KR20090113346A - Tadalafil having a large particle size and a process for preparation thereof - Google Patents

Abstract

The present invention provides particulate tadalafil having a particle size of about 200 to about 600 microns and a process for controlling the particle size of tadalafil.

Description

TADALAFIL HAVING A LARGE PARTICLE SIZE AND A PROCESS FOR PREPARATION THEREOF}

Related Applications

This application discloses US Provisional Application No. 60 / 733,012, filed November 2, 2005; US Provisional Application No. 60 / 748,341, filed December 6, 2005; US Provisional Application No. 60 / 656,664, filed February 25, 2005; US Provisional Application No. 60 / 736,807, filed November 14, 2005; US Provisional Application No. 60 / 737,080, filed November 15, 2005; US Provisional Application No. 60 / 683,058, filed May 19, 2005; And US Provisional Application No. 60 / 677,51, filed May 3, 2005. The contents of these applications are incorporated herein by reference.

Field of invention

The present invention relates to particulate tadalafil having a particle size of about 200 to about 600 microns and a process for preparing the same.

(6R-trans) -6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino [1 'having the formula: , 2 ': 1,6] pyrido [3,4-b] indole-1,4-dione (tadalafil) has an effect on PDE5, a phosphodiesterase enzyme specific for cyclic guanosine monophosphate (cCMP) And selective inhibitors. Inhibiting PDE5 increases the amount of cGMP, relaxes smooth muscle and increases blood flow. Thus, tadalafil is currently used for the treatment of male erectile dysfunction.

The physical properties of the solid state of an active pharmaceutical ingredient (API), such as tadalafil, can be very important for the formulation of a drug and can greatly affect the ease and reproducibility of formulation. For example, particle size can affect the flowability and admixture of the drug. Small particles can also be filtered and washed more slowly during the isolation process, increasing the manufacturing time and cost of the drug formulation.

U.S. Patent 5,859,006 discloses the synthesis of tadalafil. US Pat. No. 6,821,975 discloses the synthesis of tadalafil comprising 90% of particles having a particle size of less than about 40 microns and a pharmaceutical composition comprising tadalafil of this particle size.

There is a need in the art for large particle tadalafil and methods for its preparation.

Summary of the Invention

In one aspect, the present invention provides particulate tadalafil having a particle size of at least 90% by volume of the particles from about 200 to about 600 microns.

In another aspect, the invention

(a) combining tadalafil with a solvent selected from the group consisting of C ₃ -C ₈ ketones, aliphatic nitriles, lower aliphatic alcohols, water and mixtures thereof to obtain a slurry;

(b) heating the slurry of step (a) to about 45 ° C. to about reflux temperature to obtain a clear solution;

(c) combining the solution of step (b) with water to obtain a suspension; And

(d) recovering particulate tadalafil having a particle size of at least 90% of the particles of about 200 to about 600 microns

Provided is a method for producing particulate tadalafil, wherein the particle size is at least about 200 to about 600 microns of particles.

In another aspect, the invention

(a) providing particulate tadalafil having a particle size of at least 90% of the particles from about 200 to about 600 microns; And

(b) grinding the tadalafil of step (a) to obtain a tadalafil having a predetermined particle size;

It includes a, it provides a method for controlling the particle size of the tadalafil.

In another aspect, the present invention provides a pharmaceutical composition comprising, in any of the embodiments of the present invention, a tadalafil prepared according to the method of the present invention and at least one pharmaceutically acceptable excipient, diluent or carrier. do.

In another embodiment, the present invention provides a method of preparing a pharmaceutical formulation comprising mixing a tadalafil prepared according to the method of the present invention with a pharmaceutically acceptable carrier.

Detailed description of the invention

The present invention provides particulate tadalafil having a particle size of at least 90% by volume of the particles from about 200 to about 600 microns.

Large particle size tadalafil as described above can be easily filtered and dried. The larger particle size of tadalafil can produce a final product containing less residual solvent and water.

