HU202889B - Process for producing 2-hydroxi-propyl-alpha-, beta- and gamma- cyclodextrine - Google Patents

Abstract

The present invention relates to a process for the preparation of 2-hydroxypropyl alpha-, beta- or gamma-cyclodextrin, free of contaminants, partially, mainly, on secondary hydroxyl groups in the presence of alpha, beta or gamma cyclodextrin and propylene oxide base, \ t by reaction with an aqueous solution at 0-35 ° C under atmospheric pressure such that 1.2 to 4 moles of base per mole of cyclodextrin are used in the reaction, and after completion of the reaction, the base is neutralized with mineral acid or removed by cation exchange resin, the solution obtained is partially concentrated in vacuo, optionally the solvent having a higher boiling point of water is C2-C4 glycol and the solution is re-evaporated to a stirring point, then diluted with a C2-C6 alcohol and optionally acetone, optionally with a precipitate salt. the solution is filtered off with anhydrous precipitation In a solvent such as acetone, C2-C6 alcohol, tetrahydrofuran, the precipitated product is separated and, after partial evaporation after aqueous dissolution, clarified, filtered and dried. EN 202 889 A Scope of the description: 8 pages -1-

Description

The present invention relates to a novel industrial process for the preparation of 2-hydroxypropyl-alpha, beta or gamma-cyclodextrin, partially substituted mainly on secondary hydroxy groups, by reacting alpha, beta or gamma-cyclodextrin and propylene oxide in aqueous solution in the presence of a base. At 035 ° C under atmospheric pressure. The product is recovered by crystallization.

Cyclodextrins, as cyclic oligosaccharides, form inclusion complexes with appropriate sized guest molecules. Complex formation can advantageously be used to solubilize poorly water-soluble drugs and other active ingredients, to increase the stability of complexed substances, to enhance the selectivity of chemical reactions, and in many other areas (J. Cellul, Cyclodextrins and Their Inclusion Complexes, Budapest, 1982). ).

Chemical modifications of natural cyclodextrins may further enhance their advantageous properties and produce derivatives having the desired properties for special purposes (AP Croft, RA Bartsch, Tetrahedron 39,1417 (1982)). (1.81%, 25 'C).

Among the widely studied methylated derivatives, for example, the water solubility (571%, 25 'C) of heptakis (2,6-di-O-methyl) -beta-cyclodextrin, which is chemically uniform in crystalline form, is already quite satisfactory. In addition to the advantages, however, there are disadvantages. 30

Its water solubility decreases with increasing temperature and crystallizes upon heating. This property, for example, prevents its use in injection formulations because conventional heat sterilization cannot be used in its presence. Hemolytic activity is also increased.

Examining acute toxicity (iv rat) beta-cyclodextrin 450 mg / kg, of heptakis-2,6-di-O-methyl / beta-cyclodextrin 200 mg / kg LD _S0 values were (BW Müller, K. Brauns, Int. J. Pharm. 26, 77 40 (1985)). The disadvantages of solubility enhancement can be avoided by the addition of hydrophilic substituents under reaction conditions resulting in statistical substitution.

Comparative studies of many of the compounds prepared as described above have shown extremely advantageous properties for 2-hydroxypropyl-beta-cyclodextrin derivatives. Their water solubility is an order of magnitude better than that of the parent compound and increases with temperature. The LD ₅₀ value as measured above is greater than 2000 mg / kg. (B. W. Müller, K. Brauns, Int. J. Pharm., 1985, 26,77; J. Pitha, S. M. Harman, E. E. Michel, J. Pharm. Sci., 75,165 (1985)).

Its complexing properties are good, and the solubility properties of many drugs are preferably influenced 55 (U. Brauns, B. W. Miiller, Eur. Pat. Appl. EP149 197 (1985)).

In the case of beta-cyclodextrin, 2-hydroxypropyl derivatives can be prepared under appropriate conditions with 1,2-propylene oxide. During the reaction, the hydroxyl groups attached to the 2, 3 and 6 carbon atoms of the 7 D-glucose molecules constituting the 60 beta-cyclodextrin are also substituted in a proportion, depending on the reaction conditions, but predominantly random.

