EFFICIENT PROCESS FOR PREPARATION OF APIXABAN HAVING CRYSTALLINE PARTICLES WITH D90 GREATER THAN 89 MICRON

FIELD OF THE INVENTION: Disclosed herein is a cost-efficient single step one pot process for the preparation of crystalline Apixaban of formula (I) having mean particle size greater than 89 micron also referred herein as (pm). The said cost efficient process is characterized by insitu slow cooling crystallization without isolating crude, which not only reduces the cost and time of production but is also suitable for industrial production.

BACKGROUND OF THE INVENTION: Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, Apixaban prevents thrombin generation and thrombus development. Preclinical studies of Apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.

It is marketed under the name Eliquis Label, Apixaban was approved by the FDA on December 28, 2012. Apixaban, chemically known as 4,5,6,7-tetrahydro-l-(4-methoxyphenyl)-7-oxo-6-[4- (2-oxo-l-piperidinyl)phenyl]-lH-pyrazolo[3,4-c]pyridine-3-ca rboxamide and is represented by formula (I).

Formula I

Apixaban is available for oral administration as tablets in strengths of 2.5 mg and 5 mg. Particle size analysis gives information on the size distribution of particles. This can be used to calculate different properties of a particle and how they will act under certain conditions. This information is critical in industries to achieve different goals.

PARTICLE SIZE is an important attribute in Active Pharmaceutical Ingredients (API). It has a significant effect on drug product’s manufacturability and performance. With respect to manufacturability, particle size can affect compatibility, flowability and blend uniformity; with respect to product performance it can affect solubility, dissolution, distribution and bioavailability.

Particle size is a crucial parameter in the pharmaceutical industry, because it influences surface area and porosity and hence, has an impact on bioavailability, effectiveness and shelf life of a drug. Therefore, particle size is not only monitored in quality control, but also in the development of new active pharmaceutical ingredients (APIs). In fact, particle size distribution (PSD) is among the most important parameters to check when evaluating new drugs.

Particle size also strongly relates to absorption behavior, which is a crucial parameter in the pharmaceutical industry. Hence, product effectiveness as well as production processes are influenced by particle size, making it important to characterize both active components and excipients. Particle compressibility is also very important. Very fine particles have less ability to lock together under compression. When using a tablet press and working with very fine particles, it takes additional steps to maintain good quality product because of the lack of ability of the smaller particles to compress together. When working with very fine particles during tablet compression, pre-compression is often needed.

Powder particle size distribution is a valuable indicator of quality and performance. Particle size also greatly affects tableting and granulation processes. Small particles aid dissolution, but are also more sensitive to over compression, leading to hard tablets which barely disintegrate. Tightly controlled particle size distributions are highly important for pharmaceutical drug development. When working with very fine particles during tablet compression, pre-compression is often needed — the operator uses an initial compression at a lighter pressure first, ahead of the main compression step. If pre-compression is not carried out, it can lead to problems during normal compression known as Capping or Lamination. Capping is when the upper or lower part of a tablet separates horizontally as the tablet press ejects the tablets.

Large particles on the other hand, lead to better flow ability, compressibility and feeder clearance during the manufacturing process. Moreover, a more homogeneous distribution is achieved, if particles exhibit a narrow particle size distribution. Confirmation of polymorphic purity and particle size distribution are included in the active substance specification as these are considered critical material attributes, as they impact the solubility of the active substance.

Apixaban was first disclosed in US 6,967,208 and it is used to treat and prevent blood clots such as deep vein thrombosis and pulmonary embolism. Apixaban is a non-ionisable compound, so its solubility is not affected by changes in pH. The purity of Apixaban obtained by the process disclosed in US '208 is very low and not suitable for pharmaceutical uses.

US9603846B2 discloses a process for the preparation of Apixaban having particle size distribution with D90 equal to or greater than 100 pm suitable for formulations with crystalline Form N-l and having lower level of one or more impurities. However, the said process comprises isolation of crude Apixaban followed by crystallizing the Apixaban in one or more solvents to obtain the crystalline Form N-l of Apixaban having a mean particle size equal to or greater than 100 pm.

