Breaking Down Multi-A.I.s Fungicide Formulations Barriers: Innovative Solvents Associations for High Performing ECs.

Prothioconazole is a major broad spectrum systemic triazole fungicide with curative, preventative and eradicative action, used massively in more than 60 countries on cereals (wheat), soybean, rape and other crops. Since its commercialization in 2004 by Bayer, prothioconazole has continuously expanded, becoming the largest product in cereals fungicide market and the sixth-largest product in the soybean fungicide market, with a global sales exceeding US$ 1.1 billion in 2022 ^[1]. It is expected to continue growing considering the regulatory hurdles impacting other common fungicides. 

In terms of mode of action, after absorption, prothioconazole moves into cells of the target fungal organisms, affecting sterol biosynthesis and thereby disrupting membrane structure. This ultimately impacts hyphal growth and germ tube elongation. Fungi sensitive to prothioconazole include Early leaf spot, eyespot, Fusarium spp., powdery mildew, net blotch, phoma leaf spot, Sclerotinia sclerotiorum, Sclerotium rolfsii, Septoria tritici & nodorum, rust and tan spot.

Prothioconazole is very often combined with other fungicides in the same formulation for a patchwork of modes of action, especially with other triazoles (eg. tebuconazole), strobilurins (eg. fluoxastrobin, trifloxystrobin, picoxystrobin etc), SDHI/carboxamides (eg. Bixafen, fluxapyroxad etc. ) or picolinamide (eg. fenpicoxamid).

For foliar application, formulations tend to shift from Suspension Concentrates (SC) towards Emulsifiable Concentrates (EC) since the presence of specific solvents & emulsifiers in the system can promote active cuticular penetration upon application. This is the case for example for traditional solvent used with prothioconazole, N,N dimethyldecanamide (equivalent, Rhodiasolv^® ADMA 10) ^[2], but it has also been claimed more recently with alternative solvents associations ^[3]. This improved active foliar penetration can translate into a better biological efficacy with ultimately increased crop yield. It can also open the door to formulations displaying a lower dose rate of agrochemical actives for acceptable biological efficacy, thanks to the beneficial effect of solvents, in line with the initial EU Farm to Fork objectives targeting a 50% reduction of chemical pesticides by 2030.

Smart formulation design using adequate solvents is thus essential for the next generation of prothioconazole based combos formulations, but it can be challenging to identify solvent systems compatible with all fungicides classes targeted, with expected adequate phys-chem characteristics (high flash point, low temperature stability, low viscosity etc.), safe tox/ecotox profile and good chemical stability.

Table 1 describes key solvents to consider for such prothioconazole based ECs design, with information on phys-chem characteristics, regulatory and classification. For complex combos involving actives ingredients with different physico-chemical characteristics and/or high loading constraints, it is particularly interesting to consider associations of aprotic polar insoluble solvents (eg Rhodiasolv^® ADMA10, Lact-8, RPDE), with water-miscible polar with large spectrum (eg Rhodiasolv^® Polarclean).

Table 1: Characteristics of solvents from Syensqo portfolio, interesting for EC (or DC) fungicides formulations containing prothioconazole. Green = water-miscible solvent. Grey = low water solubility

High throughput methodologies available at Syensqo Laboratory of Future (LOF) ^[4], based on Hansen approach HSPiP, robotic experiments, quantum mechanics thermodynamics simulations (COSMO-RS) and machine learning approaches, allow to save time and help formulators identify the best and safest solvent associations for a targeted active(s) system. The use of such methodologies favored the design of innovative solvents combinations such as DV Rhodiasolv^® MATCH 51, with high solubilizing performances for fungicides e.g. triazoles, strobilurins and carboxamides. This ternary blend contains a solvent derived from biomass agricultural waste, RE:CHEMISTRY MOVE200 (butyl levulinate) from GFBiochemicals with whom Syensqo has established a close partnership. The Renewable Carbon Index (RCI) of this blend is 51%. Table 2 gives the physicochemical properties of blend DV Rhodiasolv^® MATCH 51. 

Table 2: DV Rhodiasolv^® MATCH 51 physico-chemical properties

It highlights excellent solubilizing properties for a wide range of fungicides, at both room temperature and low temperature such as -5°C (Figure 1), making it a promising and relevant system for many formulations applied worldwide. As solo, prothioconazole EC up to 350 g/L active can be designed, as exemplified in table 3. Alternative solvent blends variations are currently under development to face the many challenges of solubilizing combos of active ingredients often used at high loadings, and offer excellent stability results without crystallization issues at low temperatures.

