Pre-formulation of solid dosage forms Flashcards
Principles of Dosage Form Design
The main aim in the design of any dosage form is facilitate the delivery of therapeutic drugs into the body:
Safely,
Efficiently,
Reproducibly
Conveniently.
What is preformulation?
Preformulation is the first step in the rational development of dosage forms of a drug into a medicine
Involves characterising the physical and chemical properties of the active pharmaceutical ingredients.
Provides the formulating team the critical information for developing a stable and bioavailable dosage form that can be mass produced.
Preformulation: First step in this rational approach
Most drugs are presented as solids within medicines
For Gastro-intestinal delivery, the drug must dissolve before it can permeate the gut epithelium and enter the systemic circulation.
Thus, solubility and dissolution rate can be a controlling factor in the rate of absorption and bioavailability of a medicine.
An aqueous solubility greater than 10mg/mL is optimal.
If the solubility of the drug < 1mg/mL then a salt form of the drug, if possible, is indicated.
Otherwise, novel dosage form or solubilisation technologies may be required.
Biopharmaceutical Classification System (BCS) – only applicable for oral dosage forms
class I = high permeability and solubility
class II = high permeability and
low solubility
class III = low permeability and high solubility
class IV = low permeability and solubility
common strategies to address low drug solubility
make them into
salts
polymorphs
cyclodextrin
use surfactants
reduce particle size
add cosolvents
High risk compounds
Poorly soluble compounds as defined by the FDA biopharmaceutical classification system (Class II, IV)
Compounds may require one of the non-equilibrium methods or semi-solid/liquid formulations to enhance dissolution rate and bioavailability via the GI tract.
Amorphous
Meta-stable polymorphs
Solid dispersion
Lipid based formulations (e.g. soft liquid gelatin capsules)
Introduction to Pharmaceutical Salts
During the last decade, the pharmaceutical industry has led to an evolutionary change in the way it is discovering and developing drugs.
In the search of more potent and highly specific drug molecules, more lipophilic and water insoluble compounds are being selected.
Salt formation is thus considered critical in solving this problem.
The choice of salt form is an important step in the development process since it has an impact on physicochemical and biopharmaceutical properties.
Salt forms can have a large effect on quality, safety and efficacy of a medicine.
pros of pharmaceutical salts
enhanced solubility
increased dissolution rate
easier synthesis and purification
better taste
high bioavailability
higher melting points
advantages outweigh the dis
disadvantage of pharmaceutical salts
decreases the % of drug
additional
manufacturing steps
increased toxicity
decrease in chemical stability
increased the number of polymorphs
no change in GI due to ph solubility
salt formation
drug
ionized drug
ionic interactions
drug salt
Decision tree approach to salt selection
Target salts are chosen by considering such factors as:
Structure of the drug substance
pKa of the drug substance (pKa ~ 3)
Chemical and physical stability of the drug substance
Available literature on structurally-related compounds
Ease of large-scale preparation of the salt
Type of drug product
Anticipated loading of the drug substance in the drug product
Hydrochloride is most commonly used (note nonsense of ‘negative’ pka). In some cases this can lead to highly soluble salts but a potential problem of hygroscopicity, since the drug will dissolve in its own moisture.
for anion HCl is most commonly used
cation sodium , potassium
Crack cocaine is bought as a weak base
Does not dissolve in water.
IV users need to make a charged polarised salt by making a solution with an acidic solutions
Typically, lemon, lime juice or vinegar (acetic acid).
Creates a hydrophilic and soluble salt.
The physical form of a drug
Only applies to a drug while it is in the solid-state
The single biggest factor affecting the performance, development, patentability, manufacturing and profitability of a compound
A drug can have many different solid-state forms:
Crystalline (Polymorphs, Hydrates and Solvates)
Chiral
Habits
Amorphous
Crystalline Solids
Highly important pharmaceutical parameters change with crystalline behaviour
Following properties/ parameters of a given compound are all determined primarily by the nature of the crystal structure:
Solubility and dissolution rates
Crystal hardness (compressibility for tablets)
Chemical stability (enthalpy of solution, enthalpy of transition, hygroscopicity, melting and sublimation temperatures)
Others include: Colour and refractive index, heat capacity, conductivity, volume, density.
Crystal Morphology or Habit
The external shape of a crystal
is termed the crystal habit.
The crystal habit is associated
with the way solute molecules orientate themselves when growing.
The general shape of a crystal is related to the growth of individual crystal faces.
The slowest growing face dominates.
Crystal habit influences flow, compaction, stability and solubility
Crystal Face identification
Each crystal face has a designated index plane
These are known as Miller indices
Miller index provides information about the molecular ordering of the surface of a crystal face
Pharmaceutical effects of habit
Injectables: Plate-like crystals pass through needles better than long needle-like crystals.
Tableting: Plate-like tolbutamol crystals do not flow and have poor compressibility.
Needle-shaped paracetamol crystal powder shows poorest compression properties, showing greater capping and lamination, than the plate- or cube-shaped crystals.
Dry powder inhaler (DPI) formulations: Needle-like crystals usually have better fine particle fraction.
Crystal structure
There are a total of 7 types of crystal structures and all can be defined by the lengths and angles between each side of the unit cell.
A crystal is composed of periodical aligned building blocks called unit cells
Cubic- 3
Tetragonal- 2
Orthorhombic- 4
Trigonal
Monclinic- 2
Triclinic
Hexagonal
Drug molecules will typically form triclinic, monoclinic and orthorhombic unit cells
Molecules can arrange themselves into 14 different configurations and are known as Bravais lattices
Paracetamol
Two polymorphic forms: monoclinic (Form 1) and orthorhombic (Form 2). Form 1, more stable at room temperature, is commercially preferred but unsuitable for direct compression, requiring binding agents for tableting.
crystal form
Crystal form refers to atomic and molecular arrangement, not outer appearance (habit) of crystals/particles.
Different crystal forms of the same compound are polymorphism.
Pseudopolymorphs include solvates (solvent molecules in lattice) and hydrates (water molecules in lattice). Chiral molecules can crystallize as enantiomorphs, forming mirror images. A mix of D (dextro) and L (levo) forms creates a racemic mixture.
organic molecular solid
amorphous or crystalline
crystalline splits into
polymorphs or hydrates
polymorph splits into
monotropic or enantiotropic
Properties that may change with polymorphic form
Melting point
Dissolution rate
Compressibility
Density
Flowability
Surface properties (surface energy and morphology)
Habit and crystal shape
Hygroscopicity
Hardness
Stability
It is essential during the preformulation stage that the most thermodynamically stable polymorph is formed, since a more favourable form may be obtained upon scaling-up.
Enantiotropic
Solid phase transitions which transform reversibly without passing through the liquid or gaseous phases are called enantiotropic
monotropic
If these are not achieved prior to a phase change then they are called monotropic
- any transition from one polymorph to another below melting point will be irreversible
