Relating induction time and metastable zone width

© 2017 The Royal Society of Chemistry. A relation between induction time and metastable zone width in cooling crystallization has been developed based on the correlation between temperature and supersaturation with the induction time in the classical nucleation theory. By this relation, the nucleation times in linear cooling experiments and the induction times at constant temperature can be estimated from each other, i.e. estimating metastable zone widths from experimental induction times or interfacial energy and the pre-exponential factor from metastable zone widths. Ascorbic-water system, with 120 induction times and 192 metastable zone widths determined, and several systems reported in the literature, have been investigated to compare the estimated values of metastable zone width/induction time with experimental values, respectively. The estimated metastable zone widths are fairly consistent with the experimental values. The differences between experimental literature values of metastable zone widths and the estimated values using the literature induction times range from 0.1 K to 10 K with an average of 2.5 K. For two systems (paracetamol in ethanol and salicylic acid in ethyl acetate), estimated and experimental results are of very good consistency with an average uncertainty of only about 5%. More accurate extrapolations of the induction times from metastable zone widths have been investigated. The potential utilities of this approach in crystallization research and process understanding are discussed

Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals

Polymer Templating of Supercooled Indomethacin for Polymorph Selection

Reported here is a relatively simple technique for polymorph screening of pharmaceutical compounds that are thermally stable. Polymer libraries have previously been used as surfaces to influence, or direct, the crystalline form adopted by an active pharmaceutical ingredient on crystallization from solution. In this current work, we demonstrate the polymorph-directing effect of homopolymer surfaces in the absence of solvent by recrystallization from the supercooled melt. When the nonsteroidal anti-inflammatory drug indomethacin is melted, cooled, and subsequently reheated above its glass transition temperature on an untreated surface, it has a proclivity to crystallize as its δ polymorph. On certain polymer surfaces, however, it preferentially crystallizes as the α polymorph, as a direct result of polymer templating. The method is well-suited to implementation in multiwell plate formats requiring only small amounts of material and enabling multiple experiments to be carried out in parallel with samples readily characterized using X-ray powder diffraction

Formulation of Liquid Propofol as a Cocrystalline Solid

This work details a crystal engineering strategy to obtain a novel solid form of the liquid drug molecule propofol using isonicotinamide as a cocrystal former. Knowledge of intermolecular hydrogen bonded supramolecular synthons has been exploited to select a potential cocrystal former based on the likely growth unit formed. The structure of the cocrystal, solved using single-crystal X-ray diffraction, is reported, confirming the molecular packing and key intermolecular interactions adopted in the novel solid form. The potential to enhance a drug’s properties is demonstrated by an increased melting point compared to the native drug form, such that the liquid drug becomes a stable solid at room temperature. Unusually, the propofol/isonicotinamide complex has three structurally similar, temperature-dependent polymorphs, and the crystal structure of each form is reported herein

Complex Polymorphic System of Gallic AcidFive Monohydrates, Three Anhydrates, and over 20 Solvates

We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate crystal energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity

Combined Chemoinformatics Approach to Solvent Library Design Using clusterSim and Multidimensional Scaling

Reported here is a rational approach for the selection of solvents intended for use in physical form screening based on a novel chemoinformatics analysis of solvent properties. A comprehensive assessment of eight clustering methods was carried out on a series of 94 solvents described by calculated molecular descriptors using the clusterSim package in R. The effectiveness of clustering methods was evaluated using a range of statistical measures as well as increasing efficiency of solid form discovery using a cluster-based solvent selection approach. Multidimensional scaling was used to illustrate cluster analysis on a two-dimensional solvent map. The map presented here is a valuable tool to aid efficient solvent selection in physical form screens. This tool is equally applicable to any scientific area which requires a solubility dependent decision on solvent choice

Solid-State Forms of β-Resorcylic Acid: How Exhaustive Should a Polymorph Screen Be?

A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with <i>N</i>,<i>N</i>-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the <i>p</i>-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found

Absorbing a Little Water: The Structural, Thermodynamic, and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate

The anhydrate and the stoichiometric tetarto-hydrate of pyrogallol (0.25 mol water per mol pyrogallol) are both storage stable at ambient conditions, provided that they are phase pure, with the system being at equilibrium at <i>a</i>_w (water activity) = 0.15 at 25 °C. Structures have been derived from single crystal and powder X-ray diffraction data for the anhydrate and hydrate, respectively. It is notable that the tetarto-hydrate forms a tetragonal structure with water in channels, a framework that although stabilized by water, is found as a higher energy structure on a computationally generated crystal energy landscape, which has the anhydrate crystal structure as the most stable form. Thus, a combination of slurry experiments, X-ray diffraction, spectroscopy, moisture (de)­sorption, and thermo-analytical methods with the computationally generated crystal energy landscape and lattice energy calculations provides a consistent picture of the finely balanced hydration behavior of pyrogallol. In addition, two monotropically related dimethyl sulfoxide monosolvates were found in the accompanying solid form screen

Racemic Naproxen: A Multidisciplinary Structural and Thermodynamic Comparison with the Enantiopure Form

Following the computational prediction that (<i>RS</i>)-naproxen would be more stable than the therapeutically used and more studied homochiral (<i>S</i>)-naproxen, we performed an interdisciplinary study contrasting the two compounds. The crystal structure of the racemic compound was solved from powder X-ray diffraction data (<i>Pbca</i>) and showed no packing similarity with the homochiral structure (<i>P</i>2₁). The binary melting point phase diagram was constructed to confirm the nature of the racemic species, and differential scanning calorimetric and solubility measurements were used to estimate the enthalpy difference between the crystals (Δ<i>H</i>_{<i>R</i>+<i>S</i>→<i>RS</i>}^cry) to be −1.5 ± 0.3 kJ·mol^–1 at <i>T</i> ∼ 156 °C and −2.4 ± 1.0 kJ·mol^–1 in the range 10–40 °C. A comparison of the different approximations involved in estimating Δ<i>H</i>_{<i>R</i>+<i>S</i>→<i>RS</i>}^cry implied that the difference in the lattice energies overestimated the stability of the (<i>RS</i>) crystal. The naproxen lattice energy landscape confirmed that all the practically important crystal structures have been found and characterized and provided insights into the crystal growth problems of the racemic form. This highlights the complementarity of computational modeling in investigating chiral crystallization

Exploring the Experimental and Computed Crystal Energy Landscape of Olanzapine

An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are responsible for all the observed structures being based on the dimer. Thus, this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization