True Polymorphic Phase Transition or Dynamic Crystal Disorder? An Investigation into the Unusual Phase Behavior of Barbituric Acid Dihydrate

Abstract

Crystalline barbituric acid dihydrate (BTADH) was previously thought to undergo a subtle temperature-dependent phase transition from a high-temperature orthorhombic Pnma space group to a nonmerohedrally twinned monoclinic P21/n phase below a transition temperature of ∼217 K. Questions remain on the true nature of the unusual transformation and the structure of the high-temperature crystal phase due to difficulties in resolving the Pnma structure from X-ray diffraction data and because of the subtlety of the structural transition. In this study, terahertz (THz) spectroscopy and solid-state density functional theory (DFT) were utilized to explore this suspected phase transition and uncover the principle physical mechanisms contributing to this anomalous transition. Our findings suggest that at temperatures above the previously reported phase transition temperature of 217 K, the crystal does not exist in the Pnma space group configuration. However, two equivalent favorable energetic states with P21/n symmetry related by the twinning plane lie on either side of the proposed Pnma structure. It is these same local potential energy minima that guide the crystal system to a nonmerohedrally twinned configuration identified in the low-temperature crystal structures. At temperatures above 217 K, the system possesses the thermal energy necessary to readily transition between these degenerate states separated by the low-lying Pnma structural barrier. The evidence acquired by THz spectroscopy and DFT indicate the absence of a true temperature-dependent phase change, and rather a system that exists in a tenuous thermally disordered state above the previously alleged transition temperature.

Application of 1-Hydroxy-4,5-Dimethyl-Imidazole 3-Oxide as Coformer in Formation of Pharmaceutical Cocrystals

“…In extension of this study, we investigated crystals of BA containing two water molecules in the lattice, and the susceptibility of this form to yield cocrystals. Recently, King and coworkers reported on detailed structural studies on, and the unusual thermal phase behavior of, barbituric acid (BA) dihydrate [46]. Our results prove that during grinding at ambient temperature, this form is stable and does not undergo further transformation.…”

Advances in Low-Frequency Vibrational Spectroscopy and Applications in Crystal Engineering

“…A similar approach was used to deduce the high-temperature crystal structure and presumed phase transformation kinetics for barbituric acid dihydrate. From theoretical models and terahertz spectroscopy, Paul et al determined that rather than undergoing a temperature-dependent phase change at high temperatures barbituric acid dihydrate exists in a thermally disordered state . Low-frequency vibrational spectroscopy can even be used to confirm the structures of unknown materials, often in conjunction with other methods such as crystal structure prediction …”

“…From theoretical models and terahertz spectroscopy, Paul et al determined that rather than undergoing a temperature-dependent phase change at high temperatures barbituric dihydrate exists in a thermally disordered state. 21 Low-frequency vibrational spectroscopy can even be used to confirm the structures of unknown materials, often in conjunction with other methods such as crystal structure prediction. 161 Transformations between amorphous and crystalline phases are affected by several external factors including humidity, temperature, and pressure.…”

“…Over the years, the advantages of obtaining high-quality terahertz vibrational spectra, along with the simultaneous interpretation of the data using periodic DFT simulations, have become increasingly apparent . After early studies on the identification and characterization of crystalline polymorphs using low-frequency vibrational spectroscopy, the field grew, making use of insight gained through the binary experimental and computational approach to understand the subtle origins of polymorph stability, in many cases pinpointing the exact interaction(s) that are responsible for the preference of one crystalline form over anotherwith some examples involving differences in energies of less than a kJ mol –1 . , While not inherently a structural technique, the terahertz community learned to leverage the dependence of terahertz spectroscopy on weak intermolecular forces to uncover incredibly subtle differences in the structures and interactions found in crystals that have similar, and in some cases nearly identical, structures, where it has been shown that terahertz data can provide details that are not captured by X-ray diffraction (XRD) methods. In turn, the coupling of low-frequency vibrational spectroscopy, XRD, and ab initio simulations has yielded one of the most powerful combinations of techniques for investigating crystalline structure and dynamics, and together these techniques form the basis for new research thrusts into the field of crystal structure predictionwith the terahertz analyses often providing critical insight into overcoming ambiguous diffraction results.…”

Quantitation of Commercially Available API Solid Forms by Application of the NMR-qSRC Approach: An Optimization Strategy Based on In Silico Simulations

“…The study of API solid-state properties is nowadays considered essential by the pharmaceutical industry because it is well-recognized that focusing on solid-state characteristics allows us to optimize the in vivo performance of drugs. − In fact, APIs can show a complex and unpredictable behavior when it comes to its solid-state arrangement. , Essentially, the same molecule can exist under different crystal habits (polymorphism) or as amorphous, solvates, or hydrates, and furthermore, interconversion between two different forms might occur even under mild conditions . Accordingly, it is necessary to study these aspects not only from a qualitative point of view but also by focusing on the quantitation of the different forms potentially present in the API synthesis crude and/or its formulation.…”