The degree of substitution can be controlled by the ratio of 1,2-propylene oxide: beta-cyclodextrin used. Characterization of the degree of substitution is inconsistent in the literature.

For clarity, the following terms should be defined, taking into account possible analytical approaches. The degree of substitution (S) gives the number of substituted hydroxyl groups on a given glucose unit. It can have a value of 1,2,3.

The average degree of substitution (DS) gives the average number of hydroxyl groups substituted on a glucose unit within a given cyclodextrin ring. Its value for beta-cyclodextrin may vary continuously from 0 to 3.0.

When, as in the present case, the cyclodextrin is substituted with a hydroxyalkyl group, the hydroxyl group of the introduced substituent may also be substituted with another hydroxyalkyl group, resulting in the formation of an oligomeric or polymeric chain. In this case, the average molar degree of substitution (MS) is used, which gives the number of substituents on the glucose unit relative to a cyclodextrin ring. Its value can continuously increase from 0 to above 3. The MS / DS quotient gives the average degree of polymerization (DP).

The ring substitution degree (RS) is the number of substituents on a given cyclodextrin ring. The value for beta-cyclodextrin may be an integer between 0 and 21, but may be greater than 21 for DP> 1. The average degree of substitution (PS) of a product is the average number of substituents on a given composition of a cyclodextrin ring. Its value for beta-cyclodextrin may vary continuously from 0 to 21. In case of Dp> 1 it may rise above 21.

The product obtained from the reaction of beta-cyclodextrin with 1,2-propylene oxide is heterogeneous in several respects. A given product of degree of substitution of PS is a mixture of tens of different cyclodextrin molecules of varying degree of substitution (RS).

Within a ring of a particular degree of RS substitution in the mixture, the degree of substitution (S) of each glucose moiety is also different and, moreover, may be in a different order relative to one another.

Finally, within a given glucose unit of degree S, the substituent may be located in three different positions. It follows from the above that the product is a mixture of a very large number of isomers of 2-hydroxypropyl-beta-cyclodextrin, which is generally characterized by the degree of PS substitution.

The first preparation of 2-hydroxypropyl-beta-cyclodextrin is described by Gramera et al. (R. E. Gramera, R. J. Caimi, US Pat. 3459731 [1969]). According to their process, beta-cyclodextrin is reacted in 1,2-propylene oxide with sodium hydroxide catalyst in methanol under pressure,

HU 202 889 A

120 ° C for 27 hours. During processing, the base is neutralized with tartaric acid and the resulting salt is filtered off.

The lower polymerization fraction of the byproduct polypropylene glycol is removed by vacuum distillation and the intermediate fraction is removed by dialysis, while the higher polymerization degree of polypropylene glycol remains in the product as a contaminant.

The reaction under high temperature and pressure is not industrially advantageous because it increases the risk of the highly toxic propylene oxide boiling at 35 ° C. Under the given reaction conditions, polymerization is brought to the forefront, resulting in a very high degree of molar substitution (MS-40-50). The product can not be sufficiently purified by a given processing and is thus not solid but only an oily form.

The preparation of 2-hydroxypropyl-beta-cyclodextrin in pure form, optimization of laboratory synthesis, and detailed characterization of the product were carried out by Pitha et al., J. Pitha, J. Biol., 2, 477 (1984); J. Pitha, J. Pharm. Sci., 74,987 (1985); J. Pitha, J. Milecki, H. Fales, L. Pannell and K. Uekama, Int. J. Pharm., 29.73 (1986)). .

According to their procedure, beta-cyclodextrin in aqueous solution (0.4-0.6 g beta-cyclodextrin / ml water) was added with sodium hydroxide catalyst (10 moles sodium hydroxide). moles of beta-cildodextrin) are reacted with 1,2-propylene oxide at atmospheric pressure for 24 to 72 hours at room temperature to give the desired degree of substitution.

The reaction mixture is worked up by first neutralizing the base with hydrochloric acid and then evaporating the solution to dryness in vacuo. The crystalline syrup obtained is suspended in ethanol, the insoluble sodium chloride is filtered off. is mixed to remove residual propylene glycol and to narrow the RS distribution.

