L3&4 Polymorphs Flashcards
0
Q
Parameters that are determined by crystalline structure?
A
- solubility and dissolution rate
- crystal hardness (compressibility for tablets)
- chemical stability (enthalpy of solution, of transition, hygroscopicicity, melting and sublimination temperatures)
- others: heat. Refractive index. Heat capacity. Conductivity. Volume. Density.
1
Q
Crystalline behaviour can alter (1)
A
Pharmaceutical parameters
2
Q
Hygroscopicity
A
Ability to absorb moisture (from the atmosphere)
- this is a big problem
3
Q
What drives the crystallisation process?
A
Heat is given out - enthalpy.
Amorphous (disordered) -> crystalline (ordered)
4
Q
What would happen if we made amorphous drugs (eg. Paracetamol)
A
It would change back to the crystalline form in a matter of minutes
5
Q
Habit
A
The external shape of the crystal
6
Q
Is the habit associated with the structure inside the crystal?
A
No.
7
Q
Habit shape is associated with…
General crystal shape associated with…
A
Habit… Way the molecules orientate themselves when growing
General crystal… Growth of the individual faces
8
Q
What face dominates the crystal shape
A
Slowest growing face - an impurity will stop the crystal growing in this direction
9
Q
How does using a different solvent affect the shape of the crystal?
A
Solvent molecules adsorb to crystal faces therefore different shape crystals formed belonging to the same crystal system
10
Q
Crystal habit influences 4
A
Flow
Compaction
Solubility
Stability
11
Q
Can you patent habit?
A
Yes if it is show to be of benefit
12
Q
Effect of habit on injectables
A
Plate like crystals pass through needles better than long needle like crystals
13
Q
Effect of habit in tableting
A
Plate like tolambutamol crystals do not flow and have poor compressibility
14
Q
Effect of habit on dry power inhaler formulations
A
Needle like crystals usually have a better fine particle fraction
15
Q
Shape of crystal produced is highly dependant on 2 parameters
A
Temperature and solvent
16
Q
Solvent and temperature affect habit but not…
A
Crystal form (internal molecular order)
17
Q
Miler indicies (hkl) are
A
The designated index plane for each crystal face
18
Q
Miller index provides information about…
A
Molecular ordering of the surface of a crystal face
19
Q
How many types of crystal structure are there?
A
Seven
20
Q
A crystal is composed of unit cells(smallest building unit) which are
A
Periodically aligned building blocks
21
Q
Unit cells reveal…
And how to look?
A
Crystal structure and symmetry specific for each substance
X-ray defraction
22
Q
7 crystal structures
A
Cubic Tetragonal Orthorhombic Rhombohedral Monoclinic Triclinic Hexagonal
23
Q
The 7 crystal structures then arrange into
A
14 different brava is lattices
24
Crystal form means
The ordering of atoms and molecules to form crystal structure.
It does not mean outer appearance (habit) of the crystals
25
Polymorphism definition
When the same chemical compound exists in different crystal forms
26
Pseudomorphs
Special cases of polymorphism such as hydrates or solvates
27
Define hydrate
Water molecules in a crystal lattice
28
Define solvates
Solvent molecules in a crystal lattice
29
Enantiomorphism is
Chiral molecules crystallising as mirror images of each-other
30
Racemic define
A mixture of D(dextro) and L(Levo) crystal forms (enantiomorphs)
31
Water is easy/hard to get out of the crystalline form?
Hard
32
What is a cocrystal
Crystal with a solvent that is solid at room temperature
33
Salt in a crystal is
Counter ion
34
Form I crystals are
Like a chess board - solvent crystal solvent crystal etc.
35
Three other things that could be in form one apart from solvent
Solvent - solvates
Water - hydrate
Counter-ion - salt
Solid excipients - co-crystal
36
Problems with co crystals?
Easy to make but not successful as difficult to stabilise. The solvent just wants to come back out again.
