MX2007002609A - Purification of montelukast - Google Patents

Abstract

The present invention provides methods of purifying montelukast, a new isolated impurity of montelukast of formula I, method for its isolation, and method of using montelukast impurity as a reference marker and a reference standard.

Description

PURIFICATION OF MONTELUKAST FIELD OF THE INVENTION The present invention relates to methods for obtaining pure montelukast sodium and an isolated impurity of montelukast.

BACKGROUND OF THE INVENTION Montelukast is a selective orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene receptor CysLTi. Leukotrienes are associated with inflammation and constriction of airway muscles and the accumulation of fluids in the lungs. Montelukast sodium is an effective therapeutic agent for the treatment of respiratory diseases such as asthma and allergic rhinitis.

The chemical name for montelukast sodium is: acid [R- (E)] -1- t [[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2 - (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid, monosodium salt. Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in methanol, ethanol, and water and practically insoluble in acetonitrile.

The sodium salt of montelukast is represented by the structure: U.S. Patent No. 5,565,473 discloses a synthetic process for preparing montelukast sodium, characterized in that the compound is obtained as an oil which is then dissolved in water and lyophilized.

The amorphous form of montelukast sodium is disclosed in U.S. Patent No. 6,320,052 and WO 03/066598. The '052 patent discloses that the amorphous form is "not ideal for the pharmaceutical formulation" Col.l, lines 64-67. The '052 patent further discloses that the processes available to crystallize montelukast sodium are "not particularly suitable for large scale production" due to the "tedious chromatographic purification" technique required and because the "product yield is low". Col 1, lines 61-64. The '052 patent discloses that in any available process, the free acids are "directly converted into the corresponding sodium salts" Col 1, lines 58-61. The '052 patent also reveals a crystalline form of sodium of montelukast prepared from a solution of toluene and water and then acetonitrile (ACN) with seeding. See example 8. Seeding is the use of a small amount of crystalline montelukast to induce crystallization in a larger sample.

U.S. Patent Nos. 5,614,632 disclose a process for preparing montelukast sodium salt by dicyclohexylamine salt.

Like any synthetic compound, montelukast may contain foreign compounds or impurities that may come from different sources. They may be non-reactive starting materials, byproducts of the reaction, by-products of side reactions, or degradation products. Impurities in montelukast or in any other active pharmaceutical ingredient (API) are undesirable and, in extreme cases, could be detrimental to the patient treated with a dose containing the API.

It is also known in the art that impurities in an API can arise from the degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including chemical synthesis. The Process impurities include non-reactive initial materials, chemical derivatives of impurities in the initial materials, synthetic by-products and degradation products.

In addition to the stability, which is a factor in API life, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for manufacturing. Impurities presented during commercial manufacturing processes may be limited by very small amounts, and substantially and preferably, absent. For example, the ICH Q7A guide for API manufacturers requires that the process impurities remain below the established limits specifying the quality of the raw material, control of process parameters, such as temperature, pressure, time and proportion stoichiometric, and including the purification steps, such as, for example, crystallization, distillation and liquid-liquid extraction, in manufacturing processes.

The product mixture of a chemical reaction is rarely a simple compound with a purity sufficient to meet the pharmaceutical requirements. Secondary products and byproducts of the reaction and the accompanying reagents used in the reaction will also be present in most of the cases, in the product mix. At certain stages during the process of an API, such as, for example, (R) -montelukast, its purity must be analyzed, typically by HPLC or TLC analysis, to determine if it is adequate to continue the process and, ultimately, for its Use in a pharmaceutical product. The API needs not to be absolutely pure, since absolute purity is a theoretical idea that is commonly unattainable. Rather, the purity parameters are established with the intention of ensuring that an API is as free of impurities as possible, and thus, are as safe as possible for clinical use. As mentioned above, in the United States of America, the "Food and Drug Administration" guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.

Generally, by-products, byproducts, such as MLK-D, and adjunctive reagents ("collectively impurities") are identified spectroscopically and / or with another physical method, and then associated with a peak position, as for example in a chromatogram , or a spot on a TLC plate. (Strobel p.953, Strobel, H.A., Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3rd dd (Wiley &Sons: New York 1989)). In addition, the impurity can be identified, for example, by its relative position on the TLC plate, and characterized because the position on the plate is measured in centimeters from the baseline of the plate or its relative position in the HPLC chromatogram, where the position in a chromatogram is conventionally measured in minutes between the injection of the sample into the column and the levigation of a particular component through the detector. The relative position in the chromatogram is known as the "retention time".

The retention time can vary between a mean value based on the instrumentation condition, as well as other factors. To mitigate the effects of such variations on the exact identification of an impurity, professionals use "relative retention time" ("RRT") to identify impurities. (Strobel p.922). The RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be convenient to select a compound that is not an API that is added to the mixture, or is present therein in an amount large enough to be detectable and low enough to not saturate the column, and to use that compound as the reference marker for determining the RRT.

Experts in the field of narcotics manufacturing development and research understand that a compound in a relatively pure state can be used as a "parameter reference. "A reference parameter is similar to a reference marker, which is used only for qualitative analysis, but is also used to quantify the amount of the reference parameter compound in an unknown mixture. "external parameter" when a solution of a known concentration of the reference parameter and an unknown mixture are analyzed using the same technique (Strobel p.924, Snyder p.549, Snyder, LR, Kirkland, JJ Introduction to Modern Liquid Chromatography, 2nd, ed. (John Wiley &Sons: New York 1979).) The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response, see also United States Patent No. 6,333,198, incorporated herein. the present for reference.

