PREPARATION OF FINE PARTICLE SIZE CANDESARTAN CILEXETIL

INTRODUCTION

Aspects of the present application relate to processes that control the particle sizes of a pharmaceutical active compound, particularly candesartan cilexetil, by synchronizing the physical parameters of the reaction vessel during precipitation or crystallization.

Candesartan cilexetil is a prodrug and a selective AT1 subtype angiotensin II receptor antagonist. It is mainly used for the treatment of hypertension and heart failure. The pro drug candesartan cilexetil is marketed by AstraZeneca and Takeda, commonly using the trademark ATACAND.

Candesartan cilexetil has a chemical name (±)-1-hydroxyethyl 2-ethoxy-1-[p-(o-1 H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester), and has structural Formula I.

Formula I

Candesartan cilexetil is a white to off-white powder. Candesartan cilexetil contains one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Candesartan cilexetil undergoes hydrolysis during oral administration at the ester link to form the achiral active drug candesartan.

Candesartan cilexetil is disclosed in U.S. Patent No. 5,196,444 (hereinafter referred to as "US '444") as stable "Type C" crystals, obtained by crystallization of crude candesartan cilexetil (amorphous form) from a lower alkanol or a mixture of lower alkanol or lower ketone and water. Stable "Type C" crystals obtained by the process of US' 444 patent are variable, wherein 90% of the particles (do.g) have particle sizes less than about 70 urn to about 40 urn.

International Application Publication No. WO 2005/123720 (hereinafter referred to as "WO 720") discloses the preparation of candesartan cilexetil having particle sizes wherein d0.9 is about 25 urn or less, by cooling a clear solution of candesartan cilexetil in an organic solvent with stirring. A second process of the WO 720 application involves micronization to produce the desired particle sizes of candesartan cilexetil.

U.S. Patent Application Publication No. 2007/0082055 (hereinafter referred to as "US '055") discloses stable candesartan cilexetil having fine particle sizes, prepared by reducing the particle sizes of candesartan cilexetil to 20 urn or less by conventional particle size reduction methods, followed by slurrying the particles in a C1.4 alcoholic solvent for 16 to about 48 hours to produce stable fine particle size candesartan cilexetil.
The previous preparation of fine particle size candesartan cilexetil involve conventional particle size reduction processes such as jet milling, hammer milling, compression milling, tumble milling, and the like.

The previous processes mainly utilize conventional particle size reduction procedures involving mechanical operations, which are time consuming and may also lead to the formation of impurities. Thus, there remains a need to develop a robust method to control the particle sizes of candesartan cilexetil, without involving any mechanical operations. Fine particle sizes of candesartan cilexetil produce desired therapeutic effects.

SUMMARY

Aspects of the present application relate to efficient processes for the preparation of fine particle size candesartan cilexetil of Formula I, embodiments comprising,

a) providing a solution of candesartan cilexetil in a suitable solvent;

b) agitating the solution under controlled physical parameters in a reaction vessel;

c) cooling the solution of candesartan cilexetil to commence crystallization; and

d) optionally, agitating a crystallized product for a suitable time period at a suitable temperature to produce fine particle size candesartan cilexetil.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is a diagram of a reaction vessel utilized for the preparation of fine particle size candesartan cilexetil.

DETAILED DESCRIPTION

Aspects of the present application provide method for the preparation of candesartan cilexetil having fine particle sizes.

Solid state properties of a drug can have a great influence on the solubility of the drug. Particle sizes frequently are very critical physical parameters. Generally, the bioavailability of an active pharmaceutical ingredient is inversely proportional to the particle sizes. Reduced particle sizes increases bioavailability of low solubility active pharmaceutical ingredients. The rate of dissolution of drug in the stomach fluid has a therapeutic consequence, as it imposes an upper limit on the rate at which the orally administered drug can enter the circulatory stream of the patient.

Conventional methods of micronization involve jet or fluid energy mills and ball mill techniques. The basic principle in all these techniques involves application of forces on the particles, in the form of collisions which act at imperfections in crystal surfaces, initiating crack propagation through the particles. As the sizes of the particles decrease, the number of imperfections decreases, thereby the task of further reducing the particle sizes becomes more difficult.

Micronization by jet milling has many disadvantages, because it creates friction among particles or between particles and the mill surface. If the milled material is abrasive, it may cause considerable damage to the mill surface and may also result in contamination by metals in an active pharmaceutical ingredient. The method involves the collision of the solid particles, which generates heat and may result in thermal decomposition, rendering the technique unsuitable for heat sensitive compounds. The heat generated during micronization may also lead to changes in the physical appearance and/or polymorphic form of the active pharmaceutical ingredient.

