Pharmaceutics

Introduction to Dosage Form

design Cont’d.....
Dosage form design
 The way an API is formulated
influences the behaviour of the drug
and hence its clinical and safety profile

 i.e. excipients and method of dosage

manufacture can affect the release of
the drug from the dosage unit and can
also affect the chemical activity of the
drug thereby influencing safety and
efficacy
Dosage form design

 Obviously a lot of science and

technology goes into formulating a
proper dosage form that will effectively
accommodate our API
 This dosage form has to deliver the
proper quantity of drug in the proper
manner to the body to allow the drug
to be bioavailable.
Dosage form design

What is Bioavailability? – it is a
measurement of the rate and amount
of drug that reaches the systemic
circulation unchanged (in it’s desired
form)
 The way an API is formulated
influences the behaviour of the drug
and hence its clinical and safety profile
Dosage form design

 Bioavailability is a critical consideration in

dosage form design – Why?
 The drug must be available to reach its
intended site of action
 Solid oral dosage forms represent about
70% of all drugs
 The same API can have high or low
bioavailability depending on how it’s
formulated , its morphology and its physico-
chemical characteristics – Why?
Bioavailable Dose

 The fraction of administered dose that

reaches the systemic circulation
unchanged = the bioavailable dose

 Defined as the rate and extent of drug

absorption
Bioavailability

 IV route – directly inject drug into

bloodstream ( known as a bolus)
 100% of drug reaches
plasma/circulation immediately,
therefore, 100% bioavailable
 Other routes <<100% due to
absorption, metabolism (liver
degradation), etc.
Dosage form design
 We need to select the best, most
advantageous form of the API based
on its physical and chemical properties
 E.g.particle size, crystal type, salt
form, stability, dissolution profile
(solubility) and compatibility with
dosage form type (excipients)
 Preformulation studies will investigate
the suitability of the API and its
corresponding formulation
Dosage form design

Bioavailability

 Important term in dosage form design

 The drug must be able to be available to its
intended site of action
 Solid oral dosage forms represent about
70% of all drugs
 The same API can have high or low
bioavailability depending on its formulation
Bioavailability

 IV route – directly inject drug into

bloodstream
 100% of drug reaches
plasma/circulation
 = 100% bioavailable
 Other routes <<100% due to
absorption, metabolism
Bioavailability

 Fraction of administered dose that

reaches the systemic circulation = the
bioavailable dose
 Relative amount of a dose that
reaches circulation = bioavailability

 Defined as rate and extent of drug

absorption
Bioavailability

 For an oral dose, 100% bioavailable

means:
 1/ 100% release from dosage form
 2/ 100% dissolved in GI fluids
 3/ stable in solution in GI fluids
 4/ complete passage through GI
barrier into circulation without
metabolism
 5/ pass through liver into systemic
circulation unchanged
Bioavailability

We’re talking about absorption of drug

molecule into systemic circulation !

Therefore, the drug (API) must be in

solution in order for bioavailability to
occur and for any possibility of
therapeutic response in the patient
Bioavailability
Many factors influence rate and extent of absorption of a drug in
the plasma: e.g.

 Absorption through membranes

 Route of administration
 Food versus fasting
 Age
 Disease state
 Genetics (race, sex)
 Dosage formulation
 Physical and chemical properties of drug
 Frequency of administration
 Dosage (strength)
 etc
Bioavailability

 Variability in absorption can be a major

stumbling block in administering
certain types of drugs for all of the
reasons stated on the previous slide
Physico-chemical factors affecting
bioavailability

Dissolution and solubility is necessary for

bioavailability and can be affected by:
 Particle size
 Wettability
 Hydrophobicity
 Crystal structure
(type,shape,polymorphism, crystalline
vs amorphous)
 Molecular size
Physiological factors affecting
bioavailability

 GI motility – intestinal motions

 Surfactants in gastric juice/bile
 pH of gastric juice
 Enzymatic activity
Bioequivalence – two different
drug products having the
same bioavailability
 Comparing the same drug in a
different formulation
 Often carried out by generic
companies when comparing their
finished product with the existing name
brand competitor’s product
 Must prove bioequivalence before drug
can be marketed
What causes poor bioavailability?

