OUTLINE

I. INTRODUCTION
II. SOLUTIONS II. LIQUID PREPARATION
a. Choice of Coloring Agent
b. Choice of Flavoring Agent
c. Choice of Preservatives • Research and development protocols concerning
d. Choice of Sweetening Agents liquid compounding
e. Choice of Viscosity-building Agents
• Scale-up of bulk product compounding
f. Equipment
g. Classes of Filter Media • Physical plant control and maintenance
h. Considerations in Filling of Liquids • Equipment maintenance and renovation
III. DISPERSED SYSTEM • Continuous training of personnel and personnel
a. Suspensions compensation plans
i. Flocculated System
• Supervision of system reports
ii. Deflocculated System
b. Emulsion
i. Equipment used on Preparation of III. FILLING AND PACKING
Emulsions
ii. Emulsion stability methods of Evaluation

• Research and development protocols concerning

filling and packing
• Scale-up of the finished drug filling and packing
• Physical plant control and maintenance
INTRODUCTION
IV. SALES OF DRUG PRODUCT

• Research and development protocols concerning

product storage
• Distribution process
• Continuous training of personnel and personnel
compensation plans
• Supervision of system reports

V. VENDOR HANDLING

I. PLANNING OF MATERIAL REQUIREMENTS

• Research and development protocols concerning
precautions to maintain product stability
• Research and development protocols • Control of vendor stocks
• Acquisition and analysis of raw materials • Sales system reports
• Physical plant design, building and installation
• Equipment selection and acquisition
VI. CUSTOMER SERVICE
• Personnel selection and initial training
• Monitoring information systems
• Protocols • Research and development protocols concerning
• Patterns developed by repeating procedures and home storage and handling to maintain product
fixing the identified problems each time the stability
procedure is followed • Relationship with health insurance companies and
• They are dynamic entities that originally can be health professionals
developed in the laboratory level but must be • Educational materials for patient counseling
adjusted in every new step of the scale-up process • Customer service system reports

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 PHARMACEUTICAL MANUFACTURING AND QUALITY ASSURANCE LABORATORY

M 2 LESSON 1: SOLUTIONS • Calcium EDTA — a chelating agent that may

exhibit microbial growth, as calcium is required for
bacterial growth
The formulation of solutions presents many technical
problems to the industrial pharmacist. Some drugs are
inherently unstable. Special techniques are required for HYDROTROPHY
poorly soluble drugs. The final preparation must satisfy
the requirements of pharmaceutical elegance (the
harmony of taste, color, odor and viscosity). • Increase in the solubility of a substance, through
the addition of additives, consisting of fairly high
concentrations of alkali metal salts of various
• Poor Pharmaceutical Elegance in Liquids imply organic acid
patient non-compliance and decreased product • Uses non-micelle forming substances, capable of
acceptance dissolving insoluble compounds
• Quality Pharmaceutical Elegance increases • Use of hydrotropes like sodium benzoate, sodium
patient compliance and product acceptance citrate, urea, niacinamide, etc. and have many
advantages like, it does not require chemical
SPECIAL TECHNIQUES TO AID SOLUBILITY modification of hydrophobic drugs, use of organic
OF POORLY-SOLUBLE DRUGS solvents, or preparation of emulsion system, etc.
CO-SOLVENCY
CHEMICAL MODIFICATION OF THE DRUG
• Solubility is increased by using a water-miscible
solvent, in which the drug has good solubility • Conversion of poorly water-soluble drugs to its
• Co-solvents used may be ethanol, propylene glycol, water-soluble derivatives
sorbitoI and glycerin • The most commonly employed technique for the
pure form of drugs converted to their
corresponding water-soluble salt or ester forms
PH CONTROL
• This approach is successful in some drugs, but in
some biological activities, toxicity should be
• A large number of modern pharmaceutical agents considered
are either weak acid or weak bases
• Its solubility can be markedly influenced by _____________________________________________
modifying/adjusting its pH
• A number of buffer systems can be used to achieve
this technique • Requirement of PHARMACEUTICAL
• Functions of buffer ELEGANCE (the harmony of taste, color, odor
• Contributing toward overall isotonicity and viscosity)
• Preferential hydration of proteins and peptides • Modern pharmaceutical preparations present
the API’s (which are unpalatable and
• Serving as bulking agents in lyophilized formulation
unattractive to the patient), as colorful and
flavorful formulations attractive and appealing
SOLUBILIZATION to the senses of sight, smell and taste.
Pharmaceutical elegance implies product
acceptance to the patient.
• involves the addition/use of solubilizing agents
(usually in solid form, the salt form of the active/s),
to increase the water-solubility of the drug in water CHOICE OF COLORING AGENT
• It is also achieved through the addition of surface
active agents (ex. Polyoxyethylen (20) sorbitan
monolaurate) to form colloidal aggregates known
as micelles
• The solutes are adsorbed onto or dissolves into the
micelles

