Pre-formulation and dosage form design

PHAR2000

• early stage process of turning a potential new drug into a medicine

• needs to be formulated into a dosage form that will deliver an adequate dose of the drug via the desired route to the site of action - to be effective

• characteristics of the drug molecule and physical form need to be identified and understood

• conducted prior to designing the final dosage forms to optimise the process of turning the drug into a process

pre-formulation

• data from pre-form studies provide the necessary groundwork for formulation development

• physicochemical properties effect selection of drug

• how it is processed

• drug stability

• how it is dissolved and absorbed

• may only have small quantities to work with, reuse samples

information from pre-formulations

• assay development

• solubility, dissolution and partition coefficient

• acid/base nature and pka

• drug stability

• melting point

• physical aspects - particle size/ shape, powder flow, compressibility, if the drug possess many forms

pre-formulation studies

• solubility of the unionised drug

• possibility of make more soluble salts

• alternative solvents

• suspensions, emulsins or novel dosage form

• lipid solubility - log P

solubility

• determines degree of ionisation of drug molecules in the formulation

• impact on absorption and elimination of drug in the body

pka

• hydrolysis

• oxidation

• photolysis

• effected by temp, ph and enzymes

• influences type of dosage form, storage and packaging and shelf-life

drug stability

• The same drug may exist in different crystalline arrangements, with different properties. - particle size and shape

• a hydrate is a chemical compound that has water molecules trapped inside its solid structure.

polymorphism/presence of hydrates

• studies indicate strength of bonds within material and can indicate the presense of polymorphs or amorphous structures

melting point

are substances that have the exact same chemical "ingredients" but are put together in different shapes or structures.

• polymorphs

• describes solids where the atoms or molecules are jumbled together randomly, like a pile of dropped marbles

no defined melting point

amorphous

• tendency to add or absorb water from atmosphere

• if it is high can cause instability, microbial contamination or structural collapse

hygroscopicity

• determine how well material will flow in tablet press and blend with other excipients

flow characteristics

• indicates how material performs under compressive force tableting and whether it undergoes plastic deformation or brittle fracture

compaction properties

• relationship physicochemical properties of a drug and dosage form, route of administration governs how much of the drug and how fast it enters systemic circulation and the potential to provide therapeutic outcome

dosage form design

• drug properties

• biopharmaceutical aspects of the drug and therapeutic issues

designing a dosage form

• absorption of drug, absorption in the GI tract via skin or mucous membrane

• distrubution, metabolism and excretion

• 1st pass metabolism may limit some routes of administration

• RoA may restrict the type of dosage form

biopharmaceutical considerations for dosage form design

• nature of disease for which the drug is intended

• need for systemic or local therapy

• need for targeted and/or controlled release of drug cancer chemotherapy targeting to improve response & reduce adverse effects,

• extended release of drug for prolonged effect

• control release at particular part of GI

• age of patient group

• home of institutional administration

therapeutic consideration

• determine the onset of drug action but can also determine the duration of drug action and therapeutic outcome

• purpose of dosage form is to optimise delivery to the site of action

• advanced dosage forms need to target site of drug release, control rate of drug release and protect drug from degrading in GI tract

drug delivery for advanced dosage form

• deliver drug directly to site of action

• Prevent degradation of drug in gastro-intestinal tract

• Control drug release

Dosage forms can optimise delivery of drugs in which of the following ways

• minmum for viscous solutions

2mL