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MANUFACTURING PHARMACY

CHAPTER 1
INTRODUCTION

Manufacturing Pharmacy, presently considered as an advanced course, deals


with the technology of various official and non-official products manufactured in a
semi-commercial and commercial scale.
This rotates to the following:
1. Practice of pharmacy in some hospitals.
2. Large scale production carried out in modern pharmaceutical plants.
Since the majority of the prescriptions written today are composed of prefabricated pharmaceuticals, the well trained pharmacist should know the technology
of dosage forms, which he/she dispenses.
The more popularly known practice, Industrial Pharmacy, refers to the
pharmaceutical research and manufacturing companies providing pharmacists with
medicines in prefabricated or ready to take forms.
The industrial or manufacturing firms, the rate of organizational change has
accelerated in the recent years, with the increase in corporate growths, mergers
and diversification.

Elements of Organization
Organization is a mechanism for determining and assigning duties to people
in order to work effectively.
Business Organization in a combination of manpower, money, machines and
methods so coordinated that they can fulfill an economic objective.
Basic Elements of an Organization
1. Division of Responsibility (obligation or duty)
Responsibility must be delegated. The company objectives must be
determined and the organizational plan must be consulted with the aim of achieving
them. The types of work must be identified and grouped logically on related
elements.
2. Delegation of Authority
Authority must be defined and delegated to avoid negligence of duty.
Authority means:

The power or right to give commands

Enforcement of obedience
Ability to make final decisions
3. Determination of the Interrelationship among the Functions of each of the
Components of the Organizational Plan
This interrelationship must be clearly defined to promote harmonious
teamwork.

Basic Tools of an Organization


I.

The first basic tool is the ORGANIZATIONAL PLAANING. This is interpreted


as a CHART.
Characteristics of a chart:
1. An organizational chart lists all important positions and functions of
each division or department.
2. An organizational chart is a means of quickly showing the shape or
structure of the company to employees and other interested parties
outside the company.
Importance of a chart:
1. Can analyze organizational problems like overlapping of functions.
2. Can assess the strengths and weaknesses in the functions and
personnel.
3. Can plan changes in the structure, if not applicable.
Some drawbacks in the chart:
1. Cannot reveal company objectives and policies.
2. Cannot indicate delegated authority.
3. Reveals little about working relationships.

II.

The second basic tool is POSITION DESCRIPTION.


This will clearly define the authority, duty or responsibility of the areas in
the chart.

III.

The third basic tool is ORGANIZATIONAL MANUAL


This is also referred to as the Management Guide, which combines
the chart and position descriptions with description materials about the
organization to provide all levels of management a clear understanding of
the organizational plan, top management, philosophy and objectives of the
company.
Three Basic Levels of Top Management
And Their Functions
Level 1 Usually consists of the Board of Trustees or Board of Directors. The
functions are:

1. To protect and make the most effective use of the assets of the
company.
2. Establishes objectives and determines the basic policies and general
course of the business.
3. Represents and safeguards the interests of the stockholders.
Level 2 Consists of the president, the function being general management or
administrative. This includes active planning direction, coordination and
control of the business within the scope of policies established and
authorized by the Level 1 management.
Level 3 Consists of the Vice President, General Managers, and Department
Managers. The functions include management of the major departments
of the company. They are fully responsible and accountable to the Level
2 management for the success of their respective operations.
Level 3 embraces the topmost level of executives concerned with a
particular division of the company, rather than the enterprise, as a
whole.

Forms of Organizational Structure


There are two basic forms of the company organizational structure:
1. The functional structure groups all activities on the basis of similarity of the
functions alone. This is more appropriate for a small company or one with
closely related products.
All production is grouped under one head, all sales under one head,
and all financial activities under one head. It is flexible, facilitates
coordination, and encourages specialization in the field.
2. The divisionalized structure combines into the one unit, all different kinds of
work necessary to accomplish a specific result. The kinds of work necessary
may be grouped on a geographical basis or more commonly on a product
basis.

Line and Staff


The line constitutes the framework for the organizational structure.
Line functions are those that have direct responsibility to accomplish the
objectives of the enterprise. Only the line functions have the power or
authority to initiate and carry through other primary activities necessary to
reach thee stated goals of the company. Line is further identified as the
chain of command from top to the bottom of the organization.
The staff constitutes the work functions or the organization
components that are required to supply information and service to the line
components.

CHAPTER 2
THE PLANT DEPARTMENT
A. Production Control consists of three (3) sections:
1. Purchasing in charge of purchasing requisitioned material (both
packaging materials and raw materials), both form local and imported
sources.
2. Inventory Control watches and monitors closely. Records all materials
used in the Production controls the stocks of both raw materials packaging
materials and finished products. This section therefore is in charge of
checking stocks periodically.
3. Planning and Scheduling coordinates with the Marketing Department on
what products are required for supply, and then plans and schedules the
manufacture of the product. Then, through a manufacturing order (M.O.),
the Production department manufactures the quantity scheduled at the
time limit allowed.

