling rate should be optimised using experience of the process and solvent mixture selected.
Suitable Seed Crystal or its suspension obtained using present invention is then added into the filtrate, preferably at a temperature above the room temperature. Haziness of the solution due to saturation or nucleation may be set as visible criteria to select seeding point. Such a point of seeding should be optimised using experience of the process and solvent mixture selected.
The reaction mass is then chilled below 10 deg C so as to achieve maximum yield and to allow aging of the crystals under stirring. Such a chilling temperature, and aging time duration should be optimised with experience of a particular process and solvent mixture selected.
An anti-solvent may be added at any point of crystallization so as to achieve saturation of solution and thereby to control the rate of crystallization. Such an anti-solvent may be preferred from an aliphatic ketone or ester or alcohol.
Also in the present invention, though water is not a desired component of solvent mixture, any process benefits such as volume efficiency or acidity (pH) control which seem to be arising out of process experience, by which minimal water is added initially and thereafter yield loss is compensated by addition of anti-solvent, then such a step may be incorporated into the process.
The reaction mass is then filtered using effective filtration methods such as centrifugal filtration and washing the filter cake with a least toxic solvent, preferred from an aliphatic ketone, ester, alcohol or their mixture.
Drying of the filter cake is carried out preferably under vacuum and at temperatures below 60 deg C. Drying time and temperature should be optimised with experience of process and solvent mixture selected. In-process test of loss on drying or for residual solvent may be incorporated to study and optimise the drying time and temperature. Though not limited, preferable drying equipments include rotary cone vacuum dryer, vacuum tray dryer and fluid bed dryer.

The dried crystals may then be subjected to grinding or milling if a particular particle size distribution is required. The grinding or milling equipment is important from the fact that heat may be generated during such processes and it may cause the product to degrade. So amongst the most suitable and widely used milling techniques are pulveriser and air jet mill, which are reputed for carrying out milling without generation of heat and thereby preventing degradation of the crystals during such a process.
[Non-Solvent based re-crystallization by causing solid state crystal transition]
None of the prior arts [PTL 1 to 16 ] described or reported regarding the solid state crystal transition and regarding polymorphic conversion of sarpogrelate hydrochloride under physical impact caused by mechanical means or by fluid energy means. Therefore the inventors studied into the same wholeheartedly and found out that there exists a more convenient, efficient and industrially scalable process of achieving solid state crystal transition or performing re-crystallization using milling or grinding.
Solid state crystal transition is non-solvent based re-crystallization method. The process includes the crystal transition using impact caused by mechanical means or fluid energy means.
Though not limited to, this solid state re-crystallization technique may also be applied to sarpogrelate hydrochloride pure crystals achieved using means described in present invention. And it is also applicable to sarpogrelate hydrochloride achieved using any other means which are not described in this invention.
Amongst the grinding and milling technologies presently established and widely used for grinding of pharmaceutical powders are pulveriser and fluid jet mill. Since this technologies can cause physical stress on crystals with minimum heat generation. So, though not limited to, such techniques are described in present invention as preferred mode to conduct re-crystallization by solid state crystal transition.
The results of grinding and milling using pulveriser and air jet milling showed increase in polymorphic form-II. Thereby confirming that Form-II is the preferred physically stable polymorph when product crystal mixture is exposed to such solid state crystal transition procedures. It was also confirmed that when sarpogrelate hydrochloride is micronized, milled or grinded using such safe techniques, there is no product degradation. Rather the color of the product is improved to higher whiteness.
When the product is subject to air jet milling, particle to particle attrition causes transition of crystal mixtures and a more stable form-II is preferred. Thereby which higher content of Form-II can be achieved. It was observed during several experiments of air jet milling of sarpogrelate hydrochloride, that increase in the air pressure and increase in retention of product in grinding chamber caused more frequency of particle to particle attrition, thereby which formation of a more stable form-II was accelerated. Also it was noticed that in order to control particle size at a

given air pressure, retention times and/or air pressure may be reduced. So for faster conversion to form-II, higher air pressures are preferred with higher retention time. Where as for slower conversion to form-II lower air pressure along with lower retention time are used. Thereby which a optimum combination of particle size distribution along with polymorphic transition can be achieved.
It is established by the inventors by performing several experiments that milling causes crystal transition from Form-I to Form-II. The effect of polymorphic transition and particle size reduction was studied carefully, results of which are tabulated in [TABLE 1].
[TABLE - 1]

