Preformulation considerations Flashcards
Capsules are cheaper to manufacture than tablets. True or false?
False - tablets are cheaper
What is preformulation?
It is the process before formulating a drug where a drug candidate is turned into a drug product and the physio-chemical properties are determined
During preformulation - large amounts of sample are required for analysis to be undertaken. True or false?
False - small amounts of sample required
How can the molecular or intrinsic properties of the inherent drug be modified?
Can only be changed by modifying the structure
What are the molecular properties that can be modified by changing the chemical structure of the drug?
Stability to oxidation, hydrolysis Solubility Hygroscopicity pKa Partition coefficient
Macroscopic/bulk properties can’t be changed. True or false?
False - can be changed and change based on other excipients present
For the final drug to be given orally as a solid form, what solubility is preferred?
10mg/ml
What is hygroscopicity?
The tendency of a substance to attract water from its immediate environment by absorption or adsorption
Does water selectively bind to polar or non-polar regions of a solid surface?
Polar - so the extent of absorption is related to the degree of polarity
Adsorption of water onto most crystalline solids causes the solid to dissolve. True or false?
False - does not cause it to dissolve
Why doesn’t adsorption of water onto crystalline solids cause the solid to dissolve?
Because only a few layers of water molecules adsorb onto the surface so the volume isn’t sufficient enough to allow dissolution
Salts have a greater tendency to absorb water than free acid or base. True or false?
True
How is water uptake usually determined?
Measuring an uptake in mass -
thermogravimetric analysis (TGA)
dynamic vapour sorption (DVS)
What is the enthalpy of fusion?
The change in enthalpy resulting from heating a given quantity of a substance to change its state from solid to liquid
Melting point doesn’t give any information about the purity of a drug. True or false?
False
What technique is used to measure melting point and enthalpy of fusion?
differential scanning calorimetry
Particle size and surface area do not affect dissolution rates. True or false?
False
A scanning electron microscope is used to determine particle size and shape. True or false?
False - a light microscope is used
It’s easy to determine particle size when the particle is spherical. True or false?
True
Particles with a diameter of 50 or less have good flow properties. True or false?
False - poor flow
Why is it important for powders to have good flow properties?
To ensure blend uniformity and optimal filling of tablet presses or capsule filling machines
In preformulation testing, which two measures are used to determine powder flow?
Carr index
Angle of repose
The higher the angle of repose, the better the powder flow. True or false?
False - a high angle of repose is bad, and a low angle of repose is good
Powders with an angle of repose higher than ___ degrees have unsatisfactory flow properties.
45
Powders with an angle of repose close to ___ degrees have excellent powder flow properties
25
What are bulk density and tapped density used to measure?
compaction or compressibility (Carr index)
How is bulk density measured?
Adding a known mass of powder to a graduated cylinder. The density is calculated as mass/volume
How is tapped density measured?
Mechanically tapping the graduated cylinder to see whether further volume change is observed
Which is better for manufacturing, a powder that is compressible or non-compressible?
Non-compressible (i.e. low Carr index, higher bulk density)
Compaction is the result of ______ and ________
compression
cohesion
Compaction of drug powders is usually good. True or false?
False - usually poor so excipients are added which have good compaction properties
As amorphous materials have no lattice energy, they are unstable and overtime they will convert to a crystalline form. True or false?
True
Amorphous materials exhibit worse solubility and slower dissolution rates than crystalline equivalents. True or false?
False - better solubility and faster dissolution rates
Converting a poorly soluble compound into an amorphous material will improve its bioavailability. True or false?
True
What is meant by polymorphism?
When a compound exists in at least two different molecular arrangements in the solid state
The most stable polymorph has the highest melting point. True or false?
True
The most stable polymorph exists in a thermodynamic position of equilibrium and all other forms won’t convert to it overtime. True or false?
False - they will convert to it
What is the use of X-ray powder diffraction in pre-formulation?
Provides structural data to identify polymorphisms
Differential scanning calorimetry differentiates polymorphs based on what?
Their melting points and enthalpies of fusion
All polymorphs have the same physiochemical properties. True or false?
False - they have different physiochemical properties
The most stable polymorph always has the best bioavailability. True or false?
False - may have the worst processing ability or bioavailability
Why will an anhydrous polymorph of a drug dissolve more quickly than a trihydrous form?
Because the anhydrous is not associated with water so dissolves more quickly but as the trihydrous is already associated with water, there is less of an energy change and so will have a slower dissolution rate
Amorphous compounds have a higher solubility than crystalline compounds. True or false?
True
Which factors determine which API is chosen for formulation and in which dosage form?
Solubility
Salt formation
Rheology
Wettability
How is solubility analysed in pre-formulation?
rotating or disc methods are used
the drug is packed into a non-disintegrating disc
only one face of the disc is exposed to the dissolution medium
disc is either held in place or rotated
samples of dissolution medium are taken at given times
SA remains constant
Under these conditions, the amount of drug dissolved per unit time and unit surface area can be determined - providing the intrinsic dissolution rate
Esterification of a drug will increase its solubility. True or false?
False - reduce solubility as it is non-polar
Degree of ionisation for most polar compounds is not linked to solubility. True or false?
False
A large Ka (small pKa) implies a high or low solubility?
High
If the pKa is low i.e. less than 5 the salt is unlikely to be stable at physiological pH. True or false?
True
What is wettability?
It describes the ability of a liquid to maintain contact with a solid surface. It is defined by measuring the contact angle of a drop of fluid on its surface
Strong cohesive forces within the liquid allow for good wettability. True or false?
False - poor wettability
Strong adhesive forces between a liquid and solid are good for wettability. True or false?
True
What does a contact angle of less than 90 degrees show in terms of wettability?
wetting is very favourable
What can be used to increase wettability?
Surfactants
What is rheology?
The study of flow matter
Most pharmaceutical fluids are Newtonian. True or false?
False, non-newtonian
What is meant by plastic flow?
The material does not flow until a certain level of pressure is applied - plastic flow is exhibited by concentrated suspensions
What is meant by pseudoplastic flow?
The material flows as soon as pressure is applied and flow increases with increasing pressure
What happens in dilatant flow?
When no shear stress is applied, particles are closely packed together
When shear stress is applied, particles become displaced and form clumps
Resistance to flow rises and viscosity increases
Behaviour is reversible with removal of stress
Dilatant flow can be a problem during granulation of tablets