COMPLEXATION

• Organic compounds in solution generally tend to

associate with each other (to some extent)
• An amount of specific complexing agent is added to
form a soluble complex compound
• Complexing agents
• EDTA and citric acid

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CHOICE OF FLAVORING AGENTS CHOICE OF VISCOSITY-BUILDING AGENTS

• The choice of flavoring should be based on the • Sometimes desired to serve as:
natural “taste sensation” of the drug • Adjunct to palatability
• Natural taste sensation of drug and the • To improve drainage (pourability)
recommended flavoring agent • Examples of viscosity-controlling agents (Use with
CAUTION. Highly viscous systems resist
CHOICE OF PRESERVATIVES
PRESERVATIVES

• Substances which prevent bacterial and fungal

growth in liquid formulations
• Bacteria and fungi affect product stability and poses
as a health hazard to the patient
dissolution by the GIT fluid that may impede drug
• Characteristics of an ideal preservative
release and absorption)
o Effective against a broad-spectrum range of
o PVP
microbes
o Methyl cellulose
o Physically, chemically and microbiologically
o Carboxymethyl cellulose (CMC)
stable until the expiry date of the product is
reached
o Non-toxic EQUIPMENT
o Non-sensitizing
o Adequately soluble
o Compatible/acceptable to the taste and • Fully sanitizable stainless steel 314 or better quality
odor/color of the product is recommended.
• Equipment must be cleaned or sterilized;
appropriate disinfectants include dilute solutions of
• The USP presents standard protocols for assessing hydrogen peroxide, phenol derivatives, and
the relative efficacy of a preservative in a peracetic acid. Equipment lines can be sterilized by
formulation using the ANTIMICROBIAL using alcohol, boiling water, autoclaving, steam, or
EFFECTIVENESS TEST (AET). dry heat. Where lids are used, be cautious of the
• Briefly, by comparing the relative kill efficiency of condensate, which may be a source of microbial
the formulation containing varying concentrations of contamination.
the preservative, the formulator can determine the • Operators must conform to all sanitary presentation
minimal concentration required for preservative requirements, including head covering, gloves, and
efficacy and design the formulation accordingly. face masks. Use of portable laminar flow hoods to
expose ingredients before addition is often
desirable.

MIXING TANKS WITH AGITATORS

• Must be constructed of stainless steel

• Jacketed mechanism to allow for the heating and
cooling of the contents
• Completely covered, equipped with “see-through”
charging ports and illumination for easy observation
CHOICE OF SWEETENING AGENTS of the contents
SWEETENING AGENTS
MISCIBLE LIQUIDS ARE MOST COMMONLY
• Sucrose (refined white sugar) MIXED BY IMPELLERS ROTATING IN TANKS.
• Liquid glucose
• Synthetic/artificial sweeteners
• Examples: These impellers are classified as:
o Saccharin sodium
o Acesulfame potassium • Paddles
o Stevia powder • Propellers
o Xylitol
• Turbines
o Malitol
o Sucralose
o Monoammonium glyzirrhizinate
o Aspartame
o Sucralose

