DESC: The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR PREPARING CANDESARTAN CELEXETIL WITH FINE
PARTICLE SIZE

INTRODUCTION TO THE INVENTION

The present application relates to a process for the preparation of candesartan cilexetil with fine particles. In particular, the present application relates to a process which provides candesartan having a d (0.9) between 10 to 50 microns and d (0.5) not more than 6.0 microns.

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 prodrug 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-1H-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 poorly soluble in water, which necessitates special formulation procedures for achieving a desired pharmacokinetic profile. It is suggested in several patent references to reduce the particle size of the granules to a certain desirable range before compressing them into a tablet dosage form or before filling into capsule dosage form (US Appl. No. 20040018240; US Appl. No. 20040102502; US Appl. No. 20030198676; US Patent No. 6589547; US Patent No. 6740339, etc.).

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 i.e. d (0.9) have particle sizes less than about 70 µm to about 40 µm.

International Application Publication No. WO 2005/123720 (hereinafter referred to as “WO ‘720”) discloses the preparation of candesartan cilexetil having particle sizes wherein d (0.9) is about 25 µm 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 µm 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 of candesartan cilexetil.

The previous preparation of fine particle size of candesartan cilexetil involves conventional particle size reduction processes such as jet milling, hammer milling, compression milling, tumble milling, and the like.

Also IP.Com journal IPCOM000203830D discloses a process for the preparation of fine particle size of candesartan cilexetil by using a reaction vessel which can develop a constant impeller tip speed of about 1 to 30 meters per second which is maintained by synchronizing the physical parameters of the reaction vessel at a particular time.

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. The present inventors have also found that the techniques provided in the prior art including the method disclosed in the IP.com journal mentioned above do not provide consistent particle size distribution for the product.

Conventional methods of micronization involve jet or fluid energy mills and ball mill techniques. The basic principle in all these techniques involve 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 size becomes more difficult.

Micronization by jet milling has many disadvantages, because it creates friction among particles or between particles and the mill surface. 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.

Thus, there remains a need to develop a robust method to control the particle sizes of candesartan cilexetil, without involving any mechanical operations. 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 of candesartan cilexetil. Fine particle sizes of candesartan cilexetil produce desired therapeutic effects.

SUMMARY OF THE INVENTION

The present application relates to a process for the preparation of candesartan cilexetil with fine particles. In particular, the present invention relates to a process which provides candesartan having a d (0.9) between 1 to 50 microns and d (0.5) not more than 6.0 microns, and specifically d (0.9) between 10 to 20 microns and d (0.5) not more than 6.0 microns.

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.

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

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

b) subjecting the solution to ultrasound energy;

c) cooling the solution of candesartan cilexetil;

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

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is a diagram of a continuous ultrasonication equipment used in Example 1.

DETAILED DESCRIPTION OF THE INVENTION

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 size. Reduced particle size 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.

As used herein, the term “fine particle size” refers to a material wherein 90% of the particles (d 0.9) have a maximum dimension no greater than about 50 µm.

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 and subjecting it to ultrasound sonication.

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.

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 24 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 50°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 of candesartan cilexetil.

As used herein, the term “reaction vessel” refers to a vessel which aids in ultrasound crystallization equipment which aids in conversion of electrical energy into mechanical oscillations of a sonotrode, which provides ultrasonic energy to the reaction mass.

Ultrasound crystallization can be aided by various ultrasound crystallization equipments selected from horn ultrasonication, ultrasonication bath, or continuous ultrasonication in flow cell. These techniques differ from each other with respect to intensity of ultrasonic oscillations introducing into a fluid and possibility or impossibility of the flowing process.

The ultrasonic processors typically comprise of an ultrasonic processor, a stainless steel/ glass flow cell, sonotrodes, booster and a power meter. The parameters which can be varied during the ultrasonication process include temperature, flow rate, and residence time of the reaction mass and pump speed, power and amplitude of the ultrasonication equipment.

According to the present application, fine particle size of candesartan cilexetil is obtained by synchronizing the variables to obtain the desired particle size.

The inventors have done extensive studies to determine the effect of each of the variables on the particle size of candesartan obtained, and determined the specific ranges of each variable to obtain a defined particle size.

Hence, by varying the parameters appropriately, the applicants are able to control the particle size for candesartan cilexetil obtained from the process and obtained candesartan cilexetil having specified particle size distribution as per the requirement.

The temperature of the reaction mass may be varied from about 0 to 50 °C. The operation temperatures are important since higher temperatures have an impact on the particle size obtained.

The residence time may range from about 0.5 minute to 10 minutes. As the residence time increases, the particle size decreases, and vice versa.

The ultrasound power may range from about 100 to about 1000 watts, and the area of the ultrasound horn may range from about 1 to 20 cm2.

The working volume of the flow cell may range from about 20 to 2000 ml, and the values may change depending on the kind of equipment used.

The power is transmitted at controlled amplitude, so that the magnitude of the mechanical ultrasonic vibrations at the sonotrode is constant under all load conditions. The amplitude can be changed from 50 to 100% at the generator and by using various booster horns. The chosen amplitude is preferably held constant, while sonicating any material at any pressure, thus providing full control over the most important sonication parameter which is amplitude.

