PHAYG062: Preformulation

PHAYG062: Preformulation
Pseudopolymorphism: Consolidation questions
The questions below are designed to help you consolidate your learning. If you can answer them
all correctly, then you will do very well in the course. If not, then consult your lecture notes, the
course text (“Essentials of Pharmaceutical Preformulation” by Gaisford and Saunders), or me
([email protected])! Please note that there is no obligation to do these questions: they do not
need to be handed in and will not be marked, but they offer you the opportunity to test your
understanding of the material covered.
1. Give brief (1 sentence) definitions of the following terms: polymorph, monotropic

polymorphism; enantiotropic polymorphism; hydrate; solvate; salt; co-crystal.
A polymorph is a crystalline solid-state form of a species with a particular arrangement of

molecules in the unit cell. Different polymorphs have different arrangements of molecules, and
different unit cells.
Monotropic polymorphism describes the situation where one polymorph is always the most stable,
under all conditions of temperature and pressure. Enantiotropic polymorphism is where the most
stable polymorph varies with temperature and pressure.
A hydrate is a pseudopolymorph (a two-component system) in which the crystal structure contains

both the drug molecule and one or more water molecules. A solvate is a two-component solid state
material where the crystal structure contains both a drug molecule and a one or more solvent
molecules. The solvent is a liquid at RTP (and is not water). A co-crystal has a crystal structure
containing an API and a co-former, where the latter is a solid at RTP.
2. Give an example material for each of the terms listed in question 1.
Polymorph – paracetamol forms I, II, III
Monotropic polymorphism – furosemaide, indomethacin
Enantiotropic polymorphism – neotame, sulphathiazole
Hydrate – paracetamol hydrate or paracetamol trihydrate
Solvate – chloroform solvate of griseofulvin
Co-crystal – benzoic acid/isonicotinamide; paracetamol/citric acid
There are loads of possible examples for each – good to learn a few for each term to help illustrate
essays etc
3. How might the performance of an API hydrate differ from the properties of the anhydrous
API?
The solubility, dissolution rate, and stability may differ – usually, the hydrate dissolves more slowly,
but not always! The materials processing properties (tableting etc) of the hydrate and anhydrous
form are also likely to be different.
4. Give four reasons why we might chose to use an API salt in a formulation.
To increase solubility, or control the dissolution rate;
To increase the melting point of the API (i.e. enhance stability to heat);
To reduce the hygroscopocity of the drug (increase stability of formulation to moisture);
To increase bioavailability;
To improve the properties of the drug in processing (tableting etc)
- Among other reasons! See Dr Gaisford’s salts lecture for more!
5. List three disadvantages that API salts may have.
Reduced chemical stability;
Increased toxicity;
Increased hygroscopicity;
Increased number of polymorphs
- Among others - see Dr Gaisford’s salts lecture for more!
6. Discuss briefly the different salts of diclofenac used in pharmaceutical formulations, and their
properties.
Diclofenac potassium – used in standard tablets; relatively slow dissolution;
Diclofenac sodium – used in dispersible tablets – dissolves rapidly;
Diclofenac diethylammonium – used for topical applications – very fast dissolution; also
diethylammunium has some lipophilic properties and hence aids through skin permeation.
All these salts are MUCH more soluble than pure diclofenac!
7. Define the term “co-former”, and suggest the key properties a co-former for an API should
have.
A co-former is a second component which is combined with a species to make a two-component

co-crystal. The co-former is a solid at RTP. For an API, the co-former needs to be compatible with
the API (i.e. able to undergo favourable intermolecular interactions, such as H-bonds, with it),
biocompatible, and should not reduce the efficacy of the drug in vivo, nor cause any undesirable
side effects either alone or in combination with the API.
8. The chemical structure of salbutamol is given below. Suggest at least three potential co-
formers for salbutamol.
We are looking for species which can undergo ideally H-bonding with the drug. A wide range of
examples might be suggested, such as:
Citric acid 1,2-benzenedicarboxylic acid nicotinamide
9. Detail the potential advantages which might be obtained by developing pharmaceutical co-
crystals. Give an example of a system which offers each advantage.
Increased solubility: fluoxetine HCl co-xtls with succinic or fumaric acids;
Improved stability to light/heat: nitrofurantin co-xtls with 4-hydroxybenzoic acid;
Improved mechanical properties: 1:1 caffeine methyl gallate co-xtls have improved plasticity
Improved taste: carbamazepine co-xtls with saccharin;
Improved efficacy in vivo/bioavailability: e.g. meloxicam/aspirin co-xtls
10. What disadvantages may be associated with pharmaceutical co-crystals?
Any of the aspects detailed in the answer to Q9 (solubility, stability, mechanical properties, taste,
efficacy) can also be made worse by co-xtl formation – we need to assess systems on a case by
case basis. It is not always true that co-xtl formation is good! For instance cyanuric acid and
melamine co-xtls are very poorly soluble and the two materials even if taken separately will form
highly insoluble materials which collect in the kidneys and can cause renal failure. Similarly, methyl
gallate/theophylline co-xtls have worse mechanical properties than the API alone.
11. What techniques can be used to prepare co-cystals?
Solvent-mediated co-crystallisation; solid-state co-crystallisation; high-throughput screening;

thermal ink-jet printing.

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PHAYG062: Preformulation

Pseudopolymorphism: Consolidation questions

1. Give brief (1 sentence) definitions of the following terms: polymorph, monotropic

A polymorph is a crystalline solid-state form of a species with a particular arrangement of

A hydrate is a pseudopolymorph (a two-component system) in which the crystal structure contains

2. Give an example material for each of the terms listed in question 1.

Polymorph – paracetamol forms I, II, III

Monotropic polymorphism – furosemaide, indomethacin

Enantiotropic polymorphism – neotame, sulphathiazole

Hydrate – paracetamol hydrate or paracetamol trihydrate

Solvate – chloroform solvate of griseofulvin

Co-crystal – benzoic acid/isonicotinamide; paracetamol/citric acid

To increase solubility, or control the dissolution rate;

To reduce the hygroscopocity of the drug (increase stability of formulation to moisture);

To improve the properties of the drug in processing (tableting etc)

- Among other reasons! See Dr Gaisford’s salts lecture for more!

5. List three disadvantages that API salts may have.

Reduced chemical stability;

Increased number of polymorphs

- Among others - see Dr Gaisford’s salts lecture for more!

Diclofenac potassium – used in standard tablets; relatively slow dissolution;

Diclofenac sodium – used in dispersible tablets – dissolves rapidly;

A co-former is a second component which is combined with a species to make a two-component

Citric acid 1,2-benzenedicarboxylic acid nicotinamide

Increased solubility: fluoxetine HCl co-xtls with succinic or fumaric acids;

Improved stability to light/heat: nitrofurantin co-xtls with 4-hydroxybenzoic acid;

Improved taste: carbamazepine co-xtls with saccharin;

Improved efficacy in vivo/bioavailability: e.g. meloxicam/aspirin co-xtls

10. What disadvantages may be associated with pharmaceutical co-crystals?

11. What techniques can be used to prepare co-cystals?

Solvent-mediated co-crystallisation; solid-state co-crystallisation; high-throughput screening;

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