Lot
No. Sample Description D(0.1) um D(0.5) um D(0.9) um Polymorphic Ratio Before Milling (Form-II: I) Polymorphic Ratio After Milling (Form II: I)
1 Working Example - 1 6.9 44.1 146.5 N/A 53:47
2 Working Example - 2 5.7 36.2 126.5 N/A 70:30
3 Working Example - 3 1.2 2.4 4.8 70:30 96:04
4 Working Example - 4 3.6 13.4 69.2 N/A 100: 00
5 Controlled milling of sample obtained as per working example
-2 4.2 16.3 45.8 65:35 82:18
6 Seeding using Lot No. 5 and crystallizing as per working example -2 . 5.6 28.7 99.2 N/A 94:06
The results of Lot-1 to Lot-6 are supported by particle size analysis results shown in [Diagram 9 to 14], which shows the frequency curve for particle size distribution wherein percentage of particles by volume are plotted against particle size in micron (um = micrometer or micron). The statistics of the distribution are calculated from the results using derived diameters D[m,n] an internationally agreed method of defining the mean and moments of particle size, as per british standard BS2955:1993. D(0.1), D(0.5) and D(0.9) are standard percentile readings from the analysis.

Wherein D(0.5) is size in microns at which 50% of the sample is smaller and 50% is larger. This value is known as Mass Mean Diameter (MMD).
D(0.1) is the size of particle below which 10% of the sample lies.
D(0.9) gives a size of particle below which 90% of the sample lies.
Therefore the size distribution derived and showed in present invention is volume based.
It can be very well understood from above that particle size reduction has direct relation to increase in polymorphic Form-II. And with the help of milling, polymorphic conversion can simultaneously be achieved along with particle size reduction. Also it is shown that seeding of such milled material causes increase in the polymorphic Form-II.
It is also observed that Particle Size distribution achieved with milling is D(0.1) < 5 um, D(0.5) < 25 um and D(0.9) < 50 um as the case in Lot -3 and Lot-5, also depicted in [Drawing - 11] and [Drawing - 13] respectively.
Whereas the Particle Size distribution achieved without milling is D(0.1) > 5 um, D(0.5) > 25um, and D(0.9) > 50 um as the case in Lot-1, Lot-2 and Lot-6, also depicted in [Drawing- 9] , [Drawing- 10] and [Drawing- 14] respectively.
Also it can be derived that such a process easily increases the content of Form-II by more than 5% (with respect to Form-II content in product before milling).
By combining various techniques shown in this section and demonstrated by [Table - 1] and also working examples of this invention, one can achieve a desired polymorphic ratio along with particle size reduction.
It is of knowledge that such an increase in particle size reduction will improve the product solubility, but since along with particle size reduction there is direct increase in Form-II, the product obtained will be more physically stable during its manufacturing life cycle as well as after sales up to final consumption by end users mainly consisting of patients undergoing treatment using this medicine. Also it is known that consistent average of particle size distribution of an active pharmaceutical ingredient allows for better quality mixture when creating solid dosage forms such as tablets, capsules, fine granules etc.
Though not limited to, the present invention describes size reduction or polymorphic conversion by impact either using mechanical or fluid energy. Amongst the examples of mechanical impact mill widely used for pharma applications are pin mill, fitz mill, micro pulveriser, conical mill, etc. Whereas examples of fluid mills include spiral jet mills, loop jet mills, fluidised bed jet mills etc. Mechanical impact mills are more often operated using a specific screen size. Also in case wet grinding is essential such for slurries prepared of sarpogrelate hydrochloride, then grinding

