CZ278181B6 - Process of purifying polymers and oligomers of aliphatic hydroxy- acids - Google Patents

Abstract

The process of purifying polymers and oligomers of aliphatic hydroxyacids is based on dissolving the raw polymerisation product in a solvent with relative permittivity of epsilon r from 10.0 to 33.5 making a solution with 5 to 50 % by weight of oligomers at 35 degrees C up to the boiling point of the solvent. After dissolving the oligomers and filtration the clear solution is cooled to 35 to - 50 degrees C. The solid phase or coacervated layer is separated off. The coacervated layer is then plasticised with a polar liquid, whose relative permittivity epsilon r is higher than 25.0. The liquid phase is separated off and the solid phase is desiccated under a vacuum of 0.1 to 1.0 kPa.

Description

Process for purification of oligomers of aliphatic hydroxy acids.

Technical field

Biodegradable polyesters prepared by polycondensation of hydroxy acids have some molecular weight variation depending on the conditions of preparation. The reaction mixture contains unreacted monomers, cyclic dimers, low molecular weight oligomers, and the like. catalysts and other low molecular weight components. Admixtures alter, generally, accelerate the rate of polymer degradation. Their variable proportion makes products non-standard. Therefore, it is an effort to remove these impurities.

BACKGROUND OF THE INVENTION

The use of products without purification is exceptional and limited to oligomers. The crude products of polycondensation reactions of aliphatic hydroxy acids are considerably non-standard. Their properties depend on the quality (especially purity) of the raw materials and the accuracy of the preparation or production conditions. It has been shown that repeated precipitation of the polymerization product fulfills the function of fractionation - leading to a gradual increase in the molecular weight of the polymer. To obtain stable molecular weight products, the water precipitation process from a dioxane solution of racemic polylactic acid had to be repeated three to four times (Marcotte, N., Goosen, M.F.A., J. Controlled Release, 9, 1989, p. 75).

Purification of polymers of the above type is accomplished by precipitation from their solutions by adding a highly polar or substantially non-polar liquid. The most commonly used procedure is to dissolve the polymer in methylene chloride or chloroform and precipitate by adding (dripping) to ten times (Kricheldorf, HR, Sumbél, M., Eur. Polym. J. 25, 1989, p. 585) to thirty times (Jonté, JM). (Dunsing, R., Kricheldorf, HR, J. Macromol. Sci. Chem. Ed., A23, 1986, p. 495) of supercooled methanol. A procedure for methanol precipitation from methylene chloride solution followed by leaching of the precipitate with water in a mixer is described (Schindler, A., Harper, D., J. Polym. Sci .: Polym. Chem. Ed. 17, 1979, p. 2563; Pitt, CG) et al., J. Biomed. Mater. Res., 13, 1979, p. 497). A procedure was used to precipitate a solution in dioxane with methanol (Kricheldorf, HR, Berl, M., Scharnagl, N., Macromolecules, 21, 1988, p. 286), water (Zhou, X., Chang, MS, J). Microencapsulation, 4, 1988, p. 27), or by precipitation with methanol from a solution of dioxane mixed with acetone (Barskaja, JG et al, High Molecules. Soedin., Ser. A, 25, 1983, p. 1283) or by precipitation from ethanol from a solution in benzene (Gupta, MC, Desmukh, VG, Polymer, 24, 1983, p. 827). To remove any hydrophobic impurities, a procedure for hexane from dichloromethane solution has been described (Ogawa, Y. et al., Chem. Pharm. Bull., 26, 1988, p. 1095). A process for precipitating an acetone solution of a lactic acid-glycolic acid copolymer dropwise into petroleum ether in a kitchen mixer has been patented (Pat. Germany, DE 3,708,916).

Another principle is the procedures for the subsequent fractionation of the precipitated polymer by extraction with acetone or ethanol in a Soxhlet apparatus, followed by a long (48 hour) mixing of the insoluble phase in acetylacetone (Bloembergen, S., et al., Macromolecules, 22, 1989, p. 1656). Extraction of lactic acid-polyethylene glycol copolymer with ethyl acetate / heptane was used. The insoluble components were further extracted with distilled water (Zhu, K.J., Lin, X., Yang, S., J. Appl. Polym. Sci., 39, 1990, p. 1).

Most of these processes are demanding on the large amount of solvents used.

SUMMARY OF THE INVENTION

Process for the purification of aliphatic hydroxy acid oligomers, which comprises dissolving the crude polymerization product in a solvent having a relative permittivity e _r of 10.0 to 33.5 such as acetone, amyl alcohol, isopropyl alcohol, ethanol, methanol, butyl alcohol and mixtures or mixtures thereof of these solvents with chloroform, dichloromethane, toluene, benzene, ethyl acetate to form a solution with 5 to 50% by weight of polymer, at a temperature of 35 ° C to the boiling point of the solvent, after dissolution the clear solution is cooled to 35 to -50 ° formation of a solid phase or coacervate layer, which are separated. After separation, the solid particles precipitated from the solution are washed with clean, cooled solvent and dried. If a coacervate layer is formed, the separated coacervate layer is further kneaded with a polar liquid whose relative permittivity e _r is greater than 25.0. The liquid phase is separated by kneading and the solid phase is dried under vacuum at 0.1 to 1.0 kPa.

This process is particularly suitable for the oligoesters of glycolic acid, L-lactic acid, DL-lactic acid hydroxybutyric, hydroxyvaleric, hydroxyisovaleric, hydroxycaproic, hydroxyisocaproic, optionally products of reaction of hydroxy acids with fatty or polyhydric alcohols.

In this way, the biodegradation and liberation properties of the polymer are standardized. The degree of polydispersity of oligomers and polymers is reduced. Due to the possibility of easy regeneration of solvents, they are saved.

