FIELD OF THE INVENTION

This invention relates to co-crystals of herbicide compounds. In particular, this invention relates to co-crystals comprising 2,4-dichlorophenoxyacetic acid and a triazine herbicide, and to agrochemical compositions comprising such co-crystals.

BACKGROUND OF THE INVENTION

2.4-dichlorophenoxyacetic acid (2,4-D) is a widely used systemic herbicide which is a member of the phenoxy family of herbicides. 2,4-D acts as a synthetic auxin which is a plant hormone which is absorbed by the leaves of plants. 2,4-D is used to control broadleaf weeds, in particular for agricultural applications.

An increasing number of weed populations have been identified which show resistance to 2,4-D, and the spread of these resistant populations could have a significant impact on the effectiveness of this herbicide. For example, it has been found that intensive use of

2.4-D in southern Europe has led to the evolution of 2,4-D resistant corn poppy biotypes (Pesticide Biochemistry and Physiology, 133, Oct 2016, p 67-72).

One strategy to overcome such issues is the use of 2,4-D in combination with one or more additional herbicide compounds with alternative modes of action. For example, a herbicide product (Enlist Duo (RTM)) containing the combination of 2,4-D and glyphosate has recently been registered for use on genetically engineered crops, and

W02012/009395A1 (Dow Agrosciences LLC) describes a mixture for use as a herbicide containing the combination of the herbicides 2,4-D, aminopyralid, and atrazine.

Kamath et al (Journal of Dispersion Science and Technology, 29:1304-1310, 2008) describes the structural characterisation of composite particles of atrazine and 2,4- dichlorophenoxy acetic acid. The composite particles are not co-crystals of atrazine and

2.4-dichlorophenoxy acetic acid but rather are an admixture of some sort. It is evident from the powder XRD patterns and DSC thermograms of the composite particles that co crystals are not produced.

The development of a single formulation containing each of the herbicide compounds to be applied in combination is attractive. For example, the development of such formulations can reduce the need for multiple applications of herbicide, can help to ensure consistent relative dosing amounts of each herbicide compound, and can reduce delivery costs. However, the development of such formulations incorporating 2,4-D is challenging due to the physicochemical properties of 2,4-D. In particular, the high volatility of 2,4-D can lead to a number of issues. For example, the evaporation of 2,4-D from a formulation after application can lead to environmental issues, such as a strong odour and movement off the application site (herbicide drift). High volatility can also lead to a reduction in efficacy of the applied formulation, and a change from the desired ratio of actives in multi-component formulations.

In addition, if synergistic effects are desired, the relatively high aqueous solubility of 2,4- D can lead to potential problems in the development of combination formulations with less water soluble active agents, due to the relatively rapid release of 2,4-D after application.

There remains a need to develop new stable herbicide formulations containing 2,4-D which overcome one or more of the issues identified above.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found that triazine herbicides may be used to form co-crystals with 2,4-dichlorophenoxyacetic acid (2,4-D). Such co-crystals have been found to have high stability, a high melting point, and provide 2,4-D in a form which has reduced volatility.

Therefore, in a first aspect of the invention there are provided co-crystals of 2,4- dichlorophenoxyacetic acid (2,4-D) and a compound selected from the group of triazine herbicides.

Triazine herbicides of particular utility may be represented by formula (I):

wherein X = Cl, -OCH ₃ , or -SCH ₃ ; R1 = ethyl or isopropyl; R ₂ = ethyl, iso-propyl, cyclopropyl, tert-buty, or -C(CH3)2CN. Preferably, the triazine herbicide is selected from atrazine, simazine, cyanazine, propazine, terbutryn, prometryn or ametryn. More preferably, the triazine herbicide is cyanazine, simazine or atrazine. Typically, the molar ratio of 2,4-D: triazine herbicide is from 2:1 to 1 :1.

The co-crystals may be formed by solution or slurry crystallisation processes. Therefore, in a second aspect of the invention there is provided a method for the preparation of co crystals as described herein which comprises combining 2,4-D and a triazine herbicide in a suitable solvent.

The co-crystals may also be formed in a solvent-free method. Therefore, in a third aspect of the invention there is provided a solvent-free method for the preparation of co crystals as described herein which comprises the step of applying dual asymmetric centrifugal forces to a mixture of 2,4-D and a triazine herbicide, and optionally in the presence of milling or grinding media.

