AP286A - Physical form of an indolyl sulphonamide, processes for preparing it and pharmaceutical compositions containing it. - Google Patents

Physical form of an indolyl sulphonamide, processes for preparing it and pharmaceutical compositions containing it. Download PDF

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AP286A
AP286A APAP/P/1991/000341A AP9100341A AP286A AP 286 A AP286 A AP 286A AP 9100341 A AP9100341 A AP 9100341A AP 286 A AP286 A AP 286A
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indol
amino
physical
physical form
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Martin Paul Edwards
John David Sherwood
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Zeneca Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system

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  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A physical form of n-[4-[5-(cyclopentyloxycarbonyl)-amino-1-methyl-indol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzene-sulphonamide substantially free of other physical forms, which form is crystalline, has an x-ray powder diffraction pattern with specific peaks occuring at 20=8.1, 13.7, 16.4, 20.5 and 23.7Degress and infra-red spectrum (0.5In kbr)having sharp peaks at 3370, 1670, 1525, 1490, 1280, 890, 870 and 550 cm-1, a process for its preparation and pharmaceutical compositions containing it. Also disclosed is a flowable preparation of the physical form which is in the form of soft pellets, and a process for obtaining this preparation.

Description

HETEROCYCLIC COMPOUNDS
The present invention relates to heterocyclic compounds.
More particularly, it relates to a nev physical form of a heterocyclic amide derivative, to a process for the preparation of this physical form, and to a pharmaceutical composition containing it.
Before a compound in the solid state can be formulated in a pharmaceutical composition, a physical form of the compound is sought vhich is physically stable and can be prepared substantially free of other physical forms. This latter requirement is important because different physical forms can have markedly different bioavailabilities.
European patent application publication number EP-A2-Q199543 discloses certain heterocyclic amide derivatives vhich antagonise the pharmacological actions of one or more of the arachidonic acid metabolites knovn as leukotrienes. One of these heterocyclic amide derivatives is N-[4-[5-(cyclopentyloxycarbonyl)amino-l-methylindol-3yImethyl]- 3-methoxybenzoyl]-2-methy1benzenesulphonamide, hereinafter referred to as compound 1. Example 105 in EP-A2-0199543 discloses the preparation of compound 1 and its isolation in the solid state. The material obtained had a melting point of 138-140 °C.
It has been found that compound 1 can be isolated in the solid state as a material having a range of different physical properties, depending upon the method of isolation. This ability is cue to the fact that compound 1 can exist in more than one physical form, and mixtures of these forms can be isolated.
A method of preparing a physical form of compound 1 substantially free of other physical forms has nov been found, and this form substantially free of other physical forms is provided as the present invention.
BAD ORIGINAL s
Accordingly, the present invention provides a nev physical form of N-(4-(5-(cyclopentyloxycarbonyl)amino-l-mechylindol-3-ylmethyl]-3-methoxybenzoyl 1 -2-methylbenzenesulphonamide substantially free of other physical forms, vhich form is crystalline, has an X-ray povder diffraction pattern vith specific peaks occuring at 29=8.1, 13.7, 16.4, 20.5 and 23.7° and an infra-red spectrum (0.52 in KBr) having sharp peaks at 3370, 1670, 1525, 1490, 1280, 890, 870 and 550 cm \
The nev physical form of compound 1, vhich is referred to hereinafter as form X, is physically stable and can be prepared substantially free of other physical forms.
Vhere reference is made in this specification to form X substantially free of other physical forms, it preferably means that at least 902 by veight of the compound 1 present is in that physical form.
The advantageous nature of form X may be demonstrated by comparing its properties vith those of other physical forms of compound 1.
One other physical form of compound 1 is a monohydrate of compound 1 vhich is crystalline, has an infra-red spectrum (0.52 in KBr) having sharp peaks at 3560, 1690, 1660, 1540, 1440, 1165, 880 and 358 cm \ and an X-ray povder diffraction pattern having peaks at 2Θ = 10.0. 11.3, 14.6, 19.8 and 33.0°. It is referred to hereinafter as form 3.
Form 3 may be prepared substantially free of other physical forms by crystallisation from hot aqueous acetone. In particular, it may be prepared by dissolving a source of compound I in aqueous acetone at an elevated temperature, adding more vater, and allowing the resultant mixture to cool. The crystalline product may be dried at an elevated temperature, for example at about 60 °C or belov. If it is desired to start from an impure source of compound 1, it has BAD owe**
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- 3 been found advantageous to triturate this impure source vith hot toiuene/ethyl acetate prior to the crystallisation.
