RU2057144C1 - Method for purification of solutions of polyvinylpyrrolidone - Google Patents

Abstract

FIELD: chemical technology. SUBSTANCE: method involves passing of aqueous solution of polyvinylpyrrolidone through cross-linked cation-exchange macroporous resins on the base of styrene and divinylbenzene copolymers and through cross-linked macroporous anionites, said process being carried out step by step. Mentioned above cation-exchange resins contain sulfo-groups in Na⁺ form, mentioned above anionites contain benzyltrimethyl ammonium groups in OH^- form. The former process is carried out at pH 6.0-7.5, the latter at pH 8.5-9.5. EFFECT: improves efficiency of method.

Description

 The invention relates to chemical technology, and in particular to a method for the purification of medical polymers, in particular polyvinylpyrrolidone (PVP), which is widely used in the pharmaceutical industry for the production of detoxifying drugs: hemedes, hemodes-H, neocompensan, periston.

 To obtain injection and infusion preparations based on PVP, the latter must be completely purified from residual monomers, α-pyrrolidone, N-vinylpyrrolidone, which are toxic, as well as pyrogens and iron ions.

 A known method of purifying aqueous solutions of PVP from these impurities by extraction with methylene chloride [1] The disadvantages of this method include the multiplicity of operations to achieve a minimum level of less than 2% organic impurities, the use of expensive equipment (continuous separators), the use of large quantities of methylene chloride, the loss of which in technology is inevitable, leading to environmental pollution.

Along with organic impurities in the substance of PVP, the presence of iron ions in the form of FeCl ₃ in amounts up to 1.0-1.5 wt. which causes increased color of the resulting dosage forms, the formation of opalescence during the preparation of the drug or during its long-term storage, which is not allowed according to the requirements of the FS.

 In order to obtain drugs that meet the requirements of the FS, the current technology for the production of drugs includes additional stages of multiple prefiltration and sterile filtration on the membranes.

 However, in most cases it is not possible to achieve an effect in production and to obtain all batches of the drug stable during storage.

 All the above-mentioned shortcomings in the quality of the PVP substance significantly worsen the technical and economic indicators of plants producing PVP drugs.

 The aim of the invention is to improve the quality of PVP by freeing it from impurities and obtaining almost colorless and stable both at the time of release and during storage of PVP preparations.

The goal is achieved in that in the method for purifying polyvinylpyrrolidone, an aqueous solution is passed through two series-connected columns filled with highly cross-linked ion-exchange resins of a macroporous structure based on styrene-divinylbenzene copolymers: 1 containing sulfo groups in Na ⁺ form at pH 6.0-7.5 and 2 -containing benzyltrimethylammonium functional groups in OH ^- form at pH 8.5-9.5, at a rate of 0.3-0.5 column volumes per hour.

 The proposed method is as follows.

 A 0.25 M sodium acetate solution is passed through a column with a cation exchange resin until a pH of 7.0-7.5 is established in the column and washed with pyrogen-free water to a pH of 6.0-7.5. The anion exchange resin is washed with pyrogen-free water to a pH of 8.5-9.5.

The PVP substance is dissolved in pyrogen-free water to a concentration of 7.5-8.5% and the resulting solution is successively passed through prepared cation exchange resin and anion exchange resin in the fluidization mode of resins (from bottom to top) at a rate of 0.3-0.5 column volumes per hour (Vк / h) the process is carried out at room temperature or at 40-60 ° ^C. The load on PVP sulphocationite amounts to 1100 mg / g, while the anion resin to 980 mg / g. The purified solution is adjusted in accordance with the FS, filtered, poured into vials and sterilized the finished product for 20 minutes at 120 ^about C.

 The process of purification of PVP from associated impurities is controlled by photoelectrocolorimetry (FEK).

 Purification of aqueous solutions of PVP under the selected conditions allows to obtain sterile, pyrogen-free transparent, slightly colored dosage forms of detoxification blood substitutes that are stable during storage.

The use of ion exchangers in the technology of purifying PVP solutions in the pH range 6.0–7.5 virtually eliminates the adsorption of the polymer and makes it possible to selectively sorb with a high capacity due to high diffusion coefficients of 1 · 10 ^-6 cm ² / s (determined for a mixture of impurity components) low molecular weight impurities. Increasing the processing temperature to 40-60 ^{° C} reduces the viscosity of the PVP solutions improve the hydrodynamic process and improving the selectivity of the impurity sorption.