The product is then filtered off, dried in vacuo, then dissolved in water and lyophilized to give the purified product as a white powder. The average degree of substitution (PS) is calculated from the product's * H-NMR and FAB-MS spectra

The preparation of 2-hydroxypropyl-gamma-cyclodextrin is described in Hungarian Patent No. 198092.

It is disclosed that gamma-cyclodextrin and methyl oxirane are reacted in the presence of a base at 110 ° C under pressure in the presence of an inert solvent. After the reaction, the mixture is acidified with hydrochloric acid and the volatile components are evaporated. The salt formed (sodium chloride) is removed on an ion exchanger and the resulting material is freeze-dried. The product is uncharacterized, but the process is expected to have similar problems as the method described by Gremera et al.

Due to hydroxypropylation with 1,2-propylene oxide, the crude product contains a large amount of polypropylene glycol impurities with varying degrees of polymerization, which liquefies the substance, especially preventing its use for medicinal purposes.

In the known processes, 2-hydroxypropyl cyclodextrin was purified by dialysis and freeze-drying. However, these methods are not economically feasible on an industrial scale 10, and we therefore aim to realize an industrial method, in particular crystallization purification.

In the previous processes described above, the primary hydroxyl groups attached to the C 6 carbon atom of the glucose unit were primarily substituted under the reaction conditions described. However, the primary motive for the chemical modification of beta-cyclodextrin is to improve poor water solubility.

The crucial role in anomalously low water solubility is due to the intramolecular hydrogen bonding system formed between the secondary hydroxyl groups, so substitution of the primary hydroxyl groups contributes less to the solubility of the female than the partial substitution of the secondary hydroxyl groups.

The main object of the present invention is to provide a process on an industrial scale for the preparation of 2-hydroxypropyl-beta-cyclodextrin free of impurities. Based on the above, the tasks to be solved are as follows:

- Carry out the reaction to minimize the amount of polypropylene glycol byproduct while reducing polymerization.

- In contrast to the primary hydroxyl group at position 6, the positions 2 and 2 were Preferred substitution of the 3-position secondary hydroxyl groups.

- Removal of applied base.

- Removal of the polypropylene glycol formed.

- Narrowing down the degree of substitution (RS).

- Desolvent the product.

- Recovery of the product in solid form.

Examining the reaction conditions, water has been found to be advantageous in comparison to the inert solvents since the polymerization in the aqueous medium is suppressed, the secondary reaction being primarily hydrolysis of propylene oxide and only a low degree of polymerization of di-, tri-propylene glycol.

The base plays a dual role in the reaction, increasing the solubility of beta-cyclodextrin by 50 parts and catalyzing the reaction. In order to facilitate subsequent processing, we have examined the minimum amount of base that still provides acceptable solubility and reaction rate.

In Table 1, the solubility of BCD in aqueous sodium hydroxide solution at 25'C is plotted against the sodium hydroxide: beta cyclodextrin (BCD) ratio.

See table below. page:

HU 202 889 A

Table 1

NaOH / BCD mol / mol BCD / H ₂ O g / 100 mL 0.0 1.28 0.57 2.34 1.13 4.95 1.70 18.90 2.27 85.00 3.40 115.00

The desired solubility value is approx. 50 g of beta CD / 100 ml of water as the reaction mixture can be stirred but the dilution is not too high. It can be seen that this value is already approx. Also available with 2 moles of sodium hydroxide / mole of beta-CD, does not require the large amount (10 moles) of base used by Pitha et al.

Comparative studies of reactions conducted at 2 molar to 10 molar sodium hydroxide per mol of beta-CD have surprisingly found that lower base concentrations also have other beneficial effects.

In Table 2, the amount of propylene oxide utilized in the substitution is given as a percentage of the propylene oxide introduced as a function of the amount of base used and the degree of substitution (PS) of the product under other similar reaction conditions.

Table 2

PS utilized t / propylene oxide (%) NaOH / beta-CD ratio (mol / mol) 2 10 2 78 66 4 78 50 6 76 47 8 69 44 10 61 37

It can be clearly seen that at lower base amounts, the yield per propylene oxide is significantly higher at each degree of substitution. The salting-out effect of the base on the otherwise water-soluble propylene oxide is substantially reduced at a lower amount of base, so that the propylene oxide remains in solution.

