Crystallography Flashcards
What is a supramolecular Synthon?
During crystallisation of an organic solid, patterns of intermolecular interactions are established. Analysis of crystal structure reveals that some patterns are frequently encountered called “supramolecular synthons”
Supramolecular synthons can be used to design a supramolecular synthesis, the products being cocrystals
What different properties can Polymorphs have?
Physico-chemical – melting point, stability/reactivity, solubility, density, vapour pressure
Mechanical – hardness, particle flow, tabletting, compactability
Spectroscopic – UV/visible colour, IR and Raman, solid-state NMR
Pharmaceutically related – bioavailability, formulation properties, interactions with excipients in tablet
How can you grow metastable Polymorphs?
Nuclei of less stable polymorphs that would normally dissolve can keep growing in high supersaturation (dissolved above equilibrium solubility, the solution dries to form crystals to reach equilibrium again) regimes. This grows multiple forms, not just the most stable.
Polymorph example - Paracetamol
Has 2 well-established polymorphs, form 1 is easily obtained but does not compress well, form 2 will form tablets but not easy to obtain from solution. However as form 2 is not stable and does not appear during normal large-scale crystallisation, commercial products are made of form 1 with lots of binding material.
Polymorph example - Ritonavir
Ritonavir form 1 is a beta sheet, form 2 is a molecular stack which is not bioavailable
The new form occurred and was unable to be removed or prevented. The cause was the change of conformation (cis/trans), causing different solubility properties
What are the different processes for Crystal Screening?
- Thermal (evaporation or cooling)
- Antisolvent – add poor solvent to good solvent, changing solvent properties and solubility and therefore causing supersaturation. Used more in industry
- Sublimation/melting
- Slurrying
- Computational (crystal structure prediction)
What is the Biopharmaceutics Classification System (BCS)?
Solubility and permeability relationship - solid state formulations relate to solubility and dissolution rates
Class I - High solubility, High permeability
Class II - Low solubility, High permeability
Class III - High solubility, Low permeability
Class IV - Low solubility, Low permeability
What is a Pharmaceutical Cocrystal?
Pharmaceutical cocrystals - When at least one component is therapeutically active, and the others are pharmaceutically acceptable
Design solubility for co-crystals refers to the process of tailoring or engineering the solubility properties of a co-crystal system in order to achieve a desired dissolution rate, bioavailability, or therapeutic efficacy
What is Rational Crystal Design?
Supramolecular chemistry and molecular recognition in molecular solids. Two types:
Database searches - allows recognising repeatable motifs (supramolecular synthons). Gives us an idea of the expected structure before it is prepared
Control of reactivity using cocrystals - Crystal engineering of photoactive materials. Properties of a drug (that does not easily crystallise or has unwanted characteristics or stability issues) can be changed with cocrystals
What are the different approaches in Crystal Engineering?
- Polymorph control – difficult to achieve, polymorphs often form into the most stable one
- Salt formation – trial-and-error technique, increases aqueous solubility of compounds, used in pharmaceutical industry often
- Formation of solid solutions – forcing the molecule to adopt a lattice site in the crystal of a different compound *
- Use of steering groups – specific groups are introduced onto the parent molecule, steering it into a preferred solid-state structure. Hydrogen bonding, Cl-Cl and pi-pi interactions
- Formation of cocrystals – most recent technique, utilises supramolecular synthons to rationally construct supramolecular structures
What are some characterisation techniques for crystals?
- Diffraction – scattering of electromagnetic waves obeying Braggs Law. X-ray diffraction most common in the form of single crystal diffraction (most detailed) and powder diffraction (phase characterisation of bulk). Neutron and electrons can also be used
- Spectroscopy – IR, raman and NMR solid state
- Thermal analysis and calorimetry – differential scanning calorimetry (DSC) and therma gravimetric analysis (TGA)
- Microscopy – polarised light microscopy, hot stage microscopy (combines thermal analysis and microscopy, supports DSC or TGA), electron microscopy, AFM*
- Physical properties – hydrate/solvate formation (dynamic vapour sorption), solubility/dissolution, mechanical properties (AFM and nano-indentation)
How do we describe crystal Morphology?
The relationship between external crystal morphology and the internal crystal structure is a combined result of;
- Consequences of internal arrangement of the molecules within the crystal
- The effect of the environment/crystallization conditions
A crystal is described using unit cells, repetition of unit cells provides the crystal. The contents of neighboring unit cells are more closely connected at edges than corners.
There are 7 basis crystal systems.
Molecular interactions – the BFDH model is not sufficient in cases where strong and directional intermolecular forces exist such as hydrogen bonds.
Large bulky molecules don’t pack well, thin molecules pack better
What are the different types of energy that are used to predict Solubility?
- Crystal packing energy – costs energy to cause disorder
- Cavity formation energy – costs energy, creating a gap in the middle by disrupting h-bond network of water
- Solvation energy – produces energy, sum of favourable interactions upon insertion of solute into cavity
What are the levels of Solid Forms?
Molecular properties are largely determined by functional groups, but solid-state properties will depend on the nature of the solid that is formed (crystal shape, internal view of molecular arrangement)
3 levels of solid forms:
- Level 1 – order within solid; truly crystalline (high order) or amorphous (low order) arrangement. Most amorphous materials are more soluble. Spring and parachute concept – amorphous materials can reach a high drug concentration quickly but also drop quickly, due to high solubility. Prevention of crystallization can lead to spring and parachute concentration curve, having a high drug concentration for a longer time
Level 2 – variation in order; different arrangements/polymorphs of solid-state ordering. Typically, only one polymorph is stable, the rest are metastable and may convert to the stable polymorph
Level 3 – numerous types of species in the crystal; crystals are also achieved through formation of multicomponent systems (salts, cocrystals, solid solutions, hydrates, solvates, mixed crystals).
What is the Delta pKa rule?
The difference in the pKa values of the two components of a two-component crystal can tell us if the crystal formed is a salt (ionic) or a cocrystal (neutral).
When the pKa difference between a cocrystallising acid and base is greater than 2 or 3 (ΔpKa = pKa[protonated base] − pKa[acid] > 2 or 3), salt formation is expected.
describe the structure of solvates, hydrates and salts?
A solvate is a multicomponent crystal (like a cocrystal) where one of the components is a room temperature liquid and can be used as the solvent. Hydrates are water solvates.
Salts are ionic multicomponent crystal solids made of of at least a cation and anion.