In a fourth aspect of the invention there is provided a herbicidal composition comprising co-crystals as described herein and at least one agriculturally acceptable carrier.

Typically, such compositions may be an aqueous suspension or in the form of granules.

In a fifth aspect of the invention, there is provided the use such herbicidal compositions for controlling undesired vegetation, for example during crop cultivation.

In a sixth aspect of the invention there is provided a method for controlling undesired vegetation comprising contacting the vegetation with a composition comprising co crystals as described herein and at least one agriculturally acceptable carrier.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the x-ray powder diffraction pattern of the co-crystals of Example 1.

Figure 2 shows the differential scanning calorimetry (DSC) curve of the co-crystals of Example 1.

Figure 3 shows the x-ray powder diffraction pattern of the co-crystals of Example 2.

Figure 4 shows the differential scanning calorimetry (DSC) curve of the co-crystals of Example 2.

Figure 5 shows the x-ray powder diffraction pattern of the co-crystals of Example 3.

Figure 6 shows the differential scanning calorimetry (DSC) curve of the co-crystals of Example 3. Figure 7 shows the x-ray powder diffraction pattern of the co-crystals of Example 4.

Figure 8 shows the differential scanning calorimetry (DSC) curve of the co-crystals of Example 4.

Figure 9 shows a view of an atrazine: 2,4-D co-crystal from the crystal structure of Example 2.

Figures 10A-C illustrate how centrifugal forces are applied to materials in a SpeedMixer™.

Figure 10A is a view from above showing the base plate and basket. The base plate rotates in a clockwise direction.

Figure 10B is a side view of the base plate and basket. Figure 10C is a view from above along line A in Figure 10B. The basket rotates in an anti clockwise direction.

DETAILED DESCRIPTION OF THE INVENTION

Preferred and/or optional features of the invention will now be set out. Any aspect of the invention may be combined with any other aspect of the invention unless the context demands otherwise. Any of the preferred and/or optional features of any aspect may be combined, either singly or in combination, with any aspect of the invention unless the context demands otherwise.

The present invention relates to co-crystals comprising 2,4-dichlorophenoxyacetic acid (2,4-D) and a compound selected from the group of triazine herbicides. Co-crystals are multi-component crystalline materials in which at least two organic compounds form the crystalline material which has a defined single phase crystal structure. The at least two organic compounds interact by non-covalent bonding, such as hydrogen bonding, van der Waals interactions, P-P interactions, etc., and are not simple salts. The co-crystals may be distinguished from mixtures of 2,4-D and the selected triazine herbicide by standard analytical means which are well known to those skilled in the art, for example x-ray powder diffraction (XRPD), single crystal x-ray diffraction, or differential scanning calorimetry (DSC). The molar ratio of the components of the co-crystals may be determined using, for example, HPLC or ¹ H NMR. The co-crystals comprise 2,4-dichlorophenoxyacetic acid (2,4-D) and a triazine herbicide. T riazine herbicides are well known to those skilled in the art and comprise a 1 ,3,5- triazine core with amine substituents at the 2- and 4- positions.

Triazine herbicides of particular utility may be represented by formula (I):

wherein X = Cl, -OCH ₃ , or -SCH ₃ ; R1 = ethyl or isopropyl; R ₂ = ethyl, iso-propyl, cyclopropyl, tert-butyl, or -C(CH3)2CN.

Preferably, X = Cl or -SCH ₃ , more preferably X = Cl. Further preferred compounds have X = -OCH ₃ , R1 = isopropyl, and R ₂ = isopropyl; or X = -SCH ₃ , R1 = ethyl or iso-propyl, and R2 = iso-propyl or tert-butyl.

