Crystallisation of organic materials from the solution phase: a molecular, synthonic and crystallographic perspective

Abstract

The fundamental crystal science underpinning the industrial crystallisation of organic materials is reviewed from molecular, intermolecular (synthonic) and crystallographic perspectives. The main aspects that differentiate the crystal growth of these materials from more conventional commercial crystal growth of large single crystals and epitaxial layers for micro-electronic applications are highlighted. Building up on key concepts of intermolecular forces, crystallisation and crystal chemistry, the factors that govern the bulk structure, equilibrium external morphology and hence surface chemistry of crystals are reviewed. The non-equilibrium case of solution-phase crystallisation builds upon this, dealing with the core aspects of solubility, solution metastability, and hence crystallisability and how supersaturation relates to molecular assembly through the nucleation process and the subsequent faceting of the nuclei through the growth process into well-defined polyhedral crystalline forms. The practical implications are brought into sharp focus through a number of case-study examples whereby the crystallisation process can be engineered to produce crystals with pre- desired physico-chemical properties, notably crystal size, crystal structure, crystal morphology, purity and agglomerability. Abbreviations: 0D: Zero-dimension; 1D: One-dimension; 2D: Two-dimension; 3D: Three-dimension; ADDoPT: Advanced Digital Design Transforming Pharmaceutical Development and Manufacture; AE: Attachment energy; AFM: Atomic force microscopic; AIDS: Acquired Immuno-Deficiency Syndrome; API: Active Pharmaceutical Ingredient; ATR-FTIR: Attenuated total reflectance – Fourier transform infrared; B&S: Birth & Spread; BCF: Burton-Cabrera-Frank; BFDH: Bravais–Friedel–Donnay–Harker; Bud: Budesonide; CCDC: Cambridge Crystallographic Data Centre; CSD: Crystal size distribution; DSC: Differential scanning calorimetry; EPSRC: Engineering and Physical Sciences Research Council; EtOH: Ethanol; F: Flat faces; FP: Fluticasone propionate; FTIR: Fourier transform infrared; H-bonding: Hydrogen bonding; IN: Instantaneous nucleation; ISSCG-17: The 17th International Summer School on Crystal Growth; K: Kink faces; KBHR: Kashchiev – Borissova – Hammond – Roberts; KJR: Kevin J Roberts; LGA: L-glutamic acid; MCS: Manufacturing Classification System; MSG: Monosodium glutamate; MSZW: Metastable zone width; NA: Nornizar Anuar; PABA: Para-amino benzoic acid; PBC: Periodic Bond Chain; PN: Progressive nucleation; PXRD: Powder x-ray diffraction; R&D: Research and Development; RIG: Rough interface growth; ROY: Red-Orange-Yellow; S: Stepped faces; SB: Salbutamol; SDS: Sodium dodecyl sulphate; UiTM: Universiti Teknologi MARA; UV-Vis: Ultraviolet–visible spectroscopy; XRD: X-ray diffraction