The reference parameter can also be used to quantify the amount of another compound in the mixture if a "response factor", which compensates for differences in detector sensitivity of the two compounds has been predetermined. (Strobel p.894). For this purpose, the reference parameter is added directly to the mixture, and is known as an "internal parameter" (Strobel p.92, Snyder p.552).

The reference parameter can function as an internal parameter when, without the deliberate addition of the reference parameter, an unknown mixture contains a detectable amount of the reference parameter compound using the technique known as "parameter addition".

In the "parameter addition technique" at least two samples are prepared by adding known and different amounts of the internal parameter. (Strobel pp. 391-393, Snyder pp. 571, 572). The proportion of the detector response due to the reference parameter present in the mixture without addition can be determined by plotting the detector response against the amount of the reference parameter added to each of the samples, and extrapolating the plot to zero concentration of the parameter reference (See, for example, Strobel, Fig 11.4 p 392). The response of a detector on HPLC (eg, UV detectors or Refractive Index detectors) can and is commonly different for each compound by levigating from the HPLC column. The response factors, as is known, account for this difference in the detector response signal for different compounds levigating from the column.

As an expert in the art knows, the handling of impurities from the process is much more effective in understanding the chemical structures and synthetic pathways and identifying the parameters that influence the amount of impurities in the final product.

The detection or quantification of the reference parameter serves to establish the level of purity of the API or its intermediaries. The use of a compound as a parameter requires a resource for a sample of a substantially pure compound.

Because the processes of the prior art do not effectively remove certain impurities, there is a need for improved methods to purify montelukast. In particular, the inventors of the present invention have isolated the impurity of dehydro-montelukast and provided improved purification methods to reduce the level of these and other impurities in montelukast.

EXTRACT OF THE INVENTION In one embodiment, the present invention provides montelukast sodium containing less than 0.14% MLK-SO by weight. Preferably, the montelukast sodium contains less than about 0.10% MLK-SO by weight.

In another embodiment, the present invention provides montelukast containing less than 0.10% MLK-D by weight. Preferably, the montelukast sodium contains less than about 0.08% MLK-D by weight.

In yet another embodiment, the present invention provides a process for preparing pure montelukast sodium salt comprising: providing a montelukast free acid; converting montelukast free acid to montelukast di-n-propylamine salt; and converting the salt of montelukast di-n-propylamine into the sodium salt of montelukast. Preferably, the pure sodium salt of montelukast contains less than 0.14% MLK-SO by weight. More preferably, the pure sodium salt of montelukast contains less than about 0.10% MKS-SO thereby. Preferably, the pure sodium salt of montelukast contains less than 0.10% MLK-D thereby. More preferably, the pure sodium salt of montelukast contains less than about 0.08% MLK-D thereby.

In another embodiment, the present invention provides a recently isolated impurity, [R- (E)] -1 - [[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3 acid. - [2- (1-propenyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid (MLK-D) of the following structure: In another embodiment, the present invention provides montelukast sodium containing less than 0.14% preferably, less than about 0.10% and more preferably, less than about 0.06% MLK-SO by weight.

In yet another embodiment, the present invention provides montelukast containing less than about 0.10%, preferably, less than about 0.08% LK-D by weight.

In another embodiment, the present invention provides a process for determining the presence of a compound in a sample comprising performing HPLC or TLC with MLK-D as a reference marker. > In another embodiment, the present invention provides a process for determining the presence of MLK-D in a sample comprising performing HPLC or TLc with MLK-D as a reference marker. Specifically, the process comprises: to. determining by HPLC or TLC the corresponding retention time with MLK-D in a reference marker comprising MLK-D; b. determining by HPLC or TLC the corresponding retention time with MLK-D in a sample comprising montelukast sodium and MLK-D; Y c. determine the presence of MLK-D in the sample by comparing the retention time of step (a) with the retention time of step (b).

In yet another embodiment, the present invention provides a method for determining the amount of a compound in a sample comprising performing an HPLC or TLC with MLK-D as a reference marker.

In one embodiment, the present invention provides a method for quantifying the amount of MLK-D in a sample comprising performing an HPLC or TLC, characterized in that MLK-D is used as a reference parameter. Specifically, the process comprises the steps of: to. measuring with HPLC or TLC the area under a corresponding peak with MLK-D in a reference parameter comprising a known amount of MLK-D; b. measuring with HPLC or TLC the area under a corresponding peak with MLK-D in a sample comprising MLK-D and montelukast sodium; Y c. determine the amount of MLK-D in the sample by comparing the area of step (a) with the area of step (b).

In another embodiment, the present invention further provides a process for the preparation of montelukast from montelukast sodium having less than about 0.10% of the area by HPLC of MLK-D present comprising the steps of: to. obtain one or more samples of one or more series of montelukast sodium; b. measure the level of MLK-D in each of the samples; c. selecting a series from step a) that has a MLK-D level of approximately less than 0.10% of the area by HPLC, based on the measurement of the samples of the series; Y d. use the selected series to prepare montelukast sodium.

