Local Structural Effects Due to Micronization and Amorphization on an HIV Treatment Active Pharmaceutical Ingredient

Abstract

Processing procedures for inducing domain size reduction and/or amorphous phase generation can be crucial for enhancing the bioavailability of active pharmaceutical ingredients (APIs). It is important to quantify these reduced coherence phases and to detect and characterize associated structural changes, to ensure that no deleterious effects on safety, function, or stability occur. Here, X-ray powder diffraction (XRPD), total scattering pair distribution function (TSPDF) analysis, and solid-state nuclear magnetic resonance spectroscopy (SSNMR) have been performed on samples of GSK2838232B, an investigational drug for the treatment of human immunodeficiency virus (HIV). Preparations were obtained through different mechanical treatments resulting in varying extents of domain size reduction and amorphous phase generation. Completely amorphous formulations could be prepared by milling and microfluidic injection processes. Microfluidic injection was shown to result in a different local structure due to dispersion with dichloromethane (DCM). Implications of combined TSPDF and SSNMR studies to characterize molecular compounds are also discussed, in particular, the possibility to obtain a thorough structural understanding of disordered samples from different processes.

Improving the picture of atomic structure in nonoriented polymer domains using the pair distribution function: A study of polyamide 6

“…Refinement of the damping and scale factors of the crystalline phase are typically highly correlated due to the real‐space damping of the PDF, which comes from the limited Q ‐resolution of the measurement. However, for the typical rapid acquisition setup, [ 34 ] it was recently shown that amorphous quantification can still be reliable even when the crystalline domain size is not [98] . Thus, three cases were investigated: (a) free refinement of parameters, (b) refinement with no damping parameter for the crystalline phase, and (c) refinement of damping for the crystalline phase to the long‐ r region (20–50 Å) then fixing and refining the scale factor over the full r ‐range.…”

A previously unknown cyclic alkanolamine and molecular ranking using the pair distribution function

“…In all three cases, bond lengths, and bond and torsion angles were allowed to refine by type when not constrained by symmetry. Strategies for modeling the correlated motion of covalently bonded versus less strongly interacting intermolecular atom-pairs have been described (Rademacher et al, 2012;Prill et al, 2015;Terban et al, 2020). Here, we used two different isotropic displacement factors for the non-hydrogen (B eq1 ) and hydrogen atoms (B eq2 ) to describe the intermolecular pair peak-widths.…”

Structure determination of organic compounds by a fit to the pair distribution function from scratch without prior indexing

“…Recently, there has been growing interest in the knowledge of the local structure. The local structure may deviate from the average crystal structure (Aksel et al, 2013), especially for complex materials such as pharmaceuticals (Moore et al, 2009;Terban et al, 2020), metal-organic frameworks (Mazaj et al, 2016), organic pigments (Hunger & Schmidt, 2018;Schlesinger et al, 2020), catalysts or magnetic materials, such as semiconductors (Frandsen et al, 2016). Disorder, lattice defects or surface effects result in a local structure which differs from the average structure found by classical structure determination methods (Proffen et al, 2003;Young & Goodwin, 2011).…”

“…The reasons for this are manifold and include, among other things, the low scattering power of mainly carbon and hydrogen atoms, as well as the different PDF peak widths caused by intermolecular versus intramolecular atom pairs (Rademacher et al, 2012;Prill et al, 2015). However, the number of organic materials investigated by PDF analysis is rapidly rising due to the growing interest in their local structure (Bates et al, 2006;Davis et al, 2013;Billinge, 2015;Terban et al, 2016Terban et al, , 2020Rantanen et al, 2018). Several advances in local structure investigation by a fit to the PDF have been published.…”