Preferably, the triazine herbicide is selected from atrazine (6-chloro-4-N-ethyl-2-N- (propan-2-yl)-1 , 3, 5-triazine-2, 4-diamine), simazine (6-chloro-2-N,4-N-diethyl-1 ,3,5- triazine-2, 4-diamine), cyanazine (2-[[4-chloro-6-(ethylamino)-1 ,3,5-triazin-2-yl]amino]-2- methylpropanenitrile), propazine (6-chloro-2-N,4-N-di(propan-2-yl)-1 ,3,5-triazine-2,4- diamine), terbutryn (2-N-tert-butyl-4-N-ethyl-6-methylsulfanyl-1 , 3, 5-triazine-2, 4-diamine), prometryn (6-methylsulfanyl-2-N,4-N-di(propan-2-yl)-1 , 3, 5-triazine-2, 4-diamine) or ametryn (4-N-ethyl-6-methylsulfanyl-2-N-propan-2-yl-1 , 3, 5-triazine-2, 4-diamine). More preferably, the triazine herbicide is simazine, cyanazine, or atrazine. In one embodiment, the present invention relates to co-crystals comprising, or consisting of, 2-4-D and atrazine (6-chloro-4-N-ethyl-2-N-(propan-2-yl)-1 , 3, 5-triazine-2, 4-diamine). Such co-crystals show significantly reduced volatility of 2,4-D. The molar ratio of 2,4-D and atrazine is generally in the range from 1 :1 to 2:1 , such as 1 :1 or 2:1. However, variations are possible which typically do not exceed 20 mol% and preferably do not exceed 10 mol%.

In the case that the molar ratio of 2,4-D and atrazine is 2:1 , the current inventors have identified a crystalline form which exhibits an x-ray powder diffraction pattern (Cu Ka radiation) substantially as shown in Figure 1. The XRPD 2-theta (2Q) values are shown in Table 1. Preferably, the co-crystal shows at least 5, preferably at least 8 or at least 12, more preferably at least 15, even more preferably at least 20, or all of the reflexes shown in Table 1 as 2-Theta (2Q) values (+/- 0.2 degrees 2Q). The crystalline form may also be identified by its differential scanning calorimetry (DSC) curve as shown in Figure 2, in particular by the melting point temperature of about 129.8 °C as determined by DSC.

In the case that the molar ratio of 2,4-D and atrazine is 1 :1 , the current inventors have identified a crystalline form which exhibits an x-ray powder diffraction pattern (Cu Ka radiation) substantially as shown in Figure 3. The XRPD 2-theta (2Q) values are shown in Table 2. Preferably, the co-crystal shows at least 5, preferably at least 8 or at least 12, more preferably at least 15, even more preferably at least 20, or all of the reflexes shown in Table 2 as 2-Theta (2Q) values (+/- 0.2 degrees 2Q). The crystalline form may also be identified by its differential scanning calorimetry (DSC) curve as shown in Figure 4, in particular by the melting point temperature of about 138.2 °C as determined by DSC. The crystalline form may also be identified by the unit cell dimensions, as determined by crystal x-ray crystallography, of a = 4.251 (18) A; b = 9.889 (3) A; c = 23.442 (7) A; a= 98.748 (3)°; b= 93.047 (3)°; g = 90.288 (3)°.

In a further embodiment, the present invention relates to co-crystals comprising, or consisting of, 2-4-D and cyanazine ((2-[[4-chloro-6-(ethylamino)-1 ,3,5-triazin-2-yl]amino]- 2-methylpropanenitrile). The molar ratio of 2,4-D and cyanazine is generally in the range from 1 :1 to 2:1 , such as 1 :1. However, variations are possible which typically do not exceed 20 mol% and preferably do not exceed 10 mol%.

In the case that the molar ratio of 2,4-D and cyanazine is 1 :1 , the current inventors have identified a crystalline form which exhibits an x-ray powder diffraction pattern (Cu Ka radiation) substantially as shown in Figure 5. The XRPD 2-theta (2Q) values are shown in Table 5. Preferably, the co-crystal shows at least 5, preferably at least 8 or at least 12, more preferably at least 15, even more preferably at least 20, or all of the reflexes shown in Table 5 as 2-Theta (2Q) values (+/- 0.2 degrees 2Q). The crystalline form may also be identified by its differential scanning calorimetry (DSC) curve as shown in Figure 6, in particular by the melting point temperature of about 139.0 °C as determined by DSC.

In another embodiment, the present invention relates to co-crystals comprising, or consisting essentially of, 2-4-D and simazine ((6-chloro-2-N,4-N-diethyl-1 ,3,5-triazine- 2, 4-diamine). The molar ratio of 2,4-D and simazine is generally in the range from 1 :1 to 2:1 , such as 2:1. However, variations are possible which typically do not exceed 20 mol% and preferably do not exceed 10 mol%. In the case that the molar ratio of 2,4-D and simazine is 2:1 , the current inventors have identified a crystalline form which exhibits an x-ray powder diffraction pattern (Cu Ka radiation) substantially as shown in Figure 7. The XRPD 2-theta (2Q) values are shown in Table 6. Preferably, the co-crystal shows at least 5, preferably at least 8 or at least 12, more preferably at least 15, even more preferably at least 20, or all of the reflexes shown in Table 6 as 2-Theta (2Q) values (+/- 0.2 degrees 2Q). The crystalline form may also be identified by its differential scanning calorimetry (DSC) curve as shown in Figure 8, in particular by the melting point temperature of about 146.3 °C as determined by DSC.

