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SIU 1 GIT > Theory Of Drug Design > Flashcards

Theory Of Drug Design Flashcards

1
Q

Describe the principle of dosage form design

A

Conversion of a new chemical entity NCE into a deliverable medicine.

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2
Q

What is preformulation?

A

It is the first step in the rational development of dosage forms of a drug into a medicine.
Involves characterising the physical chemical properties of the API that enables us to develop a STABLE and BA dosage form that can be MASS PRODUCED

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3
Q

What is the aim of preformulation?

A

Produce a model for drug BEHAVIOUR in the proposed dosage form for both IN VITRO/ VIVO
Reduce development costs and time

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4
Q

What is the optimum aqueous solubility of a solid dosage?

A

> 10mg/ml

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5
Q

What if a drug has sol< 1mg/ml

A

Salt form of drug if possible

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6
Q

What’s the difference between sol and dissolution rate? Which one is constant?

A

Sol: the max amount of solute that can be dissolved in given unit of solvent
Diss: the rate of solute can be dissolved to reach that level
Solubility if constant

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7
Q

What are the factors that can affect the diss R?

A 
Noyes Whitney eq 
DA(Cs-C)/h
D. Diffusion coefficient
A. Surface area of drug
Cs. Solubility (Cmax)
C. Concentration in bulk solvent 
h. Thickness of boundary layer
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8
Q

What is BCS? What type of drug does it apply to?

A

Biopharmaceutical classification system

Only applicable for oral dosage forms

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9
Q

What are the four classes of BCS? Which characteristic can we modified and which we can’t?

A 
Class I high sol/ permeability
Class II low sol/ high perm
Class III high sol/ low perm
Class IV low/ low 
Can modify sol not perm
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10
Q

What is Brick dust?

A

Poorly soluble drugs in aqueous solutions

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11
Q

What do we mean by high risk compounds

A

Poorly soluble compounds as defined by the FDA biopharmaceutical classification system (II,IV)
Req to enhance BA and dissR

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12
Q

List the methods which can improve dissolution rate and BA in class II IV drugs

A

Amorphous
Meta stable polymorphs
Solid dispersion
Lipid based formulation (soft liquid gelatin cap)

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13
Q

When do we need to convert a weak acid or base drug into a salt form

A

When drug has low aqueous solubility

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14
Q

When does the decision on salt form have to be made during development? And why

A

Decision on a salt form must be made EARLY during PREFORMULATION, preferably BEFORE toxicity testing
Bc A large number of physiochemical properties may change upon formulation of salts

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15
Q

What is the required PKa difference between salt formation and the acid/base?

A

Delta pka=3

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16
Q

Pros of pharmaceutical salt

A 
Enhance sol
Increase dissR
Easier synthesis and purification 
Better taste 
High BA
High melting point -ionic compound
Improved photo stability
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17
Q

Cons of pharmaceutical salts

A 
Decrease % of drug
Increase hygroscopicity
Additional manufacturing steps
Increase toxicity 
Decrease chemical stability
No change in sol along GIT (acidic drug suppose to have better sol in SI)
Increase no of polymorphs
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18
Q

What is the name of the process of drug salt formation. What are the 2 common used method?

A

Micro crystallisation
Vapour diffusion

Hanging drop (drug vapour in hanging drop, volatile counterion vapour in reservoir solution, salt formed in the hanging drop)

Sitting drop (drug in a well, react w reservoir via vapour phase)

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19
Q

What are the steps involved in salt selection decision tree?

A

1) crystallinity (crystalline salt can be prepared)
2) hygroscopicity (salt can’t deliquesce at high humidity)
3) solubility
4) stability
5) polymorphism (final product)
If multiple polymorphs of salt
6) control (to produce desired form)
7) secondary/ final candidate

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20
Q

Story of crack cocaine

A

Cocaine is bought as a weak base
Does not dissolve in water
IV users use lemon, lime juice or vinegar (acetic acid) to make salt solution for injection
Soluble, hydrophilic salt

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21
Q

What is crystal habit?