The present invention provides a process for the preparation of particulate tadalafil having a particle size of at least 90% of the particles from about 200 to about 600 microns. According to the manufacturing method of this invention, the dissolution rate of tadalafil can be controlled. Treatment of the particle size of tadalafil to a particular narrow range also allows for the preparation of pharmaceutical compositions with improved bioavailability of tadalafil and can increase its manufacturing capacity. The tadalafil of the present invention is thus suitable for formulation

"Particulate tadalafil" refers to tadalafil in the form of a powder or granule consisting of individual units of a plurality of discrete particles or agglomerates. Individual particles of the particulate tadalafil of the present invention may be regular or irregular in shape. If the shape of the particles is irregular, the nominal particle size is referred to as the dimension of the so-called equivalent sphere, a concept known in the field of particle size analysis.

Individual particles of a sample or aliquot of the solid particulate tadalafil of the present invention are not uniform in size. Rather, samples or aliquots of the solid particulate tadalafil of the present invention consist of particles of different sizes that can be sized or distributed in an array of discrete particle sizes with adjacent spacing. If the gap size is small enough, the array of particle sizes approaches successive particle sizes. A set of discrete particle size intervals, together with its population, is called a particle size distribution (PSD).

Measurement and characterization of particle size distributions are known in the art. Samples of particulate tadalafil can be compared based on individual points on the cumulative particle size distribution curve. This measurement is expressed as d (0. X ) = Y where X and Y are Arabic numerals, where each “d” represents an individual point on the cumulative PSD curve. The number " X " represents the percentage (number, volume or weight) of particles in a population having a nominal size of "Y" or less. Thus, d (0.9) = 250 μ is a characteristic of PSD where 90% (number, volume or weight) of particles in a population has a nominal size of at least about 250 μ (at least some particles have a nominal dimension of 250 μ). . When PSD is measured by the well known laser diffraction method described herein, the d ( 0.X ) measurement represents the volume average.

One skilled in the art knows that PSD measurement results by one technique may be correlated with results from other techniques based on routine experimental experience.

The process of the present invention for the preparation of particulate tadalafil having a particle size of at least 90% of the particles of about 200 to about 600 microns

(a) combining tadalafil with a solvent selected from the group consisting of C ₃ -C ₈ ketones, nitriles, lower aliphatic alcohols, water and mixtures thereof to obtain a slurry;

(b) heating the slurry of step (a) to about 45 ° C. to about reflux temperature to obtain a clear solution;

(c) combining the solution of step b) with water to obtain a suspension; And

(d) recovering particulate tadalafil having a particle size of at least 90% of the particles of about 200 to about 600 microns

It includes.

Tadalafil suitable for use in step (a) is selected from the group consisting of alkyl esters of aromatic hydrocarbons, lower aliphatic alcohols and lower carboxylic acids, as disclosed in co-pending U.S. application number (patent attorney no. 1662/85204). Combining a solution of TDCl in a selected solvent with methylamine to obtain a reaction mixture, and heating the reaction mixture at about 20 ° C. or less to about reflux for about 1 to about 48 hours above the reflux temperature of the solvent. Can be. Alternatively, tadalafil can be obtained by any other means known to those skilled in the art.

C ₃ -C ₈ ketones useful as solvents in step (a) include acetone, methylisobutyl ketone (MIBK) and methylethyl ketone (MEK).

The term "nitrile" refers to a compound of the formula R-CN, wherein R represents a C ₁ -C ₆ alkyl group, preferably a C ₁ -C ₃ alkyl group. Particularly preferred nitrile solvents are acetonitrile.

The term "lower aliphatic alcohol" as used herein refers to an organic compound of the formula R-OH, wherein R is a straight or branched C ₁ -C ₆ alkyl group. Preferred lower aliphatic alcohols for use in the process of the invention include methanol, ethanol, isopropanol and butanol.

Preferred solvents in step (a) include acetone and a mixture of C ₃ -C ₈ ketones or nitriles with water or lower aliphatic alcohols. More preferably, the solvent in step (a) is a mixture of at least one C ₃ -C ₈ ketone and water, most preferably the solvent is a mixture of acetone and water. The ratio of C ₃ -C ₈ ketone or nitrile to water or lower aliphatic alcohol used in step (a) is from about 2: 1 to about 10: 1.