B. Warehouse Division: Consists of five (5) sections:


1. Raw Materials Consists of three (9) subdivision:
a. Quarantined Area
b. Approved for Use Area
c. Rejected Area
Quarantined Materials are labeled with yellow-coded labels bearing
the word QUARANTINE. This implies that the materials are subject to tests
and @@@ by the Quality Control Section, and are not yet to be used.
Approved for Use Materials are labeled with green-coded labels with
the bold letters APPROVED for USE. The materials from the Quarantine
area found to conform to the standards and specifications are transferred to
the Approved for Use area replacing the Quarantine label with the Approved
for Use label.
Rejected Materials are those found to be substandard and are
transferred from the Quarantine area to the rejected area. The quarantine
stickers are replaced with the red-coded stickers bearing the bold letters
REJECTED. These materials are either returned to the supplier (for
replacement) or disposed of properly.

2. In process this consists of products which have been bottled, @@@@ or


packed, but not yet labelled or packed into boxes or cartons because they
still await the results of the Quality control tests and essays as well as the
final disposition.
3. Finished Products/Goods this area contains the products packaged and
finished and are ready for distribution and sale.

4. Returned Goods in as much as returns cannot be avoided. The products


returned are stored in this portion of the warehouse pending disposition by
the quality control.
5. Dispensing is an ara in the Warehouse where new materials for use in
the production are weighed and/or measured. The packaging materials are
also counted upon issuance. A quality control checker should be present in
this area to avoid @@@. The inspector also perform routine checking in all
sections of the warehouse.
C. Engineering and Maintenance Section takes charge of the care,
maintenance and repair of all machines and equipment and in the plant
department, including electrical lines, water and sewage systems waste
management, telecommunication and environmental condition etc.
D. Manufacturing of Pharmaceuticals
The general procedure of the manufacture of product is as follows:
1. The parent company abroad or the Research department locally prepares
the master formula (M.F.), then passes it on to its subsidiaries for product
manufacture. The Master Formula consists of the following information:
Name of the product
Potency of the Active ingredient
Batch size; amount of yield
List of ingredients and specifications including the code numbers
Quantity of each ingredient
Signature of the competent people who prepared the M.F.
2. The quality control head is in charge of the preparation of the Master
formula. If the Master formula is not the actual amount to be
manufactured.
CHAPTER 3
LIQUIDS
Advantages of administering in liquid dosage forms:
1. Ease of administration for these who have difficulty in swallowing solid
dosage forms.
2. Immediate availability for absorption of the medicinal substance. It is more
rapidly and efficiently absorbed, compared to tablets or capsules.
Disadvantages of the medicines in liquid dosage forms
I.
II.
III.

Technical problems, such as instability of same drugs in liquid form


Special techniques required for poorly soluble drugs.
Requires pharmaceutical elegance with regards to its appearance and
viscosity.

Discussion

I.

Instability as a technical problem may be caused by the following


conditions
1. pH influence degradation by the catalytic sections of the hydrogen
(H) and hydroxyl (OH) ions. Knowledge of the pH that will provide
optimum stability is useful in the development of a stable liquid dosage
form. A more frequent method used to maintain the pH constant is the
use of the appropriate buffer solutions.
2. Temperature the rate of the degradation increased with an increase
in temperature and therefor in the development of a product.
Accelerated Stability Studies (ASS) should be conducted to determine
the appropriate temperature of storage of a liquid preparation.
3. Concentration of the Reactanct a study on the amount of the Active
ingredient present in the liquid preparation should also determine the
amount of drug lost or degraded at a certain time period.
4. Light or Radiation this can cause degradation due to some complex
chemical structure of drugs
Factors which affect the rate or reaction/degradation of liquids by
light/radiation:
a)
Intensity of the wavelength of light
b)
Size of the container
c)
Shape of the container
The product may be protected by the use of an amber/light
resistant glass container instead of a flint glass.
a) Flint/Colorless glass container light transmission above
300 mu.
b) Amber/Light resistant glass container light transmission
above 470 mu.
5. Packaging Components defective packaging of pharmaceuticals can
invalidate even most stable formulations.
The choice of the container should bear considerations on the
protecting, property during extended periods of storage under varying
environmental conditions.
The materials most commonly employed as container
components for pharmaceutical preparations include:
a)
Glass
b)
Plastic
c)
Metal
d)
Rubber
Of the these materials glass has been the container of choice,
for pharmaceutical dosage forms, because of the following
reasons:
a) Resistance to decomposition by atmosphere conditions
b) Resistance to decomposition by solid or liquid contents of
varying composition

c) By modifying the chemical composition of glass, it may be


possible to adjust the:
1. Chemical behavior of the glass
2. Radiation properties of the glass
These can be accomplished by:
1. Decreasing the soda content in the glass
2. Replacing sodium oxide with other oxides to overcome
the undesirable property of glass.