In yet another embodiment, the present invention provides a method for isolating MLK-D. The method comprises: providing a solution containing MLK-D, montelukast free acid, and a solvent; precipitate the free acid of montelukast from the solution; and isolate MLK-D. Suitable solvents include, but are not limited to, at least one of an alcohol, preferably methanol, a halogenated hydrocarbon, a C5-C8 aromatic hydrocarbon or an ester. Preferably, the method further includes a step of concentrating the solution containing MLK-D. The concentration of the solution can be carried out, for example, by evaporation of the solvent. Preferably, MLK-D is isolated by the chromatographic technique known in the art.

In one embodiment, the present invention provides pharmaceutical formulations comprising stable MLK-Na of the present invention, and a pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a process for preparing a pharmaceutical formulation comprising combining stable MLK-Na of the present invention with at least one pharmaceutically acceptable excipient.

In yet another embodiment, the present invention provides the use of stable MLK-Na of the present invention for the manufacture of a pharmaceutical composition.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates a HPLC chromatogram of sodium of montelukast.

Figure 2 and 3 illustrates an NMR spectrum for dehydro-montelukast in dimethyl sulfoxide.

Figure 4 illustrates a fast bombardment (FAB) ionization mass spectrum of dehydro-montelukast.

Figure 5 illustrates an NMR spectrum of dehydro-montelukast.

DETAILED DESCRIPTION OF THE INVENTION The process for preparing montelukast sodium salt by dicyclohexylamine salt as described in U.S. Patent Nos. 5,614,632 and 6,320,052 is not efficient in extracting particular impurities, including S- Montelukast monoxide and dehydro-montelukast (D-MLK). In fact, the impurity of dihydro-montelukast has not been identified yet.

The present invention relates to methods for purifying montelukast which comprises converting montelukast free acid to di-n-propylamine salt of montelukast and converting di-n-propylamine salt of montelukast to montelukast sodium salt. The conversion to di-n-propylamine salt is effective to reduce the impurity level of MLK-D and the impurity, which is described in detail below.

As used herein, the term "MLK-D" refers to acid [R- (E)] -1- [[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl]] phenyl] -3- [2- (1-propenyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid.

As used herein, the term "MLK-SO" refers to S- acid monoxide [R- (E)] -1- [[[1- [3- [2- (7-chloro-2- quinolinyl) ethenyl] phenyl] -3- [2- (1-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropanoacetic acid.

As used herein, the term "MLK-Na" refers to the sodium salt of acid [R- (E)] -1- [[[1- [3- [2- (7-chloro-2- quinolinyl) ethenyl] phenyl] -3- [2- (1-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropanoacetic acid.

As used herein, the term "relative retention times" (RRT) refers to a ratio of the amount of time of a compound that levigates from a column relative to MLK-Na.

The present invention provides montelukast sodium containing less than 0.14% MLK-SO by weight. Preferably, motenlukast sodium contains less than about 0.10% MLK-SO by weight.

The present invention provides montelukast containing less than 0.10% MLK-D by weight. Preferably, the montelukast sodium contains less than about 0.08% MLK-D by weight.

The present invention provides a process for preparing pure montelukast sodium salt comprising: providing a montelukast free acid; converting the montelukast free acid to the di-n-propylamine montelukast salt; and converting the di-n-propylamine salt of montelukast to montelukast sodium salt. Preferably, the sodium salt of montelukast pure contains less than 0.14% LK-SO per weight. More preferably, the pure sodium salt of montelukast contains less than about 0.10% MLK-SO by weight. Preferably, the pure sodium salt of montelukast contains less than 0.10% MLK-D by weight. More preferably, the pure sodium salt of montelukast contains less than about 0.08% MLK-D by weight.

Optionally, the process can comprise converting the montelukast free acid into an isopropylamine salt of montelukast; and converting the isopropylamine salt of montelukast to di-n-propylamine salt of montelukast. This optional step of obtaining isopropylamine salt from montelukast is useful for extracting from the S-enantiomer of montelukast. The process for preparing isopropylamine salt of montelukast comprises combining isopropylamine with montelukast free acid. Preferably, the isopropylamine is combined with the montelukast free acid solution in an organic solvent. Preferably, the organic solvent is 2-butanone. Optionally, the isopropylamine salt of montelukast is obtained by crystallization from a C5-Ce aromatic solvent or a ketone, more preferably, 2-butanone. The resulting montelukast isopropylamine salt can be isolated by means known in the art including, but not limited to, filtering, centrifuging or decanting.

Preferably, the isopropylamine salt of montelukast is dissolved in at least one organic solvent selected from the group consisting of: ether, aromatic solvent, and a saturated hydrocarbon. Preferably, the ether is THF. Preferably, the aromatic solvent is a C5-C8 aromatic solvent. Preferably, the saturated hydrocarbon is a C5-Cs saturated hydrocarbon. More preferably, the aromatic solvent is toluene. The most preferred solvent is a mixture of toluene and THF.

The isopropylamine salt of montelukast can be converted back into free acid by acidification of the solution. Preferably, the solution is acidified by the addition of acetic acid.

