Toward the Rational Design of Crystalline Surfaces for Heteroepitaxy: Role of Molecular Functionality

Abstract

The rational design of crystalline surfaces for controlling nucleation and crystal growth via heteroepitaxial mechanisms is of great importance in the manufacture of advanced functional materials, such as pharmaceuticals and semiconductors. Despite numerous studies investigating the singular effect of crystalline lattice matching, molecular functionality, or topography on epitaxial ordering, no study has been carried out investigating these effects in competition with one another in order to establish which effect is the most significant in promoting nucleation. Herein, we report the key results and conclusions from studying the heterogeneous crystallization of the stable polymorph of acetaminophen (AAP) on crystalline substrates with differing lattice parameters and surface functionalities. Induction time measurements were used to rank the ability of the different substrates in promoting heterogeneous nucleation. The results showed that nucleation was preferred on substrates whose surface functionality matched with that of AAP even when other substrates exhibited a better lattice match with specific AAP crystal faces. Furthermore through the use of single crystal X-ray diffraction and molecular modeling, the epitaxial ordering of AAP on single crystals of α-lactose monohydrate (α-LMH) and D-mannitol has been investigated in order to gain mechanistic insight into the nucleation process.

Insights into Polymorphic Transformation of l-Glutamic Acid: A Combined Experimental and Simulation Study

“…42,44 These parameters and the size of the overlayer are required to perform the calculations. The default setting for overlayer size (25b 1 *25b 2 ) was used in every case.…”

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

“…Isomorphous compounds like flufenamic acid (Lee et al, ) and dihydro‐carbamazepine (Srirambhatla et al, ) facilitated crystallization of mefenamic acid and carbamazepine, respectively, by LDE. Crystallization of paracetamol (PCM) on biocompatible carbohydrates had LDE as the most common underlying mechanism (Chadwick, Chen, Myerson, & Trout, ; Quon et al, ; Wijethunga, Baftizadeh, Stojaković, Myerson, & Trout, ). Vilmali et al reported a significant decrease in nucleation induction time for crystallization of metastable polymorph of mefenamic acid with polymeric nanoconfinement with a dihedral angle of 90° (López‐Mejías et al, ).…”

“…Air‐jet in the supersaturated solution of the API has also been investigated as one of the approaches, wherein the air bubble served as a heterosurface (Capellades et al, ). Intentional incorporation of the heterosurface in the process has been widely studied to understand the role of the surface topography and surface chemistry on the crystallization of the API (Arribas Bueno et al, ; Arribas Bueno, Crowley, Hodnett, Hudson, & Davern, ; Chadwick et al, ; Padrela et al, ; Quon et al, ). Current section deals with the variety of heterosurfaces that have been employed for pharmaceutical heterogeneous crystallization.…”

“…The isomorphous compounds have been explored to induce crystallization by mechanisms involving the crystallographic features. Biocompatible carbohydrates or sugars have been choice of heteronuclent amongst common pharmaceutical excipients (Arribas Bueno et al, ; Arribas Bueno et al, ; Chadwick et al, ; Chadwick et al, ; López‐Mejías et al, ; Padrela et al, ; Quon et al, ; Wijethunga et al, ). The sugars have been explored for a variety of applications from polymorph control to improvement in process efficiency.…”

“…Visual examination of number of vials/vessels crystallized (with time) using microscope or webcam is a common practice for determination of the nucleation kinetics (Arribas Bueno et al, ; Curcio et al, ; Diao et al, ; Hsu et al, ; Tan et al, ). Nucleation kinetics has also been determined by in‐line measurement of solution concentration using Fourier‐transform infrared spectroscopy (Verma et al, ) and turbidimetry (Chadwick et al, ; Quon et al, ). Moreover, simultaneous analysis of both physical form and concentration can be undertaken using near‐infrared spectroscopic probe as a process analyzer (Schaefer et al, ).…”