Reliable Mechanochemistry: Protocols for Reproducible Outcomes of Neat and Liquid Assisted Ball-mill Grinding Experiments

We present detailed procedures to produce experimental equilibrium curves of the phase composition as a function of solvent concentration in a solid state system under milling conditions.

Transcript

The overall goal of this procedure is to obtain reliable results from ball-mill liquid-assisted grinding, or LAG, experiments as illustrated by equilibrium crystal phase composition curves obtained using various solvent conditions. This method can help answer key questions about the final equilibrium outcomes of the ball mill grinding process and the role of solvent at equilibrium under LAG conditions. The main advantage of this technique is that the rigorous approach to experimental design allows exploration of the key factors controlling the polymorphism of very small crystals.

Our findings suggest that surface effects are significant in polymorphism at the nanoscale and that the outcomes of equilibrium milling experiments are generally controlled by thermodynamics. To begin calibration, set an air-displacement pipette to reverse pipetting mode, which aspirates an excess of solvent. Set the aspiration and dispensing speeds to the lowest values and the volume to 10.0 microliters.

Tare a capped, two-milliliter glass vial on a five-figure analytical balance. Then, fit a pipette tip to the pipette nozzle with a single, firm, vertical motion, being careful not to twist or bend the pipette tip on the pipette nozzle. Aspirate and dispense 10 microliters of the selected solvent five times in a continuous sequence to prime the pipette tip.

Then, immediately aspirate 10 microliters of the solvent with the pipette held vertically and the tip two to three milliliters below the surface of the liquid. Place the end of the pipette tip against the inner wall of the tared, two-milliliter glass vial, holding the pipette at a 30 to 45 degree angle to the vial wall. Dispense the solvent, and gently tap the tip against the vial wall to recover any exposed droplets on the tip.

Immediately cap and weigh the vial. Record the weight. Dispose of the pipette tip and any excess solvent contained therein.

Repeat the process at least three more times at this volume, using a new pipette tip each time. Calculate the average weight for that volume. Determine the actual dispensed volumes by weight in the same way at 10-microliter intervals up to 100 microliters.

Then, determine the actual dispensed volumes at one-microliter intervals over a narrower range around the target volume for the experiment. For each volume range, plot the dispensed volumes on the x-axis in the actual dispensed volumes calculated from the average weights and the solvent density on the y-axis. Apply a linear fit, and verify that the correlation coefficient is above 0.99.

To begin the procedure, sonicate 14-milliliter, screw-closure, stainless steel grinding jars with PTFE washers in acetone. Then, wash the jars with laboratory detergent, and rinse the jars with deionized water and acetone in sequence. Dry the jars in a drying cabinet at 70 degrees Celsius for at least 30 minutes.

Allow the jars to cool to room temperature before use. Next, shape greaseproof weighing paper into a U-shaped weighing boat small enough to fit into the aperture of the male half of a grinding jar. Tare the weigh boat, and then weigh 104.82 milligrams of one-one crystals in the weighing boat.

Transfer the one-one crystals quantitatively to the male half of a clean grinding jar. Weigh 97.66 milligrams of two-two, and quantitatively transfer the crystals to the same grinding jar. Thoroughly mix the reagents with a micro-spatula.

Then, carefully fix the male half of the jar to the workbench with reusable adhesive putty. Ensure that the jar is immobilized so that the ball bearings will not roll on the powder when added. Gently rest two 7.0-millimeter diameter, hardened stainless steel ball bearings on the powdered reagents.

Pipette two microliters of dbu on top of one of the ball bearings, being careful not to allow that ball bearing to roll. Set a calibrated electronic air-displacement pipette in reverse pipetting mode to 17.0 microliters with the slowest aspiration and dispensing speeds. Equip the pipette with a tip, and aspirate the acetone by the same methods used in the calibration.

Homogeneously drip the acetone on the exposed powder, being careful not to allow the pipette tip to contact the powder. Promptly but carefully screw the female half of the grinding jar onto the male half. Wrap the joint with insulating tape to seal the jar.

Install the sealed grinding jar in one arm of a ball mill grinder. Tighten the safety clamp screw until the jar is immobilized. Turn the self-locking clamping device to the lock position.

Set the grinder frequency to 30 hertz and the timer to 45 minutes, determined from preliminary kinetic studies. Start the grinder, and install an external safety screen in front of the grinder. Preliminary kinetic studies are critical to establish for how long the ball mill grinding experiments must run to reach equilibrium.

Over-grinding unnecessarily must be avoided, as decomposition can occur. Upon completion, promptly remove the insulating tape and open the jar. Take a sample of powder, and determine the chemical composition by HPLC.

