DESC:FIELD OF THE INVENTION
The present invention primarily discloses novel processes for the preparation of amorphous Edoxaban Tosylate in a suitable solvent(s) using spray drying technique.
BACKGROUND OF THE INVENTION
Edoxaban (trade names: Savaysa, Lixiana) is an oral anti-coagulant drug which acts as a direct factor Xa inhibitor. Compared to warfarin, it has fewer interactions with other medications.
It was developed by Daiichi Sankyo and approved in July, 2011in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery. It was also approved by the FDA in November, 2015 for the prevention of stroke and non-central nervous-system systemic embolism.
It is used for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant to reduce the risk of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (NVAF).
Edoxaban inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation and thrombus formation. Factor Xa (FXa) is an essential blood coagulation factor that is responsible for the initiation of the coagulation cascade. FXa cleaves prothrombin to its active form thrombin, which then acts to convert soluble fibrinogen to insoluble fibrin and to activate platelets. Stabilization of the platelet aggregation by fibrin mesh ultimately leads to clot formation.
A number of anticoagulants inhibit the activity of Factor Xa. Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and Fondaparinux inhibit the activity of factor Xa indirectly by binding to circulating Antithrombin (AT III). These agents must be injected. Warfarin, Phenprocoumon, and Acenocoumarol are orally active vitamin K antagonists (VKA) which decrease hepatic synthesis of a number of coagulation factors, including Factor X. In recent years, a new series of oral, direct acting inhibitors of Factor Xa have entered clinical development. These include Rivaroxaban, Apixaban, Betrixaban, LY517717, Darexaban (YM150), and Edoxaban (DU-176b). Andexxa has been studied as a reversal agent for Edoxaban, but has not received FDA approval so far.
Chemically, Edoxaban is N1-(5-chloropyridin-2-yl) -N2-((IS,2R/4S)-4- [(dimethylamino) carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino}eyelohexyl)ethanediamide, represented by the following formula (A) :

(A)
The p-toluenesulfonic acid monohydrate salt of compound A is represented by the following formula (B):

(B)
Several processes are known in the literature for preparing Edoxaban, for example, US patent number 7,365,205 and US publication number 20090105491.
Edoxaban (and salts/solvates thereof) may be prepared by a variety of methods. One such method involves use of an intermediate as depicted below, wherein PG is an amine protecting group (herein referred to as amine-protected (1S,2R,4S)-1,2-amino-N,N-dimethylcyclohexane-4-carboxamide).

For example, US patent number 7,365,205 discloses Edoxaban, pharmaceutical acceptable salts thereof, as well as a process for the preparation of Edoxaban using this intermediate, wherein the protecting group (PG) is Boc.
US 20150239909 A1 relates to an improved and industrially advantageous process for the preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one represented by the following formula (1):

which is a key intermediate in the synthesis of Edoxaban.
A method for synthesis of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (I) was reported in Tetrahedron Letters, 51, (2010) Pages 3433-3435 which involves reaction of (1S)-cyclohex-3-ene-1-carboxylic acid represented by the following formula (II):