Glass has 2 (two) principal faults or undesirable properties:


a. Release alkali to liquids stored in the glass
container.
b. Releases insoluble flakes
Classification of glass used in packaging pharmaceuticals
depend upon the:
1. Chemical constitution
2. Ability to resist deterioration
TYPE OF GLASS

CONSTITUENT

Type I

BIO2 + B2O3

Type II

Na2O + CaO
SO2 Treatment

Type III

Na2O + CaO

Type NP

Na2O + CaO
Non parenteral

GENERAL DECRIPTION
Highly Resistant
Borosilicate Glass
Treated Soda lime glass
Soda Lime glass for Dry
Products
General purpose soda
lime glass

Each type of glass is tested according to its resistance to water attack. The degree
of attack is determined by the amount of alkali released from the glass container.
Obviously leaching of the alkali from the glass container into the pharmaceutical
preparation inside could alter the pH and thus the stability of the product.
Type I glass is the most resistant glass of the four categories.
PLASTIC CONTAINER
These are high molecular weight polymers, such as:

Polyethylene
Polystyrene
Polypropylene
Polyvinyl chloride

The interest and widespread use of plastic containers in the pharmaceutical industry
has been generated by a number of factors including:
1.

The advantage of plastic over glass containers in the:


Lightness of weight
Resistance of impact
Lower transportation costs
Lower losses due to less container damages
2.
The versatility in container design and consumer acceptance afforded
by plastics
3.
The interest and convenience in utilizing low and medium density
polyethylene in the formation of squeeze bottles which serve a dual function
of both package and application for preparations such as ophthalmic
nasal/otic solutions and topical lotions.
4.
The advent of newer techniques in drug distribution, dispensing and
inventory control, particularly in hospitals that require development of
packaging such as strip and blister packs plastic disposable syringes for unit
dose delivery.
a.
b.
c.
d.

Today a wide variety of dosage forms maybe found packaged in plastic containers
such as:
a.
b.
c.
d.
e.

Collapsible polyethylene bags for intravenous fluids


Collapsible plastic tuber for ointment
Plastic film protected suppositories
Plastic vials for capsule and tablets
Compact type container for oral contraceptives

The disadvantages pf plastic packaging are:


1. Permeability of the container to atmospheric gases and to moisture.
Permeability is the process of solution and diffusion in which the genetrant
initially dissolves in the plastic materials on one side and diffuses through the
other side.
Permeability should be differentiated with porosity, which is a condition in
which minutes holes or cracks are present in the plastic and through which
gas or moisture may move directly.
2. Leaching of the constituents of the plastic container to the internal contents.
Leaching is the release or movement of the components of a container into
the contents.
Compounds leached from the plastic containers are generally polymer
additives, such as:
a. Plasticizers
b. Stabilizers
c. antioxidants
3. Sorption (ab or ad) of the drugs from the contents to the plastic container.
Sorption is the binding of drug molecules to the polymer material of the
plastic container. This refers to absorption or adsorption.
4. Transmission of light through the container.

5. Container-deformation contents of the plastic container may chemically or


physically react with the plastic components of the container.
METAL CONTAINER
Metals are also used as containers for pharmaceutical products. Disporse systems
having a consistency of a soft paste, gel cream, or ointment can be conveniently
packed into collapsible tubes which are commonly made of:
a.
b.
c.
d.
e.

Tin
Plastic coated tin
Tin coated lead
Aluminum
Plastic coated aluminum

Tin and tin coated tubes are generally used because of their non-reactive properties
although it was reported that tin tubes can be corroded by chloride or acid
conditions.
RUBBER COMPONENTS
Rubber of varying composition is used in pharmaceuticals and biologicals is
1.
2.
3.
4.

Stoppers
Cap liners
Parts of droper assembles
Components of drip sets/ infusion sets

A major use of the rubber stopper is that the closure for multiple dose vials
continuing solutions for injection.
Problems encountered in the use of rubber closures are:
1. Within contact with the liquid content in the vial. It may cause the absorption
of the native ingredient, preservative on the other components.
Example: the preservative chlorobutanol by the rubber form the solution.
2. The extraction of one or more components of the rubber close into the
solution.
These problems may be corrected by:
a. Using epoxy clinging material (a rosin that glues)
b. Use of Teflon in rubber shoes (tetrafluoroethylenepolymer or plastic)
II. Special techniques required for poorly soluble drugs.
The solubility of most modern chemotherapeutic agents can be favorably altered by:
1. Co-solvency
Weak electrolytes and non-polar molecules frequently possess poor water
solubility. Their solubility usually, can be increased by the addition of a water
miscible solvent in which drug has good solubility.

