Preformulation Flashcards
What is the most popular dosage form?
Tablets
Why is preformulation needed?
To give info on:
Feasibility of dosage forms
Potential drug instability
Poor in vivo dissolution
What are excipients?
Inactive substances that are used as vehicles or medium for drugs or other active substances
What is a problem with preformulation?
Only limited quantities of compound will be available
Why is it important not to skip preformulation?
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
What is minimum preformulation?
Getting as much information as possible form the small amount of material available
What two properties should be measured first?
Intrinsic solubility (C0) Dissociation constant (pKa)
What amount of drug should be used for measuring solubility?
50 mg
Why are new compounds of poor quality?
Lots of unknown impurities
Different crystal forms
What does the solubility dictate?
The ease of obtaining formulations of aqueous solutions
What does measuring the pKa allow?
Information given of pH to maintain solubility
Allows informed choice of salts which gives good bioavailability
What does solubility affect?
Drug absorption
What pH range should drugs solubility be?
Solubility of more than 1% at pH range 1-7
What temperature should drugs solubility be?
37oC
What is absorption rate limited by?
Dissolution rate
What is solution?
A mixture of two or more components that form a single phase homogeneous down to molecular level
What is solvent?
A component that determines the phase
What is solute?
The component which is dispersed
What is dissolution?
Transfer of molecules or ions from solid state into the solvent
What is a saturated solution?
A solution in which the solvent has dissolved all of the solute that it can
What is solubility?
The maximum concentration that can be attained by a solute in a specific solvent
What is the quantity per quantity expression of solubility?
1gL-1 or 0.1g per 100 mL
What is molality expressed in?
Moles per 1000g
What is molarity expressed in?
Moles per litre
What is mole fraction expressed in?
Moles per total number of moles
What is parts expressed in?
Number of weight parts solid/number of volume parts of solvent
What is the solubility if a very soluble compound?
Less than 1
What is the solubility of a practically insoluble or insoluble drug?
More than 10,000
What does an increase in solubility suggest the compound is?
A weak base
What does increased solubility in alkaline aqueous solutions suggest the compound is?
A weak acid
What does an increase in solubility under both acidic and alkaline conditions suggest?
That the compound is amphoteric or zwitterionic so two pKa values
What does no change in solubility over a range of pH suggest?
That the compound is neutral and non-ionisable (no pKa)
How can solubility be improved?
pH (use of buffers) Salts Use of co-solvents Use of surfactants Complexation Solid dispersion
What pH range buffers used?
pH 3-9
Why are extreme pH values used for buffers?
Injections would cause tissue damage and pain
What pH is acidic drugs formulated in?
Basic pH
What pH is basic drugs formulated in?
Acidic pH
What can salts do in regards to solubility?
Improve solubility
How are salts formed?
By acid base reactions
What should the pKa for each component not be?
Too close together (
Why is it better to use walk acid or base?
These says tend to be less soluble but also less hygroscopic
Give an example of salts of acidic drugs?
Sodium salicylate
Give example of salts of basic drugs?
Meperidine hydrochloride
What are acidic groups in drugs?
COOH
OH and SH (thiol) if attached to an electron-withdrawing group
What is a basic group in drugs?
Amino groups
What is co-solvency?
The mixing solvents of different polarities to form a solvent system of optimum polarity to dissolve the solute
Why are co-solvents added to water?
To increase the solubility
To increase stability
Injection formulation
What is the dielectric constant of the solvent used for?
When developing the co-solvent system
What could injections contain?
What should solubility be measured in?
Aqueous/co-solvent mixtures (formulations rarely require pure co-solvent)
What do surfactants have?
A polar head and a lipophilic tail group
What can surfactants form?
Micelles at concentrations higher than the critical micelle concentration. Hydrophobic drugs can diffuse inside the micelle
What must surfactants be?
Non-toxic
Miscible with the solvent
Compatible with other ingredients
Odourless
Give an example of non-ionic surfactants
Glycol/glycerol
Give an example of alkali metal and ammonium soaps
E.g. Sodium stearate
What are commonly used as complexing agents?
Cyclodextrins
What are Cyclodextrins?
6-8 glucopyranose units forming cyclical structures like hollow cylinders/baskets . Inside is hydrophobic and rim is hydrophilic
The more hydrophobic a drug what happens to the effect of the co-solvent?
