The behavior of impurities when subjected to crystallizations, and related processes such as recrystallization and reslurrying, has been reviewed with a particular focus on the years 2000–2015, but also including significant cases from outside that period. Small molecule pharmaceuticals and similar small organic molecules are included but not biomolecules, inorganics, or minerals. Phase impurities are only covered when a phase transformation is involved with the management of an impurity. Introductory examples illustrating some general features of crystallization as a method of purification are presented, as well as approaches to quantifying the effectiveness of purification. The review classifies cases based on the behavior of the specific impurities covered. The classes of behavior observed are the removal by washing, recrystallization, or reslurrying (Class I), impurities not being removed by these operations (Class II), and impurities which are removed in conjunction with a phase transformation (Class III). Examples of each of these types of behavior are presented, with many processes producing impurities which fall into more than one of these classes. Studies on the inclusion of extraneous molecules into crystalline materials are also covered. These particularly include the incorporation of compounds as solid solutions, but also eutectic formation and inclusion at surfaces during crystal growth. The relationship between types of impurities and behavior during processing is also examined.

•Purification and crystal structure of methyl tetra-O-acetyl-α-d-glucopyranuronate.•Occurrence of the α anomer in methyl tetra-O-acetyl-β-d-glucopyranuronate.•α Anomer effect on crystallisation of methyl tetra-O-acetyl-β-d-glucopyranuronate.Methyl tetra-O-acetyl-β-d-glucopyranuronate (1) and methyl tetra-O-acetyl-α-d-glucopyranuronate (3) were isolated as crystalline solids and their crystal structures were obtained. That of the β anomer (1) was the same as that reported by Root et al., while anomer (3) was found to crystallise in the orthorhombic space group P212121 with two independent molecules in the asymmetric unit. No other crystal forms were found for either compound upon recrystallisation from a range of solvents. The α anomer (3) was found to be an impurity in initially precipitated batches of β-anomer (1) in quantities <3%; however, it was possible to remove the α impurity either by recrystallisation or by efficient washing, i.e. the α anomer is not incorporated inside the β anomer crystals. The β anomer (1) was found to grow as prisms or needles elongated in the a crystallographic direction in the absence of the α impurity, while the presence of the α anomer (3) enhanced this elongation.

•Acetamido- and triazolyl-cellobiose derivatives were synthesised.•The acetamido derivative featured amide C(4) chains in the crystal structure.•The triazolyl derivative featured π–π stacking in the crystal structure.1-Acetamido-1-deoxy-(4-O-β-d-glucopyranosyl-β-d-glucopyranose) (5) and 1-deoxy-1-(4-phenyl-1,2,3-triazolyl)-(4-O-β-d-glucopyranosyl-β-d-glucopyranose) (7) were synthesised from 1-azido-1-deoxy-(4-O-β-d-glucopyranosyl-β-d-glucopyranose) (2) and crystallised as dihydrates. Crystal structural analysis of 5·2H2O displayed an acetamide C(4) chain and stacked cellobiose residues. The structure of 7·2H2O featured π–π stacking and stacking of the cellobiose residues.

•Primary amide functionalised glucoses and cellobioses were synthesised and crystallised.•Hydrogen bonding motifs involving both the glucopyranose and primary amide groups were observed.•In an acetylated amido-sulfoxide, the amide groups formed a ladder-like hydrogen bonding motif.A glucoside and cellobioside of glycolamide were synthesised and the crystal chemistry of these compounds investigated. The amidoglucoside crystallised in the P21 space group. The primary amide group participates in C(7) and C(17) chains also involving the pyranose oxygen and hydroxyl groups. The amidocellobioside crystallised as a methanol solvate in the P21 space group. The amide N–H groups donate hydrogen bonds to oxygen atoms on the cellobiose units, while intramolecular hydrogen bonds give rise to S(7) and S(9) motifs in addition to a R33 (9) motif. A tetra-O-acetylglucoside derivative of thioglycolamide and its sulfoxide derivative were synthesised to examine the effect of protecting the glucopyranose hydroxyl groups. The thioglycolamido derivative, which crystallised in the P212121 space group, featured amide N–H groups donating to the glucopyranose oxygen and an acetyloxy group. The sulfoxy derivative crystallised in the P21 space group and featured the primary amide groups forming R23(8) motifs generating a 21 ladder.Graphical abstract

The polymorphism of the glycoside donor methyl 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-α-d-glucopyranouronate (1) has been investigated. Two polymorphic forms (labelled Forms I and II) have been elucidated and fully characterised by DSC, PXRD and single crystal analysis, both crystallizing in the space group P21. Form I was obtained by crystallization from a wide range of solvents, while Form II was obtained only from ethyl acetate or isopropanol on certain occasions. Unit cell dimensions for Form I are a 14.0292(12), b 8.9641(8), c 16.8580(14) Å, β 94.285(2)°, and for Form IIa 11.266(3), b 6.8889(17), c 13.921(4) Å, β 101.161(6)°. Z’ is 2 for Form I and 1 for Form II. Form I displays two moderate intermolecular hydrogen bonds in the unit cell whereas Form II shows no moderate hydrogen-bonding motifs. All three molecules in the two polymorphs differ significantly in their conformations, especially with respect to the methyl carboxylate and trichloroacetimidoyl groups.

The synthesis and crystallisation of the pharmaceutically important metabolite, paracetamol-O-glucuronide, is described. Hydrated and anhydrous forms of the target molecule have been characterised by PXRD, DSC and TGA. In addition, a methanol solvate has been analysed, including single crystal analysis, which represents the first structure solution for this system.

Full crystal structural characterization of three crystal polymorphs of 2-iodo-4-nitroaniline was carried out: the triclinic, orthorhombic, and a new monoclinic form. Powder X-ray diffraction, differential scanning calorimetry, and infrared data on the three of these are reported. Solvent-mediated transformations were observed on the basis of changes in crystal morphology and data from an in situ laser probe. Transformation to the monoclinic form was observed in all cases.