may be carried out using wet grinding mill, which shall also ensure dust reduction. Thereby not limiting the present invention only to dry grinding but also including the scope of wet grinding.
Generally for the purpose of grinding sarpogrelate hydrochloride, the selected milling equipment should give consistent results, without heat generation, lowest dusting, easy to clean, without causing product contamination or degradation, with an option of inert processing using nitrogen.
Amongst the above examples, one of the superior form of milling is fluid jet mill, which is widely used in pharmaceutical processing due to most significant advantage of processing at low temperatures without causing product degradation, which is the case in other mills due to uncontrolled attritional heat. Since in a jet mill the temperature of the air (fluid) leaving the jets is cooled to about minus (-) 200 deg F due to joules Thompson effect and the product leaves no warmer than the air used for grinding. In such a mill, frictions form collisions and contact with the grinding chamber is offset by the cooling effect of the expanding air. Such a mill when combined with a classification system using mechanical or air forces can produce a consistent and narrow particle size distributions. Classification system in general can be combined to particle size reduction techniques so as to derive required fractions or particle size distributions or to remove coarses or to remove fines from the product.
The terms ' causing solid state crystal transition using mechanical impact or fluid impact' or 'forms of mechanical impact or fluid impact' wherever used in the present invention includes a process to break or disintegrate a solid by applying external stress to reduce its size, wherein any four types of force out of "compression", "shear" , "impact" and "attrition" are used.
[BEST MODE FOR CARRYING OUT THE INVENTION]
It became clear that re-crystallization and purification could be performed very efficiently by dissolving the dry crude crystals of sarpogrelate hydrochloride in solvent mixture of aliphatic ketone, preferably methyl ethyl ketone and aliphatic monocarboxylic acid, preferably formic acid (98% grade) , filtering, crystallizing, washing and vacuum drying the pure crystals. Methyl ethyl ketone is preferably 3 to 5 times w/w that of solute, whereas formic acid is preferably 0.8 to 1.2 times w/w that of solute. Dissolution is achieved by stirring and gradual heating, preferably below 60 deg C. Activated carbon is added and stirring is continued, followed by filtration to remove carbon and suspended matter. Further upon gradual cooling of the reaction mass, seed or seed mixture is added above the room temperature, and is followed by chilling and aging of crystals below 10 deg C. Following this method, crystals of sarpogrelate hydrochloride containing polymorphic mixture of Form-I and Form-II achieved, of which polymorphic ratio is between 7:3 to 9:1 (Form-II: Form-I). Typically the experiment outputs using the above process showed very high liquid chromatographic purity. Related substances tests by UPLC method

(following procedure described in Japanese Pharmacopoeia XVI) showed more than 99.8% purity, which had the specific degradation product - Impurity A (impurity BP984, retention time 0.82, limit 0.2%) in the range of 0.01% to 0.06%, whereas all other individual impurities were much less than limit of 0.1%. Typical yields were in excess of 90%. The product crystals were pure white and free flowing in nature. Residual solvent content tested using headspace gas chromatography showed presence of methyl ethyl ketone below 500 ppm levels, whereas formic acid was below detection (reporting) limit. Water content measured for all such batches was below 0.2%) levels. Output of such experiments complied to the requirements of monograph of sarpogrelate hydrochloride in Japanese pharmacopoeia XVI. It became clear that highly pure final product is achievable along with obtaining high yield and desired polymorphic mixtures.
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.
[ TEST METHODS ADOPTED ]
The below Test referred in this invention have been carried out using method described in monograph of Sarpogrelate Hydrochloride in Japanese Pharmacopoeia XVI.
1. Infrared Absorption Spectrum - test as per identification test in monograph.
2. Liquid Chromatography (High performance Liquid chromatography - HPLC)- test as per related substance test described in monograph.
3. Water - content.
The Differential Scanning Calorimetry (DSC) graph shown in the section of Drawings is obtained using below method:
Heating rate: 10 deg C / minute Atmosphere: A part for nitrogen 40mL/min Measurement temperature: 30-200 deg C.

[Method for Particle Size Determination]
Below adopted specific method is used to analyze and describe results in the present invention. However, particle size determination is not restricted to same and one may use & develop a more suitable method for particle size analysis based on the Optical Microscopy described in Japanese Pharmacopoeia XVI under <3.04> Particle size determination or based on Laser Diffraction Measurement of particle size mentioned under Solid state properties. Such adopted different method should justify their suitability by co-relating to the results with other methods and perform analytical method validation for same.
Equipment: Malvern Mastersizer 2000
Principal: Laser Diffraction Technology
Results obtained are on volume basis.
Range: 0.02 to 2000 um ; Sample Dispersion Unit: Scirocco 2000 Dry dispersion ; Particle RI: 1.529 ; Absorption: 0.01; Dispersant RI: 1.0 ; calculation: general purpose ; Sensitivity: Normal; Particle Shape: Irregular; Measurement time: 12 sec ; Measurement snaps: 12000 ; Obscuration limit: 0.5% to 6.0%, Vibration Feed Rate: 40 % ; Dispersive Air Pressure: 3.0 bar.
[ Crystal Form-I ]
In the present invention, crystal Form-I of sarpogrelate hydrochloride is the crystal which exhibits both the features described below simultaneously:
(1) In a differential scanning calorimetry, it has an endothermic peak between 149 deg C to 153 degC.
(2) In an infrared absorption spectrum, it has an absorption peak in at least two chosen from 1245**1.0, 1404**1.0, 1495**1.0, 1585**1.0,2936**1.0, 1152**1.0, 1054**1.0, and 780**1.0-cm-1.
[ Crystal Form-II ]
In the present invention, crystal Form-II of sarpogrelate hydrochloride is the crystal which exhibits both the features described below simultaneously:
(1) In a differential scanning calorimetry, it has an endothermic peak between 154 to 157 deg C. (2) In an infrared absorption spectrum, it has an absorption peak in at least two chosen from 792**1.0, 1163**1.0, 1040**1.0, 1464**1.0, 1742**1.0, 1406**1.0, 1497**1.0, and 1603**1.0-cm-1.

