WO2013041944A1

WO2013041944A1 - Process for the preparation of micronized candesartan cilexetil

Info

Publication number: WO2013041944A1
Application number: PCT/IB2012/001830
Authority: WO
Inventors: Vaibhav Gupta; Anshul Agrawal; Raghvendra Prasad
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2011-09-19
Filing date: 2012-09-19
Publication date: 2013-03-28

Abstract

Provided herein are processes for the preparation of stable micronized candesartan cilexetil Form-I (C-type crystals), its' pharmaceutical compositions and method of use.

Description

PROCESS FOR THE PREPARATION OF MICRONIZED CANDESARTAN

CILEXETIL

Field of the Invention

Provided herein are processes for the preparation of stable micronized candesartan cilexetil Form-I (C-type crystals), its pharmaceutical compositions and method of use.

Background of the Invention

Candesartan cilexetil of Formula I, disclosed in U.S. Patent No. 5,196,444 as crystalline form, i.e., Form-I (C-type crystals), is chemically described as 1- cyclohexyloxycarbonyloxyethyl 2-ethoxy-3-[[4-[2-(2H-tetrazol-5- yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate.

H

Formula I

It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure.

Candesartan cilexetil is poorly soluble in water, which is attributed to its hydrophobic nature.

Solubility plays an important role in achieving the desired concentration of a drug in systemic circulation for accomplishing the pharmacological response. Various techniques are known in literature to increase the solubility of poorly-soluble drugs, including decreasing the particle size, complexation, changing the surface characteristics of the particles, and incorporation of drug particles into colloidal systems like nanoparticles and liposomes. Among these, the most commonly used technique to increase the solubility is particle size reduction. Sometimes the rate of dissolution of a poorly-soluble drug is the rate limiting factor in its rate of absorption by the body. These drugs may be more readily bioavailable if administered in a finely divided state. Particle size reduction increases the surface area causing an increase in the dissolution rate of the compound, and hence, its bioavailability.

There are certain techniques reported in literature to reduce the particle size of such poorly-soluble drugs.

PCT Publication No. WO 2006/122254 discloses stable candesartan cilexetil of fine particle size, wherein the stable micronized candesartan cilexetil is prepared by slurrying a sample of candesartan cilexetil of fine particle size in a suitable solvent for a suitable amount of time. In this application, candesartan cilexetil of fine particle size is obtained directly from the synthesis of candesartan cilexetil or by comminuting candesartan cilexetil using milling.

PCT Publication No. WO 2005/123720 describes fine particles of candesartan cilexetil having improved pharmacokinetic profile and a process for their production, wherein fine particle size is obtained by a) dissolving candesartan cilexetil in an organic solvent; b) cooling the solution obtained in step a) under stirring to crystallize candesartan cilexetil from the solution; and c) isolating candesartan cilexetil having a particle size of with d₉₀ not more than about 25 μ.

U.S. Patent Application No. 2006/0165806 describes compositions comprising a candesartan, such as candesartan cilexitil. The candesartan particles of the composition have an effective average particle size of less than about 2000 nm.

U.S. Patent Application No. 2008/0038359 describes a nanoparticle

pharmaceutical formulation comprising a poorly soluble drug substance having an average particle size of less than about 1000 nm, a solid or semisolid dispersion vehicle, and optionally a non-surface modifying excipient.

U.S. Patent No. 7,828,996 discloses the methods for forming nanoparticles of a material of narrow polydispersity with ultrasonic waves using a partially submersed sonicator that does not touch any part of the apparatus and the point of addition of organic solvent is in the wave funnel produced by sonication and within the selected distance from the wave-source depending on the desired particle size. U.S. Patent No. 7,780,989 discloses the preparation of a dispersion of

nanocrystalline particles in an aqueous medium using ultrasound.

U.S. Patent No. 5,314,506 describes a crystallization process in which a jet of a solution containing a substance is impinged with a second jet containing an anti-solvent for the substance. The rapid mixing produced by the impinging jets results in a reduction of the crystals so formed compared to conventional slow crystallization processes. The smallest crystals disclosed are about 3 μ and the majority are in the range of from about 3 μ to about 20 μ.

PCT Publication No. WO 00/44468 describes a modification to the apparatus described in U.S. Patent No. 5,314,506, wherein ultrasound energy is applied at the point of impingement of the two jets to further enhance localized mixing and is stated to give direct formation of small crystals with a diameter of less than 1 μ. Generally, the crystalline particles described have an average size of 0.5 μ.

Conventional particle size reduction methods such as high energy milling may result in loss of yield, noise and dusting, as well as unwanted exposure to highly potent pharmaceutical compounds. Also, in the case of crystalline compounds, stress generated on crystal surfaces during milling can adversely affect labile compounds. Therefore, there is a need for a process for particle size reduction of candesartan cilexetil, which is industrially advantageous, easy to handle and is cost effective.

Summary of the Invention

Provided herein are processes for the preparation of stable micronized candesartan cilexetil Form-I (C-type crystals).

Also provided herein is a pharmaceutical composition for antagonizing an angiotensin II receptor comprising stable micronized candesartan cilexetil Form-I (C-type crystals).

Also provided herein is a method of antagonizing an angiotensin II receptor in mammals which comprises administering to the said mammal a therapeutically effective amount of stable micronized candesartan cilexetil Form-I (C-type crystals).

Detailed Description of the Invention Provided herein is stable micronized candesartan cilexetil Form-I (C-type crystals), processes for its preparation, pharmaceutical compositions and its method of use.

The micronization of candesartan cilexetil described herein is achieved by means of ultrasonic waves. The method is advantageous as it totally eliminates the need additional size reduction operations. Also, there is no powder/active pharmaceutical ingredient (API) loss and the possibility of dust explosion as observed during milling operations to reduce particle size is eliminated. Sonication promotes nuclei generation in a controlled and reproducible way, therefore there is better batch to batch consistency. Parameters, for example sonication frequency and amplitude, are easy to control and can be tuned as per particle size requirement. Ultrasonic waves do not allow agglomerates to form as observed during conventional crystallization process. Accordingly, sonication is a safe process that allows easy scale up based on constant power per unit volume.

The present inventors have observed that the reduction of particle size using milling has an adverse effect on the stability of candesartan cilexetil Form-I (type-C crystals). Especially, the content of o-desethyl candesartan cilexetil (o-desethyl impurity) of Formula II increases at a rapid rate when the sample of candesartan cilexetil Form-I (type-C crystals) is kept for stability studies. It may be attributed to the stress exposure of API during milling operations.

Formula II

Micronized candesartan cilexetil Form-I (type-C crystals) obtained by following the process described herein is stable in nature. The content of o-desethyl candesartan cilexetil of Formula II in candesartan cilexetil Form-I (type-C crystals) prepared by the process described herein is quite low when compared to that prepared by milling process, when kept for stability studies for 3 months.

Accordingly, in one aspect is provided a process for the preparation of candesartan cilexetil of reduced particle size of d (0.9) about 5 μ or less, d (0.5) about 3 μ or less and d (0.1) about 2 μ or less, comprising:

a) dissolving candesartan cilexetil in one or more organic solvents;

b) adding anti-solvent;

c) sonicating the reaction mixture of step b);

d) isolating candesartan cilexetil of reduced particle size of d (0.9) about 5 μ or less, d (0.5) about 3 μ or less and d (0.1) about 2 μ or less.

In another aspect, the process may further comprise:

a) slurrying candesartan cilexetil of reduced particle size of d (0.9) about 5 μ or less, d (0.5) about 3 μ or less and d (0.1) about 2 μ or less in C1 -C4 alcohol; b) isolating stable micronized candesartan cilexetil Form-I (type-C crystals).

In another aspect is provided a process for the preparation of stable micronized candesartan cilexetil Form-I (type-C crystals), comprising:

a) slurrying candesartan cilexetil in C1-C₄ alcohol;

b) sonicating the reaction mixture of step a);

c) isolating stable micronized candesartan cilexetil Form-I (type-C crystals).

The starting candesartan cilexetil used herein can be prepared by following any process reported in the prior art, for example, U.S. Patent No. 5,196,444. It can be in any polymorphic form or can be in an amorphous form. The starting material can be completely dissolved in the organic solvent. Examples of organic solvents can be ketones such as acetone or methyl isobutyl ketone, water, acetonitril, tetrahydrofuran, or mixtures thereof. The anti-solvent can be water. The C1-C4 alcohol can be selected from methanol, ethanol, n-propanol, isopropanol, butanol or mixtures thereof.

