PT100507B - NEW PHYSICAL FORM OF DERIVATIVES OF HETEROCYCLIC AMIDES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Abstract

The invention relates to a physical form of N-[4-[5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl]- 3-methoxybenzoyl]-2-methylbenzene sulphonamide which is virtually free from other physical forms, this physical form being crystalline, its powder having an X-ray diffraction diagram with specific peaks which occur at the values of 2θ=8.1, 13.7, 16.4, 20.5 and 23.7 degree and an infrared spectrum (0.15% in KBr) with well marked peaks at 3370, 1670, 1525, 1490, 1280, 890, 870 and 550 cm-1, and also relates to a process for its preparation and pharmaceutical compositions incorporating that physical form. The invention also relates to a fluidisable preparation of this physical form which has the appearance of smooth granules and also describes a process for obtaining this preparation.

Description

Description referring to the IMPERIAL CHEMICAL INDUSTRIES PLC, British, industrial and commercial patent, with headquarters at Imperial Chemical House, Millbank London SW1P 3JF, England, (inventors: Martin Paul Edwards and John David Sherwood, resident in England), for NOVA PHYSICAL FORM OF HETEROCYCLIC STARCH DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM

DESCRIPTION

The present invention relates to heterocyclic compounds. More particularly, it refers to a novel physical form of a heterocyclic amide derivative, a process for preparing that physical form and a pharmaceutically-containing composition.

Before a solid compound can be formulated into a pharmaceutical composition, a physical form of the compound is sought that is physically stable and can be prepared essentially free from other physical forms. This last requirement is important because different physical forms may have markedly different bioavailability.

The publication of the patent application

European number EP-A2-0199543 describes certain heterocyclic amide derivatives that antagonize the pharmacological actions of one or more of the arachidonic acid metabolites known as leukotrienes. One of these heterocyclic amide derivatives

TF

N- [4- ^ 5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-yl-methyl] -3-m-toxibenzoyl] -2-methylbenzene-sulfonamide, hereinafter referred to as compound 1. Example 105 of PE -A2-0199543 describes the preparation of compound 1 and its isolation in the solid state. The material obtained had a melting point of 138 ^o -140 ° C.

It has been found that the compound can be isolated in the solid state as a material that has a range of different physical properties, depending on the isolation method. This ability is due to the fact that compound 1 can exist in more than one physical form and mixtures of those forms can be isolated.

A method for preparing a physical form of compound 1, essentially free from other physical forms has now been found and this form essentially free from other physical forms is provided in the present invention.

Consequently, the present invention provides a new physical form of N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methyl-indol-3-yl-methylJ-3-methoxybenzoyl ^ -2-methylbenzene-sulfonamide essentially free from other forms physical, formation of diffraction of what is crystalline, occur for 20 = 8.1, infrared (0.5% powder at

13.7,

Kbr) radius

16.4 in

X with

20.5 has a specific configurapicos and 23.7 that the and a spectrum

3370, 1670, 1525,

1490, which

1280, 890, has

870 and 550 cm sharp peaks to -1

The new physical shape

1, which is stable and hereinafter referred to as the compound's form physically and can be physical forms.

prepared essentially free from other

When reference is made in this specification to form X essentially free from other physical forms, this preferably means that at least 90% by weight of the compound 1 present is in that physical form.

The advantageous nature of form X can be demonstrated by comparing its properties

I τ with those of other physical forms of compound 1.

spectrum accentuated at cm and a

Another physical form of the compound 1 monohydrate (which is in KBr)

1660, 1540, diffraction

11.2, 14.6, an infrared (0.5%

3560, 1690, configuration

20 = 10.0, peaks for lens, which has, 1165, 880 radius and 23.0 ° has peaks 858

1440 of the title is hereinafter referred to as form B.

powder

19.8 what

This can be prepared in form B essentially free from other physical forms by crystallization from a hot aqueous acetone. In particular, it can be prepared by dissolving a source of compound 1 in aqueous acetone at an elevated temperature, adding more water and allowing the resulting mixture to cool. The crystalline product can be dried at an elevated temperature, for example, approximately 60 ° C or less. If it is desired to start from an impure source of compound 1, it has been found to be advantageous to crush this impure source with hot toluene / ethyl acetate before crystallization.

