Pharmaceutical

ANUFACTURING
 PACKAGING
INTRODUCTION
OF DOSAGE FORMS

MANUFACTURING
OF DOSAGE FORMS

MANUFACTURING OUTLINE
 MANUFACTURING
OF DOSAGE FORMS

Solutions
Tablets Ointment
Suspensions Parenterals
Capsules Suppository
Emulsions

MANUFACTURING OUTLINE
 Manufacturing:
INTRODUCTION
• Pharmaceutical Manufacturing
• Manufacturing Terms
• Drug Establishments
• Departments in a Manufacturing Company
INTRODUCTION Pharmaceutical Manufacturing

Large-scale production of drugs

Manufacture, preparation, or
processing of drugs on a large-scale
basis VS

Extemporaneous Compounding
Small-scale
INTRODUCTION Pharmaceutical Manufacturing

WHO definition:

Manufacture: All operations of purchase of

materials and products, production, quality
control (QC), release, storage and distribution of
pharmaceutical products, and the related
controls.
Manufacturer: A company that carries out
operations such as production, packaging,
repackaging, labelling and relabelling of
pharmaceuticals.
 Manufacturing:
INTRODUCTION
• Pharmaceutical Manufacturing
• Manufacturing Terms
• Drug Establishments
• Departments in a Manufacturing Company
INTRODUCTION Manufacturing Terms

Levels of Manufacturing:

Tertiary Manufacturing
packaging, labeling,
repacking of finished
product

Secondary Manufacturing
Finished dosage forms

Primary Manufacturing
API and excipients
INTRODUCTION Manufacturing Terms
Other terms:

Good part of QA that ensures the products are consistently

produced to quality standards appropriate for its
Manufacturing intended use; GXP (X = Distribution, Clinical, Storage,
Practice etc.)
specific quantity of a drug or other material that is
intended to have a uniform character and quality, within
Batch specified limits and is produced according to a single
manufacturing order during the same cycle of
manufacture.
a batch or a specific portion of a batch having uniform
Lot character and quality within specified limits and a
distinctive identifying lot number
INTRODUCTION Manufacturing Terms
Tablet press: 250,000 tablets/run

1M 250K

Lot 1
250K

Lot 2
tablets
250K 250K
Batch
Lot 3 Lot 4
INTRODUCTION Manufacturing Terms
Other terms:
Any distinct combination of letters, numbers, or symbols
Batch/Lot Number used for identification and traceability of a single
batch/lot
INTRODUCTION Manufacturing Terms
Other terms:

Active Ingredient Any component that is intended to furnish

pharmacological activity or other direct effect in the
(API: Active
diagnosis, cure, mitigation, treatment or prevention of
Pharmaceutical disease or to affect the structure of the function of the
Ingredient) body of man or other animals

Inactive
Any component other than an active ingredient; provides
ingredient or the active ingredient in a form suitable for administration
Excipient
INTRODUCTION Manufacturing Terms
Other terms:
Record containing the formulation, specifications,
Master Record manufacturing procedures, quality assurance
requirements and labelling of finished product
Batch a document that is intended to give a full and
Manufacturing authoritative record of the manufacturing history of each
batch of every product
Record
SOP (Standard Step-by-step instructions for performing operational
tasks or activities
Operating *Not necessarily specific to a product: (e.g. equipment operation,
Procedures) maintenance, cleaning, etc.)
INTRODUCTION Manufacturing Terms
INTRODUCTION Manufacturing Terms
INTRODUCTION Manufacturing Terms
Other terms:

Contamination of a starting material, intermediate

Cross-
product or finished product with another starting
Contamination material or product during production
Manufacturing
addition of an active in an unstable preparation to
Overages or compensate for the loss during manufacture.
Overaging
INTRODUCTION Manufacturing Terms

Products typically containing

Cross- overages:
Contamination of a starting material, intermediate
product or finished product with another starting
Contamination material orDietary
product during production
supplements
Manufacturing (Vitamins and Minerals)
addition of an active in an unstable preparation to
Overages or compensate for the loss during manufacture.
Overaging
INTRODUCTION Manufacturing Terms

Other terms:
An area that is marked, designated or set aside for the
Quarantine holding of incoming components prior to acceptance
examination
documented evidence that a system does what it is
Validation supposed to do; documented demonstration of expected
quality and consistency.
INTRODUCTION Manufacturing Terms
Abbreviations:

Current Good Manufacturing

cGMP Practice
International Conference on
ICH Harmonization
Pharmaceutical Inspection
PIC/S Cooperation Scheme
QUICK-THINKS
Written procedure giving instructions for
performing operations NOT necessarily specific to
a given product or material
A. Master Formula
B. Master Record
C. Batch Record
D. Standard Operating Procedure
 Manufacturing:
INTRODUCTION
• Pharmaceutical Manufacturing
• Manufacturing Terms
• Drug Establishments
• Departments in a Manufacturing Company
INTRODUCTION Drug Establishments
From AO 56, Licensing of Drug Establishments and Outlets:

any establishment engaged in the operations involved in

Drug the production of a drug with the end view of storage,
Manufacturer distribution or sale of the product

✓ APIs ✓ Biologicals
✓ Ethical Products ✓ Veterinary Products
✓ Generic Products ✓ Cosmetics

*INN: International Non-Proprietary Name

INTRODUCTION Drug Establishments
INTRODUCTION Drug Establishments
From AO 56, Licensing of Drug Establishments and Outlets:

Registered owner of the drug product; subcontracts to a

toll manufacturer
• procures the raw materials and packaging
Drug Trader components, and provides the production
monographs, quality control standards and
procedures, but sub-contracts the manufacture of
such product to a licensed manufacturer
INTRODUCTION Drug Establishments
From AO 56, Licensing of Drug Establishments and Outlets:

Registered owner of the drug product; subcontracts to a

toll manufacturer
• procures the raw materials and packaging
Drug Trader components, and provides the production
monographs, quality control standards and
procedures, but sub-contracts the manufacture of
such product to a licensed manufacturer
INTRODUCTION Drug Establishments
From AO 56, Licensing of Drug Establishments and Outlets:

procures raw materials, active ingredients and/or

Drug finished products from local establishments for
Distributor/Wholesaler local distribution on wholesale basis.
imports raw materials, API and/or finished
Drug
products from other countries for distribution to
Distributor/Importer other outlets
Drug exports raw materials, API and/or finished
Distributor/Exporter products to be distributed to other countries
INTRODUCTION Drug Establishments
From AO 56, Licensing of Drug Establishments and Outlets:

procures raw materials, active ingredients and/or

Drug finished products from local establishments for
Distributor/Wholesaler local distribution on wholesale basis.
imports raw materials, API and/or finished
Drug
products from other countries for distribution to
Distributor/Importer other outlets
Drug exports raw materials, API and/or finished
Distributor/Exporter products to be distributed to other countries
 Manufacturing:
INTRODUCTION
• Pharmaceutical Manufacturing
• Manufacturing Terms
• Drug Establishments
• Departments in a Manufacturing Company
INTRODUCTION Departments in a Manufacturing Company

Research &
Production QA/QC Regulatory
Development Affairs

Engineering Human Marketing Medical

Resources
 INTRODUCTION Departments in a Manufacturing Company

Formulates, develops, and improves new and

existing products (pilot batch production)
Research &
Medical Development Does chemical/ pharmaceutical, and physiological
research
• Establishment of pharmacokinetic profile
Marketing and dose
• Toxicity analysis
• Test for allergens
 INTRODUCTION Departments in a Manufacturing Company

Receives materials and supplies

Medical Production
Manufactures and packages products
Warehousing, storage and shipping functions
Research & • In charge of inventory control of own
Development finished products
INTRODUCTION Departments in a Manufacturing Company

Ensures compliance of company to GMP

oduction QA/QC
Assures all manufacturing operations meet the
required standards of safety and efficacy before
release of the product to the market
Research &
Development
INTRODUCTION Departments in a Manufacturing Company

Locates, installs, maintains, repairs equipment

oduction Engineering
Maintains plant services
Ensures plant and employee safety
QA/QC
 INTRODUCTION Departments in a Manufacturing Company

Regulatory Ensures compliance of the company and its

gineering
Affairs products with all pertinent regulations and laws
about drugs and their marketing

QA/QC
 INTRODUCTION Departments in a Manufacturing Company

Studies/researches current market trends,

gineering Marketing
consumer behavior and product status in the
market
Responsible for advertisement and promotion of
Regulatory
products
INTRODUCTION Departments in a Manufacturing Company