The co-crystals may be formulated into a herbicidal composition with at least one agriculturally acceptable carrier. The compositions may be solids, for example powders, granules, or water-dispersable powders, or may be liquids, such as suspensions of co crystal particles.

Suitable agriculturally acceptable carriers are well known to those skilled in the art. Such carriers should not be phytotoxic to crops, in particular at the concentrations employed for the control of undesirable plants in the presence of crops, and should not react chemically with the compounds of the co-crystals or other composition components. The compositions may be applied directly, or may be formulations or concentrates which are diluted, for example with water, prior to application.

Liquid carriers that may be employed include water and organic solvents, although it is typically preferred that water is used. Solid carriers include mineral earths, such as clays, silicates, diatomaceous earths, or kaolin, fertilisers, and organic products such as woodmeal and cellulose carriers.

It will be understood by the skilled person that the compositions may also include further components, such as surfactants, viscosity modifiers, anti-freeze agents, agents for pH control, stabilisers and anti-caking agents.

The concentration of active ingredients in the composition is generally between 1 and 99 wt%, such as between 5 and 95 wt% or 10 and 90 wt%. In compositions which are designed to be diluted prior to use the concentration of active ingredients is typically between about 10 and 90 wt%. Such compositions are then diluted, typically with water, to compositions which typically contain 0.001 and 1 wt% of active material.

The compositions as described herein may be used for controlling undesirable vegetation. Undesirable vegetation is understood to mean plants considered undesirable in a particular location, e.g. in an area of crops, and may be known as weeds. Control may be achieved by a method comprising contacting the vegetation with the herbicidal composition. It will be understood by the skilled person that the composition at the point of application should contain a herbicidally effective amount of the co-crystals.

A herbicidally effective amount is an amount of the active ingredients which causes an adverse deviation of the natural development of the undesired vegetation.

In particular, the compositions have utility for controlling undesirable vegetation in a culture of crop plants, especially crop plants which are tolerant to 2,4-D and / or triazine herbicides, for example through genetic modification of the crop plants. The

compositions may also have particular utility for the control of undesirable vegetation which is resistant to either 2,4-D or the selected triazine herbicide.

The present invention also comprises a method for the preparation of co-crystals according to the present invention, the method comprising combining 2,4-D and the selected triazine herbicide in a suitable solvent.

In one embodiment of the process, 2,4-D and the triazine herbicide are dissolved in at least one solvent to form a solution, optionally with heating, and then co-crystallisation is induced, for example, by cooling the solution, evaporation of the solvent, or by precipitation. Precipitation may be induced, for example, by the addition of an anti solvent.

For example, in the case that the co-crystals comprise 2,4-D and atrazine, co

crystallisation may be achieved by the formation of a solution of 2,4-D and atrazine in a suitable solvent, such as chloroform or methyl ethyl ketone, at an elevated temperature, such as between 40 and 60 °C, and then cooling the solution to induce precipitation of the co-crystals. In the case that the co-crystals comprise 2,4-D and cyanazine, co crystallisation may be achieved by the formation a solution of 2,4-D and cyanazine in a suitable solvent, such as acetonitrile, at an elevated temperature, such as between 40 and 60 °C, and then cooling the solution to induce precipitation of the co-crystals.

In a further embodiment of the process, 2,4-D and the triazine herbicide are combined with a suitable solvent but the compounds are not dissolved so that solid material remains. Suitable solvents include but are not limited to tetrahydrofuran and water (e.g. deionised water). The mixture is then subjected to milling or grinding. The amount of time required for co-crystal formation can be readily determined by one skilled in the art and depends on factors including the temperature and the level of energy input. For example, in the case that the co-crystals comprise 2,4-D and simazine, co crystallisation may be achieved by the combination of 2,4-D and simazine with a suitable solvent, such as tetrahydrofuran, in an amount such that the compounds are not dissolved. The mixture is then ground until co-crystals are obtained.

