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Medicines design II - solid dosage forms > L3&4 Polymorphs > Flashcards

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.
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1
Q

Crystalline behaviour can alter (1)

A

Pharmaceutical parameters

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2
Q

Hygroscopicity

A

Ability to absorb moisture (from the atmosphere)

- this is a big problem

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3
Q

What drives the crystallisation process?

A

Heat is given out - enthalpy.

Amorphous (disordered) -> crystalline (ordered)

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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

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5
Q

Habit

A

The external shape of the crystal

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6
Q

Is the habit associated with the structure inside the crystal?

A

No.

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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

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8
Q

What face dominates the crystal shape

A

Slowest growing face - an impurity will stop the crystal growing in this direction

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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

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10
Q

Crystal habit influences 4

A

Flow
Compaction
Solubility
Stability

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11
Q

Can you patent habit?

A

Yes if it is show to be of benefit

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12
Q

Effect of habit on injectables

A

Plate like crystals pass through needles better than long needle like crystals

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13
Q

Effect of habit in tableting

A

Plate like tolambutamol crystals do not flow and have poor compressibility

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14
Q

Effect of habit on dry power inhaler formulations

A

Needle like crystals usually have a better fine particle fraction

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15
Q

Shape of crystal produced is highly dependant on 2 parameters

A

Temperature and solvent

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16
Q

Solvent and temperature affect habit but not…

A

Crystal form (internal molecular order)

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17
Q

Miler indicies (hkl) are

A

The designated index plane for each crystal face

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18
Q

Miller index provides information about…

A

Molecular ordering of the surface of a crystal face

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19
Q

How many types of crystal structure are there?

A

Seven

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20
Q

A crystal is composed of unit cells(smallest building unit) which are

A

Periodically aligned building blocks

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21
Q

Unit cells reveal…

And how to look?

A

Crystal structure and symmetry specific for each substance

X-ray defraction

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22
Q

7 crystal structures

A 
Cubic
Tetragonal 
Orthorhombic
Rhombohedral
Monoclinic
Triclinic
Hexagonal
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23
Q

The 7 crystal structures then arrange into

A

14 different brava is lattices

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24
Q

Crystal form means

A

The ordering of atoms and molecules to form crystal structure.
It does not mean outer appearance (habit) of the crystals

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25
Q

Polymorphism definition

A

When the same chemical compound exists in different crystal forms

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26
Q

Pseudomorphs

A

Special cases of polymorphism such as hydrates or solvates

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27
Q

Define hydrate

A

Water molecules in a crystal lattice

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28
Q

Define solvates

A

Solvent molecules in a crystal lattice

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29
Q

Enantiomorphism is

A

Chiral molecules crystallising as mirror images of each-other

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30
Q

Racemic define

A

A mixture of D(dextro) and L(Levo) crystal forms (enantiomorphs)

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31
Q

Water is easy/hard to get out of the crystalline form?

A

Hard

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32
Q

What is a cocrystal

A

Crystal with a solvent that is solid at room temperature

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33
Q

Salt in a crystal is

A

Counter ion

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34
Q

Form I crystals are

A

Like a chess board - solvent crystal solvent crystal etc.

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35
Q

Three other things that could be in form one apart from solvent

A

Solvent - solvates
Water - hydrate
Counter-ion - salt
Solid excipients - co-crystal

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36
Q

Problems with co crystals?

A

Easy to make but not successful as difficult to stabilise. The solvent just wants to come back out again.

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37
Q

Can you patent salt/hydrate/cocrystal forms?

A

Salt/solvates/hydrate no.

Co-crystal yes as you cannot predict this by theory, you need experimental data.

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38
Q

Factors influenced by crystal form

A 
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
Q

What is the difference between solubility and dissolution rate

A

Solubility is how much dissolves

Dissolution is how fast this occurs (not dependent on solubility)

40
Q

T/f Melting point can cause crystal to change form?

A

True

41
Q

In preformulation what polymorphic form are we trying to make?

A

The most thermodynamically stable one

42
Q

Two way that a crystal may change form in storage?

A

Moisture mediated and solid state phase transformation.

43
Q

Regulators line on polymorphism?

A

‘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
Q

Can we patent different polymorphic forms?

A

Yes

45
Q

1998 Abbott had to stop production of what due to the wrong polymorphic form being made?

A

HIV protease inhibitor Ritonavir

46
Q

The accidental polymorphic form of Ritonavir was a problem because…

A

Affected how the semisolid capsule dissolved

47
Q

What did Abbott do while they tried to rectify the polymorphic issue?

A

Offered a liquid dosage form to patients.

As the new polymorph had not undergone clinical trials they were back to square one.

48
Q

New crystalline forms effect on PK?

A

Dissolves more slowly which affects bioavailiblity

49
Q

You only require … of the wrong poly morphic form to set off transition of your whole factory

A

Traces

50
Q

What is the moral of the Abbott story?

A

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
Q

GlaxoWellcome and Novopharm court battle over…

A

Production of a therapeutically equivalent different polymorphic form or Ranitidine (Zantac - anti ulcer).
Glaxo lost and generic went to market.

52
Q

Chloramphenicol-3-palmitate (CAAP) is..

