Mumbai : Experts discuss how important physical and chemical attributes like particle size and surface area affect excipient functionality, performance and hence drug quality.

This discussion bears relevance in the backdrop of the Government of the Gambia looking at exploring avenues for potential legal action against Indian manufacturers in connection with the incidents of acute kidney injury (AKI) due to contaminated cough syrups in the year 2022.

Chemical equivalence of an excipient through pharmacopoeia cannot judge its quality. Unlike API, the effect of excipients depends upon various physical, chemical and other parameters that define its efficiency in a formulation thereby affecting the ultimate therapeutic effect.

“It is quite easier to establish the quality of API by chemically testing it through various pharmacopoeias. As against this, just by establishing the chemical equivalence of an excipient through pharmacopoeia, we cannot judge its quality. Excipient properties greatly affect the formulations attributes resulting in strikingly different formulation characteristics,” explained Dr Ravleen Singh Khurana, managing director, Nitika Pharmaceutical Specialties and secretary, International Pharmaceutical Excipient Council (IPEC) India while emphasizing the role of Quality by Design (QbD) in excipients.

Important physical chemical attributes affecting excipients functionality or performance are particle size, distribution, surface area, flow property, molecular weight, purity, compatibility, assay, moisture content, solubility, viscosity, density and crystallinity.

Through a traditional approach, quality is assured by testing and inspection, there is intensive data submission, rigid process, focus on reproducibility and history based specification. In the QbD approach, quality is built into the product and process by design based on scientific understanding. There is knowledge submission, flexible process, focus on robustness and performance requirement base submission in QbD.

Going by the QbD approach we need to evaluate functional related characteristics (FRCs) and concepts that are correlated with key formulation performance.

“More than 90 excipients can be used to manufacture solid dosage forms from various categories like binding agents, disintegrating agents, diluents, lubricant, glidant, opacifying agents, coating agents and sweeteners among others. Amongst them Magnesium Stearate is the most widely used hydrophobic lubricant (used in more than 95% tablet formulations) made by several manufacturers throughout the world. In India alone, there are 10 manufacturers of magnesium stearate and throughout the world, there are more than 25,” Dr Khurana informed.

To demonstrate this, Dr Khurana cited a research paper published in International Journal of Pharmaceutical Sciences and Research (IJPSR) 2012 by Saurabh Seth from Ajanta Pharma, Mumbai who compared magnesium stearate of Nitika Tablube and magnesium stearate from an MNC source.

The study reveals the critical role play of magnesium stearate in formulation development of a highly soluble drug metformin hydrochloride. It gives clarity on the decisive role of particle size of highly hydrophobic lubricant i.e. magnesium stearate, its concentration and lubrication time to establish the desired quality attributes of formulation containing highly soluble model drug metformin hydrochloride. Magnesium stearate from two sources with different Particle Size Distribution (PSD) range was selected. It was observed that the magnesium stearate with a designed PSD is controlling the drug release profile of metformin hydrochloride tablets, which can replace the use of excess quantity of magnesium stearate or addition of a rate controlling polymer like hydroxy propyl methyl cellulose in the formulation design.

“Conclusively, as demonstrated in the research article change in particle size and surface area of magnesium stearate along with concentration and lubrication time can affect the properties of the blend or tablet significantly such as disintegration time, hardness and most importantly dissolution. If we are having the QBD approach, we will evaluate the functional related characteristics of excipients magnesium stearate Tablube of Nitika so we will have the desired CQAs like dissolution profile, disintegration time and other key attributes. If you go by conventional approach, our formulation may not have the desired quality attributes,” Dr Khurana concluded.

Disadvantages of conventional practices also include poor understanding of inputs and responses, many non-conforming incidents (NCI), time consuming investigations of NCI’s, rejected batches, higher manufacturing cost, changing process requirements and stringent regulatory approvals.
“Formulation development by the QbD way with reference to excipients will ensure that we have the critical quality attributes of a formulation as our predefined objective and the knowledge of various physicochemical and performance characteristics of the excipient will help us to carry out design by the QBD way,” experts recommended.