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SIU 1 GIT > Theory Of Drug Design > Flashcards

Theory Of Drug Design Flashcards

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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
What are the 7 common type of crystal structure
``` Cubic Tetragonal Orthorhombic Rhombohedral Monclinc Triclinc Hexagonal ```
26
What's a crystal What are bravais lattices? What's the number?
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)
27
What is pseudopolymorphism
Solvate and hydrate Solvent mol in crystal lattice Water mol in crystal lattice
28
What are hydrates
Water mol in crystal lattice (Na2SO4. 10H2O)
29
A hydrate is most stable solid form in.... and least soluble form in .... (not favourable low solubility
In water | In GI environment -slow diss R
30
Which form is usually favoured in manufacturing, anhydrate or hydrates?
Anhydrates
31
What is enantiomorphism? | What is racemic mixture
When a Chiral molecule crystallises as mirror images of each other A racemate is mix of D and L crystal forms
32
What is amorphous solid?
Highly viscous solid in which there is no (long-range) order of the positions of molecules/ atoms
33
Why does amphorous solid has greater sol. And dissolution rate than crystalline solid?
High vicious liquid with solid's properties | Has higher free energy
34
Three main types of amorphous formulation:
Solid amorphous dispersions Oral fast-dissolving tablet Lyophilised powder
35
2 types of solid amorphous dispersion
1- molecular dispersion : solid solution | 2- particulate dispersion : solid suspension
36
The concerns with the stability of solid amorphous dispersion What's the solution?
Form change of drug Diffusion and crystallisation Polymer matrix -prevent diffusion Cross linking stabiliser to polymer matrix to prevent crystallisation
37
Give an example of solid solution used in formulation
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
What is a solid solution | Solid dispersion
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
Rate of drug dissolution can be adversely affected by choice of excipient give an example
Lubricant : Mg stearate. | Impacts hydrophobicity to a formulation which inhibits drug dissolution
40
List the choices of diluents (bulking agent)
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
MCC -pros cons
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
Lubricants - examples - uses
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
What are the disadvantages of magnesium stearate
Requires additional processing steps Decreases drug dissolution and weakens the bonding forces Bc its hydrophobic nature
44
Glidant (flow agents) - examples - uses
Colloid silica | Improve the flow properties of granules by reducing interparticulate friction/ adhesion
45
What is an adsorbent?
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
Examples of adsorbents used
Fumed silica and colloid silica MCC Kaolin Mg carbonate
47
Disintegrant - examples - MOAz
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
- Examples of binding agents | - MOA
``` 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
8types of tablet
Uncoated Sugar/ film coated Controlled release ``` Effervescent Soluble Chewable Sublingual Lozenges (Excipient must be soluble) ```
50
Advantages of tablet
``` Accurate dosage Convenience Mass production Greater stability Controlled release ```
51
Disadvantages of tablet
Swallowing Low solubility Bad taste or smell Oxygen and moisture sensitivity (req coating)
52
Three properties of tabletable drug
Sufficiently free flowing Particles cohere to form a compact of adquente strength when subject to force Adhesion of the TABLET should be avoided
53
Process of making tablet
``` Weighing powder Dry mixing Granulation Tabletting QC Coating Dissolution test QA (same amount of API, same weight of tablet etc) ```
54
2 types of tablet machines
Single punch presses | Rotary presses
55
When is single punch machine used?
R n D process in lab where small amount of tablet is required from limited drug substance Slow production rate
56
Process of single punch machine operation (4 steps)
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
When is a rotary tablet machine used
Mass production for commercial manufacture
58
3 stages of compression of powder--> tablet
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
Extend of densification is dictated by ...
Particle size distribution (easier for particle with same size) Frictional force bw particles
60
Plastic deformation and fragmentation | - examples of ingredients
Starch, nacl, mcc, stearin acid Sucrose, lactose, diCa phosphate, caco3
61
Describe what's Plastic deformation
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
3 mechanisms in bonding stage of powder particles
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
3 types of tablet coating
Film Sugar Press coating
64
Process of usage coating SSSCPP
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
What are the common enteric polymer coatings?
Cellulose acetate phthalate Polyvinyl acetate phthalate Copolymer of methlacrylic acid and ethyl acrylate
66
Advantages of multi-particulate instead of tablet
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
2 types of multi particulates
Extruded/ spheronised | Non pareils - sugar core, exc+ drug, enteric coat
68
What is multiple unit pallet system
A form of enteric coated tablet that consists of particulates which has been compressed.
69
An example of MUPS
Methacrylic acid copolymer with ethyl acrylate
70
How does MUPS get through the GIT
Same as enteric particles in capsule | Disintegrate in stomach and small particles pass through stomach pyloric sphincter
71
4potential prob with hard wheel capsules
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
Soft gelatin capsules
Continuous gelatin shell With liquid fill material Sealed in one operation
73
Size of hard capsules
000 large 0 medium 3 small
74
Advantage of soft gelatin cap
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
Disadvantage of soft gelatin cap
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
Water immiscible oils in formulation of SGC
Volatile or non Valatile oils | Example: veg oil, aromatic/ aliphatic chlorinated HC
77
Water miscible liquid
Low mw 400-600 PEG alcohol or glycerol
78
Non powder filling of HGC
Granules Tablet Semisolid liquid during filling become solid when inside cap
79
A drug can have many different solid state form CCHA
Crystalline -polymorphs, hydrates, solvates Chiral Habit Amorphous
80
Crystal form means | Example
Order of atoms and molecules to form crystal structure DOES NOT means the outer appearance (habit) of crystal Polymorphism Enantiomorphism
81
Polymorphism is
Same chemical compounds exist in different crystal form
82
Classes of polymorphs
``` Form 1 and 2 Salt :api with counter ions Solvate: api with solvent Hydrate: w water Co crystal: w another solid ```
83
Two types of polymorphs
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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