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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

Welcome to Formulation

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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.

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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.

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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 optimum dosage 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

Solutions, suppositoriesUrethral

Tablets, capsules, powders, suspensions, elixirsOral

Tablets, lozengesSublingual

Solutions, suspensionsParenterals

Solutions, suspensions, creams, ointmentsOcular

Creams, ointments, powders, lotions, plastersTransdermal

Inhalants, sprays, solutionsNasal

Solutions, ointments, suppositoriesRectal

Solutions, ointments, inserts, suppositoriesVaginal

AerosolsRespiratory

Dosage Form TypesRoute of Administration

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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

2-6 h45-12020-456.5-19.5Oral

Up to 24 h60-18030-605-10Patches

3-8 h30-12015-600.5-10incOintment

30-300 min4-102-51-3Buccal

10-30 min4-82-50.3-0.8Sublingual

Duration of action

(min/h)

Peak action

(min)

Onset of action

(min.)

Dosage (mg)

Dosage Form

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 systemicallyinto 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:

� 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 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 timeafter 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

�� ParacellularParacellular::

� Through gaps/pores between cells

� Small molecules e.g. urea, water

�� TranscellularTranscellular: : Through cells hence biological membranes

� Main mechanism, diffusion: follows Fick’s law molecules must have lipid solubility, unionised form

� Active transport: energy involved, against concgradient 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

28If 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

bindingLung

Peripheral tissue,

Metabolism

KidneyLiver,

drug metabolism

Bile

DrugDrug

Blood

Intestines

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 From the equation: dissolution is affected by

physicochemical properties and formulation variablesphysicochemical properties and formulation variables

C)(CshV

DA

dt

dC−−−−====

layerdiffusionofthicknessh

tcoefficiendiffussionD

areasurfaceAratendissolutiodt

dC

mediumofvolumeV

solubilityCs

mediuminionconcentratC

Noyes-Whitney Equation