Week 4 Dosage Form Design

 Why dosage form design

 Types

 Evolution in drug development

 Specialisation for administration and disease type

 Must haves, with details

 API and pharmaceutical ingredients: properties

Week 4 School of Chemical Engineering Life Impact The University of Adelaide

 LEARNING OUTCOMES

 Function of dosage form designs

Therapeutic response, reproducibility, stability, contamination, etc.

 Types of dosage form designs

Solid, semi-solid, liquid; tablets, capsules, creams, sprays etc.

 Evolution of drug dosage forms in drug development process

3 forms: balance, time of dosage, classification

 Routes of drug administration & their dosage forms

Oral, rectal, parenteral, topical, respiratory, nasal, ear

Weeks 1&2 School of Chemical Engineering Life Impact The University of Adelaide
 LEARNING OUTCOMES

 Interplay administration, disease type and dosage form design

Emergency relief, chronic therapy, local effect; age & condition

 Get to know must-haves of dosage forms

Biopharmaceutical, processing, physical/chemical, regulatory, marketing

 In-depth information about the must-haves

Biopharmaceutical, physical/chemical

 API properties, pharmaceutical ingredients

API properties & processing, appearance & palatability, preservatives etc

Weeks 1&2 School of Chemical Engineering Life Impact The University of Adelaide
 School of Chemical Engineering

Formulation / Dosage Form

• Pharmaceutical formulation is the process of combining
various chemical substances with the active drug to
form a final medicinal product, which is called a drug
mixture or drug formulation.

– Pharmacy compounding is the art and science of

preparing personalized medications for patients.

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Formulation Ingredients
– API – Active Pharmaceutical Ingredient – basic drug itself
with the desired medicinal properties. Also referred to as
Bulk Drugs.

– Intermediates –Intermediates are stable forms a few

steps away from the final API e.g. API -3, or API-5.
– Finished Dosage or Formulation – is the form in which
the drug is consumed by us. A dosage form of a drug is
usually composed of two things: The API, which is the
drug itself; and an excipient, which is the substance of
the tablet, or the liquid the API is suspended in, with
other masking, stabilising and binding agents/material
that is pharmaceutically inert.

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Dosage Form Design

• To achieve a predictable therapeutic response to a
drug included in a formulation which is capable of
large-scale with reproducible product quality.
• To consider
– Chemical and physical stability
– Suitable preservation against microbial contamination
– Uniformity of dosage of the drug
– Acceptability by patients and doctors
– Suitable packaging and labeling

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Why Dosage Form Design?

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Solid
• Tablets
• Capsules
• Lozenge
• Pastilles
• Dental cones
• Pills
• Granules
• Powders
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Liquid
• Oral solution
• Oral emulsion
• Oral suspension
• Syrup
• Elixir
• Linctuses
• Oral drops
• Gargles
• Mouthwashes
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Why Dosage Form Design

• Providing the mechanism for the safe and
convenient delivery of accurate dosage
• Protecting the drug substance from the destructive
influences of
– atmospheric oxygen or humidity (coated tablets, sealed
ampules)
– gastric acid after oral administration (enteric-coated
tablets)

• Concealing the bitter, salty, or offensive taste or

odor of a drug substance (capsules, coated
tablets, flavored syrups)

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• Providing liquid preparations of substances that

are either insoluble or unstable in the desired
vehicle (suspensions)
• Providing clear liquid dosage forms of substances
(syrups, solutions)
• Providing rate-controlled drug action (various
controlled-release tablets, capsules, and
suspensions)
• Providing optimal drug action from topical
administration sites (ointments, creams,
transdermal patches, and ophthalmic, ear, and
nasal preparations)

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• Providing for insertion of a drug into one of the

body’s orifices (rectal or vaginal suppositories)
• Providing for placement of drugs directly in the
bloodstream or body tissues (injections)
• Providing for optimal drug action through
inhalation therapy (inhalants and inhalation
aerosols)

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Evolution of Dosage Form Design

in Drug Development Process

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Journal of Internal Medicine 275(3): DOI: 10.1111/joim.12191

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Dosage Form
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GMP Phase 1 Phase 2 Phase 3 Commercial

API
batch batch batch batch campaign

Phase 1 Phase 2 Phase 3 Commercial

Drug
Dosage Dosage Dosage Dosage
Product
Form Form Form Form

Clinical Concept Dose Efficacy

Studies finding Safety
Tolerability Efficacy
Preclinical IND Phase I Phase II Phase III NDA
Animal acute Toxicity Carcinogenicity Toxicology
** Colors used for API, Drug Product and Clinical studies are matching
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Dosage Form Design

