Pre-formulation of solid dosage forms

The main aim in the design of any dosage form is facilitate the delivery of therapeutic drugs into the body: Safely, Efficiently, Reproducibly Conveniently.

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.

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.

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

make them into salts polymorphs cyclodextrin use surfactants reduce particle size add cosolvents

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)

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.

enhanced solubility increased dissolution rate easier synthesis and purification better taste high bioavailability higher melting points advantages outweigh the dis

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

drug ionized drug ionic interactions drug salt

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.

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

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.

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

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

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.

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

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 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.

amorphous or crystalline

polymorphs or hydrates

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.

Solid phase transitions which transform reversibly without passing through the liquid or gaseous phases are called enantiotropic

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