HU179755B - Process for producing cyclodextrine complex of 1-phenyl-1-bracket-3-trifluoromethyl-phenyl-aracket closed-propanol-1 - Google Patents

Abstract

1-Phenyl-1-(3- trifluoromethylphenyl)-propanol-1 forms inclusion complexes with cyclodextrins. The complexes may be prepared by contacting an aqueous solution of the cyclodextrin with 1- phenyl-1-(3-trifluoromethylphenyl)- propanol-1, in the presence of a water-miscible organic solvent having a small molecular weight. The inclusion complexes have a good stability and can easily be transformed into pharmaceutical compositions which are potent in inducing enzyme activity.

Description

The present invention relates to a process for the preparation of a cyclodextrin complex of 1-phenyl-1- (3-trifluoromethylphenyl) -propanol-1.

1-Phenyl-1- (3-trifluoromethyl-phenyl) -propan-1 (hereafter Zixoryn) is an enzyme inducing compound (U.S. Patent No. 168,432). The substance is a pungent, odorless, irritating, oily liquid with a characteristic odor. A single dose for adults is 100 mg. For therapeutic use, a precise dosage form is required, most commonly solid dosage forms. However, the problem with Zixoryn is the processing of the liquid active ingredient into a solid dosage form, as well as the unpleasant, pungent taste and irritation of the oral mucosa.

Zixoryn solid dosage forms can be prepared by two methods known in the art. In one embodiment, the oily active agent can be adsorbed onto a solid carrier having a high specific surface area and the adsorbate can be filled into a hard gelatin capsule. This method is difficult to implement under operating conditions, and the powder containing the active ingredient absorbed dust is coughing, irritating. Another possible solution is to microencapsulate the active ingredient. However, the microcapsules cannot be tableted, but may be administered by filling them in a relatively large volume hard-walled gelatin capsule.

It is an object of the present invention to provide a process by which Zixoryn can be made into a substantially tasteless solid product.

The present invention is based on the discovery that Zixoryn can be obtained from cyclodextrin in a well-defined, solid, crystalline, stable complex.

Cyclodextrins are formed from starch by the enzyme cyclodextrin transglucosylase; Macro rings of 6, 7 or 8 glucopyranose units, termed X-, β- and γ-cyclodextrin. All of the secondary hydroxyl groups of the glucopyranose moieties are located on one of the 10 edges of the macrocycle and the primary hydroxyl groups are on the other side of the macrocycle, so that the two edges of the ring are hydrophilic. The inner wall of the annular cavity is made up of ethereal oxygen bridges and hydrogen atoms and is therefore apolar. The ring is a relatively rigid structure because secondary hydroxyl groups of adjacent glucopyranose units form intramolecular hydrogen bonds with one another. When 'dissolving' cyclodextrins in water, the polar 'taste' molecules in the annular cavity contact the apolar cyclodextrin annular cavity wall 20 and are therefore energetically disadvantaged so-called high energy water molecules. By adding Zixoryn to aqueous solutions of cyclodextrin, it displaces high-energy water molecules from the cavity and thus produces an apolar-apolar interaction. This system is energetically favorable for 25, the complex is formed.

According to the invention, the cyclodextrin is present in the presence of water and optionally a low molecular weight, water miscible organic solvent.

We react with Zixory.

Cyclodextrin may be ζ-, β- or γ-cyclodextrin or a mixture thereof, preferably 3-cyclodextrin.

The low molecular weight water miscible organic solvent is preferably an aliphatic alcohol such as methanol or ethanol, an ether such as diethyl ether or dioxane or a ketone such as acetone.

In a preferred embodiment of the process of the invention, the cyclodextrin is dissolved in water or a mixture of water and ethanol with heating, preferably 50-80 ° C, and Zixoryn's ethanolic solution is slowly added and the mixture is cooled slowly over a few hours. the precipitated crystalline material is filtered off and dried.

The Zixorya Cyclodextrin Complex of the present invention is a white, almost odorless, powdery material which is well-compressible, the tablet disintegrates in water in a short time, the active compound is released from the complex in the gastrointestinal tract and is effectively absorbed. The complex may also be formulated as a suspension syrup.

The process of the invention is illustrated by the following embodiments.

β-cyclodextrin β-cyclodextrin-Zixoryn complex

2Θ 2Θ 12.3 16.8 5 14.6 17.0 15.3 17.4 16.1 17.9 17.1 19.2 10 17.7 19.9 18.0 20.7 18.9 21.9 19.5 23.7 20.8 15 21.4

The data in the table above demonstrate a crystal structure other than β-cyclodextrin for the β-cyclodextrin-Zixoryn complex. Given that the complexed molecule is liquid, the different crystal structure supports the fact of complexation.

EXAMPLE 1 β-Cyclodextrin (g, .35.7 mmol) (water content: 11.8%) was dissolved in 750 mL of water and 200 mL of ethanol at 50 ° C. A solution of Zixoryn (6.0 g, 21.4 mmol) in ethanol (50 mL) was slowly added dropwise over 1 hour to the resulting solution at 50 ° C. The mixture was then cooled to 10 ° C with constant stirring for 6 hours, the precipitated crystalline material was filtered off and air-dried. 46 g of Zixoryn (β-cyclodextrin) complex are thus obtained in the form of a white powder, having a Zixoryn content of 12.7% by weight and a moisture content of 9.7%, with no definite characteristic melting point.

The Zixoryn content of the complex was determined by dissolving 25 mg of the product in 50 ml of 50% aqueous ethanol and then photometric against 50% aqueous ethanol at 264 nm. My Zixoryn contents are determined using a calibration curve.

To verify that the resulting rooms are indeed complex, we performed the following studies.

X-ray diffraction studies

The characteristic reflection peaks of the product obtained by X-ray diffraction imaging can be observed at 2Θ angles, as shown in Table 1 below, the underlined numbers being the most intense peaks.

Table 1 β-Cyclodextrin

2Θ

4.5

6.2

8.8

9/7

10.6 β-cyclodextrin-Zixoryn complex 2Θ

5.7 h / h 6.9

11.0

Ϊ4Α

Thermoamplical tests

Differential scanning calorimetry and thermoderivatography showed significant differences between the Zixoryn-β-cyclodextrin complex and the Zyxoryn-β-cyclodextrin mixture. Zixoryn itself evaporates completely at 175 ^D C, and the differential scanning calorimetric curve shows an endothermic peak. The cyclodextrin physical mixture loses its crystal water content of below 100 ° C and 142 ^u C peak 35 wherein the drug content. Cyclodextrin itself start ⁼ 270 ° C and decomposed at 300 ° C sharp endothermic detected which refers to melting during the β-cyclodextrin decomposition. The active ingredient is released from the complex only when the cyclodextrin is degraded. 40

Mass spectrometry

Complex formation was confirmed by comparative mass spectroscopy 45. The time and temperature dependence of the mass spectra of the complex is very different from the physical mixture of Zixoryn and Zixoryn and β-cyclodextrm. Zixoryn evaporates at 120 ⁼ C during the test. In the case of β-cyclodexyrin, the degradation products 50 evaporated at about 240 ° C.

Mass spectrum data is shown in Table 2 (MS-902, 70 eV, direct addition: 240 ° C).

55 Table 2 Mass spectrum for β-cyclodextrin m / e TO / I / O 191 3.0 173 3.2 60 163 4.6 145 12 127 14 97 24 85 14 65 73 60

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m / e 1% 60 100 57 61 43 35 31 30 29 28

The physical mixture of Zixoryn (β-cyclodextrin), which contains the same amount of Zixoryn as the complex, exhibited a mass spectrum at pure 120 ° C of pure Zixoryn. Zixoryn had already dropped cl from the sample at 150 ° C, and peaks indicating degradation of β-cyclodextrin appeared only at 240-250 ° C. Mass spectral data are shown in Table 3 below (MS-902, 70 eV, direct dosing: 120 ° C).

Table 3

Mass spectrum of Zixoryn (β-cyclodextrin) physical mixture

m / e 1% Μ-X 262 3.1 M-18 261 3.3 M-19 251 100 M-29 173 57  M-107 145 15 M-135 105 12 M-175 77 9.5 M-203

The Zixoryn (β-cyclodextrin) complex only begins to evaporate at 240 ° C at the same time as β-cyclodextrin decomposes. Mass spectral data are in Table 4 (MS-902, 70 eV, direct

g: 240 C). Table 4 Zixoryn- (β-cyclodextrin) complex mass spectrum m / e 1% Comment 262 6 THE 261 4 THE 251 100 THE 173 73 THE 145 23 THE 105 18 THE 85 20 B 77 17 THE 60 13 B 57 23 B 55 17 B 43 59 B 31 64 B 29 35 B

Note: A: Zixoryn ion peaks,

B: degradation products of β-cyclodextrin.

EXAMPLE 2 β-Cyclodextrin (g, 35.7 mmol) (water content: 11.8%) was dissolved in a mixture of 380 mL of water and 130 mL of ethanol at 70 ° C, and 3 g of the solution was added dropwise over 30 minutes with vigorous stirring. 10.7 mmol) of Zixoryn in 30 ml of ethanol. The mixture was then cooled to 10 ° C over 5 hours, the precipitated crystalline material was filtered off and air dried. This gives 3 ", 0 g of product having a Zixoryn content of 8.0%.

