HU228817B1 - Process for preparing of sulphobutylated cyclodextrins of pharmaceutical additive quality - Google Patents

Abstract

The present invention relates to a process for the production of sulphobutylated cyclodextrin which can be used in pharmaceutical products. The material obtained by the process of the present invention is manufactured under suitable conditions for use in pharmaceutical products as additive, solubility enhancer, solubility reducing agent, solution structure and chemical structure stabilizer, drug carrier or base material.

Description

Cyclodextrins are cyclic, non-reducing oligosaccharides composed of 4C configurations of Dglyphopyranose units via α- (1,4) -glyazidic bonds. Each cyclodextrin is named by the number of glucose units that are assembled. For units 111. -8, β- and / or. It is distinguished by γ-elcodexyrins. The glucoptranose units constituting the cyclodextrins would be located on the surface of a truncated cone surrounded by a cavity. The inside of the molecule (cavity) is slightly apolar due to hydrogen atoms and glycosidic oxygen bonds. The narrower aperture of the truncated cone is bordered by the primary and the wider by the secondary hydroxyl groups. Due to the polar nature of the two edges of the A molecule, clclodextrins are highly soluble in water (except for β-cyclodextrin). eompiexes, Akadémiai Publishing House, Budapest, 1982),

The advantage of using elklodextrins in practice is that they are capable of binding hydrophobic molecules ("foreign molecules") to their apolar cavities by physical forces rather than chemical forces. The physical and chemical properties of a guest molecule introduced into the inclusion body may change (e.g., water solubility, stability), which may serve as a basis for. a wide range of pharmaceuticals (eg absorption of active substances), foodstuffs (eg stabilization of various aromas, vitamins), cosmetics (eg stabilization of skin care products) or

Cyclodextrins contain one primary and two secondary alcoholic hydroxyl groups per glucose unit (a total of 18, 21 to 24 free OH groups of α-, β-, γ-cyclodextrin), which are excellent opportunities for the production of a wide variety of cyclodextrins. By substitution of various hydroxyl groups, the eicodextrin cavity can be widened to become capable of interacting with larger molecules.

The sulfoalkylated cyclodexyrins were first described by Parmerter (US 3426011) in 1969, mainly as a phlooxylation promoter and as a papermaking aid. Stella et al. (WO 9402518) have been prepared with sulfoalkyl-eicodextrins as a pharmaceutical formulation excipient, mainly because of their low degree of formulation and high water solubility. These derivatives may be useful in parenteral and other pharmaceutical formulations.

The A

Generally, four compounds are required for the preparation of the sulfoalkylated cyclodextrins: cyclodextrin, solvent, alkali and alkylating agent. The reaction is essentially dependent on the type of solvent, the amount and quality of the base and alkylating agent, the temperature and the reaction time. The purpose of the use of sulfoalkylated cyclodextrins determines its desired quality. In the case of pharmaceutical applications, the product must meet particularly high quality requirements.

The carbon monobutyl cyclodextrins are. are prepared according to the following reaction scheme:

x = -oiaba-iafeSQsHa <sb>

or H

Y 6: a-CD

Y ^: ~ 7: B-CD Y ^::: 8: y ~ CD

In the case of sulfobutylcycloxiririn, this means the following requirements for the product: starting cyclodextrin <0.2% (due to renal impairment in parenteral use), alkylating agent <1 ppm (due to potential carcinogenic effect), by-products of the alkylating agent each <0.1%, heavy metal content: <ppm.

