Kevin J. Roberts

Scalable solution cocrystallization: case of carbamazepine-nicotinamide I

A framework for conceptualization of scalable solution-crystallization processes for cocrystals is developed and demonstrated using carbamazepine-nicotinamide as the model system. Calculation of intermolecular interactions and crystal lattice energy were carried out to understand the structure and strength of the binding synthons as well as to predict the likely growth morphology and overall crystal growth rate at scale. Experimental measurements of the solubility behavior of the pure components, the solid form stability domain, speciation in solution and effects on nucleation kinetics were employed to establish solvent system and optimize solution crystallization conditions including specifying the initial concentration of the coformer—nicotinamide. A seeding strategy was established, various factors affecting de-saturation kinetics, including nicotinamide concentration, were evaluated and optimized and washing strategy post filtration was developed to deliver and demonstrate a robust process at a 1 L scale with yield in excess of 90% and throughput of 14 L kg−1.

Multi-dimensional population balance modeling of the growth of rod-like L-glutamic acid crystals using growth rates estimated from in-process imaging

Abstract —Traditionally, population balance (PB) modeling of crystal growthin crystallizers has been based on a single scalar parameter for particle size, typically the volume equivalent diameter. This misses important information about particle shape, especially for crystals of high aspect ratios. In recent years attempts have been made to extend PB to two or more size dimensions by taking into consideration of the crystal shape. A key step in multi-dimensional PB (M-PB) modeling is the estimation of the growth rates of individual faces as a function of temporal operating conditions, e.g. the supersaturation. In this paper, we propose to carry out M-PB modeling based on real-time experimentally derived growth rates for different faces using in-process imaging and image analysis. Results are presented for the seeded cooling crystallisation of rod-like β-form L-glutamic acid in a 0.5-l batch reactor.

Investigation into the structures of binary-, tertiary- and quinternary-mixtures of n-alkanes and real diesel waxes using high-resolution synchrotron X-ray powder diffraction

High-resolution X-ray powder diffraction using synchrotron radiation has been used to determine the unit-cell parameters of binary (n-C20H42 /n-C21H44 and n-C20H42 /n-C22H46), tertiary (n-C19H40 to n-C21H44 and n-C20H42 to n-C22H46) and quinternary (with alkanes ranging from n-C18H38 to n-C26H54) n-alkane mixed homologous systems, together with a number of real diesel waxes. The structures have been found to conform to the orthorhombic structure with four molecules per unit cell and space group Fmmm predicted by Luth et al.8 for binary mixtures. Line profile analysis of the powder patterns revealed the existence of incipient end-chain and interchain disorder; a crystal packing model consisting of interchain mixing, end-chain twisting and chain migration is proposed to account for the observed disorder.

Theoretical analysis of the polar morphology and absolute polarity of crystalline urea

Changes to the molecular polarisation of urea associated with its crystallisation are considered through ab initio quantum-mechanical calculations starting with the isolated molecule with increasing complexity up to a full 3D calculation using periodic boundary conditions. The calculations accurately reveal the electrostatic nature of the intermolecular forces associated with the hydrogen-bonding network in the solid state. The resulting charge densities are used together with the force field of Lifson, Hagler and Dauber (J. Am. Chem. Soc., 1979, 101, 5111) in an attachment energy calculation to predict the polar morphology of the material. The resultant simulations are in good agreement with the morphology of crystals prepared from the vapour phase and are used to absolutely assign the polar forms as {1 1 1}. Habit modification effects associated with re-crystallisation from polar solvents are also discussed from a structural perspective.

The breakage behaviour of Aspirin under quasi-static indentation and single particle impact loading: Effect of crystallographic anisotropy

The influence of crystallographic structural anisotropy on the breakage behaviour of Aspirin under impact loading is highlighted. Under both quasi-static testing conditions, using nano-indentation, and dynamic impact tests, Aspirin demonstrates clear anisotropy in its slip and fracture behaviour. During nano-indentation on the (100) and (001) faces, cracks were propagated along the [010] direction. While the hardness was found to be comparatively similar for both these faces, it was observed that slip due to plastic deformation occurred more readily on the (100) than the (001) crystal planes suggesting the former as the preferred slip plane. Furthermore, the fracture toughness on the (001) planes was found to be distinctly lower than that of the (100) planes, indicating the former as the preferred cleavage plane. Observations of the crystal morphology of damaged particles after dynamic impact testing showed that both the chipping and fragmentation of Aspirin mostly occurred via cleavage in a manner consistent with the observed fracture behaviour following nano-indentation. This work highlights the importance of cleavage as a dominant factor underpinning the fracture mechanism of Aspirin under both quasi-static and impact loading conditions.

