4 Preformulation

Question 1

What is preformulation?

Answer 1

Gathering information regarding properties which may have a bearing on product formulations.
Problems are identified and ways around it can be established.

Question 2

What is the object of dosage form development?

Answer 2

To develop a stable, bioavailable product with good acceptance.

Question 3

What must the formulator develop?

Answer 3

A specific detailed formulation procedure and define specification of raw , excipients and finished product.

Question 4

What are organoleptic properties?

Answer 4

The description of drug substance, including colour, odor and taste.

Question 5

How do we remedy objectionable color?

Answer 5

By use of a colouring agents or coating the tablet

Question 6

How can we remedy objectionable odors?

Answer 6

A coating or the inclusion of an aromatic excipient

Question 7

How can we remedy objectionable taste?

Answer 7

By use of a flavouring agent, a coating or use of an insoluble salt form

Question 8

What are the 5 tastes recognized?

Answer 8

Bitter, sour, sweet, salty and umami

Question 9

What are the groups associated with each taste?

Answer 9

Bitter: Amine groups (alkaloid quinine)
Sour: Acids (citric acid)
Sweet: Hydroxyl groups (glycerol, sugars)
Salty: Inorganic salts (NaCl, KCl)
Umami: Some amino acids (glutamate)

Question 10

What should you know about the purity? Why?

Answer 10

Must know and define the level of material purity and what impurities it may present
Trace amounts of metal can affect stability, impurities may be toxic.
May require addition of excipients or limit test development.

Question 11

What are micromeretics?

Answer 11

The particle size, shape and surface area of drug material. Plays role in homogeneity of tablet.
Small particle size increases surface area which will be in contact with excipient, oxygen and moisture.

Question 12

What problems arise from milling?

Answer 12

Static electricity, agglomeration and polymorph formation.

Question 13

Why is solubility important?

Answer 13

The product must dissolve in gastrointestinal fluids prior to absorption.
Usually better dissolution means better bioavailability.
Solubility >1% does not present dissolution/bioavailabilty problems.

Question 14

What relationships must we know to solubility?

Answer 14

The relationship between medium pH, solubility and stability.

Question 15

How do we determine potentially useful salts?

Answer 15

For HCl salts of oral products you must assess the common ion effect.
Determine the pKa of drug if ionizable.

Question 16

What do you do if the drug is not ionizable?

Answer 16

May include the use of a metastable polymorph, use of complexes, solid solution techniques, incorporation of surfactants and particle size reduction (micronization).

Question 17

Why would we want reduced solubility?

Answer 17

For stability and organoleptic reasons.

Question 18

What if kd is slower than ka?

Answer 18

Then absorption is limited by dissolution rate.

Any change in kd will affect absorption rate.

Question 19

What is ka?

Answer 19

Rate of permeation across membranes.

Can be rate limiting step.

Question 20

What are the 2 steps required for absorption of drugs as oral solids?

Answer 20

Dissolution and transport of dissolved material across the GI membranes into the blood stream.

Question 21

How can we assess the partition coefficient (P)?

Answer 21

In water/octanol or water/chloroform. Usually expressed as log P.
P=[organic]/[aqueous]
Larger value, more affinity for organic phase.
log P= 1 means 10 organic:1 aqueous

Question 22

How does pKa affect where a drug is absorbed?

Answer 22

Weak acids are absorbed better in the stomach. Basic drugs are better absorbed in the intestine.

Question 23

How can we study absorption?

Answer 23

Using the everted gut technique or Franz cells.

Question 24

How may solid drug materials occur?

Answer 24

As crystalline substances with an identifiable definite shape or as amorphous particles without definite structure.

Question 25

What is the difference between amorphous and crystalline states?

Answer 25

Amorphous forms are more soluble and show better availability. Crystalline form is more stable. Chloraphenicol palmitate crystalline form is abosorbed in GI, amorphous is not. Amitriptyline and penicillin are absorbed in both forms

Question 26

What must we ensure during processing with a drug capable of forming polymorphs?

Answer 26

Must ensure that processing does not cause a transition. | Can happen after milling, granulation, drying or compression.

Question 27

What may granulation or drying cause?

Answer 27

Granulation: Polymorph transformation, formation of solvates or hydrates. Drying: Polymorph transformation, transformation to anhydrous crystalline or amorphous forms.

Question 28

What will affect the flow and compression in tableting?

Answer 28

Morphology, tensile strength and density of powders.

Question 29

What do stability studies for tablet dose form include?

Answer 29

Solid state stability of drug alone, stability in the presence of potential excipients and stability of drug in solution (granulation).

Question 30

What properties influence stability?

Answer 30

pKa, solubility, melting point, crystal habit and form and equilibrium moisture content.

Question 31

What mechanisms are more difficult to evaluate?

Answer 31

Mechanisms in solid state degradation.

Question 32

What are the most common factors for instability?

Answer 32

Light, heat, oxygen and moisture. | Interplay among factors

Question 33

How is data from stability screening analyzed?

Answer 33

Using multiple linear regression (MLR) and fit to a general equation.

Question 34

How are solid state reactions done?

Answer 34

They are slow, so stress conditions are used and extrapolated down to storage conditions (use caution) Temps 40-70 compared to 5 degree cold If no change at 60 after 30 days, stability is good

Question 35

What happens to drugs in the presence of moisture?

Answer 35

Drugs may hydrolyze, react with excipients or oxidize.

Question 36

How is humidity stability tested?

Answer 36

Increasing humidity levels under constant temperature. | Humidity levels achieved using saturated solutions of various salts.

Question 37

How does humidity stability data help?

Answer 37

Helps decide if the product should be protected from moisture in a low humidity environment, aqueous based granulation systems or whether we should be careful of excipients which absorb atmospheric moisture.

Question 38

What excipients do tablets usually contain?

Answer 38

Binders, disintegrants, lubricants and fillers. | Sometimes reaction between drug and excipient (lactose and haloperidol)

Question 39

How are pull samples examined?

Answer 39

By TLC, HPLC or differential thermal analysis (DTA).

Question 40

How is photosensitivity estimated?

Answer 40

By exposing the drug substance to 400 and 900 foot-candles of illumination for 2-4 weeks.

Question 41

How is stability to oxygen examined?

Answer 41

Samples are held in an atmosphere of high oxygen tension (40%) and compared to a sample stored in inert atmosphere.

Question 42

Why should we be concerned about density?

Answer 42

It provides a rough idea of the size of the finished product. Affects flow properties, if excipients of different density are used, blending may a problem due to segregation.

Question 43

How can we protect from oxidation?

Answer 43

Remove oxygen by putting N2 in headspace Buffer to acidic pH Include an antioxidant like bisulfite or ascorbic acid Chelate metal ions using EDTA

Question 44

How can flow properties affect the drug?

Answer 44

Good flow is essential for blending, granulation and compression. Angle of repose is used to assess. 25-45 degrees is preferred.

Question 45

What is the ideal compressibility of a drug?

Answer 45

We want a powder that forms a hard uniform compact under moderate pressure. Capping or chipping should not occur.