Polymorphs and Hydrates of Sequifenadine Hydrochloride: Crystallographic Explanation of Observed Phase Transitions and Thermodynamic Stability

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Dantrolene represents yet another interesting example of abundant molecular crystal polymorphism existing in at least six different neat polymorphs, three of which can be obtained via crystallization (I–III) and an additional three (IV– VI) via solid-state dehydration from three different monohydrates (MH-I–MH-III). The reasons for polymorph formation were rationalized by analyzing the crystal structures of the polymorphs and hydrates used in their preparation. The thermodynamic relations among the polymorphs were established from calorimetric data, solubility measurements, and lattice energy calculations.

Section: Introductionmentioning

confidence: 99%

Hexamorphism of Dantrolene: Insight into the Crystal Structures, Stability, and Phase Transformations

Kons

Mishnev

Mukhametzyanov

et al. 2021

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“…Hydration or dehydration processes may occur unexpectedly during drug development, manufacturing, storage, and pharmaceutical preparation and could affect the qualities of the final products. , Hence, it is of great significance to investigate the relative stabilities of the hydrates and figure out the phase transformation processes between hydrates and corresponding neat forms. − Previous studies have indicated that the stability of hydrates is closely related to the humidity, water activity in the solvent, and temperature. , Liu et al investigated the transformation water activity and concluded that the transformation water activity ratio of different crystal forms of theophylline was inversely proportional to the solubility ratio at a certain temperature. Ito et al found that the anhydrate of antibiotic clarithromycin reversibly transformed to dihydrate when relative humidity (RH) increased to 60% and then transformed to trihydrate at 95% RH.…”

Section: Introductionmentioning

confidence: 99%

Understanding the Role of Water in Different Solid Forms of Avibactam Sodium and Its Affecting Mechanism

Ding

Huang

et al. 2020

Hydrates are common in pharmaceutical development, and the formation of hydrates affects the performance of the final product. However, the role that water plays in crystal packing remains unclear. In this study, Avibactam sodium, which has one dihydrate (Form E), one monohydrate (Form A), and two anhydrous forms (Form B and D), was chosen as the model compound to understand this subject. Single crystal structures of four solid forms were obtained and characterized by single X-ray diffraction. The dynamic vapor sorption experiments revealed the moisture-dependent stability increased in the order: Form B < Form D < Form A < Form E. It can be envisaged that the integration of water molecules could noticeably compensate the potential intermolecular interactions, thereby significantly improving the crystal stabilities of hydrates. Furthermore, the hydration of Form B was investigated to understand the integration of water molecules by measuring the critical hydration water activities (a w). The results indicated that both water activities and temperature are vital factors to determine the amount of water molecules existing in crystal lattice. Moreover, to probe the disintegration of water molecules, the dehydration of dihydrate was investigated in detail by solid-state transformation and solvent-mediated transformation experiments. Finally, two-step dehydration and one-step dehydration + recrystallization mechanisms of these different pathways were proposed by analyzing the transformation experiment results and the crystal structure of various solid forms.

“…1 Finally, the formation of hydrates tends to decrease the void space in a crystal structure and leads to more efficient packing. 9,15 Figure 1. The molecular structure of quercetin In this work, quercetin, 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one, is chosen as the model compound.…”

Section: Introductionmentioning

confidence: 99%

Synthonic Modeling of Quercetin and Its Hydrates: Explaining Crystallization Behavior in Terms of Molecular Conformation and Crystal Packing

Klitou

Rosbottom

Simone

2019

Hydrated structures of a specific compound can often have different physiochemical properties compared to the anhydrous form. Therefore, being able to predict and understand these properties, especially the stability, is critical. In this study quercetin, a flavonoid molecule, is modelled in three different states of hydration to gain an understanding of the effect of water molecules on the 2 structure, packing and conformation energetics of the three forms. Conformational analysis and modelling of intermolecular interactions (synthonic modelling) have been performed. It was found that in the anhydrous form hydrogen bonding is the strongest type of interaction while in the two hydrate structures, the incorporation of water within the lattice leads to the formation of hydrogen bonds between the quercetin and water molecules. Within hydrates quercetin molecules adopt a more planar conformation which allows them to pack more closely by strongstacking interactions, thus resulting in a higher relative stability. The modelling results highlight the importance of water in the stabilization of the lattice and explain the preferential nucleation of the dihydrate form. It is further demonstrated how synthonic modelling can be a predictive tool for the product's properties, leading to more efficient product design and faster development.