Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced 13C and 15N Solid-State NMR Spectroscopy.

Crystallization is a widely used purification technique in the manufacture of active pharmaceutical ingredients (APIs) and precursor molecules. However, when impurities and desired compounds have similar molecular structures, separation by crystallization may become challenging. In such cases, some impurities may form crystalline solid solutions with the desired product during recrystallization. Understanding the molecular structure of these recrystallized solid solutions is crucial to devise methods for effective purification. Unfortunately, there are limited analytical techniques that provide insights into the molecular structure or spatial distribution of impurities that are incorporated within recrystallized products. In this study, we investigated model solid solutions formed by recrystallizing salicylic acid (SA) in the presence of anthranilic acid (AA). These two molecules are known to form crystalline solid solutions due to their similar molecular structures. To overcome challenges associated with the long 1H longitudinal relaxation times (T1(1H)) of SA and AA, we employed dynamic nuclear polarization (DNP) and 15N isotope enrichment to enable solid-state NMR experiments. Results of solid-state NMR experiments and DFT calculations revealed that SA and AA are homogeneously alloyed as a solid solution. Heteronuclear correlation (HETCOR) experiments and plane-wave DFT structural models provide further evidence of the molecular-level interactions between SA and AA. This research provides valuable insights into the molecular structure of recrystallized solid solutions, contributing to the development of effective purification strategies and an understanding of the physicochemical properties of solid solutions.

Terminal crystalline solid solutions, solubility enhancements and T-X phase diagram of salicylic acid - 4-hydroxybenzoic acid.

The binary T-X phase diagram of salicylic acid (SA) and 4-hydroxybenzoic acid (4HBA) has been constructed from 20 °C to melting, revealing a partially miscible system with an eutectic composition of 27.3 mol% 4HBA in SA. Terminal crystalline solid solutions were obtained at the extremes of the phase diagram with solid-state miscibility limits below 0.4% at 20 °C. The limited phase boundaries could be captured experimentally by both DSC analyses at around melting temperature and solid-liquid equilibria studies at 20 °C in two solvent systems. The NRTL model was applied to regress phase boundaries and generate the final binary T-X phase diagram. The NRTL model was also used to regress solubility data, and reproduce the ternary SA/4HBA/solvent phase diagram at 20 °C and 1 atm. 4HBA was obtained as two crystal forms, viz. anhydrate and monohydrate. It is shown how the monohydrate of 4HBA is less miscible with SA in the solid state than the anhydrous form of 4HBA. As compared to pure SA and 4HBA, the crystalline solid solutions exhibited significant changes in physical properties that are relevant for organic and pharmaceutical materials in the context of impurity effects. A lattice incorporation of just 0.2 mol% 4HBA in SA caused a 10% reduction in melting enthalpy and a 66% solubility increase in 40 wt% MeOH in H2O. The reasons for this thermodynamic effect are discussed.

Complex oiling-out behavior of procaine with stable and metastable liquid phases.

During the crystallization of a solute from solvent(s), spontaneous liquid-liquid phase separation (LLPS) might occur, under certain conditions. This phenomenon, colloquially referred to as "oiling-out" in the pharmaceutical industry, often leads to undesired outcomes, including undesired particle properties, encrustation, ineffective impurity rejection, and excessively long process time. Therefore, it is critical to understand the thermodynamic driving force and phase boundaries of this phenomenon, such that rational strategies can be developed to avoid oiling-out or minimize its negative impact. In this study, we systematically evaluated the oiling-out behavior of procaine, a low melting point drug, in the solvent systems heptane, and ethanol-heptane as a function of temperature and solvent composition. In the procaine-heptane binary system, we observed a region where the LLPS is metastable with respect to crystallization, which is most commonly observed in the crystallization of modern active pharmaceutical ingredients (APIs); however, we also identified a region of the phase diagram where the LLPS is stable with respect to crystallization, and therefore will persist indefinitely. In the procaine-ethanol-heptane ternary system we identified five different regions, including a homogeneous liquid (L) region, two solid-liquid (SLI and SLII) regions, a liquid-liquid (LILII) region, and a solid-liquid-liquid (SLILII) region. The binary and ternary phase diagrams were also predicted using a state-of-the-art thermodynamic model: the SAFT-γ-Mie equation of state, and the results were compared with experimental data. Our findings highlight the complexity of oiling-out behavior. This work also represents a combined modeling and experimental platform to identify phase boundaries that will enable rational selection of strategies to crystallize active pharmaceutical ingredients with oiling-out risks.