WO2017221209A1 discloses that formulations using Apixaban with Dgo>89 micron shows desired dissolution and bio-availability profile achieved using Apixaban with a larger particle size having D90 more than 89 micron, wherein at least 85 wt % of the crystalline Apixaban dissolves within 30 minutes at pH 6.8 phosphate buffer containing one or more surfactants.

CN 104644593 discloses crystalline Apixaban particles (N-l) having particle size D90 equal to or less than about 70 pm.

US10537524B2 discloses Apixaban solid composition comprising Apixaban having a particle size D90 more than 89 pm, wherein the Apixaban is dissolved in a wetting agent and wetting agent is an acidic substance or an organic solvent. As per their findings the restrictions on scale production from small particles of Apixaban can be overcome greatly by using Apixaban having a particle size D90 more than 89 pm.

US2017000799 discloses composition comprising Apixaban (N-l) crystal having particle size D90 is 100 pm or less, wherein a solid particle of a poorly soluble drug, having an average particle size of 100 pm or less, wherein a solubilizer is adsorbed on the surface of the poorly soluble drug.

IN3987/MUM/2015 discloses composition comprising Apixaban (N-l), crystal having particle size D90 equal to or greater than 120 micron and fine fraction of D90 equal to or less than 20 micron.

IN201841004826 (hereinafter referred as “826) discloses a method for the preparation of N-l form of Apixaban having diameter greater than 100 pm using roller compaction technology. The disadvantage associated with “826 is that it uses Apixaban with Dgo<89 micron as input material which is then converted to Apixaban with D9O>1OO micron by roller compaction technique.

IN201721022924 discloses a method for the preparation of solid oral composition using crystalline Apixaban particles having D90 more than 89 pm, wherein Apixaban may contain agglomerates with size limit of more than 89 pm specified therein.

IN201721045328 discloses a method for the preparation of Apixaban with D90 greater than 100 micron, more preferably D90 greater than 350 micron by granulation technique by adding additives.

IN201841004826 discloses a method of preparation of N-l form of Apixaban having diameter greater than 100 micron based on mechanical engineering technology. The main disadvantage of this method is that it uses Apixaban particles with D90 less than 89 micron and convert it into Apixaban crystalline particles with D9Q>100 micron.

US20160143894A1 describes process for the preparation of N-l form of Apixaban with Dgo> 120 micron. The main disadvantage of this approach is the preparation and isolation of crude Apixaban and then crystallization of Apixaban in an additional process step to get particle size with Dgo>9O pm.

IN3729/MUM/2014 discloses a process for the preparation of Apixaban having mean particle size equal to or greater than 100 micron. The main disadvantage of this process is the isolation of crude Apixaban having mean particle size less than 89 micron and then by an additional crystallization process converting it into Apixaban with mean particle size greater than 100 micron.

The production facilities of the current Apixaban tablets containing 2.5 and 5.0 mg in the market are very expensive. The decrease in compressibility of materials is rather high, which lead to a rather high risk in the homogeneity of product, and poor particle compressibility.

Foregoing prior art process/es for preparing Apixaban particle size with D90 greater than 89 micron comprises two or more step processes comprising the synthesis of crude Apixaban particles with Dgo<89 and the said crude product having particle size D90 less than 89 micron is isolated and recrystalized in a single or multiple process steps to obtain Apixaban particles with D90 greater than 89 micron.

The processes disclosed in the prior art are of minimum two process steps comprising preparing a crude Apixaban having particle size with D90 <89 micron and the said crude is isolated and used as a starting material in the subsequent process step of crystallization to obtain desired crystalline Apixaban with D90 greater than 89 micron.

Thus, there is a need to develop a simplified single step one pot process which directly lead to the preparation and isolation of Apixaban with Dgo>89 micron without isolation of crude and avoiding additional recrystallization and other techniques like roller compaction technology, agglomerates, wet granulation, dry granulation etc. thereby making the process scalable, cost effective, time effective and industrially feasible. The particle size distribution of Apixaban particles as described in the specification is characterized by D90 values. “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter.