As used herein, the term "micronized" refers to the particle size of d (0.9) 7 μ to 13 μ, d (0.5) 3 μ to 5 μ and d (0.1) 1 μ to 2 μ. As used herein, the term "stable" in reference to candesartan cilexetil Form-I (type- C crystals) refers to candesartan cilexetil Form-I (type-C crystals) having o-desethyl impurity not more than 0.08%, when measured at t=0 to t=90 days.

As used herein, the term "isolating" refers to a process of obtaining candesartan cilexetil by means of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, centrifugation, recrystallization or a combination thereof.

As used herein, the term "slurrying" refers to suspending candesartan cilexetil in an organic solvent.

As used herein, the term "about" refers to a variation of 10% from the indicated values, or in case of a range of values, means a 10% variation from both the lower and upper limits of such ranges.

Ultrasonic waves can be generated in the reaction mass by immersing an ultrasound probe or horn (direct sonication). These waves can also be generated by introducing the reaction mass container into a bath containing a liquid through which ultrasonic waves are propagated (indirect sonication). Indirect sonication can also be carried out by using flow cells for processing larger sample volumes where the liquid is pumped into the reactor made of glass or stainless steel and then exposed to the defined degree of sonication before it reaches the exit of the reactor cell. In order to cool heat- sensitive material during sonication, the flow cells can be jacketed to improve heat dissipation.

Various sonication parameters such as sonication amplitude, energy input per unit volume of reaction mass, time/duration of sonication, and point of sonication can also have an impact on particle size reduction. Generally, as the amplitude increases, total energy per unit volume increases. Sonication can be carried out to generate nuclei which can be grown by ageing the solution for a predetermined time to get the desired particle size. Sonication can be continued for varying lengths of time to avoid agglomeration, if taking place.

The sonication amplitude of the sonicator used herein is about 20% to about 50%.

Frequency of the sonication, used herein, is about 20 KHz to about 1 MHz and temperature used is about 5°C to about 40°C. Mode of sonication, used herein, is batch or flow mode in continuous or pulse mode and the duration of the sonication is about 3 minutes to about 8 hours.

Stability testing in the present invention was carried out using triple pouch packing i.e., inner pouch (low-density polyethylene (LDPE) twisted and tied), middle pouch (polyester/LDPE heat sealed) and outer pouch (polyester film/aluminium foil/LDPE heat sealed). Stability testing of the milled API was carried out at various temperature and relative humidity (RH) conditions, for example, at 40±2°C, 75±5% RH and 25±2°C, 60±5% RH. Also, the effects of silica and oxygen (0₂) absorber were evaluated on the milled batch. The study showed that o-desethyl impurity increases with time at all of the temperature and humidity conditions and there is no improvement with respect to rate of formation of o-desethyl impurity even with the use of silica and 0₂ absorber. Stability testing for sonicated batches was carried out at 40±2°C, 75±5% RH and it was observed that the amount of o-desethyl impurity does not increase significantly over a period of time, even without using silica or 0₂ absorber. The results are shown in Table 1.

In another aspect provided herein is a pharmaceutical composition for antagonizing an angiotensin II receptor comprising stable micronized candesartan cilexetil Form-I (type-C crystals).

In yet another aspect provided herein is a method of antagonizing an angiotensin II receptor in mammals, which comprises administering to the said mammal a

therapeutically effective amount of stable micronized candesartan cilexetil Form-I (type-C crystals).

Brief Description of the Drawings

Figure 1 : XRD of stable micronized candesartan cilexetil Form-I (type-C crystals) as obtained by following the process as described in Example 2.

Figure 2: XRD of stable micronized candesartan cilexetil Form-I (type-C crystals) as obtained by following the process as described in Example 3.

Figure 3: DSC of stable micronized candesartan cilexetil Form-I (type-C crystals) as obtained by following the process as described in Example 2.

Figure 4: DSC of stable micronized candesartan cilexetil Form-I (type-C crystals) as obtained by following the process as described in Example 3. While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Instrument Details

VCX 500 sonicator with net power output 500 watts, dimensions 235 x 190 x 340 mm, Model CV 33, piezoelectric lead zirconate titanate crystals (PZT) was used having a probe of tip diameter 13 mm, length 136 mm and weight 340 gm. The particle size of candesartan cilexetil can be measured by, for example, a Malvern Mastesizer.