Enantiotropic inconstancy, crystalline solid solutions and co-crystal in the salicylic acid-anthranilic acid system.

The phase boundaries and thermodynamic properties of crystal phases in the salicylic acid (SA) - anthranilic acid (AA) system have been determined experimentally. The complete binary T-X diagram reveals a total of four crystalline phases, including a co-crystal and three crystalline solid solutions. The two eutectics were determined through triplicate DSC analyses at 33 compositions. By adding a liquid solvent and generating a ternary phase diagram, a methodology is introduced to determine the solid-state miscibility limits of the solid solutions at 20 and 55 °C. The crystalline solid solutions exhibit substantial differences in physical properties relative to the pure components, including solubility enhancements that are relevant for chemical processing and material properties. The thermodynamic relationships of the three polymorphs of AA have been resolved showing an enantiotropic transition temperature of 50-55 °C between Form I and III of pure AA. However, as a result of the solid solutions with SA, the enantiotropic transition temperature was suppressed by around 30 °C at the eutectoid. In addition, a co-existence envelope is formed, wherein the two AA polymorph solid solutions exist in equilibrium with one another over a wide range of temperatures and compositions.

Prediction of solubility curves and melting properties of organic and pharmaceutical compounds.

The relationships between solubility, temperature dependence of solubility, melting temperature and melting enthalpy are investigated for the purpose of finding relations that can significantly reduce the need for experimental work in the selection of the solvent for processing of organic fine chemicals and pharmaceuticals. The relationships are investigated theoretically and by evaluation of experimental data for 41 organic and pharmaceutical compounds comprising a total of 115 solubility curves in organic and aqueous solvents. The work considers (i) selection of the equation for correlation of solubility data based on thermodynamic considerations and ability to predict melting properties of the solute from solubility data, (ii) prediction of the temperature dependence of solubility, and (iii) prediction of solubility curves in new solvents. While it is a simple task to find an equation to obtain a decent fit of experimental solubility data, it is more challenging to find relations that are sufficiently sound thermodynamically to allow for extrapolation to the melting temperature. However, with a proper choice of equation it is shown that the melting temperature of the solute can readily be predicted from solubility data in organic solvents (average accuracy of -5K, standard deviation of 26K). Relationships are identified by which the entire solubility curve can be predicted of the compound in a new solvent using only the melting properties and a single solubility data point in that solvent.

Polymorphism and thermodynamics of m-hydroxybenzoic acid.

Solution and solid-state properties of m-hydroxybenzoic acid have been investigated. Two polymorphs were found where the monoclinic modification exhibits a higher stability than the orthorhombic form. The solubility of the monoclinic polymorph was determined between 10 and 50 degrees C in methanol, acetonitrile, acetic acid, acetone, water and ethyl acetate. The solubility of the orthorhombic polymorph was determined between 10 and 50 degrees C in acetonitrile, acetic acid, acetone and ethyl acetate. A thermodynamic analysis revealed a marked correlation between the molar solubility and the van't Hoff enthalpy of solution at constant temperature. In addition, in each solvent increased temperature resulted in increased van't Hoff enthalpy of solution. It is shown that the solubility data can be used to estimate melting properties for both polymorphs. The solubility ratio of the two forms and the DSC thermogram of the orthorhombic form strongly suggest that the system is monotropic. However, according to the polymorph rules of Burger and Ramberger, the estimated higher melting enthalpy and lower melting temperature of the orthorhombic form points towards an enantiotropic system. Hence, this system appears to be an exception to the Burger and Ramberger melting enthalpy rule, and the probable reason for this is found in the difference in the heat capacity of the two solid forms.