The processes of the present application reduce the conventionally occurring disadvantages by removing the steps of mechanical operations such as jet milling, hammer milling, compression milling, tumble milling, and the like for generation of fine particle size candesartan cilexetil.

As used herein, the term "fine particle size" refers to a material wherein 90% of the particles (do.9) have a maximum dimension no greater than about 20 urn.

According to embodiments of the present application, candesartan cilexetil of fine particle size is prepared by providing a solution of candesartan cilexetil in a suitable solvent. When a solution is prepared by dissolving candesartan cilexetil in the solvent, the temperature of the mixture may be elevated for complete dissolution of the candesartan cilexetil.

Suitable solvents include, but are not limited to: lower alkyl linear or branched chain alcohols; lower aliphatic ketones; polar protic solvents, such as water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and any mixtures thereof. In embodiments, a combination of lower alkyl linear or branched chain alcohol or lower aliphatic ketone with water is employed. "Lower alkyl" and "lower aliphatic" include molecules having 1 to about 6 carbon atoms.

The volume ratios of lower alkyl linear or branched chain alcohol or lower aliphatic ketone to water may include, but are not limited to, about 4:1 to 1:1.

A solution of candesartan cilexetil is prepared in any suitable reaction vessel, including a reaction vessel of the present application. A solution of candesartan cilexetil is stirred at suitable temperatures for about 1 to 4 hours in a reaction vessel as shown in Figure 1. The stirred solution may be cooled to a suitable temperature, with or without stirring, to commence the process of crystallization. The crystallization temperatures include, but are not limited to, about 0°C to 10°C.

It is advantageous to treat the solution with activated carbon before the crystallization process.

Optionally, the product of crystallization is further stirred for about 2 to 8 hours, or longer, while maintaining the same crystallization temperature range to produce fine particle size candesartan cilexetil.

As used herein, the term "reaction vessel" refers to a vessel which may develop a constant impeller tip speed of about 2.9 to 3.75 meters/second. Tip speed of the desired range is maintained by synchronizing the physical parameters of the reaction vessel at a particular time.

The process of stirring in the present application is a relative term of tip speed and other physical parameters of the reaction vessel. The process of stirring to produce desired fine particle size candesartan cilexetil not only depends on the tip speed of 2.9 to 3.75 meters/second, but also depends over the other physical parameters of the reaction vessel. Thus, it is necessary to develop a constant tip speed of 2.9 to 3.75 meters/second along with other physical parameters of the reaction vessel in a synchronized state to obtain the desired fine particle size candesartan cilexetil.

Tip speed of the reaction vessel may be defined as the velocity experienced by the solution/particles at the tip of the impeller. Tip speed is directly related to the physical parameters of the reaction vessel and it may change by changing the other physical parameters of the reaction vessel.

According to the present application, fine particle size candesartan cilexetil is obtained by synchronizing the values of physical parameters of the reaction vessel and maintaining a tip speed of about 2.9 to 3.75 meters/second.

The physical parameters of the reaction vessel may include, but are not limited to,

1) types of impeller,

2) diameter of impeller (D), and

3) clearance of impeller (C) from the base of the reaction vessel.

In general, an impeller of the reaction vessel is used to mix a fluid or slurry. A suitable impeller is employed, which may perform such action in a constant manner. In embodiments, a radial flow impeller or axial flow impeller is used.

Radial flow impellers may be used for mixing the liquids or very viscous fluids. Such impellers may also be used for the breakage of a deformable interface.

Axial flow impellers may be used for bulk motion and to increase the fluid volumetric flow rate.

According to embodiments in the present application, a pitch blade turbine impeller is used, which may function as radial flow impeller as well as axial flow impeller. The pitch blade turbine impeller contains four 45° pitch blades while a blade width is about 0.2 times to its swept diameter. The function of a pitch blade turbine impeller is directly related to a D/T ratio.

Wherein "D" refers to the diameter of an impeller and "T" refers to the diameter of a reaction vessel, and the number of blades of the impeller. A pitch blade turbine may perform as an axial flow impeller for small D/T ratios and as radial flow impeller for large D/T ratios.

Another physical parameter of the reaction vessel is the diameter of the impeller, which may affect the particle size distribution of candesartan cilexetil. Any suitable diameter of impeller in relation to the diameter of the reaction vessel and number of pitch blade turbine is used for maintaining a tip speed of 2.9 to 3.75 meters/second. Diameter of impeller is the relative term and exemplary ratios of impeller diameter to the diameter of the reaction vessel may be about T/1.3 to T/2.2, wherein "T" refers to diameter of the reaction vessel. A typical reaction vessel according to the present application is shown in Figure 1.

