Field of the invention

The present invention relates to an improved process for the preparation of Amorphous form of Atorvastatin Calcium of formula (I) employing conductive rotary vacuum dryers.

Background of the invention

Atorvastatin is chemically known as [R(R*,R*)]-2-(4-Fluorophenyl)-ß,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, is a known useful anitlipemic agent belonging to the class of HMG-CoA reductase inhibitors. Its Calcium salt is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease. For use in the treatment of aforementioned diseases, open dihydroxy carboxylic acid, lactone and various salt forms of Atorvastatin have been synthesized.

U.S. Pat. Nos. 4,681,893, 5,273,995, 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952 and 5,397,792 disclose various processes for preparing Atorvastatin and its key intermediates.

There are several patents/applications which disclose processes for preparation of Amorphous form of Atorvastatin Calcium. U.S. Pat. No. 6,087,511 discloses process for preparation of Amorphous Atorvastatin comprising dissolving crystalline Form I of Atorvastatin in non-hydroxylic solvent and removing the solvent by drying.

Amorphous form is obtained by following the process disclosed in U.S. Pat. No. 5,273,995. The process comprises dissolution of Atorvastatin Calcium in ethyl acetate and further precipitating Amorphous form by adding hexane.

U.S. Pat. No. 6,528,660 discloses process for the preparation of Amorphous Atorvastatin Calcium by dissolving crystalline Atorvastatin Calcium in non-hydroxylic solvent like tetrahydrofuran and adding anti-solvent to precipitate out Amorphous Atorvastatin Calcium.

In U.S. Pat. No. 6,646,133 amorphous form is isolated from lower alkanol solvents. U.S. Pat. No. 7,161,012 and 7,189,861 involve sonication and ball-milling procedures to obtain Amorphous form of Atorvastatin Calcium.

The disadvantages of abovementioned prior arts is that the Amorphous form of Atorvastatin Calcium obtained by these processes is in form of lumps and difficult to filter at plant scale.

It is known that the amorphous forms of a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to crystalline forms (Konno T., Chem. Phar. Bull. 1990, 38, 2003-2007). For some therapeutic indications the bioavailability is one of the key parameters determining the form of the substance to be used in a pharmaceutical formulation. There is a constant need for processes which enable the preparation of Atorvastatin in an amorphous form without simultaneous formation of crystalline forms, or which will enable the conversion of the crystalline forms into the amorphous form.

The present invention provides a novel and industrially viable process for preparing Atorvastatin in pure amorphous form to avoid the drawback associated with the prior art.

Object of the invention

It is an object of the present invention to provide a process for the preparation of amorphous form of Atovastatin Calcium of formula (I) which is operationally simple and easy to handle at commercial scale.

Summary of the invention

It is a primary aspect of the present invention to provide a process for the preparation of Amorphous Atorvastatin Calcium of formula (I).

Another aspect of the present invention provides a process for the preparation of Atorvastatin Calcium of formula (I) employing conductive rotary vacuum dryers.

Further aspect of the present invention provides a process for the preparation of Atorvastatin Calcium of formula (I) which is operationally simple, economical and commercially viable.

Brief description of the drawings

Figure-1: Rotocone vacuum dryers
Figure-2: Cone Mixer cum Dryer
Figure-3: Rotary vacuum paddle dryer

Detailed description of the invention

Atorvastatin Calcium used for process of present invention can be prepared by any process known in the art or any method known perse and includes crystalline, hydrates and solvated forms thereof.

The present invention relates to an improved process for the preparation of Amorphous form of Atorvastatin Calcium of formula (I) employing conductive rotary vacuum dryers. The conductive rotary vacuum dryers can be horizontal/vertical mounted.

The examples of commonly employed conductive rotary vacuum dryer includes but are not limited to Rotocone vacuum dryer (RCVD), Cone Mixer cum Dryer, Rotary vacuum paddle dryer and the like.

Rotocone vacuum dryers as shown in Figure-1, are multipurpose drying unit that are extremely useful for uniform and low temperature drying of heat sensitive chemicals, pharmaceutical formulations, fine chemicals etc. It has double conical vessel with rotating system and vacuum solvent recovery system. As the Dryer is rotating, there is no charring or retention of product, the result is that one can change the material to be dried without much a do. The Rotocone vacuum dryers rotates at a very low speed (5 to 15 rpm) and thus has very low wear and tear and requires very little maintenance. This machine is ideal for crystalline products, granules used in chemical, pharmaceutical and food industries. The present invention discloses its application in preparation of Amorphous form of active ingredients.

Loss of material is effectively controlled by a specially designed pilot filter fitted on the vacuum side. The capacity of the machine ranges from 200 litres to 10,000 litres.

This equipment works under vacuum. Due to vacuum, the drying is enhanced resulting in fast drying, cutting the process time, which saves heat energy and electric energy.

