Direction of copper phthalocyanine crystallization using in situ generated tethered phthalocyanines

Copper phthalocyanine in the metastable α crystal polymorph can be obtained directly from phthalonitrile or from phthalodiimide, which would normally give the more stable β crystal form, by the inclusion of 3% or greater of the sulfide 2 or the diimide 3. The resulting α form material does not revert to the β form upon treatment in boiling xylene, unlike conventionally prepared α copper phthalocyanine

Impurity occurrence and removal in crystalline products from process reactions

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

Determination of composition distributions of multi-particle crystalline samples by sequential dissolution with concomitant particle sizing and solution analysis

Impurities arise in the production of molecular pharmaceutical and fine chemical products and are often addressed by crystallisation. However, impurities are not always adequately removed by crystallisations and in some cases impurities are to a certain extent incorporated within crystal particles. The present work aims to develop approaches to mapping the distribution of impurities within crystal particles for samples of multiple particles by controlled stepwise dissolution in conjunction with analysis by HPLC and sizing of the crystals. 2-Nitro-4-trifluoromethylacetanilide (1) was selected as the compound for study while 4-methyl-2-nitroacetanilide (2), 4-chloro-2-nitroacetanilide (3) and N-(2-nitro-4-trifluoromethylphenyl)pivalamide (4) were selected as the added impurities. The degree of incorporation of additives 2, 3 and 4 into crystals of compound 1 grown from solutions containing up to 10% of the additive was determined, using 50% aqueous ethanol and toluene as solvents. The stepwise dissolution of samples of crystals of compound 1 in hexane, in which compound 1 has low solubility, containing 2-(2-ethylhexyloxy)ethanol to inhibit flocculation, showed reasonably even dissolution of all crystal particles. Analysis of the resulting solutions by HPLC gave composition data which could be assigned to averaged dissolution regions of the crystals, generating distributions of the level of each additive throughout the crystal particle, these being found to be relatively even for additive 2 and 3, and uneven for additive 4

Methyl tetra-O-acetyl-α-d-glucopyranuronate: crystal structure and influence on the crystallisation of the β anomer

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

Scale-up and optimization of a continuous flow synthesis of an α-thio-βchloroacrylamide

Use of continuous flow processing to undertake a multistep chlorination cascade has been achieved with effective inline work-up and end-of-line crystallization in batch leading to isolation of α-thio-β-chloroacrylamide Z-3 in pure form from a complex reaction mixture, exploiting the advantage of efficient heat transfer in flow. During the development of a continuous flow strategy for the production of appreciable quantities of the α-thio-β-chloroacrylamides, difficulties surrounding a labour and resource intensive work-up followed by final product isolation were addressed. A greener solvent choice was applied to the chemical synthesis which enabled inline purification and separation, resulting in the crystallization of pure product directly from the reaction mixture. This process was readily scalable and demonstrated control over impurity formation and removal, which is key in an industrial setting

Crystal polymorphs and transformations of 2-iodo-4-nitroaniline

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. [Published as part of a virtual special issue of selected papers presented in celebration of the 40th Anniversary Conference of the British Association for Crystal Growth (BACG), which was held at Wills Hall, Bristol, UK, September 6-8, 2009

Crystal polymorphism of methyl 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-α-d-glucopyranouronate

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 II a 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 group

The impact of storage conditions upon gentamicin coated antimicrobial implants

A systematic approach was developed to investigate the stability of gentamicin sulfate (GS) and GS/poly (lactic-co-glycolic acid) (PLGA) coatings on hydroxyapatite surfaces. The influence of environmental factors (light, humidity, oxidation and heat) upon degradation of the drug in the coatings was investigated using liquid chromatography with evaporative light scattering detection and mass spectrometry. GS coated rods were found to be stable across the range of environments assessed, with only an oxidizing atmosphere resulting in significant changes to the gentamicin composition. In contrast, rods coated with GS/PLGA were more sensitive to storage conditions with compositional changes being detected after storage at 60 °C, 75% relative humidity or exposure to light. The effect of γ-irradiation on the coated rods was also investigated and found to have no significant effect. Finally, liquid chromatography–mass spectrometry analysis revealed that known gentamines C1, C1a and C2 were the major degradants formed. Forced degradation of gentamicin coatings did not produce any unexpected degradants or impurities