WO2005123720A1

WO2005123720A1 - Fine particles of the angiotensin ii antagonist candesartan cilexetil and process for production thereof

Info

Publication number: WO2005123720A1
Application number: PCT/IB2005/001713
Authority: WO
Inventors: Yatendra Kumar; Shantanu De; Swargam Sathyanarayana
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-06-18
Filing date: 2005-06-17
Publication date: 2005-12-29

Abstract

The present invention relates to fine particles of angiotensin II antagonist can desartan cilexetil having improved pharmacokinetic profile and processes for production thereof.

Description

FINE PARTICLES OF THE ANGIOTENSIN II ANTAGONIST CANDESARTAN CILEXETIL AND PROCES S FOR PRODUCTION THEREOF

Field of Invention The present invention relates to fine particles of an angiotensin II antagonist having improved pharmacokinetic profile and process for production thereof. Background of Invention (±)- 1 -[[(Cyclohexyloxy)carbonyl]oxy] ethyl 2-ethoxy- 1 -[[2 ^Λ -( lH-tetrazole-5-yl) [1,1'- biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate (candesartan cilexetil) of Formula I is an ester prodrug of 2-ethoxy-l-[[2^,-(lH-tetrazole-5-yl)[l,l'-biphenyl-4-yl]methyl]-lH-0 benzimidazole-7-carboxylic acid (candesartan), known as a potent Angiotensin II receptor antagonist. It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure.

5 FORMULA I 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 (US0 Appl. No. 20040018240; US Appl. No. 20040102502; US Appl. No. 20030198676; US Patent No. 6589547; US Patent No. 6740339, etc.). US Patent No. 5,196,444 suggests that crude candesartan cilexetil isolated by column chromatography, essentially present in amorphous form is stirred in ethanol and filtered to get pure candesartan cilexetil. Alternatively, experimental example 1 of US '444 provides a process for preparation of candesartan cilexetil, which involves crystallization of crude product from lower alkanol or a mixture of lower alkanol or lower ketone and water to get

