The pressure‑temperature behavior of anhydrous caffeine’s two polymorphs—form II (monoclinic) and form I (trigonal)—was characterized by high‑resolution powder diffraction, electron microscopy, differential scanning calorimetry and high‑pressure thermal analysis. Measured transition enthalpies are 19 J g⁻¹ for the solid‑solid conversion and 109 J g⁻¹ for melting of form I. Direct application of the Clapeyron equation to these state functions yields linear equilibrium relations with slopes of dP/dT = 4.15 MPa K⁻¹ for the I-II equilibrium and 2.6 MPa K⁻¹ for the I‑L equilibrium, values that match the direct measurements at different pressures and temperatures in this study and in the literature. The resulting phase diagram shows divergent I-II and I‑L lines with increasing pressure, placing caffeine in Bakhuis-Roozeboom’s case 2 (overall enantiotropy) and locating the I‑II‑L triple point at negative pressure, thus metastable. Form I consistently has a larger specific volume than form II, and the volume change on melting follows the typical VL/VS ratio of about 1.11 for organic solids. The close agreement between experiment and Clapeyron‑based (topological) predictions demonstrates that the topological method correctly captures polymorphic stability across broad pressure and temperature ranges.

Drug efficacy strongly relies on the solid state of the active pharmaceutical ingredient. Classical solid-state screening methods involve different solvent compositions and supersaturations. Moreover, the many repeated experiments needed to address the stochasticity of nucleation make this approach costly. This paper presents a newly developed modular microfluidic platform that provides a universal and flexible plug-and-play tool for crystallisation studies without use of surfactants. By dissolving a powder, our set-up generates saturated solutions that can be used for solubility measurements or distributed in microdroplets. Here, we describe solubility measurements performed on different forms, stable and metastable, of pharmaceutical molecules (Irbesartan, Rimonabant and Aripiprazole) in organic and aqueous solvents. In addition, we provide nucleation statistics obtained for Sulfathiazole in water and in acetonitrile. Reporting polymorph screening on Sulfathiazole and statistics for nucleated forms, we find that the cooling rate influences both nucleation and polymorphism results, reflecting the competition between thermodynamics and kinetics. Three unknown forms were discovered, with XRD patterns and Raman spectra that do not match any referenced form. We also demonstrate the limitations of microfluidics for crystallisation by cooling: reducing the crystalliser volume considerably increases nucleation induction time.

All four pyrazinamide polymorphs possess a stable domain under ordinary pressure; α is the stable form at room temperature.

Morniflumate diniflumate, a molecular compound involving niflumic acid and its beta-morpholino ethyl ester (morniflumate) in the mole ratio 2:1, is found to crystallize in a triclinic P - 1 space group with a unit-cell volume of 2203.4(5) angstrom 3. It is a cocrystal between a morniflumate+ niflumate- salt and a neutral niflumic acid molecule. The co-crystalline salt forms endothermically with a positive excess volume and it melts incongruently at 382.3(8) K. Differential scanning calorimetry executed at heating rates above 20 K.min- 1, leads to congruent melting at 387.8(9)K with an enthalpy change of Delta fusH = 80(2) J g-1. The rare occurrence that incongruent and congruent melting can be observed for the same cocrystal may be due to the conformational versatility of the niflumic acid molecule and its slow conversion between the different conformations due to weak intramolecular hydrogen bonding.

Pyrazinamide is an active pharmaceutical compound for the treatment of tuberculosis. Itpossesses at least four crystalline polymorphs. Polymorphism may cause solubility problemsas the case of ritonavir has clearly demonstrated; however, polymorphs also provideopportunities to improve pharmaceutical formulations, in particular if the stable form is notvery soluble. The four polymorphs of pyrazinamide constitute a rich system to investigate theusefulness of metastable forms and their stabilization. However, despite the existence of anumber of papers on the polymorphism of pyrazinamide, well-defined equilibrium conditionsbetween the polymorphs appear to be lacking. This paper focusses on the phase behavior ofthe so-called a and g polymorphs of pyrazinamide, its liquid phase and vapor phase. Themelting points and enthalpies of both solid phases have been determined. The equilibriumtemperature between a and g was experimentally found at 392(1) K. Moreover, vaporpressures and solubilities of both phases have been determined, clearly indicating that forma is the more stable form at room temperature. High-pressure thermal analysis and thetopological pressure-temperature phase diagram demonstrate that the g form is stabilized bypressure and becomes stable at room temperature under a pressure of 260 MPa.

Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present article, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under pressure with the I-II-L triple point coordinates for metacetamol TI-II-L = 535 ± 10 K and PI-II-L = 692 ± 70 MPa. However, whereas for paracetamol the enantiotropy under pressure can be foreseen, because the metastable polymorph is denser, in the case of metacetamol this is not possible, as the metastable polymorph is less dense than the stable one. The existence of the stability domain for the less dense polymorph of metacetamol can only be demonstrated by the construction of the topological phase diagram as presented in this article. It is a delicate interplay between the specific volume differences and the enthalpy differences causing the stability domain of the less dense polymorph to be sandwiched between the denser polymorph and the liquid. Metacetamol shares this behavior with bicalutamide and fluoxetine nitrate.

Phosphoinositide 3-kinases (PI3Ks) are involved in important cellular functions and represent desirable targets for drug discovery efforts, especially related to oncology; however, the four PI3K subtypes (α, β, γ, and δ) have highly similar binding sites, making the design of selective inhibitors challenging. A series of inhibitors with selectivity toward the β subtype over δ resulted in compound 3(S), which has entered a phase I/Ib clinical trial for patients with advanced PTEN-deficient cancer. Interestingly, X-ray crystallography revealed that the modifications making inhibitor 3(S) and related compounds selective toward the β-isoform do not interact directly with either PI3Kβ or PI3Kδ, thereby confounding rationalization of the SAR. Here, we apply explicit solvent molecular dynamics and solvent thermodynamic analysis using WaterMap in an effort to understand the unusual affinity and selectivity trends. We find that differences in solvent energetics and water networks, which are modulated upon binding of different ligands, explain the experimental affinity and selectivity trends. This study highlights the critical role of water molecules in molecular recognition and the importance of considering water networks in drug discovery efforts to rationalize and improve selectivity.

Two polymorphs of the 1:1 fumarate salt of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester, developed for the treatment of cognitive symptoms of schizophrenia and Alzheimer disease, have been characterized. The 2 crystal structures have been solved, and their phase relationships have been established. The space group of form I is P2(1)/c with a unit-cell volume of 1811.6 (5) angstrom(3) with Z = 4. The crystals of form I were 2-component nonmerohedral twins. The space group of form II is P2(1)/n with a unit-cell volume of 1818.6 (3) angstrom(3) with Z = 4. Relative stabilities have been inferred from experimental and topological P-T diagrams exhibiting an overall enantiotropic relationship between forms I and II although the solid-solid transition has never been observed. The slope of the I-II equilibrium in the P-T diagram is negative, form II is the stable phase below the solid-solid transition temperature of 371 K, and form I exhibits a stable melting equilibrium. The I-II transition temperature has been obtained from the intersection of the sublimation curves of the 2 solid forms. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.