A

The external shape of a crystal. Associated to the way solute molecule orientate themselves when growing.

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22
Q

What factor determines the general shape of crystal?

A

The growth rate of individual crystal faces

The slowest growing face dominates

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23
Q

Common Types of crystal habit

And what properties they can influence

A

Tabular
Prismatic
Acicular

Flow
Compatibility
Stability
Solubity

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24
Q

What is miller index (hkl)

A

Designated index plane of each crystal face. Provides information about the molecular ORDERING of crystal face surface.

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25
Q

What are the 7 common type of crystal structure

A 
Cubic
Tetragonal
Orthorhombic 
Rhombohedral
Monclinc 
Triclinc 
Hexagonal
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26
Q

What’s a crystal
What are bravais lattices?
What’s the number?

A

Composed of Periodically aligned building blocks -unit cells
Lattices that have periodic arrays of atoms without any gaps or holes. Implies degree of symmetry.
14 ways of arrangement, base/ body/ face centred (rhombohedral)

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27
Q

What is pseudopolymorphism

A

Solvate and hydrate
Solvent mol in crystal lattice
Water mol in crystal lattice

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28
Q

What are hydrates

A

Water mol in crystal lattice (Na2SO4. 10H2O)

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29
Q

A hydrate is most stable solid form in…. and least soluble form in …. (not favourable low solubility

A

In water

In GI environment -slow diss R

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30
Q

Which form is usually favoured in manufacturing, anhydrate or hydrates?

A

Anhydrates

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31
Q

What is enantiomorphism?

What is racemic mixture

A

When a Chiral molecule crystallises as mirror images of each other
A racemate is mix of D and L crystal forms

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32
Q

What is amorphous solid?

A

Highly viscous solid in which there is no (long-range) order of the positions of molecules/ atoms

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33
Q

Why does amphorous solid has greater sol. And dissolution rate than crystalline solid?

A

High vicious liquid with solid’s properties

Has higher free energy

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34
Q

Three main types of amorphous formulation:

A

Solid amorphous dispersions
Oral fast-dissolving tablet
Lyophilised powder

35
Q

2 types of solid amorphous dispersion

A

1- molecular dispersion : solid solution

2- particulate dispersion : solid suspension

36
Q

The concerns with the stability of solid amorphous dispersion
What’s the solution?

A

Form change of drug
Diffusion and crystallisation
Polymer matrix -prevent diffusion
Cross linking stabiliser to polymer matrix to prevent crystallisation

37
Q

Give an example of solid solution used in formulation

A

HydroxylPropylMethyl Cellulose HPMC = excipient crystal lattice matrix
+ itraconazole (poorly soluble drug)
Spray a layer of HPMC+itaconazole onto a sugar core –> packed into capsules

38
Q

What is a solid solution

Solid dispersion

A

A SOLID state solution of a drug which is molecularly DISSOLVED in solid excipient CRYSTAL LATTICE, single HOMOGENOUS phase
A drug DISPERSED in solution as CRYSTALLINE

39
Q

Rate of drug dissolution can be adversely affected by choice of excipient
give an example

A

Lubricant : Mg stearate.

Impacts hydrophobicity to a formulation which inhibits drug dissolution

40
Q

List the choices of diluents (bulking agent)

A

Lactose -sweet,soluble,not hygroscopic

Dicalcium phosphate -used in wet granules, insoluble

Starches -hygroscopic, disintegrant

Mannitol - soluble, sweet

Microcrystalline cellulose -compression, disintegrant

NACL -soluble, used in sol and tablet

Sucrose -sweet but hygroscopic

41
Q

MCC -pros cons

A

High bulk density- aids in blending
Low …-increases tablet strength /compressibility
Disintegrant
Sensitive to lubricant -prevent strong bond forming bw layers
To moisture -reduced compression
Poor flow (size)

