Pre Formulation and Formulation Flashcards
What is pre-formulation?
Pre-formulation is the stage in drug an dosage form development before formulation proper
It aims at optimising the drug candidate into a drug product.
The physicochemical properties of all drug candidates are determined and each showing activity towards to the biological target: the best one will be developed in a drug product
Pre-formulation data is used to:
- Decide which drug candidate will be the easiest to formulate
- Determine the most appropriate dosage form
- Highlight issues with processing
Physicochemical properties are divided in two categories:
- Intrinsic/molecular properties i.e. inherent properties of the molecule and can only be modified by chemical modification (e.g. solubility)
- Derived/macroscopic properties are related to the bulk behaviour e.g. intermolecular interactions.
Intrinsic property examples:
- Solubility
- pKa
- logP
- Hygroscopicity
- Stability
Technique and sample requirement for solubility:
- UV Vis spectrophotometry
- chromophore
Technique and sample requirement for pKa:
Technique :
- UV Vis spectrophotometry
- Potentiometric titrations
Sample requirement:
- Acid or base group
Technique and sample requirement for log P:
Technique :
- UV Vis spectrophotometry
- TLC, HPLC
Sample requirement:
- chromophore
Technique and sample requirement for hygroscopicity:
Technique :
- Dynamic vapour sorption
- Thermogravimetric analysis
Sample requirement: n/a
Technique and sample requirement for stability:
Technique :
- HPLC, and suitable storage conditions
Sample requirement: n/a
Examples of derived/macroscopic properties:
- Melting point
- Enthalpy of fusion
- Physical forms (e.g. polymorphs)
- Particles size, shape, morphology
- Density bulk, tapped, true
- Flow
- Compressibility
- Excipients compatibility
Melting point technique assay:
DSC or melting point apparatus
Enthalpy of fusion technique assay:
DSC
Physical forms (e.g. polymorphs) technique assay:
DSC, XRPD, microscopy
Particles size, shape, morphology technique assay:
Microscopy, particle sizing
Density technique assay:
Densitometer
Flow assay technique:
Angle of repose
Compressibility assay technique:
Carr’s index
Excipients compatibility assay technique:
HPLC, DSC
Toxicity and bioavailability data in animal models require what solubility?
a solubility > 1mg/mL.
In all solubility determinations:
- The solvent and solute must be pure
- A saturated solution must be obtained before analysis
- Separation of sample of saturated solution from undissolved material must be satisfactory
- Temperature must be adequately controlled
- Method for analysing the solution must be accurate and reliable
- Solute concentration can be determined by UV spectrometry, chromatography (e.g. HPLC) or gravimetric analysis
Determination of log P techniques:
- Shake flask method
- Chromatographic methods e.g. reversed phase TLC or reversed phase HPLC
Ways of modifying the solubility:
Molecular structure of the solute:
- Small change in structure e.g. introduction of a hydrophilic group, may improve the solubility by up to 100 fold
- Reduction of aqueous solubility of a parent drug by esterification
- Masking the taste
- Protection form extensive degradation in the GI tract
Nature of the solvent:
- Use of co-solvents (e.g. ethanol, PEG)
- Using co-solvent for metronidazole make it suitable for parental administration
Most common counter ions for salt selection:
Cation: potassium, sodium, zinc, calcium
Anion: hydrochloride, sulfate, chloride, phosphate
Disadvantages of salt form?
- Decreased percentage of active ingredient
- Increased hygroscopicity
- Decreased chemical stability
- Increased number of polymorphs
- Reduced dissolution in gastric media
- No change in solubility in buffers
- Corrosiveness
- Possible disproportionation
- Additional manufacturing step
- Increased toxicity
How does a weakly basic drug modified into a salt work?
When the salt dissolves in water, it dissociates, donating its proton, lowering the pH of the solution and increasing the drug solubility.
Drugs are often formed in organic solvents
The increased solubility of a salt is only a result of the change of pH upon dissolution
Definition of hygroscopicity?