 Need to determine cause

 Poor dissolution rate?

 Poor membrane permeability of drug?
 Drug at low concentration for a short
time in the part of the GI tract where it
is absorbed?
 Formulation effects? (ie excipients)
How can bioavailability be
increased?

 Improve dissolution rate by changing

the physical properties of the API (eg
smaller particles, different crystal type)
 Use excipients that enhance its
solubility
 Use a controlled release dosage form
 Etc etc etc
 All sorts of new and novel drug
delivery systems are developed to
overcome these problems
New challenges
 More and more new drugs have mw’s
>500
 Their properties are not compatible
with standard dosage forms (poor
solubility and/or membrane
permeability)
 The revolution in biology and genetics
provides new active macromolecules
(proteins, etc) requiring new types of
formulations
Start back at the beginning
Preformulation studies

 Need to know everything we can about

the physical and chemical properties of
the therapeutic molecule (API)

 That is to say, we need to characterize

the API to fully understand its likes,
dislikes, and its potential suitability to
be put into a finished dosage form
Preformulation

 Must know certain fundamental

physical and chemical properties of the
drug molecule as well as properties of
the drug powder (physical)
 This is the first “learning phase” of the
new drug
Preformulation – API
Investigation
 Spectroscopic characterization (eg IR, UV, NMR,
MS to confirm structure and to investigate possible
analytical methods for qualitation and quantitation)
 Solubility – aqueous, pKa, salts, solvents, partition
coefficient, dissolution, pH profile
 Melting point
 Assay development (potency)
 Stability (heat, moisture, shelf life, impurities
present))
 Microscopy (crystal type, forms, shapes)
 Powder flow properties
 Compression properties
 Excipient compatibility (binary studies = API +
excipients)
Spectroscopy

 Establish a simple analytical method

 Often the simplest is UV/VIS
 Choose an analytical wavelength to
quantify the drug in solution if possible
 Can also use HPLC or GC
 Also use spectroscopy to establish
structure, purity and in later tests the
nature of the metabolic products
Solubility of API

 Must possess some water solubility to

be ultimately absorbed and distributed
in the body
 Blood (mostly aqueous) is the main
carrier of drugs in the body
 Must have a degree of lipid solubility in
order to pass through biological
membranes (fatty tissue)
Solubility of API

 API may require dissolving when

formulating and producing the final
dosage form
(ie formulation and production
considerations)
Partition coefficient
 In order to cross cell membranes, a
drug must be somewhat lipid soluble

 Compare water solubility and lipid

solubility by determining the partition
coefficient
 Eg separatory funnel with water and
olive oil
 Add compound – determine its
solubility and amount present in each
phase
 Definition of Dissolution
 Dissolution (Webster’s Dictionary):
 Disintegrate; separation into component parts; the
act or process of dissolving

• Dissolution:
– A physico-chemical process whereby a solute
enters a solvent to form a solution

• Drug Product Dissolution:

– The amount of active ingredient in a solid dosage
form dissolved per unit time
Dissolution rate
 Speed or rate at which an API
dissolves in a given medium
 Provides an indication of the drugs
absorption potential following
administration
 Depends on the polarity of the drug,
the pH of the medium, whether drug is
acidic, basic or neutral, etc.
 The non ionized form of the drug
molecule is the species that is
absorbed in vivo – Why?
Dissolution rate

 Dissolution is arguably the most

important test performed on
pharmaceutical API and finished
dosage forms
 In vitro Dissolution should ideally
mimic in vivo conditions (why?) but so
far no one has devised a laboratory
model of the human GI tract
Dissolution rate

Due to its significance, we’ll look at

dissolution testing in more detail later
on
Will look at:
Theory
Practical
Physical form

