FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENS RULES, 2003
PROVISIONAL SPECIFICATION
[See section 10, Rule 13]
NOVEL CRYSTALLIZATION METHODS
AND NOVEL CRYSTALLINE AND
AMORPHOUS FORMS OF
HALOGENATED SUGARS;
PHARMED MEDICARE PVT. LTD., A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, WHOSE ADDRESS IS 141, WALCHAND HIRACHAND MARG, MUMBAI - 400 001, MAHARASHTRA, INDIA.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THIS INVENTION.

TECHNICAL FIELD
The present invention relates to methods of separation of solid form from their solutions used in the production of halo (chlorinated) sugars including I'-e'-Dichloro-l'-e'-DIDEOXY-p-FructofuranasyW-chloro^-deoxy-galactopyranoside (TGS) and various solid forms of this product.
BACKGROUND OF THE INVENTION
Strategies of prior art methods of production of 4,1', 6' trichlorogalactosucrose (TGS) predominantly involve chlorination of sucrose-6-ester by use of Vilsmeier-Haack reagent derived from various chlorinating agents such as phosphorus oxychloride, oxalyl chloride, phosphorus pentachloride etc, and a tertiary amide such as dimethyl formamide (DMF) or dimethyl acetamide to chlorinate Sucrose-6-ester, to form 6 acetyl 4,1', 6' trichlorogalactosucrose. After the said chlorination reaction, the reaction mass is neutralized to pH 7.0 -7.5 using appropriate alkali hydroxides of calcium, sodium, etc. to deesterify / deacetylate the 6 acetyl 4,1', 6'trichlorogalactosucrose to form 4,1', 6* trichlorogalactosucrose (TGS).
This specification covers a novel crystallization process is described herein where the n-butanol / methanol mixture in suitable proportions to facilitate formation of crystallized solid forms with mean particle size of less than 8 to 12 microns. This specification also covers a process to generate amorphous form of halosugars.
The purification steps for the isolation of the TGS involve various processes including extractive purification, Affinity chromatography, etc. After the final purification of TGS which is substantially free from all
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organic impurities as well as inorganic solids, is subjected to crystallization by suitable methods.
In one such crystallization embodiment, the isolated TGS from Affinity chromatography process is in methanol and n-butanol mixture. This mixture of solvent when is subjected to distillation, the relative proportions of methanol to butanol; changes and hence the solubility of TGS in the solution also changes. When the methanol is completely removed along with substantial quantity of n-butanol, the solubility of TGS in the solution decreases and the falling out of the TGS starts.
At this point, the solution is cooled to reduced temperature levels to facilitate complete crystallization of TGS. When the temperature reduction was gradually done following a fixed gradient, it was surprisingly found that the crystal size obtained was of reduced particle size. It was found that by altering the temperature gradient and by the suitable concentration of methanol and butanol in the solution a particle size of less than 12 microns was achieved.
This is one more process for direct production of crystalline form having crystals of size smaller than 20 microns without the need of a process of size reduction, such as jet milling, for the purpose of size reduction.
In another embodiment, it was seen that if the TGS in methanol-butanol mixture was directly subjected to spray drying or such suitable techniques, under suitable conditions where in an amorphous form of TGS was obtained. The amorphous form of TGS has been reported earlier by Ratnam et al. (2005) in patent application publication no. WO2005090374 by precipitation from other solvents. The properties and its features of the
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amorphous form obtained from methanol-butanol system are being studied and compared with the forms obtained in system reported in WO2005090374. The use of amorphous forms in formulations and its advantages are also being explored. The results given below are an account of interim results, which shall be improved upon by further work and fine tuned until complete specification is submitted. The details of work done so far disclosed below serve as illustrations and do not limit the scope of actual techniques used or scope of reaction conditions or process conditions claimed. The techniques and reaction conditions or process conditions disclosed below are subject matter of ongoing trials and fine tuning or trials in alternative or better conditions in method for direct crystallization in small particle size and production of an amorphous form.
In one experiment, the TGS along with hydrophilic impurities when subjected to Affinity chromatography process, the hydrophilic impurities were separated out and the pure TGS fraction was eluted out using 1:1 mixture of methanol and n-butanol.