This process is known as consolvency and the solvents used in combination


to increase the solubility of the solutes are known as co-solvents.
An example is a colorant soluble in alcohol but not in water. Phenobarbital is
more soluble in alcohol that in water.
2. Ph control
A large number of modern pharmacoutic agents are either weak acids or
weak bases and their solubility can be markedly influence by modifying its
pH.
3. Solubilization
This term has been defined by Mobain as the spontaneous passage of poorly
water soluble solute into an aqueous solution of soap or detergent in which
thermodynamically stable solution is formed.
The mechanism of this phenomenon has been studied quite extensively and
involves the property of surface active agents to form colloidal aggregates
known as @@@@@
When surfactants are added to the liquid at low concentration it tends to
orient at the air liquid interface as additional surfactant are added, the
interface becomes fully occupied and the
excess molecules are forced into the bulk of liquid. At still higher
concentration the molecules of the surfactant in the bulk of the liquid begin
to form oriented aggregates or @@@@@.
Solubilization is believed to occur by virtue of the solutes dissolving in or
being absorbed onto the miscelle
Example: polyoxyathylene srobitan fatty acid ester (TWEENS)
4. 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.
5. Hydrotrophy
Refers to the increase in solubility in water of various substances due to the
presence of large amounts of additives. This mechanism is not clear. Some
workers have speculated that hydrotropy is simply another type of
solubilization with the solute, dissolve to oriented clusters of the hydrotropic
solutions do not show colloidal properties.
6. Chemical modification of the drug
Conversion of poorly soluble drugs to water soluble derivatives. Example
corticosteroid B mothasone alcohol is soluble in water by 5.8 mg/100 ml while
its disodium phosphate is soluble in water by 10 g/100 ml

The approach is successful in some drugs, but is some biological activities toxicity is
to be considered
III. Pharmaceutical elegance is required as to the taste appearance and visocity
Modern pharmaceutical preparations present the drug substance which are
unpalatable and unattractive to the patient as colorful and flavorful formulations
attractive to the sight smell and taste.
FORMULATION OF LIQUIDS
To avoid problems on formulation of liquids the following considerations should be
studied:
1. Solubility
2. Stability
3. Organoleptic characteristics as taste (flavoring) odor and appearance (color
and clarity)
4. Preservatives
5. Sweetening agents
6. Viscocity
Further Discussions
1. Solubility
Co-solvants may be used in the formulation of aqueous liquids, such as
alcohol, sorbitol, glycerin, propylene glycol.
Vehicles used in the formulations are mostly blends of water and
sucrose.
Solubilizing agents are to be selected based on their effect in stability
efficacy and physical character.
2. Stability
Considers both physical and chemical stability
Physical stability is shown by the maintenance of the physical
properties such as the color, clarity, taste, viscocity and odor
throughout its shelf or until the expiry date is reached.
Physical stability includes the package and the label which involves the
effect if the package on the contencs and vice versa. Bottle caps and
liners now used as closures may undergo tests on stress-cracking or
corrosion so that the lner should be compatible with the contents
adequate seal is necessary. A torque tester measures the seal.
Torque is the measure of circular force (in lbs/ sq. inch) because the
instability is magnified in solution as against solid and suspension
systems.
3. Organoleptic Characteristics

a. Taste (flavoring) there are four basic tastes namely sweet, sout, salty
and bitter. A combination of flavoring agents is generally required to
mask these taste sensations.
Example
Menthol and chloroform are used as desensitizing agents since they
impart flavor and odor of their own to their product and have a mild
anesthetic effect on the sensory receptor organ associated with taste
The process of choosing flavouring agents may be divided into two (2)
major categories, such as:
1. Selection depends on an experiment where a panel of formulators
should conduct a trial and error selection of combination of flavors.
2. Evaluation - is conducted by a panel of three (3). They conduct the
taste tests starting from the lowest dilution to increasing
concentration.
b. Appearance depends on the color and clarity. Color should
complement/ harmonize with the flavor
Examples
Strawberry flavor should possess the red color of the strawberry. Kiwi
flavor should possess the green color of the kiwi fruit.
Clarity is improved by the filtration using sintered glass filter aids after
layers of filter or filter cloths.
4. Preservatives there are substances which prevent bacterial and fungal
growth in liquid preparations. Bacteria and fungi affect product stability as
well as health hazard to the patient.
Characteristics of an Ideal Preservative
1. Should be effective against broad spectrum of microbes.
2. Should be physically, chemically and microbiologically stable until the
expiry date of the product.
3. Should be non-toxic, non-sensitizing, adequately soluble and compatible
as well as acceptable to the taste and odor at the amounts used.
Preservatives are classified into four groups:
1. Acidic examples are ethyl asters of phydroxybenzoic acid (PABA) benzoic
acid and its salts. For external use boric acid and phenols are used.
2. Neutral examples are chlorobutanol, benzyl alcohol, and phenylethyl
alcohol.
3. Mercurials examples are thimerosal, nitromersols, phenyl mercuric
acetate/nitrate.
4. Quaternary Ammonium Compounds examples are benzalkonium chloride
and cetyl pyridinium chloride