Preferably, the slurry of step (a) comprises about 2.5 to about 4.5 volume percent tadalafil. Preferably, the slurry is heated to a temperature of about 45 to about 100 ° C, more preferably about 45 to 60 ° C to obtain a clear solution. The solution preferably does not contain undissolved tadalafil.

The solution obtained in step (b) can be filtered if necessary to remove foreign substances such as dust and activated carbon while maintaining the filtered solution and filtrate at about the same temperature. When the solution is filtered, the temperature is preferably maintained at a temperature at which the tadalafil remains dissolved in the solution to be filtered. Preferably, the temperature is maintained at about 45 to about 60 ° C.

The solution of step (b) is preferably cooled to a temperature of about 60 to about 30 ° C. before combining the solution and water.

The solution is combined with an amount of water equivalent to about 1 to about 3 times the volume of the solvent used in step (a). The amount of water used is preferably about 2 times the volume of the solvent used in step (a).

The way the solution and water are combined affects the size of the crystal nuclei formed. While combining the solution and water, a substantially constant temperature is maintained to prevent or quickly disperse localized high levels of tadalafil. In this way, we can best control the particle size of the resulting tadalafil. Thus, the solvent and water are combined in small aliquots or in portions. Preferably, it is combined in a dropwise manner, for example by adding water to the solution dropwise. The solution and water may be combined for about 30 minutes to about 15 hours, more preferably over a period of 1 to about 5 hours. Most preferably, the solution and water are combined over a period of about 3.5 to about 4 hours.

Particulate tadalafil having a particle size of about 200 to about 600 microns of at least 90% of the particles can be recovered from the suspension by methods known in the art. For example, the suspension can be cooled to about 50 to about 20 ° C. over about 30 minutes to about 24 hours, preferably about 3.5 hours. The suspension can then be filtered, preferably by centrifugation, and optionally washed with water.

Optionally, seeding the hot solution with tadalafil may be carried out after step (b).

When the suspension obtained in step (c) is heated to about 45 ° C. to about reflux temperature, the larger sized tadalafil particles remain undissolved while the smaller sized tadalafil is dissolved. Cooling the suspension then leads to crystallization of the new tadalafil with a larger particle size above the existing tadalafil precipitate. Preferably, the suspension is cooled for about 1 to about 6.5 hours, more preferably about 4 to about 5 hours.

Thus, prior to recovering the tadalafil in step (d), the suspension obtained in step (c) can optionally be heated and then cooled repeatedly until the desired particle size is obtained.

The process of the invention can be carried out on an industrial scale.

Large particle tadalafil, such as about 200 to about 600 microns, can be ground into smaller particle sized tadalafil in a grinding process that is adapted to a desired particle size. Therefore, in the grinding step, the particle size of the obtained tadalafil is controlled. For example, the grinding can be performed by a cone mill operating by grinding the particles using an impeller rotating in a conical perforated screen. There is a narrow gap of about 0.025 "between the impeller and the screen. The material to be ground is fed to the grinder by manual feed, by mechanical feeders (such as screw feeders or vibrating feeders) or by air transport. The rotating impeller strikes and wears between the screen and the impeller The ground particles are discharged from the grinder through the drilled holes and collected in a closed container attached to the grinder outlet or transported to the collector by vacuum. Can be controlled by changing the rotational speed of the impeller, selecting screens with different pore sizes, or using different types of impellers.

The present invention

(a) providing particulate tadalafil having a particle size of at least 90% of the particles from about 200 to about 600 microns; And

(b) milling the tadalafil of step (a) to obtain a tadalafil having a predetermined particle size of about 40 to 100 microns

It provides a method for obtaining a tadalafil having a predetermined particle size, by controlling the particle size of the tadalafil, including.

