DE2828074A1 - FORM II OF 2- (4-CHLORPHENYL) - ALPHA-METHYL-5-BENZOXAZOLYL-ACETIC ACID, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PRODUCTS CONTAINING IT - Google Patents

Description

3. A compound according to claim 1 or 2, characterized in that it is contaminated by less than 10% by weight of form I.

4. A process for preparing the compound of claim 1 to 3t characterized in that heating the Form I of benoxaprofen at a temperature from 90 to 170 ⁰ C.

5 »Process for the preparation of the compound according to claim 1 to 3» characterized in that benoxaprofen from a Solution in n-butyl acetate crystallizes slowly and in a controlled manner.

6. Pharmaceutical agent, characterized in that it is the form II of benoxaprofen as the active ingredient (active ingredient) according to claim 1 to 3, optionally in combination with at least one pharmaceutically acceptable one suitable therefor Carrier and / or excipient contains.

7. Use of the form II of benoxaprofen according to claim 1 to 3 in combating inflammation or inflammation related diseases.

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T 51 520-

Applicant; Lilly Industries Limited, Henrietta House, Henrietta Place, London W.1., England

Form II of 2- (4-chlorophenyl) -α-methyl 5-bensoxazolylacetic acid, method too their manufacture and pharmaceutical compositions containing them

The invention relates to a new polymorphic form of a pharmacologically active substance, a method for its Manufacture as well as pharmaceutical means or Medicines ™ means, which this new polymorphic form of the mentioned Contain substance.

In British Patent 1,435,721 and in one Article in the "Journal of Medicinal Chemistry", 18, 53 (1975), it is stated that the compound 2- (4-chlorophenyl) -ccmethyl ~ 5-benzoxazolyl-acetic acid, which is also known by its generic name "Benoxaprofen", an effective one represents anti-inflammatory agent currently

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clinically tested, is. This does not contain any references to the polymorphic properties of benoxaprofen »The manufacturing processes given in these publications, however, lead to the formation of the kinetically preferred polymorphic form of benoxaprofen _y, which is referred to below as" Form I "« This kinetically favored polymorphic form does not represent the thermodynamic one represents a stable form, hereinafter referred to as "Form II", and therefore tends to undergo polymorphic transformation upon storage. For example, statistical cyclical treatments carried out at temperatures between 4 and 37 C have shown that after 2 years there is a 20% conversion of form I to form II, taking into account that pharmaceutical preparations, de active ingredients of this type should generally have a service life of the order of magnitude of 5 years, it can be seen from this that the metastable nature of form I poses serious problems with regard to commercially available preparations such as tablets, creams and suspensions. For the discussion of some of the problems associated with the use of metastable forms of active ingredients in pharmaceutical preparations, reference may be made to the summarizing article in the "Journal of Pharmaceutical Sciences", 5J3, 8, 911 (1969).

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An object of the present invention is to provide a polymorphic form of 2- (4-chlorophenyl) ~ a-methyl-5-benzoxazolyl-acetic acid (Benoxaprofen) that is stable enough to be used for the manufacture of pharmaceutical preparations are used with a satisfactory service life or useful life to be able to.

This goal is achieved according to the invention with a polymorphic form (form II) of 2- (4-chlorophenyl) -a ~ methyl-5-benzo2: azolyl-acetic acid (benoxaprofen), its Crystals when using filtered plucking nickel radiation at λ = »1.5405 the following powder diffraction diagram exhibit:

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X-

"d" in A 11.77 8.06 7.07 5.67 5.30 5.06 4.79 4.41 4.17 3.93 3.65 3.56 3.24 3.09 3.03 2.97 2.81 2.75 2.66 2.57 2.37 j 2.29; 2.15 2.04 1.98 1.91 1.78

I / I c

10 10

70 100

10

20th

10

50

80

05

30th

90

60

40

15th

05

20th

05

02 8098S2 / 0939

The form II of. Benoxaprofen can also use its infrared spectrum can be distinguished from Form I. When using a Perkin Elmer 297 spectrophotometer, where the benoxaprofen homogeneously in a potassium bromide disk is dispersed (distributed), the following differences can be observed:

1 ») Form I has a sharp, moderately strong band

-1

at 880 cm, while Form II has a corresponding band at 885 cm "j

2.) in the range from 1200 to 1330 cm "both point Forms similar positions of the bands, but the strengths are different; In the form I the bands at 1220 and 1250 cm "are considerably stronger than the others, while in Form II all bands are of similar strength;

3f) the strong band near 1700 cm is at shape I considerably sharper than shape

Infrared analysis, which is the typical test procedure for a commercially available material, is sensitive enough to detect as little as 10% by weight of Form I in batches of Form II material. Form II lots examined using this spectral analysis method have turned out in pharmaceutical preparations, e.g. in tablets,

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~ t 2828CH4

Capsules or suspensions, proved to be completely satisfactory, so that these preparations are not in storage deteriorated or degraded.

