DE2449927A1 - NEW STABLE POLYMORPHIC CRYSTALLINE SHAPE OF 1-HYDROXY-3- (1 ', 1'-DIMETHYLHEPTYL) -6,6-DIMETHYL-6,6A, 7,8,10,10A-HEXAHYDRO-9H-DIBENZO SQUARE CLAMP ON B, SQUARE CLAMP FOR PYRAN-9-ON - Google Patents

Description

P ATE NTAN WÄLTS

DR. L MAAS

DR.'e. Mockery

8000 MONKS 40

SCHLEiSSHEfMERSTa 299

TEL. 3592201/205

X-4153 FRG

Eli Lilly and Company, Indianapolis , Indiana, V ^ St.A.

New stable polymorphic crystalline form of 1-hydroxy- Γ 3- (1 ', 1'-dimethylheptyl) -6, 6-dimethyl-6, 6a, 7, 8,10,1Oa-hexa hydro-9H-dibenzo / b, d / pyran-9-one

The invention relates to a new stable polymorphic crystalline form of 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6 ν6a, 7 _f 8,1O _r 10a-hexahydro-9H-dibenzo / b , d / pyran-9-one, which is capable of producing considerable blood levels in mammals long after oral administration of the medicinal product.

1-Hydroxy-3- ^ alkyl-6,6-dimethyl-6, 6a, 1, 8,10,1 Oa-hexahydro-9H-dibenzo / b, d / pyran-9-one, the ethers and esters of which are in US-PS 3,5Ο7,885 as intermediates for the preparation of

8 9 8 Q

- or A ₁ -Tetrahydrocannabinolen (£ \ - or / ^ -THC)

described. Apart from their use as intermediates, no other type of application is specified for these compounds.

/ \ "-THC and other structurally related dibenzopyrans, obtained either from natural sources or by various synthetic methods, are known to be extremely insoluble in aqueous media. The problem has always existed

509819 / 1U7

the determination of the pharmacological effects of this type of compound after oral administration, since it was impossible to know at all how much of this extremely insoluble one Substance was actually absorbed after oral administration. This difficulty determining the extent of the Absorption of these compounds is further complicated by the fact that the compounds are in a solid state may exist in several polymorphic forms.

According to the invention, a new stable polymorphic form of 1-hydroxy-3- (1 ·, 1 · -dimethylheptyl) -6,6-dimethyl-6,6a, 7, 8,10,1Oa-hexahydro-9H-dibenzo / b created d / pyran-9-one, which has the following physical characteristics: it shows under a polarizing microscope birefringence, has in differential thermal analysis at 156 ° C and 162 ⁰ C endotherms and has in the powdered state following Rontgenbeugungsspektrum when measured at chrominium radiation with a wavelength of 2.2896 A * works:

Diffraction in A

14.5 100

10.5 30

8.4 60

7.2 40

6.50 20

5.90 ao

4.85 60

4.10 05

3.90 40

3.35 30

50981 9 / 1U7

The novel polymorphic crystalline form of the present invention is made as follows: An ethanol solution of a physiologically not * available, orally not absorbable polymorphic crystalline form of 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6 , 6a, 7,8,10,10a-hexahydro-9H-dibenzo / b, d / pyran-9-one, with the oral administration of the medicinal product to mammals no significant Let blood levels build up. and that by recrystallization Made from acetone or hexane, it gets under very quickly. Stir. Added to a large amount of water. The dibenzopyranone, which is practically insoluble in water, precipitates immediately. One continues to stir for a short time, itfor one precipitated active ingredient of the desired polymorphic form with the physical properties indicated above is filtered off and dries.

To convert the new polymorphic form into the more common one to avoid crystalline forms, such as those obtained by recrystallizing the active ingredient from acetone or hexane, Crystallization inhibitors can be added such as polyvinylpyrrolidone, methy! cellulose, sodium alginate, Dextran, gelatin or acacia. If you work with such agents, then you should add them to the water add before this is mixed with the ethanolic solution of the active ingredient.

