FIELD OF INVENTION:
The present invention discloses a new polymorphic form designated as Form M of
Canagliflozin along with novel processes for its preparation. The new polymorphic
form M shows only 3 characteristic peaks in its powder XRD pattern at 2-theta 27.4,
31.7 & 45.5. Also disclosed are two novel methods of preparation crystalline form of
Canagliflozin Hemihydrate.
BACKGROUD OF INVENTION:
Canagliflozin Hemihydrate or (1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-
thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate or (2S,3R,4R,5S,6R)-2-{3-
[5-(4-Fluorophenyl)-thiophen-2-yl-methyl]-4-methylphenyl}-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol hemihydrate an inhibitor of sodiumglucose
co-transporter 2 (SGLT2), is useful for the treatment of type 2 diabetes, has
the Formula I, as given below:
S
F
O
OH
OH
OH OH
1/2. H2O
(Formula I)
3
Canagliflozin is an anti-diabetic drug used to improve glycemic control in people
with type 2 diabetes. In extensive clinical Trials, Canagliflozin produced a consistent
dose-dependent decrease in HbA1c levels of 0.77% to 1.16% when administered
either as monotherapy, in combination with metformin, in combination with
metformin and a sulfonylurea, in combination with metformin and pioglitazone, or in
combination with insulin, from initial HbA1c levels of 7.8% to 8.1%. When added to
metformin, Canagliflozin 100 mg daily dose was shown to be non-inferior to both
sitagliptin 100 mg daily and glimepiride in reducing HbA1c levels at one year, whilst
Canagliflozin 300 mg successfully demonstrated statistical superiority over both
sitagliptin and glimiperide in decreasing HbA1c levels. Secondary efficacy endpoints
of higher reductions in weight and blood pressure (versus sitagliptin and glimiperide)
were also observed in studies. Canagliflozin produces beneficial effects on HDL
cholesterol whilst increasing LDL cholesterol to produce no change in total
cholesterol.
The US patent document US 7,943,788 discloses Canagliflozin in example 84, which
is prepared in accordance with examples 1 through 4. The examples disclose the
isolation of the crude desired compound in the form of a residue, which is then
purified by column chromatography.
Patents U.S 7,943,582 B2 and US 8,513,202 B2 discloses crystalline form of 1-(β-Dglucopyranosyl)-
4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene
hemihydrate and process for preparation thereof. Other patents US 3 582 B2 and US
4
'202 B2 further discloses the preparation of the crystalline form of hemi-hydrate
Canagliflozin typically which involves dissolving of crude or amorphous compound
prepared in accordance with the procedures described in WO 2005/012326 pamphlet
in ketone or ester solvent followed by addition of anti-solvent like water and alkanes
or ethers to the resulting solution, followed by isolation of product by filtration. The
crystalline form of Canagliflozin Hemihydrate was first disclosed in patent US
8,513,202.
PCT Publication No. WO 2009/035969 discloses a crystalline form of Canagliflozin,
designated as I-S.
PCT Publication No. WO 2013/064909 discloses crystalline complexes of
Canagliflozin with L-proline, D-proline, and L-phenylalanine, and the processes for
their preparation.
PCT Publication No. WO 2014/180872 discloses crystalline non-stoichiometric
hydrates of Canagliflozin (HxA and HxB), and the process for their preparation.
PCT Publication No. WO 2015/071761 discloses crystalline Forms B, C, and D of
Canagliflozin. Chinese Publication Nos. CN 103980262, CN 103936726, CN
103936725, CN 103980261, CN 103641822, CN 104230907, CN 104447722, CN
104447721, and CN 104130246 disclose different crystalline polymorphs of
Canagliflozin.
5
Various polymorphs of Canagliflozin and process for their preparation have been
reported in the patent publications US9024009B2, US9056850B2, US8999941 B2,
US8772512, WO2012154812, WO2015071761 A2, CN103936725A,
CN103896930A and WO2014195966A2.