5. Esters the most useful preservatives are the esters of phydroxybanzoic


acids (PABA or parabens) because they are:
a. Chemically stable
b. Neutral in pH
c. Non-toxic, non-irritating, non-allergenic
d. Possess both antifungal and antibacterial properties
Combinination of the methyl and propyl parabens are used for synergistic
preservatives effects.
The three groups of preservatives (neutral, mercurial, and quarternary
ammonium compounds) are often used for ophthalmic, nasal and parenteral
products but not in oral products.
Syrups with 85% sucrose resist bacterial growth by virtue of its osmotic
pressure effect on microorganisms while those with lower concentration
(containing polyols) also exhibit exosmotic effect and will resist bacterial
growth.
5. Sweetening Agents generally comprise a major portion of the solids content of
liquid preparations. The sweetening agents used in pharmaceutical preparations
are:
1. Sucrose had a long history of use due to the following advantages (white
sugar)
a. can be obtained in highly purified form
b. chemically and physically stable at pH 4 to 8
c. can be used in conjunction with polyols to prevent crystallization
of sucrose
Disadvantage of sucrose cap-locking (wherein the sucrose content
crystallizes along the thread of the bottle cap, which interferes with the cap
removal)
2. Liquid Glucose is an extremely sweet viscous substance which imparts
both body (viscosity) and sweetness to liquid formulations.
This is prepared by partial hydrolysis of starch with strong acids and contains
dextrose (as the main component) with trace amounts of dextrin and
maltose.
3. Artificial Sweeteners like saccharin and cyclamates are used. Some
chracteristics are as follows:
1. Sodium and calcium slats of saccharin are soluble in water, alcohol and
polyols.
2. Stable st pH 3 to 8
3. Produce the desired sweetness at a much lower concentration than
sucrose
Cyclamates 15 to 30 times sweeter than sucrose
Saccharin 250 to 500 times sweeter than sucrose

To avoid the bitter aftertaste of both artificial sweeteners (if used individually)
cyclamate is used in ratio of 20 parts to 2 parts of saccharin to produce a 1%
w/v formulation.
6. Viscosity highly viscous systems are not also desirable since they resist dilution
by gastrointestinal fluid therefore might impede drug release and absorption.
If high concentrations of carboxymethylcellulose (CMC) are used
incorporation of Al*, FC ***, and CA** are done.
Viscosity is sometimes desired either to serve as an adjunct to palatability on
to improve pourability and drainage. Viscocity controlling agents are PVP,
methylcellulose and sodium CMS.
Manufacturing Considerations in Liquids
The basic principles involved in the preparation of homogenous liquids are
the same, regardless of the quantity of materials involved. The solubility of the
solute and the intra/inter molecular interaction in the final solution at equilibrium at
independent of the manner in which the solution is made.
This assumes that the method of compounding does not affect the final
composition of the system, as would be the case of the volatile component were
charged to a heated solution.
The rate at which the equilibrium is achieved is highly dependent in the
details of the following
a.
b.
c.
d.
e.

Equipment
Compounding procedure
Packaging methods
Labelling
Storage

Further discussions
A. Equipment in general the type of equipment used in the manufacture of oral
solutions consist of:
a. Mixing tanks equipped with agitators
This are tanks constructed of polished stainless steel are
jacketed to allow heating and cooling of the contents. They can be
obtained in a number of different sizes. The tanks are completely
covered and equipped with see through charging ports and illumination
for easy observation of the contents.
After compounding the liquid is clarified by filtration into another
adjacent task called storage tanks until release by the quality control
after the release, the liquid may be transported manually by filling into
portable transport tanks or by pumping through suitable liquid delivery
container.
b. Measuring and weighing devices

Used for large and small amounts of liquid and solid ingredients
such as cylinders, pipets and balances.
c. Filtration system for final polishing of the solution.
Filtration is a unit operation in which a mixture of liquids and
solids slurry or feed is forced through a porous medium in which solids
form a cake on the surface and the clear liquid is collected.
The usual objective of filtration or clarification is a sparkling
liquid trace from amorphous/ crystalline precipitates colloidal hazes or
insoluble liquid droplets. IN filtration system, the filter medium is the
surface upon which the solids are deposited on the filter.
Filter Media
1. Filter Cloth