Preferably, the montelukast free acid or the isopropylamine salt of montelukast is converted to the isopropylamine salt of montelukast by dissolving the montelukast free acid or isopropylamine salt of montelukast in at least one ether, an aromatic solvent or a saturated hydrocarbon and adding a -n-propylamine. Preferably, the solvent is toluene or THF. Preferably, the molar ratio of the montelukast free acid to di-n-propylamine from montelukast is approximately 1: 2. The resulting di-n-propylamine salt of montelukast can be isolated by means known in the art, including, but not limited to, filtering, centrifuging, or decanting. Preferably, the di-n-propylamine salt of montelukast is crystallized from at least one C5-C8 aromatic solvent, preferably toluene, or a saturated C5-C8 hydrocarbon.

The method can also be carried out with the isolation of the isopropylamine salt.

Preferably, the process for preparing montelukast sodium salt from di-n-propylamine salt of montelukast comprises: dissolving the di-n-propylamine salt of montelukast in at least one C5-Cs aromatic solvent or a saturated Cs-Cg hydrocarbon; acidify the solution with an acid to form free acid of montelukas.t; and adding at least one source of sodium ion to form sodium salt of montelukast. Preferably, the aromatic solvent is toluene. Preferably, the acid is acetic acid.

The montelukast free acid can be prepared by any method known in the art. See, for example, Requests from the United States of America Nos. 11 / 048,276 filed on January 31, 2005 and 11 / 112,790, filed on January 21, 2005.

April 2005, both incorporated herein by reference. The montelukast free acid can be a solid form isolated or prepared in situ. Preferably, the montelukast free acid is prepared in situ. For example, the free acid of montelukast can be prepared by reacting methyl ester of 1- (mercaptomethyl) cyclopropane acetic acid (CYTA) with 2- (2- (3 (S) - (3- (7-chloro-2-quinolinyl)) -ethenyl) phenyl) -3-methanesulfonyl oxypropyl) phenyl-2-propanol (mesylate). For the next conversion step, the starting materials for the in situ preparation of the montelukast free acid can be dissolved in an organic solvent. In both cases, the organic solvent is at least one of an ether, an aromatic solvent or a saturated hydrocarbon. Preferably, the ether is tetrahydrofuran (THF); the aromatic solvent an aromatic solvent Cs-Cs, and the saturated hydrocarbon is a C5-C8 hydrocarbon. More preferably, the aromatic solvent is toluene.

The present invention provides a recently isolated impurity, acid [R- (E)] -1 - [[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1-propenyl) phenyl] propyl] thio] methyl] cyclopropane acetic of the following structure: having the formula C35H34C1NO2 S and a molecular weight of 567.90. The impurity of MLK-D can be characterized by a RRT of about 1.65 relative to MLK-Na.

The present invention provides montelukast sodium containing less than 0.14% preferably, less than about 0.10% and more preferably, less than about 0.06% MLK-SO by weight.

The present invention further provides montelukast containing less than 0.10%, preferably, less than 0.08% MLK-D by weight.

The tablet analysis shows a level of impurities of about 0.17% MLK-SO by weight, and about 0.10% MLK-D by weight.

The present invention further provides a process for determining the presence of MLK-D in a sample comprising performing an HPLC or TLC with MLK-D as a reference marker.

The present invention further provides a process for determining the presence of MLK-D in a sample comprising performing HPLC or TLC with MLK-D as a reference marker. Specifically, this process includes:to. determining by HPLC or TLC the retention time corresponding to MLK-D in a reference marker comprising MLK-D; b. determining by HPLC or TLC the retention time corresponding to MLK-D in a sample comprising montelukast sodium and MLK-D; Y c. determine the presence of MLK-D in the sample by purchasing the retention time of step (a) with the retention time of step (b).

The present invention provides a process for determining the amount of a compound in a sample comprising performing an HPLC or TLC with MLK-D as a reference parameter.

The present invention further provides a method for quantifying the amount of MLK-D in a sample comprising performing an HPLC or TLC, characterized in that MLK-D is used as a reference parameter. Specifically, the process comprises the steps of: to. measuring by HPLC or TLC, the area below a corresponding peak with MLK-D at a reference parameter comprising a known amount of MLK-D; b. measuring by HPLC or TLC, the area below a corresponding peak with MLK-D in a sample comprising MLK-D and montelukast sodium; Y c. determine the amount of MLK-D in the sample by comparing the area of step (a) with the area of step (b).

The present invention further provides a process for preparing montelukast from montelukast sodium having less than about 0.10% of the area by HPLC of MLK-D present comprising the steps of: to. obtain one or more samples of one or more series of montelukast sodium; b. measure the level of MLK-D in each of the samples; c. selecting a series from step a) that has a MLK-D level of less than about 0.10% of the area by HPLC, based on the measurement of the samples of the series; Y d. use the selected series to prepare montelukast sodium.

The present invention provides a method for isolating MLK-D. The method comprises: providing a solution containing MLK-D, montelukast free acid, and a solvent; precipitate the free acid of montelukast from the solution; and asylum MLK-D. Suitable solvents include, but are not limited to, at least one of alcohol, preferably methanol, a halogenated hydrocarbon, a C5-C8 aromatic hydrocarbon, or an ester. Preferably, the method further includes a step of concentrating the solution containing MLK-D. Concentrating the solution can be done, for example, by evaporating the solvent. Preferably, MLK-D is isolated by a chromatographic technique known in the art.