42
Q

Lubricants

  • examples
  • uses
A

Talc, mg stearate -punch
Stearic acid -die
Prevent adherence of the formulation to punches and dies
Ensure smooth ejection of the tablet from the die

43
Q

What are the disadvantages of magnesium stearate

A

Requires additional processing steps
Decreases drug dissolution and weakens the bonding forces
Bc its hydrophobic nature

44
Q

Glidant (flow agents)

  • examples
  • uses
A

Colloid silica

Improve the flow properties of granules by reducing interparticulate friction/ adhesion

45
Q

What is an adsorbent?

A

Adsorbents are substances which are capable of holding quantities of fluids in a dry state (liquid flavouring, oils–>mix w adsorbent–> granules–> compressed to tablet

47
Q

Examples of adsorbents used

A

Fumed silica and colloid silica
MCC
Kaolin
Mg carbonate

47
Q

Disintegrant

  • examples
  • MOAz
A

PVP, modified/starch, cellulose materials
Tablet-disintegration -granules- disaggregation -particles-rapid dissolution
Swell- porous,draw liquid into capillary-break interparticulate bonds-deformation-has produced

48
Q
  • Examples of binding agents

- MOA

A 
Starch mucilage (glue)
Gelatin
Polyvinylpyrrolidone PVP-sol in water and alcohol, release drug rapidly
  • Bind powders together in normal (compression) and wet granulation process
  • Can be added 1. Add as powder in formulation
    2. Add as solution to the mixed powder in wet granulation
  • Liquid additive must be removed before compression
  • Can affect diss rate
49
Q

8types of tablet

A

Uncoated
Sugar/ film coated
Controlled release

Effervescent 
Soluble
Chewable 
Sublingual 
Lozenges 
(Excipient must be soluble)
50
Q

Advantages of tablet

A 
Accurate dosage 
Convenience 
Mass production 
Greater stability 
Controlled release
51
Q

Disadvantages of tablet

A

Swallowing
Low solubility
Bad taste or smell
Oxygen and moisture sensitivity (req coating)

52
Q

Three properties of tabletable drug

A

Sufficiently free flowing

Particles cohere to form a compact of adquente strength when subject to force

Adhesion of the TABLET should be avoided

53
Q

Process of making tablet

A 
Weighing powder 
Dry mixing 
Granulation 
Tabletting
QC 
Coating
Dissolution test
QA (same amount of API, same weight of tablet etc)
54
Q

2 types of tablet machines

A

Single punch presses

Rotary presses

55
Q

When is single punch machine used?

A

R n D process in lab where small amount of tablet is required from limited drug substance
Slow production rate

56
Q

Process of single punch machine operation (4 steps)

A

Filling of particulate into the die by feed shoe, low punch descends

Compaction, upper punch descends, feed shoe withdrawn

Ejection of tablet, upper and lower punch ascends, feed shoe sweeps tab off the die

Repeat

57
Q

When is a rotary tablet machine used

A

Mass production for commercial manufacture

58
Q

3 stages of compression of powder–> tablet

A
  1. Rearrangement of powder in die under low level of stress via densification- minimise free space bw particles
  2. Deformation of particles by increased compression force, undergo elastic (return org shape), plastic or brittle fragmentation( permanent change in shape)
  3. Bonding between powder particles
59
Q

Extend of densification is dictated by …

A

Particle size distribution (easier for particle with same size)
Frictional force bw particles

60
Q

Plastic deformation and fragmentation

- examples of ingredients

A

Starch, nacl, mcc, stearin acid

Sucrose, lactose, diCa phosphate, caco3

61
Q

Describe what’s Plastic deformation

A

A process where stress causes particles within a powder bed to change size or shape- NOT.reversible after stress is removed

