Comparing automated titrimetry method to manual titrimetry on samples from a production unit
In hospital preparations of ursodesoxycholic acid, an essay on 10 individual capsules of the batch is achieved by titrimetric dosage (see: European pharmacopeia 01/2017:1275) to ensure its content uniformity. This method can be manual or automated. Although the manual method is widespread in preparation units, it has several drawbacks, including operator-dependent variability (eg at the end point reading) and time-consuming. This last point becomes limiting when the volume of equivalence is large and volatile. In order to improve this assay, we compared manual titrimetry, currently in use with an automated titration technique.
Materials and methods
Ursolvan® 200mg was used to obtain solutions of known concentrations at: 10, 25 and 50 mg/mL (corresponding to doses in capsules prepared in the unit). The titrant was sodium hydroxide (NaOH 0.1M). Manual titration was done by colorimetric technique (addition of phenolphthalein) and automated titration with a titrimeter 905 Titrando Metrohm® - and a pH electrode. For each concentration, 10 measurements were taken by both methods (n=60). Accuracy (measure of relative standard deviation =RSD) was compared by Fisher Snedecor’s statistical test. The average deviation from theoretical concentration (=EM, tolerated threshold - 10% of theoretical concentration) and average handling time (=D, in minutes) was compared using the Wilcoxon Average Comparison Statistical Test (unpaired samples).
RSDaut= 6.062% vs RSDman=5.722% at 10mg/mL (p>0.05), RSDaut=1.721% vs RSDman=2.583% at 25mg/mL (p<0.05), RSDaut= 0.863% vs RSDman=1.473% at 50mg/mL(p<0.05). EMaut 5.82% vs EMman=4.8% (p=0.5671), EMaut=1.43% vs EMman=6.5% (p=0.0005) and EMaut= 3.56% vs EMman=3% (p=0.4247) respectively for solutions at 10, 25 and 50mg/mL. L’EMtotal is dose-independent (p=0.0974). Finally, Daut=8.04min vs Dman=38.55min (p=0.0001), Daut=8.36min vs Dman=42min (p=0.0001) and Daut=8.25min vs Dman=47.94min (p=0.0001) for solutions 10, 25 et 50mg/mL respectively.
Analytical control by automated titration optimizes the capacity for hospital preparation analysis: significant improvement in accuracy (25 and 50mg/mL), no significant difference in EM between the two methods (10 and 50mg/mL). In addition to being significantly faster, this technique requires little presence time of the operator. The difference in EM between the two methods for 25mg/mL would be due to handling errors (human influence of the manual method). Reproducibility tests by different operators will be needed to improve the robustness of the study. This apparatus could also be used within the unit for other dosages (e.g.aqueous boric acid, acetylsalicylic acid, …).