The illustrations below show two approaches to titrating very small samples. In the first experimental design, samples of 20–100 µL were held by capillary action between a flat-surface pH electrode and a stainless steel sample stage. The titrant was added by using the oscillations of a piezoelectric ceramic device to move an angled glass rod in and out of a tube connected to a reservoir containing the titrant. Each time the glass tube was withdrawn an approximately 2 nL microdroplet of titrant was released. The microdroplets were allowed to fall onto the sample, with mixing accomplished by spinning the sample stage at 120 rpm. A total of 450 microdroplets, with a combined volume of 0.81–0.84 µL, was dispensed between each pH measurement. In this fashion a titration curve was constructed. This method was used to titrate solutions of 0.1 M HCl and 0.1 M CH3COOH with 0.1 M NaOH. Absolute errors ranged from a minimum of +0.1% to a maximum of –4.1%, with relative standard deviations from 0.15% to 4.7%. See Steele, A.; Hieftje, G. M. Anal. Chem. 1984, 56, 2884–2888 for additional details
Another approach carries out the acid–base titration in a single drop of solution. The titrant is delivered using a microburet fashioned from a glass capillary micropipet. The microburet has a 1-2 µm tip filled with an agar gel membrane. The tip of the microburet is placed within a drop of the sample solution, which is suspended in heptane, and the titrant is allowed to diffuse into the sample. The titration’s progress is monitored using an acid–base indicator, and the time needed to reach the end point is measured. The rate of the titrant’s diffusion from the microburet is determined by a prior calibration. Once calibrated the end point time can be converted to an end point volume. Samples usually consisted of picoliter volumes (10–12 liters), with the smallest sample being 0.7 pL. The precision of the titrations was usually about 2%.
For further details see (a) Gratzl, M.; Yi, C. Anal. Chem. 1993, 65, 2085–2088; (b) Yi, C.; Gratzl, M. Anal. Chem. 1994, 66, 1976–1982; (c) Hui, K. Y.; Gratzl, M. Anal. Chem. 1997, 69, 695–698; (d) Yi, C.; Huang, D.; Gratzl, M. Anal. Chem. 1996, 68, 1580–1584; (e) Xie, H.; Gratzl, M. Anal. Chem. 1996, 68, 3665–3669.