Form B has been found to be more difficult to prepare essentially free of other physical forms than Form X. In particular, it has been found that after Form B has been crystallized and filtered, it is difficult to remove the residual organic solvent without lose some of the water of crystallization.

Another physical form of compound 1 is amorphous, it has an infrared spectrum (0.5% in KBr) that has sharp peaks for 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550 cm. This amorphous form of compound 1 is referred to hereinafter as form A. As form A and amorphous it is also characterized by a powder diffraction configuration at X-ray that has no visible 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 b _are vacuo.

'i

Γ physically unstable in that of chlorofluorocarbons, in a formulation

of propellant aerosols so aerosol unstable. In particular, presence for the use of zaçao is suspended in an aerosol propellant of chlorofluorocarb, which has been found to be a grandchild, having been found to change to a suitable size.

stable in the presence of carbide.

you can put the hairs in for a crystalline form your crystals have been used for a new inhaler, in addition to a dose

There were propellants

Each form X was that of aerosols of chlorofluorouma of forms X, only conveniently characterized, for example, powder diffraction at X-ray, infrared.

be setting the configuration your of

In this specification, or only certain spectra are 0.5%, the potassium material is found in the range of -1 cm. For each X, A diffraction form of the

Colocadoθ sample placed infrared using a sample sample on a wavelength disk Examples of the spectrum, in Figures 1, 2 and

They were determined at X-ray using a support for the 4-4o carriage range by

They are to the de de

3,

2g of bromide

4000 to 400 infrared to follow.

material spectra of the

Phillips deep normalized °, counting 2Θ for 4 seconds point, for intervenes of 0.02 °, to produce a relation in function of the intensity spacings presented X-ray examples for each 6 to follow.

of spectra

To one of the X forms,

The data for this diffraction

B in Gamma Figures. from po

4, X, A and purity forms Normally, higher melting depend is verified at 190 ° c,

200 ° C;

points generally that form X has a melting point at each of its levels, for example, form A between 115 ° C and approximately

140%, for example, i

r

approximately between 124 and 132 ° C; and form B approximately for example between 145 and 155 ° C. It observed between 140 and 160 ° C,

Form B was said to lose water at a temperature of approximately 60 ° C and may not have an invention providing a strong melting point.

According to a process with another aspect, for the preparation of this form X is essentially free from other physical forms than the dissolution of a source of compound 1 in the reduction of toluene and reduction in the volume of the solution resulting from the additional volume of aqueous acetone evaporation, addition by by hot evaporation, which is ethyl material

If it is desired to be relatively impure, it should be crushed, advantageously, hot, before the crystallization step.

a source

As material to use compound 1, that with toluene / acetate mentioned above, leukotriene.

antagonists of one or more of the metabolites such as leukotrienes, for example has properties

Thus, it antagonizes the actions of arachidonic acid known as pio, C ^, and / or E ^, which are known to be powerful spasmogens (particularly in the lung) vascular bility and inflammation (see J.

as well as in and have implication

Science,

L. Marx, endotoxic shock (see Pharmacol. Exp. Ther (see C. Denzlinger, to 1 is so., 1985, 235, et al., Science, suitable in the treatment of leukotrienes and the example is desired, hay, bronchitis, eczema diseases in

J.

470)

1985,

1380-1383) et al. , J.

traumatic action involved. Such allergies and certain diseases include, due to asthma, fever of the ectopic and atopic inflammatory diseases, vasospastic psoriasis and conditions such as by do, for increasing the permeapathogenesis of asthma 1982, 215, A. CooK, and shock

230, 330). It comprises diseases in which pulmonary diseases are antagonistic to allergic rhinitis such as cardiovascular and traumatic endotoxic shock.

itself, for example or in a pharmaceutical composition.