Surprisingly, it has been found that the amount of the base also substantially affects the position of the substitution. Substitution of the secondary hydroxyl groups is highly advantageous for increasing the solubility of the beta-cyclodextrin, since this effect can be achieved mainly by the strong hydroxylation of the secondary hydroxyl groups. Similar results were obtained with other alkali metal and alkaline earth metal hydroxides and oxides.

It has been surprisingly found that when the reaction mixture is neutralized with hydrochloric acid to remove the base used, the resulting aqueous concentrate is diluted with one or two volumes of ethyl alcohol, and no sodium chloride is formed.

However, it is advantageous to precipitate and filter out the sodium sulfate formed during the neutralization of sulfuric acid by diluting the concentrate with ethyl alcohol or acetone, for example the sodium sulfate content of the concentrate after precipitation with a single volume of ethyl alcohol is 8-12% by weight. Can be reduced below 0.2%.

After desalination, further purification of the product, removal of the polypropylene glycol and reduction of the degree of substitution (RS) on an industrial scale seems to be feasible primarily by crystallization. Vacuum distillation in a commonly used mixing apparatus does not allow the neutralized reaction mixture to be evaporated to dryness, leaving 60-1001% of water relative to the beta-cyclodextrin added in the dense syrup obtained at the end of the distillation.

The crystallization of propylene glycol has the potential to significantly differ in solubility from 2-hydroxypropyl-beta-cyclodextrm in several solvents according to our measurements (Table 3).

Table 3 shows the solubilities of the propylene glycol mixture (abbreviated as PPG) and 2-hydroxypropyl-beta-cyclodextrin (abbreviated as HPBCD-PS-3) in the reaction mixture without the beta-cyclodextrin in various solvents, 25 '. C.

Table 3

Solubility (g / 100 ml solvent) Solvent HPBCD PS-3 PPG Water 83 <50 methanol 83 <50 ethanol 2 <50 isopropanol 0.25 <50 N-propanol 0.15 <50 acetone 0.1 <50 tetrahydrofuran 0.1 <50 Ethyl acetate 0.1 <50

The amount of propylene glycol formed during the reaction, depending on the degree of substitution of the product

EN 202889 Changes. For PS-2, approx. 10%, while for PS-10 approx. 50% PPG is produced.

Reduction of the degree of substitution (RS) is made possible by the solubility of the product depending on the degree of substitution. Thus, the lower degree of substitution components can be precipitated in parallel with the salt precipitation, while the higher substitution levels remain in the mother liquor.

Crystallization of the product from the aqueous ethanol solution obtained after desalting has surprisingly shown that the product precipitates in a non-crystalline form when tested with a number of precipitating solvents.

A fundamental recognition of our invention is the observation that the crystallizability of the product is decisively determined by the water content of the crystallization system. If the water content exceeds the allowable value, depending on the degree of substitution, the temperature and the solvent used, the product will drain. As a result, crystallization of the product can only be accomplished by reversing the addition of the product in aqueous ethanol to an appropriate anhydrous solvent.

In Table 4, the maximum allowable water content with respect to acetone at 25 ° C, as a function of degree of substitution (PS), is given.

Table 4

Degree of Substitution (PS) Max. Allowable water reservoir, mixed (%) 2.9 5.3 3.2 4.7 5.1 3.0 5.8 2.5 7.6 1.3 9.5 0.8 11.0 0.1

In Table 5, the maximum allowable values for acetone and products with a degree of substitution of PS = 3.2 are allowed. water content as a function of temperature.

Table 5

Temperature ('C) Max. Allowable water reservoir, mixed (%) 1 6.5 12 5.5 22 4.8 31 4.0 44 3.5

In Table 6, the product of the degree of substitution PS-3.2 at 25 'C has a max. allowable water content for various precipitating solvents.

Table 6

Solvent Max. Allowable water reservoir, mixed (%) N-propanol 4.8 acetone 4.7 Tert-butanol 4.5 N-butanol 2.8 tetrahydrofuran 2.0 dioxane 1.2

From the above data, it can be seen that if the water remaining in the concentrate is about 10% of the beta-cyclodextrin input. 701%, a large amount of solvent is required to dilute the water content below the critical value.