According to a second aspect, the present invention relates to the polymorphic form II of benoxaprofen, which is contaminated by less than 10% by weight of Form I.

According to a further aspect, the present invention relates to Invention of a medicament or a pharmaceutical preparation, which as active ingredient is the form II of the above Compound benoxaprofen, possibly in combination with at least one suitable, pharmaceutically acceptable carrier and / or excipient.

The polymorphic form II of benoxaprofen in the above preparation should be used when using the above described infrared test method be pure, i.e. it should be less than 10% by weight of form I.

Form II can be prepared from Form I by heating the last-mentioned material to a temperature within the range from 90 to 170 ⁰ C.So example, the Form I by ER

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heat in a fluid bed dryer or fluid bed dryer to a temperature of about 115 C for a period of up to 3 hours into Form II being transformed. The higher the temperature used, the faster the polymorphic occurs Conversion of the form I into the form II. The form II can also be slow and controlled Crystallization as solutions of benoxaprofen in n-butyl acetate can be produced.

Form II crystals of benoxaprofen can also be prepared by the thermal decomposition of the Ammonium salt of benoxaprofen. . Temperatures within the range of 90 to 160 G after that in the U.S. Patent 4,098,437. In one aspect of this method, the benoxaprofen ammonium salt is used directly from the hydrolysis of 2- (p-chlorophenyl) -2-methyl-5-benzoxazoIy / acetonitrile isolated in the form of an insoluble precipitate. The precipitate is collected and stored at a temperature dried within the range given above, during the drying period the ammonium salt decomposes to give dry form II crystals of benoxaprofen. The drying will take so long continued until the decomposition of the ammonium salt is practically complete. The yield of material Form II is usually within the range of 95 to 98%.

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However, the ammonium salt can also be used in a solvent boiling within the range from 90 to 160.degree be suspended and the resulting suspension or slurry can preferably refluxed, i.e. it can be heated to the boiling point of the solvent, until the ammonium salt is almost completely converted to ammonia and the free, purified alkanoic acid is decomposed. When the purified acid formed in this way in the slurry used for the Ammonium salt (e.g. n-octane) is practically insoluble, form II obtained from benoxaprofen by heating the salt in the absence of a solvent. if Benoxaprofen in the solvent used to slurry the ammonium salt (e.g. n-butyl acetate) is soluble, an uncrystallized product is obtained. With any type of solvent can Benoxaprofen can be separated from the solvent by decanting or filtering «If benoxaprofen is soluble in the solvent used, the solution is usually concentrated and / or cooled, to improve the crystallization ^ and you get more crystals from the mother liquor.

The invention is illustrated by the following examples which illustrate the nature and advantages of the invention, approaches, but is not limited to

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example 1

The procedure described on page 55 of the Journal of Medicinal Chemistry, JL8 (1975), Method D, was meticulous repeated. A conventional recrystallization procedure, i.e. the ben- oxaprofen solution, was used in ethanol was prepared by heating on a steam bath and the resulting solution was cooled using an ice bath. The infrared analysis and the X-ray powder diffraction diagram both showed that only form I of benoxaprofen had formed.

Example 2

41 kg of 2- (4-chlorophenyl) -a-methyl-5 »benzoxazolylacetronitrile were hydrolyzed in 12N aqueous hydrochloric acid with stirring at 80 ° C. for about 2 hours.

o The reaction mixture was cooled to about 40 C and then slowly poured into cold water with vigorous stirring poured. The solid precipitate thus produced from 2- (4-chlorophenyl) -a-methyl-5-benzoxazolyl-acetic acid was collected by filtration and the filter cake was washed with water until the wash waters opposite Litmus no longer gave an acidic reaction. The filter cake was dried at 70 to 80 C, the yield was 40 kg (purity 77%). The filter cake was then dissolved in 48.3 l of dimethylformamide at 55 ° C. and

