Preformulation Flashcards
1
Q
What is the most popular dosage form?
A
Tablets
2
Q
Why is preformulation needed?
A
To give info on:
Feasibility of dosage forms
Potential drug instability
Poor in vivo dissolution
3
Q
What are excipients?
A
Inactive substances that are used as vehicles or medium for drugs or other active substances
4
Q
What is a problem with preformulation?
A
Only limited quantities of compound will be available
5
Q
Why is it important not to skip preformulation?
A
Cost of reformulation can be high
Formulation can go wrong ect. When solubility of low, formulation of injections is not possible
Concept of minimum preformulation
6
Q
What is minimum preformulation?
A
Getting as much information as possible form the small amount of material available
7
Q
What two properties should be measured first?
A
Intrinsic solubility (C0) Dissociation constant (pKa)
8
Q
What amount of drug should be used for measuring solubility?
A
50 mg
9
Q
Why are new compounds of poor quality?
A
Lots of unknown impurities
Different crystal forms
10
Q
What does the solubility dictate?
A
The ease of obtaining formulations of aqueous solutions
11
Q
What does measuring the pKa allow?
A
Information given of pH to maintain solubility
Allows informed choice of salts which gives good bioavailability
12
Q
What does solubility affect?
A
Drug absorption
13
Q
What pH range should drugs solubility be?
A
Solubility of more than 1% at pH range 1-7
14
Q
What temperature should drugs solubility be?
A
37oC
15
Q
What is absorption rate limited by?
A
Dissolution rate
16
Q
What is solution?
A
A mixture of two or more components that form a single phase homogeneous down to molecular level
17
Q
What is solvent?
A
A component that determines the phase
18
Q
What is solute?
A
The component which is dispersed
19
Q
What is dissolution?
A
Transfer of molecules or ions from solid state into the solvent
20
Q
What is a saturated solution?
A
A solution in which the solvent has dissolved all of the solute that it can
21
Q
What is solubility?
A
The maximum concentration that can be attained by a solute in a specific solvent
22
Q
What is the quantity per quantity expression of solubility?
A
1gL-1 or 0.1g per 100 mL
23
Q
What is molality expressed in?
A
Moles per 1000g
24
Q
What is molarity expressed in?
A
Moles per litre
25
What is mole fraction expressed in?
Moles per total number of moles
26
What is parts expressed in?
Number of weight parts solid/number of volume parts of solvent
27
What is the solubility if a very soluble compound?
Less than 1
28
What is the solubility of a practically insoluble or insoluble drug?
More than 10,000
29
What does an increase in solubility suggest the compound is?
A weak base
30
What does increased solubility in alkaline aqueous solutions suggest the compound is?
A weak acid
31
What does an increase in solubility under both acidic and alkaline conditions suggest?
That the compound is amphoteric or zwitterionic so two pKa values
32
What does no change in solubility over a range of pH suggest?
That the compound is neutral and non-ionisable (no pKa)
33
How can solubility be improved?
```
pH (use of buffers)
Salts
Use of co-solvents
Use of surfactants
Complexation
Solid dispersion
```
34
What pH range buffers used?
pH 3-9
35
Why are extreme pH values used for buffers?
Injections would cause tissue damage and pain
36
What pH is acidic drugs formulated in?
Basic pH
37
What pH is basic drugs formulated in?
Acidic pH
38
What can salts do in regards to solubility?
Improve solubility
39
How are salts formed?
By acid base reactions
40
What should the pKa for each component not be?
Too close together (
41
Why is it better to use walk acid or base?
These says tend to be less soluble but also less hygroscopic
42
Give an example of salts of acidic drugs?
Sodium salicylate
43
Give example of salts of basic drugs?
Meperidine hydrochloride
44
What are acidic groups in drugs?
COOH
| OH and SH (thiol) if attached to an electron-withdrawing group
45
What is a basic group in drugs?
Amino groups
46
What is co-solvency?
The mixing solvents of different polarities to form a solvent system of optimum polarity to dissolve the solute
47
Why are co-solvents added to water?
To increase the solubility
To increase stability
Injection formulation
48
What is the dielectric constant of the solvent used for?
When developing the co-solvent system
49
What could injections contain?
50
What should solubility be measured in?
Aqueous/co-solvent mixtures (formulations rarely require pure co-solvent)
51
What do surfactants have?
A polar head and a lipophilic tail group
52
What can surfactants form?
Micelles at concentrations higher than the critical micelle concentration. Hydrophobic drugs can diffuse inside the micelle
53
What must surfactants be?
Non-toxic
Miscible with the solvent
Compatible with other ingredients
Odourless
54
Give an example of non-ionic surfactants
Glycol/glycerol
55
Give an example of alkali metal and ammonium soaps
E.g. Sodium stearate
56
What are commonly used as complexing agents?
Cyclodextrins
57
What are Cyclodextrins?
6-8 glucopyranose units forming cyclical structures like hollow cylinders/baskets . Inside is hydrophobic and rim is hydrophilic
58
The more hydrophobic a drug what happens to the effect of the co-solvent?
Increases
59
What is lipophilicity measured using?
