Welcome to Formulation

Module: CH4106: Formulation of active pharmaceutical

ingredients (API) dosage forms
Contacts: Zaher Judeh
Tel: 6790-6738
zaher@ntu.edu.sg
N1.2 B1-14
Textbook: H.C. Ansel, L.V. Allen Jr., N.G. Popovich,
Pharmaceutical dosage forms and drug
delivery systems, 8th Edition, Lippincott
Williams & Wilkins

Examinations

Closed book exams may include multiple choice,

true/false, short/long answer, essay questions, and
problems anything!
Exams can be on any selected topic:
 CAI - Tuesday 05/10/2010 5:35-6:35 pm up to 15%
 CAII - Tuesday 16/11/2010 5:35-6:35 pm up to 15%
 Activity and participation!
Anytime!
up to 10%
 Final Exam University sets date
up to 60%
Students are expected to take examinations at the
scheduled time.
2

CA Policy

If student misses CA due to following reasons:


Valid MC (not from Chinese doctor)

Passing away of immediate family (parents, siblings,
grandparents)

Participate in an activity representing NTU

There will be no makeup CA.
Marks will be computed according to NTU prevailing
policy.

Attention
The slides represent points for discussion
You must refer to the textbook for a complete account

If it is mentioned, it is required, otherwise it is for your

reading pleasure!

Have Fun and Good Luck

Course Contents

Section I: Introduction to Drugs, Drug Dosage Forms

and Drug Delivery Systems

Introduction to Drugs and Pharmacy

New Drug Development and Approval Process

Current Good Manufacturing Practices
Section II: Drug Dosage Form and Drug Delivery
System Design

Dosage Form Design: Pharmaceutics and
Formulation Considerations

Dosage Form Design: Biopharmaceutic and
Pharmacokinetic Considerations
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Course Contents Cont.

Section III: Solid Dosage Forms and Solid ModifiedRelease Drug Delivery Systems

Powders and Granules

Capsules

Tablets

Solid Oral Modified-Release Dosage Forms and Drug
Delivery Systems
Section IV: Semi-Solid Dosage Forms and Transdermal
Systems

Ointments, Creams and Gels

Transdermal Drug Delivery Systems
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Course Contents Cont.

Section V: Pharmaceutical Inserts

 Suppositories and Inserts
Section VI: Liquid Dosage Forms
 Solutions
 Disperse Systems
Section VII: Sterile Dosage Forms and Delivery
Systems
 Parenterals
 Ophthalmic Solutions and Suspensions

Overall Goals

For a given drug, understand how to select an

appropriate drug delivery system, formulation, route of
administration based upon the chemical, physical and
biological attributes of the drug
Inspire YOU: This is a great field where more research
and development for optimum dosage form design is to
be done!

Course Objectives: Understand

The process of drug development and approval

The pre-formulation considerations applicable to the
design of specific dosage forms
The biological and physicochemical properties of drugs
that must be considered in the design of pharmaceutical
dosage forms
The concepts of chemical kinetics, drug stability and the
factors that impact dosage forms stability
Different dosage forms and outline their advantages and
shortcomings
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Course Objectives Cont.

Be familiar with common dosage forms in use today and

current development in drug delivery systems -- Research
Understand formulation of a dosage form with respect to:
 Types and functions of the additives/excipients used
 Problems encountered during the formulation of a
specific dosage form
 Techniques used in the production of different dosage
forms

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What is Pharmaceutics?

The science of dosage form design where the API is

made into a safe and effective medication
It applies science and engineering knowledge to the
multidimensional problems of the formulation,
development, evaluation, production, distribution,
selection and administration of safe, effective, reliable,
drug delivery systems
Pharmaceutics include:
 Pharmacokinetics, Pharmacodynamics,
Pharmacogenomics, Pharmaceutical formulation,
Pharmaceutical technology
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Preformulation / Pharmaceutical
Formulation

Preformulation: characterization of a drug's physical,

chemical, and mechanical properties in order to choose
what other ingredients should be used in the preparation
Formulation: the process in which the API (drug) and
excipients are combined to produce a final medicinal
product
The API must be delivered to the patient in some way
 Dosage Form

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Dosage Form

The physical form in which a drug is produced for

administration by the appropriate route to the recipient
It functions as a drug delivery system (DDS)  get the
drug to its site of action
The design and formulation of a dosage form affects the
rate and amount of drug delivered  bioavailability
When designing a dosage form we must consider:

Rate of delivery

Site of release

Target delivery to specific cells/receptors (action)
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Routes of Administrations and Dosage

Forms
Route of
Administration

Dosage Form Types

Oral

Tablets, capsules, powders, suspensions, elixirs

Sublingual

Tablets, lozenges

Parenterals

Solutions, suspensions

Ocular

Solutions, suspensions, creams, ointments

Transdermal

Creams, ointments, powders, lotions, plasters

Nasal

Inhalants, sprays, solutions

Respiratory

Aerosols

Vaginal

Solutions, ointments, inserts, suppositories

Urethral

Solutions, suppositories

Rectal

Solutions, ointments, suppositories

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Current R&D Scenario:

Pharmaceutical industry

Activities broadly divided into

 Search for novel molecules/treatment modalities
 Development of novel drug delivery systems ( or novel
dosage forms)
Situation very similar to arms / weapons industry:

New and more powerful bombs

Programmable & smarter rockets/delivery systems
Mutually complementary:
 To be effective a bomb must hit the correct target
 Many obstacles to reach the target
 Delivery system suppose to overcome obstacles
 A good rocket with no potent warhead is ineffective
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Likewise in Drug Therapy!

