Pharmaceutical

Formulation and
Biopharmaceutics

Aniruddha Roy
Drug Design
What must a drug do other than bind?
An oral drug must be able
to:
 Dissolve
 Survive a range of pHs
bladder (1.5 to 8.0)
 Survive intestinal bacteria
 Cross membranes
kidneys BBB  Survive liver metabolism
 Avoid active transport to
bile
bile  Avoid excretion by kidneys
duct  Partition into target organ
 Avoid partition into
undesired places (e.g.
liver brain, foetus)
 Why are physical properties
important?
 So, before the drug reaches its active site, there are
many hurdles to overcome.

 However, many complicated biological processes can

be modelled using simple physical chemistry models
or properties – and understanding these often drives
both the lead optimisation and lead identification
phases of a drug discovery program forward.

 This lecture will focus on oral therapy, but remember

that there are lots of other methods of administration
e.g. intravenous, inhalation, topical. These will have
some of the same, and some different, hurdles.
 Reducing the complexity
Biological process Underlying physical Physical chemistry
in drug action chemistry model

Energy of dissolution;
Dissolution of drug in Solubility in buffer,
lipophilicity & crystal
gastrointestinal fluids acid or base
packing
logP, logD, polar
Diffusion rate,
Absorption from surface area,
membrane partition
small intestine hydrogen bond
coefficient
counts, MWt

Binding affinity to Plasma protein

Blood protein
blood proteins e.g. binding, logP and
binding
albumin logD

Distribution of Binding affinity to

logP, acid or base
compound in tissues cellular membranes
 Ionisation
 Ionisation = protonation or deprotonation resulting in
charged molecules
 About 85% of marketed drugs contain functional groups
that are ionised to some extent at physiological pH (pH
The1.5 – 8).or basicity of a compound plays a major role in
acidity
controlling:
 Absorption and transport to site of action
• Solubility, bioavailability, absorption and cell penetration,
plasma binding, volume of distribution
 Binding of a compound at its site of action
• un-ionised form involved in hydrogen bonding
• ionised form influences strength of salt bridges or H-bonds
 Elimination of compound
• Biliary and renal excretion
 How does pH vary in the body?
Fluid pH
So the same compound
Aqueous humour 7.2 will be ionised to different
Blood 7.4 extents in different parts
Colon 5-8 of the body.
Duodenum (fed) 4.4-6.6
Duodenum 5.2-6.2 This means that, for
(fasting) example, basic
Saliva 6.4 compounds will not be so
Small intestine 6.5 well absorbed in the
Stomach (fed) 1.4-2.1 stomach than acidic
Stomach 3-5
compounds since it is
(fasting) generally the unionised
Sweat 5.4 form of the drug which
diffuses into the blood
Urine 5.5-7.0
stream.
Drugs are only absorbed passively when they are
unionised. This is because the compound has to pass
through a lipophilic membrane and this process will be
unfavourable for charged molecules. In a more acidic
medium, such as the stomach, the percentage ionised
for an acidic compound will be less than at pH 7.4 and
so more compound will have the capacity to be
passively absorbed. In comparison, a basic compound in
an acidic medium will be more ionised and so less of the
compound will be in the neutral form and have the
capacity to undergo passive absorption.
Ionisation of an acid – 2,4-dinitrophenol

OH O
100 NO2 NO2
-H+
90

80

70 NO2 NO2
60
percent

% neutral
50
pKa = 4.1 % anion
40

30

20

10

0
3 4 5 6 7 8 9 10 11
pH
Ionisation of an base – 4-aminopyridine
NH2 NH2

100 -H+
90 +
80
N N
70 H
60
pKa = 9.1
percent

% neutral
50
% cation
40

30

20

10

0
3 4 5 6 7 8 9 10 11
pH
when the pH value of the
medium is close to or higher
than the pKa of an acidic drug,
the drug’s solubility will
increase significantly as the pH
value increases; when the pH
value of the medium is close to
or higher than the pKb of a
basic drug, the drug’s
solubility will decrease
significantly as the pH value
increases. For amphoteric
drugs that can react as an acid
as well as a base, such as
sulfadimethoxine and cefprozil,
the aqueous solubility will be
higher at either acidic or basic
media.
Contrast of the solubility data of cefprozil monohydrate in water as a function
of pH at 283.15, 298.15, and 308.15 K
Effect of ionisation on antibacterial
potency of sulphonamides
6.5
6 Anion
Cation
5.5
5
potency

4.5

4
3.5
3
2.5
2
2 3 4 5 6 7 8 9 10 11
pH
pKa
Identify functional groups
in drugs:

Basic
A useful formula for calculating the % ionisation of
a compound at a particular pH from its pKa is

(Where charge = 1 for bases and -1 for acids)

 Distribution Coefficient

Distribution Coefficient

LogD is related to LogP and the pKa by the

following equations:
Log D at pH 7.4 Implications for drug development

Below 0
o Intestinal and CNS permeability 0 to 1
o May show a good balance
problems.
o Susceptible to renal clearance. between permeability and
o If MW < 300, may be absorbed solubility.
o At lower values, CNS
by the slower paracellular route.
permeability may suffer.