Human Hires qualified personnel

arketing
Resources Physical and medical examination of employees

Regulatory
INTRODUCTION Departments in a Manufacturing Company

Concerned with the physical examination, and

arketing Medical
medical treatment of employees
Performs clinical studies
Regulatory
QUICK-THINKS
Which of the following records shall be
controlled by the Quality Control
Department?
A. Inventory records
B. Returned goods records
C. Production records
D. In-process records
E. Master Formula
QUICK-THINKS
The objective of the stability study is to
determine:
A. By-products of drug decomposition
B. Optimum storage conditions
C. Shelf-life
D. Potency of the drug
QUICK-THINKS
Performed during production in order to monitor,
and adjust the process to ensure that the product
conforms to the specifications
A. In-process control
B. Quality control
C. Critical operation
D. AOTA
 Manufacturing:
INTRODUCTION
• Pharmaceutical Manufacturing
• Manufacturing Terms
• Drug Establishments
• Departments in a Manufacturing Company
 MANUFACTURE OF DOSAGE FORMS
• Solution • Capsules
• Suspension • Ointments • Parenterals
• Emulsion • Suppositories • Cosmetics
• Tablets
DOSAGE FORMS Manufacture of Dosage Forms

DOSAGE PROBLEMS &

FORM REMEDIES

FORMULA & PROCESS &

INGREDIENTS EQUIPMENT
SOLUTIONS
DOSAGE FORMS Solutions

GENERAL FORMULA

Flavors & Colorants

Sweeteners Buffers
Preservatives Viscosity Enhancers
Cosolvent

Solvent

Active Ingredient
DOSAGE FORMS Solutions

Active Ingredient
- Soluble/miscible in the vehicle
- Partly soluble/miscible in the vehicle

Solvent
Cosolvent
Viscosity Enhancers
Preservatives
Buffers
Sweeteners
Flavors
Colorants
QUICK-THINKS

BCS Classification Class II

A. High solubility, High permeability
B. Low solubility, High permeability
C. High solubility, Low permeability
D. Low solubility, Low permeability
DOSAGE FORMS Solutions

Active Ingredient
Description and Solubility, USP
Parts of SOLVENT needed for 1
Descriptive Terms
part Solute
Very soluble <1
Freely soluble 1 – 10
Solvent Soluble 10 – 30
Cosolvent Sparingly soluble 30 – 100
Viscosity Enhancers
Preservatives Slightly soluble 100 – 1000
Buffers Very slightly soluble 1000 – 10,000
Sweeteners
Practically insoluble or
Flavors >10,000
Colorants
Insoluble
DOSAGE FORMS Solutions

Solvent
Aqueous Solvent
Water for Pharmaceutical Purposes, USP

Bulk Waters Sterile Waters

Cosolvent ✓ Purified Water ✓ Sterile Water for
Viscosity Enhancers
Preservatives
✓ Water for Injection Injection (SWFI)
Buffers (WFI) ✓ Bacteriostatic
Sweeteners
Flavors Water for Injection
Colorants
DOSAGE FORMS Solutions

Solvent: Purified Water, USP

Prepared by deionization, distillation, ion exchange,
reverse osmosis, filtration, or other suitable purification
process

Use: production of NP preparations and

Cosolvent in other applications (e.g., cleaning of
Viscosity Enhancers
Preservatives equipment, tests and assays)
Buffers
Sweeteners
Flavors
Colorants
DOSAGE FORMS Solutions

Solvent: Water for Injection, USP

Purified water that is pyrogen free (pass bacterial
endotoxin specification); NOT sterile
Prepared by distillation

Use: Production of parenteral and other

Cosolvent preparations where endotoxin content
Viscosity Enhancers
Preservatives must be controlled
Buffers
Sweeteners
Flavors
Colorants
DOSAGE FORMS Solutions

Cosolvent
For API that are partly soluble/ miscible in the vehicle
Used to increase the solubility of solute
Requirement: Used to increase the solubility of solute
Also used to improve solubility of other components
such as flavors
Viscosity Enhancers Examples:
Preservatives ✓ Ethanol, Sorbitol
Buffers
Sweeteners
✓ Glycerin, Propylene Glycol,
Flavors ✓ PEG Polymer
Colorants
DOSAGE FORMS Solutions

Viscosity Enhancers
Used to improve palatability / mouth feel
Improve pourability

Examples:
Preservatives ✓ Polyvinylpyrrolidone (PVP),
Buffers ✓ Cellulose derivatives (Methylcellulose, Na
Sweeteners Carboxymethylcellulose)
Flavors
Colorants
DOSAGE FORMS Solutions

Preservatives
Used to keep the stability of the product
Requirements:
Must be effective against broad spectrum of
microorganisms
Must be physically, chemically and microbiologically
stable throughout the shelf life of the product
Examples:
Buffers
✓ Parabens, Benzoates
Sweeteners
Flavors
✓ Alcohols and Phenols
Colorants ✓ Mercurial, Quaternary ammonium salts
DOSAGE FORMS Solutions

Preservatives
effective against bacteria and molds
Parabens
(broad spectrum)
Quaternary often used for ophthalmic, nasal, and
Ammonium parenteral products but NOT in liquid
Compounds preparations (e.g., benzalkonium chloride)
Thimerosal Mercurial®

Buffers
Sweeteners
Flavors
Colorants
DOSAGE FORMS Solutions

Preservatives
effective against bacteria and molds
Parabens
(broad spectrum)
Quaternary often used for ophthalmic, nasal, and
Ammonium parenteral products but NOT in liquid
Compounds preparations (e.g., benzalkonium chloride)
Thimerosal Mercurial®

Buffers
Sweeteners
Flavors
Colorants
QUICK-THINKS
Benzalkonium chloride and edetate is a
mixture of preservatives that is most
effective for:
A. Otic preparations
B. Ophthalmic preparations
C. Oral preparations
D. Topical preparations
QUICK-THINKS
The following are antimicrobial preservatives,
except:
A. Methylparaben
B. Benzoic Acid
C. Imidurea
D. NOTA
DOSAGE FORMS Solutions

Buffer/Acidifiers/pH Adjusters
pH environment affects the drug solubility and
stability
Most commonly used for oral liquid preparation is
pH 4-7

Examples:
✓ Citric Acid
Sweeteners
✓ Glutaric Acid
Flavors ✓ Lactic Acid
Colorants
DOSAGE FORMS Solutions

Buffer/Acidifiers/pH Adjusters
Requirements:
Adequate capacity in the desired pH
Biologically safe for the intended use
Little or no significant damaging effect to the final
product
Permit acceptable flavoring and coloring of the
product
Sweeteners
Flavors
Colorants
DOSAGE FORMS Solutions

Sweetening Agents
For palatability
Mask /improve taste of the product
Usually combination of sucrose and synthetic
sweetener to decrease crystallization

Examples:
✓ Aspartame,
✓ Saccharin,
Flavors ✓ Sorbitol
Colorants
DOSAGE FORMS Solutions

Flavors
Oil-based flavors require co-solvents
Flavor selection may be based on taste sensation of the API
Salty Butterscotch, maple, apricot, peach, vanilla, mint
wild cherry, walnut, chocolate, anise, passion fruit,
Bitter
mint
Sweet fruit, berry, vanilla
Sour citrus, licorice, rootbeer, raspberry

Colorants
DOSAGE FORMS Solutions

Colorants
Should be consistent with flavor
e.g., red : cherry, yellow : lemon, brown : chocolate
3 Types (Synthetic):
✓ FD & C *Note: Natural colors –
✓ D&C fades through time; possible
batch-to-batch variation
✓ External D & C
DOSAGE FORMS Solutions

UNIT OPERATIONS

Dispensing
Mixing
Filtration/Clarification
Storage & Aging
Filling & Packaging
DOSAGE FORMS Solutions

Dispensing

Mixing
Critical step: dissolution of solute in solvent
✓ Agitation ✓ With the aid of heat
Critical step: addition of dye

Filtration/Clarification
Storage & Aging
Filling & Packaging
QUICK-THINKS
Which of the following will more likely result
to slower solubility?
A. Increased temperature
B. Higher particle size
C. Salting In
D. Both A and B
E. Both A and C
DOSAGE FORMS Solutions

Dispensing

Mixing
Equipment: Mixing Tank
✓ polished stainless steel
(SS 304 or 316)
SS 316: added 2.5% Mo for
improved resistance to corrosion

Filtration/Clarification
Storage & Aging
Filling & Packaging
QUICK-THINKS

Most inert grade of stainless steel

A. SS 304
B. SS 316
C. SS 3004
D. SS 3016
DOSAGE FORMS Solutions

Dispensing

Mixing
Equipment: Mixing Tank
✓ Jacketed for ✓ Selection of Mixer:
heating/cooling Under Inadequate
✓ Equipped with agitation sized distribution
and measuring devices Incorporate
Too
excessive amount
fast
Filtration/Clarification
of air
Storage & Aging
Filling & Packaging
DOSAGE FORMS Solutions