пор от 400 до 1200

) с высокоразвитой удельной поверхностью (до 350 мг/г) позволяет полностью очистить субстанцию ПВП от примесей α-пирролидона, метилпирролидона, молекул ПВП с раскрытыми лактамными циклами и др. и получить лекарственные формы высокого качества с улучшенными дезинтоксикационными свойствами.The developed technology using ion-exchange resins of a macroporous structure (

then from 400 to 1200

) with a highly developed specific surface (up to 350 mg / g) allows you to completely clean the substance of PVP from impurities of α-pyrrolidone, methylpyrrolidone, PVP molecules with open lactam cycles, etc. and to obtain high-quality dosage forms with improved detoxification properties.

 Example 1. A 0.25 M sodium acetate solution was passed through a column filled with 100 ml of cation-exchange macroporous resin of the KU-23 type and washed with pyrogen-free water to pH 6.1. A column filled with 100 ml of anion-exchange macroporous resin of the AM-p type is washed with pyrogen-free water to a pH of 8.96. 39.0 g of the substance of PVP is dissolved in 500 ml of pyrogen-free water. The resulting solution with C 7.52% (refractometric) was successively passed from bottom to top through prepared columns with KU-23 cation exchanger and AM-p anion exchanger at room temperature at a speed of 0.3 Vc / h. 505 ml of purified 7.09% PVP solution are obtained (yield 95.3%), from which a dosage form is prepared in the usual way.

Get a sterile, pyrogen-free, transparent, slightly yellow hemodesis product: color 0.141 srvc. units (FEC), binding activity 1,0675 srvc. units Control: hemodesis obtained by current technology: color 0.457 conv. unit binding activity of 0.9425 srvc. units The formulation obtained according to the claimed method, was kept for 14 days at 80 ° ^C (control: gemodez obtained by the current technology). Get a clear light yellow solution, color 0.231 srvc. units; in the control sample appeared "snake", the color of 0.571 conv. units

PRI me R 2. Through a column filled with 100 ml of cation-exchange macroporous resin type KU-23, a 0.25 M sodium acetate solution is passed and washed with pyrogen-free water to a pH of 6.7. A column filled with 100 ml of anion-exchange macroporous resin of the AM-p type is washed with pyrogen-free water to a pH of 9.57. Column thermostated at 60 ± 1 ° ^C. 44.0 g of PVP substance was dissolved in 500 ml of apyrogenic water. The resulting solution with C 8.47% (refractometric) was successively passed from bottom to top through prepared columns with KU-23 cation exchanger and AM-p anion exchanger at a rate of 0.5 Vc / h. 512 ml of purified 8.11% PVP solution are obtained (yield 95.1%), from which a dosage form is prepared in the usual way.

 Get a sterile, pyrogen-free, transparent, slightly yellow hemodesis product: color 0.138 conv. units (FEC), the binding activity of 1.0721 conv. units Control: hemodesis obtained by current technology: color 0.457 conv. units binding activity 0.9425 srvc units

The formulation obtained according to the claimed method, was kept for 14 days at 80 ° ^C (control: gemodez obtained by the current technology). Get a clear, light yellow solution, color 0.223 srvc. units in the control sample appeared "snake", the color of 0.571 conv. units

PRI me R 3. Through a column filled with 1000 ml of cation-exchange macroporous resin KU-23i, a 0.25 M sodium acetate solution is passed and washed with pyrogen-free water to a pH of 7.48. A column filled with 1000 ml of anion-exchange macroporous resin AM-p is washed with pyrogen-free water to a pH of 8.49. Column thermostated at 40 ± 1 ° ^C. 420 g of substance were dissolved in 5000 ml of pyrogen-free water. The resulting solution with C 8.1% (refractometry) is successively passed from the bottom up through the prepared columns with KU-23i cation exchanger and AM-p anion exchanger at a rate of 0.4 Vc / h.

 5190 ml of purified 7.74% PVP solution are obtained (95.6% yield), from which a dosage form is prepared in the usual way.

 Get a sterile, pyrogen-free, transparent, light yellow haemodesis product: color 0.144 srvc. units (FEC), the binding activity of 1.0697 conv. units (control: hemodesis obtained by current technology), color 0.457 srvc. units binding activity 0.9425 srvc units

The formulation obtained according to the claimed method, was kept for 14 days at 80 ° ^C (control: gemodez obtained by the current technology). Get a clear, light yellow solution, color 0.229 srvc. units in the control sample appeared "snake", the color of 0.571 conv. units

Claims (1)

METHOD FOR CLEANING AQUEOUS SOLUTIONS OF POLYVINYL-PYRROLIDONE by treatment with a chemical reagent, characterized in that an ion-exchange resin is used as a chemical reagent, and the treatment is carried out by sequentially passing through a macroporous structure based on a copolymer of styrene with divinylbenzene containing 6 ⁺ pH 6 sulfon 7.5, and then through an ion-exchange resin of a macroporous structure based on a styrene-divinylbenzene copolymer containing benzyltrimethylammonium groups, in H ^- -form at pH 8.5 - 9.5.