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 to which this invention pertains will easily understand how to vary the exemplified preparations to obtain the desired results.
[ EXAMPLES ]
Working Example 1
25g crude crystals of sarpogrelate hydrochloride were added to 125 mL methyl ethyl ketone. Formic acid (20 ml of 98% grade) is added gradually under stirring and complete dissolution of solute is achieved before 60 deg C. Activated carbon is added to the reaction mass and stirred. Filtration to remove activated carbon and other unwanted suspended matter is carried out. Filtrate is gradually cooled and chilled below 10 deg C. Aging of crystals was allowed for 3 hours. Crystals were filtered and washed with methyl ethyl ketone 25mL. Wet crystals were dried under vacuum below 60 deg C temperature. Yield obtained was 92%. Polymorphic ratio obtained was 53:47 (Form-II: Form-I). Liquid chromatographic purity was 99.85%), Impurity-A detected was calculated to be 0.02%. Residual solvent by headspace gas chromatography, detected methyl ethyl ketone at 440 ppm. Water content of dried crystals was 0.14%>.
Working Example 2
120g crude crystals of sarpogrelate hydrochloride were added to 600 mL methyl ethyl ketone. Formic acid (95 ml of 98%> grade) is added gradually under stirring and complete dissolution of solute is achieved before 60 deg C. Activated carbon is added to the reaction mass and stirred. Filtration to remove activated carbon and other unwanted suspended matter is carried out. Filtrate is collected and kept under stirring. Upon appearance of haziness (non-transparency) of solution, seed mixture obtained in example-1 is charged and thereafter reaction mass is gradually cooled and chilled below 10 deg C. Aging of crystals was allowed for 3 hours. Crystals were filtered and washed with methyl ethyl ketone lOOmL. Wet crystals were dried under vacuum below 60 deg C temperature. Yield obtained was 94%. Polymorphic ratio obtained was 70:30 (Form-II: Form-I). Liquid chromatographic purity was 99.87%), Impurity-A detected was calculated to be 0.03%>. Residual solvent by headspace gas chromatography, detected methyl ethyl ketone at 460 ppm. Water content of dried crystals was 0.12%.

Working Example 3
lOOg dried & pure crystals of sarpogrelate hydrochloride obtained in example-2 were milled using air jet mill. Yield obtained was 99.6%. Polymorphic ratio obtained was 96:04 (Form-II: Form-I). Liquid chromatographic purity was 99.88%, Impurity-A detected was calculated to be 0.03%). Residual solvent by headspace gas chromatography, detected methyl ethyl ketone at 230 ppm. Water content of dried crystals was 0.11%. Colour of crystals improved in terms of whiteness.
Working Example 4
25g of crude crystals were processed as per working example-2 wherein seeding was done using the crystals obtained as per working example-3. 23.4g of dried crystals were obtained. Crystals obtained showed presence of Form-II crystals only. Form-II content in final product was 100%) by DSC. Liquid chromatographic purity was 99.86%), Impurity-A detected was calculated to be 0.02%). Residual solvent by headspace gas chromatography, detected methyl ethyl ketone at 360 ppm. Water content of dried crystals was 0.14%>.
Working Example 5
25g of crude crystals were dissolved using 55 mL methyl ethyl ketone and Formic acid (20 ml of 98%o grade). Activated carbon treatment and filtration was done. To the collected Filtrate, gradual addition of acetone 70mL is done at temperature between 25 to 45 deg C under stirring so as to saturate the product solution and achieve crystallization known as anti-solvent crystallization. Further reaction mass is gradually cooled and chilled below 10 deg C. Aging of crystals was allowed for 3 hours. Crystals were filtered and washed with acetone 25mL. Wet crystals were dried under vacuum below 60 deg C temperature. Yield obtained was 93%. Polymorphic ratio obtained was 58:42 (Form-II: Form-I). Liquid chromatographic purity was 99.87%o, Impurity-A detected was calculated to be 0.03%>. Residual solvent by headspace gas chromatography, detected acetone and methyl ethyl ketone below 500 ppm. Water content of dried crystals was 0.12%.
Working Example 6
20g crude crystals of sarpogrelate hydrochloride were added to 100 mL Ethyl acetate. Formic Acid (20 ml of 98%> grade) is added gradually under stirring and complete dissolution of solute is achieved below 60 deg C. Activated carbon treatment and filtration is performed. Crystal seed mixture as obtained per example -1 are added and Filtrate is gradually cooled causing cooling crystallization and chilled below 10 deg C. Aging of crystals was allowed for 3 hours. Crystals were filtered and washed with ethyl acetate 25mL. Wet crystals were dried under vacuum below 60 deg C temperature. Yield obtained was 93%. Polymorphic ratio obtained was 83:17 (Form-II: Form-I). Liquid chromatographic purity was 99.87%), Impurity-A detected was calculated to be