 The crystal form and particle size of a

solid drug can influence how rapidly it
dissolves
 Microscopic examination  crystal
form and particle size (also special
particle size determining instruments
using lasers on the market)
 Different crystal forms can have
different mps (another reason why
mp’s are important)
Physical form of API
 Some crystal forms are more stable
than others
 Do not want the drug to change its
crystal form once it is formulated –
may alter the effectiveness of the drug
and may damage the formulation
 Also, want powdered API to flow
smoothly
 Some crystal forms flow poorly
depending on their shape
Physical form
 Polymorphism – defined as different
crystal structures of the same chemical
compound (API)
 Can affect the solubility and stability of
the compound
 Chemicals will revert to their most
comfortable (stable) form so
polymorphic forms may revert to a
previous form thus changing their
properties
Physical form

Usually, chemicals will revert to their

most comfortable (stable) form when
they are stressed (polymorphs do this)
This conversion may alter the physico-
chemical properties of the chemical,
resulting in undesired behaviour
When might drug chemicals (API’s) be
stressed?
Physical form

 Particle size
 Can affect dissolution rate,
bioavailability, absorption, taste, colour
stability, flow, mixability
 Even distribution of drug throughout a
solid dosage form can depend critically
on particle size
 (more about that when we look at
mixing)
Stability

 Need to know what causes the API to

break down
 Might oxidize, hydrolyze
 Water, heat, light sensitivity?
 Will influence the type of dosage form
designed
 Also may influence the shelf life of the
product as well as setting the
standards to be used for packaging
Stability

 Chemical – degradation
 Physical – appearance, dissolution,
palatability, suspendability
 Microbiologic- foreign growth
 Therapeutic – no change in
therapeutic effect with time
 Toxicologic – no change in toxic
properties with time
 (will look at stability testing later)
Different forms of the API

 Many drugs are acidic or basic (ie.

Salts of weak acids or bases)
 The properties of the drug are
influenced by the form it is in – eg is it
dissociated or non-dissociated?
 i.e is it ionized or non ionized
Different forms of the API

 The salt form of acids and bases are

most often more water soluble and
more chemically stable (they have
ionized)
 But , the non-ionized molecular form is
more lipid soluble (more non polar)
and therefore more membrane
permeable so this is the desired form
for effective bioavailabilty
API investigation –
“Characterization”

Characterizing API’s and excipients is

essential not only in producing a final
product but is also a requirement
(TPD, FDA)
By what means do we characterize API?

In other words, what do we need to do

and how can we do it?
API investigation –
“Characterization”

We need to test for article ISQP !

We do this using test methods that have

associated specifications (limits) that
have to be met

Where do the test methods come from?

API investigation –
“Characterization”

1.“ In house” methods

2. Compendeial methods – USP

If we use these methods to test for ISQP,

we need to understand which of these
methods tests identity, which test
strength, which test quality and which
test purity
API investigation –
“Characterization”

I – Identity: is the article what it is

supposed to be? Can we prove that?
Lets verify its authenticity using physical/
chemical/instrumental tests

S – Strength: does the article posses the

potency it is said to have or must
have?
API investigation –
“Characterization”
Q – Quality: does the article posses the
necessary quality attributes? Colour,
shape,size, etc. Will it perform as
expected?
Physical tests –
disintegration/dissolution/etc
API investigation –
“Characterization”

P – Purity: is the article pure? Related to

potency, is the article free from impure
substances contained within?
“Pure” – containing nothing that does not
properly belong

Why would this matter? Where do these

impurities come from?
API investigation –
“Characterization”

Identification / UV absorption <197U> ?

Melting range <741> between 168-172?
Water Method 1 <921> NMT 0.5%?
Sulfide no test paper coloration or
spotting occurs?
Free p-aminophenol absorbance of test
solution does not exceed Std Abs,
corresponds to NMT 0.005% p-
aminophenol?