In the case that the co-crystals comprise 2,4-D and a triazine herbicide selected from the group consisting of atrazine, simazine and cyanazine, co-crystallisation may be achieved by the combination of 2,4-D and the triazine herbicide with water in an amount such that the compounds are not dissolved. The mixture is then ground (e.g. using low energy ball milling or low energy grinding) until the co-crystals are obtained.

Alternatively, co-crystals may be formed in a method comprising the step of applying dual asymmetric centrifugal forces to a mixture of 2,4-D and a triazine herbicide as described herein, and optionally in the presence of milling or grinding media to form the co-crystals. The method is carried out in a substantially dry environment i.e. in the absence of a solvent.

The co-crystals are formed using dual asymmetric centrifugal forces. By“dual asymmetric centrifugal forces” we mean that two centrifugal forces, at an angle to each other, are simultaneously applied to the particles. In order to create an efficient mixing environment, the centrifugal forces preferably rotate in opposite directions. The

Speedmixer™ by Hauschild (http://www.speedmixer.co.uk/index.php) utilises this dual rotation method whereby the motor of the Speedmixer™ rotates the base plate of the mixing unit in a clockwise direction (see Figure 10A) and the basket is spun in an anti clockwise direction (see Figures 10B and 10C).

The method may be controlled by various parameters including the rotation speed at which the method takes place, the length of processing time, the level to which the mixing container is filled, the use of milling media and/or the control of the temperature of the components within the milling pot.

The dual asymmetric centrifugal forces may be applied for a continuous period of time.

By“continuous” we mean a period of time without interruption. The period of time may be from about 1 second to about 30 minutes, such as about 5 seconds to about 27 minutes, for example, about 10 seconds to about 25 minutes. In one embodiment, the period of time may be about 20 minutes.

Alternatively, the dual asymmetric centrifugal forces may be applied for an aggregate period of time. By“aggregate” we mean the sum or total of more than one periods of time (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times). The advantage of applying the centrifugal forces in a stepwise manner is that excessive heating of the particles can be avoided. The dual asymmetric centrifugal forces may be applied for an aggregate period of about 1 second to about 30 minutes, for example about 5 seconds to about 27 minutes, such as about 10 seconds to about 25 minutes. In one embodiment, the period of time may be 10 periods of time of two minutes each i.e. an aggregate period of time of about 20 minutes. In one embodiment, the dual asymmetric centrifugal forces are applied in a stepwise manner with periods of cooling therebetween. In another embodiment, the dual asymmetric centrifugal forces may be applied in a stepwise manner at one or more different speeds.

The speed of the dual asymmetric centrifugal forces may be from about 200 rpm to about 4000 rpm. In one embodiment, the speed may be from about 300 rpm to about 3000 rpm, for example about 500 rpm to about 2500 rpm. In one embodiment, the speed may be about 1900 rpm.

The level to which the mixing container is filled is determined by various factors which will be apparent to the skilled person. These factors include the apparent density of the 2,4-D and triazine herbicide, the volume of the mixing container and the weight restrictions imposed on the mixer itself.

Milling or grinding media may be used to assist the reaction. In this instance, the incorporation of hard, non-contaminating media can additionally assist in the breakdown of particles where agglomeration has occurred, for example, as a result of the

manufacturing process or during transit. Such breakdown of the agglomerates further enhances the reaction of 2,4-D and triazine herbicide. The use of milling/grinding media is well-known within the field of powder processing and materials such as stabilised zirconia and other ceramics are suitable provided they are sufficiently hard or ball bearings, such as stainless steel beads.

The present invention will now be described with reference to the following examples, which are provided to assist with understanding the present invention, and are not intended to limit its scope.

Examples

Example 1 - 2,4-D: Atrazine (2:1) co-crystal

Atrazine (98 mg) (Tokyo Chemical Industry) and 2,4-D (182 mg, 0.5 mol eq.) (Tokyo Chemical Industry) were dissolved in chloroform (7 ml) at 50°C with stirring. The clear solution was cooled to 5°C at 0.2°C min ¹ to give a slurry. This slurry was filtered, then dried under suction to yield a crystalline product (69% yield).

The co-crystals were also analysed by ¹ H NMR which confirmed a molar ratio of 2,4-D: atrazine of 2:1. The co-crystals were also analysed by XRPD which showed a crystalline material and yielded a diffractogram as provided in Figure 1.