0.02%. Residual solvent by headspace gas chromatography, detected ethyl acetate at 420 ppm. Water content of dried crystals was 0.11%.
Working Example 7
20g crude crystals of sarpogrelate hydrochloride were added to 120 mL Iso-propyl alcohol. Formic Acid (20 ml of 98% grade) is added gradually under stirring and complete dissolution of solute is achieved below 60 deg C. Activated carbon treatment and filtration is performed. Crystal seed mixture as obtained per example -1 are added and Filtrate is gradually cooled causing cooling crystallization and chilled below 10 deg C. Aging of crystals was allowed for 3 hours. Crystals were filtered and washed with iso-propyl alcohol 25mL. Wet crystals were dried under vacuum below 60 deg C temperature. Yield obtained was 94%. Polymorphic ratio obtained was 76:24 (Form-II: Form-I). Liquid chromatographic purity was 99.88%), Impurity-A detected was calculated to be 0.03%>. Residual solvent by headspace gas chromatography, detected isopropyl alcohol at 390 ppm. Water content of dried crystals was 0.12%.
Working Example 8
20g crude crystals of sarpogrelate hydrochloride were added to 100 mL Metyl Iso-butyl ketone (MIBK). Methanol 50mL is added under stirring and complete dissolution of solute is achieved at about 60 deg C. Activated carbon treatment and filtration is performed. Methanol is than distilled out from the solution causing evaporative crystallization. Filtrate is gradually cooled and chilled below 10 deg C. Aging of crystals was allowed for 3 hours. Crystals were filtered and washed with acetone 25mL. Wet crystals were dried under vacuum below 60 deg C temperature. Yield obtained was 95.5%. Polymorphic ratio obtained was 79:21 (Form-II: Form-I). Liquid chromatographic purity was 99.83%>, Impurity-A detected was calculated to be 0.05%. Residual solvent by headspace gas chromatography, detected acetone, methanol and MIBK below 500 ppm. Water content of dried crystals was 0.14%.

[BRIEF DESCRIPTION OF THE DRAWINGS]
[Drawing 1]
It is the Differential Scanning Calorimetry curve of the polymorphic mixture, 53: 47 (Form-II: Form-I) obtained in working example -1.
[Drawing 2]
It is the Infrared absorption spectrum of the of the polymorphic mixture, 53:47 (Form-II: Form-I) obtained in working example-1.
[Drawing 3]
It is the Differential Scanning Calorimetry curve of the polymorphic mixture, 70: 30 (Form-II: Form-I) obtained in working example -2.
[Drawing 4]
It is the Infrared absorption spectrum of the of the polymorphic mixture, 70:30 (Form-II: Form-I) obtained in working example-2.
[Drawing 5]
It is the Differential Scanning Calorimetry curve of the polymorphic mixture, 96: 04 (Form-II: Form-I) obtained in working example -3.
[Drawing 6]
It is the Infrared absorption spectrum of the of the polymorphic mixture, 96:04 (Form-II: Form-I) obtained in working example-3.
[Drawing 7]
It is the Differential Scanning Calorimetry curve of the 100% pure polymorph Form-II obtained in working example -4.
[Drawing 8]
It is the Infrared absorption spectrum of the of the 100% pure polymorph Form-II obtained in working example -4.