Example
Nylon

Composition

Filter cloth

2. Filter media
Non woven

Stainless wire
cloth
Felt cloth

Bonded fabrics

Fibrous mass free


from bonding
agents
mechanically
interlocked to yield
pore diameters
with controlled
porosity
Blended textile
fabrics with rasins,
solvents and
plasticizers

Kraft paper

3. membrane filter
media

a. esters or
cellulose
b. nylon, Teflon,
PVC silver

Properties
a. Superior type
unaffected by
molds/fungus.
b. can be sterilized
by autoclaving
c. Negligable
absorption
properties
a. For straining
syrupy liquids

a. for gelatinous
solutions

a. non widely used


(due to interaction
with additives)
a. used as
pharmaceutical
standard
b. controlled
porosity
c. limited
absorption capacity
d. low cost
a. for sterile
solutions
b. 150 micron
thickness

5. Filter Aids

Diatomite
Infusorial earth
Kiesalgur
Celite
Cellulose
asbestos

c. porosity of 0.05
14 microns
d. ideal for microfiltration
a. form highly
porous and noncompressible cake
which retain solid
b. forms a line
surface deposit
which screens out
all solids prevents
the clogging of
supporting filter
media.

The most important factor for filter aid is inertness. Filtration


efficacy may be affected by changes in the temperature since there is
an inverse relationship between the flow rate and viscosity of liquids.
Increase of temperature of heavy syrups lower viscosity and
increase filtration rate. The quantity of filter aids added likewise affect
filtration rate. Generally amount added is NMT 0.05%
Filter aid contribute to the
a. Clarity improvement
b. Increase in flow rate
B. Compounding procedure
i. Dilute solutions where the rate of solute dissolution is rapid are simply
prepared by charging the solute to the solvent and agitating until the
solution is homogenous.
ii. Solutes present in small concentrations (such as colorants and
preservatives) should be pre-dissolved prior to mixing with the main
portion of the batch.
iii. In the laboratory, liquids are usually measured by the volume. When large
quantities of liquid materials are handed it is more convenient and
accurate to use gravimetric means of measurement. For this reason, all
liquid components of the cited formula are expressed in unis of both
volume and weight.
C. Packaging and labeling storage
a. Packaging Filling of Liquids
The somatic method used for filling of pharmaceutical liquids varies
greatly, depending on the
a. Characteristics of the liquid (viscosity, surface tension, foam
producing properties and compatibility with the materials used in
the construction of the filling machine)
b. Type of package into which the liquid product is placed
c. Required production output
Three (3) Basic Liquid Filling Methods

1. Gravimetric Method is limited to very large containers or highly


viscous products.
2. Volumetric method is accomplished by pumping the liquid at
constant pressure, through an orifice of constant diameter and size
for a pre-determined period of time.
The final amount is measured by the stroke of the piston in
which all filling machines is varied to a limited degree. Major
changes in the fill amount needs changing piston and cylinder
assembly.
An inherent problem with volumetric filling is encountered whrn
the containers used are not dimensionally uniform. In this case,
even if the fill amount is accurate the fill height varies inversely
with the container capacity.
3. Constant level method uses the container as the measure of
controlling fill amount of each unit. The fill amount is varied by
adjusting the height to which the container is filled. Any
dimensional variations in the container results to comparable
variations in the net fill per unit
A common problem to all types of liquid filling machines (which
is quite bothersome) with high speed automatic filling mechanism
is the formation of excessive foam.
D. Labelling
Labelling includes not only the labels placed on the immediate container and
packaging but also the package inserts accompanying he product as well as
the following advertising and promotional materials pertaining to the drug
products.
Brochure
Booklets
@@@@ pieces
Filling cards
Bulletins
Price lists, catalogs
Sound recordings
Film strips
Motion pictures
Lantern slide exhibits
Displays
Literature reprints
a. Labeling of Legend Drugs
1. Non-proprietary name/s of the drug/s present. The trade name of the
product (if one is used)
2. Name and address of the manufacturer or distributor of the product
3. A quantitative statement of the amount of each drug present per unit
weight, volume, or dosage unit whichever is most appropriate.
WALA YUNGKASUNOD NITO SA NASEND SA AKIN