• Balance of Dosage Form Requirements
 Biopharmaceutics, Physical/Chemical, Process,
Marketing, Regulatory
• Evolution with Time of Dosage Form Requirements
& Knowledge
 Phase I through Phase III, Commercial
Form, Product Line Extensions
• Classification of Various Dosage Forms
 Route of Administration
 Time Course of Drug Delivery
 Target Organ, Tissue or Cell for Drug Delivery
 Physical forms

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Design of Medicine

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Design of Medicine
• Effectiveness • Convenience
• Safety – Ease of use
– Dosing frequency
• Reliability
– Consumer acceptance
• Stability
– Physical
– Chemical
– Microbiological

• Pharmaceutical elegance
– Appearance
– organoleptic properties
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Evolution of Dosage Form Needs

• Preclinical (Toxicology) Dosage Forms
– Biopharmaceutics-Emphasis is on Exposure, High
Drug Concentration
• Suspensions (NaCMC), Drug/Feed Mixtures
• Specialized Forms (Yogurt)

• Phase I Clinical Dosage Forms

– Biopharmaceutics-Simple, Flexible Dosing
• Single/Multiple Dose Tolerability Studies, Healthy
Volunteers
• Efficacy Marker -Proof of Concept, Attrition Curve
• Solutions, Powder-in-a-Bottle, Hard Gelatin Capsules
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• Phase II Clinical Dosage Forms

– Biopharmaceutics, Physico-Chemical, Processing-Larger,
Longer Studies
• Patients, Dose Finding and Proof of Concept
• Blinded Capsules or Tablets

• Phase III Clinical Dosage Forms

– Biopharmaceutics, Phy/Chemical, Processing-Even Larger,
Longer Studies
• Patients, Pivotal Efficacy and Safety
• Capsules or Tablets, Blinded or Branded (Double
Dummy)

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• Marketed Forms
– Biopharmaceutics, Physico-Chemical, Processing, Market,
Regulatory
• Consumers
• Size, Shape, Color, Branded Tablets or Capsules

• Product Line Extensions

– Biopharmaceutics, Physico-Chemical, Processing, Market,
Regulatory
• Protection from Generic Erosion
• Controlled Release, Fixed Combination, Alternate
Delivery Forms

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Generic Erosion
– Generic pharmaceutical price decay is what happens once
the originator brand has lost its patent exclusivity (patent
expiry) and generic versions of the originator brand have
been launched.

Cetirizine price decline

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Dosage Design Principles

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Dosage Form Design

• (1) Biopharmaceutical considerations (linking to

administration routes and type of dosage forms)
– Mechanism of Action
– Target Organ
– Dose (Potency)
– Permeability (Passive, Active, Efflux)
– Pharmacokinetics: ADME

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Therapeutic Considerations
• Nature of clinical indications, disease, or illness
– Most single drugs are prepared in different dosage forms

– Non-emergency (systemic use or oral) : tablet or capsule

– Emergency in which the patient may be in coma or unable to take

oral medication: injection

– Motion sickness, nausea, and vomiting: tablets and skin patches

are used for prevention and suppositories and injections for
treatment.

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• Age
– Infants and children younger than 5 years of age: flavored liquid
preparations

– young patient who has a productive cough or is vomiting, gagging,

or simply rebellious: injection, suppository

• Anticipated condition of the patient

– patients who have difficulty in swallowing tablets whole: chewable
tablets

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• Others
– Body weight
– Administration time ( morning/afternoon, day / night)
– Pregnancy
– Sex
– Race
– Menopause
– Tolerance
– Physiological reserve
– Milieu
– Temperature

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Drug Presentation to Patients

• Routes of administrating drugs into the body
• Physical form of the drug product
• Design and formulation of the product
• Method of manufacture of the product
• Physicochemical properties of the drug,
excipients, and drug product
• Control and maintenance of location of drug at the
absorption site
• Control of the release rate of the drug from the
drug product
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Biopharmaceutics
• Related to the rate and
extent of drug
absorption.
• Depending on routes of
administration, dosage
form, and rate of
entering into systemic
circulation
• Pharmacokinetics:
ADME.

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Dosage Form Design

• (2)API/excipients physical and chemical properties

– Solubility(Dissolution)
– Log P, PSA, H-donors, H-acceptors
– MW
– Stability (Heat, humidity, light)
– pH(API/excipients)
– Excipient compatibility
– Morphology
– Flow Properties
– Density (Bulk and Tap)
– Compressibility
– Particle Size
– Hygroscopic
– Wetting (surface energy)
– Polymorphism
– Static Properties
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LogP
Partition
coefficient of a
molecule
between an
aqueous and
lipophilic phases,
usually octanol
and water

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“A rational approach to dosage form

design requires a complete
understanding of the physicochemical
and biopharmaceutical properties of the
drug substance.”

