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PURPOSESalt and Cocrystal Screening of Pyrimethanil to Identify a Material with Improved Properties• One of the biggest challenges in the agrochemical

industry is evolution of resistance to existing AI’s.• No new AI developed with new modes of action in

last 15 years.• Current actives have issues:➢ low melting point➢ high solubility➢ high volatility

• Cocrystals or salts of a combination of products offer one technology solution to these problems.

• pKa of pyrimethanil is 4.06 meaning that both salts and cocrystals are readily accessible.

Aim was to develop a library of salts/cocrystals of pyrimethanil and to identify the most promising system.

See poster M1530-06-044 for details on the crystallization

development work (joe.harris@matthey.com).

CONCLUSIONSSuccessful Solid Form ScreeningGreater than 50 new crystalline forms were identifiedand their single crystal structures determined.Scale Up and Characterisation AchievedOver 20 samples scaled (1-2 g) and characterised.Intrinsic Dissolution Rate ImprovedOxalic acid cocrystal has a 30 fold increase in IDR.

Pyrimethanil• Melting point 96 °C.• Dissolution Rate 18.5 µg/min/cm2.• Solubility 0.08 mg/ml.Pyrimethanil Salts/Cocrystals• Melting points range from 49 °C - 188 °C.• 2 to 100 fold decrease in volatility compared to

Pyrimethanil.• 30 fold increase to 7 fold decrease in dissolution rate

compared to Pyrimethanil.

RESULTS

METHODSSolid Form ScreeningMilling, Slow Cooling, Evaporation, Antisolvent Addition, Heat/Cool Cycles (Maturation), Isothermal Slurries.Crystal Structure DeterminationOver 50 structures have been solved including salts, cocrystals, intermediates (where the proton is exactly between the two moieties), structures with both ionised and non-ionised molecules. Scale Up of Selected FormsOver 20 forms were selected for scale up (1-2 g) and solid-state characterisation by:• XRPD, NMR, TGA, DSC, GVS, Volatility (by TGA),

solubility, Stability – water and 40 °C/70% RH.Dissolution Rate DeterminationThe IDR was measured using a Sirius inForm using in-situ UV probes for a selection of the forms identified.

CONTACT INFORMATION: samuel.stratford@matthey.com

M1030 -07-054

Salt/Cocrystal Continuum

Structural Highlights

Scale Up & CharacterisationDissolution Rate Determination

N

N

NH N

N

NH

A. R. Eberlin et. al. Acta Crystallogr E Crystallogr Commun. 2017 Jun, 1; 73(Pt 6): 886–889.

Increasing pKa

N

N

H+

NH

R1

O O

DpKa ≥ 1

N

N NH

R1

OH

O

DpKa < 1

N

N NH

R1

O O

H

DpKa ~ 0

Coformer Ratio Product pKa Space Group↑ All cocrystals above pKa 4.1 ↑

Pyrimethanil, Form 1 N/A Freebase 4.06 P-1Pyrimethanil, Form 2 N/A Freebase 4.06 P21/n4-Iodobenzoic acid 1:1 Cocrystal 4.02 P21/c4-Chlorobenzoic acid 1:1 Cocrystal 3.97 PccnDiphenylacetic acid 1:1 Cocrystal 3.94 P-13-Chlorobenzoic acid 1:1 Cocrystal 3.83 PbcaFormic acid 1:1 Cocrystal 3.77 P21/c1-Naphthoic acid 1:1 Cocrystal 3.69 P21/nThiazole-4-carboxylic acid 1:1 Salt 3.57 Cc3-Nitrobenzoic acid, Form 1 1:1 Cocrystal 3.45 P21/n3-Nitrobenzoic acid, Form 2 1:1 Salt 3.45 P-14-Nitrobenzoic acid 1:1 Intermediate 3.44 Pbcn4-(Methylsulfonyl)benzoic acid 1:1 Intermediate 3.42 PbcaR/S-Mandelic acid 1:1 Salt 3.41 P-1R-Mandelic acid 1:1 Salt & Cocrystal 3.41 P12,4 dihydroxybenzoic acid 1:1 Salt 3.32 P2121212,5 dihydroxybenzoic acid 1:1 Salt 3.012,5 dihydroxybenzoic acid:DMSO

1:1:1 Salt/Solvate 3.01 P21/n

DL-Tartaric acid:IPA 2:1:0.5 Salt & Cocrystal2.96/4.24 P21/n2-Chlorobenzoic acid 1:1 Cocrystal 2.97 P21/nPyrazinecarboxylic acid, Form 1 1:1 Cocrystal 2.91 P21/cPyrazinecarboxylic acid, Form 2 1:1 Cocrystal 2.91 P-12-Bromobenzoic acid 1:1 Salt 2.85 P21/n2-Nitrobenzoic acid 1:1 Salt 2.16 Pca21

↓ All salts below pKa 2 ↓

pka values are 2.96 and 4.24DL-Tartaric Acid

pka value is 3.41 (salt & cocrystal in same asymmetric unit)R-Mandelic Acid

Oxalic acid

Stearic and Palmitic acid

Maleic acid

Pyrimethanil

Adamantane carboxylic acid

0

20

40

60

80

100

120

140

160

180

200

Tem

p °

C

Melting point

Volatility measurements performed using a TGA method developed in-house.

Cocrystal Interaction

Salt Interaction

Salt Interaction

Cocrystal Interaction

pka value is 3.44 (H between both moieties)

4-Nitrobenzoic Acid

Varying the Rate of Dissolution: Choose the Correct Co-crystal PartnerSam Stratford, Joe Harris, Olana Couzins, Christopher S. Frampton, Osama Suleiman and Thierry Bonnaud

Pharmorphix, Johnson Matthey