Acetone of at least fifteen times the volume of PS-3,2 and at least thirty-five times the volume of PS = 5,1 must be used for beta-cyclodextrin.

In order to reduce solvent consumption, it is desirable to further reduce the amount of water remaining, particularly when producing a higher degree of substitution.

It has been found that this can be achieved by using a solvent having a higher boiling point than water, which is well soluble in the product, by adding it to the concentrate in a quantity comparable to the water to be removed and further distillation. Examples of suitable solvents are glycols. To avoid the introduction of a new impurity component, 1,2-propylene glycol is preferred. In this case, the particular situation arises that the amount of the impurity is further increased to remove the polypropylene glycol mixture which also contains a large amount of the impurity polypropylene glycol.

The present invention thus relates to a novel industrial process for the preparation of 2-hydroxypropyl-alpha, -beta- or-gamma-cyclodextrin partially free of contaminants, mainly substituted on secondary hydroxy groups, in the presence of a base of alpha, beta or gamma-cyclodextrin and propylene oxide. in an aqueous solution at 0-35 DEG C., at atmospheric pressure using 1.2-4 moles of base per mole of cyclodextrin, after which the base is neutralized with mineral acid or removed with a cation exchange resin. the resulting solution is partially concentrated in vacuo, the residue is optionally added to C2-C4 glycol as a boiling solvent above water, and the solution is again evaporated to mixability, diluted with a C2-C6 alcohol and optionally acetone, and the precipitated salt is optionally filtered, then stirring the solution víz5

Addition of the free precipitating solvent, such as acetone, C 2 -C 6 alcohol, tetrahydrofuran, the precipitated product is separated, and after partial evaporation after aqueous dissolution, it is purified by filtration and dried.

In a preferred embodiment of the process of the invention, the reaction between beta-cyclodextrin and propylene oxide is preferably carried out in the presence of 1.22.5 moles of base per mole of cyclodextrin. The base may be an alkali metal, alkaline earth metal hydroxide or oxide, preferably sodium or potassium hydroxide.

After completion of the reaction, the reaction mixture is neutralized with a cation exchange resin or a mineral acid, preferably sulfuric acid, and then distilled under reduced pressure to stir.

For a higher degree of substitution product, the solvent is added to the concentrate in an amount exceeding the boiling point of water, which is well soluble in the product, up to half the amount of cyclodextrin added, and the evaporation is repeated until stirring. Preferably, the solvent is 1,2-propylene glycol.

The concentrate is then diluted preferably with a single volume of ethyl alcohol or, in the case of a higher degree of substitution product, with propanol, butanol or acetone, or a mixture thereof. If a mineral acid is used, the precipitated salt is filtered off. The filtrate is mixed with vigorous stirring, preferably cooling, in an amount of water, preferably about cyclohextrin. The precipitated product as a fine white precipitate is centrifuged and washed with the precipitating solvent and then dried. The product is precipitated in a precipitate which is approximately 15 times more concentrated in acetone, n-propanol, tert-butanol, tetrahydrofuran. The solvent content of the product can remain 1-2% even after vigorous drying. To remove residual solvent, the product was dissolved in a few volumes of deionized water, part of the water was distilled off at atmospheric pressure, and the residue was clarified and filtered by spray drying.

The process of the present invention is also well applicable to the preparation of 2-hydroxypropyl derivatives of other cyclodextrins, such as 2-hydroxypropyl-alpha-cyclodextrin and 2-hydroxypropyl-gamma-cyclodextrin. In the process described, both alpha-cyclodextrin and gamma-cyclodextrin exhibit similar behavior to beta-cyclodextrin. For example, in the crystallization of 2-hydroxypropyl-alpha-cyclodextrin (PS-3.8), max. the permissible water content is 4.8% by weight and, in the case of 2-hydroxypropyl-gamma-cyclodextrin (PS-3,4), 4.2% by weight.

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

Example 1

Preparation of 2-hydroxypropyl-beta-cyclodextrin (PS-3,2)

To a 2501 mixer was added 76 kg water, 2.4 kg sodium hydroxide, then 40 kg (about 13% water content) beta-cyclodextrin and stirred until dissolved.

