High throughput continuous titration based on a flow ratiometry controlled with feedback-based variable triangular waves and subsequent fixed triangular waves.

We propose a new approach for high-throughput continuous titration based on a flow ratiometry. The method was applied to potentiometric titrations of acids and bases. A base solution, the flow rate F(B) of which was varied in response to controller output voltage V(c), was merged with an acid solution under constant total (acid+base) flow rate. Downstream, the pH of the mixed solution was measured with a flow-through glass electrode. Initially, V(c), and thus F(B) was increased linearly. At the instant the equivalence point (EP) was sensed, the ramp direction of V(c) was reversed from upward to downward. The direction was reversed to upward when EP was sensed again. Such the feedback-based operation gives a triangular waveform of V(c), because there is a delay corresponding mainly to the transit time of merged solutions to reach the sensor. The value of V(c) that gives EP composition, V(E), was estimated by averaging the most recent maximum and minimum values of V(c). Next, fixed triangular waves of V(c) was used to control F(B). The amplitude and the scan rate of the waves were fixed narrower and faster, respectively, than those in the feedback-based operation in order to improve the throughput rate. The EP can be located as long as the scan range covers V(E). These automated processes limited the titration to just the narrow range around EP, and thus realized extremely high throughput rate of maximally 17.6 titrations per minute (=3.4s per titration) at R.S.D.=0.35%.