Advanced Agrochem 1 (2022) 39–60

Contents lists available at ScienceDirect

Advanced Agrochem
journal homepage: www.keaipublishing.com/en/journals/advanced-agrochem

Crystal engineering in the development of improved pesticide products

Xiaofang Niu , Rui Yang , Huimin Zhang , Jingxiang Yang *
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin, 300071, China

A R T I C L E I N F O A B S T R A C T

Keywords: Pesticides might be the only group of poisonous chemicals that are widely sprayed into the environment, but the
Pesticides use of pesticides is inevitable for crop protection and infectious disease control. When an ideal new pesticide
Crystal engineering compound is selected, its properties must be optimized to realize the full potential of the compound and extend its
Polymorphs
lifespan in the market. Crystal engineering has proven to be a viable strategy for manipulating the properties of
Solid forms
solid-state pesticides. This review describes basic concepts of crystal engineering and its application in pesticide
development through representative cases reported mainly by large agrochemical companies. The solid forms that
present improved properties could justify patent protection, extending the market exclusivity of the pesticide
product. The purpose of this review is to present the potential impact of crystal engineering strategies on the
improvement of pesticide products, with emphasis on the importance of comprehensive characterization of the
crystallization behaviors of a selected pesticide during its entire life cycle.

1. Introduction and environmentally friendly pesticide products has been an important

Pesticides are substances intended for preventing, destroying, repel-
ling, or mitigating any pest.1 Since the discovery of the insecticidal effect
of DDT, the most famous pesticide in history, human society has stepped
into the era of chemical pesticides.2 Though DDT was widely banned the
world for agricultural use under the Stockholm Convention on Persistent
Organic Pollutants since 2004 due to environmental and health concerns,
more than 6 million tons of pesticides are still used each year for food
production and public health applications, with global sales in excess of
60 billion USD.3
Humans have benefited from the intensive use of pesticides, mainly in
increased yields of crops. According to the National Research Council,
removing pesticides from U.S. agriculture would cause crop production
to decline as much as 50%, depending on the crop species. Moreover,
farm exports would decrease by 50%, and consumer expenditures for
food would increase - and be accompanied by an increase in inflation - as
food prices increase.4 It was concluded that synthetic pesticides remain
to be the most effective strategy to increase grain yields in the foreseeable
future.5,6
Despite their importance, these chemicals are often closely scruti-
nized for environmental impact and off-target toxicities. As the largest
group of poisonous chemicals that are widely sprayed, the entire life
cycle of the development, distribution and application of pesticides is
under strict regulation. The development of effective, safe, economical,
goal for the agrochemical industry.
However, developing a new pesticide with outstanding properties is
no easy task, and the increasingly stringent regulatory standards have
made the discovery of acceptable new pesticides even more challenging.
The average development time of a new compound has increased to
exceed 11 years since the 2010s.7 The success ratio (the number of
compounds screened per product found) for discovering the new product
has declined from 1/1200 to 1/159574 over sixty years (Fig. 1).8–10 The
development cost of a new pesticide rose from $184 million (2000) to
$286 million (2014), representing a 55% increase over 14 years.
After all the time and cost investigated in the lead generation, envi-
ronmental and toxicological evaluation, large field trials, registration and
manufacture, finally, a new effective, safe, and environmentally friendly
pesticide is able to be launched to the market and start its role as a pest
control tool for attaining the desired crop yields.
Naturally, after great effort and expense, the new pesticide should not
only better the collective welfare but should do so for a considerable
period of time before the cycle of discovery and development needs to be
repeated. Therefore, a strategy that can improve a currently used pesti-
cide while to extending its life would be valuable.
Most pesticides exist as solids in technical materials or formula-
tions.11 This fact provides a chance to optimize the properties of the
pesticides by solid-state chemistry study, i.e., crystal engineering
strategy.

* Corresponding author. 94 Weijin Road, Tianjin, 300071, China.

E-mail address: jingxiangyang@nankai.edu.cn (J. Yang).

https://doi.org/10.1016/j.aac.2022.09.001
Received 7 August 2022; Received in revised form 7 September 2022; Accepted 9 September 2022
Available online 15 September 2022
2773-2371/© 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Fig. 1. Cost of agrochemical development (dashed line) versus screening success (solid line). Screening success ratio ¼ 1/number of compounds that need to be
screened for each product found. Reprinted with permission from Ref. 8. Copyright 2017 John Wiley & Sons.

The importance of crystal engineering has been well-known in the
pharmaceutical industry. Research on the solid-state forms of organic
materials has been flourishing during the last decades.12 In modern
agrochemical chemistry, this topic not widely as widely represented in the
literature giving the consequences of solid-state considerations, in our
view. A few solid-state considerations can be dated to the beginning of the
green revolution (1950s).13 During the 1980s, agrochemical companies
started to realize the problems associated with solid forms of the active
ingredients (AIs). For example, in 1986, S.I.P.C.A.M. (Societa Italiana
Prodotti Chimici e per L'Agricoltura Milano S.P.A.) found that a new
polymorph of chlorothalonil exhibited a reduced biological activity.14
By reviewing the representative cases on crystal engineering strate-
gies applied to solve the problems encountered during manufacture,
formulation and application of pesticide products, this review aims to
highlight the important role of crystal engineering strategies in the
development of improved pesticide products, furthermore, increase the
awareness of the solid-state chemistry of pesticides. To achieve this goal,
this review will start with a brief description on the background
knowledge of the solid-state forms of organic materials, followed by a
detailed illustration on the application of crystal engineering in pesticide
development.
2. Solid-state forms
Organic compounds can exist in varieties of distinct solid forms, such
as polymorphs, solvates (including hydrates), salts, cocrystals and
amorphous solids (Fig. 2). Each form typically displays unique physical
and chemical properties that can profoundly influence the solubility,
dissolution rate, bioavailability, hygroscopicity, melting point, stability
and all other physical and chemical properties besides.11,15,16 In this
section, we will provide the definition and background knowledge of all
kinds of solid forms and briefly introduce the application of solid form
research in the pharmaceutical industry.
2.1. Polymorphs
A polymorph is a solid crystalline phase of a given compound
resulting from the possibility of at least two different arrangements of the
molecules of that compound in the solid state.17 In other words, poly-
morphism describes crystalline substances in more than one form or
crystal structure can exist with distinct molecular conformations and
intermolecular interactions.18
The first description of polymorphism in an organic molecular crystal

Fig. 2. Schematic diagram of different solid forms.