The various industrial ultrasonic devices available are categorized based on the liquid volume the instrument can handle, and they include UIP1000hd (1000W, 20kHz), UIP1500hd (1500W, 20kHz), UIP2000hd (2000W, 20kHz), UIP4000 (4000W, 20kHz), UIP10000 (10000W, 20kHz), UIP16000 (16000W, 18kHz).

In an embodiment, the ultrasonic flow cell used in our invention is a UIP1000hd (20 kHz, 1000W) which is powerful ultrasonic device for lab testing and industrial processing of liquids.

The UIP1000hd is the powerful link between laboratory testing and the industrial processing of liquids. It combines the flexibility and easy handling required in the research and development with an outstanding performance in heavy-duty operation. For this reason, this single device is used for lab scale feasibility testing, process optimization, and process demonstration for ultrasonic crystallization processes.

For the processing of batches larger than 5 liters, it is recommended to sonicate using a flow cell reactor (flow mode)/batch reactor with recirculator mode in order to obtain a better processing quality. When used with a flow cell larger samples can be run in recirculation to establish the correlation between parameters, such as amplitude, pressure and liquid composition, and the process results and efficiency. When used for the sonication of liquids in flow mode, the UIP1000hd can typically process between 20 to 2000 ml per minute. As the UIP1000hd is full industrial grade, it can be operated 24 hours per day (24h/7d). A UIP1000hd can typically process approx. 0.1 to 3 m³ per day.

The UIP1000hd is very simple to setup and to use. The accessories e.g. flow cells and booster horns can be easily mounted.

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 of candesartan cilexetil

Acetone (280 ml) and candesartan cilexetil (40 g) were taken into a round bottom flask, and the mixture was heated to about 50 °C. 4 g of carbon was added to it, and stirred for about 30 minutes. The mixture was filtered and the filtered bed was washed with acetone. Water (160 ml) was added to it at the same temperature and stirred for about 30 minutes.

The reaction mass was cooled to a temperature of about 40 °C, and then transferred to the ultrasound flow cell (Hielscher, Germany, UIP100hd, 1000 Watt power, 20 kHz frequency), and the mass was fed at a flow rate of 60-200 ml per minute through ultrasound flow cell for 20 minutes. The obtained reaction mass was cooled to about 5 °C, and maintained for about 1-15 hours. The separated solid was filtered and washed with a 1:1 mixture of acetone and water. The obtained compound was dried at about 60 °C for 8 hours.

Examples 2-9: To study the impact of variable parameters of the ultrasonication equipment on the particle size of candesartan cilexetil:

The reaction conditions were kept similar to that described above expect for the parameters which were varied for studying its impact on the particle size of candesartan cilexetil.

Study of the impact of Pump Speed on the particle size of candesartan cilexetil:

Example No. d (0.9) d (0.5) Pump Speed (Varied) Amplitude

Example 2 17.29 4.57 2.0 100%

Example 3 13.25 3.59 3.0 100%

Example 4 10.75 4.17 6.0 100%

Study of the impact of Amplitude on the particle size of candesartan cilexetil:

Example No. d (0.9) d (0.5) Amplitude

Example 5 15.27 4.8 50%

Example 6 12.54 4.46 75%

Example 7 10.75 4.17 100%

Study of the impact of power on the particle size of candesartan cilexetil:

Example No. d (0.9) d (0.5) Power in Watts

Example 8 15.27 4.8 140-150

Example 9 12.54 4.46 160-165

Example 10 10.75 4.17 400-450

CLAIMS:

We Claim:

1. A process for the preparation of candesartan cilexetil having a particle size wherein d (0.9) is about 50 microns or less and d (0.5) is about 6 microns or less, wherein the process comprises:

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

b) subjecting the solution to ultrasound energy;

c) cooling the solution of candesartan cilexetil;

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

2. The process according to claim 1, wherein the particle size of candesartan cilexetil having a d (0.9) is about 10 to 20 microns and d (0.5) is about 6 microns or less.

3. The process according to claim 1, wherein the suitable solvent is selected from alcohols, ketones, water, polar protic solvents or a mixture thereof.

4. The process according to claim 3, wherein the alcohol is methanol, ethanol, isopropanol or a mixture thereof.

5. The process according to claim 3, wherein the ketone is acetone, methyl ethyl ketone, methyl isobutyl ketone or a mixture thereof.

6. The process according to claim 3, wherein the polar protic solvent is water, alcohol or a mixture thereof.

7. The process according to claim 1, wherein the ultrasound energy is the energy which is converted from electrical energy into mechanical oscillations of a sonotrode.

8. The process according to claim 1, wherein the crystallization of candesartan cilexetil is carried out at suitable temperatures for about suitable time in a reaction vessel.

9. The process according to claim 8, wherein the suitable temperature is about 50°C or less and suitable time is about 1-24 hours.

10. The process according to claim 1, wherein the ultrasound crystallization is carried out by horn ultrasonication, ultrasonication bath or a continuous ultrasonication