Example 1 : Preparation of Candesartan Cilexetil of Reduced Particle Size

Crude candesartan cilexetil (10 gm) was dissolved in acetone (90 mL) and the resulting solution was stirred for 15 minutes to 20 minutes at 35°C to 40°C to obtain a clear solution. The solution was filtered to remove any foreign particles and the bed was washed with acetone (10 mL). The filtrate was then collected and DI water (43 mL) was added to it over a period of 45 minutes to 60 minutes. A sonication probe was added to the reaction mass. The reaction mass was cooled to about 2°C to 8°C and stirred for about 3 hours to 5 hours under sonication. The reaction mass was filtered, washed with acetone- water mixture and then dried under vacuum to obtain candesartan cilexetil of reduced particle size (8.4 gm)

Purity by HPLC: 99.19%

Particle size by Malvern (in μ):

Example 2: Preparation of Stable Micronized Candesartan Cilexetil Form-I (C-Type Crystals)

Candesartan cilexetil of reduced particle size (5.0 gm) (from Example 1) was slurried in methanol (45 mL). This solution was heated to a temperature of 30°C to 40°C and stirred for 1 hour to 1.5 hours. The reaction mass was cooled to 13°C to 17°C and further stirred for 6 hours to 8 hours at the same temperature. The reaction mass was filtered and the solid thus obtained was washed with prechilled methanol and dried under vacuum to obtain stable micronized candesartan cilexetil Form-I (C-type crystals) (4.0 gm).

Purity by HPLC: 99.50%

Particle size by Malvern (in μ):

Example 3: Preparation of Stable Micronized Candesartan Cilexetil Form-I (C-Type Crystals) from Crude Candesartan Cilexetil

Crude candesartan cilexetil (5.0 gm) was slurried in methanol (45 mL). The mixture was heated to a temperature of 30°C to 40°C and stirred for about 1 hour to 1.5 hours. The reaction mass was cooled to 13°C to 17°C. A sonication probe was added to this reaction mass and it was sonicated for about 5 hours at 13°C to 17°C. The reaction mass was filtered at the same temperature and the solid was washed with prechilled methanol (2.0 mL). The obtained product was dried at 35°C to 40°C under vacuum (3.9 gm).

Purity by HPLC: 99.45%

Particle size by Malvern (in μ):

D(0.9) D(0.5) D(0.1)

9.56 4.17 1.87 Table 1: Stability data of milled batch (without adsorbent and with silica and 0₂ absorber) vs batches of candesartan cilexetil as prepared by Example 2 and Example 3

Claims

We Claim:

1. A process for the preparation of candesartan cilexetil of reduced particle size of d (0.9) about 5 μ or less, d (0.5) about 3 μ or less and d (0.1) about 2 μ or less, comprising: a) dissolving candesartan cilexetil in one or more organic solvents;

b) adding anti solvent;

c) sonicating the reaction mixture of step b);

2. The process according to claim 1, further comprising:

a) slurrying candesartan cilexetil of reduced particle size of d (0.9) about 5 μ or less, d (0.5) about 3 μ or less and d (0.1) about 2 μ or less in Ci-C₄ alcohol; b) isolating stable micronized candesartan cilexetil Form-I (type-C crystals).

3. A process for the preparation of stable micronized candesartan cilexetil Form-I (type-C crystals), comprising:

a) slurrying candesartan cilexetil in Ci-C₄ alcohol;

b) sonicating the reaction mixture of step a);

c) isolating stable micronized candesartan cilexetil Form-I (type-C crystals).

4. The process according to claim 1, wherein the organic solvent is selected from ketone, water, acetonitrile, tetrahydrofuran or a mixture thereof.

5. The process according to claim 4, wherein the ketone is acetone or methyl isobutyl ketone.

6. The process according to claim 1, wherein the anti-solvent is water.

7. The process according to claims 2 or 3, wherein the C1-C4 alcohol is selected from methanol, ethanol, n-propanol, isopropanol, butanol or a mixture thereof.

8. A pharmaceutical composition for antagonizing an angiotensin II receptor comprising stable micronized candesartan cilexetil Form-I (C-type crystals).

9. A method of antagonizing an angiotensin II receptor in mammals, wh ich comprises adm inistering to the said mammal a therapeutical ly effective amount of stable micronized candesartan cilexetil Fonn-I (C-type crystals)