Background technology
Immunomodulator carboxymethylstach sodium (pulpous state) records in two ones the 6th of Ministry of Health of the People's Republic of China's drug standard promulgated by the ministries or commissions of the Central Government (abbreviation ministerial standard), the carboxymethylstach sodium that it is made after partial hydrolysis for starch, calculate according to dry product, containing sodium carboxymethyl is more than 12.5%, the specific optical rotation of carboxymethylstach sodium is more than+175 °, intrinsic viscosity is 20~45, and muriate must not cross 5 ‰.
Chinese patent CN85103760A, application number 85103760, denomination of invention is sodium starch glycolate and the manufacture method that contains the preparation of this material.Wherein disclose starch and after hydrolysis, carboxymethylation, prepared the Preparation of sodium carboxymethy starch method.When the contriver prepares carboxymethylstach sodium in this method of application, discovery can't prepare the carboxymethylstach sodium that meets the drug standard: its finished product clarity is poor, gelling hydrolysed starch and make its molecular size consistent as far as possible at a certain temperature not, carboxymethylstach sodium according to embodiment 1 production, clarity is poor, a large amount of white pieces are arranged, substitution value is also extremely low, require to differ greatly with ministerial standard, do not meet the regulation of two ones the 6th of Ministry of Health of the People's Republic of China's drug standard promulgated by the ministries or commissions of the Central Government, so need the technology of this patent disclosure is improved.
Summary of the invention
Owing to the product clarity that the preparation method's preparation that has carboxymethylstach sodium now gets is poor, a large amount of white pieces are arranged, substitution value is also extremely low, require to differ greatly with ministerial standard, technical problem solved by the invention is that the carboxymethylstach sodium prior preparation method is improved, the product water white transparency, the uniform and smooth that prepare and get meet the drug standard.
The preparation method of carboxymethylstach sodium provided by the present invention comprises the steps:
A, with starch hydrolysis gelatinization in aqueous solution of alcohol;
B, carboxymethylation;
C, sedimentation pulpous state product, standing over night is filtered, and alcohol precipitation dissolves repeatedly, precipitates, and promptly gets carboxymethylstach sodium;
Its improvement is when steps A hydrolysis gelatinization to adopt the mode of gradient increased temperature to rise to 85 ℃ by room temperature to heat.Starch suspension is when heating to certain temperature gradually, and its particle can expand suddenly, and volume can increase tens of even hundreds of times, and that starch suspension becomes is transparent, the colloidal liquid of the no white heart, claims that traditionally this process is gelatinization.Its essence is that water molecules enters starch granules inside, broken the hydrogen bond structure between starch molecule, destroyed particulate crystalline texture, high degree of hydration claims reticulated structure, continue stirring heating, viscosity degradation, so gradient increased temperature is to gelatinization point slowly, continuing after gelatinization is finished heats up again stirs is to guarantee that intrinsic viscosity is in one of key of expecting scope.Too fast if heat up, the inequality of being heated can form white piece, and this white piece can enter in the finished product always, is not dissolved in water, can not guarantee that promptly finished product is dissolved in the solution that forms water white transparency, uniform and smooth behind the water, influences the quality of carboxymethylstach sodium.Facts have proved, reaction solution gelatinization in the time of about 72 ℃, thinning in the time of about 82 ℃.
The carboxymethylstach sodium that gets by above-mentioned preparation method preparation meets in the ministerial standard requirement to carboxymethylstach sodium fully.Can satisfy carboxymethylstach sodium and use, the diseases such as bronchial asthma that are used for the treatment of infantile respiratory tract infection repeatedly and bring out thus as immunomodulator.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment
Below by specific description of embodiments of the present invention the explanation but do not limit the present invention.
The prior art for preparing carboxymethylstach sodium: direct temperature reaction during the hydrolysis gelatinization, at 50~100 ℃ of hydrolysis 0.2~3.5h.
Preparation method of the present invention prepares carboxymethylstach sodium: adopt the mode of gradient increased temperature to rise to 85 ℃ by room temperature during the hydrolysis gelatinization and heat.Concrete heating mode is for rising to 60 ℃ by room temperature, 0.5-1 ℃ of per minute intensification earlier; Rise to 85 ℃ by 60 ℃ again, 0.05-0.5 ℃ of per minute intensification.Table 1 is for investigating different the intensification to the result of the deliquescent influence of finished product.