The new polymorphic crystalline form of 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo / b, d / Pyran-9-one can optionally also be prepared by preparing an ethanolic solution of the compound and then removing the solvent by evaporation at a temperature in the range from 20 to 30 ^° C. A rotary evaporator is preferably used for this purpose. The evaporation temperature can easily be kept at the desired value by using a large-volume water bath.

50981 9/1147

. A portion of 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a, 7, 8,10,10a-hexahydro-9H-dibenzo ^ b is mixed to produce a pharmaceutical preparation , & / pyran-9-one, in a polymorphic form which can be absorbed in accordance with the above requirements, thoroughly with new parts of corn starch, whereupon the mixture obtained is put into telescopic gelatine capsules and examined on two dogs with regard to its absorption capacity. The compound is administered orally in capsule form. The side effects observed with other orally absorbable forms or with parenteral injection can also be determined here * such as nods of the head, swaying of the body and ataxia. The starch preparation in capsule form is examined again two weeks later, and then again after 10 weeks, and identical results are obtained, which shows that the polymorphic form according to the invention is stable in the presence of starch. Other polymorphic forms of 1-hydroxy-3- ( 1 ' Λ ' -dimethylheptyl) -6, S-eimethyl-

\ 6 _f 6a, 7,8,10,10a-hexyhydro-9H-dibenzo / b, d / pyran-9-one are effective in solution or shortly after mixing with starch, but they slowly recrystallize or form one Complex with starch, adversely affecting its bioavailability.

The invention is illustrated in more detail by means of the following examples.

example 1

A solution of 1 g of 1-hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethy1-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo / b, d / pyran -

9-one in 25 ml of ethanol turns into a · »- _

Liters of water with a temperature of about 25 C. After the addition of the ethanol solution is complete, the mixture is stirred for about

509819/1 147

4 hours further. 1-Hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,63,7,8,10,10a-hexahydro-9H-dibenzoA>, d / pyran-9-one precipitates off, and the resulting precipitate is filtered off. The precipitated dibenzopyranone thus produced has the polymorphic form with the properties given above. The shape produced in this way is microcrystalline having a particle size range of 2.2 to 26 microns, with 50 volume percent having a particle size smaller than 7.2 microns to have.

Example 2

A solution of 1 g of 1-hydroxy ~ 3- (1 ', 1'-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10, iOa-hexahydro-9H-dibenzo / b, d / pyran -9-one in 25 ml of ethanol is placed in a rotary evaporator. The evaporation flask is located in a water bath kept ^{at 20 to 30 ° C.} The solution is then evaporated to dryness, whereby the dibenzopyranone is obtained in the polymorphic form with the properties indicated above.

509819/1147

Claims (2)

Claims 1.) -New stable polyxnorphic form of 1-hydroxy-3- (1 ', 1' -dimethylheptyl) -6,6-dimethyl-6,63,7,8,10,10a-hexahydro-9H-dibenzo / b , d / pyran-9-one having the following physical properties: birefringence under a polarizing microscope, endotherms under differential thermal analysis at 156 ⁰ C and 162 C and the following X-ray diffraction spectrum of the powder using a filtered Chrominiumstrahlung with a wavelength of 2.2896 S: Diffraction in S I / 1 14.5 100 10.5 30 8.4 60 7.2 40 6.50 20 5.90 30 4.85 60 4.10 05 3.90 40 3.35 30 2. Pharmaceutical preparation, characterized by a content of a new stable polymorphic form of 1-Hydroxy-3- (1 ', 1'-dimethylheptyl) -6,6-dimethy1-6,6a, 7,8,10,1Oa-hexahydro-9H-dibenzo / b, d / pyran-9-one according to claim 1 as an active ingredient and customary pharmaceutical auxiliaries and carriers. 5 09819/1147