No flow to lift
particles up and
suspend them in fluid
Employ:
✓ Installing baffles in
tanks
✓ Offset angle mounting
of mixers
✓ Offset vertical
UN-BAFFLED CYLINDRICAL TANK mounting of mixers
DOSAGE FORMS Solutions
DOSAGE FORMS Solutions

Dispensing
Mixing

Filtration/Clarification
Filtration is through 3-5 microns or less
Clarifying/filtering agent: talc
Kinds of filtration according to driving force:
✓ Gravity ✓ Pressure ✓ Vacuum

Storage & Aging

Filling & Packaging
DOSAGE FORMS Solutions

Dispensing
Mixing

Filtration/Clarification
Filtration Systems:
✓ Series ✓ Parallel

Storage & Aging

Filling & Packaging
DOSAGE FORMS Solutions

Dispensing
Mixing

Filtration/Clarification
Types of Filter Media:
✓ Membrane filter media
✓ Woven filter cloth
✓ Non-woven filter cloth

Bacterial Challenge Test:

Storage & Aging
Brevundimonas diminuta
Filling & Packaging
DOSAGE FORMS Solutions

Dispensing
Mixing
Filtration/Clarification

Storage & Aging

Optional step
Usually done in presence of essential oils
Improves flavor / odor

Filling & Packaging

DOSAGE FORMS Solutions

Dispensing
Mixing
Filtration/Clarification
Storage & Packaging

Filling & Packaging

Gravimetric Filling: limited to large containers or to highly viscous
products; slow
Volumetric Filling: accomplished by positive displacement piston
action; gives constant volume regardless of size; fill amount is
measured by the stoke of the piston
Constant-Level Filling: uses the container as the means for
controlling the fill of each unit
QUICK-THINKS
A method of filling viscous liquid
preparations in very large containers:
A. Volumetric
B. Constant level
C. Gravimetric
D. AOTA
E. NOTA
DOSAGE FORMS Solutions

Other reminders:
✓ charge the solute to the solvent and agitate until
solution is homogenous

✓ Ensure and verify complete solution of the substance

before proceeding to the next step

✓ Solutes in small concentrations (e.g. dyes) should be

pre-dissolved prior to mixing with the bulk preparation
 MANUFACTURE OF DOSAGE FORMS
• Solution • Capsules
• Suspension • Ointments • Parenterals
• Emulsion • Suppositories • Cosmetics
• Tablets
SUSPENSIONS
SUSPENSIONS
DOSAGE FORMS Suspension
✓ API must be soluble  Solution;
✓ API is not soluble, liquid preparation  Suspension

Pharmaceutical Suspensions:
• two-phase system  solid uniformly dispersed in liquid
system
• Drugs are formulated into suspension if unstable as
solution
Particle size range:
10 to 100 micrometers  dispersed systems
If colloidal suspension: particle size <1 micron
DOSAGE FORMS Suspension
Characteristics:
• More bioavailable than tablets & capsules:
Solution > suspension > compressed tablet > capsule
• Possible to modify bioavailability of the drug
BA is dependent on viscosity
Inc viscosity, Dec drug-release
• Greater compliance to drug regimen, especially for
pediatric and geriatric patients
DOSAGE FORMS Suspension
Types of Suspension:
Small particle Larger particle
size size
Settles slowly Settles rapidly
Dec sediment Inc sediment
volume volume

DEFLOCCULATED FLOCCULATED
DOSAGE FORMS Suspension
Sediment Volume FLOCCULATED

100
mL 70
mL 65
mL

Time
DOSAGE FORMS Suspension
Sediment Volume DEFLOCCULATED

100
mL
50
mL
30
mL

Time
DOSAGE FORMS Suspension
Types of Suspension:
Small particle Larger particle
size size
Settles slowly Settles rapidly
Dec sediment Inc sediment
volume volume
Loose structure
Prone to caking  Easily
redispersed

DEFLOCCULATED FLOCCULATED
QUICK-THINKS
Which of the following is true about
Flocculated suspensions?

A. Faster sedimentation rate

B. Can easily be redispersed
C. Possibility to form cake
D. Both A and B
DOSAGE FORMS Suspension
Requirements of a Good Suspension:
✓ Suspended should not settle rapidly

✓ Must not form a hard cake but should be readily

redispersed into a uniform mixture when the container
is shaken
✓ not be too viscous to pour freely from the orifice
of the bottle or to flow from syringe needle
DOSAGE FORMS Suspension

GENERAL FORMULA

Flavors, Colorants,
Preservatives, Perfume
Sweeteners Buffers
Viscosity Modifier Wetting Agents
Suspending Agents

Dispersion
Medium (Solvent)
Active Ingredient
DOSAGE FORMS Suspension

Suspending Agent
Viscosity Enhancers
• Hydrophilic colloids: Acacia, tragacanth, cellulose
derivatives
• Clays: Bentonite, kaolin (topical application)
• Other agents: Agar, Gelatin, Pectin, Gelatinized
Starch

Wetting Agents
Flocculating Agents
DOSAGE FORMS Suspension

Suspending Agent
Factors to consider in selecting suspending agents:
• Suspending ability
• Chemical compatibility with other ingredients
• Effect of pH range on the drug
• Appearance
• Cost

Wetting Agents
Flocculating Agents
DOSAGE FORMS Suspension

Wetting Agent
• Allow displacement of air from hydrophobic material
• Suspending agents and insoluble drug need to be
“wet” before they even be dispersed
• usually 0.05 - 0.5% of the formula

Examples:
Glycerin, PEG, Syrup
Flocculating Agents
DOSAGE FORMS Suspension

Flocculating Agent
• Agents added to facilitate the formation of
floccules/aggregates
Flocculation: to avoid formation of cake
Flocs/Floccules: “light, fluffy” particles
• Alter charges surrounding
Examples:
particles and the whole
Electrolytes (AlCl3 ,
suspension to allow formation
KCl, NaCl, K3PO4)
of loose aggregates
DOSAGE FORMS Suspension

Flocculating Agent

-
+

- - Na

- + +
+ Na Na
Na
- -
+ -
Na
-
DOSAGE FORMS Suspension

Flocculating Agent
+
- Na

- - +
Na +
+ Na
Na
- -
+
-
Na
-
DOSAGE FORMS Suspensions

UNIT OPERATIONS

Dispensing
Milling
Wetting
Addition of Suspending & Flocculating Agent
Filling & Packaging
DOSAGE FORMS Suspension

Problems Encountered
• Caking
• Settling too rapidly
• Solubilization of dispersed
phase
• Polymorphism
 MANUFACTURE OF DOSAGE FORMS
• Solution • Capsules
• Suspension • Ointments • Parenterals
• Emulsion • Suppositories • Cosmetics
• Tablets
EMULSION
EMULSION
DOSAGE FORMS Emulsion

Emulsions:
• 2-phase liquid system combining 2 immiscible liquids:

Dispersion Medium/External/Continuous Phase

• liquid or semisolid (e.g. creams, lotions)

Dispersed/Internal/Discontinuous Phase
• API must be soluble here
Emulsifying Agents:
• Stabilizer of the droplet forms (globules) of the internal
phase
• Acts as a bridge between the 2 phases while at the same
time provides a protective film around the globules and
retards coalescence
DOSAGE FORMS Emulsion

General Considerations: Advantages:

• Emulsions are ✓ improved dissolution and BA of
unstable nature poorly soluble drugs
• Internal phase ✓ effective masking of tastes
should represent 40- within the dispersed phase
60% of the total ✓ control of absorption rate
volume.

Types: ✓ O/W or W/O ✓ Mixed emulsion (W/O/W or O/W/O)

✓ Microemulsion
QUICK-THINKS

Which of the following is false?