1 to 3
o Probably an optimum range for 3 to 5
o Solubility tends to become
CNS and non-CNS orally active
lower.
drugs. o Metabolic liabilities tend to
o Low metabolic liabilities.
o Generally good CNS increase.
penetration.
Above 5
o Low solubility and poor oral bioavailability.
o Erratic absorption.
o High metabolic liability, although potency may still be high.
o Basic amines tend to show high to very high VD (Volume of
o distribution ¼ ratio of overall tissue binding to plasma protein
binding)
 Lipophilicity
Lipophilicity (‘fat-liking’) is the most important physical
property of a drug in relation to its absorption, distribution,
potency, and elimination.
Lipophilicity is often an important factor in all of the following,
which include both biological and physicochemical properties:

 Solubility  Biliary and renal

 Absorption clearance
 Plasma protein binding  CNS penetration
 Metabolic clearance  Storage in tissues
 Volume of distribution  Bioavailability
 Enzyme / receptor  Toxicity
binding
 The hydrophobic effect
Molecular interactions – why don’t oil and water mix?
H

H O O H H
H H H
H O H H
H O H O O H H

H H H H
H H
H
O O O H O H H
H H
H H H H H
O O O
H H
H H H H H H
O

 This is entropy driven. Hydrophobic molecules are encouraged

to associate with each other in water.
 Placing a non-polar surface into water disturbs network of
water-water hydrogen bonds. This causes a reorientation of the
network of hydrogen bonds to give fewer, but stronger, water-
water H-bonds close to the non-polar surface.
 Water molecules close to a non-polar surface consequently
exhibit much greater orientational ordering and hence lower
entropy than bulk water.
 The hydrophobic effect
This principle also applies to the physical properties of drug
molecules.

If a compound is too lipophilic, it may

 be insoluble in aqueous media (e.g. gastrointestinal fluid or
blood)
 bind too strongly to plasma proteins and therefore the free
blood concentration will be too low to produce the desired
effect
Conversely,
distributeifinto
thelipid
compound
bilayersisand
too be
polar, it may
unable not bethe
to reach absorbed
inside
through
of thethe
cellgut wall due to lack of membrane solubility.

So it is important that the lipophilicity of a potential drug molecule

is correct.
 What else does logP affect?

Binding Aqueous Binding to Absorption Binding to Binding to

logP to solubility P450 through blood / hERG heart
enzyme / metabolisin membrane tissue ion channel
receptor g enzymes proteins – -
less drug cardiotoxicit
free to act y risk

So log P needs to be optimised

What do Log P values mean in practice?
From a survey of the literature, it is possible to
obtain some general guidelines about the
optimum Log P values for certain classes of
drugs. When designing drug molecules some
thought should be given to the following:
Studies have found:
• Optimum CNS penetration around Log P = 2 +/- 0.7
(Hansch)
• Optimum Oral absorption around Log P = 1.8
• Optimum Intestinal absorption Log P =1.35
• Optimum Colonic absorption LogP = 1.32
• Optimum Sub lingual absorption Log P = 5.5
• Optimum Percutaneous Log P = 2.6 (& low mw)
Formulation and dosing forms:
• Low Log P (below 0) Injectable
• Medium (0-3) Oral
• High (3-4) Transdermal
• Very High (4-7) Toxic build up in fatty tissues
Drug Clearance and Toxicity
 Increasing LogD7.4 above 0 will decrease renal
clearance and increase metabolic clearance.
 High Log D7.4 compounds will tend to be metabolized by
P450 enzymes in the liver.
 A high degree of ionization keeps drugs out of cells
and decreases systemic toxicity.
 pKa in range 6 to 8 is advantageous for membrane
penetration.
 Drugs should be designed with the lowest possible
Log P, to reduce toxicity, non-specific binding, increase
ease of formulation and bioavailability. Drugs should
also be as low mw as possible to lower the risk of
allergic reactions.
 Hydrogen bonding and
bioavailability
Remember: Most oral drugs are absorbed through the
gut wall by transcellular absorption.
H
H
H O O
O H
H H O
O H O
O
H O H H N H
N H O
O H H
O H + H H N N
H N N
O
O H H O H O H
O H H
H H H H
O O O
H H H
H