The solution was cooled to 20 ° C and 9.9 kg of 1.2 propylene oxide was added. The apparatus was sealed and the reaction mixture was stirred at 25 ° C for 24 hours.

The reaction mixture was then neutralized with 12 L of 5N sulfuric acid and then distilled in vacuo to 64 kg of water. 83 kg of ethanol are added to the concentrate with stirring, and then, under vigorous stirring, pressed through a 1001 pressure filter into 540 kg of acetone. The apparatus and the precipitate filtered through the filter were washed with ethanol (24 kg).

The crystalline mass was cooled to 10 ° C, then centrifuged and washed with acetone. After drying, white crystalline product weighs 39 kg,

The dried product is dissolved in 120 kg of deionized water in a 250 L apparatus and then 40 kg of water are distilled off at atmospheric pressure. The concentrate was clarified with charcoal, filtered through a pressure filter and dried in an atomizer.

Weight of product obtained as fine white powder:

36.5 kg (91%), degree of substitution, PS-3.2 (based on 1 H NMR), m.p. 266-271 ° C. 1 H-NMR (D ₂ O) 0.9-1.2 ppm: CH ₃ -CHOH-CH ₂ -.

doublet

3.1-4.1 ppm: CH ₃ CHOH-CH ₂ - + BCD frame protons, multiplet

4.9-5.2 ppm: BCD anomeric protons, doublet sulfate ash 0.1t% water content 3.11% propylene glycol content <0.1t%

Example 2

Preparation of 2-hydroxypropyl-beta-cyclodextrin (PS-3,2)

The procedure described in Example 1 was followed except that the reaction mixture was neutralized with 60 kg Varion-KS cation exchange resin. The dried solution (57 kg) was dissolved in 120 kg of deionized water without drying and then 60 kg of acetone-water were distilled off. The product obtained after spray drying weighed 36.1 kg (90%). Its quality is the same as in the first example.

Example 3

Preparation of 2-hydroxypropyl-beta-cyclodextrin (PS-5,1)

Weigh 76 kg of water, 2.4 kg of sodium hydroxide and 40 kg (about 13% by weight of water) of beta-cyclodextrin into a 250 L apparatus. Stir until dissolved, cool to 20 ° C and add 15.5 kg of 1.2 propylene oxide.

After stirring at 'C for 24 hours, it is neutralized with 1215 N sulfuric acid. 63 kg of water was removed in vacuo from the solution, 14 kg of 1,2-propylene glycol was added to the concentrate and an additional 14 kg of water was distilled off. The concentrate was diluted with 20 kg of ethanol and 70 kg of acetone and, with stirring through a pressure filter, pressed into 540 kg of acetone cooled to 10 ° C. The crystalline mass was cooled to 0 ° C, centrifuged and washed with a total of 120 kg of acetone. The resulting 59 kg fuganed-61

The etching agent is dissolved in 130 kg of deionized water without drying, and 70 kg of acetone-water are then distilled off at atmospheric pressure. The concentrate was clarified with charcoal, filtered and dried by spray drying.

The resulting white powder was 38.3 kg (89%). Degree of substitution, based on PS-5.1 (1 H-NMR spectrum) m.p. 225-230 ° C 1 H-NMR (D ₂ O): identical to that described in Example 1.

sulfate ash: 0.11% water content: 3.01% propylene glycol content: <0.51%

Example 4

Preparation of 2-hydroxypropyl-alpha-cyclodextrin (PS-3,8)

Weigh 20 kg of water into a 1001 mixer,

1.1 kg of potassium hydroxide followed by 9.9 kg of alpha-cyclodextrin (1.61% water content). Stir until dissolved, cool the solution to 20 ° C and add 2.8 kg of 1.2 propylene oxide. The reaction mixture was stirred in a sealed apparatus at 30 ° C for 24 hours.

Subsequently, 201 neutral washed Varion-KS cation exchange resins were added to the reaction mixture. After stirring for 15 minutes, the resin is filtered off and washed with 2x5 water. The filtrate was distilled under vacuum under a kg of water and then concentrated to 16 kg of abs. ethanol is added. The resulting solution was stirred into 150 L of acetone (250 L) with stirring. The crystalline mass was cooled to 10 ° C, centrifuged and washed with acetone.