A. O/W emulsion is miscible with water

B. W/O emulsion is miscible with water
C. O/W conducts electricity
D. W/O emulsion is miscible with oil
DOSAGE FORMS Emulsion

Emulsifying Agent
Natural
Acacia, tragacanth, gums
(vegetable sources)
Finely divided solids, aka Bentonite (Colloidal hydrated Al
colloidal clays Silicate), Veegum (Mg Al Silicate)
effective in lowering surface tension
Synthetic because of both hydrophilic and
hydrophobic groups

Anionic Cationic Non-ionic

DOSAGE FORMS Emulsion

Emulsifying Agent: Synthetic

SLS, SLES, Dioctyl
Anionic effective at HIGH pH
sodium sulfosuccinate
Benzalkonium chloride;
Cationic effective at LOW pH
Cetylpyridinium Cl
Spans (sorbitan) and
Tweens
Non-ionic NOT affected by pH
(polyoxyethylene
sorbitan esters)
DOSAGE FORMS Emulsion

Emulsifying Agent: Non-ionic

Spans Tweens
• hydrophobic; • hydrophilic;
• low HLB value; • high HLB value;
• form w/o emulsions • form o/w emulsions
DOSAGE FORMS Emulsion

Emulsifying Agent: Surfactant

(Surface-active agent)

organic compounds with

surface-active polar group
DOSAGE FORMS Emulsion

Emulsifying Agent: Surfactant

Hydrophilic
Head

Hydrophobic
Tail

Micelle
DOSAGE FORMS Emulsion

Emulsifying Agent: Surfactant

- + +/-

Anionic Cationic Non-ionic Amphoteric

DOSAGE FORMS Emulsion

Emulsifying Agent: Surfactant

Anionic Cationic Non-ionic Amphoteric
• Polar part: (-) • Polar part: (+) • Polar part: no • Polar part:
charge charge charge BOTH (+) and (-)
• Good foamers • Poor foamers; • Not sensitive to charge
• Sensitive to no washing water hardness • Ex: Betaine
water hardness ability • Ex: Cetyl
• Ex: Soaps, SLS, • Ex: Alcohol,
SLES Benzalkonium Cocamide DEA
Cl, Cetyl
pyridinium Cl
DOSAGE FORMS Emulsion

EQUIPMENT:
✓ Colloid Mills
✓ Homogenizers
✓ Mechanical stirrers
✓ Ultrasonic Devices
DOSAGE FORMS Emulsion

EQUIPMENT:
✓ Colloid Mills
✓ Homogenizers
✓ Mechanical stirrers
✓ Ultrasonic Devices
DOSAGE FORMS Emulsion

UNIT OPERATIONS

Dispensing

Mixing

Filling & Packaging

DOSAGE FORMS Emulsion

Dispensing

Mixing
Oil Phase Water Phase

(2) 70-72 degrees

(1) Add gradually
(3) Mix slowly while
cooling.
43-45 degrees Add perfume.
Filling & Packaging
DOSAGE FORMS Emulsion

Problems Encountered

Creaming Sedimentation
DOSAGE FORMS Emulsion

Problems Encountered

Flocculation Breaking Phase Inversion

reversible IRreversible Reversible/Irreversible
DOSAGE FORMS Emulsion

HLB System (Griffin System):

Antifoaming 1-3
W/O 4-6
Wetting 7-9
O/W 8-18
Detergent 13-15
Solubilizer 10-18
Higher HLB value, hydrophilic; Lower HLB value, hydrophobic
QUICK-THINKS
According to the Griffin Scale, which of the
following has an HLB value of 7?
A. Wetting Agent
B. Detergent
C. Solubilizing agent
D. Antifoaming agent
E. Both A and C
 MANUFACTURE OF DOSAGE FORMS
• Solution • Capsules
• Suspension • Ointments • Parenterals
• Emulsion • Suppositories • Cosmetics
• Tablets
TABLETS
DOSAGE FORMS Tablet

GENERAL FORMULA
Diluent
Binder
Disintegrant

Antifrictionals
Flavorants, Sweeteners,
Colorants
DOSAGE FORMS Tablet

Diluent
- aka filler/ bulking agent
- added to increase tablet size to make it
suitable for compression
Requirements:
✓ must be inert and compatible with other components
✓ must NOT interfere with the BA of the drug
Binder
Disintegrant ✓ must be physically and chemically stable
Antifrictionals
Flavorant
Sweeteners
Colorants
DOSAGE FORMS Tablet

Diluent
most common, cheap, incompatible with Mg
Lactose stearate, amine drugs and strong oxidizers
has negative heat of solution producing a
Mannitol & Xylitol pleasant mouthfeel; used in chewable tablets

Starch Microcrystalline Cellulose

Binder Sucrose (MCC)
Disintegrant
Antifrictionals
Flavorant
Sweeteners
Colorants
DOSAGE FORMS Tablet

Binder
- imparts cohesiveness to powder mixture
Inadequate Binder Too much Binder
• Soft granules • Too hard tablets
• Too much fines • Difficulty in dry screening
• Inadequately hard • Hampered disintegration and
tablets dissolution (low BA)
Disintegrant
Antifrictionals
Examples: starch paste, povidone,
Flavorant
Sweeteners copovidone, HPMC, CMC
Colorants
QUICK-THINKS
Which of the following is/are sucrose-based
tablet diluent-binder?
A. Avicel
B. Cab-o-sil
C. NuTab
D. Both A and B
E. Both B and C
QUICK-THINKS
What is a Pharmaceutical Glaze?
A. Hydroalcoholic solution of starch
B. Denatured alcoholic solution of PVP
C. Denatured alcoholic solution of Shellac
D. Hydroalcoholic solution of NaCMC
E. NOTA
DOSAGE FORMS Tablet

Disintegrant
- facilitates the breaking apart of a tablet when
placed in aqueous environment
Mechanisms of Action:
✓ Swelling (Starch) ✓ deformation
✓ capillary action/wicking
(MCC)
Antifrictionals
Flavorant
✓ due to release of gases/effervescence or
Sweeteners
Colorants
other chemical reaction
DOSAGE FORMS Tablet
DOSAGE FORMS Tablet
DOSAGE FORMS Tablet

Disintegrant
Double Disintegration:
- A portion of disintegrant is added with the lubricant in
the last mixing step
- The portion that is added first breaks the pieces of
tablet into fine particles.
- The portion that is added last causes the
Antifrictionals tablet to break into small pieces
Flavorant
Sweeteners
Colorants
QUICK-THINKS
Some cross-linked molecules make up materials
that are known as super disintegrants. They are
termed as such because:
A. They cause rapid disintegration
B. They are completely effective at low doses
C. They disintegrate tablets by a bursting action
D. A and B
DOSAGE FORMS Tablet

Antifrictionals
- low percentages in formulation
(max 5-10%);
- usually 0.5-2% for hydrophobics
- added only prior to compression;

Flavorant
Sweeteners
Colorants
DOSAGE FORMS Tablet

Antifrictionals
Types:
Decreases friction between a tablet’s surface
Lubricant and die wall to facilitate ejection from die
cavity
Enhances flow of the granulation, between
Glidant particles/granules
Prevents particles from sticking to the
Antiadherent punches

Flavorant
Sweeteners
Colorants
DOSAGE FORMS Tablet

Flavorant
Salty cinnamon, orange, cherry, butterscotch
Bitter chocolate, cherry, raspberry, mint
Sour/Acrid raspberry, lemon, other fruity flavors
Oily mint, lemon, orange
Unpleasantly
vanilla, fruits
sweet
Sweeteners
Colorants
DOSAGE FORMS Tablet

Sweeteners
1000x Sucralose (unaffected by heat)
500x Saccharin
300x Saccharin Na
180-200x Acesulfame K, Aspartame
30x Na Cyclamate “Magic sugar”
Colorants
DOSAGE FORMS Tablet

Colorants
Dyes Lakes
Water soluble Water insoluble
oil-dispersible
DOSAGE FORMS TS ao bl ul et ito n s

UNIT OPERATIONS
Dispensing
Milling
Mixing
Granulation
Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s

Dispensing
- weighing and measuring
- critical step: weight of ingredient according to dose
Methods:
✓ hand scooping and weighing
✓ weighing with material lifting assistance
✓ manual/assisted transfer with automated
weighing
Milling
✓ manual/assisted filling of loss-in weight
Mixing
Granulation dispensing system
Compression ✓ automated dispensaries
Coating
DOSAGE FORMS TS ao bl ul et ito n s

Dispensing
Issues/Problems:
✓ weighing accuracy
✓ dust control
✓ lot control of each ingredient
✓ material movement (into and out
Milling of dispensary)
Mixing
Granulation
Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s

Dispensing

Milling
aka size reduction, sizing, crushing, grinding,
pulverization
important step: easier and more uniform mixing for
greater uniformity of dose

Mixing
Granulation
Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s

Dispensing
Milling

Mixing
process of putting together ingredients in one mass with
more or less thorough dispersion of the constituted
elements among one another
Goal: to obtain dosage units each of which contains the
same quantity of drug substance

Granulation
Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s

Twin-Shell or V-Shell Blender

DOSAGE FORMS TS ao bl ul et ito n s

Double Cone Blender

DOSAGE FORMS TS ao bl ul et ito n s

Sigma Blade Mixer

DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation
process of powder size enlargement to granules,
rendering them into a freely flowing state
improves flowability and compressibility

Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation Mesh Number:

Types of Granules: No. of square openings per
linear inch
Good Granules Fine Granules
pass through
pass through sieve #20 The higher the Meshsieve #40;
Number, the
but not through sieve #40 smaller
used the particles
to fill which are
interparticulate
able pass
space; through
limit it. of
to 10%
granulation
Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation
Types of Granulation:
Dry Granulation Wet Granulation
Direct Compression Fluid Bed Granulation

Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation: Dry Granulation

powder mixture is compacted in large pieces and subsequently
broken down into granules
Multiple compaction  strengthening of bonds that hold
tablet together
Use: for materials which do not compress well after granulation
and are sensitive to heat and/or moisture
(Eliminates wetting and drying step)
Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation: Dry Granulation

Examples: Aspirin Tablets and multi-vitamin tablets
Advantages: less equipment and space
Disadvantages: uneven distribution of color; dusty

Slugging Roller Compaction

Slugs: large flat tablets formation of
about 1 inch in diameter sheets/ribbons
Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation: Wet Granulation

granulating liquid or binder solution (or suspension, or slurry) is
added to turn the powders to a single wet mass
- wetting powders make granules more flowable &
compressible
Drying Process: required to remove the solvent used in forming the
aggregates

Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation: Wet Granulation

Disadvantages: • labor-intensive • time-consuming
• not for moisture- or heat-sensitive drugs

Overwet Underwet
too hard granules; too soft granules;
increase in drying time; break back into powders;
wear and tear of tablet press difficulty in forming tablets

Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation: Direct Granulation

Few crystalline substances may be compressed directly
✓ should have excellent flowability and compressibility

Examples: KCl, NaCl, NaBr

Diluents: Microcrystalline cellulose (Avicel), anhydrous
lactose

Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation: Fluid Bed Granulation

materials are suspended while granulating fluid is
being sprayed

Compression
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing

Granulation: Fluid Bed Granulation

Advantages:
✓ ↑ flowability and compressibility
✓ suitable for drugs that have poor flow
characteristics
✓ uniformity in content and weight
✓ good color distribution
✓ less dusty
Compression
Coating
QUICK-THINKS
Method of wet granulation wherein a granulating
solution is sprayed onto suspended particles,
which would dry rapidly in the suspending air:
A. Spheronization
B. Fluid Bed Granulation
C. Spray-drying
D. Spray-congealing
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling
Mixing
Granulation

Compression
Principle: compression of tablet formulation within a
steel die cavity by the pressure exerted by the
movement of 2 steel punches
2 Requirements for Materials Used in Tableting:
✓ Flowability
✓ Compressibility
Coating
DOSAGE FORMS TS ao bl ul et ito n s
Parts of the Tableting Machine
contains/holds the powder
Hopper or granules
Feed Shoe/ transfers the materials into
Frame the die
DOSAGE FORMS TS ao bl ul et ito n s
Parts of the Tableting Machine

for guiding the

Cam movement of the
Tracks punches
DOSAGE FORMS TS ao bl ul et ito n s
Parts of the Tableting Machine

for compacting the

materials within the die;
Punch somehow influences the
shape of the tablet
responsible for the size
Die and shape of the tablet
QUICK-THINKS
Which is incorrect?
A. Hopper: holds/stores materials for
compression
B. Feed frame: guides materials into the dies
C. Cams: compacts the material within the
die
D. Dies: controls size and shape of tablet
DOSAGE FORMS TS ao bl ul et ito n s

Problems
Arching/Bridging Rat Holing

an arch-shaped occurs when

obstruction discharge takes
forms above the place only in a
hopper outlet and flow channel
stops flow located above
the outlet
DOSAGE FORMS TS ao bl ul et ito n s
Dispensing
Milling Reasons:
Mixing ✓ protection [to reduce influence of
Granulation moisture]
Compression ✓ improve product identity and
Coating appearance
✓ modify release [ex: enteric coated
Principle: application of tablets]
coating material to a ✓ mask unpleasant taste [ex: sugar-
coated tablets]
moving bed of solids with
concurrent use of heated Types:
air to facilitate evaporation
✓ Sugar coating ✓ Film coating
of solvent
DOSAGE FORMS TS ao bl ul et ito n s
Sugar Coating

• successive coating of Disadvantages:

water-soluble ✓ increase in weight [almost 50%
which ↑ shipping costs]
sucrose-based ✓ time-consuming
solution which quickly ✓ requires expertise
dissolves after Methods:
swallowing ✓ Pan Pouring
✓ Pan Spraying
• Oldest method ✓ Pan Coating: most widely used
DOSAGE FORMS TS ao bl ul et ito n s

Steps in Sugar Coating

5 Polishing
4 Color Coating
3 Smoothing
2 Subcoating
1 Seal Coating/Sealing
DOSAGE FORMS Tablet

1 Seal Coating/Sealing
• aka waterproofing Sealcoating agents:
(10-30% alcoholic solutions of)
• separate tablet core
from water [since a water- ✓ Shellac
soluble coating solution will be ✓ Zein
used] ✓ Cellulose acetate phthalate (CAP)
• strengthen tablet core ✓ Polyvinyl acetate phthalate
(PVAP)
DOSAGE FORMS Tablet

2 Subcoating
• Most critical step (basis • alternate layers of gum and
for elegant tablet profile) dusting powder
• step that adds most • dusting powders are used
increase in weight (50- to prevent “tack”
100%)
Subcoating binders:
• rounds off the tablet
✓ Gelatin
edges
✓ Acacia
DOSAGE FORMS Tablet

3 Smoothing 4 Color Coating

• smoothes out the • Critical step since it gives the
subcoated surface tablet its color
• uses 60-70% syrup • uses 60-70% syrup solution
solution Steps:
✓ Grossing - develops color base
✓ Heavy Syruping - build up solid color
rapidly
✓ Regular Syruping - final color &
elegance
DOSAGE FORMS Tablet

5 Polishing
• produces the characteristic gloss/shine
Agents:
✓ beeswax
✓ carnauba wax
✓ candelila wax
✓ hard paraffin wax
QUICK-THINKS

Step in sugar-coating tablets wherein the

core is separated or protected from water:

A. Sealing
B. Subcoating
C. Syruping
D. Finishing
DOSAGE FORMS TS ao bl ul et ito n s

Film Coating
• deposition of a thin Components:
film of polymer • Film formers
surrounding the tablet • Plasticizers
core • Surfactant
• Alloying Substance
Advantages:
• Glossant
✓ minimal increase in weight (2-3%
only) • Colorant
✓ easier and faster • Volatile Solvent/Vehicle
✓ single coating step
DOSAGE FORMS Film-coated Tablet

Film Formers
- produces smooth, thin films reproducible under
conventional coating conditions
Examples:
✓ cellulose derivative (HPMC, MC)
✓ acrylic copolymers (methacrylate)
✓ polyvinyl alcohol
Plasticizers
Surfactant ✓ PVP
Alloying Substance
Glossant
Colorants
Volatile Solvent/Vehicle
DOSAGE FORMS Film-coated Tablet

Plasticizers
- produces flexibility and elasticity of the coating and thus
provides durability
Examples:
✓ castor oil
✓ glycerin
✓ phthalate esters
Surfactant
Alloying Substance
Glossant
Colorants
Volatile Solvent/Vehicle
DOSAGE FORMS Film-coated Tablet

Surfactant
enhances the spreadability of the film during application

Examples:
✓ polyoxyethylene sorbitan derivatives

Alloying Substance
Glossant
Colorants
Volatile Solvent/Vehicle
DOSAGE FORMS Film-coated Tablet

Alloying Substance
provides water solubility or permeability of the film to
ensure penetration by body fluids and therapeutic
availability of the active ingredient in a film-coated tablet
Examples:
✓ Polyethylene Glycol

Glossant
Colorants
Volatile Solvent/Vehicle
DOSAGE FORMS Film-coated Tablet

Glossant Vehicle
To provide luster to the To allow the spread of the
tablets without a separate other components over the
polishing operation tablets while allowing rapid
evaporation
Examples: Examples:
✓ Beeswax ✓ Alcohol mixed with
acetone

Colorants
QUICK-THINKS
In non-aqueous film-coating, an alloying
substance:
A. Produces flexibility and elasticity to
the coat
B. Provides water solubility or
permeability
C. Enhances spreadability of the coat
D. AOTA
DOSAGE FORMS TS ao bl ul et ito n s

TABLET DEFECTS
Tableting Process Excipient Machine Combined Factors

Capping Chipping Double Mottling

Lamination Impression
Sticking
Cracking Picking
DOSAGE FORMS TS ao bl ul et ito Dn se f e c t s

Due to Tableting Process

removal of top and bottom (due to air
Capping entrapment in the granular material)
separation to 1 or more layers (due to air
Lamination entrapment in the granular material)
due to rapid expansion of tablets when deep
Cracking concave punches are used
DOSAGE FORMS TS ao bl ul et ito Dn se f e c t s