The co-crystal of 2,4-D and atrazine shows at least 5, preferably at least 8 or at least 12, more preferably at least 15, even more preferably at least 20, or all of the reflexes shown in Table 1 as 2-Theta (2Q) values.

Table 1 - 2,4-D: Atrazine (2:1) co-crystal XRPD data

DSC analysis (Figure 2) indicated a melting point of 129.8 °C.

Example 2 - 2,4-D: Atrazine (1 :1) co-crystal Atrazine (200 mg) (Tokyo Chemical Industry) and of 2,4-D (190 mg, 1 mol eq.) were dissolved in methyl ethyl ketone (3 ml) at 50°C with stirring. The clear solution was cooled to 5 °C at 0.2°C min ¹ to give a slurry. This slurry was filtered, then dried under suction to yield a crystalline product. The co-crystals were also analysed by ¹ H NMR which confirmed a molar ratio of 2,4-D: atrazine of 1 :1.

The co-crystals were also analysed by XRPD which showed a crystalline material and yielded a diffractogram as provided in Figure 3. The co-crystal of 2,4-D and atrazine shows at least 5, preferably at least 8 or at least 12, more preferably at least 15, even more preferably at least 20, or all of the reflexes shown in Table 2 as 2-Theta (2Q) values.

Table 2 - 2,4-D: Atrazine (1 :1) co-crystal XRPD data

DSC analysis (Figure 4) indicated a melting point of 138.2 °C.

The sample was further analysed by single crystal x-ray crystallography to determine the crystal structure as follows:

Table 3. Data collection and structure refinement. Diffractometer SuperNova, Dual, Cu at zero, Atlas

Radiation source SuperNova (Cu) X-ray Source, CuKa Data collection method omega scans

Theta range for data collection 3.821 to 74.942° Index ranges -4 < h £ 5, -12 < k £ 12, -28 < / < 29 Reflections collected 18533

Independent reflections 3940 [R(int) = 0.0529]

Coverage of independent reflections 100.0 %

Variation in check reflections n/a

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 1.00000 and 0.63795

Structure solution technique Direct Methods

Structure solution program SHELXTL (Sheldrick, 2013)

Refinement technique Full-matrix least-squares on F^

Refinement program SHELXL-2014/6 (Sheldrick, 2014)

Function minimized

Data / restraints / parameters 3940 / 0 / 259

Goodness-of-fit on F^ 1.064

D/< _3c 0.001

Final R indices

3391 data; l>2o(l) R1 = 0.0374, U)R2 = 0.1006

all data R1 = 0.0455, U)R2 = 0.1077

Weighting scheme w =1 / [a ² (F _O ² )+( 0.0641 P) ² +0.2677P] where

P=(F _O ² +2F _c ² )/3

Extinction coefficient n/a

Largest diff. peak and hole 0.551 and -0.377 eA ³

Refinement summary:

Ordered Non-H atoms, XYZ Freely refining

Ordered Non-H atoms, U Anisotropic

H atoms (on carbon), XYZ Idealised positions riding on attached atoms

H atoms (on carbon), U Appropriate multiple of U(eq) for bonded atom

H atoms (on heteroatoms), XYZ Freely refined on all hetero atoms

H atoms (on heteroatoms), U isotropic

Disordered atoms, OCC No disorder

Disordered atoms, XYZ No disorder

Disordered atoms, U No disorder Table 4: Sample and crystal data for Example 2:

Compound number Atrazine/2,4-D Form A

Crystallisation solvents Acetone

Crystallisation method Slow cooling

Empirical formula C16H20CI3N5O3

Formula weight 436.72

Temperature 100(2) K

Wavelength 1.54184 A

Crystal size 0.700 x 0.050 x 0.040 mm

Crystal habit colourless rod

Crystal system Triclinic

Space group P-1

Unit cell dimensions a = 4.25112(18) A 0= 98.748(3)°

b = 9.8887(3) A b= 93.047(3)° c = 23.4421(7) A g = 90.288(3)°

Volume 972.53(6) A ³

Z 2

Density (calculated) 1.491 Mg/m ³

Absorption coefficient 4.514 mm 1

F(000) 452

The asymmetric unit contains a single, fully ordered molecule of Atrazine and 2,4- dichlorophenoxyacetic acid co-crystal, (designated Form A).

Final R1 [I>2s(I)] = 3.74 %.