Form X can be inhaled as a micronized powder can be administered

According to another aspect, this invention provides a pharmaceutical composition that includes form X essentially free from other physical forms and a pharmaceutically acceptable carrier.

be formulated in a

The composition, conventional and pharmaceutical form, can normally be in the form of oral administration;

rectal; in the form of a suspension in the form of an inhaler tablets, capsules in the form of suppositories for administration of administration of measurement of powders together with solid diluents pharmaceutically such inhalation.

or suspensions for administration suspension for parenteral nebulizer; dose inhalation; and in the form of inerts acceptable as lactose for administration by and especially dose-dosing. In

As before, Form X for use in a medi-inhaler provides

X essentially others acceptable.

suitable according to a preferred aspect pharmaceutical composition a ceutically ceutically acceptable inhaler of physical measurement suitable dose, this invention for administration includes the form forms and a pharmaceutical propellant can conventionally in toxic dose inhalers used.

Examples of propellants not any measurement of propellants include chlorofluorocarbons, by trichlorofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane; and 1,1,1,2-tetrafluoroethane.

The pharmaceutical composition suitable for administration by a dose metering inhaler may additionally include one or more other ingredients conventionally used in dose metering inhalers, for example, oleic acid, sorbitan trioleate or lecithin.

aerodynamic mass average diameter of form X used in the aerosol composition is conventionally less than 50 microns, preferably in the range of 1 to 50 microns, more preferably 1 to 10 microns, especially at 5 microns.

ί

The amount of form X present in the aerosol composition is conveniently between 0.01 and 10% by weight, preferably between 0.03 and 2%, more preferably between 0.05 and 1%.

to one of the disease the disease depends on being treated and

The amount of the form

X administered the patient's weight and unit of aerosol unit of gravity administration a dose and 2.0 mg of the preferable of 1

if it is conveniently necessary, and 1.0 mg, carry out, preferably between 0.02, 6 mg.

typical day

Administration preferably for a patient between may 1

0.01 more times form X, between 0.05 to 8 times

One mg daily dose, preferably 0.02 to 4 mg.

0.01 to 16 having the adherence to properties of poor fluency. Additionally, volumetric powder inhaler.

with

Kg can

It was found that form X very poor and different from surfaces. These are because a powder with characteristics of handling fluency characteristics and several disadvantageous types is difficult, such dust is dry, especially a micro industrial school.

unsuitable for use in a measurement

It has been found fluent in the form X which is provided as an end of this invention.

now an additional aspect state accordingly provides an X shape in the form of particles, less than 50 to 900 t and an agglomeration has a diameter and diameter in the range of this invention soft granules which consist of micron, micron.

least 90% of which granules having a diameter are, microns, of which for example or 200, is yours in the range of

500 microns,

use.

of the micron granules, from 100 to 200 from 250 to 400 microns, at 250 can depending

It was found that form X in the form of soft granules, as previously defined, has good creep characteristics. Additionally, it verified 7 ϊ

that the

granules broke quickly in the original particles when exposed to cutting forces. These properties are particularly desirable in a powder intended for use in a dry powder inhaler, especially those using volumetric measurement. Thus, in a dry powder inhaler that uses volumetric measurement, it is important that powder is able to flow freely from a powder reservoir to the dosing hole. It is also important, in any dry powder inhaler, that any clumps of particles break before leaving the device, and on the other hand they must be large enough to be able to penetrate the lungs.

According to another aspect, the invention provides a process for obtaining form X in the form of soft granules which includes extrusion of micronised form X through a sieve having openings with a diameter in the range 150 to 700 microns, rotation of the material extruded and then separates the material subject to rotation.

The micronised X-shape is preferably extruded through a sieve that has openings with a diameter in the range of 175 to 600 microns. The extrusion can conveniently be carried out by passing the surface of a blade through the powder over the surface of the sieve.

The function of the rotation step in the process is to strengthen the particle agglomerates formed in the extrusion phase and to shape them into a spherical shape. The rotation can be carried out conveniently, allowing the pellets to fall into a rotation vessel, preferably a cylindrical vessel.

separation step removes the granules without adequate size. It is conveniently carried out using two sieves with openings that define the upper and lower diameters of the desired granules.

