FI106021B - Process for preparing a physical form of N-[4-[5- (cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3- methoxybenzoyl]-2-methylbenzenesulphonamide - Google Patents

Description

1 106021

Process for the preparation of the physical form of N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide.

Divided by application 915826.

The present invention relates to a process for the preparation of a physical form of N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -103-methoxybenzoyl] -2-methylbenzenesulfonamide.

European Patent Application A2 0 199 543 discloses certain heterocyclic amide derivatives which are opposed to one or more of the arachidonic acid metabolites known as leukotrienes, for example C4, D4 and / or E4, which are known to be potent spasmogens (especially in the lungs), pharmacologically active. they increase vascular permeability and are associated with asthma. and the pathogenesis of inflammation [see J.L. Marx, Science 20: 215, 1380-1383 (1982)] as well as endotoxic shock. * [See J.A. Cook et al., J. Pharmacol. Exp. Ther. 235 • · · *; *; 470 (1985)] and traumatic shock [see C.

Denzlinger et al., Science 230: 330 (1985)]. Thus, these compounds are useful in the treatment of diseases in which leukotrienes are involved and in which antagonism of their action is required. Such diseases include, for example; 1; allergic lung disorders such as asthma, hay fever and allergic disease. rhinitis as well as certain inflammatory diseases such as bronchitis, inflammation, ectopic and atopic dermatitis, psoriasis as well as vasospastic cardiovascular disease, endo- • * *. ·. * toxic and traumatic shock conditions.

One of the above-mentioned EP patent applications • · · ·. The heterocyclic amine derivative described in A2 0 199 543 is N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methyl-35 indol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide. This compound is described in Example 105 of the specification and is subsequently expressed as Compound 1.

2 106021

In recent clinical trials, Compound 1 has been found to be effective in the treatment of asthma when administered orally to patients with asthma. The efficacy of this compound 1 when administered orally is unusual and 5 highly desirable.

The pharmaceutical composition used in the above clinical trials was not completely satisfactory and therefore an improved formulation has been sought. As will be described in more detail below, 10 many technical problems must be solved in order to obtain such a composition.

Compound 1 is relatively poorly soluble in water. Therefore, there is a need to develop a pharmaceutical composition suitable for oral administration that contains Compound 1 in solid form.

It has been found that Compound 1 can be obtained in solid form as a material having a variety of physical properties, depending on the manner in which it is ·. *. isolated and subsequently treated. With this, ·,; 20 vin has been found to be due to the fact that compound 1 'may exist in more than one physical form; of which at least one has poor physical stability, and which physical forms may be obtained in a mixture. In addition, it has been found that the samples have different bioavailability.

: 1: It's not tempting to develop a formulation that • · · · ** '; contains a mixture of physical forms of the compound with different bioavailability, particularly if the mixture is physically unstable because the effective dose of the compound cannot be properly controlled. For this reason, there is a need to find methods for the physical • • · ·; ; to form physical shapes without having other physical forms.

Methods for preparing the physical forms of the three compounds 1, which have substantially no other physical forms, have been developed and the physical stability and bioavailability of these three forms have been investigated. Of these, two forms, hereinafter referred to as forms B and X, have been found to be physically stable but have relatively poor bioavailability. A third of these three forms, Form A, has been found to have relatively good bioavailability. However, it has been found that this physical form tends to convert to Form B in the presence of water. This property is disadvantageous for a substance which is intended to be formulated as a solid composition, since water must be used as an adjuvant in the granulation during the mixing process. Indeed, the tablets used in the above-mentioned clinical trials were prepared by the water granulation method of Form A and were found to contain Form B in an amount of about 25-30% by weight of Compound 1.

Therefore, there is a need for a pharmaceutical composition suitable for oral administration that contains Compound 1 in one physical form. which is substantially free of other physical forms and which has a physically stable composition, and which is reproducible and has a good bioavailability.

• · ·

It has been found that pharmaceutical compositions meeting the above requirements can be obtained with a choice of Form A active ingredient and polyvinylpyrrolidone additive.

: 1: These pharmaceutical compositions contain the active ingredient N- [4- [5- (cyclopentyloxycarbonyl) -] · · * as the active ingredient. amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl-2-methylbenzenesulfonamide (Form A) in physical form, which is substantially free of other physical forms , and this physical form has infrared • · · · - <; spectrum (0.5% KBr) with peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550 cm -1, and polyvin-3 5-yl pyrrolidone.

