Lecture 14 - pre-formulation of solid dosage form 1

Question 1

What is pre-formulation?

Answer 1

• the first step in the development of dosage forms of a drug into a medicine
• provides information for developing a stable and bioavailable dosage form that can be mass produced
• involves characterising the physical and chemical properties of the API.

Question 2

What is the aim of the pre-formulation stage?

Answer 2

mathematical and statistical data is produced to develop an efficient, effective and stable dosage form. Aim is to produce a mathematical model for the drug behaviour in the dosage form both in vitro and vivo

Question 3

A drug must

Answer 3

dissolve

Question 4

Controlling factors in rate of absorption and bioavailability of a medicine.

Answer 4

solubility and dissolution rate.

Question 5

What solubility is optimal?

Answer 5

10mg/ml

Question 6

If solubility is less than 1mg/ml, what can be done?

Answer 6

a salt/ionized form of the drug to make it more soluble.

Question 7

What is solubility?

Answer 7

The maximum concentration of a solute that can be attained in a given solvent under given conditions.

Question 8

Dissolution rate is how fast a drug dissolves. How does it vary to solubility?

Answer 8

dissolution rate is a variable, whereas solubility of a drug is a constant value.

Question 9

Dissolution rate can be describe through the Noyes-Whitney equation. Give this equation.

Answer 9

Question 10

give the biopharmaceutical classification system (BCS) for oral dosage forms

Answer 10

1. High solubility and high permeability
2. Low solubility and high permeability
3. High solubility and low permeability
4. Low solubility and low permeability

Question 11

What does brick dust refer to?

Answer 11

drugs with really low solubility.

Question 12

Modifications can be made to improve solubility of drugs. Give examples

Answer 12

salts, particle size reduction, cosolvents, polymorphs, surfactants, lipid-based systems (soft liquid gelatine capsules), co-crystals, amorphous solid dispersions, cyclodextrins

Question 13

We only have a limited amount of drug compound available from the drug discovery team. How does this effect decisions in the pre-formulation stage?

Answer 13

• You need to make a critical decision about which form of the compound is going to be carried through the stages of development- salt or polymorphic
• If a change in decision is made later in drug development, it delays time to market.

Question 14

Physicochemical tests that occur in pre-formulation

Answer 14

Spectroscopy, pKa, LogP and LogD, initial solution solubility, solution stability, crystallinity investigations, initial solid stability, hygroscopicity (moisture absorption)

Question 15

If a drug has an ionizable group, when will solubility change?

Answer 15

When pH changes.

Question 16

The decision on a salt form is made early during pre-formulation. Why is this?

Answer 16

salts can change the properties

Question 17

Salt formulation requires sufficient difference in pKa between the acid and the base. What is the difference in pKa needed?

Answer 17

~3

Question 18

When is the conversion to salt form a good idea?

Answer 18

• drug is poorly soluble and a weak acid/base

Question 19

Give some positives of pharmaceutical salts.

Answer 19

• Solubility increases
• Higher dissolution rate
• Easier synthesis
• Better taste
• More photostable
• Higher bioavailability
• Higher melting point.

Question 20

What are some cons of pharmaceutical salts?

Answer 20

• Decrease percentage of drug
• Additional steps in manufacturing
• Increased hygroscopicity
• Increased toxicity
• Less stable
• No change in solubility at different pH in the GI tract
• Increased number of polymorphs.

Question 21

outline the drug salt formation process

Answer 21

Question 22

Outline the factors that are considered to choose target salts.

Answer 22

• Structure of the drug substance
• pKa of the drug substance- pKa between acid and base of about 3
• chemical and physical stability
• ease of large scale preparation
• type of drug product