[Drawing 9]
It is the particle size distribution curve of the sample obtained in working example -1 and also which is described as Lot-1 in [Table -1]
[Drawing 10]
It is the particle size distribution curve of the sample obtained in working example -2 and also which is described as Lot-2 in [Table -1]
[Drawing 11]
It is the particle size distribution curve of the sample obtained in working example -3 and also which is described as Lot-3 in [Table -1]
[Drawing 12]
It is the particle size distribution curve of the sample obtained in working example -4 and which is described as Lot-4 in [Table -1]
[Drawing 13]
It is the particle size distribution curve of the sample described as Lot - 5 in [Table -1]
[Drawing 14]
It is the particle size distribution curve of the sample described as Lot - 6 in [Table -1]
[Industrial applicability]
[0044]
This invention is applicable for the industrial production of sarpogrelate hydrochloride which is
used for clinical and medicinal purposes. The present invention shall help in reducing the overall
cost of manufacture of sarpogrelate hydrochloride.

[CLAIMS ]
[CLAIM 1 ]
A manufacturing method involving re-crystallization of sarpogrelate hydrochloride wherein dissolution of sarpogrelate hydrochloride crystals in any less toxic solvent or solvent mixture(s) is achieved by addition of less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid (methanoic acid), acetic acid (ethanoic acid), propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.
[CLAIM 2 ]
A manufacturing method involving re-crystallization of sarpogrelate hydrochloride wherein dissolution of sarpogrelate hydrochloride crystals is achieved in less toxic aliphatic ketone(s) or their mixtures, preferably acetone (propanone), methyl ethyl ketone (butanone), methyl isobutyl ketone (4-Methylpentan-2-one), by using less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid (methanoic acid), acetic acid (ethanoic acid) propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.
[CLAIM 3 ]
A manufacturing method involving re-crystallization of sarpogrelate hydrochloride wherein dissolution of sarpogrelate hydrochloride crystals is achieved in less toxic alcohol(s) or their mixtures, preferably methanol, ethanol, 1-Butanol, 2-Butanol, 1-Propanol, 2-Propanol, 1-Pentanol, 3-Methyl-1-butanol, 2-methyl-l-propanol, ethylene glycol by using less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid (methanoic acid), acetic acid (ethanoic acid) , propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.
[CLAIM 4 ]
A manufacturing method involving re-crystallization of sarpogrelate hydrochloride wherein dissolution of sarpogrelate hydrochloride crystals is achieved in less toxic ester(s) or their mixtures, preferably ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate, Isopropyl aceate, Propyl acetate by using less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid (methanoic acid), acetic acid (ethanoic acid) propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.

[CLAIM 5 ]
A manufacturing method involving re-crystallization of sarpogrelate hydrochloride wherein dissolution of sarpogrelate hydrochloride crystals is achieved in the solvent mixtures consisting of less toxic ester(s) and/or alcohol(s) and/or aliphatic ketone(s) by using less toxic aliphatic monocarboxylic acid(s) or their mixtures, preferably formic acid (methanoic acid), acetic acid (ethanoic acid) propionic acid (propanoic acid), so as to obtain polymorphic mixture (form-I and form-II) of sarpogrelate hydrochloride.
[CLAIM 6 ]
A manufacturing method involving re-crystallization of sarpogrelate hydrochloride using maximum 8 times (w/w of solute) of aliphatic ketone(s) and/or alcohol(s) and/or ester(s) or their mixtures along with maximum 2 times (w/w of solute) of aliphatic monocarboxylic acid(s) or their mixtures , so as to limit the total solvent volume required for re-crystallization below 10 times (w/w of solute).
[CLAIM 7 ]
A manufacturing method of sarpogrelate hydrochloride which either adds water to solvent mixtures described from claim (1) to claim (6), so as to aid dissolution of solute or to reduce total solvent volume or to control acidity of solvent mixture or to increase content of Form-I crystal in the product or a manufacturing method which limits the water (moisture) content in solvent or solvent mixtures described from claim (1) to claim(6) by passing it over drying agent, so as to achieve higher yield or to minimize impurity by hydrolysis or to achieve higher content of Form-II crystal in the product.
[CLAIM 8 ]
A manufacturing method which involves any specific or combination of below set of operations (though not limited to same) for carrying out re-crystallization and refining of sarpogrelate hydrochloride crude crystals, so as to obtain polymorphic mixture (Form-I and Form-II) of sarpogrelate hydrochloride, using solvent mixtures described from claim (1) to claim (7) :
(a) Suspending and stirring of crude crystals in solvent or solvent mixture consisting of esters and/or alcohols and/or aliphatic ketones.
(b) Gradual Addition of specific or mixture of aliphatic monocarboxylic acid under stirring.
(c) Heating the reaction mass gradually so as to cause dissolution.