The US patent application document US8999941 B2 discloses the amorphous
Canagliflozin is hygroscopic as per Dynamic vapor sorption (DVS) analysis.
Amorphous form undergoes physical changes. It further discloses the preparation of
amorphous Canagliflozin by adding a solution of Canagliflozin in toluene to nheptane.
New crystalline polymorphic forms of a drug substance may display different melting
point, hygroscopicity, stability, solubility and/or dissolution rate, crystallinity, Crystal
habits, bioavailability, toxicity and formulation handling characteristics, which are
among the numerous properties that need to be considered in preparing medicament
that can be effectively administered. Therefore, the regulatory agencies require a
definitive control of polymorphic form of the active component in solid
pharmaceutical dosage forms.
Accordingly, there was an ongoing need to search new polymorphic forms of
Canagliflozin Hemihydrate that may have better stability and good material flow
character, lower residual solvent contents, and may offer advantages for preparing
reproducible pharmaceutical formulations. The new polymorphic form of
6
Canagliflozin of present invention is having very low residual solvent contents and
therefore will be of use.
BFIEF DESCRIPTION OF DRAWINGS
Figure 1: XRD diffractogram of Polymorphic form M of Canagliflozin prepared as
per example 1 & 2.
Figure 2: XRD diffractogram of Crystalline Canagliflozin Hemihydrate (as disclosed
in US 8,513,202) as per Example 3.
Figure 3: XRD diffractogram of Crystalline Canagliflozin Hemihydrate (as
disclosed in US 8,513,202) as per Example 4.
Figure 4: XRD diffractogram of Crystalline Canagliflozin Hemihydrate (as disclosed
in US 8,513,202) as per Example 5.
SUMMARY OF INVENTION:
The present invention discloses a novel polymorphic form M of Canagliflozin which
is characterized by three major & only peaks at 2-theta 27.4, 31.7 & 45.5. Its
preparation comprises, deprotection of Tetraacetyl Canagliflozin in an aliphatic
alcohol in presence of caustic solution. After reaction completion, the product is
extracted in ethyl acetate or any other aliphatic straight chain or branched chain ester
at almost neutral pH followed by complete recovery of solvent. The resulting residue
is redissolved in an aliphatic alcohol followed by complete recovery of solvent to get
7
Canagliflozin Form M by adding an anti-solvent such as aliphatic hydrocarbons like
hexane, heptane or mixture thereof.
Another process for the preparation of Canagliflozin Form M is also disclosed which
comprises deprotection of Tetraacetyl Canagliflozin in an aliphatic alcohol in
presence of caustic solution. After reaction completion, the product is extracted in
ethyl acetate or any other aliphatic straight chain or branched chain ester at almost
neutral pH followed by complete recovery of solvent. The resulting residue is
redissolved in an aliphatic alcohol followed by complete recovery of solvent to get
Canagliflozin Form M without adding any anti-solvent.
Also disclosed are two novel methods for preparation of Crystalline Canagliflozin
Hemihydrate which was initially disclosed in innovator’s patent US 8,513,202 B2.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a new polymorphic
form of Canagliflozin designated as Canagliflozin form M is disclosed which is
characterized by the XRD pattern having major peaks as tabulated below.
S.No 2 theta Relative intensity (%)
1. 27.4035 11.27
2. 31.7314 100.00
3. 45.5005 42.85
8
According to the second embodiment of the present invention, a process for
preparation of new polymorphic form M of Canagliflozin which comprises (Example
1):
1) Tetraacetyl Canagliflozin is taken in an round bottom flask
2) addition of an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-
propanol, butanol, monoethylene glycol & diethylene glycol or cyclic
ether like Tetrahydrofuran, dioxane or a mixture thereof.
3) addition of aq caustic solution (12%)
4) heating of reaction mass to 40-50 °C.
5) stirring for 3-5 hours at 40-50 °C.
6) Checking of TLC/HPLC for confirmation of reaction completion.
7) Cooling of reaction mass & pH adjustment to 6.5-7.5 with 1N
Hydrochloric acid.
