Statistical Analysis Helps the Medicine Go Down

Most people prefer taking tablets to getting shots, but what if you have difficulty swallowing?

medication in pill form 

Fast-dissolving tablets allow even those who find swallowing difficult to enjoy the benefits of oral medication. Unfortunately, fast-dissolving tablets only work if the active ingredient dissolves well enough for the body to process it.

A team of researchers in Nepal recently demonstrated a method to improve the solubility of domperidone, a drug used to treat vomiting and nausea, allowing it to be delivered in fast-dissolving tablet form.

Some molecules, including domperidone, don’t dissolve well on their own. However, combining them with other molecules can improve their absorption. Ingredients added to a drug to improve its delivery are called excipients.

The researchers in Nepal wanted to determine what excipients or combination of excipients best improve the dissolution of domperidone. They were concerned both with how thoroughly it dissolved and with how quickly it did so.

They used Minitab Statistical Software and a statistical method known as “design of experiments” to conduct their research. A designed experiment lets scientists change more than one factor at a time, then use statistical analysis to get meaningful results about all factors simultaneously.

There are two broad types of designed experiments. Screening experiments let researchers evaluate a large number of factors and rule out the ones that show little effect. Optimization experiments help researchers fine-tune the important factors in a process to achieve maximum efficiency.

The Nepalese researchers began by creating a screening experiment with a Plackett-Burman Design, which let them test the combined and individual effects of nine excipients with just 12 experimental runs.

Following the Plackett-Burman experimental design created with Minitab, the researchers made tablets using various formulations and combinations of the excipients. Each tablet was dissolved in acid and tested for absorbance. Then they analyzed their data with Minitab, which provided a main effects plot that made it easy to see which excipients had the greatest impact on dissolution and absorbance.

main effects plot

The main effects plot for dissolution showed that 2-hydroxypropyl ß-Cyclodextrin (HP-β-CD) had the greatest effect on how thoroughly the domperidone dissolved.

main effects plot

The main effects plot for disintegration time showed that sodium starch glycolate (SSG) had the greatest effect on how long it took the active ingredient to dissolve.

Having discovered that HP-β-CD and SSG have the greatest impact on dissolution amount and time, respectively, the team then used Minitab to design a second experiment in order to optimize the formulation of the two ingredients. They selected a two-factor, two-level central composite design that enabled them to optimize the formulation by making and testing just 13 tablet variations.

contour plot of dissolution

The contour plot of dissolution vs. SSG and HP-β-CD shows the amount of domperidone that dissolves at various combinations of SSG and HP-β-CD. The dark blue area indicates the formulation levels that had the most complete dissolution.

contour plot

 
The contour plot of dissolution time versus SSG and HP-β-CD shows the effect various combinations of SSG and HP-β-CD have on dissolution time.

After analyzing their experimental results in Minitab, the researchers found that the optimum concentration of HP-β-CD is a 1:2 molar ratio, and that the optimal concentration of SSG is 7% mass to mass.

In the final phase of this study, the researchers compared their optimized formula with a commercial sample from their local pharmacy. The test formula dissolved more quickly and more fully than the sample, demonstrating that HP-β-CD and SSG effectively improve the solubility of domperidone. The researchers’ formulation not only dissolved well, but also formed durable tablets that met pharmacopeial standards.

The success of their research, as demonstrated using carefully designed experiments and statistical analysis, could contribute to more and faster-dissolving tablet formulations for a variety of poorly-soluble drugs.

This research was published in an article in Volume 5, Issue 3 of Pharmacology and Pharmacy.

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