Form 3 has been found to be more difficult to prepare substantially free of other physical forms than form X. In particular, it has been found that after form B has been crystallised and filtered off, it is difficult to remove the residual organic solvent vithout losing some of the vater of crystallisation.
Another physical form of compound 1 is amorphous, has an infra-red spectrum (0.5X in KBr) having sharp peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550 cm-1. This amorphous form of compound 1 is referred to hereinafter as form A. Because form A is amorphous, it is also characterised by an X-ray povder diffraction pattern having no discernable peaks.
Form A may be prepared substantially free of other physical forms by dehydrating form B, prepared as described above, at a temperature of about 120 °C under vacuum.
Form A has been found to be physically unstable in the presence of chlorofluorocarbon aerosol propellants, and is therefore unsuitable for use in an aerosol formulation. In particular, vhen suspended in a chlorofluorocarbon aerosol propellant, it has been found to change to a new, crystalline form, the crystals of vhich have been found to grov beyond a size suitable for use in a metered dose inhaler .
Form X has been found to be stable in the presence of chlorofluorocarbon aerosol propellants.
Each of the forms X, A, and B may conveniently be characterised for example by their X-ray povder diffraction pattern alone, or their infra-red pattern alone.
BAD ORIGINAL
In this specification, infra-red spectra vere determined using a 0.52 dispersion of sample material in a potassium bromide disc over the wave number range 4QC0 to 400cm \ Examples of infra-red spectra for each of forms X, A and B are given in Figures 1, 2 and 3 hereinafter.
X-ray povder diffraction spectra vere determined using 2g of sample material mounted in a Philips standard deep pack holder over the scanning range of 4-40° 2Θ counting for 4 seconds per point at 0.02 0 intervals to produce a trace of spacings against intensity for this range. Examples of X-ray povder diffraction spectra for each of forms X, A and B are given in Figures 4, 5 and 6 hereinafter.
The melting points of each of the forms X, A and B generally depend upon their level of purity. Typically, form X has been found to have a melting point of above 190 °C, for example about 200 °C; form A betveen 115 °C and 140 °C, for example about 124 to 132 °C; and form B about 140 to 160 ’C, for example from 145 to 155°C. Form B has been observed to lose vater at a temperature of from about 60 °C, and may not shov a sharp melting point.
According to another aspect, the invention provides a process for the preparation of form X substantially free of other physical forms, vhich comprises dissolving a source of compound 1 in ho: aqueous acetone, reducing the volume of the resultant solution by evaporation, adding toluene anc further reducing the volume by evaporation.
If it is desired to employ material vhich is a relatively impure source of compound 1, such material may advantageously be triturated vith hot toluene/ethyl acetate prior to the crystallisation step.
As stated previously, compound 1 possesses leukotriene antagonist properties. Thus, it antagonises the actions of one or more of the arachidonic acid metabolites knovn as leukotrienes, for
AP Ο Ο Ο 2 8 6
- 5 example, C^, and/or E^, vhich are known to be powerful spasmogens (particularly in the lung), to increase vascular permeability and have been implicated in the pathogenesis of asthma and inflammation (see J. L. Marx, Science, 1982, 215, 1380-1383) as veil as of endotoxic shock (see J. A. Cook, et al-, J. Pharmacol. Exp. Ther., 1985, 235, 470) and traumatic shock (see C. Denzlinger, et al., Science, 1985, 230, 330). Compound 1 is thus useful in the treatment of diseases in vhich leukotrienes are implicated and in vhich antagonism of their action is desired. Such diseases include, for example, allergic pulmonary disorders such as asthma, hay fever and allergic rhinitis and certain inflammatory diseases such as bronchitis, ectopic and atopic eczema, psoriasis, as veil as vasospastic cardiovascular disease, and endotoxic and traumatic shock conditions.
Form X may be administered by itself, for example by inhalation as a micronised povder, or in a pharmaceutical composition.
According to another aspect, the invention provides a pharmaceutical composition, vhich comprises form X substantially free of other physical forms and a pharmaceutically acceptable carrier.