Dependence of the critical undercooling for crystallization on the cooling rate.

Crystallization in solutions under steady cooling is considered in the case of instantaneous nucleation, in which all crystallites appear at once in the solution and grow in the absence of crystallites born subsequently. Expressions are obtained for the total crystallite volume as a function of the steadily increasing undercooling. These expressions are employed for determining the dependence of the relative critical undercooling u(c) for crystallization on the cooling rate q. The resulting u(c)(q) formula reveals the physical meaning of the parameters in the linear relationship, often reported experimentally, between u(c) and q in double logarithmic coordinates. The results obtained are also directly applicable to overall crystallization of melts at sufficiently small undercoolings.

Characterization of particle size and its distribution during the crystallization of organic fine chemical products as measured in situ using ultrasonic attenuation spectroscopy

The potential application of ultrasonic attenuation spectroscopy to the in situ examination of solution phase crystallization processes is examined through studies carried out on two organic compounds: urea and (L)-glutamic acid. For this study a commercial ultrasonic spectrometer [Ultrasizer by Malvern Instruments Ltd., F. Alba, U.S. Patent 5,121,629 (1992)] was used. A particle size analysis was carried out in an attempt to monitor the crystal size distributions of the crystals growing within the mother liquor. While this technique was found to be of limited effectiveness for the monitoring of the crystallization of urea, due to the formation of high aspect ratio needle crystals, whose long axial size is beyond the range of the technique (0.01 μm–1000 μm), good results were obtained with prismatic (L)-glutamic acid crystals. The size evolution of the latter during crystal growth was successfully monitored throughout the crystallization process.

An examination of the solution phase and nucleation properties of sodium, potassium and rubidium dodecyl sulphates

The nucleation of sodium, rubidium and potassium dodecyl sulphates are examined using temperature programmed milli-scale batch crystallisation experiments using optical turbidometry detection. As sodium dodecyl sulphate (SDS) crystallises as a hydrated system from aqueous solution, studies have also been carried out in the presence of sodium citrate, which causes the anhydrous phase to crystallise. The meta-stable zone widths (MSZW) and solution properties (the enthalpies and entropies of dissolution) as well as the nucleation reaction orders, are measured. The temperature of dissolution decreases with the decrease in cooling/heating rate whilst the temperature of crystallisation increases for all the systems, resulting in a decrease in the meta-stable zone width with decreasing temperature change rate. The enthalpies and entropies of dissolution of sodium, potassium and rubidium dodecyl sulphate increased with increasing alkali metal ionic radii. Very large values of MSZW for sodium citrate containing solutions occur. Extremely high reaction orders occur with SDS, at high concentrations when pure and at low concentrations when with sodium citrate.

Precision measurement of the growth rate and mechanism of ibuprofen {001} and {011} as a function of crystallization environment

The crystallisation of ibuprofen under diffusion-limited conditions measured as a function of supersaturation, solvent (95% ethanol/water, ethyl acetate, acetonitrile and toluene) and reactor scale is examined. Measurement of solubility as a function of temperature reveals less than ideal behaviour, consistent with strong solute–solute interactions, particularly in the case of acetonitrile. The crystal growth rates of the {001} and {011} faces of spontaneously nucleated crystals are precisely measured in situ using optical microscopy revealing that their respective growth rates increase with increasing supersaturation to different extents, depending on the solvent type, with concomitant impact on the crystal habit. The measured growth rates, as a function of supersaturation, are generally higher at the 15 mL than the 0.5 mL scale size. Analysis of the growth rates versus supersaturation is consistent with a 2-D surface nucleation (Birth and Spread) model for both faces and at both scale sizes. The growth rates of the {001} and {011} faces exhibit much less growth rate dispersion when compared to literature data for a stirred batch crystallizer. The data are rationalised by examining the surface chemistry of the growing faces revealing, e.g. that polar protic solvents inhibit the growth rate of faces containing available binding sites for hydrogen bond formation, such as carboxylic acid groups.

Refinement of hydrogen atomic position in a hydrogen bond using a combination of solid-state NMR and computation.

DFT computations of the proton chemical shift for the intermolecular hydrogen bond in the white form of methylnitroacetanilide, together with the experimental value obtained by high-speed magic-angle spinning NMR, enable the N-H distance to be determined as 1.03 +/- 0.02 A.