with N-bromosuccinimide in the presence of molecular sieves using dichloromethane as a solvent.
Example 45 of EP 1405852 B1 discloses preparation of Edoxaban Tosylate monohydrate from the Edoxaban free base dissolved in methylene chloride and p-toluensulfonic acid dissolved in ethanol. The solvent system is distilled off to change the solvent to ethanol/water and the product is crystallized from this mixture.
Reference Example 3 of US 8,686,189 B2 discloses preparation of Edoxaban Tosylate monohydrate by reacting the Edoxaban free base and p-toluensulfonic acid monohydrate in 30% hydrous ethanol. The product is crystallized from the reaction mixture after adding more ethanol.
Test Example 3 of EP 2371830 B1 discloses a preparation process of Edoxaban Tosylate monohydrate in ethanol/water with stable high yields based on dissolution at a certain temperature of the Edoxaban free base and an amount of p-toluensulfonic acid monohydrate below the stoichiometric amount, and adding an excess of p-toluensulfonic acid under low temperature. None of these documents disclose the purity obtained of the Edoxaban Tosylate monohydrate thus obtained.
WO 2015129603 A1 discloses a method of purification of Edoxaban Tosylate monohydrate from some process impurities using a mixture of ethanol/water based on dissolving the compound in a mixture of aqueous ethanol 70%v/v and adding more ethanol at a low temperature to crystallize the product. According to this document, the maximum content of any type of impurity following the purification method disclosed therein is 0.03%a/a and the total content of all impurities is 0.13% a/a or less by HPLC (detection wavelength 290 nm) with respect to the HPLC area value of a free form of the Edoxaban. Taking into account that all the Examples were carried out from a starting material having a purity of 99.84% with all the impurities being in the amount of 0.03% a/a or less by HPLC and the total content of all impurities being 0.16% a/a or less by HPLC, and that the products obtained in Examples 1-3 have 99.87-99.88% a/a, the effect on the purification is not significant. Besides, this recrystallization process uses a huge amount of ethanol with respect to the amount of the starting material (21.6 volumes ethanol per weight starting material and 2.4 volumes water per weight of starting material) which is a drawback in terms of process economy.