b. Contents of the Pharmacologic Categorization of Drug Product


1. Description of the product, including the propriety and non-propriety
names dosage form and route of administration, quantitative product
composition, pharmacologic/therapeutic class of the drug, chemical
name and structural formula of the drug compound and important
chemical and physical information.
2. Clinical pharmacology including a summary of clinical actions of the
drug in humans relevant invitro and animal studies essential to the
biochemical/physiological basis for action pharmacokinetic information
on rate and degree of absorption, biotransformation and metabolite
formation, degrees of drug binding to plasma proteins rate of halftime
of elimination uptake by a particular organ or fetus any toxic effects.
3. Indications and usage, including the BFAD approved indications in the
treatment prevention or diagnosis of a disease or condition evidence of
effectiveness demonstrated by results of controlled clinical trials
special conditions of the drugs use for short/long term use.
4. Contraindications, states these situations in which the drug should not
be used because of the risk of use clearly outweighs any possible
beneficial effect. Included are contraindications associated with drug
hypersensitivity, concomitant therapy disease state and/or factors of
age or gender.
5. Warnings including descriptions of serious adverse reactions and
potential safety hazards limitations to use imposed by them and stops
to be taken if they occur.
6. Precautions, including special care to be exercised by the prescriber
and patiet in the use of the drug, effects on fertility, use in pregnancy
use in nursing mothers, and use in pediatric patients.
7. Adverse reactions, including predictable and potential unpredictable
undesired (side) effects, categorized by organ system or severity of
reaction and frequency of occurrence.
8. Drug Abuse and Dependence, including legal schedule if a controlled
substance types of abuse and resistant adverse reactions,
psychological and physical dependence potential and treatment of
withdrawal.
9. Overdose, including signs symptoms usual doses and laboratory
findings of acute over dosage along with specifics or general principles
of treatment.
10.Dosage and Administration, stating the recommended usual dose,
usual dosage range, the safe upper limit of dosage duration of
treatment, modification of dosage in special patient populations and
special rate/s of administration.
11.How supplied, including information on available dosage forms,
strengths and means of dosage form identification as color coating
scoring and national Drug Code.
E. Storage

The labelling of each product generally includes the desired conditions of


storage for that particular product, to insure the stability for the period of its
intended shelf life.
When no specific storage or limitations are provided, it understood that the
storage conditions include protection from the following:
1. Moisture
2. Freezing
3. Excessive heat
CHAPTER 4
PHARMACEUTICAL SUSPENSIONS
These liquids are heterogenous systems consisting of two phases:
1. The continuous phase also called the external phase or dispersion system
2. The discontinuous phase aslo called the internal phase or disperse system
The continuous phase is generally a liquid or semisolid and the discontinuous phase
is made up of particulate matter which is essentially insoluble but dispersed through
the continuous phase. The insoluble matter may be intended for physiological
absorption or for internal coating functions.
Almost all suspension systems separate upon standing the main concern of the
formulation is not necessarily to try to eliminate the separation but rather:
a. Decrease the rate of the setting
b. Permit easy resuspendability of any settled particulate matter
A satisfactory suspension must remain sufficiently homogenous for at least the time
necessary to remove and administer the required dose after shaking the container.
Certain kinds of pharmaceutical suspensions have been given separate designations
such as:
1. Gels these are semisolid systems consisting of fine dispersions made up of
either small inorganic particles or large organic molecules, enclosing and the
interdependent by a liquid. It exhibits thixotropic properties.
2. Magmas and Milks a suspension that appears as masses of gel consist of
floccules of small, distinct particles.
3. Lotions mostly contain finely powdered substance that are insoluble in the
dispersion medium and are suspended through the use of suspending agents
and dispersing agents,
4. Mixtures and Emulsions
Theoretical Consideration in the Manufacture of the Oharmaceutical Suspensions
The following considerations should be understood to help in the selection of
ingredients and equipment for good formulatory decisions:
1. Wetting/Wettability Property

A frequently encountered and a factor of prime importance in


suspension formulation. It concerns the wetting of the solid phase by the
suspension medium.
When a strong affinity exists between a liquid and a solid, the liquid
will easily form a film over the surface of the solid but when this affinity Is
weak or nonexistent the liquid has difficulty in displacing the air surrounding
the solid and there exist an angle of contact between the liquid media while
others are not.
Solids are said to be hydrophilic (lyophilic or solvent lover) or
hydrophobic (lyophobic or solvent fearing)
Hydrophobic substance are easily wet by water or other polar liquids
and may greatly increase the viscosity of the aqueous suspension
Hydrophobic substance repel water but can easily be wetted by nonpolar liquids. It does not alter the viscosity of the aqueous suspension.
Hydrophilic substance can be incorporated into suspensions without
the need of wetting agent. But hydrophobic materials are difficult to disperse
and frequently float on the surface of the liquid due to poor wetting of the
particles or due to the presence of tiny air pockets.
To modify the wetting chracteristics of powders the following procedure
can be adopted.
1. Use of surfactants to decrease the solid-liquid interfacial tensions.
The action of the surfactant is to have its chain absorbed by the
hydrophobic surface and its polar moiety is directed to the aqueous
phase.
2. Other aids for dispersion of hydrophobic solids as hydrophilic
polymer such as SCMC and certain water insoluble hydrophilic
materials such as:
a. Bentonite (hydrated aluminum solicate clay)
b. Voogum (aluminum magnesium silicate)
c. Colloidal silica
These materials exert viscosity building effect depending on the type
and concentration used. These hydrophilic agents, if too high concentration
cause undesirable getting instead of just the desired degree of viscosity or
thixotrophy.
2. Particle Interaction and Behavior
The terms lyophobic is synonymous with non wetting and lyophilic with
the wetting. The primary difference is the sensitivity to electrolytes.
Lyophobic materials in suspension are very sensitive to the addition of
salts whereas lyophilic materials are not. A lyophilic material such as a gum,
is readily wet by water although in this instance, large amount of
electrolytes may affect the solution by salting out effects as distinct from
lyophilic materials dilution with the vehicle reverse, the precipitation of
lyophilic solids.
According to the Schulze Hardy Rule, the valence of ions having a
charge opposite to that of the hydrophobic particle determines the