40
X. Niu et al.
was reported 190 years ago.19 In 1832, W€ ohler and von Liebig found that
the needle-like crystal of benzamide transformed into a rhombohedra.
The crystal structures of these two habits were determined to be different
only in 2005 with the help of the third-generation synchrotron sources.20
Fifteen years later, the structure of needle-like Form II was further refined
using a new set of high-resolution synchrotron data and crystal structure
prediction methods.21 The difference between crystal structures of a
polymorphic molecular compound, resorcinol, was first established by
Robertson in 1935, in the early days of crystallography.22
Polymorphism was thought to be exceptional at first, but as single
crystal structure determination became faster, it was recognized that it is
the norm for organic molecules. Over 80% of the pharmaceutical mole-
cules can crystallize in multiple crystalline lattices.23 It has been claimed
that “every compound has different polymorphic forms, and that, in general,
the number of forms known for a given compound is proportional to the time
and money spent in research on that compound".17,24 For example, imida-
cloprid, one of the world's leading insecticides, was long thought to have
only two polymorphs, forms I and II. Recently, seven new polymorphs of
this insecticide were found, making the number of forms known for
imidacloprid rise from two to nine.25
2.2. Amorphous solid state
In a mono-component system, the organic molecules do not really
have to pack in a long-range highly ordered periodic arrangement, which
means the solid is not necessarily crystalline. If the solids consist of
molecules with no periodic arrangement at the microscopical level, and
do not possess a distinguishable crystal lattice, it is called an amorphous
solid.26 Though “amorphous solid” might be used synonymously with
“glassy solid”, nowadays, “glassy solid” is considered to be a particular
case of “amorphous solid”: glassy solid commonly refers to an amorphous
solid below its glass transition temperature.27 In contrast to a crystalline
solid, an amorphous solid does not have a melting point, instead, it has a
more extended softening process. In other words, amorphous solids melt
over a range of temperature.
Compared to polymorphism, amorphism is an even more frequent
phenomenon. Any given crystalline solid can be made amorphous, as
long as the cooling/quenching is rapid enough. For example, while all ice
on earth is crystalline, water can also form amorphous ice by cooling to
its glass transition temperature (137  C) in milliseconds.28
The same compound may display more than one distinct amorphous
phase.29 This phenomenon has been called amorphous polymorphism, in
analogy with crystalline polymorphism, or more succinctly,
polyamorphism.
41
Advanced Agrochem 1 (2022) 39–60
2.3. Solvates (pseudopolymorphs)
The most common method for polymorph screening is solution
crystallization, which involves the presence of at least two kinds of
molecules, the organic compound and solvent. If the solvent molecules
are incorporated into the host crystal lattice in the process of crystalli-
zation, the formed crystal is called a solvate, and if the solvent is water, it
is called a hydrate. The solvates can be formed under many circum-
stances involving the presence of a solvent, such as crystallization, slur-
ring, wet granulation, storage, and so on.
A solvate displays unique unit cell parameters and molecular packing,
and this phenomenon is analogous to polymorphism in that the AI can
occupy a new crystalline state. To distinguish solvates from polymorphs,
the solvates were sometimes called as “pseudopolymorph” in books or
literature,30 though this term is misleading.31 Polymorphs have the same
composition but different geometries. Thus, it is a misnomer to then
collect crystals with different compositions under the banner of poly-
morphism no matter how qualified, and pseudo is not a very clarifying
prefix. This term should be avoided.
A solvate is the simplest form of an inclusion compound. Solvates can
be classified into two categories based on the incorporation mode of
solvent molecules in the crystal lattice.32 In Type 1 solvates (Fig. 3a), the
solvent molecules occupy isolated sites; Type 2 solvates (Fig. 3b) collect
solvent molecules in channels and are often called channel solvates.
Type I solvent molecules form hydrogen bonds and van der Waals
interactions only with host molecules and make an essential component
of the crystal structure, thus the host compound and solvent are generally
in a stoichiometric ratio. During the desolvation process, the solvent
molecules escape, and the original crystal structure will collapse,
resulting in phase transformation to an amorphous state or a solvent-free
crystalline form.
For channel solvates, the solvent molecules form connections with
adjacent solvent molecules, resulting in “channels” along a crystallo-
graphic axis. In such systems, the interactions between solvent molecules
and host molecules are relatively weak. During the solvation process, the
crystal lattice may undergo expansion in a crystallographic direction and
result in changes in unit cell dimensions, which can be observed as shifts
in diffraction peaks of powder X-ray diffraction (PXRD) pattern. During
the desolvation process, whether the crystal lattice will collapse depends
on the extent of the mechanical effects of removing solvent molecules
from the depths of the lattice structure.32 Most of the channel solvates
can sorb and liberate solvent molecules in a continuous manner, resulting
in continuous changes in the stoichiometry of solvent to host compound
and changes in crystal lattice parameters according to solvent content in
the environment.
Fig. 3. Schematic diagram of two types of
solvates formation and desolvation pro-
cesses. (a) Stoichiometric solvates: Solvent
molecules are bonded into the host crystal
lattice at a stoichiometric ratio. Desolvation
will cause the lattice structure to collapse.
(b) Non-stoichiometric solvates: Solvent
molecules are non-stoichiometrically incor-
porated into voids or channels of the host
crystal lattice. Desolvation may not result in
the collapse of the lattice structure, which
depends on the extent of the mechanical ef-
fects of removing solvent molecules from the
depths of the lattice structure.
X. Niu et al.
2.4. Salts and cocrystals
The definition of salts is widely known by the chemistry community
as a substance produced by the reaction of an acid with a base. In
contrast, the concept of cocrystals is relatively less well-publicized.
Cocrystals are solids that are crystalline single-phase materials
composed of two or more different molecular and/or ionic compounds
generally in a stoichiometric ratio which are neither solvates nor simple
salts.33,34 The first molecular cocrystal was reported as early as 1844,
when W€ ohler mixed solutions of quinone (yellow) and hydroquinone
(colorless) and produced a green crystalline substance.35 The crystal
structure of the green substance was solved in 1958, and showed alter-
nate quinone and hydroquinone molecules connected by hydrogen bonds
in the unit cell.36
Apparently, cocrystals, salts and solvates are all multicomponent
molecular crystals.37,38 Cocrystals/Salts differ from solvates and hydrates
in that the components are all solids when they exist as single-component
forms. Cocrystals can be distinguished from salts if the intermolecular
interactions in the cocrystal lattice are nonionic; the molecules of
different components are held together by interactions, such as hydrogen
bonds, π-π stacking, van der Waals interactions and halogen bonds.
The distinction of cocrystals and salts is whether the proton transfer
occurs between AIs and co-formers. Proton transfer is complete in a salt,
while absent in a cocrystal. Otherwise, a continuum state exists between
the salt and cocrystal, in which the proton can be equipoised. The dy-
namic position of proton in the multicomponent crystals can be deter-
mined with a variety of techniques, such as X-ray diffraction, X-ray
photoelectron spectroscopy (XPS), solid-state NMR spectroscopy and IR
spectra.34,39,40 The acidity (ΔpKa) rule is commonly applied for pre-
dicting whether the two molecules can form salt or cocrystal. When the
ΔpKa value between an acidic/basic AIs and basic/acidic co-former is
greater than 3, a salt generally forms. When the ΔpKa < 0, a cocrystal
formation is predominant. However, when the ΔpKa between 0 and 3, the
extent of proton transfer in the solid state is difficult to predict, and a
continuum state exists.41
2.5. Crystal engineering in the pharmaceutical industry
Different solid forms of APIs (active pharmaceutical ingredients)
normally possess different physicochemical properties, such as solubility,
dissolution rate, melting point, stability, especially, the bioavailability of
APIs, as shown in the famous case of ritonavir.42
Ritonavir was marketed in 1996 as capsules of Form I by Abbott (now
AbbVie). However, Form I of ritonavir transformed to a less soluble Form
II in capsules, leading to a significantly lower bioavailability and more
than $250 million USD lost.43 Since then, a thorough polymorphic
investigation of APIs has been a must-do in the development pipeline of
pharmaceutical products. Recently, a third polymorph of ritonavir was
discovered via melt crystallization by AbbVie researchers.44
Other than polymorph, other solid-state forms have their character-
istics. Amorphous solids are normally less thermodynamically stable than
their crystalline forms, they usually have higher solubility, faster disso-
lution and improved bioavailability.45–47 Traditionally, salts have been a
topic option for improving the pharmacokinetic properties of a phar-
maceutical molecule.48,49 Now cocrystals have emerged as a strategy for
systematically properties manipulation by selection of an appropriate
co-former molecule.50,51 Though solvates containing organic solvent
molecules are always not preferred for further formulation development,
the screening of solvates is still necessary to prevent the formation of
undesired solvent crystals.52,53
As one can learn from above, the unique advantage of the crystal
engineering approach is that the chemical structure of the compound can
remain unchanged, while the physicochemical properties of this com-
pound, including bioavailability, can be manipulated according to the
requirement of the manufacture, formulation, and application process.
Because of this advantage, crystal engineering has become an important
42
Advanced Agrochem 1 (2022) 39–60
tool for manipulating the desired physicochemical properties during
drug development.
The dramatic change in physicochemical properties resulting from
the various crystal forms not only impacts patients and the pharmaceu-
tical manufacturer, but also influences the US Food and Drug Adminis-
tration (FDA). Several regulatory documents addressing crystal forms
and changes in solid forms have been released by FDA in the last 20 years,
as shown in Table 1.
For the pharmaceutical manufacturer, one other significant benefit of
conducting solid form studies is that solid-state forms are patentable. The
patents on crystal forms may provide an extra duration of protection for
the marketed products and thus bring additional commercial benefits.
The crystal engineering of organic compounds has also been flourishing,
more than 2000 literature have been published each year globally since
1996, and the number is still rising (Fig. 4).
3. Application of crystal engineering in pesticide development
Compared to the popularity of crystal engineering in the pharma-
ceutical industry, the solid-state chemistry study of pesticides has not
gained comparable attention in the agrochemical industry. According to
incomplete statistics by authors, there are only around two hundred
publications, including patents and peer-reviewed literature, on agro-
chemical solid forms, far fewer than for active pharmaceutical in-
gredients (APIs). Since the variation of solid forms can result in
prominent properties modification of the compound, regardless of its
application, it is reasonable to believe that the crystal engineering
strategy can contribute to the development of better pesticide products.
Indeed, there are excellent cases where crystal engineering technologies
have been applied to solve the problems encountered during the devel-
opment of pesticide products. In this section, representative cases will be
reviewed to show the application of crystal engineering in pesticide
development.
3.1. Bioactivity
Since the discovery of synthetic pesticides, bioactivity has been the
most important property of a pesticide. The bioactivity of a compound
against pests makes the compound a potential pesticide. Though crystal
engineering of pesticides has never been a sharp focus in solid-state
chemistry and pesticide science communities, just 8 years after the dis-
covery of DDT's insecticidal action, it was found that the plate-shaped
DDT crystals were more toxic than the needle-shaped crystals.13 This
first case indicated a correlation between the crystal state and the
bioactivity of pesticides.
It is becoming acutely well-known in the pharmaceutical industry
that different solid forms of APIs possess distinct bioactivity and
bioavailability in 1998, when the ritonavir capsule supplies failed due to
the sudden appearance of a new much less bioactive polymorph. The
crystallographic-dependent bioactivity of pesticides, however, has not
been systematically studied until the 2010s.59 Nevertheless, this does not
mean that pesticides are less likely to have polymorphs, or the bioactivity
difference between pesticide polymorphs is trivial. As stated, the
Table 1
Several regulatory documents addressing crystal forms and changes in solid
forms released by FDA in the last 20 years.
Year Regulatory documents
2000 Q6A Specifications: Test Procedures and Acceptance Criteria for New
Substances and New Drug Products: Chemical Substances 54
2007 ANDAs: Pharmaceutical Solid Polymorphism: Chemistry, Manufacturing, and
Controls Information55
2013 Guidance for Industry on Regulatory Classification of Pharmaceutical Co-
Crystals 56
2018 Regulatory Classification of Pharmaceutical Co-Crystals: Guidance for
Industry 57
X. Niu et al.
Fig. 4. Number of publications reported with the solid forms including the keyword polymorph, amorphous, cocrystal/co-crystal, solvate/hydrate in title during the
period 1960–2021 in the Scopus database.58
inevitable polymorphism of organic compounds resulted in a reduced
biological activity of chlorothalonil, one of the most used fungicides in
the world.14
3.1.1. The first report
The case of ritonavir is the most famous example where the genera-
tion of an undesired polymorph results in decay in bioactivity for mar-
keted products, whereas the problems with chlorothalonil polymorphism
were identified twelve years earlier than the ritonavir event.
Chlorothalonil: In 1986, S.I.P.C.A.M. filed a patent on chlorothalonil
(called chlorothalonyl in the original file), in which two “crystallographic
structures of chlorothalonyl” were disclosed. It was stated that “The com-
positions produced starting from technical chlorothalonyl with a type II crys-
tallographic structure have also evidenced - parallelly to a physical decay - a
reduced biological activity in respect of similar composition produced starting
from chlorothalonyl with a type I crystallographic structure”. When saying
“physical decay”, the patent was referring to decay in bioactivity without
a chemical change. The structure of the so-called “type II”, i.e., Form II
(not to be confused with type II solvates), was not characterized until
2004. Both X-ray diffraction techniques and crystal structure prediction
methods were used (Fig. 5).60
Since the less active Form II always concomitantly nucleates with
Fig. 5. (a) Molecule structure of chlorothalonil, (b) crystal structure of Form I and (c) crystal structure of Form II.
43
Advanced Agrochem 1 (2022) 39–60
commercially available Form I during the crystallization process, tech-
nologies to produce pure Form I, which possesses higher activity, have
been extensively pursued by manufacturers.61–64
3.1.2. Polymorphic-dependent bioactivity of contact insecticides
Since the case of chlorothalonil, little attention has been paid to the
correlations between solid forms and bioactivity of pesticides during the
past decades.
Until recently, a research group from New York University (NYU)
discovered that the lethality of contact insecticides increased with
decreasing thermodynamic stability of the crystalline forms. The group
“began a study of the solid-state chemistry of DDT because stock micrographs of
crystals posted online revealed optical signatures of helicoidal twisting”, while
found not only the expected crystals but also more jumbled, chaotic pat-
terns, which was further considered as a new polymorph of DDT, Form II
(Fig. 6).59 It was later discovered by members of the same group that the
Form II with chaotic patterns was actually observed by McCrone in 1948.65
However, no structure and comparative bioactivity data were reported by
then.
Considering that DDT is a contact insecticide and the uptake of
insecticide molecules is directly related to insect tarsi contacting micro-
crystals, it is reasonable to hypothesize that the efficacy of crystalline
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Fig. 6. (a) Molecule structure of DDT, (b) polarizing microscope photograph of two forms, (c) crystal structure of Form I and (d) crystal structure of Form II. Adapted
with permission from Ref. 59. Copyright 2017 Wiley-VCH.

DDT might be dependent on its crystal structure. Further bioassays
indicated that the Form II of DDT was more active than Form I against
Drosophila melanogaster.59
The DDT work further emphasized the importance of the solid-state
structure of crystals, especially crystals of contact insecticides, which
the insects directly encounter. In the following work, two new
polymorphs of lindane were well characterized. Bioassay for three
polymorphs of lindane against Drosophila melanogaster revealed an in-
verse correlation between lethality and thermodynamic stability of
polymorphs.66 This correlation was later verified by the difluoro
congener of DDT, DFDT. The amorphous form of DFDT, solid form which
possessed the highest free energy, was more active than the two

Fig. 7. (A) Molecular structure of DM. (B) Microcrystals in suspension concentrate (Suspend SC, DM concentration: 5%), a formulation used for indoor residual
spraying (IRS). (C and D) Melt grown DM (C) Form I and (D) Form II spherulites observed between crossed polarizers. PXRD confirmed that the fibers in the spherulite
were oriented along the crystallographic <010> direction. (E) PXRD data for Form I (blue) and Form II (orange) from their respective films. (F and G) Single crystal
structures of forms (F) I and (G) II determined at 100 K. Reprinted with permission from Ref.70. Copyright 2020. Published under the PNAS license.

44
X. Niu et al.
crystalline forms towards Anopheles quadrimaculatus.67
Deltamethrin: Deltamethrin (DM), first developed in 1973, was the
most active synthetic insecticide at the time.68 As one of the most
commonly used pyrethroids with high selectivity, it has been reputed as
Michael Eillott's billion-dollar crystal and “crowning achievement”.69 By
melt crystallization, a new polymorph of deltamethrin, Form II (Fig. 7),
was developed and found to be twelve times faster acting than the
commercially available Form I against Anopheles quadrimaculatus
mosquitoes (Fig. 8).70 The simple preparation method and markedly
greater efficacy of Form II provided an affordable tool for infectious
diseases and crop protection. A researcher from International Vector
Control Consortium (IVCC), an organization that specializes in producing
tools for vector-borne disease control, commented that “this is another
great example demonstrating how critical the physical structure of an active
ingredient is in the interaction with insects”.71
Imidacloprid: Imidacloprid (IMI) is an insecticide belonging to a
class of chemicals called the neonicotinoids, which act on the central
nervous system of insects. As the world's leading insecticide, the poly-
morphism of imidacloprid has been extensively studied and it has long
been thought to have two polymorphs.72–75 By both solution crystalli-
zation and melt crystallization, seven new imidacloprid polymorphs were
developed in 2021.25 The thermodynamic stability of all nine poly-
morphs was evaluated from melting points and phase transformations
(Fig. 9). The bioactivity of three newly developed polymorphs and Form I
were correlated with their free energy ranking. It was found that Form IX
was almost nine times faster acting than the commercial Form I against
Aedes, Anopheles, and Culex mosquitoes as well as Drosophila. Notably, the
highly active Form IX was stable against transformation for at least six
months, making it a potential tool for practical use in the field.
3.2. Aggregation and particle enlargement
One of the most obvious differences between pesticides and drugs is
the delivery methods. While most solid pharmaceutical formulations are
oral doses, most solid pesticide formulations are designed for foliar
treatment, such as wettable powders, water-dispersible granules, sus-
pension, and so on. In other words, for crystalline pesticides, the mi-
crocrystals of AIs should be small enough, so that the particle can pass the
spray nozzles, or can be made as a stable suspension formulation.
However, possible aggregation and particle enlargement of solid
microparticles in suspension make it difficult to maintain the product as a
homogeneous formulation. Besides, the spray nozzle may be blocked by
45
Advanced Agrochem 1 (2022) 39–60
larger particles during the field application of the product. Therefore,
aggregation and particle enlargement of technical materials or AIs in
formulation should be avoided or eliminated. Considering that low
melting points, inappropriate solid forms and undesired phase trans-
formation are common mechanisms behind the aggregation and particle
enlargement phenomenon, crystal engineering tools have been applied
accordingly to tackle the challenges.
3.2.1. Technical materials with a low melting point
Melting point is an essential consideration for pesticide development.
For processing, formulation and storage purposes, the AI should be a
material having a high melting point. However, a large amount of such
organic compounds are amorphous or have a melting point lower than
60  C (Table 2).
Low melting AI solids are prone to melt when the pesticide is pro-
duced, dried, transported, stored, or used.15,80,81 Also, it will accompany
material thickening, which leads the pesticides to grind difficultly, clog
the filter equipment, adhere to the container walls, or even block spray
nozzles. Moreover, due to substantial temperature fluctuations that may
occur during the processing and storage of pesticide formulations, the
solid particles of AI may go through cycles of melting and recrystalliza-
tion, leading to the generation of large and undesirable particles, which
may block spray nozzles during the application of the product.
Fortunately, the melting point can typically be tuned by crystal en-
gineering. Pyraclostrobin, developed by BASF SE (Badische Anilin-und-
Soda-Fabrik Societas Europaea) is the best-known example.
Pyraclostrobin: Pyraclostrobin, as a quinone outside inhibitor (QoI)
fungicide discovered in 1993, quickly became the second-largest fungi-
cide in the world by sales.82 This broad-spectrum fungicide has protec-
tive, curative, eradicative and systemic properties. The most glaring
disadvantage of pyraclostrobin is its low melting point.
Before 2006, the commercially available pyraclostrobin was amor-
phous, its glass transition temperature was lower than 55  C.83 When
suspensions or granules were prepared, the pesticide technical material
will melt, aggregate, and then block the grinding equipment.84 To solve
this problem, BASF SE discovered four new polymorphs of pyraclos-
trobin, dubbed Form I to IV.85 Form IV had the highest melting point at
62–72  C. The new polymorph could be formulated as a suspension
concentrate. Form V of pyraclostrobin was prepared in 2016, further
increasing the melting point (Fig. 10).86 Polymorphs of pyraclostrobin
with a higher melting point had better physical properties, avoiding the
melting and aggregation during mechanically grinding, thus overcoming
Fig. 8. Lethality of DM crystalline forms I and
II against A. aegypti and A. quadrimaculatus
mosquitoes. (A) The motions of A. aegypti
mosquitoes exposed to dusts. The dots repre-
sent the average speed of all mosquitoes in
1 min. Solid lines are smoothed trend lines (as
in C). (B) Comparison of A. aegypti KTs for
forms I and II dusts. KT50 values are indicated,
as in D. (C) Motions of A. quadrimaculatus
mosquitoes exposed to dusts. (D) Comparison
of A. quadrimaculatus KTs using dusts.
Reprinted with permission from Ref. 70.
Copyright 2020. Published under the PNAS
license.
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Fig. 9. Imidacloprid polymorphism. Reprinted with permission from Ref. 25. Copyright 2021 American Chemical Society.