Phase equilibria and thermodynamics of p-hydroxybenzoic acid.

The prevalence of phases and associated solubilities of p-hydroxybenzoic acid have been investigated in methanol, acetonitrile, acetic acid, acetone, water, and ethyl acetate at temperatures from 10 to 50 degrees C. Thermodynamic data was acquired through determination of van't Hoff enthalpy of solution, enthalpy of fusion, and melting temperature. Indications of polymorphic enantiotropy were found primarily through solubility analysis and FTIR-ATR. A comprehensive thermodynamic investigation disclosed correlation between the van't Hoff enthalpy of solution and the solubility in different solvents. A higher solubility is linked to a lower van't Hoff enthalpy of solution. A thermodynamic analysis to discriminate between different solid phases is presented.

Analysis of solution nonideality of a pseudomorphic drug system through a comprehensive thermodynamic framework for the design of a crystallization process.

Solutions of a semipolar drug belonging to the alpha(V) beta(iii) integrin antagonist class of compounds were studied in a comprehensive thermodynamic framework. The solubility of two pseudomorphic forms (an anhydrate and a monohydrate) was measured at several temperatures and various solvent mixtures of acetonitrile and water. Both forms displayed a "bell"-shaped solubility behavior as a function of cosolvent composition. Thermodynamic framework used to analyze the data comprised van't Hoff and enthalpy-entropy compensation analyses. The two pseudomorphs exhibited linear temperature dependence from 25 to 65 degrees C at all solvent compositions (i.e., ideal behavior with temperature for fixed solvent composition). Plots of enthalpy of solublization and Gibbs free energy showed two distinct regions with contrasting thermodynamic, and consequently, underlying structural properties (indicating non-deal behavior with solvent composition for a fixed temperature). Solubility increased due to entropy effects in the acetonitrile rich region, whereas enthalpy effects dominated solublization in the water-rich region. Quantification of this phenomenon by plotting DeltaH versus DeltaG showed considerable nonlinearity, and that the two regions were separated by a significant discontinuity-a trend rarely seen before in the literature. The reason behind this behavior is believed to be due to the complex interactions in the solution of the drug in water acetonitrile solvent system. A very significant aspect of the comprehensive thermodynamic analysis is that it helped explain the puzzling feature of the data, which showed that the free energy of phase transformation between the two pseudomorphic forms for a given temperature was not independent of the solvent composition. The resulting explanation has major consequences for crystallization process development.

Advanced mercury removal from gold leachate solutions prior to gold and silver extraction: a field study from an active gold mine in Peru.

Mercury contamination in the Gold-Cyanide Process (GCP) is a serious health and environmental problem. Following the heap leaching of gold and silver ores with NaCN solutions, portions of the mercury-cyano complexes often adhere to the activated carbon (AC) used to extract the gold. During the electrowinning and retorting steps, mercury can be (and often is) emitted to the air as a vapor. This poses a severe health hazard to plant workers and the local environment. Additional concerns relate to the safety of workers when handling the mercury-laden AC. Currently, mercury treatment from the heap leach solution is nonexistent. This is due to the fact that chelating ligands which can effectively work under the adverse pH conditions (as present in the heap leachate solutions) do not exist. In an effort to economically and effectively treat the leachate solution prior to passing over the AC, a dipotassium salt of 1,3-benzenediamidoethanethiol (BDET2-) has been developed to irreversibly bind and precipitate the mercury. The ligand has proven to be highly effective by selectively reducing mercury levels from average initial concentrations of 34.5 ppm (parts per million) to 0.014 ppm within 10 min and to 0.008 ppm within 15 min. X-ray powder diffraction (XRD), proton nuclear magnetic resonance (1H NMR), Raman, and infrared (IR) spectroscopy demonstrate the formation of a mercury-ligand compound, which remains insoluble over pH ranges of 0.0-14.0. Leachate samples from an active gold mine in Peru have been analyzed using cold vapor atomic fluorescence (CVAF) and inductively coupled plasma optical emission spectroscopy (ICP-OES) for metal concentrations before and after treatment with the BDET2- ligand.