Preformulation Flashcards
What is preformulaton? What is it used for?
Preformulation is gathering information regarding drug properties which may have a bearing on product formulation
Potential problems are identified and means of avoiding or circumventing them can be established
First step in development of dosage forms with object of developing stable, bioavailable product with good patient acceptance
Formulator must develop specific detailed formulation procedure and and define specification of API, excipients and finished product
What are organoleptic properties?
Description of drug substance including colour, odour and taste
The five tastes recognized
What needs to be done if any of the description of the drug substance, including colour, odour and taste, is objectionable?
If any of these are objectionable, may need to take step stop modify the problematic characteristics
Objectionable colours, a colouring agent may be included or tablets may be coated
Objectionable odours can be contained by coating or inclusion of an aromatic excipient
Objectionable taste masked by flavouring agents, coating or use of an insoluble salt form
Any excipient or strategy must be screened for adverse effect on stability or bioavailability
What are the five tastes recognized?
Bitter, sour, sweet, salty and umami
What is bitter associated with?
Bitter is associated with amine groups and example is alkaloid quinine
What is sour associated with?
Acids (example: citric acid)
What is sweet associated with?
Hydroxyl groups (glycerol, sugars)
What is salty associated with?
Inorganic salts (NaCl, KCl)
What is umami associated with?
Some amino acids (glutamate)
Why is purity important? Explain
You must know and define the level of material purity and what impurities may be present
Presence of trace amounts of metals may affect stability and some impurities may be toxic
Presence of some may require addition of excipients such as EDTA
Some may require limit test development, e.g., 4-hydroxymethylfurfrual in dextrose and amphetamine in phenylpropanolamine
What is micromimetics? Why is it important
Particle sieze, shape and surface area of the drug
It may affect physical and biopharmaceutical properties of the finished dose form
It might play a role in the homogeneity of the tablet
Small particle size will increase surface area, which will be in contact with excipient and atmospheric moisture and oxygen
If processing such as milling is required, must determine if this will generate new problems (static electricity, agglomeration, polymorph formation)
Why is solubility important?
The product must dissolve in GI fluids prior to absorption
Generally the better the dissolution, the better the bioavailability
Drugs with solubility exceeding 1% do not present dissolution/bioavailability problems
Exceptions do exist especially where drugs with apparently poor solubility are still absorbed (Biopharmaceutics Classification System (BCS))
Solubility is only one factor in absorption
Must know relationship between medium pH and solubility and stability
Determine pKa of the drug and if it’s ionizable and determine potentially useful salts
What must be considered with HCl salts
For HCl salts of oral products, must assess common ion effects with chloride
When drug is not ionizable, other means of enhancing solubility must be explored:
This may include use of metastable polymorphs, use of complexes, solid solution techniques, incorporation of surfactants and particle size reduction (micronization)
In some cases, may want to reduce solubility for stability or organoleptic reasons
What happens if the rate of dissolution is slower than the rate of absorption?
Than absorption will be dissolution rate limited and change in the rate of dissolution will affect absorption rate (pharmaceutics may help)
The rate of permeation across the membrane (absorption) may be the rate limiting step. For these, molecular modification of drug may be appropriate to modify partition character of the drug.
It is important to determine this early since much time and effort could be spent improving dissolution rate when the real problem is membrane tranpsort
What is the partition coefficient?
Often expressed as logP
Larger the value, the more affinity for organic phase (than aqueous phase)
What type of studies are used for determining GI absorption?
Everted gut techniques
Franz cells
Solid drug materials may occur as crystalline substances with an identifiable definite shape or as amorphous particles without definite structure. Why is this important?
Some exist in either state and generally amorphous form is more soluble and shows better availability but the crystalline form is often more stable
Chloramphenicol palmitate crystalline form is not absorbed from the GI tract but the amorphous form is)
With amitriptyline and penicillin-G, both forms are absorbed from GI tract but the crystalline forms are much more stabl
What is polymorphism?
Drugs which exist in crystalline form that are able to form different types of crystals
Only one form is stable and the others (metastable) forms will convert over time to the stable form
Once in solution, the forms no longer differ
Why is it important to know if there are polymorphs?
Important to know if polymorphic forms of drug exist in order to avoid future problems with stability, solubility, bioavailability and processing
How can polymorphs be used to our advantage?
If absorption is dissolution rate limited, it may be possible to use a metastable polymorph provided it does not revert to the stable form during the life of the product
What needs to be considered when using a metastable polymorph?
Metastable polymorph must exhibit sufficient chemical and physical stability to justify use in a product
When a drug is capable of forming polymorphs used, must ensure that processing does not cause a transition
Polymorph transformation has been reported after milling, granulation, drying and compression
Granulations may also cause the formation of solvates or hydrates while drying may cause transformation to anhydrous crystalline or amorphous forms
Why is stability important?
You must have some knowledge of inherent stability of the drug in order to know which excipients may be needed and which are most effective
How do we determine the stability of a tablet dose form?
For tablet dose form, stability studies include solid state stability of drug alone, stability in presence of potential excipients and stability of the drug in solution