4, 106021

The X-ray powder diffraction pattern of Form A has no detectable peaks, and therefore Form A is amorphous.

It has been found that these compositions have sufficient physical stability and can be repeatedly prepared and have surprisingly high bioavailability.

When referring in this specification to Form A, which is substantially free of other physical forms, it is preferably meant that at least 90% by weight of Compound 1 is in this physical form, more preferably at least 95%, for example at least 96%, 97%, 98% or 99%. %.

The composition may be in any conventional form suitable for oral administration, for example in the form of tablets, capsules, pills or powders. Preferably it is in tablet form.

The active ingredient will usually contain from about 1% to about 90% by weight, based on the size of the composition. for example, 10 to 50% by weight.

Polyvinylpyrrolidone is usually present in at least 1% by weight based on the total weight of the composition.

It may, together with the active ingredient, make up the total weight of the composition. However, the composition will generally also contain at least one pharmaceutically acceptable carrier. For example, from the total amount of the composition, polyvinylpyrrolidone may be from 1 to 20% by weight, preferably from 2 to 6% by weight. -%.

• · ·

Examples of suitable pharmaceutically acceptable- ···, ·. carriers include sugar derivatives such as mannitol, lactose, sorbitol, glucose, sucrose, dextrose, fructose and xylitol, and cellulose derivatives such as microcrystalline cellulose, powdered cellulose and hydroxypropyl. ···, · **. methylcellulose. Preferably, the composition contains a sugar derivative, especially lactose, and a cellulose-35 derivative, especially microcrystalline cellulose. For example, the amount of Blood 106021 derivative may range from 10 to 30% by weight of the total weight of the composition. For example, the amount of cellulose derivative may range from 25 to 70% by weight of the total weight of the composition.

The composition may further contain one or more processing adjuvants, such as disintegrants, for example croscaramellose sodium, starch glycolate sodium and starch, and lubricants, for example magnesium stearate, stearic acid, talc and powdered plant stearin. The amount of disintegrant may vary, for example, from 1 to 10% by weight of the total weight of the composition. The amount of lubricant may vary, for example, from 0.25 to 2% by weight of the total weight of the composition.

The composition may be prepared by mixing the ingredients by a conventional method, for example, by granulation.

The pharmaceutical compositions are prepared by mixing Form A, which is substantially free of other physical forms, with polyvinylpyrrolidone. and water and drying the mixture thus obtained.

The amount of water used will depend on the type of pharmaceutical composition required (e.g., tablet, capsule, powder or pill), and the amount of water used in each formulation.

The nature of the ingredient. Conventionally water and form A

• · i * · * weight ratio is between 0.1 and 100: 1.

When the composition is in the form of a tablet, the tablet will typically weigh between 25 and 500 mg, such as 50 to 250 mg, ***: for example 100 to 200 mg. The tablet may be coated with · · ·. ***. or uncoated. The coating may be a conventional coating and the tablet may be coated in a conventional manner.

• · · • ·. The present invention relates to a process for the preparation of Form A which is essentially free of other physical ····. . ** ·. forms by heating Form B above.

The present invention relates to a process for the preparation of N- [4- [5- (cyclopen-35yloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide. For the preparation of a physical form substantially free of other physical forms with sharp peaks in the infrared (0.5% KBr) spectrum of the physical form at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550 cm &lt; -1 &gt; The process is characterized by heating N- [4- [5- (cyclopentyloxycarbonyl) amino-1'-methylindol-3-ylmethyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide. another physical form which is substantially free of other crystalline forms and which physical form is N- [4- [5- (cyclopentyloxy- [.] carbonyl) amino-1-methylindol-3-ylmethyl] -3 -methoxybenzoyl] -2-methylbenzenesulfonamide crystalline. * monohydrate, having an infrared spectrum (0.5% KBr). «·« *; · 'Sharp peaks are at 3560, 1690, 1660, 1540, 1440, • · ·' · '· 1165, 880 and 858 cm "1, and whose X-ray powder diffraction peaks:' * lissa have peaks at 2θ = 10.0, 11.2, 14.6, 19.8, and T: 25 23.0 °, at a blast temperature range of 90-125 ° C under reduced pressure.

The dehydration of Form B is preferably carried out at a temperature in the range of 115 ° C to 122 ° C.