the difficulties in formulation development. Polymorph manipulation large particles and clogging spray nozzles. In 2008, Syngenta Ltd.
can improve melting points, but normally, in a relatively small range. designed cocrystals of propiconazole with high melting co-formers, such
Development of cocrystals of AIs provides another option for melting
point adjustment in a larger range. For example, if a higher melting
cocrystal is desired, then a higher melting co-former should be selected
and vice versa.
BASF SE designed two cocrystals of pyraclostrobin (PYR) with 4-
hydroxybenzoic acid (4HBA, melting point of 213  C 87) and
thiophanate-methyl (TM, melting point of 175  C 88), respectively
(Fig. 11).89,90 The melting point of cocrystal of pyraclostrobin with 4HBA
was increased to 114  C, and the melting point of PYR-TM cocrystal
increased to 150  C. As shown in Fig. 10, the cocrystals with high melting
co-former possessed much higher melting points than the pure crystalline
pyraclostrobin.
Propiconazole: Propiconazole has a low melting point and melts
quickly during production and storage. This pesticide might recrystallize
from the melt when the environment temperature drops again, producing

Table 2
Melting point data of some pesticides.
Pesticides Melting point ( C)

Pyraclostrobin 55-72 76
Flusilazole 5377
Pendimethalin 55-57 78
Lambda-cyhalothrin 49.2 79
Fig. 10. The melting point of different solid forms of pyraclostrobin.

46
X. Niu et al.
Fig. 11. Molecular structures of pyraclostrobin, 4-hydroxybenzoic acid and thiophanate-methyl.
as 4,40 -dihydroxybiphenyl (Fig. 12, melting point of 283  C). The coc-
rystal had a higher melting point (around 130  C) than the commercially
available versions of propiconazole.91
This new solid state of propiconazole had a melting point above the
temperature range normally associated with processing and storage, thus
it will not undergo aggregation and particle enlargement events during
its formulation and storage. In addition, the cocrystal with a higher
melting point could also now be manufactured as suspension
concentrates.
Flupyradifurone: Flupyradifurone has a low melting point, about
72  C. It is easy to melt and adheres to the wall of the container during
storage and transportation. In 2010, Bayer designed and synthesized two
cocrystals of flupyradifurone with salicylic acid and oxalic acid, respec-
tively (Fig. 13).92,93 The melting point of the flupyradifurone-oxalic acid
cocrystal was about 122  C, much higher than that of the pure flupyr-
adifurone. The elevated melting point allowed flupyradifurone to be
treated at elevated temperatures. Similar work with flusilazole and imi-
dacloprid could be found in the literature.77,94
Fig. 12. Molecular structures of propiconazole and 4,40 -dihydroxybiphenyl.
Fig. 13. Molecular structures of flupyradifurone, salicylic acid and oxalic acid.
Fig. 14. (a) Molecular structure of pendimethalin, (b) crystal structure of Form I (orange) and (c) crystal structure of Form II (yellow).
47
Advanced Agrochem 1 (2022) 39–60
3.2.2. Phase transformation
In addition to a low melting point, phase transformation is another
common reason for aggregation and particle enlargement. As mentioned
above, different crystal forms of pesticides have different thermodynamic
stabilities, which may lead to a phase transformation. For most solution
crystallizations, solvents mediate phase transformation happens. The
metastable solid forms tend to transform to a more stable solid form,
where molecules detach from the metastable solid forms and then attach
to a more stable solid form, resulting growth of the stable solid form.
Solid-in-liquid dispersions, for example, suspensions, are stable only
within a narrow range of particle size. Thus, the elimination of crystal
growth which accompanies the phase transformation is significant for
development of a stable formulation suitable for agricultural use.95,96
Pendimethalin: Pendimethalin is a broad-spectrum herbicide for
pre-emergence and early post-emergence control of weeds. In the solid
state, this herbicide exhibits two polymorphs, one orange-colored, the
thermodynamically stable form, Form I, and the bright-yellow meta-
stable form, Form II (Fig. 14). The yellow Form II slowly converts to the
more stable orange Form I, which can take months or years to complete.
The slow transformation leads to crystal growth of stable Form I,
resulting in a significant problem in manufacturing stable suspension of
the herbicide for commercial use.97
For systems like pendimethalin, it is important to control the poly-
morphic purity of technical material, so that the most stable form is
selected and manufactured for formulation preparation.
Prothioconazole: Prothioconazole is a triazolthione fungicide
developed by Bayer, which quickly gained popularity due to its broad
spectrum of activity. The thermodynamically metastable Form I of pro-
thioconazole leads to unwanted crystal growth during preparation or
storage. In 2003, Bayer developed a thermodynamically stable new
polymorph of prothioconazole, Form II, preventing the occurrence of
crystal transformation, causing no problems in preparation or storage,
neat or in the form of suspension concentrates.98 Both polymorphs of
prothioconazole were systematically investigated by polarized optical
microscopy and X-ray diffraction (Fig. 15).11
Polymorphs can be monotropic or enantiotropic.99 Monotropic
polymorphs, such as pendimethalin and prothioconazole mentioned
above, retain their relative thermodynamic stabilities at all temperatures
before melting. For such systems, using the thermodynamically stable
polymorph as neat material or in the formulation will cause no problems.
The thermodynamically stable polymorph in monotropic systems are not
subject to unexpected or troublesome transformation. In the case of
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

enantiotropic systems, however, there is a transition point in which the

Fig. 15. (a) Calculated morphologies in comparison to recrystallized sample
and (b) crystal structures of forms I and II (i.e., Mod. I and Mod. II) of pro-
thioconazole. Adapted with permission from Ref. 11. Copyright 2022 John
Wiley & Sons.
stability relation is reversed.
Metazachlor: Developed by BASF in 1976, the chloroacetanilide
herbicide metazachlor has become one of the most widely applied her-
bicides.100 Initially, this compound was marketed as an aqueous sus-
pension (e.g., Butisan®) containing Form IA of metazachlor.101 In 1989,
BASF published a patent claiming that this known Form IA of metaza-
chlor may form agglomerates in aqueous suspension formulations, which
often caused clogging of spray nozzles.102 Therefore, a new polymorph
Form IB was developed to prevent the agglomeration of metazachlor
even after long-term storage.
A systematic solid-state study for such an important herbicide, was
not conducted until 2004 (Fig. 16). Among all five polymorphs of met-
azachlor, Form I, Form II (i.e., Form IA in BASF patent) and Form III (i.e.,
Form IB in BASF patent) showed great thermodynamic and kinetic sta-
bility. This is also the reason why the reported melting point of meta-
zachlor varies significantly from different sources, ranging from 74  C to
85  C.100,103,104
However, those three forms are pairwise related enantiotropically. As
shown in Table 3, Form I is thermodynamic stable above 63  C, Form III
is thermodynamic stable below 55  C, and Form II is thermodynamic
stable only in the small window between these temperatures.
As one can tell, no form of metazachlor is thermodynamic stable over
the entire temperature range. To maintain a homogeneous aqueous
suspension, the form should be thermodynamic stable at the temperature
range which is generally associated with processing and storage. In this
case, the Form III should be the best option among all polymorphs, which
is also the choice made by BASF in 1989.102
Nevertheless, the transition temperature point between Form III and
Form II is only one degree higher than the temperature point (54  C) for
thermal stability evaluation. If the transition temperature point between
the enantiotropically related polymorphs is even lower, reaching the
temperature range during the processing and storage, for example, 30  C,
how should we tackle the challenge? The case of cyprodinil provided a
great solution to this problem.
Cyprodinil: Cyprodinil is a broad-spectrum fungicide introduced in

Fig. 16. (a) Molecular structure of metazachlor, crystal structures of (b) orthorhombic Form I, (c) triclinic Form II and (d) monoclinic Form III of metazachlor.

48
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Table 3 3.2.3. Formation of solvate

Physicochemical data for metazachlor polymorphs.101 For AIs in emulsifiable concentrates (ECs), especially emulsion con-
Polymorphs Form I Form II Form III centration, the preferred formulation for agrochemicals, the AI may form
unwanted solvate crystals with organic solvents added in the formula-
Designation in the literature Orthorhombic IA IB
105
Triclinic Monoclinic tion, thus leading to the aggregation or particle enlargement of AIs.
102 102 As reported by Bayer researchers, unexpected butyrolactone solvate
Melting point/ C 83 80 76 of fluoxastrobin was found in the commercialized EC 200 formulation
Transformation temperature III/I II/I III/II Fandango, which contained both fluoxastrobin and prothioconazole.11
(calculated)/ C 60-65 (58) 61-67 (63) 59  2 (55)
Relatively stable temperature above 63 55–63 below 55
The solvate had never been observed during the development of the
range/ C formulation. However, years after the introduction of this product to the
market, the formation of solid precipitation, confirmed to be the butyr-
olactone solvate latterly, led to customer complaints. Similar issues
existed with bixafen, the solvate of this fungicide with the solvent
1993, used to control a range of pathogens.106 Cyprodinil has two poly- butyrolactone recrystallized during the development of an EC formula-
morphic forms, forms A and B. The thermodynamic stability of poly- tion (Fig. 18).
morphic forms A and B is enantiotropically related. The transition These examples show that not only for suspensions, which contain
temperature point is between 15 and 40  C, falling into the temperature microcrystals of AIs, but also for “true” liquid formulation of pesticides,
range that occurs during the handling and storage of pesticide formulations the solid state of the AIs should be systematically investigated during the
(typically between 10  C and 50  C). Therefore, neither of the two development of the formulation. Besides, the knowledge of the thermo-
polymorphs can be thermodynamic stable under storage conditions. No dynamically stable polymorph, cocrystal preparation, the formation of
matter which form is chosen for formulation preparation, particle solvates should also be paid attention to. Considering that most pesticide
enlargement is inevitable due to phase transformation under temperature formulations will eventually be diluted in water, the knowledge on the
fluctuation. formation of hydrates, in particular, should be obtained during the
Under such a situation, the co-crystallization strategy provides a way formulation development process.
out. In 2008 and 2011, Syngenta developed a serious of cocrystals of
cyprodinil (Fig. 17).107,108 The formation of new cocrystal forms did not 3.2.4. Presence of amorphous solid
exhibit phase transformation and particle enlargement during storage Amorphous forms of organic compounds are always prone to aggre-
compared to the commercially available versions of this fungicide. gation during storage, as technical materials or in formulations. For

Fig. 17. Molecular structures of cyprodinil and representative co-formers.