(d) Achieving dissolution of reaction mass below 40 deg C by using higher proportion of solvent in comparison to anti-solvent, and later in the process compensating the same by adding anti-solvent.
(e) Addition of activated carbon in slurry form to aid purification.
(f) Filtration of solution from filter(s) which retain carbon and other suspended matter whereas allow the filtrate to pass.
(g) Addition of seed crystal or suspension at a particular temperature or at defined stage.
(h) Controlling cooling rate of reaction mass and thereafter chilling below 10 deg C, so as to obtain crystals in high yield, by a cooling crystallization technique.
(i) Controlling saturation and crystallization rate of reaction mass by controlled addition of anti-solvent into the reaction mass at a given temperature or temperature range under stirring, so as to obtain higher content of form-II crystal. Such crystals are obtained using anti-solvent crystallization.
(j) A three component solvent mixture in which any two amongst ester/alcohol/aliphatic ketone achieve dissolution using aliphatic monocarboxylic acid. And further during re-crystallization, one of the solvent amongst ester/alcohol/aliphatic ketone is distilled with or without vacuum, so as to achieve saturation and crystallization. And optimising of such a process which is known as evaporative crystallization.
(k) Allowing aging of the crystals, preferably below 10 deg C.
(1) Filtration of reaction mass so as to isolate the crystals.
(m) Washing of crystals obtained using least toxic solvent or solvent mixture.
(n) Drying of crystals obtained, preferably under reduced pressure and preferably at temperature below 60 deg C.
(o) Milling of the product, preferably using pulveriser or air jet mill.
[CLAIM 9 ]
Addition of hydrogen chloride to sarpogrelate free base using any of solvent mixtures described in claim (1) to (7) and by using manufacturing process described in claim (8) so as to precipitate sarpogrelate hydrochloride. Such addition of hydrogen chloride may be caused by any means such as purging of anhydrous hydrochloric gas, or by charging solvent enriched with hydrogen chloride, so as to obtain polymorphic mixture (Form-I and Form-II) of sarpogrelate hydrochloride.

[CLAIM 10 ]
The Non-solvent based Re-crystallization process of sarpogrelate hydrochloride, causing solid-state crystal transition by mechanical impact or fluid impact whereby the polymorphic ratio of both the forms - I and II is modified using such techniques. Such a crystal transition process being carried out by pharmaceutically preferable forms of mechanical impaction and fluid impaction at low temperature such as pulveriser and fluid jet mill using air or nitrogen. And combining this method alongwith classification system so as to derive desired particle size distribution. And application of such a process to sarpogrelate hydrochloride achieved using claims (1) to (9) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled along with other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.
[CLAIM 11 ]
The Non-solvent based Re-crystallization process of sarpogrelate hydrochloride, causing solid-state crystal transition by mechanical impact or fluid impact wherein the content of crystal Form-II is increased due to such a process so as to achieve preferably more than 75%, more preferably greater than 85% and most preferably greater than 98% of Form-II content in the final product. Such a crystal transition process being carried out by pharmaceutically preferable forms of mechanical impaction and fluid impaction at low temperature such as pulveriser and fluid jet mill using air or nitrogen. And combining this method along with classification system so as to derive desired particle size distribution. And application of such a process to sarpogrelate hydrochloride achieved using claims (1) to (10) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled along with other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.
[CLAIM 12 ]
The Non-solvent Re-crystallization process of sarpogrelate hydrochloride, causing solid state crystal transition by mechanical impact or fluid impact so as to increase the crystal content of Form-II to more than 70% and to simultaneously achieve a particle size distribution having D(0.1) < 5 um, D(0.5) < 25 um and D(0.9) < 50um or still a finer particle size distribution such as D(0.1) < 2 um, D(0.5) < 5um and D(0.9) < 10 um . Such a crystal transition process being carried out by pharmaceutically preferable forms of mechanical impaction and fluid impaction at low temperature such as pulveriser and fluid jet mill using air or nitrogen. And combining this method alongwith classification system so as to derive desired particle size distribution. And application of such a process to sarpogrelate hydrochloride achieved using claims (1) to (11) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled along with other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.

