Formulation Challenges in a Global Environment

Whilst the world has been struggling to cope with a global pandemic, the agrochemical formulator has still been grappling with familiar problems related to the holy grail of the product suitable for the global market. The formulator has to consider a range of regional differences relating to, for instance:

•    different pests
•    different crops
•    different agrochemical practices
•    the thorny issues of pricing and competitors and
•    the overarching issue of different regulations.

In this article we will discuss difficulties relating to some of these factors. However, we first wanted to outline how the use of a structured design process can help the formulator to consider and address these issues. We have looked at the Quality by Design (QbD) approach used in the pharmaceutical industry and simplified it to make it more appropriate to applications such as agrochemical formulation development. We call this process “Design for Formulation"¹.

In this multifunctional approach, the initial stage is to determine exactly the “Customer Promise” i.e., what the customer expects and, critically, what the company promises to deliver with the new product. From this promise follow the business brief and the technical brief. In each of these, there can be specifics relating to different regions and their requirements. As long as these specifics are considered, defined and reviewed as the product development process continues, then the chances of commercial success at the end of the process are considerably increased.

As an example, if you were developing an Emulsifiable Concentrate (EC) formulation for Europe, you would exclude the use of nonylphenol ethoxylates (NPE) as emulsifiers. These are excluded above 0.1% by weight in EU REACH Annex XVII for new products²  and will be completely phased out as co-formulants by March 2023³ . If the product was destined for the US market, then they can still be considered although you would need to ask the EPA to carry out a review as this would be classed as a “Significant New Use Rule"⁴. You could still consider the use of NPEs in other regions although if you wished a truly global product then you would exclude them completely.

As we discussed in last year’s article, the demise of EC formulations has been long predicted, but there are few signs of this actually taking place. Although a relatively simple formulation, the choice of emulsifier is often a challenge for the formulator, and the exclusion of NPEs can present a challenge. As part a well-designed formulation development plan, the formulator needs to understand and characterise the properties of the key co-formulants (in this case the emulsifier and the oil/solvent) and use techniques to choose them in a systematic way. Examples of techniques which can help include:

•    Matching the HLB (hydrophilic-lipophilic balance) of the emulsifier to the required HLB of the oil – this is a relatively simple “rule of thumb” technique;
•    Using HLD-NAC (hydrophilic-lipophilic difference – net average curvature) theory which is a more scientifically-based and wide-ranging method than HLB but does require more work and more knowledge of the co-formulants used;
•    Using Hansen Solubility Parameter methodology (HSP) to help choose solvents (or oils) or mixtures of solvents which will be suitable for the active ingredient.

Returning to the design process, it is important to establish via experimentation what the critical quality attributes (i.e., the most important measures of performance or quality) of the formulation are, as well as the critical properties of the raw materials which establish these. A full understanding of the impact of processing conditions should not be dismissed, for example the rate of addition of various ingredients and how long a product needs to be processed to establish a homogeneous formulation. The use of good statistical experimental design techniques can be a valuable tool in establishing the relationship between the large number of variables that can be deemed critical⁵.  

A well-designed formulation development process will also take into account as comprehensively as possible how, where and when the product will be used. These factors are often connected. The application process has a big influence over the choice of formulation type, and this can vary considerably between regions and crop type. If the application is via spray tank, then your main candidate formulation types will be water dispersible types such as Emulsifiable Concentrate (EC), Water Dispersible Granule (WG) and Suspension Concentrate (SC) formulations. These types are common in most regions, but for herbicides and fungicides used in rice cultivation in Asia the most common formulation type is probably the Granule (GR) for dry application – these can be added directly to rice paddies without the use of a spray tank.

Another application increasing in interest and popularity is the use of UAV (drones) to spray crops. Again, there is a regional factor here, with much early interest coming from Asia. This application method offers potential advantages in terms of improved precision, higher efficiency and a lower environmental impact. However, for the formulator, application by drone creates a challenge because weight limit of the vehicle will restrict the tank volume. The formulator may have to consider options such as formulations that contain adjuvants as well as being highly concentrated or even water-free (e.g., oil-based).

An important regional factor which we have already alluded to is that of regulatory approvals. One relevant development has been the recent publication of the EU’s “negative list” for co-formulants used in plant protection products (EU Commission Regulation 2021/383³) which was issued in March 2021. This covers use both as co-formulants and as tank adjuvants and is focused on eliminating ingredients that are:

•    carcinogenic, mutagenic or toxic to reproduction (CMR);
•    persistent, bio-accumulative and toxic (PBT);
•    very persistent and very bio-accumulative (vPvB);
•    endocrine disruptors;
•    persistent organic pollutants (POP).

Over 140 co-formulants are included in Annex III of this Regulation and must be phased out by March 2023. They include:

•    Common solvents such as N,N-dimethylformamide (DMF), tetrahydrofurfuryl alcohol, 2-ethoxyethanol and 2-methoxyethanol;
•    Adjuvants such as tallow amine ethoxylates;
•    Certain hydrocarbon solvents (e.g., naphthenic or paraffinic distillates or heavy and light naphtha fractions) with ≥ 3% of specific impurities;
•    Heavy or light naphtha containing ≥ 0.1% benzene;
•    Nonylphenols and ethoxylated nonylphenols (as mentioned above, in the past the latter have been commonly used as surfactants in agrochemical formulations;
•    Octylphenols and ethoxylated octylphenols.

Apart from those factors discussed above, there are many further questions that the formulator needs to address as part of the design process, preferably at an early stage. These include:

•    What is the (chemical, physical and biological) stability of the active ingredient(s)?
•    How might active ingredients and co-formulants interact undesirably?
•    Will the formulation be mixed in the tank with further plant protection products, fertilisers and tank adjuvants, and what undesirable interactions may take place?
•    What packaging materials and container types are going to be used for the product?
•    What standard formulation performance tests will need to be passed?
•    What performance claims are desirable in order to market the product successfully?
•    What are the attributes of the main competing products?
•    What equipment is available for manufacturing the formulation, or will investment be needed?
•    What cost constraints are there on the co-formulants to be used or the manufacturing process?

In an article of this length, it is clearly not possible to address these questions in any detail. However, if formulators start off by using a systematic “Design for Formulation” process of the type that we have outlined then they will have an excellent chance to successfully develop a robust product and manufacturing route that meets the expectations not only of the company, but also of its customers and the regulators.

Reference:
¹ iFormulate Webinar Recording “Design for Formulation” https://iformulate.biz/training-and-events/iformulate-introduces-ian-jolliffe-formulationdesign/
² ECHA Annex XVII to REACH: https://echa.europa.eu/documents/10162/e5842a1e-e9f9-6096-2829-72f71c00eaab
³ EU Commission Regulation 2021/383: https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32021R0383&from=EN
⁴ US EPA - Risk Management for Nonylphenol and Nonylphenol Ethoxylates: https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/risk-management-nonylphenol-and-nonylphenol-ethoxylates
⁵ iFormulate Webinar Recording “Design of Experiments for Formulators” https://iformulate.biz/training-and-events/webinar-recording-design-of-experiments-for-formulators/