In view of above, inventors of the present invention based on their intellect and exhaustive R&D efforts without any teaching or motivation from the prior art have successfully developed and disclose herein a novel and inventive process addressing the process shortcomings in the prior art process comprising obtaining a substantially pure subject matter product having particle size D90 greater than 89 microns and said novel and inventive process avoids isolation of crude product thus restricting the process to a one pot single step process compared to minimum two steps in the processes disclosed therein in the prior art.

TECHNICAL PROBLEMS ASSOCIATED WITH THE PRIOR ART:

The most prominent shortcoming associated with process disclosed in the prior art for the preparation of Apixaban comprises minimum two stage process for the isolation of Apixaban particle with D90 greater than 89 micron, wherein first step comprises the synthesis and isolation of crude Apixaban particles with Dgo<89 micron while step 2 comprises the various techniques like recrystallization, purification and other techniques like roller compaction technology, agglomerates, wet granulation, dry granulation and the likes, thereby making the process expensive, time consuming, laborious to get Apixaban particles with desired particle size having D90 greater than 89 micron.

ADVANTAGES AND TECHNICAL SOLUTION OF THE PRESENT INVENTION: Considering problems associated with the preparation of Apixaban having particle size D90 greater than 89 micron, inventors of the present invention based on their expertise and R&D activity found a few notable and most prominent advantages/solutions over prior arts which include:

(i) Use of cheap and readily available solvent selected from the group comprising C1-C4 aliphatic alcohol and water and the likes.

(ii) Single stage isolation,

(iii) Simple operation,

(iv) No mixture of organic solvents for crystallization,

(v) Use of Me0H/H20 system as a commercially viable solvent,

(vi) Moderate to good yield, (70-85%)

(vii) No need to isolate crude Apixaban and then subjecting it for further crystallization or purification and no more applications of various techniques like roller compaction technology, agglomerates, wet granulation, dry granulation etc.

(viii) High purity (>99.7%) Apixaban is isolated by this technique which does not require further purification.

(ix) Exclusive formation of N-l form of Apixaban

(x) No polymorph change/Polymorphic impurities.

(xi) Direct isolation of crystalline Apixaban with D90 greater than 89 micron from the reaction vessel in a one pot single step process.

(xii) The Apixaban with PSD Dgo>89 micron have advantage of better dissolution profile as disclosed in prior art , WO2017221209A1 and illustrated herein below in Table- 1.

Table- 1 : Dissolution data of Apixaban formulation where Apixaban with Dgo>89 micron is used.

SUMMARY OF THE INVENTION:

As evident from foregoing the inventors of the present invention disclose herein a novel, cost effective, commercially viable and inventive one pot single step process represented by Scheme - 1 for the preparation of Apixaban. The present invention relates to the process for the preparation of crystalline Apixaban of formula (I) with D90 greater than 89 micron. This is achieved in single stage obe pot process which comprises preparation of Apixaban with standard process by amidation of Apixaban ethyl ester represented by Formula II with methanolic ammonia and isolation of N-l form of Apixaban represented by Formula I having particles with D90 >89 micron from the reaction mass containing mixture of C1-C4 aliphatic alcohol/water preferably methanol/water by slow cooling crystallization technique.

Formula II Formula I Apixaban ethyl ester Apixaban D90>89 p

SCHEME I: Method of preparation of Apixaban with particle size D90>89 micron

OBJECTS OF THE INVENTION: One of the aspects of the present invention is to provide an improved, cost effective, novel and non-obvious, inventive one pot single step process for the preparation of Apixaban having particle size D90 greater than 89 micron.

One of the aspect is to provide a one pot single step process for the preparation of substantially pure Apixaban having purity more than 99% in good yield (upto 85%).

One of the aspects of the present invention is to avoid the isolation of crude Apixaban and additional process step for its crystalization or purification.

One of the aspects of the present invention is to avoid the various techniques like roller compaction technology, agglomerates, wet granulation, dry granulation etc. to get the Apixaban with particle size Dgo>89 micron.

