Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Doctor of Philosophy


Chemical and Biochemical Engineering


Rohani, Sohrab


Multicomponent crystallization, a prominent strategy in crystal engineering, offers the ability to modify the physicochemical properties of crystals by introducing a secondary component to their lattice structure. Such multicomponent crystals have found widespread application in the pharmaceutical industry. This thesis explores the experimental screening, characterization, application, and theoretical prediction of multicomponent crystals of Active Pharmaceutical Ingredients (APIs).

The first case study investigates a new solvate of Dasatinib which exhibits high instability at room temperature and transforms into a different polymorph upon desolvation. The crystal structure of this compound is obtained, revealing insights into its transient nature and the potential application of desolvation for particle size reduction.

Another case study focuses on synthesizing a new cocrystal of zinc-phenylacetate (Zn-PA) with isonicotinamide (INAM). The resulting Zn-PA-INAM ionic cocrystal resolves the hydrophobicity issue of Zn-PA, enhancing solubility and dissolution rate. The crystal structure of Zn-PA-INAM, lattice energy comparison, and crystal morphology studies provide scientific explanations for these alterations.

Additionally, this thesis proposes computational prediction strategies to discover new multicomponent crystals. Quantitative predictive approaches based on hydrogen bonding strength are investigated, employing DFT-derived electrostatic potential (ESP) maps, hydrogen bond energy (HBE) and propensity (HBP) calculations. We demonstrate the enhanced classification capability achieved by combining HBE and HBP through multivariate logistic regression.

Expanding on cocrystal prediction strategies, we performed DFT calculations for a comprehensive database of 6,388 cocrystals from literature reports of both successful and unsuccessful experimental attempts. The extracted ESP surfaces were utilized to develop robust machine learning models that demonstrated exceptional discriminatory performance and achieved up to 94% accuracy on unseen test data.

Lastly, an investigation is conducted on the crystal morphology of Rufinamide (RUF), utilizing temperature cycling, solvent screening, and additive selection to modify its thread-like morphology into a more isometric shape. The crystal structures of three RUF polymorphs are determined, and a connection between the microscopic structure and the macroscopic morphologies is established through face indexing.

This thesis provides valuable insights into the application and systematic discovery of multicomponent crystals. By combining experimental screening, characterization, and predictive tools, it contributes to advancing the field’s understanding and utilization of multicomponent crystals.

Summary for Lay Audience

From common medications like aspirin and paracetamol to a more specialized pill, they are all manufactured with small crystals of an Active Pharmaceutical Ingredient (API). But what if we could make these crystals more effective by adding another safe substance to them while preserving their chemical nature? By adding a secondary safe substance to an API, we can improve important properties like solubility, which affects how well the drug can dissolve in our bodies and reach the targeted areas. In this research, our goal is to discover new multicomponent crystals by testing different combinations of ingredients and studying their properties. We also use chemistry-based knowledge and computer simulations to predict the outcome of different combinations before even making them in the lab.

One interesting finding was with Dasatinib, where we discovered that when crystallized with methanol, the crystals would crack immediately, creating many smaller crystals. This entails particle size reduction that can be advantageous in certain cases. Another discovery we made in the lab was the significance of adding isonicotinamide (INAM) to zinc phenylacetate (Zn-PA), an ammonia-scavenging drug. The crystal we made addressed the issue of Zn-PA being water-repellent, making it dissolve better and work more effectively as a medicine.

But we did not stop at lab work. We also developed computer models to quickly select the secondary compound without having to conduct an extensive experimental search. Using advanced statistical techniques and analyzing the strength of chemical interactions, we were able to accurately predict the formation of new multicomponent crystals.

We also determined the crystal structure of Rufinamide (RUF) in order to investigate the root of its problematically thin crystals. Our goal was to promote the growth of a more symmetrical crystal of RUF. We employed temperature cycling, solvent screening, and additive screening in our study.

This research provides insight into how crystals can be modified to create new materials with improved properties. By combining experimental testing, computer modeling, and predictive tools, we contribute to the advancement of multicomponent crystals, especially in medicine.

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.