 De-solvation and formation of a neutral molecule is

unfavourable if the compound forms many hydrogen or ionic
bonds with water.
 So, as a good rule of thumb, you don’t want too many
hydrogen bond donors or acceptors, otherwise the drug won’t
get from the gut into the blood.
 There are some exceptions to this – sugars, for example, but
these have special transport mechanisms.
 Molecular size
Molecular size is one of the most important factors
affecting biological activity, but it’s also one of the
most difficult to measure.

There are various ways of investigating the molecular

size, including measurement of:

 Molecular weight
 Electron density
 Polar surface area
 Van der Waals surface
 Molar refractivity
 25 Molecular weight

20

15
Plot of frequency of
frequency %

occurrence against
molecular weight for 594
marketed oral drugs
10

Molecular Weight

Most oral drugs have molecular weight < 500

 Number of rotatable bonds
A rotatable bond is defined as any single non-ring
bond, attached to a non-terminal, non-hydrogen
atom. Amide C-N bonds are not counted because of
their high barrier to rotation.
No. of rotatable
OH
H bonds
O N
O
Atenolol
H2N

OH
H
O N
Propranolol
 Number of rotatable bonds
A rotatable bond is defined as any single non-ring
bond, attached to a non-terminal, non-hydrogen
atom. Amide C-N bonds are not counted because of
their high barrier to rotation.
No. of rotatable Bioavailabilit
OH
H bonds y
O N
O
Atenolol 8 50%
H2N

OH
H
O N
Propranolol 6 90%

The number of rotatable bonds influences, in

particular, bioavailability and binding potency. Why
should this be so?
In the case of flexible drug molecules, there is a loss of
entropy on binding due to conformational restriction, so
if a molecule is more rigid to start off with, less entropy
is lost on binding. Of course, the problem with removing
rotatable bonds from a molecule to make it more rigid is
that potentially you will lose all potency as you may have
restricted the molecule into the wrong conformation.

About 65% of fairly rigid compounds (those with seven or

fewer rotatable bonds) exhibited good-to-excellent oral
bioavailability, independent of molecular weight. In
contrast, more than 75% of floppy compounds (those with
more than 10 rotatable bonds) had poor oral bioavailability.
Compounds of intermediate rigidity fell somewhere in
between.
 70
60
50
Percentage of 40
compounds MW 0-499
with F >20% 30 MW 500+
20
10
0
# Rot 0-7 # Rot 8-10 # Rot 11+

The bar chart shows how the number of rotatable bonds (# Rot)
affects the bioavailability (F) for some compounds. A
bioavailability of 20% is chosen as the cut off for an acceptable
compound as this is about the minimum necessary for a good
oral drug. As you can see, the bioavailability decreases as the
flexibility of the molecule increases, and this is independent of
molecular weight.
This seems like a lot to remember!
There are various guidelines to help, the most
well-known of which is the Lipinski Rule of Five
 Molecular weight < 500
 logP < 5
 < 5 H-bond donors (sum of NH and OH)
 < 10 H-bond acceptors (sum of N and O)
 < 10 rotatable bonds
Otherwise absorption and bioavailability are likely
to be poor.

* NB This is for oral drugs only.