Table 1 is investigated different the intensification to the deliquescent influence of finished product
By investigating heat-up rate to deliquescent influence, rise to 60 ℃ by 30 ℃, the time that every intensification is 1 ℃ white piece can not occur in the product during greater than 1min.From time and cost consideration, preferred 30 ℃ of times that rise to 1 ℃ of 60 ℃ of every intensification are 1min, and then investigate by 60 ℃ and rise to 75 ℃, the time that every intensification is 1 ℃ during greater than 2min product white piece can not appear.From time and cost consideration, preferred 60 ℃ of times that rise to 1 ℃ of 75 ℃ of every intensification are 2min, and then investigate by 75 ℃ and rise to 80 ℃, the time that every intensification is 1 ℃ during greater than 6min product white piece can not appear.From time and cost consideration, preferred 75 ℃ of times that rise to 1 ℃ of 80 ℃ of every intensification are 6min, and then investigate by 80 ℃ and rise to 85 ℃, the time that every intensification is 1 ℃ during greater than 12min product white piece can not appear, from time and cost consideration, the time that preferred every intensification is 1 ℃ is 12min.
After the intensification condition of having investigated the hydrolysis gelatinization, the aqueous solution of alcohol that the contriver has also investigated the hydrolysis gelatinization contains alcohol amount and pure kind, pH value, hydrolysis time; Carboxymethylation material mole ratio, pH value, temperature of reaction and time; Settling conditions etc. influence the factor of carboxymethylstach sodium quality.Determined that finally following preparation method is used to prepare carboxymethylstach sodium:
A, with starch hydrolysis gelatinization in aqueous solution of alcohol.
Wherein, to heat be earlier to rise to 60 ℃ by room temperature, 0.5-1 ℃ of per minute intensification to the mode of above-mentioned gradient increased temperature; Rise to 85 ℃ by 60 ℃ again, 0.05-0.5 ℃ of per minute intensification.
Because of heat-up rate has very big influence to the product solvability, so the contriver has done following screening to heat-up rate: when rising to 60 ℃ for 30 ℃, with the speed intensification of 1 ℃ of intensification in every 1-2 minute; When rising to 85 ℃ for 60 ℃: 60 ℃ heat up with 1 ℃ the speed of heating up in every 2-3 minute when rising to 75 ℃, and 75 ℃ heat up with 1 ℃ the speed of heating up in every 6-9 minute when rising to 80 ℃, and 80 ℃ heat up with 1 ℃ the speed of heating up in per 1218 minutes when rising to 85 ℃.
Hydrolysis gelatinization condition is: it is 20%~50% that aqueous solution of alcohol contains the alcohol amount, and the pH value is 1.5~3.0, and the time is 2.5~5h.To the condition optimizing of hydrolysis gelatinization be aqueous solution of alcohol to contain the alcohol amount be 25%~30%, the pH value is 1.6~1.8.Alcohol in the aqueous solution of alcohol is methyl alcohol, ethanol, propyl alcohol, butanols, Virahol or isopropylcarbinol.
B, carboxymethylation.
Carboxymethylation material mole ratio is: 1 part of starch, 1.8~2.5 parts in sodium hydroxide, 1~1.5 part of Mono Chloro Acetic Acid.Particularly, behind the employing of the starch after hydrolysis gelatinization sodium hydroxide adjust pH to 6~8, add chloroacetic acid solution, add sodium hydroxide solution again, be warming up to 50 ℃~70 ℃, reaction 3~5h.
C, sedimentation pulpous state product, standing over night is filtered, and alcohol precipitation dissolves repeatedly, precipitates, and promptly gets carboxymethylstach sodium.
Usually can directly will handle again after the solution sedimentation after the carboxymethylation, the standing over night.But the contriver finds, if before sedimentation, earlier with sedimentation again behind solution adjust pH to 5~8 after the step B carboxymethylation, standing over night, then can improve the stability of product, and product clarification, long storage do not produce precipitation.
Medicinal carboxymethylstach sodium is to its purity requirement height, the contriver has adopted the separation purification method (in the past adopting charcoal absorption) that is different from common carboxymethylstach sodium, with centrifugal settling and the removal of impurities of Plate Filtration bonded mode, with pure and mild purified water repeated treatments carboxymethylstach sodium, avoid using gac and bring into and come unnecessary impurity, reduced cost, the carboxymethylstach sodium clarification, the long storage that have guaranteed to adopt the carboxymethylstach sodium of the inventive method preparation to make do not produce precipitation yet.
By carboxymethylstach sodium water white transparency, the uniform and smooth that method for preparing gets, containing sodium carboxymethyl is more than 12.5%, and the specific optical rotation of carboxymethylstach sodium is more than+175 °, and intrinsic viscosity is 20~45, and muriate must not cross 5 ‰, meets ministerial standard.