· »·

The pressure during form B hydration is preferably not · · ·. ·. higher than 100 mbar, more preferably smaller than 30 · 50 mbar. For example, the pressure may range from 5 - «· * ♦ ·· '50 mbar.

Form B can be prepared substantially free of <Ml ·· *. from other crystalline forms by crystallization from hot aqueous «* ♦ acetone. In particular, it can be prepared by dissolving starting compound 1 in aqueous acetone at elevated temperature, adding more water and allowing the resulting mixture to cool. Preferably, water is added rapidly, so that compound 1 initially separates as an oil. The material thus prepared has Form A in a particularly morphologically pure state.

The crystalline product may be dried at an elevated temperature, for example at about 60 ° C or lower. If it is desired to start from the crude starting material of compound 1, it is preferable to triturate this crude material with hot toluene / ethyl acetate before crystallization.

It is estimated that if Form B is dried at a high temperature, for example above 60 ° C, then conversion to Form A may occur. Material prepared by drying Form B at or below about 60 ° C has been found to be substantially free of other physical forms of Compound 1.

It is believed that Form B is new.

Form A, which is substantially free of other physical forms of Compound 1, may also be prepared. by evaporating the solvent rapidly to 1 · · 1 /. 20 solution. For example, it may be prepared by spray-drying a solution of compound 1.

»M #; The solvent may be any liquid capable of dissolving Compound 1 and evaporating at a temperature below the melting point of Form A. Examples of complete solvents are ketones, such as acetone, and nitriles, such as acetonitrile, optionally in admixture with water. Aqueous acetone is a particularly suitable solvent.

· Φ ·. * · *. The temperature at which the solvent evaporates should be

• M

don A below the melting point. Usually it is less than • · · ***** 3 0 125 ° C, preferably below 120 ° C. When ··· · ... * acetone is used as solvent, it is observed that a significant amount of crystalline material is obtained at temperatures below 100 ° C. Thus, pre- * «·». ···. for example, the temperature at which the solvent is evaporated may range from 100 to 125 ° C.

A solution of Compound 1 is usually prepared by dissolving a crystalline form of Compound 1, such as Form B, in solution 106021. The solution prepared in this manner contains a minimum amount of non-volatile impurities.

Based on the foregoing, it is believed that aqueous acetone is a particularly preferred solvent for the preparation of Form A, which is substantially free of other physical forms. It has been found that the organic solvent content of Form A prepared via Form B is very low. Therefore, in another aspect, the present invention provides a solution of Compound 1 in aqueous acetone 10. For example, the solution may contain 5 to 15% by weight, preferably 6 to 13% by weight, of Compound 1. The solvent may contain, for example, 3 to 9% by weight, preferably 4 to 8% by weight, of water.

The advantageous nature of the compositions made from the compounds of the invention can be described by comparing their properties with the corresponding compositions in which Form A has been replaced by Form B or Form X and a composition containing Form A containing polyvinyl, lipyrrolidone.

Form X is the physical form of Compound 1 which is crystalline and has an X-ray diffraction pattern with a specific form. physical peaks at 20 = 8.1, 13.7, 16.4, 20.5 and 23.7 ° · · · '·'! and an infrared spectrum (0.5% KBr) with sharp peaks at t · • * '· at 3370, 1670, 1525, 1490, 1280, 890, 870 and 0: 25 550 cm -1.

Form X can be prepared substantially free of: ***; from other physical forms by the method of solution · · ·. · **. the starting compound 1 is hot-acetylated, the volume of the resulting solution is reduced by evaporation, the toluene is added and the volume is further reduced

Ml * ... * by evaporation. If you want to use a material that is relatively impure starting material 1, you may · · · · · *. such material is preferably triturated with hot toluene / ethyl acetate before the crystallization step.

9 106021

Each of the forms A, B, and X may be conventionally characterized, for example, solely by their X-ray powder diffraction pattern or solely by their infrared pattern.

In this specification, infrared spectra were determined using a 0.5% dispersion of sample material on a potassium bromide plate at a wavelength range of 400 to 400 cm -1. Examples of infrared spectra of each of the forms X, A and B are given in Figures 1, 2 and 3 below.