A two pitch blade turbine mounted over a single stirring rod, with a total eight blades is used for maintaining a tip speed of 2.9 to 3.75 meters/second. The volume of the stirred solution may also affect the tip speed and fine particle size candesartan cilexetil. A sufficient volume of stirred solution may be used and maintained in such a way that the impeller may be completely or partially covered by the reaction volume during stirring.

The clearance of impeller from the base of the reaction vessel is also affecting the fine particle size candesartan cilexetil. The clearance of impeller from the base of the reaction vessel may be adjusted in such a way that it maintain a tip speed of 2.9 to 3.75 meters/second and does not affect the fine particle size candesartan cilexetil.

In embodiments, the clearance of the impeller from the base of the reaction vessel is maintained in a ratio of D/13 to D/22, wherein "D" refers to diameter of the impeller.
Any desired rotational speed of the impeller is maintained in relation to the other parameters of the reaction vessel along with tip speed of 2.9 to 3.75 meters/second to produce fine particle size candesartan cilexetil.

Reaction vessels of the present application is used with or without baffles support for generating high turbulence, which in turn produces a high shear impact on the particles during the crystallization or precipitation of the product with desired particle sizes.
Having described the invention with reference to certain embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further explained by reference to the following examples, where certain specific aspects and embodiments are described. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention, and the invention is not to be limited by the examples.

EXAMPLES

EXAMPLE 1: Preparation of fine particle size candesartan cilexetil.

To a clear solution of candesartan cilexetil (5 kg) in acetone (40 L) and water (20 L) activated charcoal 500 gm was added and stirred for 30 minutes at 45-50°C. The stirred solution was filtered and the filtrate was transferred to the reaction vessel as shown in Figure 1, having the specifications in the table below, and heated to 45-50°C. To the hot solution, a mixture of acetone (5 L) and water (5 L) was added. The resulting solution was cooled to 0-5°C and stirred for 2 hours. The crystallized solid was separated and dried to afford the title compound (Yield 4.13 kg, do.9=14-15 urn).

Reactor Specifications

EXAMPLE 2: Preparation of fine particle size candesartan cilexetil.

To a clear solution of candesartan cilexetil (5 kg) in acetone (40 L) and water (20 L) activated charcoal 500 gm was added and stirred for 30 minutes at 45-50°C in a reaction vessel as described in Example 1. The stirred solution was filtered and the filtrate was heated to 45-50°C. To the hot solution a mixture of acetone (5 L) and water (5 L) was added. The resulting solution was cooled to 0-5°C and stirred for 2 hours. The crystallized solid was separated and dried to afford the title compound (Yield 4.30 kg, d0.9=11-12 mm).

We Claims:

Claim 1: A process for the preparation of fine particle size candesartan cilexetil of
Formula I, which comprises,

a) providing a solution of candesartan cilexetil in a suitable solvent,

b) agitating the solution under controlled physical parameters in a reaction vessel,

c) cooling the solution of candesartan cilexetil to commence crystallization; and,

d) optionally, agitating the crystallized product for a suitable time period at a suitable temperature to produce fine particle size candesartan cilexetil.

Claim 2: The process of claim 1, wherein suitable solvent in step a) is selected from
water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl
ketone; and any mixtures thereof.

Claim 3: The process of claim 2, wherein suitable solvent is a mixture of lower alkyl
linear/branched chain alcohol or lower aliphatic ketone with water.

Claim 4: The process of claim 1, wherein controlled physical parameters in step b) is
attained by,

a) maintaining a tip speed of 2.9 to 3.75 meters/second; and/or,

b) adjusting the ratios of impeller diameter to the diameter of the reaction vessel in an about T/1.3 to T/2.2; and/or,

c) adjusting the clearance of impeller from the base of the reaction vessel inanaboutD/13toD/22.

Claim 5: The process of claim 1, wherein step a) solution is treated with activated
carbon.

Claim 6: The process of claim 1, wherein step c) solution is cooled to 0°C to 10°C.

Claim 7: The process of claim 1, wherein step d) solution is stirred for about 2 to 8
hoursatO°Cto10°C.

Claim 8: The process of claim 4, wherein impeller used in step b) and c) is a pitch
blade turbine impeller.

Claim 9: The process of claim 4, wherein impeller used in step b) and c) contains
four 45° pitch blades while a blade width is about 0.2 times to its swept diameter.

Claim 10: The process of claim 1, wherein fine particle size candesartan cilexetil of Formula I refers to a material wherein 90% of the particles (d0.9) have a maximum dimension no greater than about 20 mm.