"Type C" crystals of candesartan cilexetil. The particle size of the pure "Type C" crystals of candesartan cilexetil obtained by following US '444 patent is variable, wherein 90% of the particles are having particle size less than (do.₉) about 70 microns to about 40 microns. Summary of Invention The present inventors have found that by formulating candesartan cilexetil, having do.9 about 70 microns to about 40 microns, in a solid dosage form, the pharmacokinetic profile of the dosage form is not predictable and desired therapeutic effect is not achieved. While working on the problem, the present inventors have found that when particle size of candesartan cilexetil is reduced and the fine particles so produced are used in the formulation of solid dosage form, the pharmacokinetic profile of the dosage form improved significantly and the desired bioavailability profile can be achieved. Detailed Description of Invention In one aspect, the invention provides candesartan cilexetil having a particle size wherein do.₉ is about 25 microns or less. In another aspect, the invention provides candesartan cilexetil having a particle size wherein d₀.₉ is about 25 microns or less and d₀.₅ is about 15 microns or less. In yet another aspect, the present invention provides candesartan cilexetil having a particle size wherein do.₉ is about 25 microns or less, d₀.₅ is about 15 microns or less and drj is about 7 microns or less. In still another aspect, the present invention provides a process for preparation of candesartan cilexetil having a particle size wherein d₀.₉ is about 25 microns or less, wherein the process comprises: a) dissolving candesartan cilexetil in a suitable 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 wherein is do ₉ about 25 microns or less. The starting material used can be in any polymorphic form or present in an amorphous form. The starting material can be completely dissolved in an organic solvent which is characterized by the fact that at ambient or higher temperatures, the solvent has greater solubility for candesartan cilexetil whereas at lower temperatures candesartan cilexetil has significantly reduced solubility in it. Examples of such solvents are lower alkanols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl isobutyl ketone; acetonitrile, tetrahydrofuran or mixtures thereof. The solution obtained is then optionally clarified to remove undissolved solids. The clear solution thus obtained is cooled gradually under stirring to induce crystallization. The stirring rate may play a significant role in achieving the desired particle size and is dependent upon the size of the vessel, quantity of reactants and the type of stirrer used in the process. For example, stirring rates of approximately 250 rpm can produce particles with do.₉ of about 25 microns or less. Stirring rates of approximately 150 rpm can produce particles with do.₉ of about 50 microns or less, and stirring rates of approximately 100 rpm can produce particles having do.₉ of about 75 microns or less. Under large scale production conditions (reactor size 1000 L, stirred at about 50 rpm with an anchor-type agitator), the particle size distribution was do.₉ of about 13 microns and do.₅ of about 4 to 5 microns. The shear generated by anchor-type agitators appears to result in generally lower particle size distributions. After complete crystallization of candesartan cilexetil from the solution, the product is isolated from the reaction mass and dried suitably to get candesartan cilexetil having particle size, wherein do.₉ is about 25 microns or less, for example 15 microns or less, for example 13 microns or less. If "C-type" crystals are used as starting material, it may be dissolved in a suitable second organic solvent characterized by the fact that crystalline candesartan cilexetil is soluble in it. Examples of the second organic solvent are chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and ethylene dichloride; polar aprotic solvents such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylacetamide, N,N- dimethylformamide and dimethylsulphoxide; aromatic hydrocarbons such as toluene, benzene or xylene; esters such as ethyl acetate, isopropyl acetate, ethyl formate, methyl formate, n- propyl acetate and butyl acetate or mixtures thereof. The resultant solution obtained can be concentrated to dryness. The residue so obtained is then dissolved in suitable organic solvents and crystallized by the process mentioned above. Optionally the residue so obtained is treated with a third organic solvent characterized by the fact that candesartan cilexetil is insoluble, sparingly soluble or less soluble in it. The powdered product obtained is isolated by means of filtration and optionally dried. The powder of candesartan cilexetil thus obtained is dissolved in suitable organic solvent and crystallized by the process mentioned above. In yet still another aspect, the present invention a process for preparation of candesartan cilexetil having a particle size wherein do.₉ is about 25 microns or less, and wherein the process comprises micronization of candesartan cilexetil. The micronization can be carried out using any conventionally known process of milling, grinding such as jet milling, media milling, pulverization and the like. In another aspect, the present invention provides a pharmaceutical composition for antagonizing angiotensin II comprising candesartan cilexetil having a particle size wherein do.₉ is about 25 microns or less. In yet a further aspect, the present invention provides a method of antagonizing angiotensin II in mammal which comprises administering to the said mammal a therapeutically effective amount of candesartan cilexetil having a particle size wherein do.₉ is about 25 microns or less. The particle size of candesartan cilexetil in the present invention can be measured by, for example, a Malvern Mastersizer. While the present 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. Example 1 : Preparation of Candesartan Cilexetil Crystalline candesartan cilexetil (300 g, Type C crystals) was dissolved in dichloromethane (300 ml) at 25 to 30°C. The clear solution thus obtained was filtered through a bed of celite. The solvent was recovered under vacuum to get a residue. To this residue was added cyclohexane (2100 ml). The resultant mixture was stirred for 2 hours and then filtered. The wet cake was washed with cyclohexane (300 ml) and then dried. The dried product was dissolved completely in methanol (2700 ml) at 25 to 30°C and stirred for 10 to 15 minutes. The clear solution thus obtained was filtered through a bed of celite. The clear filtrate was cooled to 13 to 17°C and stirred at this temperature for a period of 6 to 8 hours. The reaction mass was filtered, washed with chilled methanol and dried to get title compound in the form of "Type C" crystals, in a yield of 253 g, assayed at 99.2% purity, and with Chromatographic purity by HPLC: 99.516%.

Particle size: Dfv.O.n Dfv.0.5 ,- Dfv.0.9,- Mean 4.20 10.31 23.17

RSD% 0.14 0.16 0.55

Claims

We Claim: 1. Candesartan cilexetil having a particle size wherein do_.9 is about 25 microns or less.

2. Candesartan cilexetil having a particle size wherein do.₉ is about 25 microns or less and d₀.₅ is about 15 microns or less.

3. Candesartan cilexetil having a particle size wherein do.₉ is about 25 microns or less, d₀.₅ is about 15 microns or less and doα is about 7 microns or less.

4. A process for preparation of candesartan cilexetil having a particle size wherein do_.9 is about 25 microns or less, wherein the process comprises: a) completely dissolving candesartan cilexetil in an organic solvent; b) cooling the clear solution obtained in step a) under stirring to crystallize candesartan cilexetil from the solution; and c) isolating candesartan cilexetil having a particle size, wherein do.₉ about 25 microns or less .

5. A process as claimed in claim 4, wherein the organic solvent has greater solubility for candesartan cilexetil at ambient or higher temperatures, and has significantly reduced solubility for candesartan cilexetil at lower temperatures.

6. A process as claimed in claim 5, wherein the organic solvent is selected from methanol, ethanol, isopropanol, acetone, methyl isobutyl ketone, acetonitrile, and tetrahydrofuran.

7. A process for preparation of candesartan cilexetil having particle size, wherein do.₉ about 25 microns or less, wherein the process comprises micronization of candesartan cilexetil.

8. A process as claimed in claim 7, wherein micronization is carried out by grinding, milling, jet milling, media milling or pulverization.

9. A pharmaceutical composition for antagonizing angiotensin II comprising candesartan cilexetil having a particle size wherein do.₉ about 25 microns or less.

10. A method of antagonizing angiotensin II in mammal which comprises administering to the mammal a therapeutically effective amount of candesartan cilexetil having a particle size wherein do.₉ is about 25 microns or less.