8) Again heating reaction mass to 55 °C.
9) Recovery of solvent under vacuum followed by addition of water
10) Extraction of product using a C1-C3 aliphatic ester. e.g. ethyl acetate,
propyl acetate, butyl acetate or a mixture thereof .
11) Charcoaling of organic layer
12) Again heating reaction mass to 60 °C followed by complete solvent
recovery.
13) Again addition of aliphatic alcohol such as methanol, ethanol, 1-propanol,
2-propanol, butanol, monoethylene glycol & diethylene glycol or a
9
mixture thereof
14) Stirring for dissolution followed by heating again for solvent recovery
15) Complete recovery of aliphatic alcohol from reaction mass
16) Addition of C4-C8 straight or branched chain aliphatic hydrocarbons like
butane, pentane, hexane, heptane, octane or a mixture thereof to the
resulting residue of step 15.
17) Stirring for complete crystallization of material
18) Filtration of product as wet cake
19) Drying at 40-50 °C for 4-15 hours to get Canagliflozin Form M.
According to the third embodiment of current invention, a process for preparation of
new polymorphic form M of Canagliflozin which comprises (Example 2):
1) Tetraacetyl Canagliflozin is taken in an round bottom flask
2) addition of an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-
propanol, butanol, monoethylene glycol & diethylene glycol or a mixture
thereof.
3) addition of aq caustic solution (12%)
4) heating of reaction mass to 40-50 °C.
5) stirring for 3-5 hours at 40-50 °C.
6) Checking of TLC/HPLC for confirmation of reaction completion.
7) Cooling of reaction mass & pH adjustment to 6.5-7.5 with 1N
Hydrochloric acid.
10
8) Again heating reaction mass to 55 °C.
9) Recovery of solvent under vacuum followed by addition of water
10) Extraction of product using a C1-C3 aliphatic ester. e.g. ethyl acetate,
propyl acetate, butyl acetate or a mixture thereof .
11) Charcoaling of organic layer
12) Again heating reaction mass to 60 °C followed by complete solvent
recovery.
13) Again addition of aliphatic alcohol such as methanol, ethanol, 1-propanol,
2-propanol, butanol, monoethylene glycol & diethylene glycol or a
mixture thereof
14) Stirring for dissolution followed by heating again for solvent recovery
15) Complete recovery of aliphatic alcohol from reaction mass
16) Further drying of resulting solid to remove traces of solvents at 40-50 °C
for 4-15 hours to get Canagliflozin Form M.
According to the Fourth embodiment of current invention, a process for preparation
of crystalline Canagliflozin Hemihydrate (as disclosed in US 8,513,202) which
comprises (Example 3 & 4):
1) Canagliflozin hemihydrate is taken in a solvent under stirring.
2) Heating the reaction mass to 30-40 °C.
3) Stirring till complete dissolution.
4) Performed slow addition of water in 30-60 min.
5) Now stirred the reaction mass for 20-24 hours at 20-30 °C.
11
6) Cooling of reaction mass to 0-10 °C.
7) Further stirring for 1-2 hours.
8) Filtration of product as wet cake at 0-10 °C.
9) Slurry washing of this wet cake with water at 40-50 °C for 1-2 hours.
10) Isolation of product by filtration at 40-50 °C.
11) Further running washing with water.
12) Unloading & drying of wet cake at 40-50 °C for 8-10 hours to get
Crystalline Canagliflozin Hemihydrate.
According to one aspect of this embodiment solvent used in step 1) can be an
aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol,
monoethylene glycol & diethylene glycol or a mixture thereof.
According to yet another aspect of this embodiment solvent used in step 1) can be a
aliphatic nitrile such as acetonitrile, propionitrile or mixture thereof.
According to the Fifth embodiment of current invention, a process for preparation of
crystalline Canagliflozin Hemihydrate (as disclosed in US 8,513,202) which
comprises (Example 5):
1) Canagliflozin hemihydrate is taken in a aliphatic ether which is selected
from Diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl
ether or mixture thereof under stirring.
