Agrochemical Formulators – You are Not Alone

Dr. David Calvert

Director and Co-founder at iFormulate Limited, UK

Whilst there are many definitions of formulation science, one which is most applicable is "a  technology used to deliver an active ingredient safely and effectively to the right place at the right time″. Looking at this closely it is obvious that this applies to a large number of applications such as pharmaceuticals, inks, coatings, homecare, food, drink, cosmetics and of course agrochemicals. A skilled formulator will often look outside their own industry for solutions and in this article, we examine examples and opportunities where the agrochemical formulator could learn from other sectors.

A driver across many markets is often regulations and when applied to specific categories or individual ingredients, then these can have an impact on a large number of different markets. The agrochemical market is not immune from this as we have seen with the banning of products such as  nonyl phenol ethoxylated alcohols (NPE) and polyethoxylated tallow amine (POEA) surfactants from new products introduced in Europe.

When alternative ingredients are being proposed, one of the issues which is commonly encountered is that of economics. In many cases the use of a particular ingredient in agrochemicals is relatively small in volume and if that were the only application, then market acceptance would be restricted, and introduction would be reduced. Once again, it is here where other markets can be advantageous and a good example of this is the area of alternative solvents. 

Whilst the agrochemical market uses solvents in products such as Emulsifiable Concentrates (EC), agricultural products can, in an interesting example of the circular economy, also provide green solvents for other industries such as coatings. Ethyl lactate, for example, is derived from the processing of corn and was one of the early ″green″ solvents adopted in coatings^ⅰ 

Vertec Biosolvents^ⅱ have developed their ethyl lactate further and have applications in cleaning, inks, coatings and sanitization. With the driver of volume from other applications, a large number of companies have developed solvent alternatives to synthetic chemical solvents such as N-methyl pyrrolidone (NMP) and there are products available from the likes of Solvay (now Syensqo)^ⅲ, BASF^ⅳ, Nouryon^ⅴ, Circa Group^ⅵ  and Corbion^ⅶ which are being promoted and used in agrochemicals.

Another area where regulation is driving change across sectors in addition to agrochemicals is the issue of microplastics. Whilst the initial driver was in cosmetics, formulators are being challenged to remove microplastics in agrochemicals. In his 2023 AgroPages article^ⅷ, my colleague Jim Bullock reviewed some potential solutions such as the use of naturally derived polymers such as alginates, cellulose and chitosan. Jim also touched on how Eden Research have used ready-made natural capsules (empty yeast cells) in their Sustaine^® technology which is used in commercial products such as Mevalone^ⅸ. A similar analogous approach has been used by Sporomex^ⅹ, who remove the internal genetic material of plant pollens or spores to produce an exine which can then be filled with active ingredients and is interest in cosmetics and personal care.

The formulation of biological entities rather than chemicals is becoming key in markets such as cosmetics, pharmaceuticals and homecare in addition to agrochemicals. The highest profile example of formulating biology came with the development of vaccines during the COVID pandemic. Delivery of the messenger RNA (mRNA) in the Pfizer-BioNTech or Moderna vaccines into cells is achieved via a lipid nanoparticle (LNP). LNPs in the vaccines typically contain just four ingredients^ⅺ: 

• ionizable lipids which bind to the mRNA

• pegylated lipids which stabilise the particle

• phospholipids and so-called ″helper lipids″ which support stability during storage and circulation, 

  and

• cholesterol molecules which help to structure the lipid phase and can reduce leakage of the mRNA for the LNP 

A more detailed review of the functions of each component can be found in an article published in 2022^ⅻ. The public interest in the development of the vaccines has led to much of the formulation work being published^xiii, ^xiv and this is helping with the development of RNA interference (RNAi) products for agriculture^xv. There are many companies active in this area and they include Agrospheres^xvi, PlantArcBio^xvii, Renaissance Bioscience^xviii and TrilliumAg^xix.

There are many other biological entities being explored for their use in agrochemicals and many of these have their foundations in other markets. 

Enzymes are a form of peptides and are often referred to as ″biological catalysts″. The major initial use for these was in detergent applications and the formulation work focussed on stabilising these in liquid and solid formulations. Early approaches included the use of proteins such as casein (US Patent 4842767), various carboxylic acids (US Patent 4305837), boric acid (US Patent 4537707) and glycolic acid (US Patent 5877141A). Infinita Biotech published a good overview of the role of enzymes in detergent products in 2023^xx whilst Novozymes looked at drivers and challenges for enzymes in detergents^xxi and there can be little doubt that the knowledge gained from detergents has been an advantage for Novozymes as they enter the agrochemical market^xxii. Work still continues to improve the stability of enzymes via formulation. For example, in European Patent 3722418A1 AB Enzymes claim a solution stable enzyme composition including a stabiliser comprising an organic polyhydroxy compound that has three or more hydroxyl groups per molecule. 