10 X-ray powder diffraction spectra were determined using 2 g of sample material placed in a Philips standard deep container in a scanning range of 4 to 40 ° 2Θ, counting for 4 seconds at 0.02 ° intervals to obtain a distance trace against the intensity in these 15 areas. Examples of X-ray powder diffraction spectra of each of Form X, A and B are shown in Figures 4, 5 and 6 below.

The melting points of each of the forms A, B, and X depend generally on their purity level. Typically, the form X

t I I

The melting point of the form A is greater than 190 ° C, for example 200 ° C, the melting point of the form A is between 115 ° C and 140 ° C, for example about 124 ° C to 132 ° C, and B has a melting point of about 140-160 ° C, for example 145-155 ° C. Form B has been found to lose water at temperatures above about 60 ° C and therefore has a "t": · · 25 melting point may not be sharp.

As stated above, Form A is acceptable; ***: Stable in the compositions of the present invention. However, in very humid and warm conditions »··. ·. a conversion of Form A to Form B has been observed.

Similarly, under certain circumstances, it may be desirable to retain a desiccant, such as silica gel, for pharmaceutical formulations containing Form A. It may also be desirable to keep them in an airtight container (1 pack, such as in a blister.

10 10602 Ί

The dose of Compound 1 in the composition of the present invention to be administered to a patient will depend on the severity, age and size of the condition being treated. In general, the compound is administered in an amount of 0.1 to 10 mg / kg, for example 0.2 to 5 mg / kg.

Acute toxicity studies have been performed on Compound 1 to obtain LD50 values. For example, in mice and rats, the LD50 value of compound 1 is> 500 mg / kg.

The following non-limiting examples illustrate the invention.

Example 1

Preparation of Form A a) Preparation of the crude starting material of Compound 1

Methyl 3-methoxy-4- (1-methyl-5-nitroindol-3-yl-15-methyl) benzoate (prepared as described in Example 4 of European Patent Application A2 0 199 543) was converted to the free acid by treatment with aqueous sodium hydroxide . The free acid was then converted to the acid chloride by treatment with thionyl chloride in dichloromethane: 2 O. The acid chloride was then reacted with o-toluene.

«I I

with eenenesulfonamide in dichloromethane in the presence of • <·! 2.2 equivalents of 4-dimethylaminopyridine, to give 4- (1-methyl-5-nitroindol-3-ylmethyl) -3-methoxybenzoyl-2-methyl-benzylsulfonamide dimethylaminopyridine salt.

With a solution of 4- (1-methyl-5-nitroindole-3-dimethyl) -3-methoxybenzoyl-2-methylbenzene sulphonate: dimethylaminopyridine salt of phonamide (30 g) in 2-methoxy - 4. * ·. in ethanol (130 ml) and concentrated sodium hydroxide. In 30 solutions (3.2 ml), a nitrogen purged flask containing 105 palladium on carbon (3.3 g of 60.9% water .. * · * wetted pulp) was charged. The mixture was then stirred under hydrogen sweet at 3 bar for 2.5 hours. The mixture was then filtered through diatomaceous earth and washed well with 2-methoxyethane-35 (37.5 mL). Cyclo-106021 µl pentyl chloroformate (9.2 mL) was added to the combined solutions and the mixture was allowed to stir under nitrogen overnight. The temperature was then adjusted to 30-33 ° C and 0.8 M hydrochloric acid (68 ml) was added over 20 minutes with vigorous stirring. The mixture was then allowed to cool to 15-20 ° C and stirred for 1 hour. The crude crystalline product was then filtered, washed with water and dried at 50 ° C. It was then used in the next step, b) Trituration of crude compound 1 A mixture of 60 g (0.101 gmol) of the product of step a), 240 ml of toluene (4 volumes) and 150 ml of ethyl acetate (2.5 volumes) was slowly warmed to reflux. and 30 ml (0.5 volumes) of distillate was collected to remove most of the water released. The mixture was heated at reflux for one hour (88-90 ° C) and then cooled to 10-15 ° C. After stirring the mixture for 3 hours at 10-15 ° C, the solid was filtered through a sintered glass. and washed with a 2: 1 mixture of toluene (80 mL) and ethyl acetate (40 mL). The product was then dried to constant weight in a sinter to give 53.2 g of dry product; Concentrate 1 (91.5% yield).