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-methyl-5-nitroindol-3-yl-methyl) -benzoate (prepared as described in Example 4 of PE-A2-0199543) 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, in the presence of 2.2 equivalents of 4-dimethylamino-pyridine to produce the dimethyl amino pyridine salt of (4- (1-methyl-5- nitrindol-3-yl-methyl) -3-methoxybenzoyl-2-methylbenzenesulfonamide.

A solution of the dimethylaminopyridine salt of 4- (1-methyl-5-nitrindol-3-ylmethyl) -3-methoxybenzoyl-2-methylbenzene-sulfonamide (30g) in 2-methoxyethanol (130 ml) and hydroxide hydroxide was loaded. concentrated sodium (3.2ml) in a nitrogen purge flask containing 10% palladium on coal (3.3g of a 60.9% wet-water paste). The mixture was then stirred under a hydrogen atmosphere at a pressure of 3 bar for 2.5 hours. The mixture was then filtered through diatomaceous earth and washed with 2-methoxyethanol (37.5 ml). Cyclopentyl chloroformate (9.2 ml) was added to the combined liquors and the mixture was allowed to stir under a nitrogen atmosphere overnight. The temperature was then adjusted to 30-33 ° C and 0.8M hydrochloric acid (68 ml) was added over 20 minutes with vigorous stirring. The mixture was then cooled to 15-20 ° C and stirred for one hour. The crystalline product was then filtered, washed with water and dried at 50 ° C. It was then used in the next phase.

b) Crushing of impure compound 1

60g (0.101gmol) of the product from phase a), 240 ml of toluene (4 volumes) and 150 ml of ethyl acetate (2.5 volumes) were slowly heated to reflux and 30 m (0.5 volumes) were collected ) of the distillate to remove most of the water released. The mixture was heated under reflux for one hour (88-90 ° C) and then cooled to 10-15 ° C. After stirring for three hours at 10-15 ° C, the solid was filtered through a glass filter and washed with a 2: 1 mixture of toluene (80 ml) and ethyl acetate (40 ml). The product was then dried to constant weight on the filter to provide 53.2 g of dry compound 1 (yield 91.5%).

c) Preparation of Form X

The product from step b) (30, Og, 0.0521g / mole) was dissolved in acetone (150 ml) and water (4.7 ml) by gentle heating to reflux, and the solution was separated by means of a funnel. sintered glass. The filtrate was heated to boiling and 90 ml of the distillate was collected. Toluene (120 ml) was added and an additional 75 ml of the distillate was collected. More toluene (120 ml) was added and an additional 75 ml of the distillate was collected. After heating for another four hours at reflux, the mixture was cooled to 15-20 ° C, and the product was collected and washed with toluene (2x30 ml). The yield after drying on the sintered funnel was 29.5 g (98.3%).

Preparation of Form B

30 g of the product from step b), 210 ml of acetone and 12 ml of water were loaded into a 500 ml reaction flask. The mixture was then heated under reflux for 15 minutes and then and separated at 45-50Â ° C by filling diatomaceous earth over a glass pellet directly in a 500 ml reaction flask. The flask and the glass filter were washed with a mixture of acetone (60 ml) and water (3 ml). The combined liquors were then stirred in a water bath at approximately 40 ° C and water (120 ml) was added over five minutes. First the mixture was oily, but then it crystallized quickly. The mixture was then cooled to 20 ° C for one hour, stirred for two hours at 15-20 ° C and then filtered. The product was washed

with water (60 ml) it was dried as much as possible on the filter due and then dried in an air oven at 60 ° C (max.), the yield of form B was 30.0 g (97%).

It was found that the drying conditions for form B should be strictly controlled in order to avoid water loss.

Preparation of Form A

Form B prepared as previously described (15.0 g) was placed in a 500 ml round bottom flask in which the vacuum was made on a rotary evaporator at 20 mbar. The flask and contents were then immersed in an oil bath preheated to 118 ° C and swirled slowly at this temperature for 6 hours. The dough broke on cooling to provide Form A as a white powder.

