The COVID-19 pandemic created a demand for a fast response to provide vaccines to a concerned world population. In this post, we will describe how Polypure developed monodisperse, heterobifunctional PEGs of higher molecular weights for advanced pharmaceutical applications based on the COVID-19 vaccine R&D project.

The technology of mRNA incorporated into lipid nanoparticles was a suitable alternative to traditional vaccines and was quickly approved for mass vaccination. One of the critical components in vaccine function is polyethylene glycol, or PEG, which prevents particle agglomeration and reduces immune response. Since we were involved in a vaccine project, we analyzed a sample from a commercial source to investigate the PEG component of the PEG-lipid DMG-PEG 2000. Fig. 1. shows mPEG glycerol ether submitted for analysis by HPLC.

The analysis below shows an expected broad peak from the polydisperse mPEG glycerol ether but also a minor distribution at higher retention time (Fig. 2.)

MALDI-TOF analysis confirms the presence of higher molecular weight impurities, confirmed as the homobifunctional bis-glycerol ether, which is an expected impurity present in polydisperse mPEG (Fig. 3).

A sample from another manufacturer indicates that the problem was recognised and the cross-binding impurity was removed to a large extent. However, the action also removed a large part of the original Gaussian distribution of the methoxy-PEG derivative (Fig.4.), which may or may not have consequences for performance. Nevertheless, it does reveal that a polydisperse product may not contain the expected material, and that batch-to-batch variation can be significant.

With this learning, we decided to prepare a monodisperse product based on our PEG-45 that matches the intended molecular weight of 2.000 Dalton. As seen from the analytical data, the chromatographic pattern as well as MALDI-TOF analysis show that our product overlaps one of the components in the polydisperse compounds. It also demonstrates the expected pattern from the MALDI-TOF analysis, giving an estimated 98% of the target oligomer (n=45) (Fig. 5.).

By expanding the MALDI-TOF spectrum of Polypure mPEG-45 glycerol ether displaying sodium adducts primarily, one can see signals corresponding to M+H+ at 2088 and M+Na+ at 2110 (Fig. 6.). The maximum peak corresponds to the average one C13 carbon. There is a very low content of n-1 oligomer present in the sample.

In conclusion, the polydisperse PEG derivatives were certainly able to achieve the intended function, but the lack of control is obvious. For a product which is based on a single oligomer, the expected performance can be anticipated every time, with a reproducibility from batch-to-batch that simplifies processing.

Monodisperse Polyethylene glycol (PEG) has long been widely used in nanoformulations to improve solubility and biocompatibility in pharmaceutical systems.

At the same time, monodisperse Polypropylene Glycol (PPG) is attracting increasing interest as a potential alternative material, particularly for hydrophobic drug delivery.

Why is this interesting?

PPG possesses a unique molecular duality: a hydrophilic ether group in its backbone that can form hydrogen bonds, combined with hydrophobic methyl side groups. This balance between hydrophilic and hydrophobic interactions allows PPG to respond dynamically to changes in its environment.

At certain temperatures, PPG can transition from a soluble to a phase-separated state — a hallmark of LCST behavior. Such responsiveness may support controlled drug release, self-assembly into nanostructures such as micelles and nanogels, and the development of smart responsive materials.

Molecular weight plays an important role in this behavior. Lower molecular weight PPGs have been observed to remain water-soluble while exhibiting LCST transitions in aqueous systems. In contrast, higher molecular weight variants often display LCST values below room temperature, significantly influencing their behavior and formulation potential.

Beyond water-based systems, LCST behavior has also been observed in ionic liquids, opening additional opportunities for formulation science. Recent studies have even reported unexpected co-solvency effects, where small amounts of water influence PPG solubility in ionic liquid systems and alter LCST behavior in meaningful ways.

Why is it not used now?

One of the key barriers to broader biomedical use of PPG has been material consistency. Conventional commercial PPG often contains compositional variability and unsaturated impurities, creating challenges for reproducibility in sensitive applications.

As part of an internal research initiative, Polypure has developed a high-purity, monodisperse PPG designed to address these limitations and support further research into advanced drug delivery systems.

The question now becomes: could high-purity monodisperse PPG emerge as an important next-generation material platform for nanoformulations?

DrugDelivery #Nanomedicine #PolymerScience #Biomaterial

Poly(ethylene glycol) (PEG) is one of the most widely used polymers in pharmaceuticals and personal care applications, playing a key role as a surfactant, emulsifier, and in drug delivery systems by improving solubility and extending circulation time. However, standard PEG is typically polydisperse, consisting of mixtures of different chain lengths that can introduce variability in analysis, reproducibility, and formulation performance.

https://www.chemistryworld.com/industry/advantages-of-monodisperse-peg-in-drug-development/4023224.article