The jet-wet product was dissolved in 1001 in 36 kg deionized water. 18 kg of acetone-water are distilled off from the solution at atmospheric pressure. The concentrate was clarified, filtered and dried by spray drying.

The resulting white powdery product weighed 10.8 kg (91%). Degree of substitution PS-3.8 (1 H NMR spectrum).

Melting point: 256-260 ° C.

Propylene glycol content: <0.11%

Example 5

Preparation of 2-hydroxypropyl-beta-cyclodextrin (PS-3,4)

Weigh 27 kg of water, 0.8 kg of sodium hydroxide and 13.5 kg (3.81% water) of gamma-cyclodextrin into a 100 L apparatus. After stirring until dissolved, the solution was cooled to 20 ° C and 2.9 kg of 1.2 propylene oxide was added. The reaction mixture was stirred at 30 ° C for 1 hour in the apparatus described. The reaction mixture was then neutralized with 201 neutral washed Varion-KS cation exchange resins. The resin was filtered off and washed with 2x5 kg water. The filtrate was distilled under vacuum to 30 kg of water and the concentrate was dissolved in 21 kg of abs. ethanol.

The solution was stirred with stirring into 165 kg of acetone weighed into a 250 L apparatus. The crystalline mass was cooled to 5 'C, centrifuged and washed with acetone.

The jet-wet product was dissolved in 1001 in 45 kg deionized water. The solution was distilled at atmospheric pressure with 22 kg of acetone-water. The concentrate was clarified, filtered and dried by spray drying.

The resulting white crystalline product weighed 13.9 kg (94%). Degree of substitution PS-3.4 (based on 1 H-NMR spectrum)

Melting point: 260-265 ° C.

Propylene glycol15 content: <0.11%

Example 6

Preparation of 2-hydroxypropyl-beta-cyclodextrin (PS-3,2)

All were carried out as in Example 1 except that 530 kg of n-propanol was used as the precipitant instead of 540 kg of acetone.

The product formed is the same as in Example 1.

Example 7

Preparation of 2-hydroxypropyl-beta-cyclodextrin (PS-3,2)

All proceed as in Example 1 except that 1270 kg of tetrahydrofuran is used as the precipitant instead of 540 kg of acetone.

The product formed is the same as in Example 1.

Example 8

Preparation of 2-hydroxypropyl-beta-cyclodextrin (PS-3,2)

All proceed as in Example 1 except that 570 kg of tert-butanol is used as a precipitant instead of 540 kg of acetone.

Claims (7)

PATENT CLAIMS CLAIMS 1. A process for the preparation of 2-hydroxypropyl-alpha, -beta- or gamma-cyclodextrin, partially free of impurities, mainly substituted on the secondary hydroxy groups, in the presence of an aqueous base, propylene oxide and propylene oxide. solution at 0-35 ° C under atmospheric pressure, characterized in that 1.24 moles of base per mole of cyclodextrin are used, after which the base is neutralized with mineral acid or removed with a cation exchange resin. solution obtained Partially concentrate under vacuum, add 2-C4 glycol as the solvent, optionally at a higher boiling point than water, re-evaporate to stir and dilute with C2-C6 alcohol and optionally acetone, optionally filter off the precipitated salt. ol7 The data was added with stirring to anhydrous precipitating solvent such as acetone, C2-C6 alcohol, tetrahydrofuran, the precipitated product was separated off, and after partial evaporation after dilution with water, it was purified by filtration and dried. Process according to claim 1, characterized in that the base is sodium or potassium hydroxide. The process according to claim 1, wherein the molar ratio of base to cyclodextrin is preferably (1,2-2,5): 1. 4. The process of claim 1 wherein the mineral acid is sulfuric acid. The process of claim 1, wherein the solvent is a boiling point higher than water 1,2-propylene glycol is used as the 5 C 2 -C 4 glycols added. 6. A process according to claim 1, wherein the C 2 -C 6 alcohol is added as the precipitating solvent and is n-propanol or tert-butanol. The process of claim 1, wherein the product is spray dried.