Figure 1: Solubilization performance radar of DV Rhodiasolv^® MATCH 51 for fungicides. Benchmark: Rhodiasolv^® ADMA 10 (Syensqo)

Table 3:  Example of complete EC design with DV Rhodiasolv^® MATCH 51

The foliar active penetration efficiency of diluted EC based on DV Rhodiasolv^® MATCH 51 was assessed and compared against the one of other solvent benchmarks.

Methodology for cuticle extraction and kinetics study:

The soybean cuticles were extracted from a soybean plant, grown in a pot from germinated seeds. The extraction was done using enzymatic degradation (using 2 enzymes, i.e. pectinase and cellulose), after the plant had followed a temperature cycle: 1 week at 28°C 35%RH during days and 22°C, 48%RH for nights. Cuticles, extracted at a final enzyme concentration of 0.027%, were placed in Petri dishes in a dark place. The finally extracted cuticles were washed with DI water, placed on membrane and left to dry. Dry cuticles were pre-cut and mounted in a trans-well insert (24-well plates) with molten paraffin. The receiving chamber was filled with deionized water as a receiving medium.

For the active penetration study, the concentrated EC formulations (250g/L ai prothioconazole) were diluted in CIPAC Water D, at 1 wt% and 1 µL was applied on top of the cuticle. The solution on top of the cuticle was allowed to air dry, before the insert was placed in the receiving chamber. The final set-up was placed into an environmental chamber (22°C and 50% RH) for 24h. The amount of prothioconazole (initial and transported through cuticle after 24 hours) was quantified with HPLC-UV. The % of prothioconazole, calculated as a ratio between the amount detected in the chamber and the starting prothioconazole concentration multiplied by 100,  was additionally  normalized per surface area of the droplet measured on soybean leaf.

Figure 2: Evaluation of a.i penetration: methodology and comparison of prothioconazole EC formulations based on different solvent systems. 

The effect of the different solvents on prothioconazole transport through isolated cuticles was investigated with this in-house made diffusion cell. Three EC formulations at 250g/L active prothioconazole, with three different solvent systems were prepared and tested. Two formulations had Rhodiasolv^® ADMA 10 and N-Butyl-2-pyrrolidone (NBP) as solvents and were used as a control to compare with formulations prepared with the new blend DV Rhodiasolv^® MATCH 51.  The amount of prothioconazole transported through the soybean leaf cuticle after 24h was quantified by HPLC. As seen from Fig 2, formulation prepared with blend DV Rhodiasolv^® MATCH 51 has the highest % of active transported per surface area after 24h. The lowest % of actives after passing through cuticle was observed for the formulation with NBP as a solvent. At the same time, the formulation made with Rhodiasolv^® ADMA 10 had higher % of actives than NBP containing formulation, but still the % was lower than formulation prepared with blend DV Rhodiasolv^® MATCH 51.

From the transport study we can conclude that the blend DV Rhodiasolv^® MATCH 51 increases the % of prothioconazole transported through leaf cuticle as compared to currently commercially used Rhodiasolv^® ADMA 10 and NBP solvents under investigated conditions.

Conclusion

Thanks in part to the use of high throughput methodologies and modeling approaches, specific associations of safe, non-toxic solvents including biobased ones such as DV Rhodiasolv^® MATCH 51 have been identified for the design of complex high load ECs containing prothioconazole and other families of fungicides. Interestingly, a high penetration efficacy of the active has been evidenced with such systems. From a regulatory side, as the solvents toolbox is shrinking in Europe with recent reprotoxic re-classifications of classical, versatile solvents, it is even more crucial to consider blend approaches of safe solvents showing solubilization synergies. Syensqo is strongly committed to support formulators' challenges with adequate solvents and co-formulants propositions. In parallel, Syensqo is investing in the development of breakthrough new solvent molecules with increased solubilization spectrum. 

Please do not hesitate to contact us at monique.adamy@syensqo.com and claire.darre@syensqo.com.

References

[1] S&P Global, Fungicides – 2022 Market & S&P Global Market Leading Active Ingredients

[2] US9124564B2

[3] W02021197106A1, WO21152509A1

[4] https://news.agropages.com/News/NewsDetail---46207.htm

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