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Flashcards in AP - An Introduction to Pre-formulation Deck (40):
1

Why do we need to administer drugs in an appropriate dosage form? Why can't we just give the API to the patient?

1. The patient will obviously not like it. They will most likely just spit it out
2. Do not know how much you are administering because there is no control of how much is getting into the system
3. Do not know if it is going to reach the site of action or not
4. MAIN issue is compliance

2

In order to maintain patient compliance, we must ensure:

- The drug does not smell horrible
- The drug does not taste horrible

3

What are the 5 events in product development?

1. Synthesis/ isolation of API
2. Biological activity
3. Pre-formulation stage
4. Pre-clinical and clinical testing
5. NDA application

4

What is considered during the first stage of product development?

- What is the disease/ condition that we are going to treat?
- What is the drug that we are going to isolate/ synthesise.

5

What is happens during the second stage of product development?

Whichever analytical method is used e.g. QSAR, you will end up with 1000s of compounds. Not every compound is tested. A few are selected from certain groups (e.g. amides/ esters/ primary amines). Around 100 drugs are selected and given to the pharmacologist. They will analyse to see which will be effective (through cell culture system) for the medical condition. This will possible narrow it down to around 10. The best 5 are selected and taken to pre-formulation stage.

6

What is happens during the third stage of product development?

At this point you have one drug, possibly two. This is taken to the next stage

7

What is happens during the fourth stage of product development?

Here, the drug is tested on animals to make sure it is effective. Then Phase I (healthy volunteers) - toxicity
and then Phase II (unhealthy volunteers) - efficacy

8

What is happens during the fifth stage of product development?

A permit is required for finalisation.

9

What is the product development cycle?

A product development cycle will help you feedback into the developmental process. The two wheels (pre formulation and formulation development) are contributed by various spokes of toxicology, chemistry, biochemistry, medicinal chemistry, analytical pharmacology, marketing/ post marketing surveillance etc. Information is continually needed back therefore you can keep improving or improvise on what you have so that you do not fall short and are not taken by surprise.

10

What is QSAR?

Quantitative Structure Activity Relationship is a modern tool where one molecule is continually changed so that it fits the pattern that you want. You can generate a series of compounds that will be useful (lead generation). These lead compounds are optimised to ensure they have the exact activity that you want them to.

11

What are other modern tools other than QSAR?

Combinatorial chemistry
High Throughput Screening

12

What is the aim of a formulation scientist?

To develop a pharmaceutical product for a drug that is suitable for administration to humans.

13

The criteria for development are?

- Effective (when administered it should not break down immediately. e.g. if an oral tablet is developed, is administered via mouth, goes down to stomach and breaks down completely in the presence of stomach acid --> not effective!)

- Ideal for administration (e.g. if an oral tablet causes gastric irritation it will affect patient compliance)

- Stable (e.g. if working with an ester drug and you have developed it into a solution (water based) --> upon steerage it will just get hydrolysed (it will break down) --> not stable!

- Ideal for large scale production (is it cost effective? Not only cost of API but also excipients and packaging)

14

What is pre-formulation?

- The first step of formulation development process
- It is a collation of steps that are performed before actual formulation development is started
- a logical sequence of events

15

Pre-requisites for pre-formulation:

- synthesis: should have a small but sufficient quantity of the pure (or as pure as possible; > 99% purity) drug -- around 100mg

- pharmacology: should have demonstrated some pharmacological effect in animals

- toxicity: toxicity profile of drug should be determined

16

What are some identification methods?

NMR
Mass spec
UV/ Visible spec
IR

17

Why do we need identification methods?

They not only give us the chemical properties of the drug but also indicate its contaminants or breakdown products. They can also suggest possible metabolites that are likely to happen once administered. Also gives us the purity of the drug molecule.

18

Why do you need accurate analytical data?

- Ensure you know if storage has not resulted in loss of drug.
- It is still the same drug as when started

19

Traditional analytical methods:

TLC
Simple HPLC
UV/ Viscible

20

Traditional modern methods:

HPLC-MS
UPLC-MS
GC-MS

21

Analytical methods MUST be:

Sensitive - detect very low concentrations
Selective - identify exactly what substance you set it to
Reproducible - method + sample should be exactly the same, each time (even in different labs)

22

What is the required diameter of particle size for inhalation?

1 - 5 um

23

What is the required diameter of particle size for suspension

> 1um

24

For good bioabsorption, what must the aqueous solubility be and at what pH?

> 10mg/ml at ph 1-7

25

What can you learn from DSC analysis?

- How many polymorphs are stable
- How stable each form is
- Is there a glass transition state
- Can the metastable form be stabilised
- How will processing and storage affect the stability of the polymorph
- What is the solubility of each polymorph

26

What are the types of crystals?

Polymorphs
Hydrates - water bound to drug molecules
Solvates - contains trace amounts of solvent used for crystallising the drug
Amorphous - has no solvent attached

27

How does partition coefficient affect membrane permeability?

The higher the partition coefficient, the greater the membrane permeability.

28

What is better to pass through membrane barrier? Acid or salt?

Acid

29

What can be done if aqueous solubility is too low? e.g. <1mg/ml?

This indicates the need for a salt. You can convert an acid to a salt depending on pKa (ionisability)

30

What is the most common method of determining the partition coefficient? And how is it done?

Shake-flask method. Known conc of drug is dissolved in water. Octanol added. Shake flash. Determine concentration in both layers.

31

Define dissolution.

The rate at which a drug goes into solution.

32

What can you do if the common ion effect is a problem?

The intrinsic dissolution rate of a compound can be reduced due to common ion effect. For example, HCL salt of a drug e.g. Tramadol Hydrochloride will have less solubility once it reaches the stomach. If this is a problem then you can look at alternatives e.g. mesylate, tosylat. This way, Tramadol is NOT affected. It just goes further down the stomach and undergoes dissolution. Salt form few not matter --> as long as active ingredient is not affected.

33

Natural sweetener

Saccharin
Sorbitol

34

Natural colouring agent

Beta carotene

35

Artifical colouring agent

Amaranth

36

Why forced drug stability testing?

- to determine the stability of drug in extreme conditions
- identify breakdown products
- excipient incompatibilities
- storage conditions
- package conditions + incompatibilities
- protective additives
- formulation approach

37

Define solubility

The maximum amount of drug that can dissolve in a selected solvent under equilibrium conditions.

38

How can you improve powder flow?

Add a surfactant e.g. Magnesium Stearate

39

Uneven crystal shapes will cause a problem in powder flow and how you develop the final product (during compression). It will be a problem unless you're making a...?

Solution

40

Melting point of crystals are useful because?

They indicate if any contaminants are present. Can do this via capillary melting point apparatus, hot stage microscopy. These methods will tell you if there are any solutes or polymorphs present