Indian patent application 201641023903 relates generally to the synthesis of active pharmaceutical agents and more specifically to the preparation of an amine-protected (1S,2R,4S)-1,2-amino-N,N­dimethylcyclohexane-4-carboxamide) camphor sulfonate, which may be an intermediate used in the synthesis of Edoxaban and pharmaceutically acceptable salts, solvates, or salt of solvates thereof. Further, the present invention further provides methods for the synthesis of this intermediate with improved purity.
US patent number 8,686,189 discloses this Boc-protected intermediate as well, along with acid addition salts thereof. Although the use of an azidation reagent (like ‘205 Patent) in this process has been reduced to one step, an azidation process is still required. Additionally, the required azidation step is lengthy, generally taking in excess of 70 hours to complete, which leads to a corresponding increase in product cycle times if the process is used commercially.
US patent number 8,357,808 discloses a process for preparation of Edoxaban using an oxalate salt of the Boc-protected intermediate involving class II and costly solvent acetonitrile. It discloses conditions for the preparation of Edoxaban intermediate. In this process, the generation of ‘Impurity X’, which is formed during the subsequent reaction of oxalate salt (X-A), is reportedly minimized by controlling the order of addition of reaction components and adding a tertiary amine in divided portions. However, this approach to impurity control can be operationally challenging to implement on an industrial scale.
US 8,541,443 reports two polymorphic forms of Edoxaban Tosylate Monohydrate- Form I and Form II. Only Form II is claimed herein. Form I has origin from Japanese patent JP 2010254615 A.
As none of the literature process reports commercially applicable process for preparation amorphous Edoxaban Tosylate, therefore, there was a need to develop a process which could be used at commercial scale for the production of amorphous Edoxaban Tosylate. To fulfill this requirement, a process for highly pure amorphous Edoxaban Tosylate was developed which can be used at commercial scale for the production of highly pure amorphous Edoxaban Tosylate in plant.
The X-Ray diffraction (XRD) study for amorphous Edoxaban Tosylate (API) thus prepared shows the formation of amorphous Edoxaban Tosylate free from any crystalline form of Edoxaban Tosylate.
SUMMARY OF THE INVENTION
The present invention primarily describes a novel process for preparation of amorphous Edoxaban Tosylate using spray drying technique in a suitable solvent. To start with, feed stock solution of Edoxaban Tosylate is conveniently prepared by dissolving Edoxaban Tosylate in an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof with halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or a mixture thereof. The second step involves isolation of an amorphous form of Edoxaban Tosylate from the fine filtered feed solution. The isolation may be affected by removing the solvent. Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), and the like or any other suitable technique.
The present invention provides spray drying a solution of Edoxaban Tosylate that involves the spray drying of feed stock, wherein any crystalline form of Edoxaban Tosylate may be used. The feedstock is dozed into the spray-drying instrument JISL Mini Spray-drier LSD-48 and spray drying is carried out under the specific parameters which are elaborated in further part of the current invention.
In another preferred feature, the spray drying of Edoxaban Tosylate may be performed on JISL Mini Spray-drier LSD-48 by maintaining the following parameters: a) maintaining the feed rate of the feed stock preferably at 15-20 ml/hour; b) maintaining the inlet temperature in the range of 55°C-70°C; c) maintaining the aspirator rate between 30-60 rpm; d) maintaining the outlet temperature in the range of 25°C to 30° C; e) maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm; and f) maintaining the vacuum at 40-80 mm of Hg.
In the present invention, feedstock of Edoxaban Tosylate in solvent system is spray-dried. The thus obtained spray-dried compound is in amorphous form, this fact is again confirmed by the X-ray powder diffractogram of spray-dried Edoxaban Tosylate. The parameters of obtaining the XRD diffractogram are mentioned below:
a) Scan Axis - Gonio
b) Start Position [°2?] - 4.00
c) End Position [°2?] - 50.00
d) Step Size [°2?] - 0.0170
e) Scan Step Time [s] - 40.0050
f) Scan Type - Continuous
g) PSD Mode - Scanning
h) PSD Length [°2?] - 2.12
i) Offset [°2?] - 0.0000
j) Divergence Slit Type - Fixed
k) Divergence Slit Size [°] - 0.4354
l) Specimen Length [mm] - 10.00
m) Measurement Temperature [°C] - 25.00
n) Anode Material - Cu
o) K-Alpha1 [Å] - 1.54060
p) K-Alpha2 [Å] - 1.54443
q) K-Beta [Å] - 1.39225
r) K-A2 / K-A1 Ratio - 0.50000
s) Generator Settings - 40 mA, 45 kV
t) Diffractometer Type - 0000000011023505
u) Diffractometer Number - 0
v) Goniometer Radius [mm] - 240.00
w) Dist. Focus-Diverg. Slit [mm] - 100.00
x) Incident Beam Monochromator - No
y) Spinning - Yes
The complete process details are disclosed in the next section.
DETAILED DESCRIPTION OF THE INVENTION
According to the current embodiment of the present invention, a novel process for preparation of amorphous N’-(5-Chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(di methylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino] cyclohexyl]oxamide; 4-Methylbenzenesulphonic acid or amorphous Edoxaban Tosylate is disclosed which comprises:
i. dissolving any crystalline form N’-(5-Chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(di methylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl) amino]cyclohexyl]oxamide; 4-Methylbenzenesulphonic acid or Edoxaban Tosylate in a suitable solvent mixture of an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol with a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof;
ii. stirring the reaction mass to 25-35°C for 10 minutes to ensure complete dissolution followed by fine filtration and using it as feed stock/solution in a spray drier;
iii. performing the spray drying of Edoxaban Tosylate on JISL Mini Spray-drier LSD-48 by a) maintaining the feed rate of the feed stock preferably at 15-20 ml/hour; b) maintaining the inlet temperature in the range of 55°C-70°C; c) maintaining the aspirator rate between 30-60 rpm; d) maintaining the outlet temperature in the range of 25°C to 30° C; e) maintaining the air flow at 2-4 Kg/cm, preferably 2 Kg/cm; and f) maintaining the vacuum at 40-80 mm of Hg; and
iv. isolating the pure amorphous Edoxaban Tosylate from cyclone flask in almost powdered form which is further dried at 40-50°C for 8-20 hours.
According to another aspect of the current invention, another viable solvent system used for dissolution is 2:1 and 1:5 mixture of an aliphatic alcohol such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof with a halogenated hydrocarbon such as methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
The current invention is supported by the following non-limited examples:
Example 1:
20g of Edoxaban Tosylate was dissolved in a mixture of Methanol (80ml) and Methylene Chloride (40ml). The reaction mass was stirred for 10 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under the below conditions:
S.No. Parameter Conditions
a) Feed Pump Rate 20 rpm
b) Inlet Temperature 56°C
c) Outlet Temperature 28-31°C
d) Aspiration Rate 31-60 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2

