CS256702B1 - A method for producing microbially safe inorganic components for the preparation of medicaments - Google Patents

Abstract

The solution concerns the method of producing microbially harmless inorganic components for the preparation of medicines, mainly for sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium and sodium sulfate, sodium nitrite, potassium chloride, or other inorganic substances (talc). The essence of the solution is that the produced inorganic component is brought into contact with an aqueous solution of hydrogen peroxide of a suitable concentration, but not to exceed the value of 0.3 °/o mass. throughout the suspension. Antimicrobial treatment is carried out at an appropriate stage, before centrifugation on the given technological equipment. This method can also be modified so that the separated crystals are washed directly in a centrifuge, but the concentration of hydrogen peroxide must not exceed the value of 0.3% by mass. (sodium nitrite). The advantage of the mentioned method is that hydrogen peroxide of a suitable concentration antimicrobially treats the necessary component, but does not leave any foreign residues in the substance affecting its composition.

Description

The present invention provides a process for the production of microbially harmless inorganic components for the preparation of medicaments, in particular the production of sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium and sodium sulphate, sodium nitrite or potassium chloride, which must comply with the requirements of the valid Czechoslovak pharmacopoeia. Part 5, Prague 1970).

Even with maximum adherence to the regulations applicable to the manufacture of microbially harmless inorganic components for the preparation of pharmaceuticals recommended by WHO GMP (good manufacturing practice), there is no guarantee that the product will be microbially harmless.

Good manufacturing practice assumes harmless already primary sources of microbial) contamination such as production environment, air, technological equipment, raw materials, workers, etc., ie all factors coming into contact with the production technology of the given inorganic component.

According to the known processes, microbiologically acceptable inorganic components for the preparation of medicaments are produced by treating them additionally after manufacture. Among the best known, for example. radiation irradiation, hot air sterilization, use of sterilizing media. However, all of these processes require additional care outside the production facility, most often at a different workplace, which greatly increases the cost of production from a financial or material point of view.

Disadvantages of the prior art are eliminated by the process according to the invention, which is based on a process for the production of microbially harmless inorganic components for the preparation of medicaments, mainly for the preparation of sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium and sodium sulphate, sodium nitrite or potassium chloride. The reaction mixture is contacted with a solution of hydrogen peroxide whose final concentration in the treated suspension is up to 0.3% by weight.

This substance can be applied directly to the last stage of production before centrifugation of the product or treated directly in a dilute aqueous solution on a centrifuge.

Using this knowledge, it has been found that the microbial safety of the final product is ensured by treating the inorganic components for the preparation of medicaments with hydrogen peroxide in an appropriate percentage by weight.

After treatment of the product, hydrogen peroxide residues in the product were not detected after two days by known analytical methods. Example 1

In the production of sodium hydrogen phosphate, 900 kg of distilled water and 162 kg of sodium hydroxide are metered into the reaction boiler. The solution is neutralized by stirring under stirring of 226 kg of concentrated phosphoric acid, the heat of reaction being removed with vigorous cooling. Upon cooling, a suspension of Na 2 HPO 4, 12 H 2 O crystals and mother liquor formed. The total volume of the resulting suspension is about 1,000 liters. 3.3 L of 32 wt. of an aqueous solution of pharmaceutical hydrogen peroxide and allowed to react for 30 minutes with stirring. Before starting to separate the solution from the crystals, the centrifuge is washed with 10 liters of 1- to 3% (w / w aqueous hydrogen peroxide solution) and allowed to centrifuge freely. The antimicrobially treated centrifuge is then impregnated with a sodium hydrogen phosphate suspension after sufficient separation of the crystals from the mother liquor. Analysis of the sample treated with sodium hydrogen phosphate after 2 days of storage makes it impossible to detect the presence of a peroxide group by photometric method.

Example 2

In the production of sodium dihydrogen phosphate, stoichiometric neutralization is carried out with phosphoric acid and sodium hydroxide to give a solution of 1300 liters. After cooling the solution in the reactor, 4 liters of 32 wt. of an aqueous solution of pharmaceutical hydrogen peroxide and allowed to react for 30 minutes with stirring. The next procedure is as in Example 1.