The pharmaceutical composition may be formulated in a conventional manner, and may typically be in the form of tablets, capsules or suspensions for oral administration; in the form of suppositories for rectal administration; in the form of suspensions for parenteral administration; in the form of suspensions for inhalation administration by metered dose inhaler or nebuliser; and in the form of powders together vith pharmaceutically acceptable inert solid diluents such as lactose for administration by inhalation.
As stated hereinbefore, form X is especially suitable for use in a metered dose inhaler. According to a preferred aspect, therefore, the invention provides a pharmaceutical composition suitable for administration by a metered dose inhaler, vhich comprises form X substantially free of other physical forms and a pharmaceutically acceptable propellant.
BAD QR1G'.MAt
The non toxic pharmaceutically acceptable propellant may be any of those conventionally used in metered dose inhalers. Examples of propellants include chlorofluorocarbons, for example tricnlorofluoromethane, dichiorodifluoromethane and dichlorotetrafluoroethane; and 1,1,1,2-tetrafluoroethane.
The pharmaceutical composition suitable for administration by a metered dose inhaler may further comprise one or more other ingredients conventionally used in metered dose inhalers, for example oleic acid, sorbitan trioleate or lecithin.
The mean mass aerodynamic diameter of form X used in the aerosol composition is conveniently less than 50 microns, preferably in the range of from 1 to 50 microns, more preferably 1 to 10 microns, especially 1 to 5 microns.
The amount of form X present in the aerosol composition is conveniently from 0.01 to 10% by weight, preferably from 0.03 to 2%, more preferably from 0.05 to 1%.
The amount.of form X administered to a patient vill depend upon the weight of the patient and the severity of the disorder being treated, and the route of administration. Conveniently, a unit aerosol dose will comprise from 0.01 to 2.0 mg of form X, preferably from 0.02 to 1.0 mg, more preferably from 0.05 to 0.6 mg.
Administration may take place from 1 to 3 times per day, preferably from 1 to 4 times per day. A typical daily dose fcr a 70 kg patient will be from 0.01 to 16 mg, preferably 0.02 to * mg.
It has been found that micronised form X has very poor flow characteristics, and tends to adhere to many different types of surface. These properties are disadvantageous, because a powder vith poor flow characteristics is difficult to handle on a manufacturing scale. Furthermore, such a powder is unsuitable for use in a dry powder inhaler, especially one that utilises volumetric metering.
bad ob'G'NWAP Ο Ο Ο 2 8 6
- 7 A flowable state of form X has now been found, and is provided as a further feature of the invention.
Accordingly, the invention provides form X in the form of soft pellets consisting of an agglomeration of particles, at least 90% of which have a diameter of less than 10 microns, which pellets have a diameter in the range of from 50 to 900 microns.
The diameter of the pellets may be, for example in the range of from 75 to 250 microns, such as from 100 to 200 microns, or from 200 to 500 microns, such as from 250 to 400 microns, depending upon their intended use.
It has been found that form X in the form of soft pellets as defined above has good flow characteristics. Furthermore, it has been found that the pellets readily break down to the original particles vhen exposed to shear forces. These properties are particularily desirable in a povder intended for use in a dry povder inhaler, especially one that utilises volumetric metering. Thus, in a dry povder inhaler which utilises volumetric metering, it is important for povder to be .able to flow freely from a povder reservoir into-a dosing hole. It is also important, in any dry povder inhaler, that any agglomerates of particles are broken up before leaving the device, otherwise they vill be too large to be able to penetrate into the lungs .
According to another aspect, the invention provides a process for obtaining form X in the form of soft pellets, which comprises extruding micronised form X through a sieve having apertures vith a diameter in the range of from 150 to 700 microns, rolling the extruded material, and then screening the rolled material.
The micronised form X is preferably extruded through a sieve having apertures vith a diameter in the range of from 175 to 600 microns. The extrusion may conveniently be performed by passing the surface of a blade across povder on the surface of the sieve.
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- 8 The function of the rolling step in the process is to strengthen the agglomerates of particles formed in the extrusion step, and to mould them into a spherical shape. The rolling may conveniently be effected by allowing the agglomerates to tumble in a rotating vessel, preferably a cylindrical vessel.
The screening step removes over and undersized pellets. It is conveniently performed using two sieves vith apertures defining the upper and lover desired pellet diameters.
The following Examples illustrate the invention.