.

A

Broad spectrum antibiotic

53
Q

CAAP can crystallise into …..polymorphic forms

A

At least three

54
Q

Which version of CAAP is marketed

A

A - the most thermodynamically stable.

55
Q

Form B CAAP is a problem because

A

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
Q

Aripiprazole is formulated as a

A

Anhydrate.

Forms a monohydrate on exposure to humidity.

57
Q

Aripiprazole is a stored….

A

In a blister pack too recent exposure to humidity,

Cannot be put into a dosette box.

58
Q

How is criteria set for appropriate polymorphism?

A

Decision tree approach

59
Q

Tree 1 considers…

A

Whether polymorphism is exhibited by compound

60
Q

Tree 2 considers

A

Whether the polymorphism can affect performance if the drug

61
Q

Tree 3 is only applied when

A

Only morphic mis demonstrated and affects drug properties

62
Q

Tree 3 considers…

A

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
Q

Sulphathizole has … polymorphic forms

A

4 established. 2 recently discovered.

64
Q

Which a form of sulphthiazole has the lowest yield stress?

A

Form I

Therefore easiest to compress into tablets

65
Q

During industrial crystallisation of sulphthiazole which forms are produces?

A

Possible to produce all 6

66
Q

Differences between form I & III sulphthiazole?

A

I orthorhombic - spaces between are larger

III monoclinic

67
Q

Vibrational spectroscopy eg …. Or …. Looks at ….

A

IR or RAMAN

Qualitative identifications of polymorphs.

68
Q

X-ray diffraction
single crystal method
powder X-ray diffraction look at…

A

Crystal structure

Quantitative detection of polymorphs and crystallinity

69
Q

Thermal analysis
Differential screening calorimetery (DSC)
Thermal gravimetric analysis (TGA)

A

Melting behaviour

Quantitative detection of crystal forms. (Hydrates, solvates, polymorphs).

70
Q

Isothermal moisture calorimetry looks at ….

A

Moisture induced thermodynamic processes

Recrystallisation of polymorphic forms

71
Q

Why do we want to make the free drug into salt

A
  • 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
Q

For a new substance the two fundamental properties are

A 
Intrinsic solubility (So) - dictates ease of formulation
Dissociation constant (IC50) - allows informed use of pH to maintain solubility and choose salts
73
Q

Looking at IC50 and So determines …

A

Need and possibility of making salt form of the drug

74
Q

75% of drugs are…
25%…
5%….

A

75% weak bases
25% weak acids
5% non-ionic
Therefore salts are often needed

75
Q

Target salts are chosen by factors such as… 7

A
  • 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
Q

Six common salts used (for basic drugs)

A 
Hydrochloride
Sulphate
Maleate
Acetate
Lactate
Salicylate
77
Q

6 Common salts used (for acidic drugs)

A 
Potassium
Sodium
Calcium
Lithium
Aluminium
Diethanolamin
78
Q

propoxyphene hydrochloride salt has what property?

And is commonly with what drug…

A

Analgesic properties

Aspirin

79
Q

Propoxyphene with aspirin was a problem becuase… Therefore….

A

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
Q

Some ions are associated with toxic effects eg. 2

A

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
Q

Reduce toxicity of the salt form by…

A

Changing the salt form

82
Q

Which salt forms are typically more toxic

A

Those that are rapidly absorbed from the GI

83
Q

Stability of a salt form can be affected by degree of …

A

Hygroscopicity

84
Q

Salts of minerals acids (hydrochlorides, sulphates) are

A

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
Q

Reduce hygroscopicity of the salt form by…

A

Using a hydrophobic salt-forming acid

86
Q

Xilobam stability is an issue why?

A

Contain highly water soluble sulphate salt of the drug - readily hydrolysed and dissolves in surface moisture.

87
Q

How was stability of Xilobam improved?

A

Aryl sulphonic acid indroduced - hydrophobic and presents barrier to dissolution

88
Q

An example of thermal stability of the salt form being an issue.

A

Licomycin Hydrochloride - thermal degredation
Licomycin cyclamate - stable

Penicillin G Na/K - stable
Penicillin G procaine - thermal degredation

89
Q

Conversion of salt to the stable form depends on

A

Free energy released by the change

90
Q

Which drugs are least likely to have polymorphic changes affect activity

A

High solubility/ low potency

91
Q

Levo and dextro indicate

A

Direction of rotation of polarised light

Enantiomorphs are optically active

92
Q

Which form of thalidomide was teratogenic?

A

L for tetragenic
D effective sedative
Racimises in the body due to pH

93
Q

What is a Racemic switch?

A

Development of a single enantiomer form of a drug that was first approved as a Racemate.

94
Q

Example of a Racemic switch

A

Sepracor producing L isomer of salbutamol

Avoids possible side effects of D form in racemate salbutamol (ventolin)

95
Q

Understanding crystallisation structures possible and their properties provides a ….3…. manufacturing process

A

Stable
Cheaper
More active

96
Q

Crystallisation processes

A
  • acid-base
  • antisolvent recrystallisation
  • evaporative crystallisation

Medicines design II - solid dosage forms (11 decks)

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