Figure 9 shows a view of a molecule of Atrazine/2,4-D cocrystal, Form A from the crystal structure. Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius. Example 3 - 2,4-D: Cyanazine (1 :1 ) co-crystal

217 mg of cyanazine (Bond Chemicals Ltd) and 200 mg of 2,4-D (1 mol eq.) (Tokyo Chemical Industry) were dissolved in 10 ml acetonitrile at 50 °C with stirring. The clear solution was cooled to 5 °C at 0.2 °C min ¹ to give a slurry. This slurry was filtered, then dried in a vacuum oven for a few days (Yield 52%).

The co-crystals were analysed by ¹ H NMR which confirmed a molar ratio of 2,4-D: cyanazine of 1 :1.

The co-crystals were also analysed by XRPD which showed a crystalline material and yielded a diffractogram as provided in Figure 5. This co-crystal of 2,4-D and cyanazine shows at least 5, preferably at least 8 or at least 12, more preferably at least 15, even more preferably at least 20, or all of the reflexes shown in Table 5 as 2-Theta (2Q) values.

Table 5 - 2,4-D: Cyanazine (1 :1 ) co-crystal XRPD data

DSC analysis (Figure 6) indicated a melting point of 139.0 °C.

Example 4 - 2,4-D: Simazine (2:1 ) co-crystal

A mixture of 91 mg of simazine (Atlantic Research Chemicals Ltd) and 200 mg of 2,4-D (2 mol eq) (Tokyo chemical industry) was placed in a stainless steel jar lined with zirconium with a zirconium grinding bead. The mixture was initially wetted with 200 pi of tetrahydrofuran and shaken for 30 mins at 30 Hz using a Retsch Mixer Miller MM300. Samples obtained after this grinding procedure were air dried for 5 min, and analysed by XRPD. (Yield 68%) The co-crystals were analysed by ¹ H NMR which confirmed a molar ratio of 2,4-D: simazine of 2:1.

The co-crystals were also analysed by XRPD which showed a crystalline material and yielded a diffractogram as provided in Figure 7. This co-crystal of 2,4-D and simazine shows at least 5, preferably at least 8 or at least 12, more preferably at least 15, even more preferably at least 20, or all of the reflexes shown in Table 6 as 2-Theta (2Q) values.

Table 6 - 2,4-D: Simazine (2:1) co-crystal XRPD data

DSC analysis (Figure 8) indicated a melting point of 146.3 °C.

Example 5 - Water assisted grinding

Atrazine:2,4-D

Atrazine (Tokyo chemical industry) (20 mg), 2,4-D (20.5 mg; 1 mol eq) (Tokyo chemical industry) was placed in a 2 ml HPLC vial with two grinding beads. The mixture was initially wetted with 20 pi of deionised water, and ground for 2 h at 500 rpm using a

Fritsch milling system with an Automaxion adapter. Samples obtained after this grinding procedure were air dried for 5 min, and analysed by XRPD. Example 6 - Water assisted grinding

Simazine:2,4-D

Simazine (Atlantic research chemicals Ltd) (20 mg), 2,4-D (21.9 mg; 1 mol eq) (Tokyo chemical industry) was placed in a 2 ml HPLC vial with two grinding beads. The mixture was initially wetted with 20 pi of deionised water, and ground for 2 h at 500 rpm using a Fritsch milling system with an Automaxion adapter. Samples obtained after this grinding procedure were air dried for 5 min, and analysed by XRPD.

Example 7 - Water assisted grinding

Cvanazine:2,4-D

Cyanazine (Bond chemical Ltd) (20 mg), 2,4-D (Tokyo chemical industry) (18.9 mg; 1 mol eq) was placed in a 2 ml HPLC vial with two grinding beads. The mixture was initially wetted with 20 mI of deionised water, and ground for 2 h at 500 rpm using a Fritsch milling system with an Automaxion adapter. Samples obtained after this grinding procedure were air dried for 5 min, and analysed by XRPD.

Example 8 - solvent-free process

A mixture of atrazine (245 mg) (Tokyo chemical industry) and 2,4-D (500 mg, 2 mol eq.) (Tokyo chemical industry) was placed in a 40 ml plastic beaker with 3 mm stainless steel beads. The dry mixture was milled at 1900 rpm for 20 min in a DAC 150-FVZK

Speedmixer™ Samples obtained after this milling procedure were air-dried overnight before analysis. XRPD data and DSC analysis indicated a co-crystal consistent with Example 1 and Figures 1 and 2.