Oil-water partition coefficient (log P)
60
What does it mean when P=1?
The drug has equal affinity for both oil and water
61
What does it mean if P>1?
The drug is lipophilic (hydrophobic)
62
What does it mean if P
The drug is hydrophilic
63
Why is the logarithm scale used?
As the values of P may be very large
64
Name the variety of methods used for determining melting point
Capillary melting-observation of melting in a capillary tube in a heated metal block
Hot stage microscopy- observation of melting under a microscope (more precise)
Differential scanning calorimetry or differential thermal analysis
65
What is the pro/con of capillary melting?
Gives information on melting range but accuracy is low
66
What are the advantages of hot stage microscopy?
Heating rate of controlled
| Other transitions can be observed/recorded
67
What does differential scanning calorimetry measure?
The amount of energy required to keep the sample at the same temperature as the reference. The enthalpy of the transition is measured
68
What is differential thermal analysis?
DTA measures the temperature difference between the sample and a reference as function of temperature or time while the sample and the reference are subjected to a controlled temperature program
69
What changes of state are DSC and DTA useful for quantifying?
```
Crystalline transitions
Fusion
Evaporation
Sublimation
Crystal purity
Polymorphism
```
70
What is s polymorph?
A solid material with at least two different molecular arrangements. Distinct crystal species
71
What can polymorphism affect?
Stability, dissolution rates and solubility
72
What are highest melting polymorph have in regards to stability and solubility?
Most stable
| Least soluble
73
What are polymorphs numbered in?
Order of stability at room temperature
| E.g. Form I > Form II> Form III ect.
74
What do crystals with weak bonds have?
Low melting point and low heat of fusion
75
What are the majority of drugs and excipients?
Crystalline solids
76
What are the two consecutive stages of dissolution?
An interfacial reaction which is liberation of solute molecules
A migration step
77
What does dissolution involve?
The replacement of crystal molecules by solvent molecules
78
What must solvent/solute attraction forces overcome?
Cohesive forces of attraction between molecules of the solid
79
What are liquids thought to contain?
Free volume in the form of holes not occupied by solvent molecules
80
What occupied theses holes in liquids?
Solute molecules
81
What does the migration step involve?
Transport of drug molecules away from solid/liquid interface and into the bulk liquid
82
What does the migration step occur through?
Diffusion or convection
83
What are boundary layers?
Static/ slow-moving liquid layers that surround all solid surfaces surrounded by liquids
84
What does slow mass transfer result in?
Inhibition of movement of drug from solid surface and into bulk liquid
85
During diffusion, what does the concentration of solution in boundary layers go from?
Saturated at the crystal surface to being equal to the concentration in the bulk
86
What is intrinsic solubility (C0)?
The solubility of the drug compound when it is completely unionised
87
For the intrinsic solubility what do you measure the solubility of a weak acid in?
In a acidic solution
88
For the intrinsic solubility what do you measure the solubility of a weak base in ?
Alkaline solution
89
What two temperatures should the solubility of a drug be measured at?
4oC- water solubility is minimum
| 37oC- the solubility at body temperature
90
What can impurities do in regards to solubility of a drug compound?
Increase, decrease or have no effect
91
What can reasonable estimation of C0 be made by using?
A phase solubility diagram
92
What are phase solubility diagrams?
These are obtained by varying the drug : solvent ratio, measuring the solubility and plotting the resulting data
93
What does it mean if phase solubility diagram has deviation from horizontal?
Sample contains no impurities
94
What does it mean if the line in extrapolated to zero phase ratio on a phase solubility diagram?
C0
95
Name a super-solvent?
Dimethylsulfoxide DMSO
96
How can solubility be measured?
SiriusT3 and 96-well micro-titre plate
97
What % of drugs are weak bases?
75%
98
What % of drugs are weak acids?
20%
99
What % of drugs are non-ionic,amphoteric of alcohols?
5%
100
What is the degree of ionisation in a drug measured by?
pKa
101
What does an increase in solubility in acidic aqueous solution suggest?
That the compound is a weak base
102
What does an increase in solubility on alkaline aqueous solution suggest?
That the compound is a weak acid
103
What does an increase in solubility in both acidic and alkaline conditions suggest?
That the compound is either amphoteric or zwitterionic
104
What does no change in solubility over a range of pH suggest?
That compound is neutral and non-ionisable (no pKa)
105
What can Henderson-Hasselbach equation be used to?
Determine pKa by following changes in solubility
| Predict solubility at any pH (knowing C0 and pKa)
106
What is Cs?
The total solubility so the ionised and unionised form
107
What is the solubility in for acid to = Cs?
In 0.1M HCL
108
What is the solubility at for acids to = Cs?
pH 6 and 8
109
What is the solubility in for a base to = C0?
0.1M NaOH
110
What is the solubility at for base = Cs?
pH 4 and 6
111
What does an increase in pH of a base mean in regards to solubility?
Decrease
112
What does increase in pH of acid mean in regards to solubility?
Increase
113
What does at increase in pH of an amphoteric mean in regards to pH?
Decrease up to pH 7 then increase
114
What is preformulation?
It is the determination of certain fundamental physical and chemical properties of a potential new drug.