Limited cyclodextrin / 1,4-baranesynthone / sodium used in prior art processes. hydroxide ratios determine the product substitutional capsule (Partner US 3420001; Stella WO 9402518, WO 91-1722; Skhvmmos EP 0889056). In the prior art, excess butane sultone is precipitated by ethanol precipitation; or by adding excess alkali to the expected amount. Furthermore, in one case, the need to remove the reagent residue was ignored

The crude reaction mixture formed in the first stage of the process of the invention contains a significant amount of 1,4-butanesulfone (1000-5000 ppm), which is not fully eluted after 1-4 hours due to complexation with the starting cyclodexnans and / or the resulting product. 111. Reaction This technologically disadvantageous process of converting reactive butane sulton into a stable and relatively inert inclusion complex form can be eliminated by methods of other inventions, including the addition of a base to reduce the amount of residual bntansultone.

The basis of the present procedure is the recognition that the following technological steps are also suitable for reducing the amount of unreacted builder sultan:

a) promoting the dissociation of the resulting complex with a process-initiating additive followed by hydrolysis of the liberated buultan sulton with excess base in the reaction mixture;

(b) partial or total alcoholysis of small aliphatic alcohols with or without complex decomposition;

Combining process a) and b) increases the efficiency of the process.

The present invention offers the following advantages over prior art solutions:

the present process does not require the addition of a substantial amount of base to the reaction mixture, which, on the one hand, increases the number of steps in the technology and, on the other hand, makes subsequent removal of excess base difficult;

A preferred embodiment of the present invention involves the selective use of ion-exchange resins for the treatment of ionic-type by-products (4-bidroxybabansulfonic acid and its sodium salt, and 5-oxanonan-1,9-orsulfonic acid and its diacid salt) and / or ultrafiltration by labor cost (typically one business day), economical use of deionized water (up to 50%), and reduction of residual unsubstituted cyclodextrins using a cation exchange resin.

The use of an ammonesizing resin for similar purposes is exemplified in U. S. Patent Application Serial No. 56,584, but is novel in the preferred embodiment of the present invention. - Cation exchange resin may also be used.

In the present process, starting materials are α, β and γ-cyclodextrins. The present invention prefers the use of β-cyclodextrm.

The invention is further illustrated by the following non-limiting examples.

1

Example 1 illustrates the commercial scale applicability of the sulbutylation reaction.

Reaction sizing and reagent ratios are shown in the table below;

1 month mol • | Mok 5 β-eiklodsxírin 37.9 29.4 11 (.12% water content) 1 33.37 dry I Sodium hydroxide 10.7 268.4 j 9.13 t, 4-butanes (lton I) 33.6 247.0 ί 8> 4 Water ί 52.9 2940.0 1100

procedure:

Was charged with 52.9 1 of water was added to the reactor and 25 Co ^ö «37.9 kg cihlodextrín hidrától at such a rate that end, obtain a free keveríethetö suspension with stirring. Thereafter, 10.7 kg of sodium hydroxide are sprayed in several portions, while the internal temperature is ca. 50-55 ° C ~ Ig. Then start the reaction mixture was heated and when the internal temperature reached-62 ^C OO "C. Carefully start to add 33.63 kg (25.3 L) of butanesulfon (30-60 rpm). During dosing, during the initial period, the internal temperature gradually rises to 70-75 ° C. The temperature is maintained at 70-75 ° C throughout the addition. The addition funnel. Wash with 2x500 nd water. After completion of the gas addition, the temperature was maintained at 70-75 ° C for 4 hours, then 51% 96% ethanol was added to the reaction mixture, which was stirred for 20 hours at 70-75 ° C, and the reaction mixture was left at room temperature (20 ° C). -25 ° C)

Example 2

Describes further purification of reaction reagent 2 during which all impurities can be reduced below acceptable levels,

The reaction mixture obtained in Example 1 was worked up as follows: Brake A reaction mixture at room temperature (20-25 ° C) was added with enough ion exchange resin in the form T to reduce the reaction mixture to 2.5-3.0. The ion exchange resin is filtered off, washed with 10 L of water and 5 kg of activated carbon is added to the solution. The clarification is carried out for 3 hours at room temperature. The carbon is filtered off, washed with 10 L of water and the ion exchange resin in the form of OlT - is added to the filtrate to bind the anionic impurities. The pH of the solution is strongly alkaline, and then the ion exchange resin in H-form is added to the system to reduce the reaction mixture to a pH of 2.5-3.0 under these conditions. the mixture was stirred for 8 hours.