Co-crystal testing

X-Ray Powder Diffraction (XRPD)

XRPD diffractograms were collected on a Bruker D8 diffractometer.

Brucker D8 uses Cu Ka radiation (40 kV, 40 mA) and a Q-2Q goniometer fitted with a Ge monochromator. The incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge. The diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively. Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane. Data collection method is:

• Angular range: 2 to 42° 2Q

• Step size: 0.05° 2Q

• Collection time: 0.5 s/step (total collection time: 6.40 min)

Stability in water The stability in water over a period of three weeks was assessed by storing 50 mg of the compound with agitation in 1 ml water for 3 weeks at 25 °C then tested by XRPD.

Thermodynamic solubility in water

Aqueous solubility was determined by suspending sufficient amount of compound in deionised water to give a maximum final concentration of ³10 mg/ml of the compound. The suspension was equilibrated at 25 °C, on a Heidolph plate shaker set to 750 rpm for 24 hours. The pH of the saturated solution was then measured and the suspension filtered through a glass fibre C filter (particle retention 1.2 pm) and diluted appropriately. Quantitation was by HPLC with reference to a standard solution of approximately 0.15 mg/ml in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.

Analysis was performed on an Agilent HP1100 series system equipped with a diode array detector and using ChemStation software. Table 7 - HPLC method for solubility measurements

Volatility

Volatility data were collected on a TA Instruments Discovery TGA, equipped with a 25 position auto-sampler. Typically, >5 mg, to cover the surface of the pan of each sample was loaded onto a pre-tared aluminium pan (6.5 mm diameter) and heated at 10 °C/min from ambient temperature to 70 °C then held for 12 hours. A nitrogen purge at 25 ml/min was maintained over the sample. Volatility is calculated by measuring the weight loss between two time points once a steady state has been achieved, typically separated by 300-400 minutes, then dividing the weight loss by the time difference to get mg/min. Differential Scanning calorimetry (DSC)

DSC (melting point) was assessed using either a TA Instruments Q2000 or TA

Instruments Discovery DSC. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 300 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample. Thermogravimetric analysis (TGA)

TGA was assessed using either a TA Instruments Q500 TGA or TA Instruments

Discovery TGA. Typically, 5 - 10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 ml/min was maintained over the sample. Gravimetric Vapour Sorption Hygroscopicity was assessed by Gravimetric vapour sorption. Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software. The sample temperature was maintained at 25 °C by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min The relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0 - 100 %RH), located near the sample. The weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by a microbalance (accuracy ±0.005 mg).

Typically, 5 - 30 mg of sample was placed in a fared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40 %RH and 25 °C (typical room conditions). A moisture sorption isotherm was performed as outlined below (2 scans per complete cycle). The standard isotherm was performed at 25 °C at 10 %RH intervals over a 0 - 90 %RH range. Typically, a double cycle (4 scans) was carried out. Data analysis was carried out within Microsoft Excel using the DVS Analysis Suite. Table 8 - Method for SMS DVS Intrinsic experiments

The sample was recovered after completion of the isotherm and re-analysed by XRPD. Example 1 and Example 2

The physicochemical properties of the 2,4-D: atrazine co-crystals formed in Example 1 and 2 were tested alongside the individual compounds 2,4-D and atrazine. The results are provided in Table 9. Table 9 - Results of the testing of physicochemical properties of co-crystals formed in Example 1 and Example 2.

Example 3

The physicochemical properties of the 2,4-D:cyanazine co-crystals formed in Example 3 were tested alongside the individual compounds 2,4-D and cyanazine. The results are provided in Table 10. Table 10 - Results of the testing of physicochemical properties of co-crystals formed in Example 3.

Example 4

The physicochemical properties of the 2,4-D: simazine co-crystals formed in Example 4 were tested alongside the individual compounds 2,4-D and simazine. The results are provided in Table 11.

Table 11 - Results of the testing of physicochemical properties of co-crystals formed in Example 4.

The results of the testing of the physicochemical properties testing of the co-crystals generated in Examples 1-4 indicates that the 2,4-D / triazine co-crystals show good stability and a high melting point. In each case the volatility of the co-crystals is significantly lower than the volatility of 2,4-D alone. In addition, the solubility of the active agents is closely matched.