Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Doctor of Philosophy


Chemical and Biochemical Engineering


Rohani, Sohrab


Crystallization is an important technique to obtain solid-state drugs from solutions. Physicochemical properties of the active pharmaceutical ingredients (APIs) are determined by crystallization. More than half of the active pharmaceutical ingredients exhibit polymorphism, the phenomenon of chemical species showing more than one unit-cell structure in the solid state. Controlling polymorphism is one of the most important goals during pharmaceutical manufacturing. Nevertheless, the control of polymorphism is sometimes not enough to realize the targeted physicochemical properties. Suitable additives (coformers/salt formers) are explored to generate new multi-component solid phases of poorly soluble/bioavailable active pharmaceutical ingredients (APIs). The design of pharmaceutical cocrystals and salts has thus become significantly important in recent years. With the introduction of suitable coformers or salt formers, the targeted physicochemical property can be well improved.

This work aims to provide insights into the design, characterization, optimization and control of API solid states in crystallization processes. The characterization of crystal packing structures, melting points, and tuned solubilities is carried out for all cases studied in the thesis. First, the solvent screening for an API, which is the basis of solution crystallization, is researched based on the solubility prediction using Hansen solubility parameters. Next, the optimal working conditions for harvesting the desired polymorph in continuous crystallization are investigated both experimentally and numerically. Numerical models of single-stage and two-stage mixed-suspension mixed-product removal (MSMPR) crystallizers are developed to test different working environments. The production of kinetically unfavorable polymorph of L-glutamic acid is realized by experiment. Subsequently, for APIs of low solubility (biopharmaceutics classification system (BCS) class II or IV), a screening method using hydrogen-bond propensity and hydrogen-bond coordination calculations is developed to improve the drug solubility and dissolution. Lastly, regardless of single-component or multicomponent API solid phases, poor morphology such as needle-like or plate-like would impede the downstream processes. A new spherical crystallization method depending on the liquid-liquid phase separation is developed with the help of an in-situ Pixact Crystallization Monitoring (PCM) system. Spherical crystals are successfully produced to avoid the original plate-like morphology of vanillin crystals.

Summary for Lay Audience

The production of fine chemicals and pharmaceuticals always uses crystallization process as the final purification step. The shape, purity, and other physicochemical properties of the crystalline products are directly determined by the crystallization process. Hence, the design and the control of the final solid states is the core issue in the pharmaceutical and fine chemical industries.

Polymorphism describes the phenomenon of chemical species showing more than one unit-cell structure in the solid state and has an influence on the product stability, solubility, and processability of the active pharmaceutical ingredient (API). In batch crystallization, seeding is often used as a means of controlling product polymorphism. Nevertheless, initial seeds would be washed out during continuous production. An investigation on seeding strategy in continuous crystallization process was conducted based on the kinetic modelling.

Although polymorph control can improve the targeted physicochemical product property, the effect is still restricted by the API itself. To improve the targeted property significantly, suitable additives (coformers/salt formers) are often needed to generate new multi-component solid phases. Screening and selection of the potential multi-component solid states (pharmaceutical cocrystals and salts) of an API is one of the most critical early stages of drug development.

After the design and control of the crystal unit cell, the crystalline product may exhibit poor morphology that would affect the flowability and bulk density of the product. Spherical crystals have smaller contact areas compared with needle, and other poor-shaped crystals. Therefore, spherical crystallization technology is developed in this thesis as it directly combines the downstream granulation processes with crystallization and thus significantly reduces the total equipment and energy cost. With the optimized crystal solid state, the product value is significantly increased, and the efficiency of the crystallization process design is improved.