The present invention further provides pharmaceutical formulations comprising stable MLK-Na of the present invention, and a pharmaceutically acceptable excipient.

The present invention further provides a process for preparing a pharmaceutical formulation comprising combining stable MLK-Na of the present invention with at least one pharmaceutically acceptable excipient.

The present invention further provides the use of stable MLK-Na of the present invention for the manufacture of a pharmaceutical composition.

The methods of administration of a pharmaceutical composition of the present invention can be administered in various preparations depending on the age, sex and symptoms of the patient. The pharmaceutical compositions can be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection (solutions and suspensions) and others.

The pharmaceutical compositions of the present invention can optionally be mixed with other forms of MLK-Na and / or other active ingredients. In addition, the pharmaceutical compositions of the present invention may contain inactive ingredients such as, for example, diluents, carriers, fillers, thickeners, binders, diluents, disintegration inhibitors, absorption accelerators, emulsifying agents, lubricants, glidants, surface active agents, flavoring agents and the like.

The diluents increase the volume of a solid pharmaceutical composition, and can make a pharmaceutical dosage containing the composition easier for the patient to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL ©), microfine cellulose, lactose, starch, pregelatinized starch, sodium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, phosphate dihydrate. of calcium dibasic, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (for example, BUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted in a dosage form, such as for example a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, gum arabic, vegetable oil hydrogenated, hydroxyethyl cellulose, hydroxypropyl cellulose (for example, KLUCEL®), hydroxypropyl methyl cellulose (for example METHOCEL®), liquid glucose, aluminum magnesium silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (for example, KOLLIDON®, PLASDONE®), pregelatized starch, sodium alginate and starch.

The average dissolution of a solid pharmaceutical composition compacted in the stomach of a patient can be increased by the addition of a solvent of the composition. The solvents include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose. (eg, AC-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg, KOLLIDON®, POLYPLASDONE®) gum arabic, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (for example, EXPLO ®) and starch.

The glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of the dose. The excipients that can function as glidants include colloidal silicon dioxide, magnesium trislicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

When a dosage form such as for example a tablet is made by compaction of a powder composition, the composition is passed under the pressure of a perforator and coloration. Some excipients and active ingredients have a tendency to adhere to the surfaces of the perforator and coloration, which causes the product to have marks and other irregularities on the surface. A lubricant can be added to the composition to reduce adhesion and facilitate product release from coloration. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil. , polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form more pleasant for the patient. Flavoring agents and flavor enhancers common for pharmaceuticals that can be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

The solid and liquid compositions can furthermore have coloration using any pharmaceutically acceptable dye to improve the appearance and / or so that the patient can identify the product and the unit dose level easily.

In the liquid pharmaceutical compositions of the present invention, stable MLK-Na and any other solid excipient is dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

The liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse through the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be effective in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, condrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

The pharmaceutical compositions of the present invention may further contain an agent which increases the viscosity to improve the mouthfeel of the product and / or cover the walls of the gastrointestinal tract. Such agents include acacia, bentonite, alginic acid, carbomer, calcium or sodium carboxymethylcellulose, cetostearyl alcohol, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, carbonate. of propylene, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve flavor.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at safe levels for ingestion to improve storage stability.

According to the present invention, a liquid composition may contain a buffer such as, for example, guconic acid, lactic acid, citric acid or acetic acid, sodium gumonate, sodium lactate, sodium citrate or sodium acetate. The choice of excipients and the quantities used can be easily determined by the scientific formulation based on the experience and consideration of the parameter procedures and the reference works in the field.

When the injectable (parenteral) pharmaceutical compositions are prepared, the solutions and suspensions are sterilized and preferably made isotonic for the blood. Injection preparations can utilize carriers commonly known in the art. For example, carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. A person skilled in the art can easily determine the amount of sodium chloride, glucose, or glycerin necessary for the injectable preparation to be isotonic. Additional ingredients, such as dissolution agents, buffer and analgesic agents, may be added.

The solid compositions of the present invention include powders, granules, aggregates and compacted compositions. Doses include adequate doses for the oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhaler, and ophthalmic. Although the most suitable administration depends on the nature and severity of the poorly treated, the oral administration route of the present invention is preferred. Doses may be conventionally present in a unit dosage form and prepared by any of the methods known in the pharmaceutical art.

The dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, pills, as well as liquid syrups, suspensions and elixirs.

The dosage form of the present invention can be a capsule containing the composition, preferably a granulated or powdered solid composition of the invention, with a hard or soft covering. The coating may be gelatin and optionally contain a plascifier such as glycerin and sorbitol and an opacifying or coloring agent.

The active ingredient and the excipients may be formulated into compositions and dosage forms according to methods known in the art.

A composition for tablets or capsule fillers can be prepared by wet granulation. In wet granulation, some or all of the excipients and active ingredients in powder are combined and then mixed in the presence of a liquid, commonly water that causes the powders to granulate. The granulate is monitored and / or milled, dried and then monitored and / or milled to the desired particle size. The granulate can then be in the form of a tablet or other excipients can be added before being compressed, such as for example a glidant and / or a lubricant.

A tablet composition can be prepared conventionally by dry combination. For example, the combined composition of the active ingredients and excipients can be compacted into a sheet and then comminuted into compacted granules. The compacted granules can be subsequently compressed into a tablet.