Example 3

In the production of potassium sulfate, the aqueous solution of potassium hydroxide with sulfuric acid is neutralized. After cooling the solution, 2 liters of 32% by weight are added to the suspension. aqueous hydrogen peroxide solution with stirring and allowed to react for 30 minutes. The further procedure is identical to Example 1.

Example 1 and d 4

The sodium sulphate obtained by the neutralization process was prepared according to Example 3 for a disposable batch of about 800 liters.

In the production of sodium sulphate by recrystallization of the technical feedstock, 2 liters of 32% by weight must be added to the cooled reactor before centrifugation. of an aqueous solution of hydrogen peroxide per 800 liter batch and centrifuged. The procedure is as in Example 1.

Example 5

In the production of sodium nitrite, 250 kg of distilled water is metered into the reaction boiler and 326 kg of industrial nitrite is added. By raising the temperature to 10 ° C, the crystals dissolve, filter to the next, and then cool. The suspension obtained is gradually infused into the centrifuge in 80 kg portions, based on the solid phase.

After thorough centrifugation of the mother liquor, the crystals are washed loosely with 10 liters of 0.3% by weight. aqueous hydrogen peroxide solution and allowed to centrifuge for 1 hour.

The contents of the centrifuge are removed and adjusted. The whole batch is processed in a similar manner.

The nitrate content before and after treatment shows no differences. No pharmacopoeial standard prescribes this determination.

Example 6

In the production of potassium chloride, 4 liters of 32 wt.% Are added to the cooled reactor after chemical treatment of the technical salt. aqueous hydrogen peroxide solution to 1600 liters in suspension. After separating the crystals in the centrifuge, drying is carried out in a hot-air drying oven, where it can no longer be contaminated and is immediately adjusted.

In all examples, a microbiological safety test is carried out within 1 month for manufacturers and within 1 year for consumers. The test result corresponds to the requirements of the Czechoslovak Pharmacopoeia, where the total number of microorganisms is maximum 10 000 or maximum 100 molds and yeasts per 1 g of the substance. No pathogens and faecal contaminants are present.

In addition to the above examples, this method of antimicrobial treatment can also be utilized in other inorganic compounds such as talc.

Claims (4)

5 256702 of the cauldron dispense 250 kg of distillate and 326 kg of sodium nitrite are added. By raising the temperature to 10 ° C, the saccharates are dissolved, filtered to a further reactor and then cooled. The resulting suspension is gradually added to the centrifuge in 80 kg portions based on solid phase. After centrifugation of the mother liquor, the crystals were washed free with 10 liters of 0.3% w / w. aqueous hydrogen peroxide solution and centrifuged well for 1 hour. The contents of the centrifuge are removed and adjusted. Nitrate content before and after treatment does not show differences. This determination is not prescribed by any pharmacopoeial standard. Example 6 In the production of potassium chloride, 4 liters of 22% w / w was added to the cooled reactor after chemical treatment of the technical salt. aqueous hydrogen peroxide solution per 600 liters in suspension. After separation of the crystals in the centrifuge, the drying room is carried out in an additional hot air dryer, where the subsequent contamination is no longer possible and the product is immediately adjusted. In all examples, the microbiological safety test is carried out up to 1 month for manufacturers and up to 1 year for the consumer. The test result corresponds to the requirement of the Czechoslovak Pharmacopoeia, where the total number of microorganisms is a maximum of 10,000 or a maximum of 100 fungi and yeast v1 g of the substance. There are no pathogens and indicators of faecal contamination. In addition to the above examples, this method of antimicrobial treatment can be used with other inorganic compounds, such as talc. P R E D Μ E I A process for the production of microbially non-organic components for the preparation of formulations, especially for the preparation of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium sulphate, sodium sulphate or potassium chloride, characterized in that, after neutralization or recrystallization, the reaction mixture is cooled and before or after centrifugation, the reaction mixture is contacted with a solution of peroxydisoric acid, the final concentration of which in the treated suspension is up to 0.3% by weight. 2. A process according to claim 1, wherein the hydrogen peroxide solution is used with a final concentration of 0.1 to 0.3% by weight. 3. The method of manufacture according to claim 1, wherein in the production of the nitrite it is washed with the diluted nitrite crystals ε j by dilution with a solution of a concentration of up to 0.3% by weight. 4. A process according to claim 1, wherein a peroxide solution of about 32% by weight is added to the recovery solution.