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the resulting solution was diluted with about 180 liters of acetone. The resulting solution was filtered, the filtrate was collected and about 11 l of a 28% aqueous ammonium

hydroxide solution was slowly added to the filtrate kept at about 35 ° C. over a period of about 1/2 hour. During the addition of aqueous ammonium hydroxide was the Anmoniumsalz of 2- (4-chlorophenyl) -a-meth.yl-5-benzoxazolyl _e ssigsäure slowly to give a slurry erhielt.Nachdem the addition of the ammonium hydroxide had been completed, was the The pH of the slurry was checked and it was found to be about 9 °. Then the slurry was cooled to about 0 ° C. in an ice / water mixture and the precipitated ammonium salt; was separated by filtration. The filter cake was washed with cold acetone (0 C) and the washed filter cake was dried in a tray dryer at 125 C for 3 hours. During this heating and drying period the ammonium salt decomposed, whereby the free acid 2- (4-chlorophenyl) -ct-methyl-5-benzoxazolyl-acetic acid was first obtained as Form I, which then underwent a thermal conversion into Form II? ? lay. 29.65 kg of purified free acid were obtained, which, as indicated by a corresponding evidence

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28280 ^ 4

was found to have a purity of about 95% ₀ The presence of Form II was shown by the X-ray powder diffraction diagram and infrared analysis. Using the same drying system, at the times and temperatures given below, Form II was obtained (in a purity of 97% or higher s) for 6 hours at 95 C, 2.5 hours at 125 ⁰ C, 1.5 hours at 140 ⁰ C, 0.5 hours at 155 ° C.

Example 3

892 g of Form I of benoxaprofen was suspended in 9.8 liters of n-butyl acetate and the stirred suspension was heated to the reflux temperature of the solvent to produce a solution. The temperature of the solution was then slowly reduced (at 10 C per hour) until Room temperature had been reached. The benoxaprofen crystals thereby obtained were filtered, washed with 892 ml of ethanol and dried in vacuo at 80 C, yield 760 g _# showed The infrared spectrum and the X-ray powder diffraction pattern of the crystals that the pure form II had been obtained.

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282807 *

Example 4

Using the components indicated below, tablets were prepared which had the form II of Benoxaprofen contained:

Form II of benoxaprofen 100 rag

Strength 55.1 mg

Polyvinylpyrrolidone 8.25 mg

Magnesium stearate 1.65 mg

The form II of benoxaprofen and the starch were used together mixed and granulated with the polyvinylpyrrolidone in the form of a 20% solution in water. then additional water was added to obtain a suitable granulate, which passed through a sieve stainless steel with a mesh size of 1 mm was passed. The granules thereby obtained became dried on a dish in a steam oven at 50 to 60 g. The dried granules were then passed through a sieve (with a mesh size of 0.5 mm), mixed with magnesium stearate and pressed into tablets. The tablets produced in this way were stored at 4, 25 and 40 ° C. for 2 years stored. There was no deterioration (deterioration) in the physical properties of the tablets or their appearance within this period.

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Example 5

The Form I of benoxaprofen was in 5 ml glass ampoules filled in and then subjected to cyclical temperature changes over a period of 2 years. The applied weekly cyclical program was the following:

Monday Tuesday Wednesday Thursday 37 ° C 4 ⁰ C 15 ⁰ C 37 ⁰ C Friday Saturday Sunday 4 ° C '15 ⁰ C 15 ° C

This test served to mimic the practical storage conditions. After 2 years the benoxaprofen was analyzed and it was found (by infrared analysis) that not less than 20% by weight of the Form ^v 4i had been converted into the Form II by a polymorphic conversion . This experiment clearly demonstrates the metastable nature of Form I benoxaprofen.

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Claims (2)

Claims; / 1 «" Form II of 2- (4-chlorophenyl) - i £ -methyl ~ 5 - t> enzoxazolyl- ^y acetic acid (benoxaprofen). 2. Form II of (2- (4-chlorophenyl) - <£ -methyl ~ 5-benzoxazolylacetic acid, characterized by the following powder diffraction diagram when using a filtered one Copper-nickel radiation with λ = 1.5405: "d" in X I / I 11.77 10 8.06 10 7.07 70 5.67 100 5.30 10 5.06 20th 4.79 10 4.41 50 4.17 80 3.93 05 3.65 30th 3.56 90 3.24 60 3.09 40 3.03 15th 2.97 15th 2.81 05 2.75 05 2.66 05 2.57 05 2.37 10 2.29 05 0FW31NAL! HSPECTCD 809862/0939