49
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Fig. 18. Schematic representation of the formation of bixafen butyrolactone solvate. Adapted with permission from Ref. 11. Copyright 2022 John Wiley & Sons.

example, commercially available picoxystrobin (Fig. 19) was marketed in Table 4

amorphous form, having a high tendency to aggregate, particularly after Aqueous solubility of low water-soluble pesticides.
prolonged storage. In 2017, a novel polymorph form of picoxystrobin was Pesticides Solubility in water Temperature Ref.
prepared, Form I. After a month of storage at 54  C, there was no sign of (mg/L) ( C)
aggregation.109 Similar issues existed with chlorfenapyr and spirote- Prothioconazole Form I 28 20 115

tramat, and solved by the development of a new polymorph Prothioconazole Form 15 20 115

(Fig. 19).110,111 II
116
Atrazine 33 22
117
Simazine 5 20
118, 119
Azoxystrobin 6.7 20
3.3. Water solubility Chlorantraniliprole 1 20 120
121
Fipronil 1.9 20
122, 123
Water is everywhere during the lifecycle of pesticides, including Dufulin 40 22
124
formulation preparation, plant uptake, rainfall, leaching, environmental Thiram 16.5 20
125, 126,
Tebuconazole 36 25
decomposition, and so on. Therefore, during the period, the bioavailability 127
and environmental toxicity of pesticides are all impacted by water Boscalid 4.6 20 128

solubility.

3.3.1. Water insoluble pesticides

Many pesticides have low water solubility as seen in Table 4. Typi- solubility of ametryn by 9 and 20 times, respectively (Table 5). These salt
cally, low water solubility will reduce the efficiency of a pesticide formations could reduce the use dosages of active ingredients by 2.5
formulation.112 Besides, insoluble pesticides are more likely to stick to times, realizing the reduction in the use of pesticides.
the soil in the environment. They will not travel as much with water as it In addition to salts, co-crystallization is a newly emerged strategy for
moves, so low-soluble preparations are also more likely to pollute the solubility manipulation of organic compounds.15,131–133 Primarily man-
environment.113,114 Developing salts has always been the top option for ufactured by Syngenta, atrazine is also a poorly soluble triazine-class
improving the water solubility of organic compounds. herbicide used to prevent the pre-emergence of broadleaf weeds in
Ametryn: Ametryn is a poorly soluble s-triazine herbicide. The sol- crops. Its solubility in water is 0.682 mg/mL at 25  C. The crystallization
ubility of ametryn in water at 22  C is only 0.209 mg/mL. The poor water of atrazine with fumaric acid yielded dehydrated cocrystals which
solubility limits the efficiency of the herbicide; thus, overdosed pesticides
are often applied to ensure the weeds can be killed rapidly, resulting in
impacts including leaching, toxicity, and persistence in the environment. Table 5
Determined equilibrium aqueous solubility of ametryn salts and ametryn.129
Therefore, ametryn with higher solubility should be safer and more eco-
friendly. A series of organic salts were prepared, including ametryn- Water solubility at 22  C (mg/mL) Times
fumaric acid salt, ametryn-maleic acid salt, ametryn-nitric acid salt and Ametryn 0.209  0.02 –
ametryn-trifluoracetic acid salt (Fig. 20).129,130 The formation of salts Ametryn-fumaric acid salt 1.89  0.05 9
provided a significant improvement in water solubility. Significantly, Ametryn-maleic acid salt Form I 4.67  0.06 22
Ametryn-maleic acid salt Form II 4.05  0.04 19
salts of ametryn with fumaric acid and maleic acid increased the

Fig. 19. Molecular structures of picoxystrobin, chlorfenapyr and spirotetramat.

50
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Fig. 20. (a) Molecular structure of ametryn, crystal structures of (b) ametryn-fumaric acid salt, (c) Form I and (d) Form II of ametryn-maleic acid salt.

showed improved solubility, 6-fold more soluble than the corresponding

pure forms.130
Prothioconazole: Prothioconazole has a low water solubility, so that
it cannot exert its efficacy well when acting on the target site. Then the
residual pesticide will enrich the soil, causing environmental pollu-
tion.134 Two crystalline forms of prothioconazole, Form I and Form II,
were developed by Bayer. Form II was a thermodynamically stable form,
suitable for preparations. However, Form II was less soluble than Form I.
It is highly desirable to obtain new forms having improved solubility. In
2009, an amorphous prothioconazole and a DMSO (dimethylsulfoxide)
solvate of prothioconazole were developed by Makhteshim Ltd.115 It was
shown that both the amorphous form (34 ppm) and the DMSO solvate
(30 ppm) were 2-fold more soluble than Form II (15 ppm). Considering
that solvates are more suitable for long-term storage when compared to
the highly metastable amorphous phases, developing solvates with better
solubility becomes a way to go. In 2018, a toluene solvate of prothio-
conazole was prepared, which was the most soluble solid form (38 ppm)
at that time.135 This record was soon broken by the 1,4-dioxane solvate
(Fig. 21) developed in 2020, which improved the solubility of prothio-
conazole by more than 3-fold when compared with Form II.134 The sol-
ubility of all reported solid forms of prothioconazole were shown in Fig. 22. The solubility of different solid forms of prothioconazole.
Fig. 22.
In this subsection, three examples show the application potential of
and solvates often improve the solubility in a limited range, usually, 2–3
salts, cocrystals, amorphous solid, polymorphs and solvates in improving
fold. As we will emphasize in the following subsection, high water sol-
water solubility of water-insoluble pesticides. There is no doubt that the
ubility is not always better. The final goal is to tune the solubility of a
formation of salt can often provide the most prominent elevation in
given pesticide according to the requirement of the specific usage sce-
solubility of AIs. Cocrystal engineering could be a good option, especially
narios in crop protection or disease control. The crystal engineering
when the formation of salt is not possible. In comparison, polymorphs

Fig. 21. Schematic representation of the formation of prothioconazole 1, 4-dioxane solvate.

51
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Fig. 23. A series of highly soluble neonicotinoids.

toolbox, including salts, cocrystals, amorphous solid, polymorphs and
solvates, provides a possibility to achieve such a goal. Following, we will
exhibit how crystal engineering toolbox helps to overcome the shortages
of highly soluble pesticides.
3.3.2. Highly soluble pesticides
Lots of pesticides are regarded as highly soluble pesticides, especially
when their water solubilities are greater than 1000 ppm. Highly soluble
pesticides will travel with water through the soil as it moves in the
environment, which may increase their probability of reaching
groundwater.
Besides, the high-dissolving pesticides will quickly leach out before
acting on the target,136 resulting in a short effective duration.113,137 To
achieve a long-lasting pest control effect, pesticides are often applied at a
high frequency, causing unnecessary economic costs and further envi-
ronmental pollution.138,139
To solve these problems, controlled release of highly soluble pesti-
cides has been a widely studied field in formulation development.137
Various materials, such as alginate,140 biodegradable polymers,
gel-based nanocomposites,141 and porous calcium carbonate micro-
spheres142 have been applied as the carrier for the development of a
slow-release formulation of highly soluble pesticides.
While scale-up of herbicide encapsulation technologies is developing,
the crystal engineering toolbox, which has been proved to be a solid
strategy to manipulate the release profile of bioactive compounds in the
pharmaceutical industry, offers a different way to tackle the challenge. As
one can imagine, the formation of salt is less likely to be able to reduce
water solubility, thus, co-crystallization has been the most frequent
option.
Neonicotinoids are a class of neuro-active insecticides developed
based on the chemical structure of nicotine. High insecticidal potency
and low mammalian toxicity143,144 ensured the popularity of neon-
icotinoids, which occupy a 24% market share as the most widely used
insecticide worldwide.145
However, the high solubility of neonicotinoids (Fig. 23, Table 6) led
to excessive exposure to air, soil,146 water, or living organisms, which
poses a massive threat to the environment147 and biological safety.148
Therefore, maintaining effects over a long period and reducing the
phytotoxicity and pesticide pollution by controlling the release of
neonicotinoid pesticides have been considered.149,150
Acetamiprid: Acetamiprid, an odorless neonicotinoid insecticide
marketed by Nippon Soda, is highly soluble in water (4200 ppm at
25  C). In 2006, Nippon Soda developed four cocrystals of acetamiprid,
which showed a good capability of control release, the solubility of
acetamiprid was reduced by about 10 times (Fig. 24).159
In 2014, a series of novel cocrystals consisting of a diamide insecticide
and a neonicotinoid, such as acetamiprid, imidacloprid, thiamethoxam,
clothianidin, thiacloprid, dinotefuran, were further developed to modify
the water solubility of neonicotinoids.160 The newly developed cocrystal
of neonicotinoids showed much lower water solubility than the corre-
sponding neonicotinoid itself. Thus, the cocrystals enabled a release of
neonicotinoids into the water at an adequate rate, and thereby excellent
insecticidal effects were maintained over a long period without causing
phytotoxicity on useful plants.
Metalaxyl: Metalaxyl is a systemic fungicide with high water

Table 6
The water solubility of highly soluble neonicotinoids.
Pesticides Water solubility (g/L) Temperature ( C)
151
Acetamiprid 4.2 25
Imidacloprid 0.61 152 20
Thiamethoxam 4.1153 20
Clothianidin 0.327 154 20
Thiacloprid 0.185 155 20
Dinotefuran 40 156 20
Nitenpyram 590 157 20
Fig. 24. Dissolution-time profiles of acetamiprid and its cocrystals in water
Flupyradifurone 3.2 158 20
at 25  C.159

52
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

3.4. Stability

Many pesticides decompose. For example, pyrethroid insecticides are

Fig. 25. Molecular structures of metalaxyl and prothioconazole.
easy to photolyze,162 brassinolide plant hormones can easily hydro-
lyze,163 etc. Given that most of the pesticide compounds applied in the
field may exist in a water-surrounding environment and undergo direct
sunlight exposure for a long time, the problems with chemical stability
and sublimation always reduce the bioactivity of pesticide products. As a
result, a higher amount of pesticide has to be applied to the field in
shorter intervals. Therefore, it is necessary to develop solid forms of a
given pesticide with better stability.

3.4.1. Hydrolyzation
Both pinoxaden and mesosulfuron have a problem of stability
(Fig. 26). Their formulations often result in the rapid degradation of the
compound due to hydrolyzation, which has a negative impact on the
quality of the product and limits its useful shelf life. To solve this prob-
lem, the cocrystals of pinoxaden with an antioxidant, such as butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT) or tert-butyhy-
droquinone (TBHQ), were developed by Adama Agan Ltd. to improve the
chemical stability.164 The formulation of cocrystal had a stabilizing effect
Fig. 26. Molecular structures of pinoxaden and mesosulfuron. on pinoxaden, delaying its chemical degradation (Table 7).
Amitraz: Amitraz is practically insoluble in water and relatively
Table 7 stable to temperature and light under anhydrous conditions. However,
Stability test of the cocrystal of pinoxaden with antioxidant BHA and compared when it encounters water, it is prone to hydrolysis. If the product is stored
with the reference formulation.164 in humid regions for a long period, it deteriorates rapidly.165 However,
Concentrations of pinoxaden in Formulation of Formulation of three crystalline forms (forms A-C) and an amorphous form of amitraz
the formulation (w/w%) Pinoxaden Pinoxaden-BHA cocrystal (Fig. 27a) showed completely different hydrolysis rates.166 As shown in
Starting 6.12 Fig. 27b, the decomposition rate of the amorphous form decreased more
2 weeks at 54  C 5.58 6.07 rapidly with time compared to the other forms, while Form C exhibited a
(-8.82%)a (-0.82%)
relatively slow decomposition rate. Thus, the suspension stability of
3 weeks at 54  C 5.55 6.00
(-9.31%) (-1.96%)
amitraz can be improved by replacing polymorphs, which provided an
a
additional possibility for formulation development.
The number in brackets reflects for each concentration of the herbicide Propionyl brassinolide: Propionyl brassinolide is a plant growth
pinoxaden was reduced, with respect to the initial concentration.
regulator discovered from rape pollen in 1979.167 It is effective on lots of
crops but cannot be stored for a long time in a humid environment due to
hydrolyzation. The commercially available propionyl brassinolide was
solubility (8.4 g/L at 22  C). The compound is poorly adsorbed by the soil usually manufactured as an amorphous solid, extremely susceptible to
particles, thus susceptible to mobility or runoff from treated areas, and hydrolysis. Once the material was stored under a humid and hot envi-
negatively impacting the environment. By selecting a water-insoluble ronment or dispersed in water, hydrolysis occurred. Therefore, a higher
pesticide, prothioconazole, as a co-former, Bayer developed a cocrystal amount of the product had to be applied to ensure the growth regulation
consisting of metalaxyl in 2013 (Fig. 25), reducing the water solubility of effect.
metalaxyl by 30 times, and achieved the goals of controlling release.161 A crystalline form of propionyl brassinolide was prepared by Rotam
Agrochem.163 After one week of storage as a suspension at 54  C, the new

Fig. 27. (a) SEM photomicrographs of the amitraz four solid forms. (b) Amount vs time hydrolysis plots for amitraz suspensions in aqueous phosphate buffer (pH 5.8)
at 30  C. Reprinted with permission from Ref. 166. Copyright 2004 American Chemical Society.

