Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED

WO2016016774, CRYSTALLINE FORMS OF CANAGLIFLOZIN

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

SANTRA, Ramkinkar; (IN).
NAGDA, Devendra, Prakash; (IN).
THAIMATTAM, Ram; (IN).
ARYAN, Satish, Kumar; (IN).
SINGH, Tarun, Kumar; (IN).
PRASAD, Mohan; (IN).
GANGULY, Somenath; (IN).
WADHWA, Deepika; (IN)

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus. A crystalline Form R1of canagliflozin emihydrate. The crystalline Form R1 of canagliflozin hemihydrate of claim 1, characterized by an X-ray powder diffraction peaks having d-spacing values at about 3.1, 3.7, 4.6, and 8.9 A

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus.

Canagliflozin hemihydrate, chemically designated as (l<S)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Its chemical structure is represented by Formula I.

Formula I

U.S. Patent Nos. 7,943,582 and 8,513,202 disclose crystalline forms of canagliflozin hemihydrate.

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.

In the pharmaceutical industry, there is a constant need to identify critical physicochemical parameters of a drug substance such as novel salts, polymorphic forms, and co-crystals, that affect the drug's performance, solubility, and stability, and which may play a key role in determining the drug's market acceptance and success.

The discovery of new forms of a drug substance may improve desirable processing properties of the drug, such as ease of handling, storage stability, and ease of purification. Accordingly, the present invention provides novel crystalline forms of canagliflozin having enhanced stability over known crystalline forms of canagliflozin.

EXAMPLES

Example 1 : Preparation of a crystalline Form Rl of canagliflozin hemihydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours to obtain a solid. The solid was further dried under vacuum at 60°C for 6 hours.

Yield: 4.71 g

Example 2: Preparation of a crystalline Form R2 of canagliflozin monohydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours at room temperature.

Yield: 4.71 g

Example 3 : Preparation of a crystalline Form R2 of canagliflozin monohydrate

Canagliflozin hemihydrate (0.15 g; Form Rl obtained as per Example 1) was suspended in de-ionized water (3 mL). The suspension was stirred at room temperature for 24 hours. The reaction mixture was filtered, then dried at room temperature under vacuum for 5 hours.

Yield: 0.143 g

Example 4: Preparation of a crystalline Form R3 of canagliflozin hydrate

Amorphous canagliflozin (100 g) was suspended in an aqueous solution of sodium formate (1224 g of sodium formate in 1600 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water

(2000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for one hour. De-ionized water (1000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for another one hour. The reaction mixture was filtered, then washed with de-ionized water (6000 mL), and then dried under vacuum for 30 minutes to obtain a solid. The solid was then dried under vacuum at 30°C to 35°C until a water content of 8% to 16% was attained.

Yield: 100 g

 

From top left: Abhay Gandhi (CEO-India Business-Sun Pharma), Kal Sundaram (CEO-TARO). Middle row (L-R): Israel Makov (chairman, Sun Pharma), Dilip Shanghvi (Founder and MD, Sun Pharma) Uday Baldota (CFO, Sun Pharma). Bottom: Kirti Ganorkar (Senior VP, Business development, Sun Pharma)

./////////////Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED

WO 2016012938, New patent, LINACLOTIDE, DR. REDDY’S LABORATORIES LIMITED,

WO2016012938,  IMPROVED PROCESS FOR PREPARATION OF AMORPHOUS LINACLOTIDE

DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No 3, Banjara Hills, Telangana, INDIA Hyderabad 500034 (IN)

KALITA, Dipak; (IN).
NIVRUTTI, Ramrao Jogdand; (IN).
BALAKUMARAN, Kesavan; (IN).
DESHMUKH, Shivshankar; (IN).
VUTUKURU, Naga Chandra Sekhar; (IN).
KASINA, Vara Prasad; (IN).
NALAMOTHU, Sivannarayana; (IN).
VILVA, Mohan Sundaram; (IN).
KHAN, Rashid Abdul Rehman; (IN).
TIRUMALAREDDY, Ramreddy; (IN).
MUSTOORI, Sairam; (IN)

The present application relates to an improved process for the formation of disulfide bonds in linaclotide. The present application also relates to an improved process for the purification of linaclotide.

The present application relates to an improved process for the preparation of amorphous linaclotide. Specifically, the present application relates to an improved process for the formation of disulfide bonds in linaclotide. The present application further relates to a purification process for the preparation of amorphous linaclotide.

INTRODUCTION

Linaclotide is a 14-residue peptide which is an agonist of the guanylate cyclase type-C receptor. Linaclotide may be used for the treatment of chronic constipation and irritable bowel syndrome. Structurally, linaclotide has three disulfide bonds and they are present between Cys¹-Cys⁶, Cys²-Cys-¹⁰ and Cys⁵-Cys¹³. The structure of linaclotide is shown below:

1 2 3 4 5 6 7 8- 9 10 11 12 13 14

Benitez et al. Peptide Science, 2010, Vol. 96, No. 1 , 69-80 discloses a process for the preparation of linaclotide. The process involves the use of 2-chlorotrityl (CTC) resin and 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. The Cys residues are protected by Trt (trityl) group. The amino acids are coupled to one another using 3 equivalents of 1 -[bis(dimethylamino)methylene]-6-chloro-1 H-benzotriazolium hexafluorophosphate 3-oxide (HCTU) as coupling agent and 6 equivalents of diisoprpylethylamine (DIEA) as base in dimethylformamide (DMF). The Fmoc group is removed using piperidine-DMF (1 :4). The Cys residues are incorporated using 3 equivalents of Ν,Ν'-diisopropylcarbodiimide (DIPCDI) as coupling agent and 3 equivalents of 1 -hydroxybenzotriazole (HOBt) as an activating agent. After the elongation of the peptide chain, the peptide was cleaved from the solid support (CTC resin) by first treating with 1 % trifluoroacetic acid (TFA) and then with a mixture of TFA, triisoprpylsilane (TIS) and water in the ratio of 95:2.5:2.5. The disulfide bonds are prepared by subjecting the linear peptide to air oxidation in sodium dihydrogen phosphate (100 mM) and guanidine hydrochloride buffer (2 mM).

US2010/261877A1 discloses a process for purification of linaclotide. The process involves first purification of crude peptide by reverse-phase chromatographic purification followed by concentrating the purified pools and dissolving the purified linaclotide in aqueous-isopropanol or aqueous-ethanol and spray-drying the solution to afford pure Linaclotide.

The synthesis of a peptide containing disulfide bridges is difficult for two main reasons; one is potential risk of racemization during the formation of linear chain and the other is mis-folding of the disulfide bridges. Hence, there is a need in the art to a cost-effective process for the preparation of pure linaclotide.

EXAMPLES

Example 1 : Preparation of Crude Linaclotide using polyvinyl polymer bound complex of sulfur trioxide-pyridine

The linear chain of peptide of formula (I) (0.1 g) and polyvinyl polymer bound complex of sulfur trioxide-pyridine (0.062 g) was charged in water (100 mL). The pH of the reaction mass was adjusted to 8.5 to 9 by addition of ammonium hydroxide. The reaction mass was stirred at 25 °C for 15 hours and trifluoroacetic acid (2 mL) was added to the reaction mass to adjust the pH up to 2-2.5. The reaction mass was stirred for 3 hours at the same temperature to afford crude linaclotide.

HPLC Purity: 59.92%

Example 2: Preparation of Crude Linaclotide using DMSO in water

The pH of water (100 ml_) was adjusted to 9.1 by the addition of aqueous ammonia. DMSO (1 ml_) and linear chain of peptide of formula (I) (100 mg) were charged. The reaction mass was stirred for 17 hours at 25 °C and acidified with trifluoroacetic acid to pH 1 .9 and stirred for 8 hours at the same temperature to afford crude linaclotide.

HPLC Purity: 57%

Example 3: Preparation of Crude Linaclotide using DMSO in water

The pH of water (1500 ml_) was adjusted to 9 by the addition of aqueous ammonia. DMSO (15 ml_) and linear chain of peptide of formula (I) (15 g) were charged. The reaction mass was stirred for 17 hours at 25 °C and acidified with acetic acid to pH 1 .9 and stirred for 8 hours at the same temperature to obtain crude linaclotide.

HPLC Purity: 46.02%

Example 4: Preparation of Crude Linaclotide in water

To a mixture of water (1900 mL) and ammonium sulfate (26.4 g), ammonium hydroxide was added drop wise to adjust the pH up to 8.5. Linear chain of peptide of formula (I) (26.4 g) was added and the reaction mass was stirred for 8 hours at 25 °C. Trifluoroacetic acid (20 mL) was added drop wise and the reaction mixture was stirred for 15 hours at 25 °C to afford crude linaclotide.

HPLC Purity: 63.38%

Example 5: Preparation of Crude Linaclotide using a complex of pyridine-sulfur trioxide

Linear chain of peptide of formula (I) (0.2 g) was added to water (250 mL) and the pH of the reaction mass was adjusted to 8.91 by the drop wise addition of aqueous ammonia. A complex of pyridine-sulfur trioxide (0.124 g) was added to the reaction mass and stirred for 16 hours at 25 °C. Another lot of complex of pyridine-sulfur trioxide (0.124 g) was added to the reaction mass and stirred for 5 hours at 25 °C to afford crude linaclotide.

Example 6: Preparation of Crude Linaclotide using guanidine hydrochloride

To a solution of sodium bicarbonate (0.89 g) in water (100 mL), cysteine (0.363 g), cysteine (0.072 g) and guanidine hydrochloride (9.50 g) were charged. Acetonitrile (15 mL) and linear chain of peptide of formula (I) (0.1 g) was added to the reaction mass.

The reaction mass was stirred for 3 hours at 25 °C and trifluoroacetic acid (2 mL) was added. The reaction mass was stirred for 18 hours at the same temperature. Another lot of trifluoroacetic acid (2 mL) was added to the reaction mass and stirred for 18 hours at the same temperature to afford crude linaclotide.

Example 7: Preparation of Crude Linaclotide using Clear-OX™

Pre-conditioned Clear-Ox™ (0.5 g) was added to a solution of ammonium sulfate (1 .32 g) in water (100 mL) of pH 8.5, adjusted by addition of ammonium hydroxide. The linear chain of peptide of formula (I) (0.1 g) was added to the reaction mass and stirred for 3 hours at 25 °C. Another lot of Pre-conditioned Clear-Ox™ (0.5 g) was added to the reaction mass and stirred for 1 .30 hours. Trifluoroacetic acid (2 mL) was added to the reaction mass and stirred for 16 hours at the same temperature to afford crude linaclotide.