As an alternative for dry granulation, a combined composition can be directly compressed into a compacted dose form using direct comprehension techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly suitable for tablets by direct compression include cellulose microcrystalline, lactose in dry steam, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients to make tablets by direct compression is known to those skilled in the art. the art with knowledge in challenges of particular formulation of tablets by direct compression.

A capsule filler of the present invention can comprise any aforementioned combination and granules which are described with reference to making tablets, however, it does not undergo the final step of plating.

The solid compositions of the. present invention comprise powders, granules, aggregates and compacted compositions. Doses include doses suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhaler, and ophthalmic administration. Although the most appropriate route in any given case will depend on the nature and severity of the poorly treated, in most cases the preferred route is oral. Doses may conveniently be presented in dosage unit forms and prepared by any other method known in the pharmaceutical art.

Having described the invention with reference to certain preferred embodiments, other embodiments will be apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the compound of the present invention. It will be apparent to those skilled in the art that many modifications, both of materials and methods, can be practiced without departing from the spirit or scope of the invention.

Instruments Determination of sodium impurity profile of montelukast by HPLC HPLC was performed using the following specifications: Column and packaging: LUNA C18 (2) 100A 250x4, 6 mm, 5 μ? T ?, P.N. 00-G-4252-EO Buffer: Solution I: 3 ml of TFA diluted to 100 ml with water Solution II: 3 ml of TFA diluted to 100 ml with acetonit rile.

Levigante A: 1 ml of solution I for 2 L of water Levigant B: 1 ml of solution II for 2 L of acetonitrile Levigante Gradient: Detention time: 40 minutes Balancing time: 10 minutes Flow: 1, 5ml / minute Detector: 225 minutes Injection volume: 20μ? Diluent: 80% acetonitrile: 20 Column temperature: 25 ° C Autosampler temperature: 5 ° C EXAMPLES Example 1: The preparation of acid [R- (E)] -1 - [[[3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1-hydroxy-1) -methylethyl) phenyl] propyl] io] methyl] cyclopropane acetic acid.

A cold solution of mesylate (2- (2- (3- (S) - (3- (-chloro-2-quinolinyl) -ethenyl) phenyl) -3-methanesulfonyl oxypropyl) phenyl-2-propanol) (about -5 ° C, 38 ml) was prepared from 10.1 g of diol (KT) ((S) -1- [[[1- [3- [2 (E) -7-chloro-2-quinolinyl) ethenyl] phenyl ]] -3- [2- (1-hydroxy-l-methylethyl) phenyl] -1-propanol)). The mesylate solution was added to a cold solution of CYTAM methyl ester of (1- (mercaptomethyl) -cyclopropane acetic acid) (5.05 g) in, N-dimethylacetamide (-7 ° C, 20 ml). 47% NaOH (4.55 g) was added dropwise during 9 minutes, under intensive mixing. The reaction was exothermic; the temperature reached -1 ° C. The viscous, clear reaction mixture was stirred for 1 hour at -6 ° C, 1.5 hours at 18 ° C, and heated to 38 ° C in one hour. 47% NaOH (5.12 g) was added at once and stirred overnight at 38 ° C. The reaction mixture (liquid with solid) was placed on a laboratory dish with 5% NaCl (50 ml), mixing at 38 ° C. The lower aqueous phase was separated and discarded. The organic phase was diluted with THF (30ml) and washed with 5% NaCl (50ml). The aqueous phase was separated and discarded. The organic phase diluted with THF (10ml) and treated with 7.5% tartaric acid (50ml) to adjust the pH to 3-5. The aqueous phase was separated and discarded. The organic solution was used directly in the next step.

Example 2: Enantiomeric purification by the preparation of the isopropylamine salt of [R- (E)] -1 - [[[3- [2- (7-chloro-2-quinolinyl) ethenyl] enyl] -3- [2 - (1-hydroxy-l-methylethyl) phenyl] propyl] thio] methylcyclopropane acetic acid.

Isopropylamine (1.95 g) was added to the reaction mixture of the previous example. The clear reaction solution was stirred for 0.5 hour at room temperature, and the volatiles were removed by evaporation in a 55 ° C bath under reduced pressure (20 mbar). The oily residue was dissolved in methyl ethyl ketone (40 ml) at 50 ° C, and the residual THP was dissolved with methyl ethyl ketone. The operation was repeated.

The residue, the heavy oil, was dissolved in hot methyl ethyl ketone (120 ml) at 71 ° C. The clear solution was gradually cooled for 0.5 hour at 37 ° C to induce crystallization. The suspension was maintained for 0.5 hour at this temperature and gradually cooled to 0 ° C in 1 hour. The mixture was maintained for 1.3 hour at 0 ° C and filtered. The cake was washed with cold methyl ethyl ketone (0 ° C, 50 ml) to provide 21.22 g of the moist product, which was dried overnight at room temperature and for 3 hours at 50 ° C under reduced pressure (20 mbar) to provide 9, 5 g of the dried crude product as a bone-colored solution (purity 98.4%).

The isolated yield was 68% relative to KT. The level of S-enantiomer was reduced from 0.28% to an undetectable level. The MLK-SO level was reduced from 0.16% to 0.09%.

