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Medicinal Chemistry 2 > Importance of Solid Forms > Flashcards

Importance of Solid Forms Flashcards

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1
Q

What are the types of solid structure and what are the differences?

A

Amorphous solids - lacking long-range structure
Crystals - anisotropic structure and properties, packed in an ordered way

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2
Q

What is a crystal?

A

Crystal defined by three-dimensional translational symmetry.

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3
Q

How is crystal structure determined and what condition is related to determination?

A

Crystals diffract X-rays and produce patterns. Patterns can be used to determine structure using Bragg condition (nλ = 2dsinθ)

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4
Q

What do we need to describe crystal structure?

A

Space groups:
Bravais lattice (lattice, unit cell, crystal system. lattice type)
Crystal class (point groups)
Translational symmetry elements

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5
Q

What is a crystal lattice?

A

Set of infinite, arranged points related to each other by translational symmetry

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6
Q

What is the unit cell?

A

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

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7
Q

What are the crystal systems?

A

Based on relations between unit cell vectors - three lengths and three angles for repetitive units.
Cubic, tetragonal, orthorhombic, trigonal, hexagonal, monoclinic, triclinic

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8
Q

What are the four lattice types?

A

P - primitive
I - body centred
F - face centred
C - side-centred (one face only)

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9
Q

What are the Bravais lattices?

A

Combination of crystal systems and lattice types.

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10
Q

What are the different symmetry elements?

A

Identity, mirror planes, rotation axes, inversion, improper rotations

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11
Q

What is the crystal class?

A

Combination of point group elements gives 32 crystal classes.
1 - identity
m - mirror
n - rotation axis
1 bar - inversion

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12
Q

What are the three translational symmetry elements?

A

Translations, glide planes (reflection and translation by 1/2 unit), screw axes (rotation and translation)

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13
Q

What is a space group?

A

Set of symmetry elements and operations which describe spatial arrangement of 3D lattices

Looks like: (lattice type)(screw axis)/(glide plane)

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14
Q

What holds molecules together in crystals?

A

Intermolecular interactions

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15
Q

List all the relevant interactions that hold molecules together in crystals, dividing them into physical and chemical interactions.

A

Physical nature: Electrostatic, polarisation, dispersion, repulsion
Chemical nature: Hydrogen bonding, halogen bonds, aromatic interactions, ionic interactions, van der Waals

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16
Q

What is a hydrogen bond?

A

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

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17
Q

What is a halogen bond?

A

Non-covalent interaction between a σ-hole in a halogen atom and a negative site with a lone pair of electrons

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18
Q

What impacts strength of halogen bonds?

A

Size of halogen. Larger halogens develop bigger σ-holes in structure, producing larger partial positive charge

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19
Q

What are aromatic interactions?

A

Attractive interactions between aromatic rings, dominated by dispersion
Off-set face-to-face or edge-to-face interactions.

20
Q

What are Van der Waals interactions?

A

Attractive interactions present between molecules at all times due to instantaneous dipole-induced dipole interactions. Cumulative effects.

21
Q

What are ionic interactions?

A

Ionic bonding - attraction between positively and negatively charged ions.

22
Q

What is the close-packing principle?

A

Molecules will try to fill space via close-packing, energy minimised by intermolecular interaction optimisation

23
Q

How do we improve solubility in pipeline drugs?

A

Via solid form optimisation. Different solid forms can impact solubility of API.

24
Q

What properties can be impacted via solid form?

A

Physicochemical stability, hydration propensity, mechanical properties, tabletability, intrinsic solubility, dissolution rate

25
Q

How can salts be used to affect solubility?

A

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.

26
Q

What can change the solubility of salts?

A

Identity of salt (counterion/drug), pH

27
Q

How can cocrystals be used to enhance dissolution rates?

A

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]

28
Q

What is the cocrystal spring effect and what can be done to avoid it?

A

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.

29
Q

Why is polymorphism important?

A

Solubility and other properties depend on structure. Polymorphs will have different properties which can lead to drug failure/recall.

30
Q

What is crystal engineering?

A

Design and synthesis of solid-state structures with desired properties through deliberate control of intermolecular interactions

31
Q

What are the key intermolecular interactions that crystal engineering looks at?

A

Hydrogen bonding, halogen bonds, electrostatic interactions, aromatic interactions

32
Q

What is a supramolecular synthon?

A

Structural unit within supermolecules which can be formed/assembled by known or conceivable synthetic operations involving intermolecular interactions

33
Q

What are homosynthons?

A

Same molecules

34
Q

What are heterosynthons and how does their strength compare to homosynthons?

A

Different FG interactions, generally stronger than homosynthons

35
Q

What is the difference between cocrystals and salts in acid-base heterosynthons?

A

Difference arises from degree of proton transfer, dependence on species pKas.

36
Q

How do you describe hydrogen bond patterns?

A

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)

37
Q

What is the ΔpKa rule?

A

ΔpKa = pKa[protonated base] - pKa [acid]
ΔpKa > 4 = salt
ΔpKa < 0 = cocrystal
0 < ΔpKa < 4 = both

38
Q

How does acid-base equilibrium theory transfer to solid state?

A

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.

39
Q

What happens in the middle region of salt-cocrystal range and what can impact this?

A

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.

40
Q

Is there a preferred species between salt and cocrystal and if so, why?

A

Cocrystals: more amenable to crystal engineering, precitable stoichiometry and composition
Salt: unexpected stoichiometry and composition, more likely to be hydrated
Both have solubility advantages.

41
Q

What is an important consideration in crystal formation?

A

Thermodynamic stability of lattice, multicomponent system lattice needs to be more stable than individual lattices.

42
Q

How does screening for forms work?

A

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.

43
Q

What techniques are used to determine exact crystal structure and do extensive solid form characterisation?

A

Single crystal XRD, pXRD, TGA, DSC, ss-NMR, morphology, properties

44
Q

How can sublimation be used to screen for forms?

A

Put the components under vacuum, heat and then crystallise in a cold finger to make a cocrystal.

45
Q

What are four methods that can be used to screen for forms?

A

Crystallisation, milling, melt, sublimation

46
Q

How are the 2nd components for cocrystals and salts chosen?

A

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

Medicinal Chemistry 2 (4 decks)

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