HPLC Purity: 67.5%

Example 8: Preparation of Crude Linaclotide using reduced Glutathione

To a mixture of ammonium sulphate (5.28 g) in water (400 mL) and isopropyl alcohol (400 mL), reduced glutathione (0.248 g) was added and the pH was adjusted to 8.5 by using aqueous ammonia. The linear chain of peptide of formula (I) (0.81 g) was added to the reaction mixture and stirred at ambient temperature for 17 hours. Isopropyl alcohol was evaporated under vacuum to afford crude linaclotide.

HPLC Purity: 69.56%%

Example 9: Preparation of Crude Linaclotide using DMSO and air bubbling

To a mixture of water (95 mL) and ammonium sulfate (1 .32 g), ammonium hydroxide was added drop wise to adjust the pH up to 8.5. Linear chain of peptide of formula (I) (0.1 g) and DMSO (5 mL) was added and the reaction mass was stirred for 20 hours at 25 °C with continuous air bubbling. Trifluoroacetic acid (2 mL) was added to the reaction mass and stirred for 19 hours with continuous air bubbling at the same temperature to afford the title product.

HPLC Purity: 59.1 1 %

Example 10: Preparation of Crude Linaclotide using solid supported TEMPO

To a mixture of water (100 mL) and silica bound TEMPO (0.01 g), linear chain of peptide of formula (I) (0.1 g) and sodium hypochlorite solution (1 mL) were added and the reaction mass was stirred 18 hours at 25 °C. Another lot of sodium hypochlorite solution (0.5 mL) was added to the reaction mass and stirred for further 7 hours at the same temperature to afford title product.

HPLC Purity: 42.70%..................see more in patent

Linaclotide

Systematic (IUPAC) name
L-Cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-L-tyrosine cyclo(1-6),(2-10),(5-13)-tris(disulfide)
Clinical data
Trade names	Linzess
Licence data	US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral
Identifiers
CAS Number	851199-59-2
ATC code	A06AX04
PubChem	CID 16158208
IUPHAR/BPS	5017
ChemSpider	17314504
UNII	N0TXR0XR5X
KEGG	D09355
Chemical data
Formula	C59H79N15O21S6
Molar mass	1526.74 g/mol

///////WO 2016012938, DR. REDDY’S LABORATORIES LIMITED , Telangana, INDIA , Hyderabad, LINACLOTIDE, new patent

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WO 2016012539, Tadalafil , New patent, KRKA, D.D., NOVO MESTO

WO 2016012539,  A PROCESS FOR THE PREPARATION OF CGMP-PHOSPHODIESTERASE INHIBITOR AND ORAL PHARMACEUTICAL FORMULATION COMPRISING TADALAFIL CO-PRECIPITATES

KRKA, D.D., NOVO MESTO [SI/SI]; Smarjeska cesta 6 8000 Novo mesto (SI)

BARIC, Matej; (SI).
BENKIC, Primoz; (SI).
BOMBEK, Sergeja; (SI).
KRASOVEC, Dusan; (SI).
SKRABANJA, Vida; (SI).
VRECER, Franc; (SI).
BUKOVEC, Polona; (SI).
HUDOVORNIK, Grega; (SI).
KROSELJ, Vesna; (SI)

The present Invention relates to an improved process for preparation of tadalafil and crystallization and/or purification thereof, wherein the processes are conducted at increased pressure. The invention relates also to a process for preparation of tadalafil co-precipitates and to a solid pharmaceutical composition comprising tadalafil co-precipitates and at least one water soluble diluent and/or water insoluble non-swellable diluent, wherein the composition is substantially free of water insoluble swellable diluents

The present invention relates to a process for the preparation of CGMP-phosphodiesterase inhibitor, particularly tadalafil, a method for production co-precipitate thereof and to solid oral pharmaceutical formulations comprising tadalafil co-precipitate.

Tadalafil, chemically known as (6R-trans)-6-(1,3-benzodioxol-5-il)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino.1′, 2′:1,6]pyrido[3,4-b]indole-1,4-dione, is a potent and selective inhibitor of the cyclic guanosine monophosphate (cGMP) – specific phosphodiesterase enzyme PDE5. It is shown below as structural formula I:

Tadalafil is marketed under the tradename CIALIS* and is used for the treatment of erectile dysfunction. The product is available as a film-coated tablet for oral administration containing 2.5, 5, 10 and 20 mg of active ingredient and the following inactive ingredients: lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, croscarmellose sodium, microcrystaliine cellulose, magnesium stearate, hypromellose, triacetin, titanium dioxide (E171), iron oxide (E172) and talc.

Tadalafil is practically insoluble in water and very slightly soluble in organic solvent such as ethanol, methanol and acetone.

Problems associated with low solubility of tadalafil in ethanol and most of other organic solvents resulted in the need of large quantities of solvents required to perform synthesis and crystallization of tadalafil at industrial scale, which have unwanted technological, environmental and economical impact.

US Patent No. 5 859 006 describes the synthesis of the tadalafil and its intermediate (A) which involves reacting D-tryptophan methyl ester with a piperonal in the presence of dichloromethane and trifluoroacetic acid which provides a mixture of desired cis and undesired trans isomer of intermediate A with poor selectivity. The isomers are further separated by column chromatography. The cis isomer is further reacted with chloroacetyl chloride in chloroform, providing another intermediate of tadalafil (B) which reacted with methylamine to give tadalafil of formula (1) in methanol slurry requiring an additional purification step by flash chromatography.