Hygroscopicity: tendency of a substance to attract water from its immediate environment either by absorption or by adsorption.
Appropriate steps need to be taken to protect hygroscopic formulations in humid conditions:
- Suitable packaging
- Advising correct storage conditions
Problems of water content during formulation?
During formulation increased water content leads to wet powder, increased cohesion and reduced flowability.
Water can mediate solid state reactions:
- Increase rate of degradation or interaction with excipients
- If substance is amorphous, absorption of water results in plasticisation of the matrix
- If amorphous matrix is a freeze dried product absorption causes the structure to collapse
- Absorption of water may result in the crystallisation of the compound.
What is enthalpy of fusion?
The enthalpy of fusion, , is the change in enthalpy resulting from heating a given substance to change its state from solid to liquid
The temperature at which fusion occur is the melting point (50%).
How is size and shape of particle determined?
Size and shape of particle will be determined by light microscopy (unless it is spray-dried or micronised in which case SEM is used).
The compressibility (or compaction) is calculated by measuring the bulk density and tapped density (Carr’s index). What is bulk density and what is tapped density?
Bulk density is obtained by adding a known mass of powder to a graduated cylinder. The density is calculated as mass/volume
Tapped density is obtained by mechanically tapping the graduated cylinder to see whether further volume change is observed
What is polymorphism?
when a compound exists in at least two different molecular arrangements in the solid state.
Stable polymorphic form and metastable forms
Each polymorph is different in crystal structure but identical in the liquid and vapour state.
What are amorphous materials?
- Macroscopic property
Amorphous materials are not characterised by a repeating unit arrangement - the matrix they form is termed amorphous
High molecular weight molecules (polymers, biological materials) can have difficulty orientating themselves uniformly.
As they have no lattice energy, they are unstable and over time they will convert to a crystalline form.
Amorphous compounds are less stable but more soluble, so often exhibit faster absorption and enhanced bioavailability
What is wettability?
Wettability (wetting) describes the ability of a liquid to maintain contact with a solid surface
Poor wetting results in limited ability to dissolve
Adhesive forces between the liquid and solid cause the liquid to spread.
Cohesive forces with the liquid cause the liquid to drop and limit its contact with the solid
What can be used to reduce the surface tension and improve wetting?
Surfactants
What is rheology?
Rheology is the science of flow and deformation of matter.
The viscosity of a fluid is its resistance to flow or movement
Simple fluids such as water are said to be Newtonian: the rate of flow is proportional to the applied stress
Example of plastic flow?
(e. g. ketchup)
- No flow until a certain force is applied
- At lower stress behaves like an elastic solid
- Observed for concentrated suspensions, especially if the continuous phase is highly viscous or if particles are flocculated.
Example of pseudoplastic flow?
e.g. quicksand)
Material flows as soon as pressure is applied and flow rate increases with increasing pressure but not linearly
Hydrocolloids such as methylcellulose or carmellose, wynthetic polymers sias polyvinylpyrollidone
High molecular weigh polymers become entangle in immobilised solvent i.e. w/o force
What is Dilatant flow (e.g. starch and water)?
Viscosity increases with shear rate (force frequency)
Occurs in dispersion containing at least 50% small deflocculated particles
Without shear particles are closely packed
When shear is applied particles are displaced and form clumps
Creates larger voids into which the vehicle drains, so resistance to flow is increased
Behaviour I reversible with removal of stress.
What are disperse systems?
- Disperse systems are made of a disperse/internal phase (particles or droplets) dispersed in another component (continuous phase).
Colloidal dispersion definition?
is used between 1nm-1mm and coarse dispersion above 1 mm.
What is a solution?
a colloidal dispersion of solid particles in a liquid
What is an emulsion?
is a mixture of two immiscible liquids
How is a foam formed?
formed when gas particles are trapped in a liquid or a solid
What is an aerosol?
contains solid or liquid dispersed in a gas