Due to Equipment

removal of small portion

Chipping (due to very dry granules)
material in die (due to excess
Sticking binder / wet granules
Picking material in punch
DOSAGE FORMS TS ao bl ul et ito Dn se f e c t s

Due to Machine
Double due to free rotation of the punches which have
Impression some engraving on the punch faces

Due to Combined Factors

uneven color; may be due to:
✓ colored drug which has different color than the
rest of the granular material;
Mottling ✓ improper mixing of granular material
✓ degradation of one or more material/s
✓ dirt in the granules or on punch faces
QUICK-THINKS
Tablet processing problem in which there is
complete or partial separation of the top or
bottom of the tablet from the main body
A. Capping
B. Lamination
C. Chipping
D. All
E. None
QUICK-THINKS
Tablet processing problem in which there is
unequal color distribution on surface
A. Picking
B. Sticking
C. Mottling
D. Weight variation
E. Hardness variation
DOSAGE FORMS TS ao bl ul et ito n s

COATING DEFECTS
Sweating Bridging
Wrinkling
Flaking Blistering
Bloom
Mottling Orange Peel
DOSAGE FORMS S o lautti inogn sD e f e c t s
C
uneven color distribution (due to migration of
Mottling soluble dye if aqueous coating was used)
oily film or droplets of liquid (due to
Sweating incompatibilities in the ingredients)
monogrammed/bisected tablets (results to
Bridging markings may be obscured)
Bloom dull film (due to humid conditions)

Flaking Due to rapid drying

reduced adhesion of film from the core (due to
Blistering rapid drying which is too fast for film to
accommodate)
DOSAGE FORMS S o lautti inogn sD e f e c t s
C

due to rapid drying or film former

Wrinkling defect
rough, non-glossy film surface (due to
Orange
inadequate spreading of coating
Peel solution before drying
QUICK-THINKS
Definition of picking:
A. Separation into 2 or more distinct
horizontal layers
B. Adherence to the face of the punch
C. Partial or complete separation of the top or
bottom part of the tablet from the main
body.
D. Breaking of the tablet edges.
DOSAGE FORMS TS ao bl ul et ito n s

TABLET DEFECTS
 MANUFACTURE OF DOSAGE FORMS
• Solution • Capsules
• Suspension • Ointments • Parenterals
• Emulsion • Suppositories • Cosmetics
• Tablets
CAPSULES
QUICK-THINKS

Largest capsule size

A. 1
B. 0
C. 000
D. 5
DOSAGE FORMS S oa lpustui loenss
C
Dispensing
Milling 2. Ready availability of
Mixing contained drug: since
Granulation
Compression minimal excipient and
Encapsulation little pressure are
required to compact the
Advantage vs Tablet:
material
1. Elegance: provide a
smooth, slippery, Types:
easily swallowed
✓ Hard Gelatin Capsule
and tasteless shell
✓ Soft Gelatin Capsule
for drugs
DOSAGE FORMS S oa lpustui loenss
C

Hard Gelatin Capsule

✓ aka hard shell capsule, starch capsule, Vegetel or
HPMC
✓ made from a mixture of gelatin, sugar, water, and
0.15% sulfur dioxide (+ colorants / opacifying
agents)
✓ Not used for highly efflorescent (cause the capsule
to soften) or deliquescent (dry the capsule shell to
excessive brittleness)
DOSAGE FORMS S oa lpustui loenss
C

Hard Gelatin Capsule

✓ Moisture Content: 13-16% (below 10% it may
become brittle while above 16% it will become soft
and may deform)
✓ stored at 21-25°C and 30-35% RH

✓ shells are manufactured in a separate operation

from filling
✓ composed of a body and a cap
DOSAGE FORMS Capsules
Dispensing
Milling
Mixing Hard Gelatin Capsule
Granulation
Compression 1. Supply
Encapsulation 2. Rectification
3. Separation
4. Filling
5. Joining
6. Finishing
(Dusting/Polishing)
DOSAGE FORMS Hard Gelatin Capsules
Dispensing
Milling
Mixing
Granulation
Compression

Encapsulation
Additional/Special Techniques:
1. Banding
2. Imprinting - best
performed on empty
capsules
3. Coating - to modify
solubility characteristics
(shellac, cellulose
acetate phthalate, salol)
DOSAGE FORMS S oa lpustui loenss
C

Soft Gelatin Capsule

✓ formed, filled and sealed in a single operation

✓ filled with pumpable solutions or

suspensions of drugs in liquids which will
not solubilize the shell; also pasty materials
and dry powders
DOSAGE FORMS S oa lpustui loenss
C

Soft Gelatin Capsule

✓ liquids that are both water-miscible and volatile
cannot be included as major constituents of the
capsule (since they can migrate into the gelatin
shell and volatilize from its surface)

✓ shells are prepared from gelatin, water and a

plasticizer such as glycerin or a polyhydric alcohol
(such as sorbitol) to render them elastic
DOSAGE FORMS Soft Gelatin Capsules
Dispensing
Milling
Mixing Method of Manufacture:
Granulation
Compression 1. Plate Process
✓ oldest commercial method of manufacture
✓ not anymore used today
✓ a warm sheet of gelatin is placed on the bottom
plate of the mold and the liquid-containing
medication is evenly poured on it. A second sheet of
gelatin is placed on top of the medication and the
top of the mold is put into place

Encapsulation
DOSAGE FORMS Soft Gelatin Capsules
Dispensing
Milling
Mixing Method of Manufacture:
Granulation
Compression 2. Rotary Process
✓ liquid gelatin capsules are prepared by this method
✓ liquid gelatin flow from an overhead tank and
formed into two continuous ribbons by the machine
and brought together between rotating dies.
Metered fill material is injected between the ribbons
precisely at the moment that the dies form pockets
of the gelatin ribbon

Encapsulation
 MANUFACTURE OF DOSAGE FORMS
• Solution • Capsules
• Suspension • Ointments • Parenterals
• Emulsion • Suppositories • Cosmetics
• Tablets
OINTMENT
DOSAGE FORMS Ointments

Ointments
External application to skin or
mucus membranes
Ointment Bases:
1Oleaginous/ 3Water-

Hydrocarbon removable
2Absorption 4Water-soluble
DOSAGE FORMS Ointments

Ointment Bases:
Oleaginous/ ✓ Petrolatum
greasy, difficult to ✓ Yellow Ointment
Hydrocarbon remove, most stable ✓ Mineral Oil (Liquid
Bases Petrolatum)
either anhydrous or ✓ Hydrophilic
hydrous bases Petrolatum
Absorption
capable of absorbing ✓ Anhydrous Lanolin
Bases water; ✓ Cold Cream (Cetyl
W/O Emulsions esters wax)
DOSAGE FORMS Ointments

Ointment Bases:
✓ O/W emulsion
Water- ✓ Allows absorption
✓ Hydrophilic
Removable of serous Ointment
Bases discharges
✓ Most common

Water-Soluble Completely water ✓ PEGs (Polyethylene

Bases washable Glycol)
DOSAGE FORMS Ointments

Methods of Manufacture
1.Incorporation 2. Fusion
✓ mixing/levigating until ✓ involves melting of
uniform some components,
✓ Equipment: Ointment mixing, then cooled
Roller Mills with constant stirring
until congealed; for
Preservation: presence of
anhydrous ointments
Staphylococcus aureus and
Pseudomonas aeruginosa need to ✓ Equipment: Large
be controlled in topical products steam-jacketed kettles
QUICK-THINKS
Which of the following could be used as
humectants?
A. Bentonite
B. SLS
C. Glycerine
D. EDTA
E. Petrolatum
QUICK-THINKS

Common levigating agent

A. Glycerin
B. Mineral Oil
C. Alcohol
D. Water
SUPPOSITORIES
DOSAGE FORMS Suppositories

Methods of Manufacture
1. Rolling or Hand Shaping 3. Pour Molding
✓ No longer used ✓ Most commonly used method on
both small and large scale
2. Compression Molding
✓ Base is melted on a steam bath
✓ Disadvantage: unavoidable and then active ingredients are
air entrapment (difficult to emulsified or suspended in it
control weight and may ✓ Mass is poured into cooled
lead to oxidation of base chrome- or nickel-plated molds
and API)
4. Compression on Regular Tablet
Press
DOSAGE FORMS Suppositories