An improved process in the synthesis of tadalafil via modified Pictet-Spengler reaction is described in WO 04/011463 in which D-tryptophan methyl ester hydrochloride and piperonal are condensed in anhydrous isopropyl alcohol to provide hydrochloride of intermediate A. After isolation of desirable cis isomer, the product is further reacted with chloroacetyl chloride and then with methylamine in THF to give tadalafil.

Therefore there still exists a need for an improved process for a synthesis and purification of tadalafil, which would overcome the disadvantages of the prior art processes.

Low solubility of tadalafil in aqueous solutions is further disadvantageous because in vivo absorption is typically dissolution rate-limited which may result in poor bioavailability of the drug. Different approaches in the processes of preparation of pharmaceutical compositions have been applied to overcome the poor solubility.

For example, EP 1 200 092 Bl describes a pharmaceutical composition of free drug particulate form of tadalafil wherein at least 90% of the particles have a particle size of less than about 40 μm as well as composition comprising tadalafil, wherein the compound is present as solid particles not embedded in polymeric co-precipitate. Apparently, preferably at least 90% of the particles have a particle size of less than 10 μm. The technological drawback of such small particles is possible chargeability and secondary agglomeration due to increased surface energy which can cause problems during the micronization and further processing.

WO 2008/134557 describes another approach to overcome the low-solubility problem by pharmaceutical composition comprising starch and tadalafil characterized by particle size having d(90) greater than 40 μm wherein the weight ratio of starch to tadalafil is 4.5 to 1 or greater. Apparently, the preferred ratio is at least 15 to 1.

Yet another approach to overcome the low-solubility problem is to use a “co-precipitate” of tadalafil and a carrier or excipient. For example, EP 828 479 Bl describes a solvent based process wherein tadalafil and a carrier are co-precipitated with a medium in which the tadalafil and carrier are substantially insoluble. EP 828 479 describes a solvent based process wherein tadalafil and hydroxypropyl methylcellulose phthalate are co-precipitated in weakly acidic medium from a combination of non-aqueous water miscible solvent and water. However, pharmaceutical composition prepared according to EP 828479 exhibit deviations in release rate of tadalafil which was due to poor reproducibility of a process for preparation of co-precipitate. It was found that precipitation in acidic media causes unwanted degradation of hydroxypropyl methylcellulose phthalate and that precipitation at higher temperatures does not produce desired product.

WO 2008/005039 also describes a solid composite including tadalafil being in intimate contact with a carrier. The carriers include hydrophilic polymers such as povidone, cellulose derivatives, polyethylene glycol and polymethacrylates. The compositions are prepared by combining tadalafil with hydrophilic polymer and removal of the solvent by evaporation.

WO 2010/115886 describes an adsorbate comprising poorly soluble active ingredient with a particulate and/or porous carrier wherein the adsorbate is prepared by using non-polar solvent. Apparently, the solvents used are selected from the group of chlorinated hydrocarbon (dichloromethane or trichloromethane), diisopropylether and hexane, which is also the main drawback of this solution.

Co-precipitates of phosphodiesterase-5-inhibitor and copolymer of different acrylic acid derivatives are described in WO 2011/012217. The procedures described involve the use of tetrahydrofurane.

Poor solubility can also be solved with co-crystals. WO 2010/099323 discloses crystalline molecular complexes of tadalafil with co-former selected from the group of a short to medium chain organic acids, alcohols and amines.

WO 2012/107541 and WO 2012/107092 disclose co-granulate of tadalafil with cyclodextrines.

WO 2014/003677 discloses a pharmaceutical composition comprising solid dispersion particles containing tadalafil and a dispersing component, which composition further comprises a solubilizer.

Based on the above, there is still a need for an improved dosage form containing tadalafil and improved technological process for the preparation thereof.

The process for preparing tadalafil according to a preferred embodiment of the present invention is disclosed in Scheme 1.

Scheme 1

Example 1: Synthesis of tadalafil intermediate B via intermediate A

D-tryptophan methyl ester hydrochloride (9g) and piperonai (6g) was suspended in acetonitrile (60mL). The reaction mixture was stirred and heated at about 105*C for three to five hours in an autoclave. The reaction suspension was cooled to ambient temperature and aqueous solution (60m L) of sodium carbonate (4.1g) was added. The mixture was then cooled in an ice bath and the solution of chloroacetyl chloride (5.1mL) in acetonitrile was slowly added to the reaction mixture. A solid was obtained, filtered and washed twice with aqueous solution of acetonitrile. The crude product was dried, and intermediate B (13.4g) with a purity of 97% (HPLC area%) was obtained.

Example 1A:

D-tryptophan methyl ester hydrochloride (8.2kg) and piperonai (5.1kg) was suspended in acetonitrile (55L). The reaction mixture was stirred and heated at about to 105″C for three hours in the reactor vessel. The reaction suspension was cooled to ambient temperature and aqueous solution (55L) of sodium carbonate (4.8kg) was added. The mixture was then cooled in an ice bath and the solution of chloroacetyl chloride (5.2L) was slowly added to the reaction mixture at 5-10°C. A solid was obtained, centrifuged and washed twice with aqueous solution of acetonitrile (2x 121). The crude product was dried at temperature up to 50″C, and intermediate B (12.3kg) with a purity of 98% (HPLC area%) was obtained.