37
Can you patent salt/hydrate/cocrystal forms?
Salt/solvates/hydrate no.
| Co-crystal yes as you cannot predict this by theory, you need experimental data.
38
Factors influenced by crystal form
```
1 solubility and dissolution
2 density, crystal shape
3 compaction behaviour
4 flow properties
5 melting point solid state
6 rate of uptake into the body (and therefore activity)
7 enantiomers may be tetragenic
```
39
What is the difference between solubility and dissolution rate
Solubility is how much dissolves
| Dissolution is how fast this occurs (not dependent on solubility)
40
T/f Melting point can cause crystal to change form?
True
41
In preformulation what polymorphic form are we trying to make?
The most thermodynamically stable one
42
Two way that a crystal may change form in storage?
Moisture mediated and solid state phase transformation.
43
Regulators line on polymorphism?
'What assurance can be provided that not other crystalline forms of this compound exist?'
Require manufacturer to indicate characterisation of the various forms of the drug
44
Can we patent different polymorphic forms?
Yes
45
1998 Abbott had to stop production of what due to the wrong polymorphic form being made?
HIV protease inhibitor Ritonavir
46
The accidental polymorphic form of Ritonavir was a problem because...
Affected how the semisolid capsule dissolved
47
What did Abbott do while they tried to rectify the polymorphic issue?
Offered a liquid dosage form to patients.
| As the new polymorph had not undergone clinical trials they were back to square one.
48
New crystalline forms effect on PK?
Dissolves more slowly which affects bioavailiblity
49
You only require ... of the wrong poly morphic form to set off transition of your whole factory
Traces
50
What is the moral of the Abbott story?
Make sure you start on form II. They could nt
| It get back to pure form I so they had to find a way to make form II product
51
GlaxoWellcome and Novopharm court battle over...
Production of a therapeutically equivalent different polymorphic form or Ranitidine (Zantac - anti ulcer).
Glaxo lost and generic went to market.
52
Chloramphenicol-3-palmitate (CAAP) is..
| .
Broad spectrum antibiotic
53
CAAP can crystallise into .....polymorphic forms
At least three
54
Which version of CAAP is marketed
A - the most thermodynamically stable.
55
Form B CAAP is a problem because
8x higher biological activity - risk of toxicity.
| Risk of fatal overdose if inter conversation to the unwanted polymorph during storage or alterations in the process.
56
Aripiprazole is formulated as a
Anhydrate.
| Forms a monohydrate on exposure to humidity.
57
Aripiprazole is a stored....
In a blister pack too recent exposure to humidity,
| Cannot be put into a dosette box.
58
How is criteria set for appropriate polymorphism?
Decision tree approach
59
Tree 1 considers...
Whether polymorphism is exhibited by compound
60
Tree 2 considers
Whether the polymorphism can affect performance if the drug
61
Tree 3 is only applied when
Only morphic mis demonstrated and affects drug properties
62
Tree 3 considers...
The potential for change in polymorphic form of the drug and whether such a change affects performance.
(Via performance testing and testing if the change alters safety/efficacy)
63
Sulphathizole has ... polymorphic forms
4 established. 2 recently discovered.
64
Which a form of sulphthiazole has the lowest yield stress?
Form I
| Therefore easiest to compress into tablets
65
During industrial crystallisation of sulphthiazole which forms are produces?
Possible to produce all 6
66
Differences between form I & III sulphthiazole?
I orthorhombic - spaces between are larger
| III monoclinic
67
Vibrational spectroscopy eg .... Or .... Looks at ....
IR or RAMAN
| Qualitative identifications of polymorphs.
68
X-ray diffraction
single crystal method
powder X-ray diffraction look at...
Crystal structure
| Quantitative detection of polymorphs and crystallinity
69
Thermal analysis
Differential screening calorimetery (DSC)
Thermal gravimetric analysis (TGA)
Melting behaviour
| Quantitative detection of crystal forms. (Hydrates, solvates, polymorphs).
