(224a) Crystallization Process Design Dealing with Impurity Rejection: The Case of Lactose

Many tablets and drug powder inhaler formulations contain pharmaceutical-grade lactose as the most abundant excipient. Its recovery and purification are achieved through a cooling crystallization step of concentrated dairy waste streams, but the process is lengthy and suffers from batch-to-batch variability [1].

In aqueous solution, lactose undergoes an intramolecular reaction leading to two diastereomers, alpha- and beta-lactose, that slowly interconvert until equilibrium: the reaction is called mutarotation. Below 93 °C, alpha-lactose is the least soluble compound and is traditionally recovered as monohydrate via seeded batch cooling crystallization [2], after an initial concentration step by evaporation. Beta-lactose is known to influence the crystallization kinetics by acting as a nucleation and growth rate inhibitor [1] whereas acidic impurities arising in the upstream cheese making process are easily incorporated in the crystal lattice. They make commercial lactose powder more acidic than similar sugars and have been reported to be a natural strong growth retarder [3].

Therefore, the objective of this work is the model-based design of lactose crystallization, relying on particle size distribution data, the impurity incorporation rate and a recently developed chromatographic protocol to monitor the composition of a lactose solution [4]. The goal is reducing the unexplained variability in lactose crystallization outcome through an enhanced process understanding.

Using a step-by-step procedure, the mutarotation [5] and the dissolution and crystallization [6] kinetics of lactose have been experimentally investigated and correlated to process variables of interest. Figure 1 shows an example of seeded batch desupersaturation experiment and population balance model fit highlighting the interplay between mutarotation and crystallization. A pre-treatment step to remove acidic impurities before seeded-batch desupersaturation experiments is critically evaluated as part of an optimal policy to improve lactose recovery and end-product quality.

[1] A.H.J. Paterson (2017): Lactose processing: From fundamental understanding to industrial application, Int. Dairy J. 67, 80-90.

[2] E. Simone, A.I.I. Tyler, D. Kuah, X. Bao, M.E. Ries, and D. Baker (2019): Optimal Design of Crystallization Processes for the Recovery of a Slow-Nucleating Sugar with a Complex Chemical Equilibrium In Aqueous Solution: The Case of Lactose, Org. Process Res. Dev. 23, 220−233.

[3] E.V. Lifran, T.T.L. Vu, R.J. Durham, J.A. Hourigan., R.W. Sleigh (2007): Crystallization Kinetics of Lactose in the Presence of Lactose Phosphate, Powder Technology, 179, 43-54.

[4] S. Trespi, M. Mazzotti (2024): HPLC Method Development for the Quantification of a Mixture of Reacting Species: The Case of Lactose, J. Chromatogr. A 1715, 464553.

[5] S. Trespi, M. Mazzotti (2024): Kinetics and Thermodynamics of Lactose Mutarotation through Chromatography, Ind. Eng. Chem. Res. 63, 12, 5028-5038.

[6] S. Trespi, M. Mazzotti: manuscript in preparation.