Example 2

Pharmaceutical Composition of Form X suitable for administration by a dose metering inhaler

Active ingredient 0.02g Oleic acid 0.01g Trichloromonofluoromethane 4.97g (chlorofluorocarbon 11) Dichlorodifluoromethane 10.5g (chlorofluorocarbon 12) Dichlorotetrafluoroethane 4.5g (chlorofluorocarbon 114)

Oleic acid and then the micronised active ingredient were added to a tank containing trichloromonofluoromethane. The mixture was then homogenized and transferred to an aerosol can. A valve was then placed over the aerosol can and then chlorofluorocarbons were introduced.

Comparison of Form X Stability in an Aerosol Formulation with Form A

Compositions including form X or form A were prepared as described in Example 2 and stored at various levels of temperature and humidity for

1.3 and 6 months. Samples of the material were then sprayed onto a microscope slide and examined under a microscope. The results are summarized in Tables 1 and 2.

Samples from each stability test were also studied for cascade impact.

The results They are summarized in Tables 3 and 4. The results of these essay comparatives demonstrate form A in a formulation of aerosol superiority. form X on

Example 3

Pharmaceutical Composition of Form X suitable for administration by a dose metering inhaler.

Active ingredient 0.02g Sorbitan trioleate 0.04g Trichloromonofluoromethane 7.0g (chlorofluorocarbon 11) Dichlorodifluoromethane 13.Og (chlorofluorocarbon 12)

The composition was prepared by a method analogous to that described in Example 2.

»

Microscopic Observations of Form X Formulation for Dose Measurement Inhalers

Storage Conditions

Particle Characteristics

Initial

Highly crystalline irregularly shaped particles that are / 5um; some agglomerates (up to 12.5 µm) of these particles ° C month

NV months

NV months

NV

TA month

NV months

NV months

NV

C / 80ZHR month

NV

NV no

HR

TA months months month months months vary relative humidity room temperature

NV

NV

NV

NV

NV

Table 2

Microscopic Observations of the Dose Measurement Inhaler Form A Formulation

Storage Conditions

Initial ° C ^Λ months months months

TA month months months ° C / 80% HR month months months ° C month months months

Particles Characteristics needles needles needles needles needles needles needles needles, rods (several; up to 20x600um) needles, rods (only a few; up to 6x173um) needles, rods (more; up to 15x289um) needles, rods (several; up to 20x220um) 1

HR = relative humidity

TA = room temperature

Summary of Cascading Infraction Results for the Product

Containing Dose Measurement Inhaler Form X

Storage Conditions DAMM (one) DPG Initial 3.94 1.67 5 ° C 1 1 Month 3.60 1.95 3 months 3.60 1.64 6 months 3.16 1.53 OK 1 month 3.64 1.78 3 months 3.53 1.66 6 months 3.67 1.62 30 ° C / 80% RH 1 month 3.74 1.89 3 months 4.25 1.75 6 months 3.98 1.66 40 ° C 1 month 3.73 1.89 3 months 3.76 1.64 6 months 3.67 1.62

DAMM = aerodynamic diameter of mass average

DPG = geometric standard deviation

TA = room temperature

HR = relative humidity

Table 4

Summary of Cascade Impaction Results for Product containing Dose Measurement Inhaler Form A

Armory Conditions DAMM (one) DPG Initial 2.00 1.82 4 ° C 1 month 1.45 1.95 3 months 1.32 1.74 6 months 1.70 1.81 OK 1 month 1.70 1.87 3 months 1.53 1.77 6 months 1.80 1.85 30 ° C / 80% RH 1 month 1.76 1.77 3 months 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 -

DAMM = aerodynamic diameter of average mass

DPG = geometric standard deviation

TA = room temperature

HR = relative humidity

Material of

Ingredient

Form X Tablet Formulation

Granulation mg / active tablet

Croscarmellose sodium

Polyvinylpyrrolidone

Microcrystalline cellulose

Lactose

Purified water for injection

Final Mix Material

Ground granulation

Lactose

Sodium dry croscarmellose

Microcrystalline cellulose Magnesium stearate

153

The wet ingredients.

granulation are dry and ground granules. The granulated granulation mix ingredients with other tablets.