Chirality
One of the most silent chemical parameters that define the
pharmacological activity is the type of isomer. Many molecular
entities exist in racemic form, but only one form gives the
desirable pharmacological activity. Other present isomer may
be devoid of pharmacological activity or may exhibit deleterious
side effects. Most of us are known to teratogenic tragedy of
thalidomide. Thalidomide exists as racemic form. It was
introduced as a sedative agent. The S-enantiomer of thalidomide
was a teratogenic agent, while R-enantiomer was effective as a
sedative agent. Lack of knowledge about chiral selectivity leads to
disastrous consequence.
Several single enantiomers are preferred over racemic form (e.g.,
levofloxacin (ofloxacin), esomeprazole (omeprazole), escitalopram
(citalopram), and desloratadine (loratadine)).
Overview of the same is given in Table. For better clinical
performance of the molecule, it has become necessity to study
the chirality of the molecule. In most of the cases, it can be
studied by optical rotatory dispersion and circular dichroism.
Read this article: https://www.nature.com/articles/s41598-018-35457-6
Drug in racemic Used active
Advantage offered
form enantiomer
Levofloxacin
Ofloxacin Enhanced activity against pneumococci
S(−)-enantiomer
Levocetirizine
Cetirizine Less sedative action with same activity
R(−)-enantiomer
Dexketoprofen Reduction is dose of ketoprofen (half) with same
Ketoprofen
S(+)-enantiomer effectiveness and lesser GT-related side effects
(S)-ibuprofen is over 100-fold more potent
Ibuprofen S(+)-enantiomer inhibitor of cyclooxygenase. So three times dose
reduction was achieved than racemic mixture
Esomeprazole has lower first-pass metabolism and
Esomeprazole shows better bioavailability than R-eneantiomer
Omeprazole
S(+)-enantiomer and maintains pH above 4 in patients with GERD
with least variability
Racemic for and S-enantiomer
hyperresponsiveness in sensitized patients with
Salbutamol Levalbuterol loss of bronchodilator activity. (R)-salbutamol
produces significantly greater bronchodilation than
the equivalent dose of the racemate
 Biopharmaceutical Classification
System (BCS)
• Biopharmaceutics Classification System (BCS) is a
predictive approach to relate certain
physicochemical characteristics of a drug
substance and drug product to in-vivo
bioavailability
• BCS categorized drugs according to two key
physico-chemical parameters:
– Solubility
– Permeability
• These two factors were selected because most
orally administered drugs are absorbed via a
passive diffusion process through the small
intestine, where the extent of oral absorption is
largely influenced by a drug’s membrane
• According to the FDA guidelines, a high
solubility drug is defined as one that, in the
largest dose strength, fully dissolves in 250 mL of
aqueous medium with the pH ranging from 1 to
7.5 at 37 ° C. Otherwise, drugs are considered
poorly soluble. In other words, the highest
therapeutic dose must dissolve in 250 mL of
water at any physiological pH

• In the same guidance as mentioned above, a

drug is considered highly permeable if the
extent of oral absorption is greater than
90%.
 BCS Classes

Class I Class II
Highly permeable Highly permeable
Highly soluble Poorly soluble

Class III Class IV

Poorly permeable Poorly permeable
Highly soluble Poorly soluble
 BCS Class I: High Solubility and
High Permeability
• Compounds belonging to this class are normally
expected to dissolve quickly in gastric and intestinal
fluids, and readily cross the intestinal wall through
passive diffusion

• BCS Class I are unlikely to show bioavailability or

bioequivalence issues

• Therefore, for BCS class I drugs, in vitro dissolution

studies are thought to provide sufficient
information to assure in vivo product
performance making full in vivo bioavailability /
bioequivalence studies unnecessary.
 BCS Class I: High Solubility and
High Permeability
• Although class I compounds are expected to have
excellent oral absorption, given their high solubility
and high permeability, additional absorption
barriers may exist, which is beyond the scope
of the BCS.

• For example, luminal complexation and

degradation can significantly limit the amount of
drug available for absorption. Even after the drug
crosses the intestinal membrane, it may be
metabolized within the enterocytes/hepatocytes
and/or pumped out of the cells due to efflux
mechanisms.
 BCS Class II: Poor Solubility and
High Permeability
• By definition, poor solubility and/or slow dissolution
are the rate-limiting steps for oral absorption of BCS
class II compounds

• For compounds with a very large dose-to-solubility ratio,

poor solubility is likely to be the rate-limiting step for
absorption.

• In other words, the compounds may dissolve quickly

enough to reach their equilibrium solubility, but the
solubility is too low to establish a wide enough
concentration gradient to drive passive diffusion
 BCS Class II: Poor Solubility and
High Permeability
• Formulations designed to overcome
solubility or dissolution rate problems:
– Salt formation
– Particle size reduction
– Metastable forms
– Solid dispersion
– Complexation
– Lipid based formulations
– Precipitation inhibitors
 BCS Class III: High Solubility and
Low Permeability
• Since passive diffusion is the rate-
limiting step for oral absorption of BCS class
III compounds, the most effective way to
improve absorption and bioavailability of this
class of compounds is to increase the
membrane permeability.

