Solubility is an important intrinsic property of agrochemical molecules. It is used in multiple processes including solid form screening (to identify a suitable solid form for formulation and patenting), stability studies (to understand if the molecule will remain at the site of action or will suffer from run-off due to high water solubility), and crystallization.
Crystallization is a commonly used process within the agrochemical sector. It is primarily used as a purification method but also to produce solids for suspension concentrate formulation. At the heart of any robust crystallization process is a thorough understanding of the solubility landscape of the molecule in a range of solvents. With this understanding it would be possible to select suitable solvent systems that would deliver the desired results including controlling solid form, influencing particle size distribution, and a high yield and purity. The Crystal16 provides fast, reliable, and reproducible way to collect solubility and metastable zone data, which can be used to design robust crystallization process.
Solubility
Solubility is a thermodynamic property and is defined as the equilibrium amount of a solid that can be dissolved in a specific solvent system and is heavily influenced by temperature. Typically, as temperature increases solubility increases. There are 3 main ways solubility can be collected: equilibrium, solvent addition, and temperature variation.
The Crystal16 utilizes the temperature variation method to measure solubility. This is where suspensions are heated gradually until the solids dissolve. The transmissivity of the sample is used to detect the dissolution temperature. Using this method, it is possible to also detect when crystallization occurs during cooling which can be used to plot the metastable zone width (MSZW). The MSZW is a critical piece of information that can be collected using transmissivity and temperature variation method, which is used to design seeding strategies in crystallization process. The benefit of this method is that it can be automated to reduce the lab hours to collect data.
Figure 1 Solubility collection methods
Case Study: MCPA
Agrochemicals are bulk goods that are used around the world in large quantities. As such, there is a requirement to deliver a high-yield, robust crystallization process at a low cost for farmers, allowing them in turn to keep produce costs low for the public. MCPA (2-Methyl-4-ChloroPhenoxyAcetic acid) is a broad leaf herbicide used in the protection of cereal crops such as wheat, oats and rye.
When designing a solubility screen, it is important to use several types of functional groups in order to understand the solubility landscape. Screening consisted of testing neat ethanol (EtOH), ethyl acetate (EtOAc), acetone and isopropyl alcohol (IPA). The initial results of the solubility assessment showed very high solubility in neat solvent. Ideal solvents for cooling crystallization show a high solubility at high temperature and a low solubility at a low temperature ensuring a high yield. If the solubility at low temperatures is too high, then an antisolvent (low solubility solvent) is employed to improve the final yield. If a molecule shows high solubility in polar solvents such as alcohols and acetates, then it is probable that non-polar solvents such as heptane will be a good antisolvent. A second screen was conducted using solvent mixtures with heptane (20/80) to find a solvent/antisolvent combination that lowers to solubility at low temperature to investigate further.
Figure 2 Solubility Curves for solvent/heptane (20:80)
Based on the results of the solvent/antisolvent (20/80) mixtures, further ethyl acetate/heptane mixtures were selected for investigation to explore the solubility landscape of the solvent system.
Figure 3 Solubility curves of EtOAc and EtOAc/Heptane mixtures
The solubility in neat EtOAc solvent was found to be very high at high temperature (>500 mg/ml) which would make an ideal place to start an antisolvent cooling crystallization. From the data collected a final solvent/antisolvent composition of 20:80 at 5 °C would be good conditions for isolation and it would ensure a high yield as 50:50 would not be enough antisolvent. An additional consideration to make with antisolvent crystallization is the dilution effect of increasing solvent volume, which can offset yield benefits from the low solubility. However, despite needing 4X volume of antisolvent the max final yield would still be 98 %. The additional information from the solubility curve in 50:50 mixture modelling software could be used to further optimize the cooling and antisolvent profiles.
Conclusion
Rapid collection of solubility data This has been demonstrated with the agrochemical MCPA. Using the Crystal16, several solvents and solvent compositions were screened rapidly. The Technobis range of instruments offer a fast, reproduceable, and reliable way of determining the solubility and MSZW using the polythermal method couple with non-invasive real time transmissivity data. This means a solubility curve and supersaturation curve can be collected in as little as 4 hrs or overnight with the system automation. This allowed for the identification of conditions that would produce a high yield low volume antisolvent cooling crystallization using EtOAc as solvent and heptane as antisolvent.
Acknowledgments
Technobis would like to thank Monica David, Claudia Brăilă, Mihaela Pop and TeraCrystal for their help with this application note.