Pharmaceutics

Introduction to Dosage Form

design continued. Chapter 5 –
Pharmaceutical Dosage Forms
and Drug Delivery Design pg 142-
143, 148-150,pg 162 table 5.3
Dosage Forms &
Bioavailability

 Which department within a

Pharmaceutical company is
responsible for producing the
prototype of the finished dosage form
design?
 What types of things would this
department need to study and
investigate, and why?
Dosage Forms &
Bioavailability

When considering dosage form design,

we must understand what the ultimate
goal of a dosage form is, and what
types of issue can prevent us from
reaching this goal.
This is a huge area of knowledge and
one that has gained much importance
and focus over the last few years
Dosage Forms &
Bioavailability

Necessary Definitions:
Bioavailability – the rate and extent to
which a drug becomes available to the
systemic circulation in it’s unchanged
form
Bioequivalence – the comparisons of the
bioavailabilities of different drug
product formulations
Dosage Forms &
Bioavailability

Necessary Definitions:
Drug – (API) a compound which exerts a
therapeutic effect on a biological system
Drug Product – (Dosage Form) a formulation
design that contains a drug, along with other
non-active ingredients, and is intended to
deliver that drug to its site of action in a safe
and effective way.
Dosage Forms &
Bioavailability

Necessary Definitions:
Pharmacokinetics – the study and
investigation of the time course of drug
concentration in the body (blood and
tissues) as indicated by its absorption,
distribution, metabolism and
elimination (ADME)
Dosage Forms &
Bioavailability

Necessary Definitions:
Biopharmaceutics – concerns the
relationship between the physical and
chemical properties of a drug in a
dosage form and the pharmacological
or clinical response observed after its
administration.
Dosage Forms &
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/ pass through GI barrier into
mesenteric circulation without
metabolism
 5/ pass through liver into systemic
circulation unchanged
Dosage Forms &
Bioavailability
Many factors influence rate and extent of absorption of a drug in
the plasma
 Absorption through membranes
 Route of administration
 Food
 Age
 Disease state
 Genetics
 Dosage formulation
 Physical and chemical properties of drug
 Frequency of administration
 Dosage
 etc
Dosage Forms &
Bioavailability

 Obviously, with so many variables that

could possibly affect drug absorption,
variability in systemic absorption can
be a major concern in administering
certain types of drugs ( see previous
slide)
Physicochemical factors affecting
bioavailability

 Dissolution and solubility

 Affected by:
 Particle size
 Wettability
 Hydrophobicity
 Crystal structure
 Molecular size
 complexation
Dosage Forms &
Bioavailability
Physiological factors affecting
bioavailability

 GI motility
 Surfactants in gastric juice/bile
 pH of gastric juice
 Enzymatic activity
Bioequivalence

 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?

 Drug at low concentration for a short

time in the part of the GI tract where it
is absorbed?
 Formulation effects? (excipients,etc)
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
 Properties not compatible with
standard dosage forms
 The revolution in biology and genetics
provides new active macromolecules
(proteins, etc) requiring new types of
formulations
Start back at the beginning
Preformulation studies

 alot of new drugs have solubility problems

i.e. poorly soluble – which makes in vitro
evaluation of these hard to do and also may
limit in-vivo absorption

 Need to know everything we can about the

physical and chemical properties of the API
i.e. we need to fully Characterize it
Preformulation

 Must know certain fundamental

physical and chemical properties of the
drug molecule (theory) as well as
properties of the drug powder
(practical)
 This is the first “learning phase” of new
drug development
Preformulation
 Spectroscopic characterization (eg IR, UV, NMR,
MS)
 Solubility – aqueous, pKa, salts, solvents, partition
coefficient, dissolution
 Melting point
 Assay development
 Stability
 Microscopy
 Powder flow properties
 Compression properties
 Excipient compatibility
Spectroscopy

 Establish a simple analytical method

 Often the simplest is UV/VIS
 Choose an analytical wavelength to
quantify the drug in solution
 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 absorbed and distributed in the
body
 Blood (mostly aqueous) is the main
carrier of drugs in the body
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 in each layer
Dissolution rate

 Speed or rate at which an API

dissolves in a 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.
 Lots of work done on dissolution rates
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 melting points (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
 Particle size

 Can affect dissolution rate,

bioavailability, absorption, taste, colour
and stability
 Even distribution of drug throughout a
solid dosage form can depend critically
on particle size
 (more about that when we look at
mixing)
Physical form

 Polymorphism
Definition - Different crystal structures or
forms of the same substance
 Can affect the solubility of the drug
Stability

 Need to know what causes the API to

break down
 Might oxidize, hydrolyze
 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 –
 Physical – appearance, dissolution,
palatability, suspendability
 Microbiologic-
 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

 The properties of the drug are
influenced by the form it is in – eg is it
dissociated or non-dissociated?

 The salt form of acids and bases are

most often more water soluble and
more chemically stable
Summary – factors affecting
bioavailability

1. Physico-chemical properties (API)

2. Pharmaceutical ingredients
(excipients)
3. Dosage form characteristics
(performance)
4. Physiological factors (patient
dependent)
Summary – factors affecting
bioavailability

1) Physico-chemical (API)
Particle size
Crystal form/structure
Solubility
pH/pka
Partition coefficients
Etc…
Summary – factors affecting
bioavailability

2) Pharmaceutical ingredients
(excipients)
Coatings
Disintegrants
Fillers/diluents
Binders
Lubricants
Etc….
Summary – factors affecting
bioavailability

3) Dosage form characteristics (product

performance)
Hardness
Disintegration (tablets)
Dissolution
Stability / product age (effects)
Etc…..
Summary – factors affecting
bioavailability

4) Physiological factors ( patient)

Age
Other drugs/ food
Gastric emptying times
Intestinal transit times
Pathologic conditions
Etc……