Packaging
✓ Some suppositories are
✓ Usually overwrapped in not individually wrapped
foils, paper, or plastic but are placed into
cardboard boxes or plastic
containers that have been
✓ Must not touch each
molded to provide
other (since they can compartments
fuse together when
there is change in ✓ If appropriate, a
ambient temperature) “Refrigerate” label should
appear on the container
 MANUFACTURE OF DOSAGE FORMS
• Solution • Capsules
• Suspension • Ointments • Parenterals
• Emulsion • Suppositories • Cosmetics
• Tablets
STERILE DOSAGE FORM
DOSAGE FORMS Sterile Preparations

Parenterals
✓ injectable routes of Pyrogens:
administration (IV/SC/IM) • Sources:
Injections: sterile, pyrogen-free ✓ water, containers, equipment,
(fever-producing substances) solutes (processed with water
that is not depyrogenated)
✓ Ophthalmic and irrigation ✓ endotoxin - most potent
solutions also need to be pyrogenic substance
sterile produced by gram (-) bacteria

Destruction of Pyrogens:
✓ 180°C for 4 hrs ✓ 250°C for 45 min ✓ 650°C for 1 min
DOSAGE FORMS Sterile Preparations

GENERAL FORMULA
Formulation: may be solution, emulsions, or
suspensions
✓ Emulsion: Propofol
✓ Suspension: Insulin Zinc
Components:
• Active/s • Tonicity adjusters - reduce
• Solvent/vehicle the pain of injection in
• Antimicrobials areas with nerve endings
• Preservatives • Buffers - to maintain the
required pH; change in pH
affects stability
DOSAGE FORMS Sterile Preparations

Solvent
Aqueous Solvent
Water for Pharmaceutical Purposes, USP

Bulk Waters Sterile Waters

✓ Purified Water ✓ Sterile Water for
✓ Water for Injection Injection (SWFI)
(WFI) ✓ Bacteriostatic
Water for Injection
DOSAGE FORMS Sterile Preparations

Solvent: Sterile Water for Injection, USP

• Water for Injection, packaged and rendered
sterile
• Packaged in single-dose containers, not larger
than 1 L in size (single use only)
Use: For extemporaneous prescription
compounding and as a sterile diluent for
parenteral products
DOSAGE FORMS Sterile Preparations

Solvent: Bacteriostatic Water for Injection, USP

• Sterile Water for Injection to which has been added one
or more suitable antimicrobial preservatives.
• Packaged in single-dose or multiple-dose containers
not larger than 30 mL.
Use: Used as a diluent in the preparation of parenteral
product, typically multi-dose products.
Examples: ✓ NaCl Injection, USP
✓ Ringer’s and Lactated Ringer’s Solution USP: NaCl, KCl,
CaCl2, Sodium Lactate (buffering Agent)
QUICK-THINKS
Water purified by distillation, or a purification process
that is equivalent or superior to distillation in the
removal of chemicals or microorganisms, for use in the
preparation of parenteral solutions:
A. Purified Water
B. Sterile Purified Water
C. Water for Injection
D. Bacteriostatic Water for Injection
QUICK-THINKS
Preservatives that are effective over a wide pH
range with broad spectrum antimicrobial activity,
with notable antifungal properties:
A. Benzoic acid
B. Parabens
C. Alcohol
D. PEG
QUICK-THINKS
The following conditions reduce the
preservative efficacy of parabens, except:

A. Presence of non-ionic surfactants

B. Alkaline solutions
C. Addition of Propylene Glycol
D. A&B
DOSAGE FORMS Sterile Preparations

Solvent
Oleaginous Solvent
Fixed Vegetable Oils (SeCoCoPea)
✓ Sesame Oil
✓ Corn Oil
✓ Cottonseed Oil
✓ Peanut Oil
QUICK-THINKS
What is the usual maximum volume allowed as a
parenteral package for Bacteriostatic Water for
Injection?
A. 10 mL
B. 20 mL
C. 30 mL
D. 50 mL
DOSAGE FORMS Sterile Preparations

Classification: Based on Sterilization

✓ process-tolerant
Terminally sterilized ✓ sterilization after sealed in final container
✓ method of choice where possible
Sterilized by ✓ considered only if all methods of terminal
Filtration sterilization are inappropriate
✓ sterile components are used; techniques and
Aseptic Processing equipment are critical; most critical

*Aseptic: free from disease-causing microorganisms

DOSAGE FORMS Sterile Preparations

Sterile Production Areas

Air Lock or Anteroom ✓ Separates sterile areas from non-sterile areas
✓ cleaning and assembly of equipment
Material Support
✓ Class 100,000 environment ( NMT 100,000
Area particles of > 0.5 μm per cubic foot of air)
✓ surfaces of the floor should be continuous
Compounding Area ✓ Class 100 environment
✓ Class 100 environment
Aseptic Filling Area ✓ Equipment: Laminar Flow Hood with HEPA
Filter (99.97% efficiency)
*Quarantine Area and Finishing Area
QUICK-THINKS
An enclosed space with 2 or more doors,
interposed between 2 or more rooms, for purpose
of controlling airflow between those rooms.
A. Airlock
B. Anteroom
C. Clean Area
D. Quarantine Area
QUICK-THINKS

An area with defined environmental control

of particle and microbial contamination

A. Airlock
B. Anteroom
C. Clean Area
D. Quarantine Area
DOSAGE FORMS Aseptic Filling Area

High Efficiency Particulate Air (HEPA) Filter:

at least 99.97% efficient in
removing particles of 0.3 μm
size and larger and composed of
glass fibers and fillers or
electrostatic precipitators
Parts of HEPA Filter:
QC Tests for HEPA Filter:
• Blower
• Dioctylphthalate
• Pre-filter
(DOP) Test
• Electrostatic
• HC Emery 3004
precipitator
QUICK-THINKS
Measures the air flow rate of HEPA-
filtered air:
A. Air Velometer
B. Air Flow Meter
C. HEPA Flow Meter
D. HEPA Stream Calculator
DOSAGE FORMS Aseptic Filling Area

Laminar Air Flow

May be:
used to achieve clean ✓ Vertical flow: risk of introducing contaminants
is low
room; entire body of air
within a confined area ✓ Horizontal flow: protect processing lines and
moves with in one used most frequently for workbenches;
appears to superior to vertical-flow because
direction with uniform the air movement is less likely to wash
velocity along parallel organisms from the operators hands or
flow lines. equipment into the sterility test media
Disadvantage: any airborne particulate
matter is blown directly into the room and
against the working personnel
DOSAGE FORMS Sterile Preparations

Aseptic Filling Area

DOSAGE FORMS Sterile Production Area

ISO Classification of Particulate Matter in Room Air

Class Name Particle Count
ISO Class US FS 209E ISO, m3 FS 209E, ft3
3 Class 1 35.2 1
4 Class 10 352 10
5 Class 100 3520 100
6 Class 1000 35200 1000
7 Class 10,000 352000 10,000
8 Class 100,000 3520000 100,000
QUICK-THINKS
What cleanroom class is specified for the
production of parenteral pharmaceutical
products?
A. Class 1
B. Class 10
C. Class 100
D. Class 1000
DOSAGE FORMS SC toaelpursitulieloenPssr o d u c t i o n A r e a
Cleaning

Compounding
1. Spray Drying: 2. Freeze Drying/Lyophilization:
produces finely divided involves the removal
particles by spraying a of water content of an
mist of liquid through a
aqueous preparation
heated chamber, drying
immediately and
collecting the dried
Filtration powders in a clean
Filling receptacle
Sealing
DOSAGE FORMS SC toaelpursitulieloenPssr o d u c t i o n A r e a
Cleaning
Compounding

Filtration
1. Clarification Method: removal of 2-3
micrometer size

2. Cold Filtration Method: removal of 0.2 to 0.3

micrometer (bacterial
filtration)
Filling
Sealing
DOSAGE FORMS SC toaelpursitulieloenPssr o d u c t i o n A r e a
Cleaning
Compounding
Filtration
Sealing Methods:
Filling 1. Tip Sealing / Bead
Sealing - melt top of
Nitrogen gas is used in ampule
filling ampules (inert) 2. Pull Sealing - melt top of
ampule and pull to seal
Sealing Test for leak –
Leaker’s test
(Methylene blue)
DOSAGE FORMS Sterile Preparations

Methods of Sterilization
Method Description MOA
✓ the most dependable and widely used
method for sterilization (also
characterized as most effective and protein
Steam efficient) coagulation
✓ USP Definition: autoclave [121°C, 15psi,
15-20mins]
✓ For materials which cannot withstand
steam sterilization (e.g., petroleum jelly,
Dry Heat mineral oils, greases)
Oxidation
✓ Use of Oven
DOSAGE FORMS Sterile Preparations

Methods of Sterilization
Method Description MOA
Ionizing ✓ employs the technology of gamma rays
Mutation
Radiation and cathode rays
✓ use of ethylene oxide; for materials that
Gas are heat labile
Alkylation