• Approaches to improve permeability:

– Prodrugs
– Permeation enhancers
 BCS Class IV: Low Solubility and
Low Permeability
• Class IV compounds exhibit both poor solubility
and poor permeability, and they pose
tremendous challenges to formulation
development

• As a result, a substantial investment in dosage

form development with no guarantee of success
should be expected

• A combination of class II and class III

technologies could be used to formulate class IV
compounds, although the success rate is not
expected to be high
BCS can be used as a key component to guide drug
delivery system design for any route of
administration
 IVIVC Expectations Based on BCS
Class Solub Perme Absorption IVIVC expectations for
ilit ability rate control Immediate release product
y
I High High Dissolution/ IVIVC expected, if dissolution
Gastric rate is slower than gastric
emptying emptying rate, otherwise
limited or no correlations
II Low High Dissolution IVIVC expected, if in vitro
dissolution rate is similar to in
vivo dissolution rate, unless
dose is very high.
III High Low Permeability Absorption (permeability) is
rate determining and limited
or no IVIVC with dissolution.

IV Low Low Case by case Limited or no IVIVC is

expected.
Example 1

o Aspirin tablet is stable but not as a

liquid dosage form
o How to design liquid form?
o Soluble or dispersible aspirin tablets-to
be dissolved in water
o Note: the resulting solution or
suspension is to be taken immediately
Example 2
o Benzylpenicillin is inactivated by gastric acid

o Susceptible to hydrolysis if stored as a solution

o How to administer to human?

o Formulated for parenteral, rather than for oral

and packed as powder

o Use of sodium or potassium salt which readily

dissolve upon reconstitution
Example 3
o Diclofenac sodium is inactivated in gastric acid

o It is to be taken orally

o How to administer to human?

o Formulated for enteric coated tablet

o Enteric coat protects the tablet from destruction

within the gastric chamber

o Enteric coated dissolves in the small intestine

Phase of Drug
Development
Why dosage form?
• Mechanism for the safe and convenient delivery of accurate dosage
• Protection of a drug substance from destructive influences of
atmospheric oxygen or humidity
• Protection from influence of gastric acid after oral administration
• To mask taste of offensive drugs
• To provide liquid preparation of substances that are either insoluble
or unstable
• To provide clear liquid dosage form
• To provide time-controlled release of drug
• To provide optimal topical administration
• To provide for the insertion of a drug into one of the body’s orifices
• Provide for placement of drugs into the blood stream
• Provide for lung inhalation of drug
The Importance of Product Design
It may seem obvious to state that a new product should be
adequately defined before any serious product
development is undertaken.

In many cases, the value of the design phase is often

underestimated in the rush to start development and get
products to the market quickly.

This can result in much wasted time and valuable resources.

It can also lead to reduced staff motivation if a product is
developed that is not wanted or if the product definition is
constantly changing during development.

The quality of the design activities can strongly influence

the success of development of the right product to the
market and ultimate return on investment (ROI).
The following recent example of inhalable insulin has been
described as “one of the drug industry’s costliest failures
ever,” estimated to be $2.8 billion from the cost of
development, closure of dedicated manufacturing plants, and
unsold product (Johnson, 2007).

The idea was that diabetics did not like to prick themselves
with needles several times a day to deliver the insulin.

The biggest hurdle was to deliver insulin by inhaler as

consistently as with a standard needle and syringe.

It took a technological breakthrough to develop and launch the

first inhalable insulin product in July 2006, only to abandon it in
October 2007, after the product’s disappointing sales
performance.

The company predicted that inhalable insulin would be a $2

billion-a-year product by 2010, but it only sold $12 million in
the first year. There were several reasons attributed to the
The device drew unfavorable reviews from doctors and
investors. Some patients likened it to a bong for
smoking marijuana and were embarrassed to use the
device in public.
o It was taking much longer to teach patients how
to use the inhaler device compared with an insulin
pen, and diabetic specialists said it was hard to use.
o There were concerns about safety as only 10% of
the insulin reaches the bloodstream, raising the
question about the long-term effects of the other
90% remaining in the lungs.
o The inhaled treatment was approximately twice
as expensive per day as the injectable insulin and
some payers refused to accept the inhaled product
on costs alone.
A simple definition of “product design” is “the initial stage
of product development, where ‘global’ agreement is
required about the nature of the product to be
developed.”
Effective product design is considered to have the following
important benefits:
o To provide clear direction and objectives for the project team
o To gain buy-in and input from all the key functions at the start
of development (such as pharmaceutical development, safety,
clinical, manufacturing operations, quality assurance,
regulatory, and commercial/marketing)
o To assess the feasibility of the project in commercial and
technical terms
o To identify any risks early and hence manage them
o To avoid wasting valuable resources on developing a product
that is not needed or wanted
o To provide a good reference source for the development plan
Product Design Considerations
A useful outcome of the initial product design phase is a product
design report. This should document the careful evaluation of the
following key elements:
o Target product profile (TPP)/minimum product profile (MPP)

