The effect of the solution environment on the solubility of short chain peptides

Solubility is one of the important parameters in designing a suitable dosage form for peptide drugs. The effects of solution environment on the solubility of short chain peptides are not clearly understood. The objective of this research is to develop a mathematical equation for solubility and activity coefficient prediction of a series of model peptides by using a combination of computational chemistry and a series of solubility determinations.^ Molecular mechanic calculations were used to calculate minimized force field energy of glycine peptides with two to six amino acid residues. The results from the molecular surface area, the dipole moment and the radius of gyration calculations indicate that the minimized energy conformation of the peptides is folded.^ The solubility and activity coefficient determinations reveal that when different salts are used to adjust the ionic strength, the solubility and activity coefficient of glycine peptides change. The results indicate that sodium chloride and potassium chloride have a similar effect on the activity coefficient of diglycine and tetraglycine. However they have a different effect on triglycine, pentaglycine and hexaglycine. In addition, instead of using the net charge of zero as the charge of the zwitterionic species of the peptide in the solution for the ionic strength and activity coefficient calculations, the charge assignment of two gives the best fit between the experimental data and the theoretical calculation for non-ideal solutions.^ The commonly used equations to calculate activity coefficients of electrolytes, such as the Debye-Huckel limiting equation, the extended Debye-Huckel equation, and the Davies, Bromley or Kirkwood equations, fail to predict the activity coefficient of glycine peptides. A new mathematical model was successfully developed using the molecular characteristics from the computational chemistry calculations and the principles of modern electrochemistry. The results of this investigation provide a basis for further research for the development of activity coefficient predictions of other peptides.* ftn*Originally published in DAI Vol. 58, No. 2. Reprinted here with corrected author name.