Salt Stability - The Effect of pHmax on Salt to Free Base Conversion.

Pharmaceutical research (2015-04-16)
Yi-Ling Hsieh, Jeremy M Merritt, Weili Yu, Lynne S Taylor
ABSTRACT

The aim of this study was to investigate how the disproportionation process can be impacted by the properties of the salt, specifically pHmax. Five miconazole salts and four sertraline salts were selected for this study. The extent of conversion was quantified using Raman spectroscopy. A mathematical model was utilized to estimate the theoretical amount of conversion. A trend was observed that for a given series of salts of a particular basic compound (both sertraline and miconazole are bases), the extent of disproportionation increases as pHmax decreases. Miconazole phosphate monohydrate and sertraline mesylate, although exhibiting significantly different pHmax values (more than 2 units apart), underwent a similar extent of disproportionation, which may be attributed to the lower buffering capacity of sertraline salts. This work shows that the disproportionation tendency can be influenced by pHmax and buffering capacity and thus highlights the importance of selecting the appropriate salt form during the screening process in order to avoid salt-to-free form conversion.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Methanesulfonic acid, ≥99.0%
Sigma-Aldrich
Benzoic acid, ACS reagent, ≥99.5%
Sigma-Aldrich
p-Toluenesulfonic acid monohydrate, ACS reagent, ≥98.5%
Sigma-Aldrich
Phosphoric acid, 85 wt. % in H2O, 99.99% trace metals basis
Sigma-Aldrich
L-(+)-Tartaric acid, ACS reagent, ≥99.5%
Sigma-Aldrich
Sodium phosphate tribasic dodecahydrate, ≥98%
Sigma-Aldrich
Phosphoric acid solution, 85 wt. % in H2O, FCC, FG
Sigma-Aldrich
p-Toluenesulfonic acid monohydrate, ReagentPlus®, ≥98%
Sigma-Aldrich
Phosphoric acid, crystalline, ≥99.999% trace metals basis
Sigma-Aldrich
(1S)-(+)-10-Camphorsulfonic acid, 99%
Sigma-Aldrich
Benzoic acid, ≥99.5%, FCC, FG
Sigma-Aldrich
Sodium bromide, BioUltra, ≥99.5% (AT)
Sigma-Aldrich
Benzoic acid, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥99.9% (alkalimetric)
Sigma-Aldrich
Phosphoric acid, BioUltra, ≥85% (T)
Sigma-Aldrich
L-(+)-Tartaric acid, ≥99.5%
Sigma-Aldrich
Phosphoric acid, BioReagent, suitable for insect cell culture, 85%
Sigma-Aldrich
p-Toluenesulfonic acid monohydrate, ≥99% (calc. to H2O free subst.)
Sigma-Aldrich
Sodium bromide, ≥99.99% trace metals basis
Sigma-Aldrich
Methanesulfonic acid solution, 70 wt. % in H2O
Sigma-Aldrich
Phosphoric acid, ≥85 wt. % in H2O, ≥99.999% trace metals basis
Sigma-Aldrich
Sodium bromide, BioXtra, ≥99.0%
Sigma-Aldrich
Benzoic acid, ReagentPlus®, 99%
Sigma-Aldrich
L-(+)-Tartaric acid, puriss. p.a., reag. ISO, 99.5-101.0% (calc. to the dried substance)
Sigma-Aldrich
Benzoic acid, meets analytical specification of Ph. Eur., BP, USP, FCC, E210, 99.5-100.5% (alkalimetric)
Sigma-Aldrich
L-(+)-Tartaric acid, puriss., meets analytical specification of Ph. Eur., NF, 99.7-100.5% (calc. to the dried substance), powder
Sigma-Aldrich
Sodium phosphate tribasic dodecahydrate, BioXtra, ≥98.0% (titration)
Sigma-Aldrich
Sodium bromide, anhydrous, free-flowing, Redi-Dri, ACS reagent, ≥99%
Sigma-Aldrich
Phosphoric acid solution, NMR reference standard, 85% in D2O (99.9 atom % D), NMR tube size 4.2 mm × 8 in. , WGS-5BL Coaxial NMR tube
Sigma-Aldrich
L-(+)-Tartaric acid, ≥99.7%, FCC, FG
Sigma-Aldrich
(±)-Miconazole nitrate salt, imidazole antibiotic