The 1:1 mixture of methanol and n-butanol containing pure TGS was taken for crystallization. The mixture was taken for distillation under vacuum at 45°C to 70°C more preferably between 50 - 55°C. The methanol is completely removed along with butanol. The distillation was stopped when the TGS concentration in the solution reached around 50 -65%. This solution was then cooled from 55°C to 30°C over a period of 4-6 hours, then cooled from 30°C to 15°C over a period of 2 - 4 hours and then further cooled from 15"C to -5°C over a period of 4-6 hours to facilitate almost complete crystallization of TGS. The slurry obtained was
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then filtered and slurry washed with 1:0.5 to 1:1.2 more preferably 1:0.5-
0.7 w/v of ester solvent such as ethyl acetate, butyl acetate, etc at
reduced temperature of -5° to 15°C.
The solids obtained were subjected to drying operation below 40 - 50°C
under vacuum. The resultant product was analyzed for purity and particle
size and was found to be 99.12% and 90% were less than 8 microns
respectively.
The mixture for crystallization apart from the aforementioned mixture of
methanol and n-butanol can contain other higher alcoholic solvents such
as n-propanol, Iso butanol, t-butanol, secondary butanol, pentanol, Amyl
alcohol, etc.
In another process described is a drying technique applied directly to the
pure eluant obtained from the Affinity chromatography process. These
drying techniques could be one or more of a spray drying, an Agitated thin
film drying, drying in forced circulation evaporators, etc. Here the TGS in
alcoholic solvent mixtures such as methanol and butanol or other solvents
such as n-propanol, Iso butanol, t-butanol, secondary butanol, pentanol,
Amyl alcohol, etc. is subjected to any drying technique such as spray
drying.
The spray dryer system should have a solvent recovery system to recover
the solvent during the drying operation. The inlet temperature of the spray
drier was adjusted to 160 -200°C more preferably 180 -185°C. The solid
obtained from the spray drier outlet and cyclonic separator was found to
be amorphous in nature. The purity of the product was not altered during
the drying operation. The nature and feature of the amorphous form of
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TGS are being investigated. Also its formulation and subsequent use is
being explored,
It may be appreciated by any one skilled in the art that solutions of TGS as
mentioned above in the solvents specified or equivalent may be obtained
by methods other than affinity chromatography, and all such embodiments
are included within the scope of this invention.
In One experiment, 10 kg of TGS eluted from Affinity chromatography
resin columns in 200 L of 1:1 n-butanol methanol mixture was taken for
crystallization.
200 L of the TGS in methanol-butanol mixture was taken in a reactor.
200g of pharma grade charcoal was added to the contents in the reactor
and heated to 55 - 60°C under stirring for 30 minutes. Then the solution
was filtered to make it free from charcoal and extraneous matter. The
filtrate was then subjected to concentration under vacuum below 55°C till
the TGS concentration reached to 55%. Some amount of crystals of TGS
started appearing during this stage.
The reactor was equipped with a control system to facilitate gradual
cooling of the TGS solution. The solution was cooled from 55°C to 30°C
in about 4-6 hours, then from 30°C to 15°C in about 2 hours and then
further cooled to -5°C in about 3.5 hours. The crystal slurry was then
filtered and suck dried.
The wet solids obtained were then re-slurried in 5 L of ethyl acetate and
stirred for 30 minutes at -5°C. Then the slurry was filtered and suck dried.
Further the solids were dried in Vacuum Tray drier below 45°C.
The TGS crystals obtained were tested for purity and particle size. The
purity was found to be 99.23% by HPLC and particle size distribution at
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90% was below 8 microns. The overall yield from the process was found to be 80%. The mother liquor from the process was recycled. In another experiment, 10 kg of TGS eluted from Affinity chromatography resin columns in 200 L of 1:1 Isopropanol and methanol was taken for spray drying.
The spray drier was equilibrated setting the inlet temperature to 182°C and peristaltic pump flow rate to 30 L per hour. The inlet was DM water, which was switched on to the above said TGS feed. As the Isopropanol and methanol mixture was atomized into thin droplets on to the spray drier top chamber, the fine powder of TGS started collecting in the chamber end and the fines were collected from the cyclonic separator. The solds obtained were tested for purity, particle size and X ray diffraction for the nature of solid obtained. The purity was found to be 99.28% and particle size distribution at 90% was below 6 microns. The overall yield from the process was found to be 86%. The nature of the crystals as per X-ray crystallography showed no peaks confirming the product to be amorphous in nature.
Dated this 22nd day of March, 2006.