c) Preparation of Form B c) A mixture of 30.0 g of the product of step b), 25 ml, 210 ml of acetone and 12 ml of water. was placed in a 500 mL reaction flask, then heated at reflux for 15: ***: minutes, then filtered at 45-50 ° C · ***: through a diatomaceous earth glass flask directly into a 500 mL reaction flask. The flask and sinter were washed with a mixture of acetone (60 mL) and 30 mL water (3 mL), then the combined solutions were stirred in a water bath at about 40 ° C and water was added; 1 (120 ml) for 5 minutes, the mixture initially oiled, but then crystallized rapidly, then cooled to »20 ° C for 1 hour, stirred for 2 hours. At -20 ° C and then filtered The product was washed with water (60ml), dried as much as possible in a 12 106021 sinter and then dried in a 60 ° C oven The yield of Form B was 30.0 g (97%).

d) Preparation of Form A

The product (15.0 g) from step c) was placed in a 5,500 mL rotary flask which was then evacuated in a rotary evaporator at 20 mbar. The flask and its contents were then immersed in an oil bath preheated to 118 ° C and rotated slowly at this temperature for 6 hours. The mass was decomposed by cooling to give Form A as a white powder.

For large-scale production, Form A can be prepared as follows: 30 kg of the product of step c) are uniformly spread on metal trays and heated at 120 ° C in a vacuum oven of 7 m for up to 24 hours. The pressure is typically about 20 mbar. Upon cooling (to 40 ° C or below), the material is removed from the furnace and milled to give the desired shape A.

\\ If desired, Form A may be micronized prior to the use of «Il: 2 0.

• i ·. ' · Production of Form X «« «

The product of step b) (30.0 g, 0.0521 g mol) * was dissolved in acetone (150 ml) and water (4.7 ml) while warming carefully to reflux, and the solution was filtered. 25 through a glass sinter funnel. The filtrate was heated to reflux and 90 ml of distillate was collected. Toluene (120 ml) was added and a further 75 ml distillate was recovered **. More toluene (120 mL) was added and another 75 mL · * · distillate was collected. After being heated for a further hour at reflux temperature, the mixture was cooled to 15-20 ° C and the product was recovered and washed with toluene (2 x 30 ml). . The yield after drying through a sinter funnel was 29.5 g (98.3%).

13 106021

Example 2

Alternative Preparation of Form A

Form B (which can be obtained as described in Example 1) was dissolved in aqueous aceto-5 to give a solution of compound 18 in 8% w / w in 6% w / w aqueous acetone. This solution was then spray dried using a Niro Laboratory Minor spray dryer (available from A / S Niro Atomizer, Gladsaxevej 305, DK-2860 Soeborg, Denmark). The solution was sparged at a flow rate of 10 2 kg / h with nitrogen at a flow rate of 6.6 kg / h using a dual-fluid nozzle spreader. The drying gas used was nitrogen at a flow rate of 70 kg / h and inlet / outlet at temperatures of 215/120 ° C, respectively. The compound of Form A produced was recovered on a bag tube filter.

15 Example 3

Form A tablet formulation

Mg / tabl of granulating material. mg / tabl. mg / tabl.

<<«« «<<. . 20 Active ingredient 2 20 50 4 t i l l

Croscarmellose Sodium NF 6 5 5 l I '' ['[Polyvinylpyrrolidone USP 7 4 8 <(<' · * Microcrystalline Cellulose NF 54 74 40 4 «'" Lactose NF 54 50 40 <(<V' 25 Purified Water USP 80 98 62:: Final mixing material • · • ♦ ·

Dried Powdered Granulation 123 153 143 • · «*, * 30 Lactose NF - 20 • ♦ • ♦ ·« · *: * Croscarmellose Sodium NF 6 5 7

Microcrystalline. cellulose NF 69 20 48

Magnesium Stearate NF 2 2 2 14 106021

The ingredients of the granulating material were wet granulated. The granules were then dried and ground. The material thus obtained was then mixed with the other ingredients of the final blend and compressed into tablets.

The percentage by weight of Form B present based on the weight of Compound 1 was determined by X-ray analysis. In the 20 mg tablet, this was <8% by weight. The more sensitive 10 X-ray methods were used for the 50 mg tablet assay. The weight percentage of Form B before formulation was 3% and after formulation <3.2%.

Note: The polyvinylpyrrolidone used in each of the examples presented has a K value of 29 to 32. It is believed that any pharmaceutical grade polyvinylpyrrolidone, for example having a K value between 10 and 100, is suitable.

