Preformulation

Question 1

What is preformulaton? What is it used for?

Answer 1

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

Question 2

What are organoleptic properties?

Answer 2

Description of drug substance including colour, odour and taste
The five tastes recognized

Question 3

What needs to be done if any of the description of the drug substance, including colour, odour and taste, is objectionable?

Answer 3

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

Question 4

What are the five tastes recognized?

Answer 4

Bitter, sour, sweet, salty and umami

Question 5

What is bitter associated with?

Answer 5

Bitter is associated with amine groups and example is alkaloid quinine

Question 6

What is sour associated with?

Answer 6

Acids (example: citric acid)

Question 7

What is sweet associated with?

Answer 7

Hydroxyl groups (glycerol, sugars)

Question 8

What is salty associated with?

Answer 8

Inorganic salts (NaCl, KCl)

Question 9

What is umami associated with?

Answer 9

Some amino acids (glutamate)

Question 10

Why is purity important? Explain

Answer 10

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

Question 11

What is micromimetics? Why is it important

Answer 11

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)

Question 12

Why is solubility important?

Answer 12

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

Question 13

What must be considered with HCl salts

Answer 13

For HCl salts of oral products, must assess common ion effects with chloride

Question 14

When drug is not ionizable, other means of enhancing solubility must be explored:

Answer 14

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

Question 15

What happens if the rate of dissolution is slower than the rate of absorption?

Answer 15

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

Question 16

What is the partition coefficient?

Answer 16

Often expressed as logP

Larger the value, the more affinity for organic phase (than aqueous phase)

Question 17

What type of studies are used for determining GI absorption?

Answer 17

Everted gut techniques

Franz cells

Question 18

Solid drug materials may occur as crystalline substances with an identifiable definite shape or as amorphous particles without definite structure. Why is this important?

Answer 18

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

Question 19

What is polymorphism?

Answer 19

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

Question 20

Why is it important to know if there are polymorphs?

Answer 20

Important to know if polymorphic forms of drug exist in order to avoid future problems with stability, solubility, bioavailability and processing

Question 21

How can polymorphs be used to our advantage?

Answer 21

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

Question 22

What needs to be considered when using a metastable polymorph?

Answer 22

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

Question 23

Why is stability important?

Answer 23

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

Question 24

How do we determine the stability of a tablet dose form?

Answer 24

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

Question 25

What properties influence stability?

Answer 25

Properties of the drug such as pKa, solubility, melting point, crystal habit and form, and equilibrium, moisture content all influence stability.
Mechanisms in solid state degradation are complex and difficult to evaluate

Question 26

What are common factors for instability?

Answer 26

Light, heat, oxygen and moisture

Interplay among these factors make it complex

Question 27

Solid state reactions are slow, so who do we determine stability?

Answer 27

We use stress conditions and extrapolate down to storage conditions
Often use temperatures of 40-70ºC and samples are compared to controls stored at 5ºC
If no change at 60ºC after 30 days, stability prognosis is quite good
In the presence of moisture, many drugs hydrolyze, react with excipients, or oxidize, so samples to be studied are stored under increasing humidity at a constant temperature and humidity levels are achieved by using saturated solutions of various salts

Question 28

Should excipients be evaluated for stability?

Answer 28

Stability in the presence of excipients is very important
Tablets usually contain binders, disintegrates, lubricants, fillers. So candidates from each of these groups should be tested at constant humidity and elevated temperatures (30-60ºC)

Question 29

Do products need to be protected from the light?

Answer 29

Yes, the light can cause the colour to fade or discolour. Degradation is usually small and at the surface, but pharmaceutical elegance is lost.
You can protect products from the light by using light resistant containers, coating the product or adding a light-stable colouring agent
Pull samples examined by TLC, HPLC or differential thermal analysis (DTA)

Question 30

What are other miscellaneous properties that are important to the formulator?

Answer 30

Density
Hydroscopicity
Flow properties
Compressibility

Question 31

Why is density important?

Answer 31

It provides a rough idea of the size of the finished product
Density affects flow properties and if excipients with quite different density is used, blending with the drug may be difficult as segregation may occur

Question 32

Why is hydroscopicity important?

Answer 32

Moisture content must be known as this may affect flow and compression properties

Question 33

Why are flow properties important?

Answer 33

Good flow is essential for blending, granulation and compression
Angle of response measurement is used to assess flow and the preferred angle is between 25-45º

Question 34

Why is compressibility important?

Answer 34

It is ideal that a powder forms a hard uniform compact under moderate pressure. Capping or chipping should not occur.