[CLAIM 13]
The Non-solvent Re-crystallization process of sarpogrelate hydrochloride, causing solid state crystal transition by mechanical impact or fluid impact so as to cause more than 5% increase in Form-II content of final product (with respect to content of Form-II in product before milling), thereby which a final product so achieved is more stable than the initial product due to more than 5% increase in Form-II. Such a crystal transition process being carried out by pharmaceutically preferable forms of mechanical impaction and fluid impaction at low temperature such as pulveriser and fluid jet mill using air or nitrogen. And combining this method along with classification system so as to derive desired particle size distribution. And application of such a process to sarpogrelate hydrochloride achieved using claims (1) to (12) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled alongwith other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.
[CLAIM 14 ]
The process of solvent based solid state crystal transition wherein slurry of sarpogrelate hydrochloride is grinded using a wet grinding mill, thereby to achieve higher content of form-II (with respect to content of Form-II in product before milling). And application of such a process to sarpogrelate hydrochloride achieved using claims (1) to (13) or by any other means or process. Also application of such a process where sarpogrelate hydrochloride is milled along with other pharmaceutical excipients as a part of pharmaceutical dosage form preparation.
[CLAIM 15 ]
A re-crystallization process of sarpogrelate hydrochloride wherein Enhancement in any process controls or process equipments as described from claim (1) to (14) are used to achieve higher efficiency for the claimed results, For example:
(a) Enhanced Process Controls such as : Rate of cooling, heating, stirring, addition, saturation, dissolution, seeding, nitrogen blanketing, temperature of milling, degree of chilling etc.
(b) Enhanced Process equipments such as : high vacuum drying, spray drying, milling or grinding under nitrogen etc.

[CLAIM 16 ]
To obtain crystal seed or crystal seed mixture or suspensions or solutions from any specific or combination of the process as described from claim (1) to claim (15). And to make use of same in sarpogrelate hydrochloride manufacturing method(s) described from claim (1) to (15) so as to achieve desired results such as by seeding so as to achieve desired polymorphic form or ratio of polymorphic forms or desired particle size distribution or achieving higher yield or achieving higher purity.
[CLAIM 17 ]
Any specific or combination of sarpogrelate hydrochloride manufacturing method described in claim (1) to (16) whereby the major impurity and degradation product BP984 (described as decomposed substance A, having impurity limit of 1/5 peak area of standard solution and hplc retention time 0.82 as per Japanese Pharmacopoeia XVI) in the final product is reduced and controlled below 1/15 peak area of standard solution, which is much less than the limits (1/5 of area) of related substances test by hplc as described in sarpogrelate hydrochloride monograph of Japanese Pharmacopoeia XVI.
[CLAIM 18 ]
Any specific or combination of sarpogrelate hydrochloride manufacturing method described in claim (1) to (17) whereby the total related substance impurity of final product is reduced and controlled below 1/5 the area of standard solution, which is much less than the limits (1/2 of area) of related substances test by hplc as described in sarpogrelate hydrochloride monograph of Japanese Pharmacopoeia XVI.
[CLAIM 19 ]
Any specific or combination of sarpogrelate hydrochloride manufacturing method described in claim (1) to (18) whereby the highest content of Form-II (DSC endotherm between 155 to 157 deg C and IR absorption peaks at least two amongst 792, 1163, 1040, 1464, 1406, 1742, 1497, 1603) is achieved consistently in the final product, preferably greater than 75%, more preferably greater than 85% and most preferably greater than 98%.
[CLAIM 20 ]
Any specific or combination of sarpogrelate hydrochloride manufacturing method described in claim (1) to (19) whereby which only class-3 solvents (as defined by ICH guidelines) are used and so their presence in the final product are controlled below 500 ppm which is much less than limits of 5000 ppm (set by ICH guidelines - Residual solvent).

[CLAIM 21 ]
Any specific or combination of sarpogrelate hydrochloride manufacturing method described in claim (1) to (20) whereby water content in final product achieved is consistently below 0.2% which is much less than limits 0.5% (described in sarpogrelate hydrochloride monograph of Japanese Pharmacopoeia XVI).
[CLAIM 22 ]
Any specific or combination of sarpogrelate hydrochloride manufacturing method described in claim (1) to (21) thereby which polymorphic mixture of Form-I and Form-II is obtained, and the polymorphic ratio of in final product is consistently achieved between 7:3 to 9:1 (Form-II: Form-I).
[CLAIM 23 ]
Any specific or combination of sarpogrelate hydrochloride manufacturing method described in claim (1) to (22) whereby dissolution and/or re-crystallization is carried out at temperature below 60 deg C to avoid product degradation.
[ TITLE OF DOCUMENT ]
METHOD FOR INDUSTRIALLY PRODUCING (2RS)-l-Dimethylamino-3-{2-[2-(3-methoxyphenyl)ethyl]phenoxy}propan-2-yl hydrogen succinate monohydrochloride
methods. Thereby providing the product having higher content of Form-II crystals.