The most famous peptide is insulin and many therapeutic peptides are delivered by injection as peptides can be easily hydrolysed by digestive enzymes in the stomach and intestine. A recent review in Nature^xxiii has highlighted how co-formulation with permeation enhancers is allowing peptides such as semaglutide to be delivered orally. 

These approaches to delivery will no doubt be looked at as companies look to evaluate the potential of peptides in agriculture. There are already encouraging signs and Elemental Enzymes recently announced approval for Vismax^®, a patented proprietary biofungicide^xxiv. Other companies active in this field include Vestaron^xxv and Micropep^xxvi.

An interesting new approach to drug therapy which could have benefits for agriculture is the development of a two headed dumbbell shaped drug called a PROTAC^®xxvii. These work with two binding ligands, one for the target protein and the other for attaching to another enzymatic protein called an E3 ligase. This in turn tags the problematic protein with ubiquitin which marks it out for degradation by the proteasome. Presently these are mainly being explored for cancer treatment, but as the ubiquitin-proteasome system is observed in many animals, insects and plants then the extension to agriculture is being explored with Oerth Bio the leading practitioner^xxviii. Their Attune™ platform has formulation in pillar three of the development and this will no doubt be informed by the experience in pharmaceuticals.

In conclusion, there are many examples of technology transfer from other markets into agrochemicals. Formulation is a key enabling technology in all markets and agrochemical formulators should look for knowledge from other sectors to allow a speedy and successful introduction of new products and technologies.

Reference

1.  https://www.pcimag.com/articles/84078-green-solvents-agrochemicals-in-place-of-petrochemicals 

2.  https://www.vertecbiosolvents.com/ 

3.  https://www.syensqo.com/en/solutions-market/agriculture/crop-protection/green-solvents 

4.  https://www.industrial-formulators.basf.com/ 

5.  https://www.nouryon.com/markets/crop-protection/ 

6.  https://circa-group.com/products/cyrene/ 

7.  https://www.corbion.com/Markets/Biochemical-specialties/Agriculture 

8.  https://news.agropages.com/News/NewsDetail---46241.htm 

9.  https://www.edenresearch.com/products/mevalone.aspx 

10.  https://www.sporomex.co.uk/technology 

11.  https://cen.acs.org/pharmaceuticals/drug-delivery/Without-lipid-shells-mRNA-vaccines/99/i8 

12.  Hald Albertsen C, Kulkarni JA, Witzigmann D, Lind M, Petersson K, Simonsen JB. The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Adv Drug Deliv Rev. 2022 Sep;188:114416. doi: 10.1016/j.addr.2022.114416. Epub 2022 Jul 3. PMID: 35787388; PMCID: PMC9250827. 

13.  https://www.sciencedirect.com/science/article/pii/S1818087613000111 

14.  Wilson B, Geetha KM. Lipid nanoparticles in the development of mRNA vaccines for COVID-19. J Drug Deliv Sci Technol. 2022 Aug;74:103553. doi: 10.1016/j.jddst.2022.103553. Epub 2022 Jun 28. PMID: 35783677; PMCID: PMC9238147. 

15.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625170/ 

16.  https://www.agrospheres.com/ 

17.  https://plantarcbio.com/ 

18.  https://renaissancebioscience.com/ 

19.  https://trillium.ag/ 

20.  https://infinitabiotech.com/blog/role-of-enzymes-in-detergent-products/ 

21.  https://biosolutions.novozymes.com/en/dish/insights/article/beginners-guide-enzymes-detergents 

22.  https://www.novozymes.com/en/news/novozymes-enters-agricultural-biocontrol-enzymes 

23.  https://www.nature.com/articles/s41392-022-00904-4 

24.  https://elementalenzymes.com/vismax-the-first-of-elemental-enzymes-peptide-based-products-to-be-epa-registered/ 

25.  https://www.vestaron.com/ 

26.  https://micro-pep.com/technology/ 

27.  https://www.forbes.com/sites/juergeneckhardt/2024/04/04/an-ingenious-technology-could-change-both-medicine-and-agriculture/ 

28.  https://www.oerthbio.com/ 

This article will be published in AgroPages' upcoming '2024 Formulation&Adjuvant Technology' magazine.

If you'd  like to participate in it to show your insights and solutions or for any promotion demands, please contact Grace Yuan: grace@agropages.com