o Design specification and critical quality parameters

o Commercial and marketing considerations

o Technical issues and risk assessment

o Safety assessment considerations

o Environmental, health, and safety considerations

o Intellectual property considerations

 Target Product Profile/Minimum
Product Profile
A TPP, which defines the product attributes, should be
established for the intended marketed product based on
all “customer” and “end-user” needs. Customers and end
users include anyone in the supply chain, including both
internal and external customers, such as those in
manufacturing and in sales and marketing, distributors,
doctors, nurses, pharmacists, and patients. Each
customer wants the right product (meeting their quality
expectations) at the right time and at the right price.
Additionally, each customer will have his or her own
specific requirements.
 Design Specifications and Critical
Quality Parameters
In addition to the preformulation information, there will be
other considerations in the selection of the excipients and
packaging components for the product.
o The pack will be acceptable to regulatory authorities in the
countries to be marketed.
o Only packs that can be multiple sourced from more than
one supplier/country will be used.
o The pack must have consistency of dimensions and
performance.
o The pack will meet function/user tests and specifications.
o Minimum acceptable shelf life for the product.
Commercial and Marketing Considerations
Any pharmaceutical company’s economic objective must
be to maximize its return on investment (ROI) after launch.
o Development costs

o Timing to market

o Market size (disease prevalence, diagnosis and

treatment rates, market value)
o Competition (current, developing, and impact on future
market)
o Unmet medical need (effectiveness of current
treatment, improvements required)
o Pricing and reimbursement (current and future)

o Cost of goods (CoG)

Advantages and Disadvantages of Outsourcing
Technical Issues and Risk Assessment
There may be a variety of issues that should be documented in
the product design report to highlight the perceived risks
involved in developing the product.
o Technical challenges anticipated in developing a novel or
complex drug delivery system or manufacturing process.
o Lack of in-house expertise

o Lack of in-house facilities or equipment to handle the

candidate drug.
o Sources of excipients and packaging components

The importance of identifying these issues in a product design

report is to make the company aware of the risks it is taking
and to make effective plans to overcome problems and manage
the risks.
Safety Assessment Considerations
In the interests of rapid product development, it is beneficial to
select well-established excipients that already have regulatory
approval in registered products.
According to ICH, an excipient is considered new or novel if it is
used for the first time in a human drug product or by a new
route of administration.
Investment in a new excipient includes the cost of safety
testing, investment in manufacturing facilities, and other
development costs, including stability testing. Safety testing of
a new excipient alone can be expensive.
It may be possible to “piggyback” the safety evaluation of the
new excipient onto the safety evaluation of the candidate drug
itself.
There may be lesser considerations for excipient safety testing
in novel treatments, where there is an overwhelming need to
treat patients quickly and effectively, for example, for life-
threatening diseases such as cancer.
Summary of Excipient Safety Testing for Different Routes of
Exposure for Humans (proposal by IPEC Europe and IPEC America)
Environmental, Health, and Safety
Considerations
There are increasing pressures on the pharmaceutical
industry to use environmentally friendly materials in
products, which are biodegradable or recyclable and do no
harm to the environment. Examples are the replacement of
CFCs in pressurized metered dose aerosols and the
replacement of polyvinyl chloride (PVC) for alternative
packaging materials in some countries.
Intellectual Property Considerations
Few pharmaceutical companies would venture into a long
and expensive development program without a strategy for
effective patent protection in place to ensure market
exclusivity. Patents are legal property that prevents others
using the invention (for 20 years in most countries) in
exchange for a full public disclosure of information.
o Three criteria be met to grant a patent: novelty, presence
of an inventive step, and industrial applicability.
o Although an invention might be novel, it might not be
patentable if it could have been predicted from “prior art,”
that is, knowledge in the public domain. Hence, there is a
need for an inventive step.
At the product design stage of development, the only patent
filed is likely to be for the new candidate drug.

There may be a patent for a candidate drug and further

patents for a new indication or a new pharmaceutical use.

For example, Minoxidil, originally developed as an

antihypertensive, had been discovered subsequently to be
useful for the treatment of male pattern baldness.

Patent protection is stronger if multiple patents can be

obtained; for example, a single product could have patents
covering a range of features from the candidate drug itself
to the method of treatment and the delivery system.