Comparative example 1:

D-tryptophan methyl ester hydrochloride (9.0g) and piperonai (5.84g) was suspended in acetonitrile (60mL). The reaction mixture was stirred and heated at about to 80-85’C for 15-20 hours in the reactor vessel. The reaction suspension was cooled to 0-10°C. The Intermediate A was then isolated on centrifuge and was dried at temperature up to 60°C.

The isolated dried Intermediate A (12,8g) was charged into reactor and suspended with ethyl acetate. The aqueous solution (60mL) of sodium carbonate (5.3g) was added to precooied suspension of Intermediate A. The chloroacetyl chloride (3.4mL) was slowly added to the above reaction mixture. The solid was obtained, centrifuge and washed twice with water (2x 10mL). The crude product was dried at temperature up to 70°C, and intermediate B (11.8g) with a purity of 99% (HPLC area%) was obtained.

Example 2: Synthesis oftadalafil

Intermediate B (4g) obtained in Example 1 and 40% aqueous methylamine solution (1.6mL) were dissolved in 70% aqueous solution of 2-propanol (120mL) while heating in a closed reaction vessel above the reflux temperature (110-120°C) for two to five hours. The solution was hot filtered and cooled on an ice bath. The precipitated product was filtered and dried. The purity of the product was 99.9% (HPLC area%) and the particle distribution of the product was D(90) of about 144 microns.

Example 2A: Synthesis of tadalaf il

Intermediate B (12.3kg) obtained in Example 1A and 40% aqueous methylamine solution (4.76L) were dissolved in 70% aqueous solution of 2-propanol (402L) while heating in a closed reaction vessel above the reflux temperature (110-120°C) for three hours. The solution was hot filtered and cooled on an ice bath. The precipitated product was filtered and dried. The final product (9.8kg) with a purity of more than 99.99% (HPLC area%) and the particle distribution of the product was D(90) of about 155 microns was obtained.

Comparative example 2:

Intermediate B (10g) obtained in the above comparative example 1 and 31% ethanolic methylamine solution (12.3mL) were suspended in absolute ethanol (150mL). The suspension

was heated up to 55°C for 3 – 6 hours. The suspension was cooled on an ice bath. The product was filtered and dried. The crude product (8.22g) with a purity of more than 99.9% (HPLC area%) was obtained and crystallized from hot DMSO solution. The product Is crystallized with addition of water.

Example 3: Recrystallization of tadalaf il

Tadalafil (700g) (99% purity) was suspended in 70% aqueous solution of 2-propanol (24.6L) and suspension was heated to about 110°C in an autoclave at pressure of 0.31MPa until the material was dissolved. The obtained solution was then hot filtrated and cooled to about 10°C. The isolated tadalafil (660g) has a purity of 99.95% (HPLC area%) and the particle distribution D(90) of about 144 microns.

Example 3A: Recrystallization of tadalafil

Tadalafil (5g) (99% purity) was suspended in 70% aqueous solution of acetone (lOOmL) and suspension was heated to about 90°C in an autoclave at pressure of 0.28MPa until the material was dissolved. The obtained solution was then hot filtrated and cooled to about 10°C. The isolated tadalafil (4.44g) has a purity of 99.99% (HPLC area%).

Example 3B: Recrystallization of tadalafil

Tadalafil (4g) (99% purity) was suspended in 70% aqueous solution of acetonitrile (lOOmL) and suspension was heated to about 85°C in an autoclave at pressure of 0.2MPa until the material was dissolved. The obtained solution was then hot filtrated and cooled to about 10°C. The isolated tadalafil (3g) has a purity of 99.99% (HPLC area%).

Example 3C: Recrystallization of tadalafil

Tadalafil (5g) (99% purity) was suspended in 70% aqueous solution of tetrahydrofuran (60mL) and suspension was heated to about 120″C in an autoclave at pressure of 0.3MPa until the material was dissolved. The obtained solution was then hot filtrated and cooled to about 10°C. The isolated tadalafil has a purity of 99.99% (HPLC area%).

Comparative example 3:

Tadalafil (lg) (99% purity) was suspended in 2-propanol (200mL) and suspension was heated up to reflux temperature until the material was dissolved. The obtained solution was then hot filtrated and cooled to about lO’C. The crystallized tadalafil was centrifuged and dried in an oven at temperature up to 70°C.

Comparative Example 4: Preparation of tadalafil co-precipitate with HPMCP HP-50, Precipitation at higher temperature

Tadalafil (100 g) and hydroxypropyl methylcellulose phthalate (100 g) were dissolved in a mixture of acetone (2430m L) and water (270mL) at reflux temperature. Solution was hot filtered and added to 0.25 M HCI in water (4150mL) at 65°C. Precipitate was collected by vacuum filtration, washed with water and dried in vacuum tray dryer up to 70°C. Dry material was milled by a pin mill. HPLC assay of tadalafil was 48.5 %; average particle size of co-precipitate was 53 μm, specific surface area 2.5 m2/g-

Example 5: Preparation of tadalafil co-precipitate with HPMCP HP-50

Tadalafil (1 kg) and hydroxypropyl methylcellulose phthalate (1 kg) were dissolved in mixture of acetone (20L) and water (3 L) at 54°C and under pressure O.lMPa. Solution was hot filtered and added to water (42 L) at 2°C. Suspension was heated up to reflux and acetone was distilled off. Tadalafil co-precipitate was collected by pressure filtration and dried in vacuum dryer. Dry material was milled by a pin mill. HPLC assay of tadalafil was 53.5%.