Example 1
Preparation of Form X
a) Preparation of an impure source of compound 1
Methyl 3-methoxy-4-(1-methy1-5-nitroindol-3-ylmethyl)benzoate (prepared as described in Example 4 of EP-A2-0199543) vas converted into the free acid by treatment with aqueous sodium hydroxide. The free acid vas then converted into the acid chloride by treatment vith thionyl chloride in dichloromethane. The acid chloride vas then reacted o-toluenesulphonamide in dichloromethane in the presence of 2.2 equivalents of 4-dimethylaminopyridine to afford the dimethylaminopyridine salt of 4-(l-methyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoyl-2-methylbenzenesulphonamide.
A solution of the dimethylaminopyridine salt of 4-(1-methy1-5-ni tro indol-3-ylme thyl )-3-me thoxy benzoyl-2-me thyl benz enesulphonamide (10 g) in 2-methoxyethanol (110 ml) and concentrated sodium hydroxide liquor (3.2 ml) vas charged to a nitrogen-purged flask containing 10% palladium on charcoal (3.3 g of a 60.9% vater-vet paste). The mixture vas then stirred under a hydrogen atmosphere at a pressure of 3 bar for 2.5 hours. The mixture vas then filtered through diatomaceous earth, and washed through vith 2-methoxyethanol (37.5 mi). To the combined liquors vas added cyclopentyl chloroformate (9.2 ml), and the mixture allowed to stir under an
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- 9 atmosphere of nitrogen overnight. The temperature was then adjusted to 3O-33°C, and 0.8M hydrochloric acid (68 ml) vas added over 20 minutes vith vigorous agitation. The mixture vas then cooled to 15-20 °C and stirred for one hour. The crystalline product vas then filtered off, vashed vith vater and dried at 50 °C. It vas then used in the next step.
b) Trituration of impure compound 1 g (0.101 gmol) of the product of step a), toluene 240 ml (4 volumes) and ethyl acetate 150 ml (2.5 volumes) vere slovly heated to reflux and 30 ml (0.5 volumes) of distillate vere collected to remove most of the released vater. The mixture vas heated under reflux for one hour (88-90 °C) and vas then cooled to 10-15 °C. After stirring for three hours at 10-15 °C, the solid vas filtered through a glass sinter and vashed vith a 2:1 mixture of toluene (80 ml) and ethyl acetate (40 ml). The product vas then dried to constant veight on the sinter to afford 53.2 g of dry compound 1 (yield 91.5X).
c) Preparation of form X (
The product of step b) (30.0 g, 0.0521 g mol) vas dissolved in acetone (150 ml) and vater (4.7 ml) by gentle heating to reflux, and the solution screened through a sintered glass funnel. The filtrate vas heated to boiling and 90 ml distillate collected.
Toluene (120 mi) vas added and a further 75 ml distillate collected. More toluene (120 ml) vas added and an additional 75 ml distillate collected. After heating for a further hour at reflux, the mixture vas cooled to 15-20 eC, and the product collected and vashed vith toluene (2x30 ml). The yield after drying on the sinter funnel vas 29.5 g (98.32).
SAD ORIGINAL (
- 10 Preparation of Form B
30.0 g of the product of step b), 210 ml acetone and 12 ml water were charged to a 500 ml reaction flask. The mixture was then heated under reflux for 15 minutes, and was then screened at 45-50 °C through a diatomaceous earth pad on a glass sinter directly into a 500 ml reaction flask. The flask and sinter vere washed vith a mixture of acetone (60 ml) and water (3 ml). The combined liquids vere then stirred in a water bath at approximately 40 °C and water (120 ml) vas added over five minutes. The mixture oiled out at first, but then rapidly crystallised. The mixture vas then cooled to 20 °C over one hour, stirred for tvo hours at 15-20 °C and then filtered. The product was washed vith water (60 ml), dried as far as possible on the sinter and then dried in an air oven at 60 °C (max.). The yield of form B vas 30.0 g (972).
It has been found that the drying conditions for form B must be strictly controlled in order to prevent loss of water.
Preparation of Form A
Form 3 prepared as described above (15.0 g) vas placed in a 500 ml round bottomed flask vhich was then evacuated on a rotary evaporator at 20 mbara. The flask and contents were then immersed in an oil bath preheated to 118 °C, and slowly rotated at this temperature for 6 hours. The mass was broken up on cooling to afford form A as a white powder.