The invention also

(a) combining tadalafil with a solvent selected from the group consisting of C ₃ -C ₈ ketones, nitriles, lower aliphatic alcohols, water and mixtures thereof to obtain a slurry;

(b) heating the slurry of step (a) to about 45 ° C. to about reflux temperature to obtain a clear solution;

(c) combining the solution of step (b) with water to obtain a suspension;

(d) recovering particulate tadalafil having a particle size of at least 90% of the particles of about 200 to about 600 microns; And

(e) milling the tadalafil of step (d) to obtain a tadalafil having a predetermined particle size of about 40 to 100 microns

It provides a method of obtaining a tadalafil having a predetermined particle size, by controlling the particle size of the tadalafil, including.

The present invention provides a pharmaceutical composition comprising particulate tadalafil prepared according to the method of the invention and one or more pharmaceutically acceptable excipients, diluents or carriers.

The present invention also encompasses a process for the manufacture of a pharmaceutical formulation comprising combining tadalafil and a pharmaceutically acceptable excipient. The term "pharmaceutical formulation" as used herein includes tablets, pills, powders, liquids, suspensions, solutions, emulsions, granules, capsules, suppositories or infusion formulations.

The term "pharmaceutical composition" as used herein includes tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or infusion formulations. Pharmaceutical compositions containing tadalafil of the present invention may be prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, surface active agents and lubricants. Various dosage forms of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, such as, for example, tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or infusion preparations.

Any excipient commonly known and widely used in the art can be used in the pharmaceutical composition. Carriers used include lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid. Binders used include water, ethanol, propanol, sweet syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone. Disintegrants used include dried starch, sodium alginate, agar powder, laminalia powder, sodium hydrogencarbonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium lauryl sulfate, monoglycerides of stearic acid , Starch and lactose. Disintegration inhibitors used include white sugar, stearin, coconut butter and hydrogenated oils. Absorption accelerators used include quaternary ammonium bases and sodium laurylsulfate. Wetting agents used include glycerin and starch. Absorbers used include starch, lactose, kaolin, bentonite and colloidal silicic acid. Lubricants used include purified talc, stearates, boric acid powders and polyethylene glycols. Tablets may be further coated with commonly known coating materials such as sugar coated tablets, gelatin membrane coated tablets, enteric coated tablets, membrane coated tablets, bilayer tablets and multilayer tablets.

When molding the pharmaceutical composition in pill form, any commonly known excipients used in the art can be used. For example, carriers include lactose, starch, coconut butter, hard vegetable oils, kaolin and talc. Binders used include gum arabic, tragacanth powder, gelatin, ethanol. Disintegrants used include agar and laminalia.

For the purpose of shaping the pharmaceutical composition in the form of suppositories, any commonly known excipients used in the art can be used. For example, excipients include polyethylene glycol, coconut butter, higher alcohols, esters of higher alcohols, gelatin and semisynthesized glycerides.

When preparing injectable pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic with blood. Infusion formulations may use a carrier commonly known in the art. For example, carriers for injectable preparations include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyoxyethylene sorbitan. One skilled in the art can readily determine the amount of sodium chloride, glucose or glycerin required to render the injectable formulation isotonic, with little or no experimentation.

Additional ingredients such as solubilizers, buffers and analgesics can be added. If desired, colorants, preservatives, flavors, seasonings, sweeteners, and other agents may also be added to the desired formulations.

The amount of tadalafil or salt thereof contained in the pharmaceutical composition should be sufficient to treat, alleviate or reduce the symptoms associated with male erectile dysfunction. Preferably, tadalafil is present at a dosage of about 1 to about 70 weight percent, more preferably about 1 to about 30 weight percent.

The pharmaceutical composition of the present invention can be administered in various ways depending on the age, sex and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules can be administered orally. Infusion formulations may be administered intravenously, either individually or in admixture with infusion fluids such as glucose and amino acid solutions. If necessary, infusion preparations can be administered intramuscularly, intradermal, subcutaneous or intraperitoneally. Suppositories can be administered rectally.

The dosage of the pharmaceutical composition for treating schizophrenia according to the present invention may vary depending on the method of use, the age, sex and condition of the patient. Preferably, tadalafil is administered in an amount of about 0.1 to about 10 mg / kg body weight / day. More preferably, about 1 to 200 mg of tadalafil may be contained in the dosage.