53
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Fig. 28. Schematic representation of the cocrystal synthesized from the combination of pyrimethanil and co-former dithianon.

crystal form sample was only hydrolyzed by less than 3%, while the
amorphous sample was hydrolyzed by 50%. With the significantly
improved chemical stability, the newly developed crystalline form of
propionyl brassinolide was stable after prolonged storage, thus suitable
for the preparation of commercial formulations such as suspension con-
centrates or oil-based suspension.
3.4.2. Sublimation
Pyrimethanil: Pyrimethanil has a high vapor pressure, is accessible
to sublimation under high-temperature conditions, thus has a short
effective duration. To overcome this shortage, development of multi-
component solid forms of pyrimethanil has been regarded as leading
remedy.
In 2004, synthesis salts of pyrimethanil were found to slow down
sublimation.168 In 2008, the famous cocrystal of pyrimethanil and
dithianone was developed by BASF SE,169 with detailed crystal structure
information provided in 2016 (Fig. 28).170
Just one year later, this cocrystal was successfully launched to the
market as the main component of fungicide product Vision Plus, making
the cocrystal of pyrimethanil and dithianone the only commercialized
pesticide cocrystal product until 2022.
The cocrystal in Vision Plus had several advantages over the formu-
lation without cocrystal. In addition to the complementary fungicidal
effect providing by two AIs, the effect and duration of pyrimethanil-

Fig. 29. Schematic representation of the cocrystals synthesized from the combination of three constituents of essential oils and two co-formers. Thumbnail images of
the corresponding crystalline structures showing the core EO-co-former assemblies. Blue dotted lines represent the EO/co-former intermolecular H-bonds. Reprinted
with permission from Ref. 172. Copyright 2019 American Chemical Society.

54
X. Niu et al.
dithianone cocrystal were less dependent on temperature fluctuation.
The cocrystal significantly reduced the sublimation of pyrimethanil at
high temperatures. In contrast, formulation without cocrystal could have
lost 70% of pyrimethanil four days after application of the product.
Therefore, the cocrystal formulation can remain effective in hot weather
for months and thus be used for a wide variety of applications.
Essential oils: Essential oils (EOs) are a category of natural compo-
nents derived from plants. Most EOs are mainly composed of terpenes,
aromatic compounds, aliphatic compounds, nitrogen and sulfur com-
pounds, etc. These components usually show good biological activities.
Currently, EOs have been shown to have a broad spectrum of activity
against pests, mites, nematodes, weeds, plant pathogens and other
fungi.171 In addition, because it is derived from natural plants and is
non-toxic to non-target organisms, such environmentally friendly pesti-
cides have a great potential to be applied in the control of crop diseases,
insect pests and sanitary pests.
However, EOs pesticides have some drawbacks. Low melting point
and low water solubility remain enormous obstacles to the processing
and spraying, but also high volatility and high degradability reduce their
efficacy and persistence, thereby limiting the broad application of EOs
pesticides. Inspired by crystal engineering, researchers have developed
an alternative formulation of EOs pesticides cocrystals, which fixes vol-
atile liquid components into solid forms. A series cocrystals of eugenol
(EUG), thymol (THY) and carvacrol (CAR) were developed with six
different co-formers (phenazine, PHE; hexamethylenetetramine, HMT;
isonicotinamide, INA; pyrazine, PYR; 2,3,5,6-tetramethylpyrazine, TMP;
2,3-dimethylquinoxaline, DMQ), as shown in Fig. 29 and Fig. 30.172,173
The results of physical properties tests showed that cocrystals could
regulate the environmental release of EOs, that is, reducing the acute
response and achieving a more persistent release at room temperature.
Notably, TMP-THY 1:1 cocrystal can convert to TMP-THY 1:2 cocrystal,
providing an attractive possibility of controlled release of more AI.173
Moreover, CAR-HMT and EUG-HMT cocrystals exhibited increased water
solubility compared to pure EOs.172 The results of bioassays exhibited
significant improvements of antibacterial and antifungal efficacy in the
treatments involving cocrystals compared to the treatments involving
pure EOs.
As mentioned above, cocrystal strategy has been applied as a
powerful tool for improved the physical and chemical stability of tech-
nical materials or AIs in formulation. Similar examples of pendimetha-
lin,78 triazole fungicides,174,175 and sulfentrazone and triazinone
herbicides176 could be found in the literature.
4. Summary
4.1. The utility of crystal engineering in pesticides
It is demonstrated in this section that the solid forms may have a great
impact on the physicochemical properties of a pesticide, including
melting point, aggregation and recrystallization tendency, water solubi-
lity, chemical stability, hygroscopicity and even bioactivity. Therefore,
since the 1980s, crystal engineering has been an effective strategy
applied by large agrochemical companies to overcome the shortage of
selected pesticide products.
It is worth noting that, normally, there is no “perfect” solid form for
all pesticides. In terms of solubility and bioactivity, amorphous solid may
show the best performance. However, the metastable nature of amor-
phous solid always leads to a high tendency of aggregation and recrys-
tallization, as well as weak chemical stability. Therefore, for most
commercialized pesticide formulation products, it is rare to choose an
amorphous solid as the first option. Fortunately, crystal engineering
strategies, including amorphous solids, polymorphs and cocrystals, pro-
vide “tools” to tune the properties of pesticides at different levels ac-
cording to the specific requirement of the processing, storage and
application scenario of the given pesticide product.
With the increasing complexity of the molecular structure and
55
Advanced Agrochem 1 (2022) 39–60
molecular weight of the newly developed or developing pesticide com-
pounds, more and more AIs exist as solids under ambient conditions.
Besides, a major part of pesticide formulation products commonly used in
agriculture, such as wettable powders and suspension concentrates,
contain solid AI particles. Therefore, in the foreseen future, more atten-
tion on crystal engineering of pesticides is expected.
4.2. Patent protection
As one can tell, most of the cases mentioned above were recorded by
published patents. Solid forms of pesticides, including polymorphs, hy-
drates, solvates, salts and cocrystals, represent new varieties of chemical
structures of the compound. Considering that the properties of a selected
pesticide and the quality of the corresponding product can be tuned by
crystal engineering, a new solid form of a pesticide could be both valu-
able and patentable.
Since the patent application protecting the chemical structure of a
pesticide is typically filed in advance of the approval and market launch,
the exact period for which the innovator company will retain market
exclusivity could be considerably less than 20 years. Therefore, for the
innovator company, patents on novel crystal forms of a compound are
valuable in terms of extending the market exclusivity of a pesticide
product. Conversely, follow-up companies can also use the patents on
novel crystal forms to join the exclusive market after the expiration of the
compound patents.
5. Outlook
There is no doubt that the crystal engineering study of pesticides has
drawn on experience developed in the pharmaceutical industry. How-
ever, applications for pesticides and drugs are significantly different.
When oral doses are taken by patients, the microcrystals of APIs
dissolve in the digestive system. Therefore, for APIs, the solubility and
dissolution modification, which are directly related to the bioavailability
of the compound, have been one of the main targets of crystal engi-
neering study.
For pesticides, the most frequently used pesticide products are for-
mulations for mixing with water and then applying as sprays. Therefore,
when pesticides are sprayed on plants, the microcrystals of pesticide will
have to stay on the surface of leaves or in the environment for a certain
amount of time, which means the microcrystals may be exposed to a
more complex environment, such as sunlight and rainfall, than just dis-
solving in the digestive juices as their pharmaceutical counterparts.
The differences in application scenarios lead to new questions that
need to be answered by future research in the crystal engineering of
pesticides.
1. Photostability: Since the pesticides need to be exposed to direct
sunlight, can the crystal engineering strategy help improve the pho-
tostability of pesticides?
2. Adhesive ability: Under rainfall, will a novel solid form of pesticides
have a better adhesive ability to the leaves so that less AIs are flushed
into the environment?
3. Bioavailability: Though the impact of solid forms on bioactivity was
reported, there is still lacking a common understanding in terms of
the correlation between solid forms and bioavailability. One possible
reason is that the correlation between bioactivity or bioavailability
and solid forms is much less frequently studied. Besides, the targets of
pesticides are more complex, including insects, weeds and fungi.
Thus, it is hard to draw a universal conclusion with solid evidence and
sound reasoning. This vacuum in knowledge implies that the research
on the correlation between solid forms and bioavailability, as well as
the essential property of pesticides will be one of the most important
challenges that need to be addressed in the future.
4. Crystallization behavior of pesticides on the biointerface: For
solution formulations containing no solids, the crystals of pesticides
X. Niu et al. Advanced Agrochem 1 (2022) 39–60

Fig. 30. Schematic representation of the cocrystals synthesized from the combination of two constituents of essential oils and four co-formers. Thumbnail of the
corresponding crystalline structures showing the core EO-co-former assemblies. Blue dotted lines represent intermolecular H-bonds. Reprinted with permission from
Ref. 173. Copyright 2022 American Chemical Society.

