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Module: CH4106: Formulation of active pharmaceutical

ingredients (API) dosage forms
Contacts: Zaher J udeh
Tel: 6790-6738
zaher@ntu.edu.sg
N1.2 B1-14
Textbook: H.C. Ansel, L.V. Allen J r., N.G. Popovich,
Pharmaceutical dosage forms and drug
delivery systems, 8th Edition, Lippincott
Williams & Wilkins
Welcome to Formulation
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Teams: Preselected 12 teams each of 8 students
with a team leader and a deputy team leader
Readiness assurance
Reading outside class time: PowerPoint slides, lecture
videos and other reading materials will be uploaded on
edventure
Individual assessment (during class, 30-35 min.)
Team assessment (during class, 30-35 min.)
Application activities
Presentation on a selected topic
Case studies discussion
Team-Based Learning
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Application activities How?
A problem will be given during class time
Teams will be given 20 minutes to discuss the problem
and arrive at a solution. Teams are allowed to refer to any
material/resource to answer the problem.
Solutions (1 written page) will be collected from all teams
Only 6 teams will be selected randomly to present their
solutions each class (10 minutes only).
Presenting teams will be marked by all teams (11 teams)
Peer assessment: within the team (in week 12). This will
also include a statement on:
One thing they appreciate from the member
One thing they request from the member
Team-Based Learning Cont.
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Assessments/Examinations
May include multiple choice, true/false, short/long answer,
essay questions, and problems anything!
Exams can be on any selected topic:
In class individual assessment up to 12%
In class team assessment I up to 10%
In class team assessment II up to 13%
Peer assessment (in week 12) up to 10%
CA Monday 20/10/2014 9:35-10:35 am up to 10%
Final exam University sets date up to 45%
Students are expected to take examinations at the
scheduled time.
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CA/Assessment Policy
If student misses CA due to following valid 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.
The best 8 assessments will be computed towards your
final mark. Students who are absent from lectures without
valid reason will get (0) zero for that assessment.
Marks will be computed according to NTU prevailing
policy.
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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
Attention
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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 Modified-
Release 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
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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 optimumdosage form design is to
be done!
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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: 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
Preformulation / Pharmaceutical
Formulation
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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
Buccal
1-3 2-5 4-10 30-300 min
Oral
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
https://rxsecure.umaryland.edu/courses
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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
IV
Oral
Systemic therapy
Drug administered systemically
into blood to be transported to
site of action
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Systemic: Oral therapy can
result in severe toxic effects
Localized therapy using meter
dose inhaler. Toxic effects can
be avoided if used properly
Drug Delivery Systems/Dosage
Forms
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Drug Delivery Systems/Dosage
Forms Classifications
Conventional/immediate release preparations:
J ob 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 time-
course 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
30 If absorption is rate limiting, bioavailability no longer governed
by physicochemical properties and formulation variables
http://www.boomer.org/c/p1/Ch03/Ch0302.html
Drug-plasma
protein complex
Adipose
tissue
storage
Effector tissues,
drug receptor
binding
Lung
Peripheral
tissue,
Metabolism
Kidney
Liver,
drug
metabolism
Bile
Drug
Drug
Blood
I ntestines
Oral
ingestion
Volatile drugs
in expired air
Drugs &
metabolites in
urine
Drugs &
metabolites in
stool
Intestinal
reabsorption
Drug Action
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From the equation: dissolution is affected by
physicochemical properties and formulation variables
C) (Cs
hV
DA
dt
dC

layer diffusion of thickness h
t coefficien diffussion D
area surface A
rate n dissolutio
dt
dC
medium of volume V
solubility Cs
medium in ion concentrat C
Noyes-Whitney Equation