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 PHARMACEUTICAL MANUFACTURING AND QUALITY ASSURANCE LABORATORY

MEASURING AND WEIGHING DEVICES • Accomplished by pumping the liquid, at constant

pressure, through the orifice of constant diameter
and size, for a predetermined period of time
• Used for small and large amounts of liquid and
solid ingredients such as:
o Top loading balances ORAL LIQUID SYRUP FILLING LINE ,ORAL
o Pipettes LIQUID PRODUCTION LINE
o Graduated cylinders CONSTANT LEVEL METHOD

CLASSES OF FILTER MEDIA • Makes use of container height as the means of

FILTRATION SYSTEM (FOR FINAL POLISHING controlling the fill amount of each bottle
OF THE LIQUID PRODUCT) • The fill amount varies by adjusting the height to
which the container is filled
• Any dimensional variations in the container which
o It is a unit operation in which mixtures of liquids results to comparable variations in the net fill per
and solids, slurry or feed is forced through a unit
porous medium, in which solids form a cake on
the surface and the clear liquid is obtained
o The usual objective of filtration or clarification is EVALUATION OF PHYSICAL STABILITY OF
to produce a sparkling liquid free from turbidity, FINISHED LIQUID PRODUCTS
precipitates, colloidal hazes or insoluble liquid
droplets
• It is shown by the maintenance of the physical
properties (color, clarity, taste, viscosity, and odor)
throughout its shelf life until the expiry date is
reached
• Includes:
o Package and the label
o Effect of the package into the contents and/or
contents into the package

• Bottle caps and closures undergo:

o Stress cracking tests
o Corrosion tests
• Cap liners
o Undergo compatibility tests
• Adequate seal
o Evaluated by torque testing
• Torque tester
o An instrument designed to check the circular
force required to open and close the closures
▪ It checks the tightness of caps and
CONSIDERATIONS IN FILLING OF LIQUIDS
closures
▪ Sample size for testing – 10 bottles
• Characteristics of the liquid (viscosity, surface ▪ Unit of force: Inch per pound
tension, foam-producing properties compatibility
with the filling machine).
M 2 LESSON 2: DISPERSED SYSTEMS
• Type of package used
DISPERSED SYSTEM
• Required production output

BASIC FILLING METHODS • Dispersed systems consist of at least two phases:

GRAVIMETRIC METHOD the substance that is dispersed known as the
dispersed (or) internal phase, and a continuous (or)
external phase.
• Limited to very large containers and/or highly • It will be based on the classification as coarse or
viscous liquid products colloidal dispersion, depending on the size of
• When large quantities of liquid materials are particles.
handled, it is more convenient and accurate to
adapt the gravimetric method of filling SUSPENSIONS
• For this reason, all liquid components of the cited
PHARMACEUTICAL SUSPENSIONS
formula are expressed in units of both volume
and weight
• These dosage forms are heterogeneous / disperse
VOLUMETRIC METHOD systems consisting of 2 phases:

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• CONTINUOUS PHASE – also called external phase • Using Spray Dryer

or dispersion system. • Produces finely divided particles by spraying a mist
• DISCONTINUOUS PHASE – also called of liquid thru a heated chamber, drying immediately
internal phase or dispersed system. and collecting the dried powders in a clean
• ALMOST ALL SUSPENSIONS SEPARATE UPON receptacle.
STANDING.
CRYSTALLIZATION / PRECIPITATION METHOD
The main concerns of the formulator are:

• A supersaturated solution is formed and quickly

• Decrease the rate of sedimentation / settling. cooled with rapid stirring.
• Permit easy re-suspendability of any settled • This causes the formation of nuclei, so that the
particulate matter (suspensoids) crystals will not grow too large.

IDEAL SUSPENSION HOMOGENIZATION METHOD

• A satisfactory suspension must remain sufficiently • It is accomplished by using a HOMOGENIZER or

homogenous, for at least the time needed to remove COLLOID MILL to produce particle size of less than
and administer the required dose, after shaking the 1 micron.
container.