56
X. Niu et al.
may emerge on the sprayed leaf surfaces as the solvents get evapo-
rated. The polymorphism and morphology may also impact the
bioavailability of the applied pesticide.
What is the future for crystal engineering of pesticides? The current
research, basically the cases mentioned here, mainly focused on the
physiochemical properties related to the processing, manufacture and
storage of the product. The interaction between crystals of pesticides and
targeted organisms, however, is directly related to the bio-efficacy of
pesticides during field application. Considering that bioactivity is the
most important property of a pesticide, and closely related to its solid
state, we believe that the interaction between the crystals of pesticides
and targeted organisms could bring more profound understanding and
more valuable suggestions for improving the field performance of
pesticide products.
6. Conclusion
Though the literature on crystal engineering of pesticides is under-
represented compared to counterparts of pharmaceutical compounds,
the cases mentioned in this review emphasized that the application of
crystal engineering had already become an important part of developing
a better pesticide product. The knowledge of the crystallization behaviors
of the selected pesticide could serve throughout the entire product life
cycle, i.e., from development to manufacture, from manufacture to field
application, thus powering the agrochemical industry for a bright and
sustainable future.
CRediT authorship contribution statement
Xiaofang Niu: Investigation, Resources, Visualization, Writing –
original draft. Rui Yang: Investigation, Resources, Writing – original
draft. Huimin Zhang: Visualization, Writing – original draft. Jingxiang
Yang: Conceptualization, Writing – original draft, Writing – review &
editing, Project administration, Supervision.
Declaration of competing interest
The author declares no conflicts of interest.
Acknowledgments
Financial support from the Fundamental Research Funds for the
Central Universities (No. 63213063), Frontiers Science Center for New
Organic Matter, Nankai University (Grant No. 63181206), Young Elite
Scientist Sponsorship Program-CAST, and Nankai University are grate-
fully acknowledged. The authors would like to thank Profs. Bart Kahr and
Michael Ward from New York University for providing helpful
comments.
References
1. What is a Pesticide? United States Environmental Protection Agency. https://www
.epa.gov/minimum-risk-pesticides/what-pesticide. Accessed July 20, 2022.
2. Kinkela D. DDT and the American Century: Global Health, Environmental Politics, and
the Pesticide that Changed the World. University of North Carolina Press; 2011.
https://www.jstor.org/stable/10.5149/9780807869307_kinkela. Accessed July
20, 2022.
3. Pesticides Market Analysis. S&P Global. https://ihsmarkit.com/products/crop-scie
nce-pesticides.html. Accessed July 20, 2022.
4. Council N. The Future Role of Pesticides in US Agriculture. Washington, DC: National
Academy Press; 2000.
5. Washuck N, Hanson M, Prosser R. Yield to the data: some perspective on crop
productivity and pesticides. Pest Manag Sci. 2022;78(5):1765–1771. https://
doi.org/10.1002/ps.6782.
6. Cooper J, Dobson H. The benefits of pesticides to mankind and the environment.
Crop Protect. 2007;26(9):1337–1348. https://doi.org/10.1016/
j.cropro.2007.03.022.
57
Advanced Agrochem 1 (2022) 39–60
7. McDougall P. The cost of new agrochemical product discovery, development and
registration, 1995, 2000, 2005–2008 and 2010 to 2014. R&D expenditure in, 2014.
8. Sparks TC, Lorsbach BA. Perspectives on the agrochemical industry and
agrochemical discovery. Pest Manag Sci. 2017;73(4):672–677. https://doi.org/
10.1002/ps.4457.
9. Sparks TC. Insecticide discovery: an evaluation and analysis. Pestic Biochem Physiol.
2013;107(1):8–17. https://doi.org/10.1016/j.pestbp.2013.05.012.
10. Menn JJ. Contemporary frontiers in chemical pesticide research. J Agric Food Chem.
1980;28(1):2–8. https://doi.org/10.1021/jf60227a012.
11. Olenik B, Keil B, Jeschke P. Importance of chemical polymorphism in modern crop
protection. Pest Manag Sci. 2022;78:2746–2758. https://doi.org/10.1002/ps.6919.
12. Byrn SR, Zografi G, Chen XS. Solid-state Properties of Pharmaceutical Materials. John
Wiley & Sons; 2017.
13. McIntosh AH. Relation between particle size and shape of insecticidal suspensions
and their contact toxicity: I. DDT suspensions against tribolium castaneum Hb. Ann
Appl Biol. 1947;34(4):586–610. https://doi.org/10.1111/j.1744-
7348.1947.tb06391.x.
14. Querzola G, Epis G, inventors; S.I.P.C.A.M. Societa' Italiana Prodotti Chimici e per
L'Agricoltura Milano S.P.A., assignee. Process for the production of chlorothalonyl.
WO patent 86/06066. October 23, 1986.
15. Sekhon BS. Co-crystals of agrochemical actives. Int J Agric Sci. 2015;5(3):472–475.
https://www.internationalscholarsjournals.com/abstract/cocrystals-of-agrochemi
cal-actives-63955.html.
16. Lu J. Crystallization and transformation of pharmaceutical solid forms. Afr J Pharm
Pharmacol. 2012;6(9):581–891. https://doi.org/10.5897/AJPP12.044.
17. Haleblian J, McCrone W. Pharmaceutical applications of polymorphism. J Pharm
Sci. 1969;58(8):911–929. https://doi.org/10.1002/jps.2600580802.
18. Nangia A. Conformational polymorphism in organic crystals. Acc Chem Res. 2008;
41(5):595–604. https://doi.org/10.1021/ar700203k.
19. Wohler F. Untersuchungen uber das Radikal der Benzoesaure. Ann For. 1832;3:
249–287. https://doi.org/10.1002/jlac.18320030302.
20. David WIF, Shankland K, Pulham CR, et al. Polymorphism in benzamide. Angew
Chem Int Ed. 2005;117(43):7194–7197. https://doi.org/10.1002/ange.200501146.
21. Shtukenberg AG, Drori R, Sturm EV, et al. Crystals of benzamide, the first
polymorphous molecular compound, are helicoidal. Angew Chem Int Ed. 2020;132:
14701–14709. https://doi.org/10.1002/ange.202005738.
22. Robertson JM. A molecular map of resorcinol. Nature. 1935;136:755–756. https://
doi.org/10.1038/136755c0.
23. Grunenberg A. Polymorphie und thermische Analyse pharmazeutischer Wirkstoffe.
Pharmazie Unserer Zeit. 1997;26(5):224–231. https://doi.org/10.1002/
pauz.19970260506.
24. Bhardwaj RM, McMahon JA, Nyman J, et al. A prolific solvate former, Galunisertib,
under the pressure of crystal structure prediction, produces ten diverse polymorphs.
J Am Chem Soc. 2019;141(35):13887–13897. https://doi.org/10.1021/
jacs.9b06634.
25. Zhu X, Hu CT, Erriah B, et al. Imidacloprid crystal polymorphs for disease vector
control and pollinator protection. J Am Chem Soc. 2021;143(41):17144–17152.
https://doi.org/10.1021/jacs.1c07610.
26. Yu LX, Furness MS, Raw A, et al. Scientific considerations of pharmaceutical solid
polymorphism in abbreviated new drug applications. Pharm Res (N Y). 2003;20(4):
531–536. https://doi.org/10.1023/a:1023285627778.
27. Zarzycki J. Les verres et l’etat vitreux. French: Elsevier Masson; 1982. https://www
.worldcat.org/title/verres-et-letat-vitreux/oclc/417566890. Accessed February 10,
2022.
28. Amann-Winkel K, Gainaru C, Handle PH, et al. Water's second glass transition. Proc
Natl Acad Sci USA. 2013;110(44):17720–17725. https://doi.org/10.1073/
pnas.1311718110.
29. Poole PH, Grande T, Sciortino F, et al. Amorphous polymorphism. Comput Mater Sci.
1995;4(4):373–382. https://doi.org/10.1016/0927-0256(95)00044-9.
30. Nangia A, Desiraju GR. Pseudopolymorphism: occurrences of hydrogen bonding
organic solvents in molecular crystals. Chem Commun. 1999;7:605–606. https://
doi.org/10.1039/A809755K.
31. Harris RK. Polymorphism studied by solid-state NMR. Encyclopedia of Spectroscopy
and Spectrometry. 2017:709–717. https://doi.org/10.1016/B978-0-12-803224-
4.00055-8.
32. Brittain HG. Polymorphism in pharmaceutical solids. Drugs Pharmaceut Sci. 1999;
95:183–226.
33. Aitipamula S, Banerjee R, Bansal AK, et al. Polymorphs, salts, and cocrystals: what's
in a name? Cryst Growth Des. 2012;12(5):2147–2152. https://doi.org/10.1021/
cg3002948.
34. Bolla G, Sarma B, Nangia AK. Crystal engineering of pharmaceutical cocrystals in
the discovery and development of improved drugs. Chem Rev. 2022;122:
11514–11603. https://doi.org/10.1021/acs.chemrev.1c00987.
35. W€ohler F. Untersuchungen über das chinons. Ann Chem Pharm. 1844;51:145–163.
https://doi.org/10.1002/jlac.18440510202.
36. Matsuda H, Osaki K, Nitta I. Crystal structure of quinhydrone, C12H10O4. Bull Chem
Soc Jpn. 1958;31(5):611–620. https://doi.org/10.1246/bcsj.31.611.
37. Yousef MAE, Vangala VR. Pharmaceutical cocrystals: molecules, crystals,
formulations, medicines. Cryst Growth Des. 2019;19(12):7420–7438. https://
doi.org/10.1021/acs.cgd.8b01898.
38. Mir NA, Dubey R, Desiraju GR. Strategy and methodology in the synthesis of
multicomponent molecular solids: the quest for higher cocrystals. Acc Chem Res.
2019;52(8):2210–2220. https://doi.org/10.1021/acs.accounts.9b00211.
X. Niu et al.
39. Tothadi S, Shaikh TR, Gupta S, et al. Can we identify the salt-cocrystal continuum
state using XPS? Cryst Growth Des. 2021;21(2):735–747. https://doi.org/10.1021/
acs.cgd.0c00661.
40. Saha S, Desiraju GR. AcidAmide supramolecular synthon in cocrystals: from
spectroscopic detection to property engineering. J Am Chem Soc. 2018;140(20):
6361–6373. https://doi.org/10.1021/jacs.8b02435.
41. Losev EA, Boldyreva EV. A salt or a co-crystal - when crystallization protocol
matters. CrystEngComm. 2018;20:2299–2305. https://doi.org/10.1039/
C7CE02204B.
42. Bauer J, Spanton S, Henry R, et al. Ritonavir: an extraordinary example of
conformational polymorphism. Pharm Res (N Y). 2001;18(6):859–866. https://
doi.org/10.1023/a:1011052932607.
43. Morissette SL, Soukasene S, Levinson D, et al. Elucidation of crystal form diversity
of the HIV protease inhibitor ritonavir by high-throughput crystallization. Proc Natl
Acad Sci USA. 2003;100(5):2180–2184. https://doi.org/10.1073/
pnas.0437744100.
44. Zhang G, Yao X, Henry R. Ritonavir Form III: A new polymorph after 24 years.
Cambridge: Cambridge Open Engage; 2022. https://doi.org/10.26434/chemrxiv-
2022-35fwp.
45. Cheng J, Xiao D, Zheng M, et al. Polymorphism of S-indoxacarb and its impact on
insecticide activity. Chin J Pesticide Sci. 2018;20(3):294–300. https://doi.org/
10.16801/j.issn.1008-7303.2018.0039.
46. Zhao D, Lin B, Hong C, et al. inventors; Qingdao KingAgroot Chemical Compound
Co., Ltd., assignee. Amorphous biscarfentrazone and preparation method and use
thereof. In: WO Patent 2018/201524. 2018. November 8.
47. Zhao D, Chen Z, Lin B, et al. inventors; Qingdao KingAgroot Chemical Compound
Co., Ltd., assignee. Amorphous triazolesulcotrione, preparation method therefor,
and use thereof. In: WO Patent 2018/192047. 2018. October 25.
48. Berge SM, Bighley LD, Monkhouse DC. Pharmaceutical salts. J Pharm Sci. 1977;
66(1):1–19. https://doi.org/10.1002/jps.2600660104.
49. Stahl PH, Wermuth CG. Handbook of pharmaceutical salts: properties, selection and
use. Chem Int. 2002;21:24. https://doi.org/10.1515/ci.2002.24.3.20b.
50. Karimi-Jafari M, Padrela L, Walker GM, et al. Creating cocrystals: a review of
pharmaceutical cocrystal preparation routes and applications. Cryst Growth Des.
2018;18(10):6370–6387. https://doi.org/10.1021/acs.cgd.8b00933.
51. Duggirala NK, Perry ML, Almarsson O, € et al. Pharmaceutical cocrystals: along the
path to improved medicines. Chem Commun. 2016;52(4):640–655. https://doi.org/
10.1039/C5CC08216A.
52. Yang H, Yang Y, Jia L, et al. The phase transformation and formation mechanism of
isostructural solvates: a case study of azoxystrobin. Cryst Growth Des. 2019;19(3):
1550–1558. https://doi.org/10.1021/acs.cgd.8b01144.
53. Du D, Shi ZP, Ren GB, et al. Preparation and characterization of several
azoxystrobin channel solvates. J Mol Struct. 2019;1189:40–50. https://doi.org/
10.1002/ps.6919.
54. US Food and Drug Administration. Q6A Specifications: Test Procedures and
Acceptance Criteria for New Drug Substances and New Drug Products: Chemical
Substances. https://www.fda.gov/regulatory-information/search-fda-guidance-d
ocuments/q6a-specifications-test-procedures-and-acceptance-criteria-new-drug-su
bstances-and-new-drug-products. Accessed July 28, 2022.
55. US Food and Drug Administration. ANDAs: Pharmaceutical Solid Polymorphism:
Chemistry, Manufacturing, and Controls Information. https://www.fda.gov/regu
latory-information/search-fda-guidance-documents/andaspharmaceutical-solid-po