Cone Mixer cum Dryer is shown in Figure-2. The working principle of the cone mixer is three dimensional originated from rotating elements in combination with a conical vessel. The salient features of Cone Mixer Dryer are as follows:
• The mixing screw conveys the product from bottom of the vessel to the products surface.
• The orbital arm orbits the mixing screw along the inner vessel wall causing convective mixing of particles and shear.
• The speed of particles in the downward mass flow when recirculated by gravity in a conical vessel increases as the vessel diameter decreases. The result of these simultaneous actions is a fast and intensive mixing with low consumption of power together with high standards of mixing accuracy.
Rotary vacuum paddle dryer is shown in Figure-3. The salient features of Rotary vacuum paddle dryer are as follows:
• The working principle of rotary vacuum paddle dryer is efficient heat transfer by mixing induced by rotating paddles mounted on central axis shaft.
• RPM is as low as 5 to 10 RPM.
• Improved product quality due to low temperature drying.
• Full recovery of solvent is achieved.
• Lower energy consumption.
• Dust catcher cleaning arrangement to prevent loses.

A preferred embodiment of the present invention provides a process for the preparation of Amorphous form of Atorvastatin Calcium of formula (I) comprising steps of:

(a) dissolving Atorvastatin Calcium in a suitable solvent to obtain a solution
(b) filtering the solution obtained in step (a)
(c) feeding the solution of step (b) to conductive rotary vacuum dryer
(d) heating and applying vacuum to remove the solvent
(e) drying the Amorphous form of Atovastatin Calcium insitu.

For the purpose of this invention the word ‘insitu’ refer as the compound is not isolated before the drying stage but after evaporation of solvent in the conductive rotary vacuum dryer the drying stage is carried out in the same reaction vessel. This stage of insitu drying process results in several advantage at industrial scale such as no requirement for filtration. Further, since mother liquor is not isolated, there is no loss of material in mother liquor and no requirement of recovering solvent from the mother liquor.

In an another preferred embodiment of the present invention, Atorvastatin Calcium is dissolved in a suitable solvent like alkyl ester the examples of which includes but are not limited to ethyl acetate, methyl acetate and the like. The dissolution takes place under heating conditions at temperature of about 50°C to about 70°C. The solution thus obtained is filtered to remove any solid unwanted impurities. The stock solution is then feed directly in to the Rotocone vacuum dryer. Further, heating and vacuum is applied to gradually distill out the solvent from the solution. The material is further evaporated to dryness insitu to obtain desired amorphous form of Atorvastatin Calcium.

The distillation can be carried out in the temperature range of about 35°C to 60°C, preferably at about 40°C to about 50°C. The temperature employed for purpose of drying is about 45°C to about 60°C.

The advantage of employing conductive rotary vacuum dryer for purpose of preparing Amorphous form of Atovastatin Calcium of formula (I) is that there is no filtration operation since the product is obtained by direct evaporative crystallization followed by insitu drying. Further since no mother liquor is obtained as the filtration step is avoided, there is increase in the yield. Also, the step of solvent recovery from the mother liquor is not required. Thereby, rendering the process for crystallization which comprises less number of operational steps and results in improved quality of product.

Additionally, in conventional process, production facility for crystallization needs multiple equipment facilities such as reaction/dissolution tank, condenser, crystallizer, centrifuge/vacuum nutch filter and other accessories. Also, above facility requires systems such as area classification, HVAC load, cleaning, maintenance and documentations thereof. these have major contribution to product cost.

In proposed ‘insitu’ process all above requirements for multiple equipments will be reduced to single equipment i.e. conductive rotary vacuum dryer.

The following example illustrates the invention further. It should be understood however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.

Example
Take 1500 ml of Ethyl acetate in RBF and dissolve 500 gm of Atorvastatin Calcium into it. Heat the solution in RBF up to 65 to 70°C and filter the solution hot through hyflo bed on Buckner filter. Wash the hyflo bed with 250 ml hot Ethyl acetate. Charge the solution in lab Rotocone vacuum dryer and distill off Ethyl acetate gradually under vacuum at temperature of 40 to 45°C. Continue drying by heating at 45°C under vacuum for 10 to 15 hours. Unload the material and weigh. The process yield about 95 to 98 % of product. The form obtained is amorphous.

We Claim,

1. A process for the preparation of Amorphous form of Atorvastatin Calcium of formula (I) comprising steps of:

(a) dissolving Atorvastatin Calcium in a suitable solvent to obtain a solution
(b) filtering the solution obtained in step (a)
(c) feeding the solution of step (b) to conductive rotary vacuum dryer
(d) heating and applying vacuum to remove the solvent
(e) drying the Amorphous form of Atovastatin Calcium insitu.

2. A process claimed in claim 1, wherein said conductive rotary vacuum dryer can be horizontal/vertical mounted.

3. A process claimed in claim 1, wherein said conductive rotary vacuum dryer comprises of Rotocone vacuum dryer (RCVD), Cone Mixer cum Dryer and Rotary vacuum paddle dryer.

4. A process claimed in claim 1, wherein said suitable solvent is alkyl ester.

5. A process claimed in claim 4, wherein said alkyl ester is ethyl acetate and methyl acetate.

6. A process claimed in claim 1, wherein said heating is carried out at 35°C to 60°C.

7. A process for the preparation of Amorphous form of Atorvastatin Calcium of formula (I) employing conductive rotary vacuum dryer.

Dated this 08th day of May, 2009

Figure-1: Rotocone vacuum dryers

Dated this 08th day of May, 2009

Figure-2: Cone Mixer cum Dryer

Dated this 08th day of May, 2009

Figure-3: Rotary vacuum paddle dryer
Dated this 08th day of May, 2009