Applying DMAIC Principles For Improving Method Performance Of Quantitative Determination Of Levothyroxine Sodium In Tablet Dosage Form Using High Performance Liquid Chromatography Technique

A simple and improved reverse phase liquid chromatographic method has been developed for the estimation of Levothyroxine Sodium in tablet formulation. The drug is official with Indian Pharmacopeia, United States Pharmacopeia British Pharmacopoeia. The separation was carried out using Nucleosil CN, 250*4.6mm, 5 mu column and the mobile phase consisting of water, acetonitrile(ACN) and o-phosphoric acid in the ratio of 650 : 350 : 10 (v/v ) in isocratic mode. The flow rate was 1.00 mL/min and effluent was monitored at 225 nm. The new method for the assay of Levothyroxine Sodium tablet was found statistically superior as compared to the official IP 2010 method. Define, Measure, Analysis, Improve and Control (DMAIC) principles were used for problem solving, root cause investigation, risk management to improve method performance. Statistical process control evaluation of the method before and after modification revealed that modified method is under statistical process control. Levothyroxine sodium in tablets formulation under acidic condition was found stable up to 42h; whereas the drug was found stable only up to 8h under alkaline condition. The marked difference was found for assay values by both the methods. The methods were found statistical different. The advantage of modified method is better extraction capacity and solution stability of Levothyroxine Sodium in tablet formulation.This study was applied in analytical quality control laboratory to improve the quality of the method, reduce method defects and increase right first time of assay test method by applying the Lean Six Sigma (LSS) methodology. LLS is considered one of the successful approaches in the field of quality improvement and cost reduction. The case study laboratory working environment was analyzed to isolate the root causes for the defects generation. Remedies and counter measures were suggested and some were implemented. The study compares the performance of the test method before and after implementation of the proposed solutions for defects reduction. We subjected a high performance liquid chromatographic (HPLC) analytical procedure used for screening drugs on authenticity to a Failure Mode and Effects Analysis (FMEA), including technical risks as well as risks related to human failure. An FMEA tool broke down the HPLC analytical method into process steps and identified possible failure modes for each step. Each failure mode was ranked on estimated frequency of occurrence (O), probability that the failure would remain undetected later in the process (D) and severity (S), each on a scale of 110. Failure risks were calculated by Risk Priority Numbers (RPNs) =OxDxS. Failure modes with the highest RPN scores were subjected to corrective actions and the FMEA was repeated, showing reductions in RPN scores and resulting in improvement indices up to 5.0. The present method was successfully used for quantitative determination of Levothyroxine sodium in tablet dosage form. The investigations showed that it was feasible to define an HPLC method with an improved quality compared to IP2010 assay method.