lymorphism-chemistry-manufacturing-and-controls-information. Accessed July 28,
2022.
56. US Food and Drug Administration. Guidance for Industry on Regulatory
Classification of Pharmaceutical Co-Crystals. https://www.federalregister.gov/d
ocuments/2013/04/26/2013-09872/guidance-for-industry-on-regulatory-classifi
cation-of-pharmaceutical-co-crystals-availability. Accessed July 28, 2022.
57. US Food and Drug Administration. Regulatory Classification of Pharmaceutical Co-
Crystals: Guidance for Industry. https://www.fda.gov/regulatory-informatio
n/search-fda-guidance-documents/regulatory-classification-pharmaceutical-co-cr
ystals. Accessed July 28, 2022.
58. https://www.scopus.com. Scopus is Elsevier’s Abstract and Citation Database.
59. Yang J, Hu CT, Zhu X, et al. DDT polymorphism and the lethality of crystal forms.
Angew Chem, Int Ed. 2017;129(34):10299–10303. https://doi.org/10.1002/
ange.201703028.
60. Tremayne M, Grice L, Pyatt JC, et al. Characterization of complicated new
polymorphs of chlorothalonil by X-ray diffraction and computer crystal structure
prediction. J Am Chem Soc. 2004;126(22):7071–7081. https://doi.org/10.1021/
ja0498235.
61. Rong H, Gu H. Polymorphs of 2, 4, 5, 6-tetrachloro-1, 3-benzenedicarbonitile and
their transformations. Thermochim Acta. 2005;428(1-2):19–23. https://doi.org/
10.1016/j.tca.2004.09.018.
62. Lu Q, Yang G, Gu H. Phase quantification of two chlorothalonil polymorphs by X-
ray powder diffraction. Anal Chim Acta. 2005;538(1-2):291–296. https://doi.org/
10.1016/j.aca.2005.01.063.
63. Xi H, Zhu F, Du X, et al. inventors; Jiangsu Polytechnic College, assignee. Method of
preparing alpha-chlorothalonil. In: CN Patent 1752069. 2006. March 29.
64. Wang J, Xu H, Zhang L, et al. inventors; Jiangyin Suli Chemical Co., Ltd., assignee.
Chlorothalonil lattice transformation device and preparation method. In: CN Patent
113019269. 2021. June 25.
65. McCrone WC. Crystallographic data: 1. DDT. Anal Chem. 1948;20(3):274–277.
https://doi.org/10.1021/ac60015a601.
66. Yang J, Zhu X, Hu CT, et al. Inverse correlation between lethality and
thermodynamic stability of contact insecticide polymorphs. Cryst Growth Des. 2019;
19(3):1839–1844. https://doi.org/10.1021/acs.cgd.8b01800.
58
Advanced Agrochem 1 (2022) 39–60
67. Zhu X, Hu CT, Yang J, et al. Manipulating solid forms of contact insecticides for
infectious disease prevention. J Am Chem Soc. 2019;141(42):16858–16864.
https://doi.org/10.1021/jacs.9b08125.
68. Elliott M, Farnham AW, Janes NF, et al. Synthetic insecticide with a new order of
activity. Nature. 1974;248:710–711. https://doi.org/10.1038/248710a0.
69. Casida JE. Michael Elliott's billion dollar crystals and other discoveries in
insecticide chemistry. Pest Manag Sci. 2010;66(11):1163–1170. https://doi.org/
10.1002/ps.1982.
70. Yang J, Erriah B, Hu CT, et al. A deltamethrin crystal polymorph for more effective
malaria control. Proc Natl Acad Sci USA. 2020;117(43):26633–26638. https://
doi.org/10.1073/pnas.2013390117.
71. Durrani J. Fast-acting insecticide polymorph could boost malaria-control efforts. htt
ps://www.chemistryworld.com/news/fast-acting-insecticide-polymorph-could-boo
st-malaria-control-efforts/4012639.article. Accessed July 20, 2022.
72. Le Questel JY, Graton J, Cer on-Carrasco JP, et al. New insights on the molecular
features and electrophysiological properties of dinotefuran, imidacloprid and
acetamiprid neonicotinoid insecticides. Bioorg Med Chem. 2011;19(24):7623–7634.
https://doi.org/10.1016/j.bmc.2011.10.019.
73. Zhao J, Wang M, Dong B, et al. Monitoring the polymorphic transformation of
imidacloprid using in situ FBRM and PVM. Org Process Res Dev. 2013;17(3):
375–381. https://doi.org/10.1021/op300320a.
74. Kagabu S, Matsuno H. Chloronicotinyl insecticides. 8. Crystal and molecular
structures of imidacloprid and analogous compounds. J Agric Food Chem. 1997;
45(1):276–281. https://doi.org/10.1021/jf960075f.
75. Chopra D, Mohan TP, Rao KS, et al. (2E)-1-[(6-Chloropyridin-3-yl) methyl]-N-
nitroimidazolidin-2-imine (imidachloprid). Acta Crystallogr E. 2004;60(12):
o2415–o2417. https://doi.org/10.1107/S1600536804029824.
76. Qu H, Jin S, Gong J, et al. Enhancing stability and formulation capability of
fungicides by cocrystallization through a novel multistep slurry conversion process.
Cryst Growth Des. 2020;20(11):7356–7367. https://doi.org/10.1021/
acs.cgd.0c01038.
77. Gong J, Jin S, Hou B, et al, inventors; Tianjin University, assignee. Flusilazole-
thiophanate methyl pesticide eutectic crystal and preparation method thereof. CN
patent 108503665. September 7, 2018.
78. Krapp M, Gregori W, Saxell HE. inventors; BASF SE, assignee. Crystalline complexes
of pendimethalin and metazachlor. In: WO Patent 2010/043607. 2010. April 22.
79. Cui B, Feng L, Pan Z, et al. Evaluation of stability and biological activity of solid
nanodispersion of lambda-cyhalothrin. PLoS One. 2015;10(8), e0135953. https://
doi.org/10.1371/journal.pone.0135953.
80. Essinger JFJ, inventor; Monsanto Company, assignee. Improved preparation of
water-dispersed formulation by nucleation and crystallization of low-melting point
pesticide active ingredient. WO patent 95/26631. October 12, 1995.
81. Kimpara M, Kawai K, Tobe Y. inventors; American Cyanamid Company, assignee.
Stable aqueous suspension concentrate composition. In: EP Patent 0249728. 1987.
December 23.
82. Morton V, Staub T. A short history of fungicides. APSnet Features. 2008:308.
83. Yin M, Zheng Y, Chen F. Pyraclostrobin-loaded poly (lactic-co-glycolic acid)
nanospheres: preparation and characteristics. J Integr Agric. 2018;17(8):1822–1832.
https://doi.org/10.1016/S2095-3119(17)61839-2.
84. Formulation of pesticides. In: Matthews GA, Bateman R, Miller P, eds. Pesticide
Application Methods. fourth ed.; 2014. Wiley; vol https://onlinelibrary.wiley.com/d
oi/book/10.1002/9781118351284. Accessed July 10, 2022.
85. Ziegler H, Mayer W, Kr€ ohl T, et al. inventors; BASF AG, assignee. Crystalline
modifications to pyraclostrobin. In: WO Patent 2006/136357. 2006. December 28.
86. Xu W, Sheng G, Liu R, et al. inventors; Shandong Kangqiao Bio-technology Co., Ltd.,
assignee. Pyraclostrobin new crystal form V and preparation method thereof. In: CN
Patent 106243040. 2016. December 21.
87. Vangala VR, Chow PS, Tan RBH. Characterization, physicochemical and photo-
stability of a co-crystal involving an antibiotic drug, nitrofurantoin, and 4-hydrox-
ybenzoic acid. CrystEngComm. 2011;13(3):759–762. https://doi.org/10.1039/
C0CE00772B.
88. Nauha E, Saxell H, Nissinen M, et al. Polymorphism and versatile solvate formation
of thiophanate-methyl. CrystEngComm. 2009;11(11):2536–2547. https://doi.org/
10.1039/B905511H.
89. Saxell HE, Israels R, Schafer A, et al. inventors; BASF SE, assignee. Crystalline
complexes of 4-hydroxy benzoic acid and selected pesticides. In: WO Patent 2011/
054741. 2011. May 12.
90. Israels R, Saxell HE, Bratz M, et al. inventors; BASF SE, assignee. Crystalline
complexes of agriculturally active organic compounds. In: WO Patent 2008/096005.
2008. August 14.
91. George N, Forrest J, Bonnett PE, et al. inventors; Syngenta Limited, assignee. Co-
crystals of propiconazole. In: WO Patent 2008/117037. 2008. October 2.
92. Weiss M, Storch D, Wirth W, et al. inventors; Bayer Technology Services GMBH,
assignee. Co-crystal of 4-{[(6-chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}
furan-2(5H)-one with salicylic acid and use thereof as pesticide. In: WO Patent
2011/051242. 2011. May 5.
93. Weiss M, Storch D, Wirth W, et al. inventors; Bayer Technology Services GMBH,
assignee. Co-crystal of 4-{[(6-chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}-
furan-2(5h)-one with oxalic acid and use thereof as pesticide. In: WO Patent 2011/
051241. 2011. May 5.
94. Weiss M, Storch D, Meier SM. inventors; Bayer Technology Services GMBH,
assignee. Co-crystal comprising imidacloprid and method for the production
thereof. In: WO Patent 2010/118833. 2010. October 21.
95. Morgan LJ, Bell M. inventors; American Cyanamid Company, assignee. Aqueous
suspension concentrate compositions of pendimethalin. In: US Patent 4,871,392.
1989. October 3.
X. Niu et al.
96. Morgan LJ, Bell M. inventors; American Cyanamid Company, assignee. Aqueous
suspension concentrate compositions. In: US Patent 4,875,929. 1989. October 24.
97. Stockton GW, Mowery PC, Walker AF. Crystal polymorphism in pendimethalin
herbicide is driven by electronic delocalization and changes in intramolecular
hydrogen bonding. A crystallographic, spectroscopic and computational study.
J Chem Soc, Perkin trans. 1998;2(9):2061–2072. https://doi.org/10.1039/
A705178F.
98. Seidel E, Vermeer R, Hasenack K, et al. inventors; Bayer Cropscience AG, assignee.
Crystal modification II of 2-[2-(1-chloro-cyclopropyl)-3-(2-chlorophenyl)-2-
hydroxy-propyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione. In: WO Patent 2004/
008860. 2004. Janaury 29.
99. Bernstein J, Davey RJ, Henck JO. Concomitant polymorphs. Angew Chem, Int Ed.
1999;38(23):3440–3461. https://doi.org/10.1002/(SICI)1521-3773(19991203)
38, 23<3440::AID-ANIE3440>3.0.CO;2-%23.
100. Eicken K, Rohr W, Zeeh B, et al. inventors; BASF AG, assignee. Acetanilide. In: DE
2648008. 1978. May 3.
101. Griesser U, Weigand D, Rollinger J, et al. The crystal polymorphs of metazachlor.
J Therm Anal Calorim. 2004;77(2):511–522. https://doi.org/10.1023/b:
jtan.0000038990.43475.db.
102. Keil M, Girgensohn B, Synnatschke G, et al. inventors; BASF AG, assignee.
Monoclinic metazachlor and process for its preparation. In: EP Patent 0,411,408.
1991. February 6.
103. Tomlin C. The pesticide manual. 10th ed. UK, farnham: British Crop Protection
Council; 1994. https://agris.fao.org/agris-search/search.do?recordID¼GB9518023.
Accessed July 8, 2022.
104. Thomas R, Draber W, Schmidt RR, et al. inventors; Bayer AG, assignee. (N)-
Heterocyclyl-methyl-halo-acetanilide derivs. - useful as herbicides, esp. for selective
control of grassy weeds. In: DE 2742583. 1979. April 5.
105. Reck G, Schulz B, Kraus WCCDC. 177699: experimental crystal structure
determination. Cambridge Crystallographic Data Centre. 2004. https://doi.org/
10.5517/cc5yx77.
106. Waechter F, Weber E, Hertner T, et al. Cyprodinil: a fungicide of the
anilinopyrimidine class. In: Robert K, ed. Hayes' Handbook of Pesticide Toxicology.
third ed. Academic Press; 2010:1903–1913. https://www.sciencedirect.com/sci
ence/article/pii/B9780123743671000896. Accessed July 6, 2022.
107. George N, Forrest J, Gavan PT, et al. inventors; Syngenta Limited, assignee. Co-
crystals of cyprodinil and pyrimethanil. In: WO Patent 2008/117060. 2008. October
2.
108. George N, Forrest JO, Burton RC, et al. inventors; Syngenta Limited, assignee. Co-
crystals of pyrimethanil or cyprodinil. In: WO Patent 2011/128618. 2011. October
20.
109. James TB, inventor; Jiangsu Rotam Chemistry Co., Ltd., assignee. Novel crystalline
form of picoxystrobin, method of preparing and use of the same. WO patent 2017/
125010. July 27, 2017.
110. James TB, inventor; Jiangsu Rotam Chemistry Co., Ltd., assignee. Novel crystalline
form of chlorfenapyr, process for its preparation and use. WO patent 2018/090787.
May 24, 2018.
111. James TB, inventor; Jiangsu Rotam Chemistry Co., Ltd., assignee. Crystalline form
of spirotetramat, process for preparation and use thereof. WO patent 2018/188356.
October 18, 2018.
112. Yang L. Problems and development trend of avermectins pesticide formulations.
World Pesticides. 2009;31:5–7. https://doi.org/10.1029/JB094iB12p17895.
113. Tiryaki O, Temur C. The fate of pesticide in the environment. J Biol Environ Sci.
2010;4(10):29–38.
114. Gao S, Jiang J, Li X, et al. An environmentally safe formulation with enhanced
solubility and fungicidal activity: self-assembly and characterization of
Difenoconazole-β-CD inclusion complex. J Mol Liq. 2021;327:114874. https://
doi.org/10.1016/j.molliq.2020.114874.
115. Zamir S, Mason D, Faktorovitch I. inventors; Makhteshim Chemical Works Ltd.,
assignee. Crystalline modifications of prothioconazole. In: WO Patent 2009/153785.
2009. December 23.
116. Dos Santos EV, S aez C, Martínez-Huitle CA, et al. Combined soil washing and CDEO
for the removal of atrazine from soils. J Hazard Mater. 2015;300:129–134. https://
doi.org/10.1016/j.jhazmat.2015.06.064.
117. Catalkaya EC, Kargi F. Advanced oxidation and mineralization of simazine using
Fenton's reagent. J Hazard Mater. 2009;168(2-3):688–694. https://doi.org/
10.1016/j.jhazmat.2009.02.091.