Example 3: 3- [2- (1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropyl acetic acid isopropiamonium salt S-MKT (4 kg) was reacted with methanesulfonyl chloride (1.4 kg) in the presence of DIPEA (2.2 Kg) in THF as solvent (20 liters) to provide the mesylate compound. During the reaction, the diisopropylethylamine hydrochloride salt (DIPEA, HC1) is formed. The salt was extracted by filtration. The mother liquor, the THF solution of MKT-Mesylate, is then reacted | with CYTA '(2.4 kg) in. the presence of sodium hydroxide (2 Kg) in a mixture of THF and DMA (4 L) to provide a solution of R-MLK-Me.

After the separation step, the reaction mixture was gradually heated to 40 ° C and treated with an additional amount of sodium hydroxide (2 kg). The solution was mixed for about 4 hours to induce hydrolysis of R-MLK-Me and provide R-LK-Na. The DMA and the other by-products were extracted by washing the reaction mixture twice with a diluted NaCl solution (each wash is with 20 liters of 5% NaCl solution) to provide the THF solution of the crude MLK-Na.

The reaction mixture was acidified with a dilute aqueous solution of tartaric acid (7.5%) until a pH of 3-4 was reached to provide MLK-H. The aqueous phase is separated to provide a THF solution of the crude MLK-H. The aqueous solution containing tartaric acid salts is discarded.

The THF solvent is distilled off at 50 ° C under vacuum until dried. The residue (a sticky foam) was dissolved in methyl ethyl ketone (MEK) and cooled to < 30 ° C. 0.78 kg of i-Propylamine (IPAM) was added and then a salt was cooled, MLK-IPAM, precipitated from the solution. The solid was filtered, washed with MEK, and used in the next step. Optionally depending on the purity the solid was recrystallized from MEK and optionally dried.

Example 4: Purification of acid [R- (E)] -1 - [[[3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] 3-2- [2- (1-hydroxy) l-meleyl) phenyl] propyl] io] methyl] cyclopropane acetic acid by crystallization of di-n-propylamine salt.

The isopropylamine salt of [R- (E)] -1 - [[[3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] 3-2- [2- (1-hydroxy-l- Methylethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid (8.51 g) was dissolved in a mixture of toluene (40 ml) and THF (10 ml) and treated with glacial acetic acid (1.42 g) to adjust the pH at 5-6. The reaction mixture was stirred for 40 minutes and washed with water (20 ml). The aqueous phase was separated and discarded. Di-n-propylamine (2.74 g) was added to the organic phase, and the clear reaction solution was stirred for 0.5 hour at room temperature. The volatiles were removed by evaporation at 55 ° C under reduced pressure (20 mbar). The residue, a heavy oil, was dissolved in toluene (40 ml), and the residual THF was dissolved with toluene.

The residue was dissolved in toluene (35 ml) at 40 ° C. The clear solution was gradually cooled to 25 ° C to induce crystallization. The mixture was kept for 0.5 hour at this temperature and cooled slowly to 0 ° C. The suspension was stirred during the night and leaked. The cake was washed with cold toluene (0 °) to provide 7.3 g of the wet product. The wet product was dried for 3.5 hours at 50 ° C under reduced pressure (20 mbar) to provide 7.2 of the crystalline dry product as an off-white solid (purity 99.7%).

The isolated yield was 53% in relation to MKT.

Example 5: Purification of acid [R- (E)] -1 - [[[3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] 3-2- [2- (1-hydroxy) l-methylethyl) phenyl] propyl] io] methyl] cyclopropane acetic acid by crystallizing the di-n-propylamine salt by crystallizing the di-n-propylamine salt.

The montelukast acid of Example 1 can also be directly converted to the di-n-propylamine salt. The organic solution obtained by Example 1 was evaporated to dryness, and the residue was dissolved in toluene as in Example 4. The remaining steps of Example 3 are carried out to provide the di-n-propylamine salt.

The amount of LK-D was reduced from 0.95% to a level of 0.03-0.08% by weight. The amount of MLK-SO was reduced to a level of 0, 04-0, 06% by weight.

Example 6: Preparation of the crystalline di-n-propylamine salt of 1- [[[1 (R) - [3 [2- (7-chloro-2-quinolinyl) ethenyl] phenyl]] 3-2- [2] - (L-hydroxy-l-methylethyl) phenyl] propyl] thiojmethyl] cyclopropane acetic (MLK-DPA) 500 g of MLK-IPAM was dissolved in 2 L of THF at room temperature and 1 L of a solution of tartaric acid in water 7.5% was added reaching a pH of 3-5. The phases were separated and the water phase was discarded. THF was extracted by vacuum distillation at < 60 ° C to dryness. The residue (sticky foam) was dissolved by addition of toluene and cooled. 118 g of di-n-propylamine (DPA) was added by inducing further cooling, finally sowing the precipitation of the crude salt, MLK-DPA. The solid was filtered by washing twice with toluene and without drying it was recrystallized from toluene. The crystallized MLK-DPA was dried in a vacuum oven at 44-45 ° C.

Example 7: Preparation of sodium salt of acid [R- (E)] -1- [[[3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] 3-2- [2- (l- hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclopropane acetic acid A 500 ml flask equipped with a mechanical mixer was charged with toluene (225 ml) and di-n-propylamine salt of montelukast (45 ml). g). The suspension was washed at room temperature for 30 minutes. Sodium terebutoxide (6.5 g) was added to the suspension, and the reaction mixture was stirred at 30-40 ° C for 30 minutes. Active carbon (2 g) was added, and the solution was filtered over active carbon.