While the invention is illustrated in certain embodiments, it is not intended to limit the invention.

The particle size of the tadalafil described herein was measured by Malvern laser diffraction using a Mastersizer S instrument. The measuring instrument was equipped with a small cell dispersion unit MS1 equipped with a digital dispersion unit controller. Measurements were performed using lens 300RF (operating range 0.05-900 mcm), beam length: 2.40 mm, presentation 3 $$ D (Franhofer), sweep number 4000, and speed 2300 ± 10 rmp. The dilution medium was 0.1% w / v Span 80 in saturated solution of tadalafil in cyclohexane. The powder was added directly to the measurement cell filled with dilution medium, then recycled and measurement started 10 seconds later. In accordance with the recognized rules of Good Manufacturing Procedures, samples of tadalafil were measured after a successful blank measurement (% obscuration NMT 0.1%).

Example  1: Crystallization of the Industrial Scale of Tadalafil

A 100 l GL reactor with a mechanical stirrer, condenser and thermometer was charged with crude tadalafil (4 kg, calculated on a dry basis), acetone (80 l) and processed water (24 l) to obtain a slurry. The slurry was heated to reflux to obtain a clear solution. The clear solution was then passed through mechanical filters (5, 1 and 0.2 microns) and the filtrate was transferred to a clean 160 l GL reactor. Optionally, the filtrate was reheated to reflux and cooled to 50 ° C. Processed water (48 1) was then added to the hot filtrate over 3.5 hours to obtain a suspension that could be seeded to induce precipitation. The suspension obtained was filtered with a centrifugal wand.

Alternatively, after the addition of water, the suspension was heated to 50-65 ° C. and then cooled to 45 ° C. and stirred at this temperature for 1 hour. The suspension was then reheated to 65 ° C. and cooled again to 20-50 ° C. over 3.5 hours. The obtained precipitate was filtered through a centrifugal rod and washed with water. Final dry material-2.7 kg, particle size, d (0.9)> 60 to 500 microns (d (0.9) is greater than 60 microns and less than about 500 microns).

Example  2: crystallization of tadalafil

A 10 l GL reactor equipped with a mechanical stirrer, condenser and thermometer was charged with crude tadalafil (250 g, calculated on a dry basis), acetone (6 l) and processed water (1.5 l) to obtain a slurry. The slurry was heated to reflux to obtain a clear solution. The solution was then cooled to 50 ° C. Processed water (37.5 l) was added to the solution at 2.5C over 2.5 hours to obtain a suspension, which was stirred for 1 hour. The suspension was filtered through a centrifuge rod.

Alternatively, after adding water, the suspension was heated to 50-65 ° C. and then cooled to 45 ° C. The suspension was stirred at this temperature for about 1 hour and then reheated to 65 ° C. The mixture was then cooled to about 20 ° C. over 1 hour, filtered through a vacuum filter and washed with processed water. Final dry material-215 g (dry), particle size, d (0.9)> about 60 microns [d (0.9)> 60 to 500 microns).

Example  3: Granular  Control

10 mg of tadalafil sample with particle size d (0.9) = 584 micron was ground using a micromill (50 mm, 40 bar feed air and 3.0 bar mill air). The resulting tadalafil particle size d (0.9) = about 228.7 microns.

Example  4: Granular  Control

10 mg of tadalafil sample with particle size d (0.9) = 584 micron was ground using a micromill (50 mm, 2.0 bar feed air and 1.0 bar grind air). The particle size d (0.9) of the resulting tadalafil was about 105.8 microns.

Example  5: Granular  Control

0.9 kg of tadalafil sample with particle size d (0.9) = 538.6 micron was ground using a Pin-Mill at a feed rate of 9.6 kg / hour and a grinding speed of 12,000 rpm. The resulting tadalafil particle size d (0.9) = about 52.4 microns.

Example  6: Granular  Control

0.9 kg of tadalafil sample with particle size d (0.9) = 553.5 microns were ground using a pin mill at a feed rate of 9.6 kg / hour and a grinding speed of 4500 rpm. The resulting tadalafil particle size d (0.9) = about 202.7 microns.