The product thus obtained can be made into a suspension syrup by the addition of flavoring, sweetening and stabilizing agents. The dissociation of the complex in aqueous media is reduced due to the favorable β-cyclodextrin-Zixoryn ratio and the detectable taste of the active ingredient is minimized.

Example 3

Dissolve 148 g (115 mmol) of β-cyclodextrin (water content: 11.8%) in 1480 ml of water at 70 ° C and add a solution of 27 g (96.3 mmol) of Zixoryn in 200 ml of ethanol under vigorous stirring for 2 hours. . The mixture was cooled to 10 ° C with constant stirring for 16 hours, the precipitated crystalline material was filtered off and air-dried. In this way, 147.6 g of product are obtained with a Zixoryn content of 18%. The product can be easily compressed, even without the addition of binders, to form hard, hard, but rapidly disintegrating tablets in water.

Example 4 g (66 mmol) of β-cyclodexyrin (water content: 11.8%) was dissolved in 550 ml of water at 80 ° C and 12 g (114.2 mmol) of Zixoryn in 50 ml of water were added dropwise to the solution with vigorous stirring for 2 hours. ethanol. The mixture was then cooled to 10 ° C at a constant rate for 8 hours, and the precipitated crystalline product was filtered off and dried. This gives 113 g of product with a Zixoryn content of 27.9%.

The complex obtained by the process of the present invention may be formulated into a pharmaceutical composition as described in the following examples.

Example 5

500 g of β-cyclodextrin are suspended in 900 ml of water at room temperature. 120 g of Zixoryn was added dropwise to the suspension with vigorous stirring over an hour, and after the addition was complete, stirring was continued for another 5 hours. The precipitated crystalline product is then filtered off and air dried. 578.5 g of product are thus obtained with a Zixoryn content of 18.8%.

Example 6

11.7 g of β-cyclodextrin are moistened in a mortar with 10 ml of water and 1.3 g of Zixoryn is added dropwise with constant rubbing. The resulting suspension was homogenized for another half hour. 11.7 g of an air-dry product having a Zixoryn content of 11.0% are obtained.

Example 7

Suspension syrup

Parts

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Example 2 Zixoryn - ([3-Cyclodextrin)

Complexes 12.5g methyl p-oxybenzoate 0.1g flavor 0.5g5

CMC-Na 0.9g microcrystalline cellulose (Avicéi RC) 1.1g

Serbian 35g of distilled water gives 100 ml

The CMC-Na is dissolved in about half of the water, the microcrystalline cellulose is suspended in the solution and the complex is added after swelling.

In the remaining water, methyl p-oxybenzoate, flavoring, sorbitol are dissolved and the resulting solution is added to the suspension prepared as above. The suspension is then made up to 100 ml with distilled water and homogenized.

Example 8

Tabletta25

Parts

Example 3 Zixoryn (p-Cyclodextrin) Complex 556g Colloidal Silica 5g30 Magnesium Stearate 5g Microcrystalline Cellulose (Avicéi PH 102) 84g

The above materials were homogenized and the powder mixture was made into tablets 13 mm in diameter and having an average weight of 650 mg.

Claims (8)

A process for the preparation of a cyclodextrin complex of 1-phenyl-1- (3-trifluoromethylphenyl) -propanol-1, characterized in that in the presence of water and optionally a low molecular weight water-miscible organic solvent, the cyclodextrin is 1-phenyl-1 (3-trifluoromethyl-phenyl) -propanol-Ig. (Priority: February 28, 1980) 2. A process according to claim 1, wherein the reaction is carried out in an aqueous solution or suspension. (Priority: December 28, 1980) 3. The process according to claim 1, wherein the reaction is carried out in an aqueous solution in the presence of a low molecular weight water miscible organic solvent. (Priority: 23rd March 1979) 4. The process of claim 1 wherein the cyclodextrin is α-cyclodextrin. (Priority: 23rd March 1979) 5. A process according to claim 1 wherein the cyclodextrin is β-cyclodextrin. (Priority: 23rd March 1979) 6. The process of claim 1 wherein the cyclodextrin is γ-cyclodextrin. (Priority: 23rd March 1979) 7. A process according to claim 1 wherein the cyclodextrin is a mixture of α-, β- and γ-cyclodextrin. (Priority: 23rd March 1979) 8. A process according to claim 1 wherein the low molecular weight water miscible organic solvent is an aliphatic alcohol such as methanol or ethanol, an ether such as diethyl ether or dioxane or a ketone such as acetone. (Priority: 23rd March 1979)