Treatment

The granule material dries are then final mixed and compressed into

Example 5 of the micronised X form for fluency characteristics to improve its characteristics. The form was micronized to produce a powder consisting of> _Λ particles that had a diameter of less than 10 microns.

at least 98%

They were then placed on a 250-micron metal sieve.

in one portion, are openings between 210 and then the powder through the

X for weight of bread,

30g a dimensionExtruded screen openings using an extruder spatula on the top.

screw formed into a v

like this

It was placed

then at 100

Glass rpm on a series of cylinders that were rotated between

and 20 minutes. The soft granules thus formed were then sieved through an 850 micron sieve and after a 150 micron sieve, the desired product being the faction retained in the 150 micron sieve.

The soft granules thus obtained flowed freely and were relatively free of dust. However, when the granules were subjected to a cutting action, for example in a double sampler, they broke showing the size distribution of the original particles of the powder. This indicates that the granules are suitable for use in a multidose dry powder inhaler that uses volumetric measurement to measure doses.

Claims (2)

Physical form of N- £ 4- £ 5- (cyclopentyl-oxy-carbonyl) amino-1-methyl-indol-3-yl-methyl2-3-methoxy-benzoyl-2-methyl-benzene-sulfonamide practically free from other physical forms, characterized by presenting its specific 20.5 and 23.7 ° crystalline, X-rays with peaks 16.4, po 20 = 8.1, 13.7, infrared (0.15% in KBr) 1670, 1525, 1490, 1280, 890, 870 and with this physical form a diffraction diagram occurs for the values a spectrum of accents at 3370, which and having peaks well 550 -1 cm. 2 ^â Process for the preparation of a physical form of N- [4- [5- (cyclopentyl-oxy-carbonyl) amino-1-methyl-indol-3-yl-methyl] -3-methoxy-benzoyl] -2-methyl- benzene-sulfonamide according to claim 1, characterized in that a source of N- [4- [5- (cyclopentyl-oxy-carbonyl) amino-1-methyl-indol-3-yl-methyl] -3- methoxy-benzoyl] -2-methyl-benzene-sulfonamide in a hot aqueous solution of acetone, if the volume of the resulting solution is reduced by evaporation, toluene is added and the volume is reduced again by evaporation. - 3- Pharmaceutical composition characterized by the fact that it incorporates a physical form of N- [4- [5- (cyclopentyl-oxy-carbonyl) amino-1-methyl-indol-3-yl-methyl] -3-methoxy-benzoyl] -2-methyl-benzene-sulfonamide according to claim 1 in conjunction with a pharmaceutically acceptable carrier. - 4 ^â - Pharmaceutical composition according to claim 3, characterized in that it is suitable for administration with a metered dose inhaler and incorporates a pharmaceutically acceptable propellant. - 5 ^The composition according to claim 4 wherein the propellant is selected from trichloro-fluoro-methane-dichloro-difluoro methane, dichloro tetrafluoro-ethane and 1,1,1,2-tetrafluoro-ethane. - 6 ^a Physical form of N - [^ 4- [5- (cyclopentyl-oxycarbonyl) amino-1-methyl-indol-3-yl-methyl] -3-methoxy-benzoyl] -2-methyl-benzene -sulfonamide practically free from other physical forms characterized by the fact that it is crystalline, its powder has an X-ray diffraction diagram with peaks occurring for the values 20 = 8.1, 13.7, 16.4, 20.5 and 23.7 ° and an infrared spectrum (0.15% in KBr) with very sharp peaks and 3370, 1670, 1525, 1490, 1280, 890, 870 and 550 cm, this form having the appearance of soft granules constituted by an agglomeration of particles of which 90% have a diameter of less than 10 microns and the granules' diameter is between 50 and 900 microns. _ 7a _ material according to Process for claim 6 obtaining one characterized by the fact that physical micronized particles extrusion of N- | 4-p5- (cyclopentyl-oxy-carbonyl) amino-1-methyl-indole-3-yl-methyl is carried out -3-methoxy-benzoyl2-2-methyl-benzene according to claim 1, across a diameter between -sulfonamide from a sieve that has holes with 150 and 700 microns, rolling The extruded material and then sieved The rolled material.