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- 11 Example 2
Pharmaceutical Composition of Form X suitable for administration by a metered dose inhaler
Active ingredient 0.02g
Oleic acid O.Olg
Trichloromonofluoromethane 4.97g (chlorofluorocarbon 11)
Dichlorodifluoromethane 10. 5g (chlorofluorocarbon 12)
Dichlorotetrafluoroetnane 4.5g (chlorofluorocarbon 114)
Oleic acid, and then micronised active ingredient vere added to a tank containing the trichloromonofluoromethane. The mixture vas then homogenised and transferred into an aerosol canister. A valve vas then crimped onto the aerosol canister, and then the remaining chlorofluorocarbons vere introduced into the canister through the valve.
Comparison of the Stability of Form X in an Aerosol Formulation vith that of Form A
Compositions comprising form X or form A were prepared as described in Example 2 and stored at various temperatures and humidity levels for i. 3 and 6 months. Samples of the materials vere then sprayed onto a microscope slide and examined under a microscope. The results are summarised in Tables 1 and 2.
Samples from each stability test vere also studied by cascade impaction. The results are summarised in Tables 3 and 4.
The results of these comparative tests demonstrate the superiority of form X over form A in an aerosol formulation.
-Original.
Example 3
Pharmaceutical Composition of Form X suitable for administration by a metered dose inhaler.
Active ingredient 0.02g
Sorbitan trioleate 0.Q4g
Trichloromonofluoromethane 7.Og (chlorofluorocarbon 11)
Dichlorodifluoromethane 13.Og (chlorofluorocarbon 12)
The composition vas prepared by a method analogous to that described in Example 2.
bad
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- 13 Table 1
Microscopic Observations of Metered Dose Inhaler Formulation of Form X
Storage conditions
Ini tial
Particle Characteristics
Highly crystalline irregularly shaped particles vhich are <5um; some agglomerates (up to 12.5um) of these particles °C month 3 months 6 months
RT month 3 months 6 months °c/sc;;rh month 3 months 6 months °C
I month 3 months 6 months
NC - no change
RH = relative humidity
RT = room temperature
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
BAD ORIGINAL
Table 2
Microscopic Observations of Metered Dose Inhaler Formulation of Form A
Storage conditions
Initial °C month 3 months 6 months
RT month 3 months ό months ’C/802RH month 3 months 6 months
-0 3C month months 6 months
Particle Characteristics needles needles needles needles needles needles needles needles needles
needles, rods (many; up to 20x600ym)
needles, rods (only a few; up to
6xl73um)
needles, rods (more; up to 15x289ym)
needles, rods (many; up to 20xl50ym)
RH
RT relative humidity room temperature
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- 15 Table 3
Summary of Cascade Impaction Results for Metered Dose
Inhaler Product Containing Form X
Storage Condition
Ini t ial °C month 3 months 6 months
RT month 3 months 6 months ’C/30XRH month 3 months 6 months ’C month 3 months 6 months
MMAD = mass median aerodynamic diameter GSD = geometric standard deviation RT = room temperature
RH = relative humidity
MMAD (ym) GSD
3.94 1.67
3.60 1.95
3.60 1.64
3.16 1.53
3.64 1.78 3.53 1.66 3.67 1.62
3.74 · 1.89 4.25 1.75 3.98 1.66
3.73 1.89 3.76 1.64 3.67 1.62
BAD ORIGINAL 0
Table 4
Summary of Cascade Impaction Results for Metered Dose
Inhaler Product Containing Form A
Storage Condi tion MMAD (pm) GSD
Ini tial 2.00 1.82
4 °c 1 month 1.45 1.95
3 months 1.32 1.74
6 months 1.70 1.31
RT 1 month 1.70 1.87
3 months 1.53 1.77
6 months 1.80 1.85
°C.80%RH
1 month 1.76 1.77
3 mon ths 1.57 1.80
6 months »9.0
40 °C
1 month 1.41 1.76
3 months 1.70 1.84
6 months >>9.0 _____
MMAD = mass median aerodynamic diameter
OSD = geometric standard deviation
RT = room temperature
RH = relative humidity
BAD ORIGINAL
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- 17 Example 4
Table: Formulation of Form X
Granulating Material mg/tablet
Active ingredient 20 Croscarmellose sodium 5 Polyvinylpyrrolidone 4 Microcrystalline cellulose 74 Lactose 50 Purified vater for injection 98
Final Blend Material
Dried milled granulation 153 Lactose 20 Iroscarmellose sodium 5 .Microcrystalline cellulose 20 Magnesium stearate 2
The ingredients of the granulating material are vet granulated. The granules are then dried and milled. The dried milled granulation is then blended vith the other ingredients of the final blend mixture and compressed into tablets.