Example 6: Preparation of tadalafil co-precipitate with HPMCP HP-50

Tadalafil (1 kg) and hydroxypropyl methylcellulose phthalate (1 kg) were dissolved in mixture of acetone (20 L) and water (3 L) at 54°C and under pressure O.lMPa. Solution was hot filtered and added to water (42 L) at 2°C. Suspension was heated up to reflux and acetone was distilled off. Tadalafil co-precipitate was collected by centrifuge and dried in a fluid bed dryer. Dry material was milled by a pin mill. HPLC assay of tadalafil was 52.5 %.

3

Example 7: Preparation of tadalafil co-precipitate with HPMCP HP-50

Tadalafil (0.786 kg) and hydroxypropyl methylcellulose phthaiate (1.140 kg) were dissolved in a mixture of acetone (24L) and water (2.3 L) at 54°C and under pressure 0.1MPa. Solution was filtered hot and added to water (42 L) at 2°C. Suspension was collected by centrifuge and dried in a vacuum tray dryer up to 70°C. Dry material was milled by a pin mill. HPLC assay of tadalafil was 43.5 %, average particle size of co-precipitate was 49 μm, specific surface area 31.0 m2/g-

Example 8: Preparation of tadalafil co-precipitate with HPMCP HP-50

Tadalafil (2 g) and hydroxypropyl methylcellulose phthaiate HP 50 (2 g) were dissolved in a mixture of acetone (48.5mL) and water (5.5mL) at reflux temperature. To obtained solution crospovidone (lg) was added. Obtained suspension was co-precipitated in water (83mL) at 2°C. Obtained material was collected with a vacuum filter and dried in vacuum dryer up to 90°C. HPLC assay of tadalafil 39.9%. Yield was 90%.

Example 9: Preparation of tadalafil co-precipitate with HPMCP HP-50

Tadalafil (2 g) and hydroxypropyl methylcellulose phthaiate HP 50 (2 g) were dissolved in a mixture of acetone (54mL) and methanol (19mL) at reflux temperature. To obtained solution crospovidone (lg) was added. Obtained suspension was co-precipitated in heptane (83mL) at 0°C. Obtained material was collected with a vacuum filter and dried in vacuum dryer up to 50°C. HPLC assay of tadalafil was 36.1 %. Yield was 90%.

Example 10: Preparation of tadalafil co-precipitate with HPMCP HP-50

Tadalafil (2 g) and hydroxypropyl methylcellulose phthaiate HP 50 (2 g) were dissolved in a mixture of aceton (54mL) and methanol (19mL) at reflux temperature. Obtained solution was co-precipitated in heptane (83mL) at 0°C. Obtained material was collected with a vacuum filter and dried in vacuum dryer up to 50°C. HPLC assay of tadalafil was 36.1 %. Yield was 90%.

Example 11: Preparation of tadalafil co-precipitate with HPMCP HP-50

Tadaiafil (1.3 kg) and hydroxypropyl methylcellulose phthalate {1.53 kg) were dissolved in mixture of acetone (32 L) and water (4 L) at 54°C and 1000 mbar. Solution was hot filtered and added to water (54 L) at 2°C. Tadalafil co-precipitate was collected by decanter centrifuge and dried in a vacuum drier. Dry material (2.4kg) was milled in a pin mill. HPLC assay of tadalafil was 48.8 %; average particle size of co-precipitate was 54 μm and specific surface area 26.1 m2/g<

Example 12: Preparation of tadalafil co-precipitate with hydroxypropyl cellulose

Tadalafil (3g) and Klucel ELF (3g) was dissolved in a mixture of acetone (73mL) and water (8mL) at 50°C. Solution was hot filtered and added to 125mL water at 90°C. After that acetone was distilled off at 65°C and suspension was stirred for additional hour. Precipitated material was filtered using preheated filter funnel and dried at 80°C. Yield 3.8 g, HPLC assay was 50.0%.

Example 13: Preparation of tadalafil co-precipitate with hydroxypropyl cellulose

Tadaiafil (3g) and Klucel ELF (3g) was dissolved in a mixture of acetone (73mL) and water (8m L) at 50°C. Solution was hot filtered and added to 125m L water at 90°C with dissolved lactose (14g) at 90°C. After that acetone was distilled off at 65°C and suspension was stirred for additional hour. Precipitated material was filtered using preheated filter funnel and dried at 80°C. Yield 5 g, HPLC assay was 48.8%.

Examples of tablets prepared according to the present Invention

Example Fl: Tablets containing tadalafil co-precipitate with HPMCP HP-50 prepared in accordance with Example 11 with water soluble mannitol and without swellable water insoluble diluents

Tadalafil co-precipitate with HPMCP HP-50 was homogeneously mixed with mannitol, croscarmellose sodium and sodium lauryl sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets. Dissolution profile of the example is shown in Figure 1.

