RU2313350C1 - Method for increasing calcium succinate, calcium malate and calcium citrate solubility for child's medicinal formulations - Google Patents

Abstract

FIELD: medicine, pediatrics, pharmacy.

SUBSTANCE: invention relates to a method for increasing solubility of calcium succinate, calcium malate and calcium citrate in aims for their using in pharmacology and medicine in preparing liquid medicinal formulations. Increasing solubility is achieved by solubilization of these salts with sorbitol aqueous solution. Method involves addition of milled calcium succinate, calcium malate or calcium citrate to sorbitol aqueous solution in the concentration 5-70% at temperature 30⁰C, not above. The mixture at periodic stirring is held at temperature 20⁰C for 6-24 h up to the complete salt dissolving followed by its purification by filtration. Invention provides preparing solutions of indicated salts with the enhanced content of active substance and pH near to neutral value. Method provides expanding assortment of medicinal formulation of calcium succinate, calcium malate and calcium citrate by development of sorbitol-base syrups.

EFFECT: improved preparing method.

1 tbl, 3 ex

Description

The invention relates to the pharmaceutical industry, relates to a method for increasing the solubility of calcium succinate, calcium malate, calcium citrate and can be used in pharmacology and medicine for the manufacture of liquid dosage forms.

Calcium is a vital element for the body and is involved in many metabolic processes. Studies have shown that calcium is absorbed better in the form of a salt with organic acid than inorganic salts (Coder, S. Calcium Citrate / S. Coder, S. Edelstein // The World of Food Ingredients. Journal of the Practicing Food Technologist. - 2001. Oct / Nov. - P.66-69).

The use of calcium in the form of salts with anions of organic acids involved in the Krebs cycle significantly increases the biological value of this combination for the body. In addition, this combination practically does not lead to anionic imbalance, as is the case, for example, when chlorides, sulfates or phosphates are introduced into the body.

The technological drawback of these salts is their low solubility in water, which does not increase bioavailability and limits the range of drugs and dietary supplements to mainly solid dosage forms: tablets, capsules, powders, etc. However, it is known that it is more convenient to use drugs in pediatric and geriatric practice. in the form of syrups.

Studies of ways to increase the solubility of these salts were carried out earlier.

A known method of producing calcium citrate malate, which has a slightly higher solubility than a mechanical mixture of these salts (US 5186965 and others).

A method for producing amorphous calcium citrate by rapid spray or freeze drying of its solution. Amorphous finely divided calcium citrate has a greater solubility compared to its crystalline analogue and is stable in solution for at least two days at room temperature (EP 1566373).

A calcium gluconate solution for oral administration with an active substance concentration of more than 3.5% is obtained by the method proposed in (JP 6192108). To prevent crystallization of calcium gluconate, 0.3-0.5% citric, 0.2-0.3% tartaric, 0.1-2.5% aminoethylsulfonic acid and 10-30% sorbitol are added.

A composition of calcium-fortified beverages and foods containing calcium gluconate, calcium citrate, calcium malate and other salts has been developed (US 4740380, US 4830862, US 5389387, US 6235322, etc.). In these sources, to increase the solubility of salts, the presence of an additional amount of acid in the system is provided.

The dependence of the solubility of calcium succinate, calcium malate and calcium citrate on the pH of the medium is known. A particularly significant increase in solubility is observed at pH values less than 4. However, the manufacture of syrups with such a pH value is impractical due to unpleasant organoleptic properties and effects on the gastric mucosa.

The aim of the present invention is to develop a more advanced method of increasing the solubility of calcium succinate, calcium malate and calcium citrate, eliminating the addition of an additional amount of acid.

The problem is solved by solubilization of these salts with an aqueous solution of sorbitol.

Our proposed method is implemented as follows. Prepare an aqueous solution of sorbitol with a concentration of 5-70%. To the resulting solution at a temperature of no higher than 30 ° C, crushed calcium succinate, or calcium malate, or calcium citrate is added in accordance with Table 1. The mixture, periodically stirring, is kept for 6-24 hours at a temperature of 20 ° C until the salt is completely dissolved, after which possible mechanical impurities are disposed of by filtration. The resulting solution contains a greater amount of the corresponding salt than its solubility in distilled water at a given temperature.

Example 1:

Dissolve 50.0 g of sorbitol at a temperature of 80 ° C in 50 ml of distilled water. After cooling to 20 ° C, not more than 0.7 g of calcium malate (in terms of anhydrous salt) is added to the solution and, while stirring periodically, the mixture is kept for 24 hours. The resulting solution was filtered under vacuum.

Example 2:

65.0 g of sorbitol are dissolved at a temperature of 80 ° C in 35 ml of distilled water. After cooling to 20 ° C, not more than 5.1 g of calcium succinate (in terms of anhydrous salt) are added to the solution and, while stirring periodically, the mixture is kept for 24 hours. The resulting solution was filtered under vacuum.

Example 3:

40.0 g of sorbitol are dissolved at a temperature of 80 ° C in 60 ml of distilled water. After cooling to 20 ° C, not more than 0.3 g of calcium citrate (in terms of anhydrous salt) is added to the solution and, while stirring periodically, the mixture is kept for 24 hours. The resulting solution was filtered under vacuum.

The proposed method for increasing the solubility of calcium succinate, calcium malate and calcium citrate allows to obtain solutions of these substances with a high content of active substance and a pH close to neutral. The described method allows to expand the range of dosage forms of calcium succinate, calcium malate and calcium citrate by developing sorbitol-based syrups.

Table 1
The dependence of the solubility of calcium malate, calcium succinate and calcium citrate on the concentration of sorbitol The concentration of sorbitol,% Solubility of salts, g / 100 g (20 ° С; in terms of anhydrous salt) Calcium malate Calcium Succinate Calcium citrate 0 0.283 1.23 0,086 5 0.334 1.51 0,110 10 0.381 1.78 0.124 fifteen 0.403 2.11 0.143 twenty 0.444 2.44 0.172 25 0.498 2.71 0.215 thirty 0.542 3.06 0.252 35 0.603 3.43 0.275 40 0.623 3.83 0,300 45 0.673 4.04 0.349 fifty 0.704 4.27 0.387 55 0.715 4,54 0.427 60 0.726 4.74 0.442 65 0.756 5.11 0.428 70 0.781 5.21 0.428

Claims (1)

A method of increasing the solubility of calcium succinate, calcium malate and calcium citrate, characterized in that in an aqueous solution of sorbitol with a concentration of 5-70%, powders of the indicated substances are dissolved in amounts exceeding their solubility in water at a given temperature, followed by vacuum filtration to remove possible mechanical impurities.