EMULSION
TYPES OF SUSPENSION SYSTEMS
FLOCCULATED SYSTEM
• A HETEROGENOUS SYSTEM OF 2 IMMISCIBLE
LIQUIDS.
• Also called Coagulated System and Colloidally • Generally, one of the liquids is a type of oil or lipid
Unstable System. (HIGH GRADE MINERAL OIL) or a variety of animal
• Particles appear like tufts of wool, with loose fibrous or vegetable oil and the other liquid is water
structure. • It may be an O/W type or W/O type.

DEFLOCCULATED SYSTEM THE MAJOR FACTORS IN THE PREPARATION

OF EMULSION ARE:
• Also called Peptized System or Colloidally
Stable System. DEGREE OF SHEAR
• Frequently results to a pharmaceutically poor
suspension. • Splitting of emulsion into tiny droplets.
• Particles settle as a dense sediment, which
becomes more compact after a given time
interval. TURBULENCE

PREPARATION TECHNIQUES • Agitation required to the given dispersion of droplets.

• The actual preparation of suspensions involves the EQUIPMENT USED IN THE PREPARATION OF
following: EMULSIONS
o Choice of ingredients MECHANICAL STIRRERS
o Type of Equipment used
• If a suspension is to be made by Dispersion
Method, it is best to achieve particle size reduction • Emulsions are stirred by means of various impellers
by: mounted on shafts, which are placed directly into the
system to be emulsified.
• The degree of agitation is controlled by the speed of
MICRONIZATION METHOD the impeller system.
• This equipment is ideal for slow mixing of finished
emulsions, which have been prepared by melting the
• Using Jet Mill
waxes.
• The particles are subjected in a turbulent air
chamber.
• Where powders collide with each other and fracture, HOMOGENIZERS
obtaining particles with sizes 5 microns and below.

• It is used to produce fine droplets, by:

SPRAY-DRYING METHOD • First compressing the liquid, with high pressure

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• Escape of liquid radically past a flat disc, held by a o To place the emulsion in a 600C oven for a
strong spring (rotor-stator) mechanism. number of hours, remove then transfer to a
• The high shearing stress produced at pressures refrigerator temperature.
ranging from 500 to 1000 PSI can produce extremely o Continued emulsion stability studies for a few
fine droplets, depending on the viscosity and more weeks at 600C, will be the basis that the
interfacial tension of the system. emulsion will be stable for the next two (2)
years.
• METHOD B (REAL TIME STUDIES)
o Perform Long Term /Real Time Stability
Studies at different climatic zones, for
o Prediction of the appropriate storage
conditions
o Projected shelf life of the product
ULTRASONIFIER/ULTRASONICATOR

• The use of this equipment will produce extremely

fine particles for moderately viscous emulsions.
• This equipment is not available for commercial
scale.

EVALUATION OF EMULSION STABILITY AND

PROPERTIES

• Emulsion stability implies consumer acceptance and

the acceptance varies with the use of the product
• Emulsion type of aerosols, though completely
separated inside, will become acceptable for use,
upon shaking the container before using
• IMPORTANCE OF THE “SHAKE WELL” LABEL:
o Creaming and Sedimentation in fluid
emulsions will be eliminated with a “Shake
Well” Label.
o This will make the product acceptable for use.

EMULSION STABILITY METHODS OF

EVALUATION
PHASE SEPARATION / SUBSIDENCE

• The rate and extent of phase separation is observed

by allowing an emulsion to stand in the container (for
a given period of time).
• The volume of the separated phases are measured.
• Such changes may be due to either Creaming,
Sedimentation or Coalescence.

PARTICLE / DROPLET SIZE ANALYSIS

• By microscopic examination, the diameter of the

droplets / particles could be measured.
• Over a period of time particles are seen to increase
in size.
• To remedy this, a higher concentration of emulsifier
is added, to produce smaller droplet / particle size
and to stabilize the product.

INFLUENCE OF TEMPERATURE

• METHOD A (ACCELERATED STUDIES)