Crystallization of Salicylic Acid via Chemical Modification

Industrial crystallization is applied for the separation and purification of compounds and mixtures. In order to design economical systems, various parameters have to be studied. Crystallization is used for the separation of chiral compounds and amino acids, or for purification of antibiotics, food additives and agrochemical compounds. Different means of crystallization include cooling, chemical modification, evaporation or pH swing. A crystallizer can be used to investigate key parameters affecting crystal development, such as cooling and rates or supersaturation. With the microscope, the crystal size and morphology can be monitored and dependencies of various factors observed. In this experiment, sodium salicylate is reacted with sulfuric acid, leading to precipitation of salicylic acid, which is a precursor of Aspirin. Samples are analyzed by UV vis, a gravimetric analysis and microscopy. This video will illustrate the concept, analysis and application of a crystallizer unit.

For a scale up of a crystallizer, it is important to estimate key parameters. These can be studied using an MSMPR unit. Although industrial crystallizers really behave like MSMPRs, the concept is still relevant for bench and pilot scale units. The MSMPR crystallizer is analogous to a continuous, stirred-tank reactor. It assumes perfect mixing of solid and liquid phases. MSMPRs are used to assess key crystallization parameters, such as the crystal nucleation rate, which is also known as the birth function and the crystal growth rate. The nucleation is catalyzed by existing crystals and solid surfaces such as the walls of the reactor. The general population balance model for a MSMPR crystallizer yields the number density N of the crystals, which is a probability density with respect to L, the primary crystal dimension. In an MSMPR, the number distribution is predicted to be an exponential distribution. The birth function and growth rate can be determined using the zeroth and first moments of this distribution. Most importantly, they can also be related to the supersaturation, which is the mass transfer driving force in crystallization, and which is, in turn, dependent on agitation rate and temperature. For a constant temperature and agitator speed, both the birth function and growth rate are directly related to supersaturation, and the powers B and G can be determined by linear regression. According to the MSMPR model, the number density of crystals decreases exponentially with length. A deviation from the exponential distribution would imply imperfect mixing of solids or liquids. In industrial applications, relatively narrow Gaussian distributions of crystal sizes are required, rather than exponential ones. Nevertheless, the MSMPR model is still useful, particularly in pilot plants, as it enables determination of growth and birth rates as well as the degree of supersaturation from raw data. Now that you are familiar with the MSMPR model, let's apply the concept to the experiment.

Wear proper PPE when handling sodium salicylate and sulfuric acid solutions. Write down the basic physical properties of the salicylic acid for later use. Before your start, familiarize yourself with the crystallization system. The apparatus consists of two feed tanks, variable speed pumps, a five liter crystallizer-stirred tank, a circulating bath for temperature control, power controller, product tank and a make-up tank for feed regeneration, using a sodium hydroxide solution. The system is operated using a distributed control system and a graphical interface, from which valves can be operated to control the temperature and flow. A schematic output providing trends of flow rate and temperature is also available.

Check that all continuous controllers are set to the manual mode, and that all solenoid valves are either in the closed, two-way or in the recycle, three-way mode. Make sure the crystallizer is full with water and some salicylic acid slurry to the overflow level of approximately 4.15 liters, as indicated on the stirred tank. Add water and salicylic acid using the addition port if tank is not full. Turn on the agitator for the crystallizer and the thermostated bath and pumps. Set the temperature controller for the bath temperature to auto, and the set point to the desired temperature, usually approximately 53 degrees Celsius for a 50 degree Celsius crystallizer. Set the pump speeds to give approximately 25 to 35 milliliters per minute for the acid solution. For the sodium salicylate, the flow rate is determined by stoichiometric equivalents. Using the known feed concentrations, set the flow rates for stoichiometric equivalents. Make sure that the product tank is not full and the drain valve is closed. Then, turn on the spectrometer, and use a provided link in the control console to check that communication between the apparatus is established.

Switch to feed mode on both three-way valves. This sets time zero for an experiment. Periodically check the overflow line for any blockage. Use a piece of steel tubing to remote the line entering the product tank using the hole provided if blockage is detected. After one hour, use a wide-mouthed pipette and insert it into the sample port of the crystallizer. Collect enough sample to fill enough five pre-weighed 15 milliliter centrifuge or test tubes. Take two sets of samples 10 to 15 minutes apart. Vary the volumetric flow rates to control TOW and adjust for two other widely-spaced residence times. Maintain the stoichiometric equivalents and collect samples as before. When finished, set the pump output to zero per cent, the three-way valves to recycle. Return the temperature controller to manual at zero per cent output and shut off the pumps, agitators and thermostated bath.

The salicylate ion concentration can be determined using UV vis and the solid salicylic acid concentration can be determined gravimetrically as kilograms per meter cubed slurry. Before the analysis, first centrifuge samples for five minutes and decant the liquid. Record the total volume of sample retrieved. Combine the liquid samples from a given set and dilute by 50 to 100 times. For the liquid, measure the absorbance of the sodium salicylate and the salicylic acid using the UV vis spectrometer. The absorbance is assumed to be additive, since the same chromophore is detected for both samples. For the gravimetric determination, use the solids remaining in the centrifuge or test tubes. Dry the tubes upright in the convection oven at 70 degrees Celsius for two days. Then reweigh the cooled test tubes to determine the weight of the crystals and the concentration in kilograms per liter. Lastly, using a microscope, determine the length distribution of the needle-shaped salicylic acid crystals.

Compute the solid crystal concentration for all runs via the gravimetric method. Generate a mass balance on salicylate. Then, calculate the supersaturation and residence time. Next, determine the crystal yields on a feed and product basis, using the moles of the product, feed, and the dissolved salicylate product. Use the crystal concentration, crystal dimension, and residence time to solve for the birth function and growth rate. Then estimate the powers G and B through linear regressions of the log functions. Here is an example of a crystallization at 50 degrees Celsius. The power of B is twice as large as G, indicating that supersaturation is affecting the birth rate more than the growth rate. These powers would be used for scale up if supersaturation is unchanged. Comparisons to other experiments can identify factors that influence the growth and birth functions, such as inadequate mixing, pH and ionic impurities in the make up water.

Industrial crystallization is widely applied in pharmaceutical, chemical and food-processing industries for separation and purification of various compounds. Danazol is synthetic steroid which is used for the treatment of endometriosis. As with many other pharmaceutical compounds, Danazol is hydrophobic and poorly soluble in water. Therefore, the raw Danazol product is initially dissolved in ethanol and then recrystallized by mixing it with some water, which produces pure, small particle sized product crystals. Industrialized crystallizers can be used in the production of lysosomes. The apparatus can be designed to produce a very narrow crystal sized distribution through the application of a pump around heat exchanger, which slightly raises the temperature to dissolve the smallest crystals. The size distribution can be regulated by separating the crystal particles on the basis of their terminal velocities. This concept also finds application in the crystallization of inorganic salts.

You've just watched Jove's introduction to industrial crystallization. You should now understand the MSMPR crystallizer model, how to operate the crystallization unit and how to analyze the results. Thanks for watching.