It has been observed that the main focus during the process development and manufacturing of an API is to meet the customer’s specifications (LSL and USL) rather than estimating and improving the natural control limits (LCL and UCL) of the process. It results in the overlap of the natural control limit and customer’s specification, which in turn increases the chance of failure with respect to the customer’s specifications. A better approach is to work on decreasing the variability of the process so that natural control limits become much tighter than customer’s specification. The statistical control charts not only help in estimating these internal/natural control limits but also raises an alert when the process goes out of control. These alerts trigger the investigation through root cause analysis leading to the process improvements which in turn lead to the decrease in variability of the process. This process continues till inherent variability of the process is due to common causes only and cannot be attributed to assignable causes. At this point, the natural control limits of the process can be taken as internal specification for an output quality parameter.

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As over 70% of pharmaceutical compounds are bases, the analysis of these basic compounds by high performance liquid chromatography (HPLC) continues to be of great value and interesting. Acetyl cholinesterase inhibitors (AChEIs), which contain the basic compounds like Rivastigmine tartrate, Galantamine hydrobromide and Donepezil with different polarities, were chosen for the study. A rapid screening of the volatile ion-pairing reagents was performed using modern techniques like ultra high performance liquid chromatography (UHPLC). The experiments were planned using the 'Design of Experiments' (DoE) approach to identify the LC-MS compatible ion-pair reagent. In this study, Heptafluorobutyric acid (HFBA) has given a very good peak shape with tailing factor at 1.4 and theoretical plates up to *5,000 were observed, compared to tailing factor at 1.9 and theoretical plates up to *3,000 with non-volatile ion-pair reagent sodium heptane sulphonate (SHS). Similarly retention with HFBA was optimum as *5 min in short run time method compared to *13 min with SHS. This ion-pair reagent has proved to be good replacement of sodium alkyl sulphonate modifiers. HFBA can also be used for semi-preparative work for isolation of impurities by just evaporating the solvents. It avoids the extraction of other inorganic modifiers.Keywords Ultra high performance liquid chromatography (UHPLC) Á Volatile ion-pair reagents Á Design of experiments (DoE) Á Acetylcholinesterase inhibitor (AChEI) Á Alzheimer's disease (AD)

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