Smooth another powder sample with an agate mortar and pestle, prepare a powder X-ray diffraction slide, and determine the phase composition with PXRD. Calculate percent R to determine the ratio of thermodynamic polymorph under equilibrium at LAG conditions, called Form B, to the total amount of heterodimer one-two synthesized. Grind the same amounts of one-one and two-two to equilibrium using other volumes of acetone, and calculate the percent R values.

Plot the percent R values versus the volumes of acetone used in the LAG experiments to generate a solvent milling equilibrium curve for acetone. First, clean 14-milliliter, stainless steel, screw-top grinding jars, and load reagents one-one and two-two into a clean jar as previously described. Mix the reagents well with a micro-spatula.

Then, transfer about 60 milligrams of the reagent mixture to a weighing boat for later use. Obtain an electronic air-displacement pipette, and set it to normal pipetting mode, which dispenses all aspirated solvent. Set the aspirating and dispensing speeds to the lowest values.

Set the volume to 65.0 microliters. Prime the calibrated pipette, and aspirate 65 microliters of methanol. Understanding if the adsorption of the solvent into the reagent powder is fast, as with acetonitrile, or very slow, as with methanol, is critical for developing a procedure that incorporates the entire solvent volume into the powder during ball mill grinding.

Homogeneously apply the methanol to the powder, being careful not to allow methanol to contact the inner wall of the jar. Gently touch the wet pipette tip to the powder surface to quantitatively transfer the solvent residue. Pour the remaining 60 milligrams of the reagent mixture over the wetted patches of powder in the grinding jar to trap the solvent in the powder.

Gently tap the jar to compact the wetted powder, taking care to avoid evaporation. Fix the bottom of the male half of the grinding jar to the bench with adhesive putty to ensure that the ball bearings will not roll on the powder when added. Then, place two 7.0-millimeter diameter, hardened stainless steel ball bearings on the reagent mixture.

Apply two microliters of dbu to one of the ball bearings. Ensure that the ball bearing with dbu does not roll on the powder. Promptly but carefully screw the female half of the grinding jar onto the male half.

Let the grinding jar stand undisturbed for 20 minutes to allow the solvent to soak into the powder. Then, tighten the joint of the jar, and secure it with insulating tape. Secure the jar in a ball mill grinder equipped with the solenoid positioned over the start button.

Set the grinder frequency to 30 hertz and the timer to 60 minutes. Install a counterweight and safety screen as previously described. Configure the solenoid to automatically start the grinder four times at 65-minute intervals.

Run the solenoid process. Analyze the heterodimer product as previously described. Repeat with other volumes of methanol to generate the equilibrium curve.

To ensure that good solvent milling equilibrium curves were obtained, pipetting accuracy was validated with weighing checks for each solvent. Correlation coefficients above 0.99 indicated acceptable pipetting technique and pipette performance. Preliminary kinetic studies of the ball mill LAG reaction of one-one and two-two using dbu were performed for each solvent to determine the grinding times required to reach milling equilibrium.

A method was developed for solvents with high affinity for the reagent mixture, such as dimethylformamide. The DMF solvent milling equilibrium curve was accurately defined with 17 ball mill LAG experiments forming one-two as Form A and Form B.13 and 30 microliters of DMF yielded Form A and Form B, respectively, in quantitative yield. 19 microliters of DMF yielded a mixture of Form A and Form B.A modified method was required to obtain good equilibrium curves for solvents with low reagent mixture affinities, such as methanol, as the previous method gave poor correlation curves.

Using an adjusted method, an accurate solvent milling equilibrium curve was defined for methanol with 17 ball mill LAG experiments. By selecting the correct method and precisely measuring reagents, good solvent milling equilibrium curves were prepared for 12 typical organic solvents. Some solvents gave Form B with a few microliters, while others required more.

Once mastered, a grinding jar containing the powder mixture, dbu, and the precise volume of solvent can be prepared in 15 minutes. Some laboratory chemicals and solvents used in this process are hazardous to health. Always wear a lab coat, safety glasses, and gloves to minimize exposure.

You can now demonstrate that the concentration of Form B at equilibrium increases sigmoidally with solvent concentration. For some solvents, such as acetonitrile and acetone, a one-microliter difference suffices to switch quantitatively from Form A to Form B.While attempting this procedure, make sure that the chosen pipetting mode is suitable for the specific solvent used. Ensure that you have developed the skills to pipette the solvents accurately and reproducibly.

We believe that such milling equilibrium curves can be obtained for any system under sufficiently well-designed, performed, and controlled ball mill LAG conditions. After watching this video, you should have a good understanding of how to carry out accurate and reliable ball mill LAG experiments. There is the potential to discover new polymorphs by varying the added solvent.

This applies to most organic and inorganic reactions, as well as to supramolecular systems, and may have practical implications in industrial settings.

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Journal (Chemistry)

Journal (Chemistry)

Reliable Mechanochemistry: Protocols for Reproducible Outcomes of Neat and Liquid Assisted Ball-mill Grinding Experiments

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