Compared to purification by precipitation, low molecular weight oligomers are easier to remove, especially during kneading. This saves the raw materials which are unreacted, which are obtained by purification and can be used again. Solvent consumption is lower.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

800 g of crude poly-L-lactic acid was dissolved in a reflux condenser in 3200 g of acetone at the boiling point of the solution. The solution after filtration was slowly cooled to 20 ° C. Filtration gave a solid phase which was washed with acetone at 0 ° C. After drying at 60 ° C and 0.5 kPa for 24 hours, 520.0 g of an acetone fraction were obtained. The acetone fraction had a weight average molecular weight of 11 23 ° and a melting point of 166 ° C. The degradation time (50% weight loss in phosphate buffer 0.154 mol.l ^-1 ; pH 7.4 at 37 ° C) of a 10 mm roller, 4 mm diameter is 92 days.

Example 2

1.500.0 g of a crude copolymer of DL-lactic acid with glycolic acid in a ratio of 8: 2 of number average molecular weight of 1,770 are dissolved in 2800 g of methanol at the boiling point of the solution. The solution is cooled to 10 ° and left at this temperature for 24 hours. The solid phase is separated from the mother liquor by centrifugation while cooling. The product obtained has a number average molecular weight of 2640. The degradation time is 24 days, the degradation time of the crude copolymer was 9 days.

Example 3

100.0 g of a star oligomer obtained from L-lactic acid and mannitol in a ratio of 500: 1 by polycondensation at 150 ° C and 0.3 kP and dissolved for 84 hours in 900 ml of isopropanol at 70 ° C. The system is filtered and cooled to 10 C. C. It is transferred to the refrigerator (5 'C) and allowed to stand for 10 hours. The solid phase is separated by a conventional procedure and dried under vacuum. The degradation time of the melt roller is 47 days for purified oligomer under simulated physiological conditions and 10 days for untreated.

Example 4

500 g of crude poly-DL-lactic acid of a number average molecular weight of 1200 are dissolved at boiling in 11 l, 99.9% by weight of ethanol. After filtration and cooling to 20 ° C, the lower coacervate layer is separated, to which 3 L of water are added and the mixture is kneaded for 5 min. This kneading procedure is repeated 3 times. After drying in vacuo at 0.5 kPa at 45 ° C, 2070 g of purified polylactic acid are obtained. The number average molecular weight of the oligomer is 1900. The degradation time of the 3 mm diameter and 10 mm length of the crude oligomer was 65 hours and purified for 12 days.

Example 5

720.0 of a 6: 1 crude L-lactic acid-glycolic acid oligomer with hexadecyl alcohol esterified carboxylic groups is dissolved under stirring in a 6, 1 mixture of 9 parts ethanol and 1 part chloroform on a water-bath in a reflux condenser flask. boiling system. The solution is filtered through a glass sinter, cooled, and left to stand for 16 hours at 5 ° C. The solid phase deposited at the bottom of the vessel was separated from the mother liquor by filtration, washed on the filter with three portions of supercooled methanol and dried at 50 ° C under vacuum. An oligomer with a number average molecular weight of 5,510 versus 2,640 for the crude intermediate is obtained.

Industrial applicability

The importance of biodegradable polyesters lies in their high compatibility with the biological environment. The final decomposition products of the polyesters are water-soluble, non-toxic monomeric units; in the case of poly-L-lactic acid, metabolism may result in carbon dioxide and water. The degradation of polyesters occurs by non-enzymatic hydrolysis. Thus, when the surrounding tissue composition is stable, the process of polyester hydrolysis is standard.

Polyglycolic acid fibers and their lactic acid copolymers have long been produced and used in surgical practice as suture materials. High molecular weight polymers have found practical application as prosthetic materials in orthopedics, either alone or in admixture with other polymers or ceramic materials.

More recent is the use of biodegradable materials as the active substance carriers. Microspheres, microcapsules, micropellets, nanoparticles intended for oral, micro-vein, intramuscular, subcutaneous, eye, peritoneum, cerebral cavities, intercostal cavity etc. are the subject of research of particulate pharmaceutical forms. a dissolved or particulate dispersed drug substance in the form of platelets, films, rollers, rods, needles and fibers. They can be implanted, e.g., into the subcutaneous tissue or into tumor tissue. A variety of hormones, antimicrobial agents, enzymes, antidiabetics, narcotics antagonists, circulatory agents, natineoplastics, peptides, proteins, etc. are studied from drug substances.

The mechanism of drug substance liberation depends on the type of polymer and drug substance. This is due to either diffusion of molecules or ions through the polymer or pores in the polymer, or hydrolytic erosion of the polymer. Liberation by hydrolytic erosion is a specificity of these polymers. By selecting appropriate conditions, the liberation time of the drug substance can be varied from a few hours to many months.

Claims (1)

PATENT CLAIMS Process for purifying aliphatic hydroxyacid oligomers, characterized in that the crude polymerization product is dissolved in a solvent with a relative permittivity e _r of 10.0 to 33.5, such as acetone, amyl alcohol, isopropyl alcohol, ethanol, methanol, butyl alcohol and mixtures thereof or mixtures of these solvents with, for example, chloroform, dichloromethane, toluene, benzene or ethyl acetate, to form a solution of 5-50% by weight oligomers, at a temperature of 35 ° C to the boiling point of the solvent, after dissolution and filtration, the clear solution is cooled to 35 to -50 ° C to form a solid phase or coacervate layer which is separated, in the case of a coacervate layer, the separated coacervate layer is further kneaded with a polar liquid whose relative permittivity e _r is greater than 25.0, the liquid phase is separated and the solid phase is dried under vacuum at 0.1 to 1.0 kPa.