✓ physical removal of microorganisms

Filtration using a membrane filter
DOSAGE FORMS Sterile Preparations

Species of Bacteria used as Biological Indicators

QUICK-THINKS

Gas sterilization uses

A. Oxygen
B. Ethylene azide
C. Propylene oxide
D. Ethylene oxide
 PACKAGING, LABELING AND STORAGE
OF DRUG PRODUCTS
• Packaging
• Type of Containers
• Safety Packaging
• Labeling
• Storage Conditions
PACKAGING,LABELING, AND
STORAGE Packaging of Drug Products

OBJECTIVE
Provide an economic way of
PROTECTING, PREPARING,
IDENTIFYING, and CONTAINING
drug product
PACKAGING,LABELING, AND
STORAGE Packaging of Drug Products

COMPONENTS
Container Closure
Holds the drug product

Primary
Secondary
Critical
Secondary
PACKAGING,LABELING, AND
STORAGE Packaging of Drug Products

Primary • Immediate container

Secondary • Has direct contact with the product
• Has direct effect on the stability of the product
Critical • May provide means of administration e.g. MDI
Secondary and aerosols
PACKAGING,LABELING, AND
STORAGE Packaging of Drug Products

Primary • Encloses 1 or more primary container

Secondary • Not always present
• Usually designed for additional protection against
Critical damage and market presentation
Secondary • Often used simply to carry labeling requirements
PACKAGING,LABELING, AND
STORAGE Packaging of Drug Products

Primary • Not in direct contact with the product but

Secondary provides essential product stability production
• Ex: primary container packed in a pouch to
Critical provide moisture, gas, light, or microbial
Secondary protection
PACKAGING,LABELING, AND
STORAGE Types of Packaging

TYPES OF PACKAGING
Protection Ability Quantity Held Material
Well closed Single unit Glass

Tight Multiple unit Plastic

Hermetic Foils and films and

laminates

Rubber

Metallic
PACKAGING,LABELING, AND
STORAGE Types of Packaging

PROTECTIVE ABILITY
Protects the contents from extraneous solids and from loss
Well Closed of article under ordinary conditions of handling, shipment,
storage, and distribution

Protects the contents from extraneous solids, liquids, or

Tight vapor, and from loss of article and from deliquescence,
efflorescence, or evaporation

Impervious to air or any other gas; generally used to hold

Hermetic preparations intended for parenteral administration
PACKAGING,LABELING, AND
STORAGE Types of Packaging

Efflorescent
Gives off water of crystallization

Deliquescent
Absorbs moisture then liquefies

Hygroscopic
Absorbs moisture but does not liquefy
PACKAGING,LABELING, AND
STORAGE Types of Packaging

QUANTITY HELD

•single dose only

•usually for parenteral administration
•has no antimicrobial agent
Single Unit •cannot be resealed once opened
•USP limit: 1,000 mL
•Water: WFI or SWFI
•Examples: ampules, pre-filled syringes and cartridges
•multiple dose
•USP limit: 30 mL
Multiple Unit •Water: Bacteriostatic WFI, USP
•Example: vials
PACKAGING,LABELING, AND
STORAGE Types of Packaging
KIND OF MATERIAL
Glass •most widely used
•major component: SiO2
Plastic •Advantages:
•strong and rigid
Foils and films and •adequate moisture protection
laminates •economical
•Disadvantages:
Rubber •fragility
•leaching - movement of components of the
Metallic container into the contents
•sorption - binding of the components to the
container
QUICK-THINKS
Which of the following refers to: penetration
into the particle leading to entry into the
system?
A. Adsorption
B. Absorption
C. Sorption
D. AOTA
PACKAGING,LABELING, AND
STORAGE Types of Packaging
TYPES OF GLASS CONTAINER
Type I Type II Type III Type IV
Highly-resistant Highly-resistant
Treated Soda Lime Highly-resistant
Soda Lime/Alkali Highly-resistant
Non-parenteral/General
borosilicate borosilicate borosilicate Purpose Soda Lime
borosilicate

• for buffered and • for buffered • for dry powders or • for oral solid and
non-buffered aqueous oily solutions liquid dosage forms
aqueous solutions of pH < • most widely used and external
solutions 7, dry powders outside parenterals preparations
• with boric oxide and oily solutions and pharma [capsules, tablets
• highly heat and • not resistant to high and topical products]
• surface is treated
chemical- temp and sudden • least resistant to
with Freon or SO2
resistant (except thermal changes leaching, chemical
producing attack and heat
for HF) • cannot be
dealkalized shock
• low coefficient of autoclaved
expansion surface
• preferred glass
type for lab use
PACKAGING,LABELING, AND
STORAGE Types of Packaging
KIND OF MATERIAL
Glass •Disadvantages:
• permeability to atmospheric oxygen and
Plastic to water vapor
• volatile oils/flavors can leave/enter the
Foils and films and
plastic
laminates
• transmission of light through the
Rubber container
• leaching of polymer additives [health
Metallic hazard]
•Types:
•Thermosqueeze - soft or squeezable
•Thermoset - firm or rigid
PACKAGING,LABELING, AND
STORAGE Types of Packaging

POLYMERS FOR PLASTIC

Polyethylene Polyethylene Polyvinyl Chloride
Polypropylene (PP)
(PE) Terephthalate (PET) (PVC)

HDPE high temp resistance for beverages least resistant

hard thermosets such as to permeation
for solid dosage for autoclavable mineral water for plastics
forms plastics bottles
used in blister
LDPE packs
flexible, durable
for sprays,
medicine droppers,
parenterals
PACKAGING,LABELING, AND
STORAGE Types of Packaging
KIND OF MATERIAL
Glass
• decoration, flexibility, heat sealability & see-
Plastic through property
• use: strip & blister packs, sachets & liners for
Foils and films and
large container
laminates

• Blister Packs - individually sealed dosage units

Rubber
which allow the consumer to see the contents
without opening the pack
Metallic
PACKAGING,LABELING, AND
STORAGE Types of Packaging
KIND OF MATERIAL
Glass

Plastic
• Basic unit: isoprene/neoprene
Foils and films and • Examples: closures for vials, IV fluids,
laminates bulbs for ophthalmic pipets and plugs for
disposable syringes
Rubber

Metallic
PACKAGING,LABELING, AND
STORAGE Types of Packaging
KIND OF MATERIAL
Glass

Plastic
Foils and films and
laminates Use: collapsible ointment
tubes
Rubber

Metallic
PACKAGING,LABELING, AND
STORAGE Safety Packaging
CHILD RESISTANT CONTAINER
• container that is significantly difficult for children
under 5 y/o to open within a reasonable amount of
time and that is not difficult for normal adults to use
properly
• Principle: a less than 5-year-old child cannot
coordinate two movements at the same time
• Reason: to reduce accidental poisonings in children
• Basic Designs: align the arrows, press down and
turn, squeeze and turn, and latch top
• Problem: elderly and those with arthritis have
difficulty opening
PACKAGING,LABELING, AND
STORAGE Safety Packaging

TAMPER-RESISTANT CONTAINER
•Principle: to determine if the drug product packaging has
been opened or tampered (must be torn or broken to
reach product)
•Reason: to reduce likelihood of malicious adulteration of
the product
•Examples:
•Tape Seal - paper/foil sealed over a carton flap or
bottle cap
•Bottle Seal - paper/foil sealed to mouth of container
under cap
•Shrink Seal - band/wrapper shrunk by heat or drying
to conform to cap
•Aerosol Container - tamper-resistant by design
PACKAGING,LABELING, AND
STORAGE Labeling

LABELING REQUIREMENTS
1. Name of product (generic name or nonproprietary name and
the proprietary name or brand name if one is used)
2. Dosage form and strength
3. Pharmacologic Category
4. Rx symbol in case of prescription drugs
5. Name and complete address of manufacturer, packer or
distributor of the product
6. Net content (1-6 in principal display panel)
7. Formulation
8. Indication(s)
9. Contraindication(s), precaution(s), warning(s)
10. Directions for use
11. Batch/Lot Number
12. Expiration date and date of manufacture
13. Registration number
14. Storage Conditions
QUICK-THINKS
The only tamper-resistant packaging by
design:
A. Ointment tubes
B. Flint bottles
C. Aerosols
D. Inhaler
PACKAGING,LABELING, AND
STORAGE Storage Conditions

STORAGE CONDITIONS
Cold temperature not greater than 8°C
Freezer -20 to -10°C
Refrigerator 2-8°C
Cool 8-15°C
Room Temp. temperature prevailing in the work area
Controlled Room Temp. 20-25°C

Warm 30-40°C

Excessive Heat >40°C

FIN
Thank you for your attention. :)