The Physicochemical Properties Of Pharmaceutical Salts With Berberine As Cation And Their Interactions With Small Biomolecules

Berberine is an alkaloid isolated from the traditional Chinese medicine Coptis chinensis.Because of its low solubility in water,its application in the pharmaceutical industry is limited.In this paper,pharmaceutical salts were synthesized by combining berberine with biodegradable organic acids to improve the physicochemical properties and bioavailability of berberine.As potential drugs,it is necessary to understand their physicochemical properties and their interactions with small biomolecules in order to gain an excellent application in pharmaceutical indusry.In the present paper,five pharmaceutical salts with berberine as the cation were designed and synthesized,namely berberine-octanoic acid([BBR][OCT]),berberine-heptanoic acid([BBR][HEP]),berberine-hexanoic acid([BBR][HEX]),berberine-DL-mandelic acid([BBR][MAN])and berberine-cinnamic acid([BBR][CIN]).The thermal stability was measured by thermal analysis.The antibacterial effect of five pharmaceutical salts was determined by antibacterial test.The solvation behavior of pharmaceutical salts in aqueous solution and their interactions with small biomolecules(amino acids,glycyl dipeptide and glycyl tripeptide)were systematically studied by volume,conductivity and UV spectroscopy.In order to better study the absorption,distribution and metabolism of the pharmaceutical salts in the body,the oil-water partition coefficient and solubility of the pharmaceutical salts in water and buffer solutions with different pH were also determined.The main conclusions are as follows:(1)The thermal stability interval of five pharmaceutical salts were measured by thermal analyzer.Thermal analyses demonstrated that five pharmaceutical salts had good thermal stability.(2)The solubility and oil-water partition coefficient KO/W of five pharmaceutical salts in water and buffer solutions with different pH were measured at different temperatures.It was found that both of them were greatly affected by pH value,and the solubility increases with the increase of temperature,the oil-water partition coefficient decreases with the increasing temperature.The solubility of five pharmaceutical salts in organic solvents was also measured,and the results show that the solubility increased with the increasing polarity of organic solvents.(3)The antibacterial effect of five pharmaceutical salts on Staphylococcus aureus,Candida albicans and Bacillus subtilis was measured and the minimum inhibitory concentration(MIC)and minimal bactericidal concentration(MBC)values were obtained.The results show that the five pharmaceutical salts have good antibacterial effect on the studied strains.(4)The critical aggregation concentration(CAC)of five pharmaceutical salts in water and aqueous small biomolecules solutions were determined by the conductivity method,and a series of thermodynamic parameters in the process of aggregation were calculated.It was found that all the aggregation process of these pharmaceutical salts were the spontaneous,exothermic and entropy increase process.In addition,the effect of temperature,anionic chain length of pharmaceutical salts and the concentration of small biomolecules on aggregation process were also studied.It was found that the CAC value decreases with the decrease in temperature,which was conducive to the aggregation of pharmaceutical salts.The aggregation of pharmaceutical salts with anionic longer chain lengths is easier.The CAC value of the pharmaceutical salts in the aqueous small biomolecules solutions are smaller than its CAC value in aqueous solution,indicating that the addition of small biomolecules in aqueous solution is beneficial to promote the aggregation process.(5)The density values of the "pharmaceutical salts+water" binary system and the "pharmaceutical salts+small biomolecules+water" ternary system at different temperatures were determined by Anton Paar densitometer.The standard partial molar volume,standard partial molar transfer volume,theoretical hydration number,partial molar expansion coefficient,Hepler’s constant and thermal expansion coefficient of solute were calculated.The standard partial molar volumes of the studied pharmaceutical salts were positive.Temperature had a greater influence on the volume change of the pharmaceutical salts solution and the dehydration effect could be enhanced by increasing temperature.The volume properties of small biomolecules in aqueous pharmaceutical salts solution revealed the strong hydrophobic-hydrophobic and ion-hydrophobic interactions between small biomolecules and pharmaceutical salts.Small biomolecules are structure-makers in pharmaceutical salts solution.The thermal expansion coefficients of small biomolecules in aqueous pharmaceutical salts solution are all positive and increase with the increasing temperature.It indicates that enhancing temperature has greater influence on the system volume.(6)The UV absorption spectrum of "pharmaceutical salts+ small biomolecules+water" ternary system were determined by UV-vis spectroscopy,which was used to obtain the binding constants of pharmaceutical salts with small biomolecules.The binding constants increase with the increasing alkyl chain length and the number of glycyl groups of small biomolecules,demonstrating that the improved interaction between them.