The ion exchange resins are filtered off, washed with 10 L of water and the acidic solution is clarified with 5 kg of activated carbon. .Carbon is filtered off. Wash with 10 L of water. The carbon derivation is repeated two more times.

The pI of the carbon-free solution is adjusted to 5.5-6.5, and the solution is deoxygenated and dried according to methods known per se (evaporation, drum drying, freeze-drying or spray-drying) to give 45 kg (yield: 73%), . typical average degree of substitution (DS) is 6.5, boulesulton content <1 ppm, ethanol content <5000 ppm.

Example 3

The reaction was carried out as in Example 1, but 2 liters of toluene were added to the reaction mixture instead of ethanol to displace the sultansulon from the cyclodextrin and stirred for another 20 hours at 70-75 ° C. such as water vapor desalination), Water is a sample. of toluene to form an azeotrope, the amount of toluene can be reduced under the reaction allowed to proceed I ppm, was allowed to cool to 20 to 25 ~ C ^fI The toluolmentes (<1 ppm) reaction mixture being.

The reaction mixture was purified as in Example 2. The carbon-free solution is freed from the solvent by methods known per se to give 47 kg of product (yield: 7756), characteristic ^::: DS 6.5, product buíánszulion toluene content of <1 ppm.

Example 4 The reaction of Example 4 was carried out as in Example 1, but after 20 hours of stirring, it was removed (eg by evaporation). The ethanol-free reaction mixture was allowed to cool to room temperature (2025 ⁿ C),

The reaction mixture was purified as described in Example 2. The carbon-free solution was de-solvented according to methods known per se to give 46 kg of product (75% yield), typical DS '~ 5. The product has an ethanol content of <30 ppm and a butane salt content of <1 ppm.

Example 5

The reaction was carried out as in Example 1, but after 20 hours of stirring, the ethanol was removed (e.g., by evaporation). The ethanol-free reaction mixture was allowed to cool to room temperature (2025 T).

To the reaction mixture at room temperature was added enough ion exchange resins on the HAfetum to lower the pH of the reaction mixture to 2.5-3.0. The ion exchange resin is filtered off, washed with water and then 5 kg of activated carbon is added to the solution. The clarification is carried out for 3 hours at room temperature, the carbon is filtered off, washed with 10 L of water and the ion exchange resin in OH form is added to the hair. The pH of the solution is strongly alkaline, and then the ion exchange resin at>-1 g is added to bring the reaction mixture to a pH of 2.5-3.0. At this. Stir at pH for 8 hours.

The ion exchange resin is filtered off, washed with W L of water and the pH of the solution is adjusted to 5.5-6.3 with 1M aqueous sodium hydroxide. A virtually neutral spy! solution is clarified with 10 kg of activated carbon. The carbon clarification is repeated two more times.

The carbon-free solution was de-solvented by methods known per se to give 41 kg (67%) of product, typical DS ^: 6.5. The products have an ethanol content of <30 ppm and a butane content of <1 ppm.

She. Example

The reaction is. The procedure was carried out as in Example 1, but without purifying the ethanol, purification was carried out as in Example 5 to give 43 kg of product (yield 70%), typical PS ^as 5. The product has an ethanol content of <5,000 ppm and a content of <RTI ID = 0.0> phylansonite </RTI><1 ppm.

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Claims (1)

CLAIMS 1. A process for the preparation of hexamethylselutylated eicodextrose in a solution of a strong base by reaction with feutaxone, characterized in that the compound is eliminated by removing the cyclodextrin inclusion complex and water at a temperature lower than about 2 ° C. C 1 -C 4 aliSs alcohols and toluene, and then the reaction mixture is purified with cation and anionic resin.