Example 4

Short-term Stability Test V. Tablets prepared by the method described in Example 3:20 containing 20 mg of the form < e &gt; were stored under several conditions for 1, 2 and 3 months.

(i> '1' I The tablets were then examined by X-ray diffraction, I I 'to determine how much of the active ingredient was converted to B. The results are shown in Table 1 below.

• · · · · · · · · · · · · · ·

• • I

• • • • • * I • • • • • • • • · · · ··························································· c.

Table 1.

Stability test with Form A containing formulation.

5 Storage conditions% conversion to Form B

original not detectable for 1 month, room temperature not detectable for 2 months, room temperature not detectable for 10 months, room temperature not detectable for 3 months, 50 ° C not detectable for 1 month, 40 ° C, 80% SK 87 2 months, 40 ° C, 80% SK 91 3 months, 40 ° C, 80% SK 82 15 _ SK = relative humidity

Tablets V. stored at room temperature and 50 ° C were in white, tight polyethylene bottles with <· ·! 20 were metal caps.

4 1 1 4 4 4 80% relative humidity tablets

I I I

'Were exposed to the air.

e «4 I«

4 · I

4 «t« • € «(« «4 4 4 4 4 4 • · • • • • • • ••••••••••••••••••••••••••••••••••••••••• • · • · · · · · «· 16 106021

Comparative Example 1

Form A Tablet Formulation Not Containing Polyvinyl Pyrrolidone 5 Granulation Material mg / tablet

Active ingredient 50.0

Pregelatinised starch NF 20.0

Lactose NF 34.55 Sodium starch glycolate NF 2.0

Microcrystalline cellulose NF 34.95

Sodium lauryl sulfate NF 0.5

Purified Water USP 100.0 15 Final Mixing Material

Dried powdered granulation 142.0

Sodium starch glycolate NF 6.0 V, Microcrystalline cellulose NF 50.0 «<2 0 Magnesium stearate NF 2.0 I s

> I I

; Ingredients of the granulating material were granulated as a trace amount. The granules were then dried and ground. Thereafter (4!), The material thus obtained was mixed with the other ingredients of the final 4 * 4 V? 25 blend and compressed into tablets.

: ***: The percentage of compound 1 as Form B was determined · · · · * '*; X-ray analysis before and after granulation.

• »Φ. *. Prior to granulation, Compound 1 was <1.5% Form B.

However, after granulation, Compound 1 was present in 28% form B.

The results clearly show an improved stability of Form A in the compositions of the present invention.

com 106021

Example 5

Capsule formulation mq / capsule 5 Active ingredient 20

Polyvinylpyrrolidone 20

Lactose 177.25

Microcrystalline cellulose 177.25

Colloidal silicon dioxide 0,5 Magnesium stearate 5

Size 0 gelatin capsule

Mix the active ingredient, polyvinylpyrrolidone, lactose and microcrystalline cellulose in a suitable blender, mix with purified water to a suitable consistency, dry, screen through a suitable milling step. Mix with colloidal silicon dioxide and magnesium stearate. Encapsulate into size 0 two-piece gelatin capsules.

f <i I _ _ ,. 20

«I I

/ Helmet mq / capsule t <1 <4 lii * I (

I I I

'! Active ingredient 10 4 4; '· Sugar spheres 200 t I 4 V' 25 Polyvinylpyrrolidone 10

Prepare a dispersion of 105 polyvinylpyrrolidone in purified water. Add the active ingredient and mix until evenly dispersed; • Sprinkle sugar on the balls, using appropriate equipment. The beads may be • ♦. * ··· * placed in size 1 two-piece capsules or may be ··· * divided into a suitable bag.

• · * · f t 106021 18

Powder formulation mg / powder

Active ingredient

Polyvinylpyrrolidine 15 5 Mannitol 364.6

Flavoring substance 0.4

Mix the active ingredient, polyvinylpyrrolidone and mannitol in a suitable blender. Mix to a suitable consistency with purified water, dry and pass through a suitable grinding step.

Comparative Example 2

Comparison of the bioavailability of Compound 1 in formulations prepared with Form A pol-15 with and without lyvinylpyrrolidone was performed in 24 healthy volunteers randomized to treatment groups. One treatment was a single 50 mg tablet prepared as described in Example 3 and another single 50 mg tablet prepared as described in Comparative Example 1. During the study, each volunteer received both preparations. Blood samples were taken at regular intervals during each treatment period and; the concentration of compound 1 was determined.