Powder reaches yield stress point

Heat energy + internal energy = stress

62
Q

3 mechanisms in bonding stage of powder particles

A

Intermolecular forces -vdw, H bind, electrostatic force

Solid bridges- solvent used to bind the powders, cause partial melting of powder. –>dried –> recrystallisation of soluble materials (wet granulation) –> dissolved sub =hardening binder

Mechanical interlocking - particles w irregular shape can form bonds

63
Q

3 types of tablet coating

A

Film
Sugar
Press coating

64
Q

Process of usage coating SSSCPP

A

1 Sealing -prevent entry of water, cellulose acetate phthalate, shellac
2 Sub coating- rounded, addition of CaCO3 or talc in sucrose solution
3 smoothing- sucrose syrup
4 colouring
5 polishing- beewax, carnauba create high gloss
6 printing of logo

65
Q

What are the common enteric polymer coatings?

A

Cellulose acetate phthalate
Polyvinyl acetate phthalate
Copolymer of methlacrylic acid and ethyl acrylate

66
Q

Advantages of multi-particulate instead of tablet

A
  1. Passage through pyloric sphincter - performance not dependent on gastric emptying, more predictable
  2. No irregular absorption doe yo variability in GI transient time
  3. Increase BA
  4. Reduced risk of local irritation whereas tablet can have a whole non disintegrated tablet deposit in GIT
  5. Failure of an individual bead does not pose risk
  6. Allow release of TWO APIs
67
Q

2 types of multi particulates

A

Extruded/ spheronised

Non pareils - sugar core, exc+ drug, enteric coat

68
Q

What is multiple unit pallet system

A

A form of enteric coated tablet that consists of particulates which has been compressed.

69
Q

An example of MUPS

A

Methacrylic acid copolymer with ethyl acrylate

70
Q

How does MUPS get through the GIT

A

Same as enteric particles in capsule

Disintegrate in stomach and small particles pass through stomach pyloric sphincter

71
Q

4potential prob with hard wheel capsules

A
  1. Cross linking of gelatin and polypeptide gives Insoluble cap
  2. Brittle capsule due to water loss
  3. Sticky capsule
  4. Leaky between cap and body joint
72
Q

Soft gelatin capsules

A

Continuous gelatin shell
With liquid fill material
Sealed in one operation

73
Q

Size of hard capsules

A

000 large
0 medium
3 small

74
Q

Advantage of soft gelatin cap

A
  1. No need to compress drug which can be hard with high doses
  2. No powder flow issues as dissolved/ disperse in oil
  3. Protect sensitivity to drug oxidation or hydrolysis
  4. Self emulsifying oils increase BA
75
Q

Disadvantage of soft gelatin cap

A

Drug containing high conc of water -incorporated
Not used for o w or. W o emulsions - unstable as water loss from shell
Surfactant affects capsule seal
PH needs to be neutral avoid degradation of gelatin

76
Q

Water immiscible oils in formulation of SGC

A

Volatile or non Valatile oils

Example: veg oil, aromatic/ aliphatic chlorinated HC

77
Q

Water miscible liquid

A

Low mw 400-600 PEG alcohol or glycerol

78
Q

Non powder filling of HGC

A

Granules
Tablet
Semisolid liquid during filling become solid when inside cap

79
Q

A drug can have many different solid state form CCHA

A

Crystalline -polymorphs, hydrates, solvates
Chiral
Habit
Amorphous

80
Q

Crystal form means

Example

A

Order of atoms and molecules to form crystal structure DOES NOT means the outer appearance (habit) of crystal
Polymorphism
Enantiomorphism

81
Q

Polymorphism is

A

Same chemical compounds exist in different crystal form

82
Q

Classes of polymorphs

A 
Form 1 and 2 
Salt :api with counter ions
Solvate: api with solvent 
Hydrate: w water 
Co crystal: w another solid
83
Q

Two types of polymorphs

A

Enantiotropic : solids phase transition which transform reversibly WITHOUT passing through liquid/gas phase

Monotropic: phase change before soild to solid transition

SIU 1 GIT (7 decks)

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