Date of Award


Document Type


Degree Name

Doctor of Philosophy in Pharmaceutical Sciences


Pharmaceutical Sciences

First Advisor

Rahul Haware

Committee Chair and Members

Rahul Haware, Chair

Kenneth Morris

Rutesh Dave

Qing Cai

Bruno Hancock


Direct compression, Drug-drug cocrystals, Metformin, Structure-mechanical, Tableting


Crystal engineering has been widely explored to design and develop crystalline forms of drugs to address issues related to solubility, permeability, stability, bioavailability, and other properties without impacting the therapeutic efficacy of the drug. In this exploration, we aim to address the existing limitation of metformin HCl (MET) using the cocrystallization technique, an effective tool of crystal engineering. MET, an FDA-approved anti-hyperglycemic drug, is one of the most widely prescribed treatments for type II diabetes mellitus. MET is known to suffer from several limitations due to physicochemical properties and poor mechanical and structural properties, which influence the tableting performance of such high-dose drugs and passively impact patient compliance. MET is currently manufactured using the wet granulation method as direct compression is very challenging due to the requirement of ~40%-50% excipients for tablet development. Co-crystallization of two active molecules is one of the approaches widely used to improve the molecular and structural properties of the drug. Therefore, in this exploration, we hypothesized that the cocrystallization strategy could help to improve the mechanical properties as well as the tableting performance of MET.

Co-crystallization of MET with sodium salicylate (SAL) as a coformer was performed using the solvent evaporation technique. The developed MET:SAL cocrystallized solid was characterized using advanced analytical methods, including powder X-ray diffraction, single-crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy. The solid-state characterization results facilitated understanding the crystalline form of the engineered solid. These findings also supported the determination of the salt/cocrystal form of the MET:SAL cocrystallized solid. Tableting performance studies revealed that MET:SAL cocrystallized solid demonstrated improved tensile strength and greater compressibility, while MET was found to be challenging to compress without the aid of excipients. Due to the enhanced tableting performance, the total volume of MET:SAL tablets were also found to display a significant reduction as compared to MET tablets. In-die Heckel analysis revealed that MET:SAL cocrystallized solid underwent plastic deformation at low compression force as compared to MET. These experimental findings were further supported by intermolecular interaction studies, which showed that MET possessed quasi-isotropic hydrogen bond networking and crystal packing. Thus, making MET a rigid material and impacting its direct compression. In comparison, SAL has less inter-plane hydrogen bond networking, which makes it a soft material thus, easy to compress. Due to this feature of SAL, the MET:SAL cocrystallized solid possesses comparatively reduced inter-plane hydrogen bond networking than MET making it suitable for direct compression. Thus, MET having poor deformation along with tableting issues such as capping or sticking problems can be subjected to direct compression after cocrystallization with SAL. This host-guest relationship of MET:SAL helped to improve the mechanical properties of the material resulting in a reduction in the amount and/number of excipients for tablet development, thereby causing a decrease in the tablet size.

While the improvement in mechanical properties and tableting performance was established due to cocrystallization of MET, impact on solubility, dissolution, and partition coefficient was also evaluated. Solubility studies displayed a reduction in the solubility of MET upon cocrystallization with SAL which was found to be pH-dependent. Interestingly, the dissolution studies did not show any significant difference in the dissolution profile of MET and MET:SAL. The similar dissolution of MET:SAL and MET, despite the difference in the solubility, was found to be because of the high solubility of MET:SAL. Partition coefficient studies revealed that the cocrystallization of MET with SAL resulted in increased lipophilicity of the engineered solid compared to MET. The findings of the current work support the hypothesis and provide an explanation for the improved mechanical and structural properties of MET after cocrystallization. The work also helps to understand the influence of intermolecular interactions of the materials on the tableting performance for designing optimized crystal engineering. Thus, this study provides valuable insights about cocrystallization and its impact on the interplay of the various properties of the material and tunability of the tableting performance.