Pre-formulation considerations Flashcards
What is the purpose of excipients?
They are used to optimise drug design
What does the choice of dosage form depend on?
The use of the drug
What are the principle objectives to achieve?
- predictable therapeutic response
- product suitable for large scale manufacture
- reproducible product quality
What dosage form does prednisolone come in?
- tablet
- injections
- eye drops
- enema
What factor should be considered in pre-formulation?
- biopharmaceutical
- physiochemical properties
- therapeutic
- financial
Why should biopharmaceutical factors be considered?
Biological effect might influence the dosage form.
What is pre-formulation?
A pilot study to enable you to optimise drug formulation
What properties of the drug are looked at?
Physiochemical properties
What factors determine bioavailability?
- stability
- dissolution
- interaction
What are the techniques used in physicochemical analysis?
- UV spectroscopy
- HPLC
- Differential scanning calorimetry (DSC)
- Dynamic vapour sorption (DVS)
- Xray powder diffraction (XRPD)
What molecular / intrinsic properties of the drug can’t be changed unless the structure is chemically modified?
- Solubuility
- stability
- hygroscopicity
- pKa
- partition coefficient
What does the solubility of a drug need to be when used in animal studies?
> 1mg/1ml
What should the solubility of the final product be?
10mg/1ml
Define hygroscopicity
the ability of a substance to attract water
What can adsorption or absorption cause?
It can cause changes in physiochemical properties of the drug affecting:
- powder flow
- drying
- ease of compact
What happens to amorphous substances when they interact with water?
they breakdown faster leading to molecular mobility or crystallisation
What kind of molecules have a greater tendency to absorb water?
Salts - this causes problems with dissolution
What do KCl and Mg(OH)2 do in the presence of water?
They are very hygroscopic - dissolve spontaneously to form solutions (deliquescence)
Define adsorption
adhesions of atoms, ions or molecules on to a surface
What happens when adsorption occurs on the surface?
small layers form which stop the drug from dissolving.
What do microporous surfaces do?
allow water into capillary spaces within the solid
Give an example of a microporous substance
Silica gel
How is water uptake determined?
By measuring a change in mass
What is Thermogravimetric analysis (TGA)?
The process of heating up a mass, and measuring how much water is absorbed by how light it is after heating.
What is dynamic vapour sorption?
Measuring a substance then introducing humidity and measure its mass after. The weight gain will tell how much has been absorbed.
What are macroscopic/bulk properties?
These can be intermolecular interactions, solid state form, shape and environment
What make up macroscopic properties?
- Melting point
- Enthalpy of fusion
- Physical form
- Particle size and shape
- Density
- Particle flow
- Compaction
- Excipient compatibility
Define enthalpy of fusion
Change in enthalpy resulting from a change in state
What is melting point defined as?
Temperature needed to break bonds
What does differential scanning calorimetry determine?
melting point and enthalpy of fusion - a drug is heated, when it undergoes a phase change there is an endothermic reaction.
The point of melting is the peak where there is a change in state
Are polymorphs stable?
No - they will slowly crystallise to the stable form
How do amorphous structures occur?
High molecular weight molecules such as polymers or biological structures.
Precipitation can also cause them to occur.
Do polymorphs have better solubility?
Yes, results in faster dissolution
When does polymorphism occur?
When a compound exists in at least 2 different molecular arrangements in the solid state
What can be said about the most stable polymorph?
- has a high melting point
- exists in a thermodynamic state of eqm (other forms convert to this over time)
What will X-ray powder diffraction do for polymorphs?
provide solid state structure
What will DSC do for polymorphs?
Give more than one melting point if there are polymorphs present
Is the amorphous form of novobiocin more soluble?
Yas
Crystalline one is used for modified release
What forms does Ampicillin exist as?
Anhydrous and trihydrate
- anhydrous dissolves faster than trihydrate so there is less of an energy change with its dissolution
How is Ferets diameter determined?
Measuring diameter is different orientations
How is Martin’s diameter determined?
Measuring the radius from different places in the particle and calculating mean radius
Particles with a diameter of …. or less have ….. flow properties
Diameter 50mcm
Poor
Why is good flow needed?
To ensure blend uniformity and optimal filling
How can flow be measured?
Angle or repose
Carr’s index
What angle of repose is unsatisfactory for flow?
> 45 degrees
What angle of repose is good for flow?
close to 25 degrees
What does Carr’s index relate to?
Flowability and compaction
How is Carr’s index calculated?
Measuring bulk density and tapped density
What is bulk density?
Adding mass of powder to cylinder then calculating density (mass / volume)
What is the tapped density?
When the cylinder is tapped to see if there is any change in volume
What is compaction?
The result of compression and cohesion
What happens when the drug is a low dose?
The majority if the tablet is the excipient
What happens the dose increases >50mg?
Compaction properties of the drug influence the properties of the tablet
What does brittleness aid?
Aid bond formation
Why is the paddle method preferred for determining solubility?
Gives reproducible results - only one face of the disc is exposed
What does introducing a hydrophilic group do?
Improves solubility 100 fold
What effect does using a metastable polymorph have on solubility?
Increases solubility as the amorphous form is more soluble
What is solvation / hydration?
Incorporation of solvent molecules into the crystal structure - less energy released for hydrated form to dissolve but in non-aq solvent there is an increase in soluble
What is Ka and what effect does it have on solubility?
It is the dissociation constant represents concs of ionised an unionised species.
Larger Ka = more dissociation = higher solubility
When are drugs converted to salts?
If they have poor aqueous solubility or if they are difficult to isolate or purify.
When are salts formed?
When an acid reacts with a base
If pKa is <5 what happens in terms of salt formation?
The salt formed is unlikely to be stable at physiological pH - it will precipitate at a concentration above its solubility.
What is needed for salt formation to occur?
There should a sufficient different in pKa between the acid and base
What happens when a basic drugs reacts with a strong acid?
The conjugate acid and base form a salt.
When it dissociates in water, it donates its H+ this lowers the pH of the solvent and increases drug solubility
What are the advantages of salt formation?
- Enhanced solubility
- Increased dissolution rate
- Increased melting point
- Reduced hygroscopicity
- Improved photostability
- Better taste
- Increased bioavailability
- Better processabilty
- Easier synthesis / purification
- Potential for controlled release
What are the disadvantages of salt formation?
- Lower % of API
- Increased hygroscopicity
- Reduced chemical stability
- Increased number polymorphs
- Reduced dissolution in gastric media
- No change in solubility buffers
- Corrosiveness
- Possible disproportionation
- Additional manufacturing step
- Increased toxicity
What is contact angle a result of?
Interfacious energies of:
- surface tension of the liquid,
- tension between solid and vapour
- tension between solid and liquid
What does a contact angle of <90° suggest?
Wetting of the surface is favourable
What does a contact angle of >90° suggest?
Wetting of the surface is unfavourable
How can surface tension be reduced?
By adding a wetting agent e.g. SLS or polysorbate
Describe plastic flow
Particles don’t flow until pressure is applied
What is pseudoplastic flow?
When pressure is applied, flow is increased
Describe dilatant flow
When particles flow at low pressure but have friction at higher pressures.