The mixture was added dropwise to a bottle containing heptane (630 ml) to form a precipitate, and the mixture was further stirred at room temperature for 1 hour.

The salt crystals of montelukast sodium were collected by filtration, washed with heptane, and dried at 45 ° C under reduced pressure. Montelukast sodium (32g) was obtained as an amorphous material containing more than 1% water. The amount of MLK-D was reduced to an undetectable level.

Example 8: Isolation of MLK-D MLK-D was separated by flash chromatography from the residue of Examples 3-5. The mobile phase is CHCl3: ether (8: 2). The mother liquor (ML) of the reactions of Examples 3-5 was concentrated by evaporating the solvent under reduced pressure at 45 ° C. The residue was dissolved in a minimum amount of MeOH and stirred overnight at room temperature. The MLK-H precipitate was filtered and ML was again concentrated by evaporation of the solvent under reduced pressure at 45 ° C. The residue was dissolved in a minimum amount of CHCl3: ether (8: 2), then charged onto silica gel. The multiple fractions were collected to obtain the LK-D sample.

Example 9: The use of MLK-D as a reference parameter and a reference marker.

A mixture containing 0.025 mg / ml sodium of montelukast (LK-Na) parameter and 0.025 mg / ml of marker MLK-D in diluent was prepared using only amber vials and vials. The sodium retention time of montelukast was approximately 20 minutes; the retention time of MLK-D was approximately 33 minutes.

A parameter solution was prepared by dissolving and diluting 10 mg of montelukast sodium parameter in a 10 ml volumetric amber bottle. This solution was diluted 1/100 and then 1/10 with diluent. A sample solution was prepared by dissolving and diluting 10 mg of montelukast sodium sample in a 10 ml volumetric amber bottle.

The parameter solution was injected with a dwell time of 25 minutes, and the solution of the sample continued with the chromatogram until the end of the gradient. The area of each impurity was calculated by the formula: % Impurity = Impurity of area X concentration (MLK-Na) parameter x Power (MLK-Na) impurity concentration parameter x area (MLK-Na) parameter The retention times are: Example 10: Repetition of the United States of America Patent No: 5,614,632

Claims (16)

1. Montelukast sodium containing less than 0.14% MLK-SO by weight

2. Montelukast containing less than 0.10% MLK-D by weight.

3. A process for preparing pure montelukast sodium salt comprising: providing a montelukast free acid; converting montelukast-free acid to the di-n-propylamine salt of montelukast; and converting di-n-propylamine salt of montelukast to montelukast sodium salt.

4. An isolated impurity, acid [R- (E)] -1- [[[1- [3- [2- (7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2- (1-propenyl) phenyl] propyl] thio] methyl] cyclopropane acetic (MLK-D) of the following structure:

Montelukast sodium containing less than 0.14% MLK-SO by weight.

6. Montelukast containing less than about 0.10% MLK-D by weight.

7. A process for determining the presence of a compound in a sample comprising performing HPLC or TLC with MLK-D as a reference marker.

8. A process for determining the presence of MLK-D in a sample comprising performing HPLC or TLC with MLK-D as a reference marker comprising: to. determining by HPLC or TLC the corresponding retention time with MLK-D in a reference marker comprising MLK-D; b. determining by -HPLC or TLC the retention time corresponding to MLK-D in a sample comprising montelukast sodium and MLK-D; Y c. determine the presence of MLK-D in the sample by comparing the reaction time of step (a) with the reaction time of step (b).

9. A method for quantifying the amount of MLK-D in a sample comprising performing an HPLC or TLC characterized in that MLK-D is used as a reference parameter. Specifically, this process comprises the steps of: to. measuring by HPLC or TLC the area under a corresponding peak with MLK-D in a reference parameter comprising a known amount of MLK-D; b. measuring by HPLC or TLC the area under a corresponding peak with MLK-D in a sample comprising MLK-D and montelukast sodium; Y c. determine the amount of MLK-D in the sample by comparing the area of step (a) with the area of step (b).

10. A process for preparing montelukast from montelukast sodium having less than about 0.10% area by HPLC of MLK-D present comprising the steps of: to. obtain one or more samples of one or more series of montelukast sodium; b. measure the level of MLK-D in each of the samples; c. selecting a series from step a) that has a MLK-D level of approximately less than 0.10% area by HPLC, based on the measurement of the samples of the series; Y d. use the selected series to prepare montelukast sodium.

11. A method for isolating MLK-D comprising: providing a solution containing MLK-D, montelukast free acid, and a solvent; precipitate montelukast free acid from the solution; and asylum MLK-D.

12. The method according to claim 11, characterized in that the solvent is at least one of a halogenated hydrocarbon alcohol, a C5-C8 aromatic hydrocarbon or an ester.

13. The method according to claim 11 further comprises concentrating the solution containing MLK-D.

14. Pharmaceutical formulations comprising MLK-Na and a pharmaceutically acceptable excipient.

15. A process for preparing a pharmaceutical formulation comprising combining stable LK-Na with at least one acceptable pharmaceutical excipient.

16. The use of stable MLK-Na of the present invention for the manufacture of a pharmaceutical composition.