2) Heating the reaction mass to 65-70 °C under stirring.
3) Continued the stirring at this temperature for 1-2 hours.
12
4) Then allowed the reaction mass to cool naturally to 20-30 °C.
5) Now stirred at this temperature for 20-24 hours.
6) Further reduced the temperature to 5-10 °C.
7) Further stirred for 1-2 hours.
8) Filtration of product as wet cake with running washing with solvent as
used in step 1).
9) Dried the wet cake at 45-50 °C for 20-24 hours to get crystalline
Canagliflozin Hemihydrate.
The above mentioned invention is supported by the following non limiting examples.
EXAMPLES:
Example 1:
Tetraacetyl Canagliflozin (15 g) is taken in Tetrahydrofuran (68 ml) & methanol (98
ml) in a round bottom flask. The reaction mass is stirred to dissolve the material
followed by addition of caustic (3.91 g) solution under stirring at 20-30 °C. The
reaction mass is stirred for 3-5 hours till reaction completion. After confirmation of
reaction completion by HPLC/TLC, the solvent is removed under vacuum by heating
the reaction mass to 50-60 °C. After solvent recovery, water (37.5 ml) is added to the
residue, followed by addition of ethyl acteate (75 ml) under stirring, to extract the
product followed by layer separation to keep organic layer. Then aq. Layer is again
extracted with ethyl aceate (45 ml) twice followed by layer separation. Now
13
combined organic layers is washed with water and brine solution (75 ml). The
washed organic layer is treated with activated carbon (1.0 g) followed by filtration
through hyflow bed to remove carbon. The resulting ethyl acetate layer is dried over
sodium sulphate followed by its complete recovery under vacuum. The resulting solid
residue is redissolved in methanol (30 ml) followed by complete recovery under
vacuum to remove traces of methanol. After complete removal of solvent, n-heptane
(75 ml) is added to it as anti-solvent and then product is isolated by filtration and
drying at 40-45 °C for 5-15 hours to get Canagliflozin Form M. XRD is as per figure
1.
Yield = 8.20 g
Purity by HPLC = 99.66%
Assay = 99.69% w/w
Moisture Content = 1.97%
Example 2:
Tetraacetyl Canagliflozin (15 g) is taken in Methanol (100ml) in a round bottom
flask. The reaction mass is stirred to dissolve the material followed by addition of
caustic (3.91 g) solution under stirring at 20-30 °C. The reaction mass is stirred for 3-
5 hours till reaction completion. After confirmation of reaction completion by
HPLC/TLC, the solvent is removed under vacuum by heating the reaction mass to
50-60 °C. After solvent recovery, water (37.5 ml) is added to the residue, followed by
addition of ethyl acteate (75 ml) under stirring, to extract the product followed by
14
layer separation to keep organic layer. Then aq. Layer is again extracted with ethyl
aceate (45 ml) twice followed by layer separation. Now combined organic layers is
washed with water and brine solution (75 ml). The washed organic layer is treated
with activated carbon (1.0 g) followed by filtration through hyflow bed to remove
carbon. The resulting ethyl acetate layer is dried over sodium sulphate followed by its
complete recovery under vacuum. The resulting solid residue is redissolved in
methanol (30 ml) followed by complete recovery under vacuum to remove traces of
methanol at 40-45 °C for 5-15 hours to get Canagliflozin Form M. XRD is as per
Figure 1.
Yield = 9.75 g
Purity by HPLC = 99.62%
Assay = 99.32% w/w
Moisture Content = 1.94 %
Example 3:
Canagliflozin Hemihydrate (5 g) is taken in Isopropyl alcohol (25 ml) under stirring.