I t {<c I {«♦ · · · ♦ ♦« # # # # # # # # # # # # # # # ♦ ♦ «·» c «· • · · 19 106021

The comparative precursor of Example 3 is the product of brand 1. main, image enor (I) image enor (I) 5

The maximum concentration (ng / ml) of compound 1 was 588 54 223 28.

Time to maximum concentration - 2.6 0.3 3.7 0.3 to 10 mouths (hours)

Half life 9.0 0.5 8.2 0.7

Area Below the Curve 2268 220 970 126 15 (ng h / ml) These results clearly demonstrate the improved bioavailability of Compound 1 in the compositions of the present invention.

20 Comparative Example 3

Comparison of Bioavailability of Compound 1 in Compositions Containing Polyvinyl Pyrrolidone and Forms A, B and X

Tablets containing 20 mg of Form A, Form B, or Form C were prepared according to the following protocol.

• · • o o o o o e e «« «« «« <<<<<<<« «4 * 4« 4 4 * 20 106021

Granulating material mq / tablet

Active ingredient

Croscarellellose Sodium NF 6 5 Polyvinylpyrrolidone USP 7

Microcrystalline cellulose NF 45

Lactose NF 45

Final mixing material

Croscarmellose sodium NF 6

Microcrystalline cellulose NF 69

Magnesium Stearate NF 2 Using a balanced crossover model, 8 dogs were given each of three tablet forms. Blood samples were periodically taken from each animal during each study period and the concentration of Compound 1 was determined. The results are summarized below.

20

Active ingredient Maximum- Half-Range curve concentration time below (μ $ / τη1) (hours) (μg h / ml) 25 Form A 1,004 5,398 4,028

Form B 0.105 3.524 0.773

Form X 0.314 3,590 1,307 These results clearly demonstrate the superior bioavailability of the present compositions compared to Form B or Form X containing compositions.

c r t

Claims (6)

A process for the preparation of a physical form of N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methyl-5-indol-3-yl-methyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide = 0 CH = / V 0 10 ° y ΤΎΛ ° 0 XCH 3 \ ch3 which physical form is substantially free from other physical forms, and whose infrared spectrum (0.5% KBr) exhibits acute peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550 cm -1, characterized in that another physical form of N- [4- [5-. . (Cyclopentyloxycarbonyl) amino-1-methyl-indol-3-yl-methyl] -3- *; [methoxybenzoyl] -2-methylbenzenesulfonamide, which is physically free from other crystalline forms, and • 4: which physical form is a crystalline monohydrate of N-: [4- [5- (cyclopentyloxycarbonyl) amino] 1-methyl-indol-3-yl- [[[methyl] -3-methoxybenzoyl] -2-methylbenzenesulfonamide, whose infrared spectrum (0.5% KBr) has acute peaks at 3560, 1690, 1660, 1540, 1440, 1165, 880 and 858 cm -1, and ···. whose X-ray powder diffraction model exhibits peaks at • · • · ·. ···. 2Θ = 10.0, 11.2, 14.6, 19.8 and 23.0 °, within the temperature range of 90 - 125 ° C under vacuum. 2. A method according to claim 1, characterized in that the pressure is between 5-50 mbar. <3. Process according to claim 1 or 2, characterized in that the monohydrate form is prepared by crystallization of hot aqueous acetone. 4. A process according to claim 3, wherein the crystallization is carried out by the rapid addition of water, so that compound 1 is initially separated as oil. A process for the preparation of a physical form of N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methyl-indol-3-yl-methyl] -3-methoxybenzoyl] -2-benzenesulfonamide, which physical form is substantially free from other physical forms and whose infrared spectrum exhibits acute peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550 cm -1, characterized in that spray-drying a solution of N- [4 - [5- (cyclopentyloxycarbonyl) amino-no-l-methyl-indol-3-yl-methyl] -3-methoxybenzoyl] -2-methylbenzene-benzenesulfonamide. ice 6. A process according to claim 5, characterized in that an aqueous solution of acetone is used. • 9 · «» «· · • ·« • «t · · • · <« · «· • · • ·« • II • I • · • «• I« * • · · • · · • ♦ · • · · • · • o • · · • * «• c-« • * ♦ • e • · · • · »• · • · • • • • • · · <4 I 4«