Azeco Cosmeceuticals

Formulations

14. Question: Question on the activity in the free acid or neutralized state: I’ve been pretty careful not to neutralize by post adding it to a PH of 5.5. Are there any differences in the free or salt state? Answer: Azelaic acid is a dicarboxylic acid and has therefore two dissociation constants. pKA1 = 4,55 & pKA2 = 5,50. As a consequence of being a weak dicarboxylic acid the ratio Azelaic acid/monosodium azelate/disodium azelate is pH dependant. To give an example of the calculation for pH=5,0 ([H3O+]= 1x10-5).

Two equilibrium equations: H2A + H2O ç è HA- + H3O+ HA- + H2O çè A2- + H3O+

With the two dissociation constants. KA1=[H3O+]x[HA-]/[H2A] = 2,82x10-5 KA2=[H3O+]x[A2-]/[HA-] = 3,16x10-6

Furthermore the mass balance reads: [H2A] + [HA-] + [A2-] = C After substitution of [H3O+]= 1x10-5): we are left with three equations with three unknowns, and that gives only one solution. Calcu lus gives: [H2A] = 0,213xC

[HA-] = 0,598xC [A2-] = 0,189xC

In other words: at pH=5,00 21,3% of the amount of Azelaic acid present as the free dicarboxylic acid, 59,8% is present as the mono sodium salt and 18,9% is present as the disodium salt. When another pH value would have been chosen another concentration profile is applicable. There is no picture for Azelaic acid, but below is q picture for another dicarboxylic acid: fumaric acid.

The picture shows that the concentration of the three species is pH dependant. At very low pH (e.g. pH=1,5 most fumaric acid is pre sent as the free acid. At very high pH the disodium salt is dominant. At pH=3 we have almost equal quantities of the free acid and the monosodium salt, and at pH=5 we have almost equal amounts of the monosodium salt and disodium salt, and only a small quantity of the free acid. So, the pH determines how much of each species is present. That is valid for fumaric acid, but also for Azelaic acid.. Does this affect the functionality of Azelaic acid ? No ! In the tallow gland where Azelaic acid must do the job all species act equally. However, at elevated pH the solubility of Azelaic acid increase.

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