After completion of feeding, the product was collected from the cyclone and dried for 8-12 hours at 40-50°C. The obtained solid (11.40g) was amorphous Edoxaban Tosylate as shown by X-Ray diffraction pattern in Fig. 01.
Example 2:
20g of Edoxaban Tosylate was dissolved in a mixture of Methanol (20ml) and Methylene Chloride (100ml). The reaction mass was stirred for 10 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under the below conditions:
S.No. Parameter Conditions
g) Feed Pump Rate 20 rpm
h) Inlet Temperature 56°C
i) Outlet Temperature 28.9°C
j) Aspiration Rate 30 rpm
k) Vacuum 60 mm of Hg
l) Hot Air Supply 2 Kg/cm2

After completion of feeding, the product was collected from the cyclone and dried for 8-12 hours at 40-50°C. The obtained solid (12.0g) was amorphous Edoxaban Tosylate as shown by X-Ray diffraction pattern in Fig. 02.
Example 3:
20g of Edoxaban Tosylate was dissolved in a mixture of Methanol (20ml) and Methylene Chloride (100ml). The reaction mass was stirred for 10 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under the below conditions:
S.No. Parameter Conditions
a) Feed Pump Rate 20 rpm
b) Inlet Temperature 70°C
c) Outlet Temperature 25.3°C
d) Aspiration Rate 39 rpm
e) Vacuum 60 mm of Hg
f) Hot Air Supply 2 Kg/cm2

After completion of feeding, the product was collected from the cyclone and dried for 8-12 hours at 40-50°C. The obtained solid (11.5g) was amorphous Edoxaban Tosylate as shown by X-Ray diffraction pattern in Fig. 03.
Example 4:
20g of Edoxaban Tosylate was dissolved in a mixture of Methanol (20ml) and Methylene Chloride (100ml). The reaction mass was stirred for 10 minutes at 25 to 35°C to get a clear solution. After fine filtration, the solution was followed by spray drying under the below conditions:
S.No. Parameter Conditions
g) Feed Pump Rate 15 rpm
h) Inlet Temperature 55°C
i) Outlet Temperature 25.2°C
j) Aspiration Rate 30 rpm
k) Vacuum 60 mm of Hg
l) Hot Air Supply 2 Kg/cm2

After completion of feeding, the product was collected from the cyclone and dried for 8-12 hours at 40-50°C. The obtained solid (10.5g) was amorphous Edoxaban Tosylate as shown by X-Ray diffraction pattern in Fig. 04.

CLAIMS:WE CLAIM:
1. An improved process for preparation of amorphous N’-(5-Chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclo hexyl] oxamide;4-Methylbenzenesulphonic acid or amorphous Edoxaban Tosylate which comprises:
i. dissolving any crystalline form N’-(5-Chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(di methylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide; 4-methyl benzene sulphonic acid or Edoxaban Tosylate in a suitable solvent mixture;
ii. stirring the reaction mass at 25-35°C for 30 minutes and using it as feed stock/solution in JISL Mini Spray-drier LSD-48;
iii. maintaining the feed rate of the feed stock preferably at 15-20 ml/hour;
iv. maintaining the inlet temperature in the range of 55°C-70°C;
v. maintaining the aspirator rate between 30-60 rpm;
vi. maintaining the outlet temperature in the range of 25°C to 30°C;
vii. maintaining air flow at 2-4 Kg/cm, preferably 2 Kg/cm;
viii. maintaining the vacuum at 40-80 mm of Hg;
ix. isolating the pure amorphous Edoxaban Tosylate from the cyclone flask in the powdered form; and
x. further drying the powder at 40-50°C for 8-20 hours to get the final amorphous Edoxaban Tosylate.

2. The process as claimed in claim 1, wherein the solvent for dissolving Edoxaban in step i can be a mixture of an aliphatic alcohol selected form methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol, with a halogenated hydrocarbon selected from methylene dichloride, chloroform and carbon tetrachloride in the ratio of 1:5 or 2:1.