118. Rodrigues ET, Lopes I. Pardal MA. ^ Occurrence, fate and effects of azoxystrobin in
aquatic ecosystems: a review. Environ Int. 2013;53:18–28. https://doi.org/10.1016/
j.envint.2012.12.005.
119. Shi ZP, Ren GB, Qi MH, et al. Multicomponent pharmaceutical adducts of
azoxystrobin: physicochemical properties, thermodynamic, and molecular
modeling study. Cryst Res Technol. 2021;56(11), 2100057. https://doi.org/
10.1002/crat.202100057.
120. Dinter A, Brugger KE, Frost NM, et al. Chlorantraniliprole (Rynaxypyr): a novel
DuPont™ insecticide with low toxicity and low risk for honey bees (Apis mellifera)
and bumble bees (Bombus terrestris) providing excellent tools for uses in integrated
pest management. Julius-Kühn-Archiv. 2009;423:84–96.
121. Tomlin C. The pesticide manual, 11th. British Crop Protection Council. 1997.
122. Lu P, Yang S, Hu D, et al. Synthesis of hapten and development of immunoassay
based on monoclonal antibody for the detection of dufulin in agricultural samples.
J Agric Food Chem. 2013;61(43):10302–10309. https://doi.org/10.1021/
jf4025954.
59
Advanced Agrochem 1 (2022) 39–60
123. Li M, Gong C, Ren G, et al. Study on structure, stability, and phase transformation of
dufulin polymorphs. Cryst Growth Des. 2021;21(12):6697–6713. https://doi.org/
10.1021/acs.cgd.1c00556.
124. Steter JR, Kossuga MH, Motheo AJ. Mechanistic proposal for the electrochemical
and sonoelectrochemical oxidation of thiram on a boron-doped diamond anode.
Ultrason Sonochem. 2016;28:21–30. https://doi.org/10.1016/
j.ultsonch.2015.06.022.
125. Campos EVR, Oliveira JL, da Silva CMG, et al. Polymeric and solid lipid
nanoparticles for sustained release of carbendazim and tebuconazole in agricultural
applications. Sci Rep. 2015;5(1):1–14. https://doi.org/10.1038/srep13809.
126. Li Z, Ren G, Xu X, et al. inventors; East China University of Science and Technology,
assignee. Tebuconazole polymorph and preparation method therefor. In: WO Patent
2019/095891. 2019. May 23.
127. Bai G, Ge J, Dong F, et al, inventors; Qingdao Hailir Pesticides & Chemicals Group
Co. Ltd., assignee. Eutectic crystal of tebuconazole and organic acid as well as
preparation method and application of eutectic crystal. CN patent 113999181.
February 1, 2022.
128. Chen MF, Huang JW, Chien HP. Residue analysis of fungicide boscalid in
cucumbers following applications of boscalid 50% water dispersible granule. J Food
Drug Anal. 2007;15(2):6. https://doi.org/10.38212/2224-6614.2425.
129. Carvalho PS, Guimar~aes GGF, Diniz LF, et al. Highly water soluble agrichemicals by
using engineered organic salts for reducing adverse environmental impacts. Green
Chem. 2019;21(23):6419–6429. https://doi.org/10.1039/C9GC02439E.
130. da Silva AK, Diniz LF, Tenorio JC, et al. Driving a sustainable application of s-
triazine ametryn and atrazine herbicides through multicomponent crystals with
improved solubility. CrystEngComm. 2021;23(24):4252–4263. https://doi.org/
10.1039/D1CE00356A.
131. Zhao D, Liu Y, Lin B, et al. inventors; Qingdao Kingagroot Chemical Compound Co.,
Ltd., assignee. Triazole sulcotrione-salicylic acid cocrystal and preparing method
and application thereof. WO patent 2019/223186. 2019. November 28.
132. Chen W, Zhang B, Hou B, et al. inventors; Tianjin University, assignee.
Nicosulfuron-urea eutectic crystal and preparation method thereof. In: CN Patent
111978293. 2020. November 24.
133. Li M, Wang J, Xu X, et al. Study of cycloxaprid co-crystals: characterization, theory
calculation, solubility, and stability. Cryst Growth Des. 2022;22(7):4437–4452.
https://doi.org/10.1021/acs.cgd.2c00394.
134. Mittapalli S, Doke S, Sawant P, et al. Novel solid form of prothioconazole and its
crystallographic analysis. J Mol Struct. 2020;1203:127406. https://doi.org/
10.1016/j.molstruc.2019.127406.
135. Shen Y, Xiong G. inventors; Anhui Jiuyi Agriculture Co., Ltd., assignee. Novel
crystal form of prothioconazole. In: WO Patent 2019/192246. 2019. October 10.
136. Celis R, Hermosín MC, Carrizosa MJ, et al. Inorganic and organic clays as carriers
for controlled release of the herbicide hexazinone. J Agric Food Chem. 2002;50(8):
2324–2330. https://doi.org/10.1021/jf011360o.
137. Li N, Sun C, Jiang J, et al. Advances in controlled-release pesticide formulations
with improved efficacy and targetability. J Agric Food Chem. 2021;69(43):
12579–12597. https://doi.org/10.1021/acs.jafc.0c05431.
138. Guyot C. Strategies to minimize the pollution of water by pesticides. Pesticides in
Ground and Surface Water. 1994:87–152. https://doi.org/10.1007/978-3-642-
79104-8_3.
139. Syafrudin M, Kristanti RA, Yuniarto A, et al. Pesticides in drinking water-a review.
Int J Environ Res Publ Health. 2021;18(2):468. https://doi.org/10.3390/
ijerph18020468.
140. Fernandez-Perez M, Garrido-Herrera FJ, Gonzalez-Pradas E. Alginate and lignin-
based formulations to control pesticides leaching in a calcareous soil. J Hazard
Mater. 2011;190:794–801. https://doi.org/10.1016/j.jhazmat.2011.03.118.
141. Zhang L, Ren S, Chen C, et al. Near infrared light-driven release of pesticide with
magnetic collectability using gel-based nanocomposite. Chem Eng J. 2021;411:
127881. https://doi.org/10.1016/j.cej.2020.127881.
142. Xiang Y, Han J, Zhang G, et al. Efficient synthesis of starch-regulated porous
calcium carbonate microspheres as a carrier for slow-release herbicide. ACS
Sustainable Chem Eng. 2018;6(3):3649–3658. https://doi.org/10.1021/
acssuschemeng.7b03973.
143. Yamamoto I, Casida JE. Nicotinoid insecticides and the nicotinic acetylcholine
receptor. https://link.springer.com/book/10.1007/978-4-431-67933-2; 1999.
144. Elbert A, Haas M, Springer B, et al. Applied aspects of neonicotinoid uses in crop
protection. Pest Manag Sci. 2008;64(11):1099–1105. https://doi.org/10.1002/
ps.1616.
145. Sparks TC, Lorsbach BA. Agrochemical discovery-building the next generation of
insect control agents. Advances in Agrochemicals: Ion Channels and G Protein-Coupled
Receptors (GPCRs) as Targets for Pest Control: Chapter 1: Ion Channels and Gap
Junctions. 2017:1–17. https://doi.org/10.1021/bk-2017-1264.ch001.
146. Aseperi AK, Busquets R, Hooda PS, et al. Behaviour of neonicotinoids in contrasting
soils. J Environ Manag. 2020;276:111329. https://doi.org/10.1016/
j.jenvman.2020.111329.
147. Goulson D. An overview of the environmental risks posed by neonicotinoid
insecticides. J Appl Ecol. 2013;50(4):977–987. https://doi.org/10.1111/1365-
2664.12111.
148. Tsvetkov N, Samson-Robert O, Sood K, et al. Chronic exposure to neonicotinoids
reduces honey bee health near corn crops. Science. 2017;356(6345):1395–1397.
https://doi.org/10.1126/science.aam7470.
149. Maekawa Y, Endo Y, Enomoto Y. inventors. Nippon Soda Co., Ltd., assignee.
Agricultural-chemical preparation having controlled releasability. In: WO Patent
2006/013972. 2006. February 9.
X. Niu et al.
150. Singh A, Kar AK, Singh D, et al. pH-responsive eco-friendly chitosan modified
cenosphere/alginate composite hydrogel beads as carrier for controlled release of
Imidacloprid towards sustainable pest control. Chem Eng J. 2022;427:131215.
https://doi.org/10.1016/j.cej.2021.131215.
151. Wen Q, Huang J, Tang H, et al. Fabricating network-link acetamiprid-loading
micelles based on dopamine-functionalized alginate and alkyl polyglucoside to
enhance folia deposition and retention. J Agric Food Chem. 2022;70(12):
3596–3607. https://doi.org/10.1021/acs.jafc.1c07324.
152. Oi M. Time-dependent sorption of imidacloprid in two different soils. J Agric Food
Chem. 1999;47(1):327–332. https://doi.org/10.1021/jf980658k.
153. Zhang P, He M, Wei Y, et al. Comparative soil distribution and dissipation of
phoxim and thiamethoxam and their efficacy in controlling Bradysia odoriphaga
Yang and Zhang in Chinese chive ecosystems. Crop Protect. 2016;90:1–8. https://
doi.org/10.1016/j.cropro.2016.07.028.
154. Mulligan RA, Parikh SJ, Tjeerdema RS. Abiotic partitioning of clothianidin under
simulated rice field conditions. Pest Manag Sci. 2015;71(10):1419–1424. https://
doi.org/10.1002/ps.3946.
155. Ying G-G, Kookana RS. Simultaneous determination of imidacloprid, thiacloprid,
and thiamethoxam in soil and water by high-performance liquid chromatography
with diode-array detection. J Environ Sci Health B. 2004;39(5-6):737–746. https://
doi.org/10.1081/LESB-200030808.
156. Yokoyama S, Ito M, Nagasawa S, et al. Runoff and degradation of aerially applied
dinotefuran in paddy fields and river. Bull Environ Contam Toxicol. 2015;94(6):
796–800. https://doi.org/10.1007/s00128-015-1554-0.
157. Zhang Z, Wang Y, Zhao Y, et al. Nitenpyram seed treatment effectively controls
against the mirid bug Apolygus lucorum in cotton seedlings. Sci Rep. 2017;7(1):1–9.
https://doi.org/10.1038/s41598-017-09251-9.
158. Fang N, Lu Z, Hou Z, et al. Hydrolysis and photolysis of flupyradifurone in aqueous
solution and natural water: degradation kinetics and pathway. Chemosphere. 2022;
298:134294. https://doi.org/10.1016/j.chemosphere.2022.134294.
159. Amanokura N, Sahara T, Suzuki H, et al. inventors; Nippon Soda Co., Ltd., assignee.
Clathrate compound, method of controlling concentration of aqueous solution of
agricultural-chemical active ingredient, and agricultural-chemical preparation. In:
WO Patent 2006/006596. 2006. January 19.
160. Ito A, Amano T, Masaki R. inventors; Nippon Soda Co., Ltd., assignee. Co-crystal
and method for producing same. In: WO Patent 2015/072355. 2015. May 21.
161. Frizzell D. inventor; Bayer Cropscience LP, assignee. Metalaxyl and prothioconazole
cocrystals and methods of making and using. In: WO Patent 2013/162725. 2013.
October 31.
60
Advanced Agrochem 1 (2022) 39–60
162. Eljarrat E. Pyrethroid Insecticides. Springer International Publishing AG. 2020.
163. James TB. inventor; Rotam Agrochem International Co., Ltd., assignee. A novel
crystalline form of epocholeone, a process for its preparation and use the same. In:
GB Patent 2555866. 2018. May 16.
164. Gubriy V, Mocatta D, Silbert G. inventors; Adama Agan Ltd., assignee. Co-crystals of
antioxidants and active ingredients and use of antioxidants as stabilizer. In: WO
Patent 2021/205448. 2021. October 14.
165. Li Y, Wu Y, Liu A, et al. inventors; Ruipu Tianjin Bio Pharmaceutical Co., Ltd.,
assignee. Crystal form of amitraz and preparation method thereof. CN patent
110724070. 2020. January 24.
166. de Villiers MM, van Eeden CM, Liebenberg W, et al. Structural characterization,
physicochemical properties, suspension stability, and adsorption properties of four
solid forms of amitraz. J Agric Food Chem. 2004;52(24):7362–7369. https://
doi.org/10.1021/jf048915a.
167. Grove MD, Spencer GF, Rohwedder WK, et al. Brassinolide, a plant growth-
promoting steroid isolated from Brassica napus pollen. Nature. 1979;281:216–217.
https://doi.org/10.1038/281216a0.
168. Sun XH, Wang HF, Liu YF, et al. Synthesis of new fungicide pyrimethanil salts. Chin
J Org Chem. 2004;24(5):506–511.
169. Sowa C, Saxell HE, Vogel R. inventors; BASF SE, assignee. Co-crystals of
pyrimethanil and dithianon. In: WO Patent 2009/047043. 2009. April 16.
170. P€
oppler AC, Corlett EK, Pearce H, et al. Single-crystal X-ray diffraction and NMR
crystallography of a 1: 1 cocrystal of dithianon and pyrimethanil. Acta Crystallogr C.
2017;73(3):149–156. https://doi.org/10.1107/S2053229617000870.
171. Liu Z, Li QX, Song B. Pesticidal activity and mode of action of monoterpenes. J Agric
Food Chem. 2022;70(15):4556–4571. https://doi.org/10.1021/acs.jafc.2c00635.
172. Mazzeo PP, Carraro C, Monica A, et al. Designing a palette of cocrystals based on
essential oil constituents for agricultural applications. ACS Sustainable Chem Eng.
2019;7(21):17929–17940. https://doi.org/10.1021/acssuschemeng.9b04576.
173. Montisci F, Mazzeo PP, Carraro C, et al. Dispensing essential oil components
through cocrystallization: sustainable and smart materials for food preservation and
agricultural applications. ACS Sustainable Chem Eng. 2022;10(26):8388–8399.
https://doi.org/10.1021/acssuschemeng.2c01257.
174. Yamamura S. inventor; Nippon Soda Co., Ltd., assignee. Co-crystal production
method. In: WO Patent 2015/093367. 2015. June 25.
175. Patel RB, Bhoge SE, Shroff JR, et al. inventors; UPL LTD, assignee. Co-crystals of
boscalid and triazoles. In: WO Patent 2019/123186. 2019. June 27.
176. Desai SD, Jadhav PM, inventors; UPL LTD, assignee. An agrochemical composition.
WO patent 2021/186406. September 23, 2021.