One of the aspects of the present invention is to avoid the use of multiple solvents for the preparation and purification or crystalization of Apixaban.

DETAILED DESCREPTION OF THE PRESENT INVENTION:

Much attention and effort has been applied in recent years and inventors of the present invention have been able to achieve this and as a result; disclose herein an efficient single step one pot process for the preparation of Apixaban having particle size D90 greater than 89 micron. With detailed reference to certain embodiments of the present invention, the example of these embodiments illustrates with structure and the formula enclosed. Although the present invention will be illustrated in conjunction with row illustrated embodiments, but it is to be understood that they are not intended to limit the invention to those embodiments. On the contrary, it is contemplated that contain all alternative forms, modification and the equivalents that may be included in the scope of the invention as defined in the claims. The invention is not restricted to method described herein and material, but include any method similar or equivalent with method described herein and material that can be used for putting into practice the present invention and material. One or more in the list of references being incorporated to, patent or similar data is different from the application (including but not limited to defined term, term usage, described technology etc. or runs counter to the application, it is as the criteria with the application

The essence of the present invention lies in the Manufacture of Apixaban having particle size, particularly D90 more than 89 pm comprising a single step one pot process is a typical feature of this invention. As specified above in the background, US9326945 is restricted to the use of smaller sized Apixaban particles, specifically having D90 equal to or less than about 89 pm in order to achieve consistent dissolution.

The particle size distribution stipulated herein refers to the particle sizes determined by using any known suitable techniques such as microscopy, sieving, sedimentation and/or laser light scattering techniques. Apixaban prepared by the advantageous process of the present invention having particle size with a D90 more than 89 pm shall be used for the various solid oral pharmaceutical compositions but are not limited to, tablets, pellets, granules, powders, capsules, microcapsules, microspheres, spheroids, pellets filled in capsules, tablets in capsules, multilayer tablets, bilayer tablets, trilayer tablets, or premixed powders filled in capsules. In a preferred embodiment of the present invention, the said solid oral dosage form is a tablet.

The present invention relates to the process for the preparation of crystalline Apixaban of formula (I) having a particle size distribution with D90 greater than 89 pm. The process comprises: a) contacting Apixaban ethyl ester of Formula II with methanolic ammonia at a pressure of 4-8 kg/cm ² and 60-70 °C to convert Apixaban ethyl ester to Apixaban of Formula I. b) removal of methanol to get residue. c) addition of C1-C4 aliphatic aclcohol/water preferably methanol/water mixture to the reaction mass d) heating the reaction mass to reflux to get clear solution and charcoalization of said clear solution. e) gradual cooling of reaction mass to get crystalline Apixaban with D90 greater than 89 micron. f) high purity (>99.7%) Apixaban is isolated which does not require further purification. g) Particle size distribution and purity details are given herein in Table-2.

Table-2: Particle size distribution and purity data.

In view of the above, the present invention provides a process for the preparation of crystalline Apixaban having particle size with D90 greater than 89 pm comprising slow cooling crystallization technique. The main advantages of this invention are:

1) Use of cheap and readily available solvent comprising mixture of C1-C4 aliphatic alcohol and water

2) Exclusive formation of N-l form of Apixaban

3) No polymorph change/Polymorphic impurities.

4) Direct isolation of crystalline Apixaban with D90 greater than 89 micron from the reaction vessel.

5) The Apixaban with particle size distribution Dgo>89 micron have advantage of better dissolution profile as reported in the prior art and illustrated herein below in Table-3. Table-3: Dissolution data of Apixaban formulation where Apixaban with Dgo>89 micron is used.

6) No separate crystallization method like first isolation of Apixaban with D90 less than 89 micron then converting it into Apixaban with D90 greater than 89 micron.

7. No additional process step like roller compaction technology, agglomerates, wet granulation, dry granulation etc. to obtain particle zize distroibution D90 greater than 89micron.

8) No additional purification is required to get high purity Apixaban.