70
Isothermal moisture calorimetry looks at ....
Moisture induced thermodynamic processes
| Recrystallisation of polymorphic forms
71
Why do we want to make the free drug into salt
- Alter chemical and biological properties without altering structure
- improve PK (solubility, absorption, dissolution)
- improve physiochemical properties (stability, hygroscopicity)
salts are distinct products with properties that relate to differences in safety and efficacy
72
For a new substance the two fundamental properties are
```
Intrinsic solubility (So) - dictates ease of formulation
Dissociation constant (IC50) - allows informed use of pH to maintain solubility and choose salts
```
73
Looking at IC50 and So determines ...
Need and possibility of making salt form of the drug
74
75% of drugs are...
25%...
5%....
75% weak bases
25% weak acids
5% non-ionic
Therefore salts are often needed
75
Target salts are chosen by factors such as... 7
- structure of the drug substance
- pKa of the drug substance (~2?????)
- chemical and physical stability
- available literature on structurally related compounds
- ease of large scale preparation of the salt
- type of drug product
- anticipated loading of the drug substance in the drug product
76
Six common salts used (for basic drugs)
```
Hydrochloride
Sulphate
Maleate
Acetate
Lactate
Salicylate
```
77
6 Common salts used (for acidic drugs)
```
Potassium
Sodium
Calcium
Lithium
Aluminium
Diethanolamin
```
78
propoxyphene hydrochloride salt has what property?
| And is commonly with what drug...
Analgesic properties
| Aspirin
79
Propoxyphene with aspirin was a problem becuase... Therefore....
Aspirin is unstable in close contact requiring additional manufacturing step to separate analgesics.
Re formulating to nypsylate salt overcame this.
Nypsylate salt also relatively insoluble so less potential for parenteral abuse.
80
Some ions are associated with toxic effects eg. 2
Li causes renal damage in large doses
| Tartrate poorly absorbed in the GI and can cause renal damage if high concentration in the circulation
81
Reduce toxicity of the salt form by...
Changing the salt form
82
Which salt forms are typically more toxic
Those that are rapidly absorbed from the GI
83
Stability of a salt form can be affected by degree of ...
Hygroscopicity
84
Salts of minerals acids (hydrochlorides, sulphates) are
Highly polar.
Ionised polar groups on crystal surface create hydrophilic surface
Favours wettability leading to hygroscopicity
This can reduce stability ( if drug is susceptible to hydrolysis degradation).
85
Reduce hygroscopicity of the salt form by...
Using a hydrophobic salt-forming acid
86
Xilobam stability is an issue why?
Contain highly water soluble sulphate salt of the drug - readily hydrolysed and dissolves in surface moisture.
87
How was stability of Xilobam improved?
Aryl sulphonic acid indroduced - hydrophobic and presents barrier to dissolution
88
An example of thermal stability of the salt form being an issue.
Licomycin Hydrochloride - thermal degredation
Licomycin cyclamate - stable
Penicillin G Na/K - stable
Penicillin G procaine - thermal degredation
89
Conversion of salt to the stable form depends on
Free energy released by the change
90
Which drugs are least likely to have polymorphic changes affect activity
High solubility/ low potency
91
Levo and dextro indicate
Direction of rotation of polarised light
| Enantiomorphs are optically active
92
Which form of thalidomide was teratogenic?
L for tetragenic
D effective sedative
Racimises in the body due to pH
93
What is a Racemic switch?
Development of a single enantiomer form of a drug that was first approved as a Racemate.
94
Example of a Racemic switch
Sepracor producing L isomer of salbutamol
| Avoids possible side effects of D form in racemate salbutamol (ventolin)
95
Understanding crystallisation structures possible and their properties provides a ....3.... manufacturing process
Stable
Cheaper
More active
96
Crystallisation processes
- acid-base
- antisolvent recrystallisation
- evaporative crystallisation
