Preliminary studies on unusual polymorphs of thymine: Structural comparison with other nucleobases

One of the long-standing challenges in working with organic hydrates in general, and channel hydrates in particular, is their propensity to lose water over time and convert (either partially or fully) to anhydrous solid forms. In this work, we demonstrate the ability to rationally increase the thermal stability of a model channel hydrate, the DNA nucleobase thymine hydrate (TH), through the systematic creation of lattice substitutions with 5-aminouracil (AUr). Mixed crystals of TH−AUr with up to 17 mol % AUr were isomorphous with the pure hydrate, confirming our molecular-level design strategy which places 5-amino groups at the one-dimensional channel surfaces. The enhanced stabilization of the water molecules afforded by the proximal 5-amino substitutions resulted in mixed crystals with significantly higher thermal stability. The magnitude of the thermal stability enhancement scaled linearly with the included AUr concentration, yielding TH−AUr dehydration temperatures nearly double that of the pure hydrate. Kinetic analyses and time-resolved synchrotron structural studies of process-induced dehydration of the mixed composition hydrate indicated changes in both the solid-state mechanism and the resultant anhydrous products compared to those generated from the pure hydrate. The strategy adopted herein should be applicable to other hydrate systems to rationally tune their thermal stabilities.

Section: Introductionmentioning

confidence: 99%

Improving Channel Hydrate Stability via Localized Chemical Tuning of the Water Environment

Watts

Niederberger

Swift

2021

“…The DNA nucleobase thymine (aka 5-methyluracil) crystallizes as a classic channel hydrate , from aqueous solution. Several solid state computational and experimental investigations have focused on this hydrate system since its structure was first reported in 1961. ,,− Gerdil referred to the structure as a monohydrate with 80% water occupancy in the original crystal structure report . More recent calculations by Braun et al indicated that the channels are too small to enable a monohydrate composition, and the authors referred to it as a 0.8-hydrate to better reflect its stoichiometry.…”

Section: Introductionmentioning

confidence: 99%

Steric Perturbation to a Channel Hydrate: The Limits of Isomorphism

Watts

Lee

Niederberger

et al. 2021

Thymine hydrate (TH) is a classic hydrate system in which water molecules are highly confined in linear one-dimensional channels. Here, we describe our efforts to tune the channel volume by preparing isomorphous mixed crystals with increasing concentrations of uracil (Ur) and 5-ethyluracil (EUr), molecular analogues with slightly smaller and larger volumes, respectively. Solutions with up to 20 mol % Ur successfully yielded isomorphous mixed crystals of TH-Ur x in phase-pure form, though analysis of the mixed crystal compositions indicated that only ∼46% of the Ur available in the initial growth solution was proportionately included in the host lattice. The thermal stability of the mixed TH-Ur x material was significantly altered, with a greater fraction of water loss occurring at low temperature compared to the pure hydrate phase. Isomorphous mixed crystals with EUr substitutions, TH-EUr x , were successfully prepared from solutions with 5–10 mol % EUr, although the fraction of EUr included was much lower (∼13–36%) than Ur. As the concentration of EUr in the growth solution increased to 15–20 mol %, an unexpected mixed composition anhydrate emerged as the dominant crystallization product. Although packing fraction estimates suggested that higher EUr substitution levels in the hydrate were theoretically possible, the formation of the mixed anhydrate presented a more favorable route to a dense material phase.

“…However, salts are sometimes more likely to form hydrates and have an inherent tendency toward hygroscopicity compared to cocrystals. , On the same line polymorphism in APIs is considered as an alternate, and over decades, it has become a major area of drug research. Polymorphs exhibit unique physicochemical properties, such as melting point, solubility, bioavailability, stability, color, and mechanical properties, correlating to their unique crystal structure and packing. − Improved aqueous solubility is a primary driving force in the development of novel solid form (amorphous, polymorphs, cocrystals, hydrates/solvates, and salts) selection. − Polymorphs and hydrates are often obtained by slow solvent evaporation or cooling crystallization dealing with the saturated solution of the target compound. , Other crystallization approaches involving variation in crystallization temperature, , milling condition, solvent polarity, humidity, etc. can be explored during polymorph screening and crystallization.…”

Section: Introductionmentioning

confidence: 99%

“…13−17 Polymorphs and hydrates are often obtained by slow solvent evaporation or cooling crystallization dealing with the saturated solution of the target compound. 18,19 Other crystallization approaches involving variation in crystallization temperature, 20,21 milling condition, 22 solvent polarity, 13 humidity, 24 etc. can be explored during polymorph screening and crystallization.…”

Section: Introductionmentioning

confidence: 99%

In Situ Metastable Form: A Route for the Generation of Hydrate and Anhydrous Forms of Ceritinib

Chennuru

Koya

Kommavarapu

et al. 2017

Self Cite

Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). This BCS class IV drug is developed by Novartis and traded under the name Zykadia. To date two forms [Form A (marketed form) and B] of ceritinib are disclosed in international patent application US 2013/0274279 A1. However, the crystal structure and insight into any solid form of this compound are not available in the literature. In order to achieve better physicochemical properties compared to known solid forms of this compound, novel polymorph identification is chosen as one of the challenging paths to address the issue. In our comprehensive polymorph screening, including in silico and experimental investigations, we discovered three novel solid forms of ceritinib. Out of these three solid forms, two are neat (Form 1 and Form 3) and the remaining one is a hydrate (Form 2). All synthesized forms are further characterized by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. It is interesting to note that the discovery of this hydrate is in sync with the prediction done using COSMO-RS theory (COSMOthermX software). The current article includes the first single crystal structure of ceritinib Form 1. All forms (Form 1, 2, and 3) of ceritinib are subjected to physicochemical property evaluation like solubility in buffers with a pH range of 1–7, dissolution, and stability. In aqueous solutions and pH 4.5 (acetate buffer), the solubility of Form 2 and 3 is high compared to Form 1, whereas in 0.1 N HCl and 0.01 N HCl Form 1 has a higher solubility compared to Forms 2 and 3. A six-month stability study indicates that all forms (Forms 1, 2, and 3) are stable in ICH stability conditions like accelerated (40 °C ± 2 °C, 75% RH ± 5% RH), long-term (25 °C ± 2 °C, 60% RH ± 5% RH), and low temperature (2–8 °C) conditions. A thorough polymorph screening protocol, including in silico prediction, single crystal structure, and physicochemical properties of different forms and structure property correlations for ceritinib are enlightened in the current paper.