Example F2: Tablets containing tadalafil co-precipitate with HPC prepared in accordance with Example 13 with water soluble mannitol and without swellable water insoluble diluents

Tadalafil co-precipitate with HPC was homogeneously mixed with mannitol, croscarmellose sodium and sodium lauryl sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets. Dissolution profile of the example is shown in Figure 1.

Example F3: Tablets containing tadalafil co-precipitate with HPMCP with water soluble spray-dried lactose and without swellable water insoluble diluents

Tadaiafil co-precipitate with HPMCP was homogeneously mixed with spray-dried lactose, starch 1500 and sodium lauryi sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets.

Example F4: Tablets containing tadalafil co-precipitate with HPMCP with water insoluble non-swellable anhydrous dibasic calcium phosphate and without swellable water insoluble diluents

Tadalafil co-precipitate with HPMCP was homogeneously mixed with calcium phosphate, croscarmellose sodium and sodium lauryi sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets.

Comparative examples of tablets containing microcrvstalline cellulose

Comparative example F5: Tablets containing tadalafil co-precipitate with HPMCP HP-50 with water soluble mannitol and water insoluble swellable microcrvstalline cellulose as diluent 

Tadalafil co-precipitate with HPMCP HP-50 was homogeneously mixed with mannitol, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets. Dissolution profile of the example is shown in Figure 1.

Comparative example F6: Tablets containing tadalafil co-precipitate with HPMCP HP-50 with water soluble lactose anhydrous and water insoluble swellable microcrystalline cellulose as diluent

Tadalafil co-precipitate with HPMCP HP-50 was homogeneously mixed with lactose anhydrous, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets. Dissolution profile of the example is shown in Figure 1.

Comparative example F7: Tablets containing tadalafil co-precipitate with HPMCP HP-50 with water soluble lactose monohydrate and spray dried lactose and water insoluble swellable microcrystalline cellulose as diluent

Tadalafil co-precipitate with HPMCP HP-50 was homogeneously mixed with lactose monohydrate, spray dried lactose, microcrystalline cellulose, croscarmeilose sodium and sodium lauryl sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets. Dissolution profile of the example is shown in Figure 1.

Comparative example F8: Tablets containing tadalafil co-precipitate with HPMCP HP-50 with water insoluble non-swellable calcium phosphate and water insoluble swellable microcrystalline cellulose as diluent

Tadalafil co-precipitate with HPMCP HP-50 was homogeneously mixed with calcium phosphate, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets. Dissolution profile of the example is shown in Figure 1.

Comparative example F9: Tablets containing tadalafil co-precipitate with HPMCP HP-50 with only water insoluble swellable microcrystalline cellulose as diluent

Tadalafil co-precipitate with HPMCP HP-50 was homogeneously mixed with microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets. Dissolution profile of the example is shown in Figure 1.

Comparative example F10: Tablets containing tadalafil co-precipitate with HPMCP HP-50 with water insoluble swellable microcrystalline cellulose and cellactose as diluents

Tadalafil co-precipitate with HPMCP HP-50 was homogeneously mixed with microcrystalline cellulose, cellactose, croscarmellose sodium and sodium lauryl sulphate. The magnesium stearate was added and mixed. The resultant blend was compressed into tablets. Dissolution profile of the example F10 is shown in Figure 2, together with dissolution profiles of the same sample, taken after two months at 22°C and 60% RH.

In comparison, dissolution profile of composition according to invention is unaffected by storage at 40°C/75% for one month (Figure 2).

The aforementioned tablet formulations were film-coated with a film-coating dispersion containing:

Figures 1 and 2 show dissolution profiles of tablet formulations comprising tadalafil co-precipitates prepared according to listed examples. Dissolution conditions comprise: basket apparatus (USP I), 100 RPM, 0.1M HCI + 0.2% SDS, 900 mL

Krka, tovarna zdravil, d.d., Novo mesto  

Raziskovalna in razvojna dejavnost na drugih področjih naravoslovja in tehnologije

 

Address: Šmarješka cesta 6, 8501 Novo mesto, Slovenia

/////////WO 2016012539, KRKA, D.D., NOVO MESTO, tadalafil, new patent

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WO 2016011767, New patent, Clopidogrel, SHENZHEN SALUBRIS/ HUIZHOU SALUBRIS

WO 2016011767

SHENZHEN SALUBRIS PHARMACEUTICALS CO.,LTD [CN/CN]; 37F Main Tower, Lvjing plaza, Che Gong Miao, No. 6009 Shennan Road, Futian District Shenzhen, Guangdong 518040 (CN).
HUIZHOU SALUBRIS PHARMACEUTICALS CO.,LTD. [CN/CN]; No.42, West petrochemical Avenue, West District，Huizhou DayaBay Huizhou, Guangdong 516083 (CN)

LI, Haidong; (CN).
TAN, Duanming; (CN).
WANG, Hai; (CN)

Provided is a preparation method for high purity clopidogrel and salt thereof. In the present method, inorganic acid solution is used to wash an organic phase containing clopidogrel till a specific pH value range is reached; during the post-processing stage, impurities including TTP can be removed from the clopidogrel product. The ensuing refining step can be avoided, thereby simplifying production techniques and ensuring the quality of the clopidogrel product.