Heated the reaction mass to 30-40°C to ensure complete dissolution. This is followed
by addition of water (50 ml) in 30-60 min. This is followed by stirring of reaction
mass at 20-30 °C for 20-24 hours. Then reaction mass is cooled to 0-10 °C to ensure
complete crystallization. Stirred at 0-10 °C for 1-2 hours. Filtration of product as wet
cake. This wet cake is again taken for a slurry wash with water (25 ml) at elevated
15
temperature (40-50 °C) for 1-2 hours. Again filtered the material, provided running
washing with water (2.5 ml). Dried the wet cake thus obtained at 40-50 °C for 8-10
hours till water content is Not more than 4.0%, so as to obtain 3.2 g of crystalline
Canagliflozin Hemihydrate as disclosed in US 8,513,202. XRD is as per Figure 2.
Yield = 3.20 g
Purity by HPLC = 99.62%
Assay = 99.32% w/w
Moisture Content = 2.24 %
Example 4:
Canagliflozin Hemihydrate (5 g) is taken in acetonitrile (25 ml) under stirring. Heated
the reaction mass to 30-40°C to ensure complete dissolution. This is followed by
addition of water (50 ml) in 30-60 min. This is followed by stirring of reaction mass
at 20-30 °C for 20-24 hours. Then reaction mass is cooled to 0-10 °C to ensure
complete crystallization. Stirred at 0-10 °C for 1-2 hours. Filtration of product as wet
cake. This wet cake is again taken for a slurry wash with water (25 ml) at elevated
temperature (40-50 °C) for 1-2 hours. Again filtered the material, provided running
washing with water (2.5 ml). Dried the wet cake thus obtained at 40-50 °C for 8-10
hours till water content is Not more than 4.0%, so as to obtain 3.6 g of crystalline
Canagliflozin Hemihydrate as disclosed in US 8,513,202. XRD is as per Figure 3.
Yield = 3.60 g
16
Purity by HPLC = 99.72%
Assay = 99.42% w/w
Moisture Content = 2.04 %
Example 5:
Canagliflozin Hemihydrate (5 g) is taken in diisopropylether (25 ml) under stirring.
Heated the reaction mass to 65-70 and stirred for 1-2 hours to ensure complete
dissolution. Now all the temperature to fall naturally to 20-30 °C followed by its
stirring for 20-24 hours. Further cooled the reaction mass to 5-10 and stirred for 1-2
hours. Filtered the product and provided running washing with diisopropylether (5
ml). Drying the wet cake at 45-50 °C for 20-24 hours to get crystalline Canagliflozin
Hemihydrate as disclosed in US 8,513,202. XRD is as per Figure 4.
Yield = 2.75 g
Purity by HPLC = 99.86%
Assay = 99.12% w/w
Moisture Content = 2.64 %

We claim:
1. A novel polymorphic crystalline form ‘M’ of the (1S)-1,5-Anhydro-1-C-[3-[[5-
(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, designated as
form ‘M’ of Canagliflozin of formula I or hydrates thereof. Here “x”
represents moles of water present.
S
F
O
OH
OH
OH OH
x. H2O
Formula I
2. Polymorphic crystalline form M of Canagliflozin having characteristic peaks
as given below & having XRD as per figure 1.
2- Theta Relative intensity (%)
27.4035 11.27
31.7314 100.00
45.5005 42.85
3. A novel process for the preparation of highly pure crystalline form ‘M’ of the
compound (1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-
18
4-methylphenyl]-D-glucitol or hydrates thereof according to claim 1, which
comprises
i) De-acetylation of Tetraacetyl Canagliflozin by its dissolution in a mixture
of aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol,
butanol, monoethylene glycol & diethylene glycol and a cyclic ether like
Tetrahydrofuran, dioxane or a mixture thereof and its treatment with
caustic solution at 40-50 °C for 3-5 hours.
ii) Cooling of reaction mass to room temperature & its pH adjustment to 6.5-
7.5 with 1N Hydrochloric acid solution.
iii) Further stirred the reaction mass at 50-55 °C for 10-20 min and performed
solvent recovery under vacuum followed by addition of water to it.
iv) Extracted product using a C1-C3 aliphatic ester. e.g. ethyl acetate, propyl
acetate, butyl acetate or a mixture thereof
v) Again heating the organic layer of step iv) to 55-60 °C followed by its
complete recovery under vacuum.
vi) Re-dissolving the crude obtained in step v) in solvent as used in step i).
vii) Re-heated reaction mass of step vi) and again performed its complete
recovery under vacuum.
viii) To the crude product obtained in step vii) performed addition of C4-C8
straight or branched chain aliphatic hydrocarbons like butane, pentane,
hexane, heptane, octane or a mixture thereof and stirred as long as to
ensure its proper crystallization.
