Pre-formulation Flashcards
What is preformulation?
Characterising physical and chemical properties of the active pharmaceutical ingredient to produce a stable and bioavailable dosage form that can be mass produced.
Optimal aqueous solubility?
> 10mg/ml
Solubility that requires salt to be made?
<1mg/ml
Noyes-Whitney equation
dm/dt= DA(Ca-C)
————-
H
D= dilution coefficient A= surface area of drug H= thickness of boundary layer Cs= solubility C= conc. in bulk solvent
Drug classes for solubility and permeability
Class 1: high permeability, high solubility
Class 2: high permeability, low solubility
Class 3: low permeability, high solubility
Class 4: low permeability, low solubility
Definition of brick dust
Poorly soluble drugs in aqueous solutions
Strategies to address low drug solubility
Use of co-solvents (ethanol/water) Use of salts Surfactants Cyclodextrins (sugar/starch compounds that form soluble structures) Particle size reduction Lipid based systems similar to micelles Polymorphs Co-crystals to form lattice structures Amorphous solid dispersions
High risk compounds
Class 2 or 4
Dissolution rate and bioavailability enhanced by non-equilibrium methods or semi-solid/liquid formulations
e.g. amorphous (change of structure), meta-stable polymorphs, solid dispersion, lipid based formulations like soft liquid gelatin capsules
Henderson Hasselbalch equation
pka= pH + log [HA/A-]
More potent and highly specific drugs
From lipophilic and water insoluble compounds
Salt forms
Effect quality, safety and efficacy
Tested separately for toxicity
Drugs suited to being salts
Drugs with poor solubility that are weak acids or bases
Requires sufficient difference in pka between acid and base (around 3 pka difference)
Advantages of salts
Enhanced solubility Decreased dissolution rate Easier synthesis and purification High bioavailability High melting point Improved photostability Better taste
Disadvantages of salt forms
Lower % of drug Increased hygroscopicity More process steps Increased toxicity Decreased chemical stability No change in solubility at various pH’s of GI tract Increased number of polymorphs
Formation of drug salt
Ionised drug and ionised counterion are liquidised and mixed, ionic interactions form the drug salt in controlled crystallisation
Methods of crystallisation
Microcrystallisation
Sitting drop method
Hanging drop method
Target salts
Consider: Structure of substance Chemical and physical stability Structurally related compounds Ease of large scale production Type of drug Formulation of final drug
Different solid state forms
Crystalline (polymorphs, hydrates, solvates)
Chiral
Habits
Amorphous
Pharmaceutical parameters that change with crystalline behaviour
Solubility and dissolution rates Crystal hardness (compressibility of tablets) Chemical stability (enthalpy of solution/transition/hygroscopy/melting/sublimination temperatures) Colour and refractive index Heat capacity Conductivity Volume Density
What is a habit
The external shape of a crystal
Associated with how solute molecules orient themselves when growing
Shape of the crystal is dictated by how each face grows (slowest growing face dominates)
Habit influences flow, compaction, stability and solubility
Pharmaceutical effects of habit
Injectables: plate like crystals pass through needles better than long thin ones
Tablets: plate like tolbutamol crystals do not flow and have poor compressibility
DPI: needle-like crystals have better fine particle fraction
What is crystal structure
Composed of periodical aligned building blocks called unit cells which revel the crystal structure and symmetry specific for each substance
7 types of cell structure with different lengths and sides
Cube Tetragonal Orthorhombic Trigonal Monoclinic Triclinic Hexagonal
Triclinic, monoclinic and orthorhombic are common
Paracetamol forms
Two polymorphic forms:
Monoclinic (more thermodynamically stable at RTP and more commonly used)
Orthorhombic (more easily compressed)
What is a crystal form
Ordering of atoms and molecules to form a crystal structure (different to outer appearance)
Different crystal forms are polymorphs
Some are pseudopolymorphs like solvates (solvents in crystal lattice) or hydrates (water molecules in crystal lattice)
Chiral molecules can crystallise as mirror images (enantiomorphs)
Enantiotrophic
Solid phase transition which transforms reversible without passing through liquid or gaseous phas
Monotrophic
Transition from one polymorph to another (not enantiotrophic) below melting point and is irreversible
Regular stacked polymorphs
Lower density Lower lattice energy Lower melting point Faster dissolution rate Possible fracture lines
Interlocking polymorphism
Higher density Higher lattice energy Higher melting point Slower dissolution rate Lower bioavailability
Properties that change with polymorphic form
Melting point Dissolution rate Density Compressibility Density Flow ability Surface properties (surface energy and morphology) Habit and crystal structure Hygroscopicity Hardness Stability
Organic compounds in preformulation
Frequently form hydrates in presence of wafer due to small molecule size of water and multidirectional hydrogen bonding capability of water
Hydration number
Number of water molecules in a compound
Hydrate stability
Most stable solid form in water and least soluble form in GI tract
Anhydrous form is usually favoured
What is an amorphous solid
Where there is no long-range order of positions of molecules/atoms
Have a higher free energy than corresponding crystalline solids and therefore have higher solubility and dissolution rate
Formulations of amorphous drugs
Solid amorphous dispersions
Lypophilised powders
Oral fast dissolving tablets
Solid amorphous dispersions
Drug dissolved in polymetric matrix
Molecular dispersion = solid solution
Particulate dispersion = solid suspension
Matrix can crystallise in parts but not completely, major concern if form change or diffusion & crystallisation
Polymer matrix inhibits drug diffusion & cross-linking stabilisers stop crystallisation