Example 5
Treatment of micronised form X to improve its flov characteristics
Form X vas micronised to produce a povder consisting of at least 982 by veight of particles having a diameter of less than 10 microns.
30g of the povder vas then placed in one heap on a brass sieve having an aperture size between 210 and 500 microns. The povder vas then
BAD ORfGfNAL
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- 18 extruded through the apertures of the sieve using a stainless steel palette knife. The extrudate thus formed vas then placed into a screw topped glass jar.
The glass jar vas then placed on to a set of rollers, vhich vere rotated at lOOrpm for between 8 and 20 minutes. The soft pellets thus formed were then sieved through an 850 micron sieve and then a 150 micron sieve, the fraction retained on the 150 micron sieve being the required product.
The soft pellets thus produced vere free flowing and relatively dust free. However the pellets vhen sheared, for example in a twin impinger, broke back down to the powder's original particle size distribution. This indicates that the pellets are suitable for use in a multidose dry povder inhaler that utilises volumetric metering to m^as.re out the doses.

Claims (7)

1. A physical form of N-[4-(5-(cyciopentyloxycarbonyl)amino-l-me thyl-indol-3-yImethyl]-3-methoxybenzoylJ-2-methylbenzenesulphonamide substantially free of other physical forms, vhich form is crystalline, has an X-ray povder diffraction pattern vith specific peaks occuring at 20=8.1, 13.7, 16.4, 20.5 and 23.7° and an infra-red spectrum (0.5X in KBr) having sharp peaks at 3370, 1670, 1525, 1490, 1280, 890, 870 and 550 cm'1.
2. A process for the preparation of a physical form of
N-( 4-(5-( cyclopentyloxycarbonyl)amino-1-me thyl-indol-3-ylmethy1]-3methoxybenzoyl]-2-methylbenzenesulphonamide as claimed in claim 1, vhich comprises dissolving a source of N-[4-[5-(cyclopentyloxycarbony1)amino-1-me thyl-indol-3-ylmethy1]-3-methoxybenzoyl]-2methylbenzenesulpnonamide in hot aqueous acetone, reducing the volume of the resultant solution by evaporation, adding toluene and further reducing the volume by evaporation.
3. A pharmaceutical composition, vhich comprises a physical form of N-(4-(5-(cyclopentyloxycarbonyl)amino-1-methyl-indol-3-ylmethyl ]-3-me tnoxybenzoyl ]-2-methylbenzenesulphqn.amide as claimed in claim 1 and a pharmaceutically acceptable carrier.
4. A pharmaceutical composition as claimed in claim 3, vhich composition is suitable for administration by a metered dose inhaler, and comprises a pharmaceutically acceptable propellant.
5. A composition as claimed in claim 4, in vhich the propellant comprises trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane or 1,1,1,2-tetrafluoroethane.
6. A physical form of N-[4-(5-(cyclopentyloxycarbonyl)amino-1-methyl-indol-3-yImethy1]-3-methoxybenzoyl]-2-methylbenzenesulphonamide substantially free of other physical forms, vhich form is crystalline, has an X-ray povder diffraction pattern vith specific badoriginm- S peaks occurring at 26=8.1, 13.7, 16.4, 20.5 and 23.7° and an infra-red spectrum (0.5% in KSr) having sharp peaks at 3370, 1670, 1525. 1490, 1230, 390, 370 and 550 cm”^, vhich is in the form of soft pellets consisting of an agglomeration of particles, at least 90% of vhich have a diameter of less than 10 microns, vhich pellets have a diameter in the range of from 50 to 900 microns.
7. A process for obtaining material as claimed in claim 6, vhich comprises extruding micronised particles of a physical form of N-[4-[5-(cyclopentyloxycarbony1)amino-1-me thy1-indol-3-ylmethy1]3-methoxybenzoyl]-2-methylbenzenesulphonamide as claimed in claim 1 through a sieve having apertures vith a diameter in the range of from 150 to 700 microns, rolling the extruded material, and then screening the rolled material.
APAP/P/1991/000341A 1990-12-12 1991-12-11 Physical form of an indolyl sulphonamide, processes for preparing it and pharmaceutical compositions containing it. AP286A (en)

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ATE145199T1 (en) 1996-11-15
EP0490649B1 (en) 1996-11-13
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