Importance of Solid Forms Flashcards
What are the types of solid structure and what are the differences?
Amorphous solids - lacking long-range structure
Crystals - anisotropic structure and properties, packed in an ordered way
What is a crystal?
Crystal defined by three-dimensional translational symmetry.
How is crystal structure determined and what condition is related to determination?
Crystals diffract X-rays and produce patterns. Patterns can be used to determine structure using Bragg condition (nλ = 2dsinθ)
What do we need to describe crystal structure?
Space groups:
Bravais lattice (lattice, unit cell, crystal system. lattice type)
Crystal class (point groups)
Translational symmetry elements
What is a crystal lattice?
Set of infinite, arranged points related to each other by translational symmetry
What is the unit cell?
Smallest pattern of lattice points that holds the overall symmetry of a crystal, that can be used to build the lattice up by 3D repetition
What are the crystal systems?
Based on relations between unit cell vectors - three lengths and three angles for repetitive units.
Cubic, tetragonal, orthorhombic, trigonal, hexagonal, monoclinic, triclinic
What are the four lattice types?
P - primitive
I - body centred
F - face centred
C - side-centred (one face only)
What are the Bravais lattices?
Combination of crystal systems and lattice types.
What are the different symmetry elements?
Identity, mirror planes, rotation axes, inversion, improper rotations
What is the crystal class?
Combination of point group elements gives 32 crystal classes.
1 - identity
m - mirror
n - rotation axis
1 bar - inversion
What are the three translational symmetry elements?
Translations, glide planes (reflection and translation by 1/2 unit), screw axes (rotation and translation)
What is a space group?
Set of symmetry elements and operations which describe spatial arrangement of 3D lattices
Looks like: (lattice type)(screw axis)/(glide plane)
What holds molecules together in crystals?
Intermolecular interactions
List all the relevant interactions that hold molecules together in crystals, dividing them into physical and chemical interactions.
Physical nature: Electrostatic, polarisation, dispersion, repulsion
Chemical nature: Hydrogen bonding, halogen bonds, aromatic interactions, ionic interactions, van der Waals
What is a hydrogen bond?
Attractive interaction between hydrogen atom bound to an electronegative atom and another electronegative atom with a lone pair of electrons
Variable strength dep. on environment
What is a halogen bond?
Non-covalent interaction between a σ-hole in a halogen atom and a negative site with a lone pair of electrons
What impacts strength of halogen bonds?
Size of halogen. Larger halogens develop bigger σ-holes in structure, producing larger partial positive charge
What are aromatic interactions?
Attractive interactions between aromatic rings, dominated by dispersion
Off-set face-to-face or edge-to-face interactions.
What are Van der Waals interactions?
Attractive interactions present between molecules at all times due to instantaneous dipole-induced dipole interactions. Cumulative effects.
What are ionic interactions?
Ionic bonding - attraction between positively and negatively charged ions.
What is the close-packing principle?
Molecules will try to fill space via close-packing, energy minimised by intermolecular interaction optimisation
How do we improve solubility in pipeline drugs?
Via solid form optimisation. Different solid forms can impact solubility of API.
What properties can be impacted via solid form?
Physicochemical stability, hydration propensity, mechanical properties, tabletability, intrinsic solubility, dissolution rate
How can salts be used to affect solubility?
Can only be achieved in APIs with acid/base groups. Electrostatic interactions can improve solubility in H2O. Different counterions can change solubility at different pHs.
What can change the solubility of salts?
Identity of salt (counterion/drug), pH
How can cocrystals be used to enhance dissolution rates?
Cocrystals can be made with APIs with no ionisable groups. Increase conc. of drug in solution, then reach equilibrium. Extended availability by preventing neat form crystallisation [adding excipients]
What is the cocrystal spring effect and what can be done to avoid it?
Sudden increase in solubility before it comes crashing out of solution. Excipients can be added to prevent neat form crystallisation and increasing longevity of solubility.
Why is polymorphism important?
Solubility and other properties depend on structure. Polymorphs will have different properties which can lead to drug failure/recall.
What is crystal engineering?
Design and synthesis of solid-state structures with desired properties through deliberate control of intermolecular interactions
What are the key intermolecular interactions that crystal engineering looks at?
Hydrogen bonding, halogen bonds, electrostatic interactions, aromatic interactions
What is a supramolecular synthon?
Structural unit within supermolecules which can be formed/assembled by known or conceivable synthetic operations involving intermolecular interactions
What are homosynthons?
Same molecules
What are heterosynthons and how does their strength compare to homosynthons?
Different FG interactions, generally stronger than homosynthons
What is the difference between cocrystals and salts in acid-base heterosynthons?
Difference arises from degree of proton transfer, dependence on species pKas.
How do you describe hydrogen bond patterns?
G ^a d (r)
G is pattern designator (S,C,R,D)
a and d are numbers of acceptors and donors
r is the degree (number of atoms in ring or repeat in chain)
What is the ΔpKa rule?
ΔpKa = pKa[protonated base] - pKa [acid]
ΔpKa > 4 = salt
ΔpKa < 0 = cocrystal
0 < ΔpKa < 4 = both
How does acid-base equilibrium theory transfer to solid state?
Solvation of species change and transfer term required for use of pKa relation with free energy –> ΔG = -2.3RT ΔpKa. Transfer term cannot be calculated, so ΔpKa used only as a guide.
What happens in the middle region of salt-cocrystal range and what can impact this?
Continuum of proton transfer, incl. sitting right in the middle. Temperature is a key factor, example shown where temperature leads to move between cocrystal and salt shown by adjacent bond lengths.
Is there a preferred species between salt and cocrystal and if so, why?
Cocrystals: more amenable to crystal engineering, precitable stoichiometry and composition
Salt: unexpected stoichiometry and composition, more likely to be hydrated
Both have solubility advantages.
What is an important consideration in crystal formation?
Thermodynamic stability of lattice, multicomponent system lattice needs to be more stable than individual lattices.
How does screening for forms work?
Design efficient crystal via modelling studies, generate solids, Raman spectrometry to identify, then undergo structure determination. Combination of modelling and experimental work done to improve through-put.
What techniques are used to determine exact crystal structure and do extensive solid form characterisation?
Single crystal XRD, pXRD, TGA, DSC, ss-NMR, morphology, properties
How can sublimation be used to screen for forms?
Put the components under vacuum, heat and then crystallise in a cold finger to make a cocrystal.
What are four methods that can be used to screen for forms?
Crystallisation, milling, melt, sublimation
How are the 2nd components for cocrystals and salts chosen?
Chosen from GRAS - list of safe, non-toxic compounds for human consumption
Properties: safe, non-toxic, formation of strong synthons with API, charge-transfer is you want a salt