Increases
What is lipophilicity measured using?
Oil-water partition coefficient (log P)
What does it mean when P=1?
The drug has equal affinity for both oil and water
What does it mean if P>1?
The drug is lipophilic (hydrophobic)
What does it mean if P
The drug is hydrophilic
Why is the logarithm scale used?
As the values of P may be very large
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
What is the pro/con of capillary melting?
Gives information on melting range but accuracy is low
What are the advantages of hot stage microscopy?
Heating rate of controlled
Other transitions can be observed/recorded
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
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
What changes of state are DSC and DTA useful for quantifying?
Crystalline transitions Fusion Evaporation Sublimation Crystal purity Polymorphism
What is s polymorph?
A solid material with at least two different molecular arrangements. Distinct crystal species
What can polymorphism affect?
Stability, dissolution rates and solubility
What are highest melting polymorph have in regards to stability and solubility?
Most stable
Least soluble
What are polymorphs numbered in?
Order of stability at room temperature
E.g. Form I > Form II> Form III ect.
What do crystals with weak bonds have?
Low melting point and low heat of fusion
What are the majority of drugs and excipients?
Crystalline solids
What are the two consecutive stages of dissolution?
An interfacial reaction which is liberation of solute molecules
A migration step
What does dissolution involve?
The replacement of crystal molecules by solvent molecules
What must solvent/solute attraction forces overcome?
Cohesive forces of attraction between molecules of the solid
What are liquids thought to contain?
Free volume in the form of holes not occupied by solvent molecules
What occupied theses holes in liquids?
Solute molecules
What does the migration step involve?
Transport of drug molecules away from solid/liquid interface and into the bulk liquid
What does the migration step occur through?
Diffusion or convection
What are boundary layers?
Static/ slow-moving liquid layers that surround all solid surfaces surrounded by liquids
What does slow mass transfer result in?
Inhibition of movement of drug from solid surface and into bulk liquid
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
What is intrinsic solubility (C0)?
The solubility of the drug compound when it is completely unionised
For the intrinsic solubility what do you measure the solubility of a weak acid in?
In a acidic solution
For the intrinsic solubility what do you measure the solubility of a weak base in ?
Alkaline solution
What two temperatures should the solubility of a drug be measured at?
4oC- water solubility is minimum
37oC- the solubility at body temperature
What can impurities do in regards to solubility of a drug compound?
Increase, decrease or have no effect
What can reasonable estimation of C0 be made by using?
A phase solubility diagram
What are phase solubility diagrams?
These are obtained by varying the drug : solvent ratio, measuring the solubility and plotting the resulting data
What does it mean if phase solubility diagram has deviation from horizontal?
Sample contains no impurities
What does it mean if the line in extrapolated to zero phase ratio on a phase solubility diagram?
C0
Name a super-solvent?
Dimethylsulfoxide DMSO
How can solubility be measured?
SiriusT3 and 96-well micro-titre plate
What % of drugs are weak bases?
75%
What % of drugs are weak acids?
20%
What % of drugs are non-ionic,amphoteric of alcohols?
5%
What is the degree of ionisation in a drug measured by?
pKa
What does an increase in solubility in acidic aqueous solution suggest?
That the compound is a weak base
What does an increase in solubility on alkaline aqueous solution suggest?
That the compound is a weak acid
What does an increase in solubility in both acidic and alkaline conditions suggest?
That the compound is either amphoteric or zwitterionic
What does no change in solubility over a range of pH suggest?
That compound is neutral and non-ionisable (no pKa)
What can Henderson-Hasselbach equation be used to?
Determine pKa by following changes in solubility
Predict solubility at any pH (knowing C0 and pKa)
What is Cs?
The total solubility so the ionised and unionised form
What is the solubility in for acid to = Cs?
In 0.1M HCL
What is the solubility at for acids to = Cs?
pH 6 and 8
What is the solubility in for a base to = C0?
0.1M NaOH
What is the solubility at for base = Cs?
pH 4 and 6
What does an increase in pH of a base mean in regards to solubility?
Decrease
What does increase in pH of acid mean in regards to solubility?
Increase
What does at increase in pH of an amphoteric mean in regards to pH?
Decrease up to pH 7 then increase
What is preformulation?
It is the determination of certain fundamental physical and chemical properties of a potential new drug.
