L14 - Pre-formultaion Of Solid Dosage Forms 1 Flashcards
What does the design of any dosage form deal with?
The conversion of a new chemical entity (NCE) into a deliverable medicine
What is the main aim in the design of any dosage form?
To facilitate the delivery of therapeutic into the body
How do you want to facilitate the delivery of therapeutic drugs into the body? (4)
- safely
- efficiently
- reproducibly
- conveniently
What is preformulation?
The first step in the rational development of dosage forms of a drug into a medicine
What does preformulation involve?
Characterising the physical and chemical properties of the active pharmaceutical ingredients
What does preformulation provide?
Provides the formulating team critical info for developing a stable and bioavailable dosage form that can be mass produced
What is the aim of preformulation exercise?
Produce a mathematical based model for drug behaviour in the proposed dosage form both in vitro and in vivo
What is the first step in the preformulation for gastro-intestinal delivery?
The drug must dissolve before it can permeate the gut epithelium and enter the systemic circulation
What can the solubility and dissolution rate be a controlling factor of?
Rate of absorption and bioavailability of a medicine
What is the optimal aq solubility?
Aq solubility greater than 10mg/mL
What happens when the solubility of the drug < 1mg/mL?
Then a salt form of the drug, if possible, is indicated
What is the Biopharmaceutical clssification system (BCS)?
Class I
- high solubility & high permeability
Class II
- low solubility & high permeability
Class III
- high solubility & low permeability
Class IV
- low solubility & low permeability
What are high risk compounds?
Poorly soluble compounds
(Defined by the FDA BCS (Class II, IV)
What may compounds require to enhance dissolution rate and bioavailability via the GI tract?
One of the non-equilibrium methods or semi-solid/liquid formulations
What are the formulations that enhance dissolution rate and bioavailability via the GI tract? (4)
- amorphous
- meta-stable polymorphs
- solid dispersion
- lipid based formulations
Why is minimum wastage important? So what is the most critical decision?
Only a limited amount of compound made available from the drug discovery team
- which compound, salt or polymorphic form to proceed into development
What happens to the solubility if a drug has ionisable groups?
Solubility will change as a function of pH
What is salt formation a critical solution for?
The selection of more lipophilic and water insoluble compounds due to search of more potent and highly specific drug molecules
What does the salt form choice have an impact on? What does it have a large effect on? (3)
- has an impact on physicochemical and biopharmaceutical properties
Large effect on
- quality
- safety
- efficafy of medicine
When is conversion of a salt form beneficial? What can happen to properties?
If a drug candidate has poor aq solubility and is a WB/WA
- many physicochemical properties may change
What does salt formation require in terms of pKa?
Sufficient difference in pKa between the acid and the base (delta pKa = 3)
What are the advantages of pharmaceutical salts? (7)
- enhance solubility
- inc dissolution rate
- easier synthesis and purification
- better taste
- improved photostability
- high bioavailability
- higher mp
What are disadvantages of pharmaceutical salts? (7)
- dec % of drug
- inc hygroscopicity
- additional manufacturing steps
- inc toxicity
- dec chem stability
- no change in solubility at dif pH in GI tract
- inc num of polymorphs
What factors are considered when target salts are chosen? (7)
- structure of drug substance
- pKa
- chem and phy stability
- available lit on structurally-related compounds
- ease of large-scale production
- type of drug product
- anticipated loading of the drug
