Method to produce lactide of medical purity

Lactide is a cyclic dimer of lactic acid and an intermediate in production of biodegradable homo- and copolymers with high molecular mass. These polymers are used to produce resorbable medical materials and products. Lactide synthesis is comprised in thermal catalytic depolymerization of D,L-lactic acid. To synthesize lactide a Russian-produced 50% lactic acid was used. Using HPLC method it was stated that lactic acid has large amount of impurities caused by synthesis method. To purify lactic acid the methods of extraction and azeotropic water distillation of acids (impurities) was used. Several esters (isoamyl, buthylacetate, etc.) and alcohols were used for extraction. However, this method was rejected since no phase boundary was observed. Other extraction agents (chlorobenzene, toluene, CCl , etc.), which can be used in azeotropic distillation, were tested. It was shown that toluene is the best extraction agent to purify lactic acid. It has high flashing temperature, is chemically stable, available, does not dissolve in lactic acid, and breaks down readily. The preliminary purification of lactic acid allows achieving higher quality of lactide. After toluene extraction the concentrating and depolymerization of oligomer in rotary evaporator took place. The major conditions to produce oligomer and its subsequent depolymerization are as follows: mixer rate of 80-120 rpm, reactor wall temperature of 250-260°C, gradual decrease of temperature in the bulk of the reactor and pressure buildup. Hydrodynamic parameters of lactide synthesis in reactor with mixer were studied in conditions of two-phase system of ''liquid-vapor-gas mixture''. The lactide yield of 72-73% was achieved at depolymerization temperature of 235-240°C and reaction time of 30-34 min. The degree of regeneration (extraction) of lactide from mother liquor was 86-88%. The purification of crude lactide was carried out using triple backboiling from ethyl acetate. Identification of the received lactides was carried out according to measurement techniques certified at Tomsk Regional Collective Use Centre. Depending on the quality of initial lactic acid the crude lactide with melting temperature of 110-115°C was obtained. The lactide yield of 70-85% was achieved. The drying of the resulting product was carried out in vacuum drying box using nitrogen blanket at 45-50°C. It was stated that to maintain the purity of lactide one should keep it in airless and water-vapor-less conditions at the temperature of no more than 4°C. Thus, in the course of work it was stated that to produce high-purity lactide to be used in production of medical polymers it is necessary to preliminary purify the lactic acid using toluene extraction and carry out the synthesis in rotary film evaporator with subsequent recrystallization from ethyl acetate, drying in vacuum drying box under nitrogen blanket at 45-50°C.

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