• DOSAGE FORM DESIGN: A PHYSICOCHEMICAL APPROACH. Michael B.

Maurin (DuPont Pharmaceuticals Company, Wilmington, Delaware, U.S.A.),
Anwar A. Hussain and Lewis W. Dittert (University of Kentucky, Lexington,
Kentucky, U.S.A.)

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API Properties
Processing stresses
– Particle size and surface area • Pressure
• Mechanical
– Solubility • Radiation
• Exposure to liquids
– Dissolution • Exposure to gases and
liquid vapors
– Partition coefficient (pKa) • Temperature

– Polymorphism Manufacturing Unit Op.

• Precipitation
– Stability • Filtration
• Emulsification
– Organoleptic properties • Milling
• Mixing
– Other drug properties • Drying
• Granulation
• …
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Pharmaceutical Ingredients
• Appearance and Palatability
– Flavoring
– Sweetening
– Coloring

• Preservatives
– Benzoic acid, boric acid: denaturation of proteins
– Phenols: lytic and denaturation action on cell membranes
– Alcohols: lytic and denaturation action on cell membranes

• Solvents
• Lubricants
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Dosage Form Design

• (3)Awareness of manufacturing process (GMP,

efficiency, exposure to manufacturing ‘stresses’ ….)
– Cost of Goods
• Capital Investments
• Dosage Form (Tablet vs. Hard Gelatin Capsules)
• Size (6mm Tablet vs. 11mm Tablet)
• Shape (Round Tablet vs. Unique Shaped -Keyed Tools)
• Excipients (Alternate Suppliers)
• Processing Efficiency (Number of Process Steps, Speed of Processing,
Volume of Process)
• Failure Rate (Rejected Batches)

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Dosage Form Design

• (4) Marketing
– Time for Development
– Patent Protection
– Competitive Advantage
• Aesthetics (Size, Shape, Color, Taste, Painless)
• Patient Compliance (Once-A-Day vs bid)
• Price (Cost of Goods)

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Dosage Form Design

• (5) Regulatory
– Documented Formula, Process and Packaging
• Active Ingredients
• Excipients
• Testing Methods
• Specifications
• Equipment
• Unit Operations
• In-Process Controls

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Dosage Form Design

• (5) Regulatory
– Validation of the Process
– Validation of the Release and Stability Testing Methods
– Stability Report on Package Drug Product (Bulk, Primary)
– Documents
• IND, NDAs, Validation Reports

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Types of Dosage Forms

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Types of Dosage Forms

Route of administration Physical form

Oral Solid
Topical Time Course of Semisolid
Rectal Drug Release liquid
Parenteral Immediate
Vaginal Sustained Target Release
Inhaled Controlled Organ specific
Ophthalmic Pulsed Tissue specific
Cell specific
Otic

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Routes of Drug Administration

• Oral dosage forms:
– solutions, syrups, suspensions, emulsions, gels, powders,
granules, capsules, tablets

• Rectal dosage forms

– Suppositories, ointments, creams, powders, enema.

• Parenteral dosage forms

– Subcutaneous; intramuscular; intravenous
– Injections (solution, suspension, emulsion forms),
implants, irrigation, and dialysis solutions

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• Topical dosage forms

– ointments, creams, pastes, lotions, gels, topical aerosols,
transdermal patches, pressurized dispensers, paints,
collodion, liniments, plasters, dusting powders, poultice

• Respiratory dosage forms

– Aerosols (solution, suspension, emulsion, powder forms),
inhalations, sprays, gases

• Nasal dosage forms

– Drops, inhalations

• Eye (Ophthalmic dosage forms)

– Drops, ointments, creams

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• Vaginal dosage forms

– Intrauterine devices
– Douche
– Vaginal ring
– Pessary

• Ear (Otic dosage forms)

– drops, suspensions, ointments, creams

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Physical Forms
 Solid Time of onset of Dosage forms
 Tablets action
 Capsules Seconds i.v. injections
 Powders Minutes i.m. and s.c. injections,
buccal tablets, aerosols,
 Semisolid gases
 Creams Minutes to hours Short-term depot injections,
 Suspensions solution, suspensions,
 Aerosols powders, granules, capsules,
tablets, modified-release
 Emulsion tablets
 Liquid Several hours Enteric-coated formulations
 Others …. Days to weeks Depot injections, implants
varies Topical preparation

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