Claims (27)

a) combining tadalafil with a solvent selected from the group consisting of C ₃ -C ₈ ketones, nitriles, C ₁ -C ₆ alcohols, water and mixtures thereof to obtain a slurry; b) heating the slurry of step a) to 45 ° C. to reflux temperature to obtain a clear solution; c) combining water in the solution of step b) in a portion-wise manner to obtain a suspension; And d) recovering the tadalafil A method for producing particulate tadalafil comprising at least 90% of the particles having a particle size of 200 to 600 microns. The process of claim 1 wherein the solvent is selected from the group consisting of acetone, methylisobutyl ketone, methylethyl ketone, acetonitrile, methanol, ethanol, isopropanol, butanol, water and mixtures thereof. The process of claim 1 wherein the solvent is a mixture of C ₃ -C ₈ ketones or nitriles with water or C ₁ -C ₆ alcohols. The method of claim 3, wherein the C ₃ -C ₈ ketone or nitrile is present in the mixture in a ratio of 2: 1 to 10: 1 relative to water or C ₁ -C ₆ alcohol. The solvent of claim 1, wherein the solvent is at least one C ₃ -C _8. A mixture of ketone and water. The method of claim 5 wherein the solvent is a mixture of acetone and water. The process according to any one of claims 1 to 4, wherein the slurry obtained in step a) contains 2.5 to 4.5% by volume of tadalafil. The process according to claim 1, wherein the slurry obtained in step a) is heated to a temperature between 45 ° C. and 100 ° C. 6. The method of claim 8, wherein the slurry obtained in step a) is heated to a temperature between 45 ° C. and 65 ° C. 10. The method of claim 1, wherein the solution of step b) is cooled to a temperature of 30 ° C. to 60 ° C. before combining with water. The method of claim 1, wherein the solution and water are combined by adding water to the solution in a dropwise manner. The method of claim 1 wherein the solution is combined with an amount of water equivalent to 1 to 3 times the volume of the solvent used in step a). The method of claim 12, wherein the solution is combined with an amount of water equivalent to twice the volume of the solvent used in step a). The method of claim 1, wherein the solution and water are combined over a period of 30 minutes to 15 hours. The method of claim 14, wherein the solution and water are combined over a period of 1 to 5 hours. The method of claim 15, wherein the solution and water are combined over a period of 3.5 to 4 hours. The method of claim 10 further comprising repeating the heating and cooling steps one or more times prior to recovery of the tadalafil. The method of claim 17, wherein the suspension is cooled for 1 to 6.5 hours. The method of claim 18, wherein the suspension is cooled for 4 to 5 hours. The method of claim 1, wherein the solution obtained in step b) is seeded with tadalafil. a) combining tadalafil with a solvent selected from the group consisting of C ₃ -C ₈ ketones, nitriles, C ₁ -C ₆ alcohols, water and mixtures thereof to obtain a slurry; b) heating the slurry of step a) to 45 ° C. to reflux temperature to obtain a clear solution; c) combining water in the solution of step b) in a portion-wise manner to obtain a suspension; d) recovering particulate tadalafil having a particle size of at least 90% of the particles between 200 and 600 microns; And e) grinding the tadalafil of step d) to obtain a tadalafil having a predetermined particle size of 40 to 100 microns. A method for obtaining a tadalafil having a predetermined particle size by controlling the particle size of the tadalafil, including. The process of claim 6, wherein the slurry obtained in step a) contains 2.5 to 4.5 volume percent tadalafil. The process of claim 6, wherein the slurry obtained in step a) is heated to a temperature between 45 ° C. and 100 ° C. 8. The method of claim 22, wherein the slurry obtained in step a) is heated to a temperature of 45 to 100 ° C. The method of claim 21, wherein the grinding is performed by a corn mill. The method of claim 25, wherein the particle size of the product is controlled by one or more of a change in rotational speed of the impeller, selection of screens with different pore sizes, or use of different types of impellers. The method of claim 26, wherein the particle size of the product is controlled by selection of screens with different pore sizes.