Controlled production of the elusive metastable form II of acetaminophen (paracetamol) : a fully scalable templating approach in a cooling environment

A scalable, transferable, cooling crystallisation route to the elusive, metastable, form II of the API acetaminophen (paracetamol) has been developed using a multicomponent "templating" approach, delivering 100% polymorphic phase pure form II at scales up to 120 g. Favourable solubility and stability properties are found for the form II samples

Isotopomeric polymorphism in a "doubly-polymorphic" multi-component molecular crystal

Isotopomeric polymorphism is observed in complexes of isonicotinamide with oxalic acid, highly unusual here in that each isotopic complex is itself polymorphic, a situation of “double polymorphism”. The four polymorphic forms exhibit different degrees of hydron transfer.</p

From evaporative to cooling crystallisation:an initial co-crystallisation study of cytosine and its fluorinated derivative with 4-chloro-3,5-dinitrobenzoic acid

Two new multi-component molecular complexes of cytosine and 5-fluorocytosine with 4-chloro-3,5-dinitrobenzoic acid are presented. Materials synthesis was achieved initially by evaporative crystallisation and the crystal structures determined. The process was then successfully transferred into a controlled small scale cooling crystallisation environment, with bulk samples shown to be representative of the multi-component product phase, by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) methods. Turbidity measurements are shown to be a valuable process analytical technology probe for characterising the initial stages of molecular complex formation in solution. The significance of these findings for scale-up of crystallisation of multi-component molecular materials and for future transfer into continuous cooling crystallisation is discussed

Intermolecular hydrogen transfer and solubility tuning in multi-component molecular crystals of the API piroxicam

Twelve multi-component molecular crystals of the active pharmaceutical ingredient (API) piroxicam (PX) are described contrasting those with basic N-heterocycles with those formed with strong haloanilic acids. The effect on the solubility of this API is discussed, with evidence of enhanced solubility in the multi-component crystals formed.</p

Crystal engineering urea organic acid hydrogen bonded networks with solvent inclusion properties

Eleven structurally similar materials based on hydrogen bonded networks of N-phenylurea and 5-nitroisophthalic acid have been engineered where nine have interesting solvent inclusion and guest release properties.</p

From structure to crystallisation and pharmaceutical manufacturing: the CSD in CMAC Workflows

Two Workflows are presented that are relevant to the design and construction of end-to-end pharmaceutiucal manufacturing processes. The Workflows target the very early stage crystallisation aspect of these processes – production of the primary crystalline solid form – and relate to establishing decision-driven approaches for the screening for multi-component forms, specifically co-crystals, and to the use of additives to control crystal and primary particle form, notably morphology. These Workflows are shown to benefit from the use of the Million-plus structures in the Cambridge Structural Database and the associated structural informatics and analysis tools and are placed into the context of the work of the CMAC Future Manufacturing Hub

When is a polymorph not a polymorph? Helical trimeric O-H···O synthons in trans-1,4-diethynylcyclohexane-1,4-diol

Two polymorphs (A and B) of trans-1,4-diethynylcyclohexane-1,4-diol represent a unique example of the simultaneous occurrence of both conformational polymorphism and conformational isomorphism, while a pseudopolymorphic monohydrate is closely related

Self-assembly synthesis of precursors to potential open framework alkali earth metal-organic complexes

A series of magnesium pyridinecarboxylic–dicarboxylic acid complexes, synthesised as precursors to potential framework materials, show a range of metal ligand and hydrogen bonding geometries. The pyridinedicarboxylic complexes show most promise as precursors for further syntheses.</p

New Route to Local Order Models for Disordered Crystalline Materials: Diffuse Scattering and Computational Modeling of Phloroglucinol Dihydrate

A new, readily tractable route to determining short-range order models for materials exhibiting occupational disorder and diffuse scattering using first-principles solid-state quantum mechanical calculations is presented and illustrated with application to the disordered, layered molecular material phloroglucinol dihydrate

Probing hydrogen positions in hydrous compounds:information from parametric neutron powder diffraction studies

We demonstrate the extent to which modern detector technology, coupled with a high flux constant wavelength neutron source, can be used to obtain high quality diffraction data from short data collections, allowing the refinement of the full structures (including hydrogen positions) of hydrous compounds from in situ neutron powder diffraction measurements. The in situ thermodiffractometry and controlled humidity studies reported here reveal that important information on the reorientations of structural water molecules with changing conditions can be easily extracted, providing insight into the effects of hydrogen bonding on bulk physical properties. Using crystalline BaCl2 center dot 2H(2)O as an example system, we analyse the structural changes in the compound and its dehydration intermediates with changing temperature and humidity levels to demonstrate the quality of the dynamic structural information on the hydrogen atoms and associated hydrogen bonding that can be obtained without resorting to sample deuteration