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Co-crystallization is known as a product formulation technology, but it can also be used as a tool to solve crystallization problems. Product removal by co-crystallization in fermentations is used as a showcase to demonstrate the potential of co-crystallization as a separation technique. In fermentations, the product solubility is often higher than the limiting concentration. Hence, the solubility should be decreased to below this limiting concentration to enable product removal by crystallization. Co-crystallization has the potential to accomplish this goal since co-crystals can have solubilities lower than pure component solubilities. Cinnamic acid (CA) forms co-crystals with 3-nitrobenzamide (NBA). The phase diagram of CA, NBA, and water shows that CA-NBA co-crystals can be formed at CA mole fractions seven times below the solubility of pure CA, facilitating the removal of CA from the solution at concentrations well below the pure CA product solubility. Co-crystal fine-tuning may lead to a substantially extended decrease of the CA co-crystal product solubility, so that product removal by co-crystallization can take place at even lower product concentrations. Co-crystallization experiments in a simulated fed-batch fermentation were performed by slowly adding a saturated solution of CA, simulating the production of CA in the fermentation process, to a suspension of pure co-former NBA. In time, the co-former crystals completely transform to CA-NBA co-crystals. During the transformation, a stationary state is achieved in which the CA and NBA mole fractions are constant because the added CA, together with the NBA from the dissolving co-former crystals, is captured in the co-crystals. In the stationary state, the process is operated near the 3-phase equilibrium point with equilibrium between co-crystals, co-former crystals, and solution. Co-crystals thus not only offer a route toward fine-tuned crystal properties of active pharmaceutical ingredients. This paper shows that, moreover, co-crystals offer solutions to crystallization problems.

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A relation between template properties and template performance has been established: template particles with a surface layer of cinnamic acid molecules, either adsorbed or covalently bonded, promote crystallization of cinnamic acid, while particles without such a layer do not. The BET surface area and dynamic light scattering (DLS) particle size were measured to gain control over the total surface area of added template particles (ZrO 2 , TiO 2 , TiO 2 -SiO 2 , and SiO 2 -CAH). Zeta-potential measurements indicated whether adsorption of cinnamate on particles occurred, while the loading of the surface layer with cinnamic acid molecules was determined by adsorption isotherm measurements and spectrophotometry. The template performance was evaluated using induction time measurements. Scanning electron microscopy (SEM) images revealed that effective templates not only improve nucleation rates, but may also affect the size and shape of crystals. Template induced crystallization (TIC), where template particles promote crystallization, can be used as an in-situ product removal (ISPR) tool in fermentation processes to alleviate inhibitory and/or toxic constraints which are due to high product titers. The established relation between template properties and template performance can be used to predict which materials are effective templates for a specific (fermentation) product.