19
ix) Isolation of novel Canagliflozin crystalline form M by routine filtration &
drying at 40-50 °C for 4-15 hours.
4. A novel process for the preparation of highly pure crystalline Canagliflozin or
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl
phenyl]-D-glucitol or hydrates thereof, which comprises
a) De-acetylation of Tetraacetyl Canagliflozin by its dissolution in aliphatic
alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol,
monoethylene glycol & diethylene glycol and its treatment with caustic
solution at 40-50 °C for 3-5 hours.
b) Cooling of reaction mass to room temperature & its pH adjustment to 6.5-
7.5 with 1N Hydrochloric acid solution.
c) Further stirred the reaction mass at 50-55 °C for 10-20 min and performed
solvent recovery under vacuum followed by addition of water to it.
d) Extracted product using a C1-C3 aliphatic ester. e.g. ethyl acetate, propyl
acetate, butyl acetate or a mixture thereof
e) Again heating the organic layer of step d) to 55-60 °C followed by its
complete recovery under vacuum.
f) Re-dissolving the crude obtained in step e) in solvent as used in step a).
g) Re-heated reaction mass of step f) and again performed its complete
recovery under vacuum.
20
h) To the crude product obtained in step g) performed addition of C4-C8
straight or branched chain aliphatic hydrocarbons like butane, pentane,
hexane, heptane, octane or a mixture thereof and stirred as long as to
ensure its proper crystallization.
i) Isolation of novel Canagliflozin crystalline form M by routine filtration &
drying at 40-50 °C for 4-15 hours.
5. A Novel process for the preparation of highly pure crystalline Canagliflozin or
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl
phenyl]-D-glucitol or hydrates thereof which comprises:
i) Dissolution of any polymorphic form of Canagliflozin Hemihydrate in a
solvent which may be selected from an aliphatic nitrile such as
acetonitrile, propionitrile or an aliphatic alcohol such as methanol,
ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol &
diethylene glycol at 30-40°C under stirring .
ii) Recrystallized the product by slow addition of water to reaction mass of
step i).
iii) Stirred the reaction mass for 20-24 hours at 20-30 °C followed by further
stirring at 0-10 °C for 1-2 hours to ensure proper crystallization.
iv) Filtration of product as wet cake at 0-10 °C.
v) Provided slurry wash to this wet cake obtained in step iv) at 40-45 °C for
1-2 hours.
21
vi) Hot filtered the product and provided running washing with water
vii)Unloading & drying of wet cake at 40-50 °C for 8-10 hours to get
Crystalline Canagliflozin or hydrates thereof.
6. A Novel process for the preparation of highly pure crystalline Canagliflozin or
(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl
phenyl]-D-glucitol or hydrates thereof, which comprises:
i) Prepared suspension of any polymorphic form of Canagliflozin
Hemihydrate in a aliphatic ether which may be selected from
Diisopropylether, methyl tert butyl ether, dimethyl ether, diethyl ether or
mixture thereof under stirring at 65-70 °C.
ii) Further stirred the reaction mass at 65-70 °C for 1-2 hours.
iii) Allowed the temperature to fall naturally to 20-30 °C and stirred for 20-24
hours.
iv) Further reduced the temperature to 5-10 °C and stirred for 1-2 hours.
v) Filtered the product as wet cake and provided running washing to wet
cake with solvent as used in step i).
vi) Dried the wet cake at 45-50 °C for 20-24 hours to get Crystalline
Canagliflozin or hydrates thereof.