Clopidogrel, molecular formula: C ₁₆ H ₁₆ ClNO ₂ S, it is an inhibitor of induced platelet aggregation by inhibiting platelet aggregation reduces the chance of arterial obstruction, to prevent stroke and heart attack efficacy, and can effectively treatment and prevention of atherosclerosis. Clopidogrel clinical use for right-handed body, clinical sulfate administered in the form of finished products on the domestic market clopidogrel main Plavix (Plavix) and Techno.

Currently it reported a variety of synthetic methods clopidogrel or a salt thereof, may be optically active or racemic α- substituted-o-chlorophenyl-acetate as a raw material, and 4,5,6,7-tetrahydro-thieno [3, 2-c] pyridine or a salt thereof under basic conditions to afford the optically active or racemic clopidogrel or a salt thereof, and further in line with the preparation of pharmaceutically acceptable Clopidogrel sulfate API standards.

Chinese Patent CN200810142388.3 using α- dextrose substituted benzenesulfonic substituted-o-chlorophenyl-acetate prepared above dextrorotatory clopidogrel free base, the process with ethyl acetate as the reaction solvent, followed by treatment using the organic phase washed with water The method of removing impurities.

Chinese Patent CN201310167933.5 prepared using the above racemic Clopidogrel hydrochloride, the method with dichloromethane as the solvent, after the reaction was washed with water and the organic layer was evaporated to dryness, the salt in ethyl acetate to give the product.

If the above process synthesis optically active or racemic clopidogrel or a salt thereof, the reaction system there is usually residual starting material 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine (referred to as "TTP ") or a salt thereof, according to the method disclosed in the prior art, after the treatment of the synthesis process commonly used water extraction - water / weak alkaline solution washed - salt-forming method, since the same TTP and clopidogrel alkaline organics neutral or alkaline solution solubility difference, and is in an acidic solution with a salt, and therefore only the wash water or weak alkaline solution generally can not be divisible TTP, usually larger residues.

 

Due to the special nature of clopidogrel API, making it even within the scope of quality control requirements of the quality standards, there are still unstable phenomenon. In the standard range of high impurity content on the one hand it can significantly affect the stability of the product, on the other hand will increase the side effects of the subsequent steps. Thus, the prior art is usually removed after the reaction by purification methods such as recrystallization include TTP including impurities, but it will increase the preparation process, in addition to loss of product due to some of the products will remain in the mother liquor caused.

From the above, in a more convenient way to remove impurities, higher purity, better stability of clopidogrel and its salts are existing technology is not yet resolved. The present invention is a departure from the deficiencies of the prior art, provides a method for preparing high purity clopidogrel and its salts, which can be removed after the treatment stage the majority of clopidogrel impurities in the product, avoiding the subsequent refining step In simplifying the production process, while ensuring the quality of clopidogrel products.

Example 1 (racemic clopidogrel hydrochloride monohydrate) Example

China Patent CN201310167933.5 using the method disclosed in Example 19 preparation of racemic clopidogrel. In TTP and α- bromo-o-chlorophenyl acetate The reaction was refluxed for 4h after the organic phase was separated, the methylene chloride solution of racemic clopidogrel. With stirring was added 5% hydrochloric acid (pH approximately 0), the aqueous phase until the pH stabilized around 4. The phases were separated and the organic phase the solvent was evaporated under reduced pressure, 75ml of ethyl acetate was added to dissolve, added dropwise with stirring 6.6g 36% hydrochloric acid to precipitate crystals. 2h After filtration, the filter cake washed with ethyl acetate. After drying in vacuo to give 17.2g white crystals. Using the same test conditions and CN201310167933.5 testing product purity of 99.8% containing impurities TTP 0.011% (area normalization method).

Example 2 (racemic clopidogrel hydrochloride monohydrate)

China Patent CN201310167933.5 using the method disclosed in Example 19 preparation of racemic clopidogrel. In TTP with α- bromo-o-chlorophenyl acetate reflux 4h reaction after the separation of the organic phase. The organic phase the solvent was evaporated under reduced pressure, 75ml of ethyl acetate was added to dissolve. 5% hydrochloric acid was added with stirring, until the aqueous phase pH stabilized around 3. Phase, the organic phase was added dropwise with stirring to 6.6g 36% hydrochloric acid to crystallize. 2h After filtration, the filter cake washed with ethyl acetate. After drying under vacuum to give 17.0g white crystals. Product purity was 99.7% containing impurities, TTP 0.014% (detecting method as in Example 1).

Example 3 (right-handed clopidogrel hydrogen sulfate)

The TTP hydrochloride 26.4g (0.15mol), ethyl acetate 50ml, 80ml mixing water and potassium carbonate 22g, stirred for 20 minutes. Joined by R-α- methyl tosylate Chloromandelic 34.1g (0.1mol) mixture of ethyl acetate and 50ml solution. The reaction temperature was raised to 45 ℃ 4h, then the reaction was heated to 60 ℃ to R-α- methyl tosylate Chloromandelic completely consumed (about 3h). Cooled to room temperature phase.

The organic phase was added with stirring to a 5% aqueous sulfuric acid until the pH of the aqueous phase is stable at around 3. After stirring 10min static phase separation. Then dried over anhydrous magnesium sulfate, and evaporated to dryness to give 30.6g dextrose clopidogrel hydrogen sulfate. Purity 98.6% by HPLC, spectrum display free of impurities TTP.

 

 

//////WO 2016011767, New patent,Clopidogrel, SHENZHEN SALUBRIS,  HUIZHOU SALUBRIS