In view of the above, the present invention provides an efficient process for the preparation of crystalline Apixaban having particle size with D90 greater than 89 pm comprising a single step one pot process, wherein neither isolation of crude Apixaban nor further purification is required. A process comprises simply amidation of Apixaban ethyl ester of Formula II using methanolic ammonia at a pressure of 4-8 kg/cm ² and 60-70 °C followed by complete removal of methanol under vacuum. To the residue thus obtained is added C1-C4 aliphatic alcohol and water to get clear solution. Charcoal treatment is done at 60-70°C. The reaction mass is filtered, stirred at 50- 70 RPM and subjected to gradual cooling at the rate of 3-5°C/h resulting in the desired N-l polymorphic form having particle size D90 greater than 89 micron.

Preferably C1-C4 aliphatic alcohol is methanol.

The main advantages of this invention, are:

1) Use of cheap and readily available solvent such as C1-C4 aliphatic alcohol and water and the likes.

2) PreferablyCl-C4 aliphatic aliphatic alcohol is methanol.

3) Exclusive formation of N-l form of Apixabana

4) No polymorph change/Polymorphic impurities. 5) Direct isolation of crystalline Apixaban with D90 greater than 89 micron from the reaction vessel.

6) The Apixaban with particle zize distribution hereinbefore and after also referred as PSD

Dgo>89 p have advantage of better dissolution profile as reported in the prior art.

7) No separate crystallization method like first isolation of crude Apixaban with D90 less than 90 micron then converting it into Apixaban with D90 greater than 89 micron.

8) No additional process steop like roller compaction technology, agglomerates, wet granulation, dry granulation etc to obtain desired PSD D90 greater than 89 micron.

9) No additional purification is required to get high purity Apixaban.

10) A single step one pot process for the preparation of substantially pure having more than

99% purity in yield more than 85%.

The process can be best understood with the following examples.

Example 1: To a methanolic solution of Apixaban ethyl ester (20 g), ammonia gas is purged (4-6 kg/cm ² ) and reaction mass is heated to 60-70 °C for 6-8 h. The methanol is distilled out completely and then mixture of Methanol: water (40 V) is added. Chracoal is added and reaction mass is heated to 70°C till get clear reaction mass. The reaction mass is filtered and then cool slowly at the rate of 5°C/h by maintaining stirring to 50-70 RPM to get suspension. The suspension is filtered and wet cake is washed with mixture of MeOH/fTO The wet material is dried in hot air oven at 60-65 °C for 8-10 h to get Apixaban with desired purity and desired particle size distributon with Dgo.>89 micron

Example 2: To a methanolic solution of Apixaban ethyl ester (20.0 g)„ ammonia gas is purged (4-6 kg/cm ² ) and reaction mass is heated to 60-70 °C for 6-8 h. The methanol is distilled out completely and then mixture of Methanol: water (35 V) is added. Charcoal is added and reaction mass is heated to 70°C till get clear reaction mass. The reaction mass is filtered and reaction mass is then cool slowly at the rate of 5°C/h by maintaining stirring to 50-70 RPM to get suspension. The suspension is filtered and wet cake is washed with mixture of MeOH/fTO The wet material is dried in hot air oven at 60-65 °C for 8-10 h to get Apixaban with desired purity and desired particle size distributon with Dgo.>89 micron.

Example 3: To a methanolic solution of Apixaban ethyl ester (20.0 g), ammonia gas is purged (2- 4 kg/cm ² ) and reaction mass is heated to 60-70 °C for 18-20 h. The methanol is distilled out completely and then mixture of Methanol: water (40 V) is added. Charcoal is added and reaction mass is heated to 70°C till get clear reaction mass. The reaction mass is filtered and then cool slowly at the rate of 2°C/h by maintaining stirring to 50-70 RPM to get suspension. The suspension is filtered and wet cake is washed with mixture of Me0H/H20. The wet material is dried in hot air oven at 60-65 °C for 8-10 h to get Apixaban. The Apixaban is finally isolation by filtration with desired purity and desired particle size distribution with Dgo>89 micron.

Contacting herein means treating, mixing, reacting and the likes.