Optimal drug response depends upon:

 Using the correct drug
 Delivery in most appropriate manner


Reach intended site only


Leave other tissues / organs alone


Sufficient quantity


Suitable duration
Problems to fulfill these requirements best exemplified in
cancer chemotherapy

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Race Between Bomb and Rocket

Development of novel molecules is the winner

Progress made in delivery systems lacking behind
Situation made worse by biotech revolution:

biotherapeutics

Cannot be delivered by conventional delivery

systems
E.g.: gene therapy

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Design Criteria for Dosage Form

Must be safe, effective and on target

Must be stable and has a reasonable shelf-life
 Components must not react with the storage container
 Tolerate physiological variables in stomach and liver
Must have patient acceptability: color, taste, smell,
appearance, size
Must permit efficient, cost-effective production that
provides accuracy and precision of dosing

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Drug Delivery: Challenges

Attaining accuracy and precision of low dose drugs

 A drug (dose = 0.1 mg) formulated into a typical 200
mg tablet has a drug/excipient ratio of 1:2000
Stabilization and delivery of large molecules (peptides
and proteins)
Overcoming the practical problem where large dose
drugs lack the properties to be formed directly into tablets
Delivery of poorly soluble and/or poorly permeable drugs
Design of customize drug delivery: provide non-constant
drug release rates; pulsed, ramped or once-a-day (24
hour) delivery
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Various Systems for Nitroglycerine

Dosage
Form

Dosage
(mg)

Onset of
action
(min.)

Peak
action
(min)

Duration of
action
(min/h)

Sublingual

0.3-0.8

2-5

4-8

10-30 min

1-3

2-5

4-10

30-300 min

6.5-19.5

20-45

45-120

2-6 h

Patches

5-10

30-60

60-180

Up to 24 h

Ointment

0.5-10inc

15-60

30-120

3-8 h

Buccal
Oral

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https://rxsecure.umaryland.edu/courses

Drug Delivery Systems/Dosage

Forms Classifications

Classification:
 Local/topical or systemic therapy
 Immediate/conventional or Modified/novel release
Local/topical therapy
 Therapeutic agent applied directly to site of action
Systemic therapy
 Drug administered systemically
into blood to be transported to
site of action

Oral

IV

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Drug Delivery Systems/Dosage

Forms
Systemic: Oral therapy can Localized therapy using meter
result in severe toxic effects dose inhaler. Toxic effects can
be avoided if used properly

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Drug Delivery Systems/Dosage

Forms Classifications

Conventional/immediate release preparations:

 Job is done after delivering drug to site of
absorption/action
 E.g.: normal tablets, capsules, creams, ointments,
injections
Novel/modified release system:
 Additional functions, e.g.: control rate of absorption,
promote absorption, site targeting, ultimate is to
function like a guided missile - essentially to maximize
therapeutic response and minimizing side effects
(discussed in more detail later)
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Modified Release Dosage Forms

Dosage forms whose drug-release characteristics of timecourse and/or location are modified:
 Delayed release
 Extended (sustained) release
Delayed Release:
 Release of a drug (or drugs) at a time other than
immediately following oral administration, e.g.

Enteric coated: Prevents release of drug in stomach;
releases after passing phyloric sphincter

Pulsatile delivery: programmable to release drug at
predetermined time or place
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Modified Release Dosage Forms

Extended (sustained) release

 Any product formulated to make the contained
medicament available over an extended period of time
after ingestion
 Provide a reduction in dosing frequency as compared
to the same drug presented in a conventional
immediate release dosage form

Controlled release

Prolonged release

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Drug Release

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Mechanism of Drug Absorption

Paracellular:

Through gaps/pores between cells

Small molecules e.g. urea, water
Transcellular: Through cells hence biological membranes

Main mechanism, diffusion: follows Ficks law
molecules must have lipid solubility, unionised form

Active transport: energy involved, against conc
gradient carrier can be saturated, eg vit B1, B2, B3 B6

Facilitated diffusion: carrier can be saturated, no
energy involved, not against conc gradient, eg B12

Pinocytosis, endocytosis molecules (large) like some
peptides, particles
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Drug Action
Blood
Oral
ingestion

Drug

Adipose
tissue
storage

Volatile drugs
in expired air

Effector tissues,
drug receptor
binding

Peripheral
tissue,
Metabolism

Drug

Drug-plasma
protein complex

Lung

Liver,
drug
metabolism

Kidney

Drugs &
metabolites in
urine

Bile
Intestinal
reabsorption
Intestines

Drugs &
metabolites in
stool
http://www.boomer.org/c/p1/Ch03/Ch0302.html

If absorption is rate limiting, bioavailability no longer governed

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by physicochemical properties and formulation variables

Noyes-Whitney Equation
dC
dt

DA
(Cs
=
hV

C)

dC
dissolution rate
dt

A surface area

D diffussion coefficient

V volume of medium

h thicknessof diffusion layer

Cs solubility
C concentrat
ion in medium

From the equation: dissolution is affected by

physicochemical properties and formulation variables

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