effectiveness of the electrolyte in the coagulating the particles. Thus


flocculating value increases with the valence of ions.
Types of Suspension System
A. Flocculated System
a. Particles appear as floccules like tufts of wool with loose fibrous
structure
b. When the system settles, two distinct layers form a clear particle free
supernatant liquid and a sediment.
c. Also known as coagulated or colloidal unstable system.
d. Appears to be coarse, because of the floccules formed.
e. Exhibits minimum, serious separation depending on the solid content
and the degree of flocculation that took place.
B. Deflocculated System
a. Particles settle as a dense sediment which becomes more compact
after a given time interval
b. Also known as peptized or colloidal stable system which frequently
results to a pharmaceutically poor suspension.
C. Sedimentation Rates
The actual setting rates depend on the sedimentation velocity of a
particle in suspension. It should be remembered that as the solid
content is increased, viscosity also increases.
The velocity of sedimentation is directly proportional to the particle
size and inversely proportional with the viscosity of the suspension.
Therefore the bigger the particles that faster it settles down upon
standing.
Methods of Production of Suspensions
1. By Dispersion Method this process is done by dispersing the finely divided
powders in an appropriate liquid vehicle. The use of surfactants is desirable
to ensure uniform wetting of the hydrophobic surfaces.
2. By Precipitation Method this is performed by effecting precipitation in the
liquid vehicle. The methods are
a. Organic Solvent Precipitation water insoluble drugs are precipitation
by dissolving them in a water miscible organic solvent. Then adding
the organic phase to purified water, under standard condition.
Examples of organic solvents used are ethyl alcohol methyl alcohol
propylene glycol, acetone and polyethylene Glycol.
A number of important considerations involved if his method is used
such as
1. Particle size control
2. Correct form of crystals obtained for suspensions intended for
parenteral or inhalation uswe the particle size should be
between 1 to 5 @@@@ range

b. Precipitation affected by changing the pH this is applicable to those


drugs in which its solubility is dependent on pH value.
c. By Double Decomposition Method where simple chemistry involved.
Example is the preparation of White Lotion, USP (made by interacting
zinc sulfate with sulfurated potash solution to form zinc polysulfide)
FORMULATION OF SUSPENSIONS
The basic concern involves the fact that suspensions settle and is necessary to
redistribute it before using or dispersing the product.
Factors to be considered in formulating suspensions
A. Type of Suspension Desired
a. Flocculated System
i. Make sure that the particles are well dispersed in the aqueous
phase or other vehicle.
ii. A surfactant will improve the dispersion by reducing the
interfacial tension.
Example
In surfactant with negative charges are absorbed on the
particles this minimizes/prevents flocculation or precipitation in the
presence of positive ions, due to the mutual repulsion of like charges.
Sodium lauryl sulfate and sodium dioctyl sulfosuccinate are nonionic surfactants which assumes negative charge in solution and are
effective as flocculating agents.
Non-ionic surfactants are used to aid dispersion of the insoluble
phase. Examples are:
a. Polyoxyethylene esters of mixed fatty acid esters of
sorbitol anyhydride (TWEENS)
b. Mixed fatty acid esters of sorbitol anhydride (SPANS)
c. Higher molecular weight polyethylene glycols (Carbowax)
iii. Flocculated system intended for oral parenteral ophthalmic or
topical use may not appear elegant due to poor drainage from
vials or bottles due to clusters of flocculated particles.
iv. The undesirable drainage properties of this system may be
improved by the addition of protective colloids.
Protective colloids differ from surfactants on the following points:
a. Protective colloids do not reduce interfacial tension
b. Protective colloids differ in viscosity and are used in
higher concentration
c. Protective colloids form a mechanical sheath or barrier
around the particles
Examples of protective colloids.
a. Silica gel used in 10% concentration and may be gelled
with the surfactants for topical suspensions

b. Aluminum Hydroxide as a vehicle used commercially in


triple sulfonamide suspensions
b. Deflocculated System
i.

The dispersing agent used should lower interfacial and act as a


viscosity imparting agent. These agents retard settling and
agglomeration of the particles by functioning as an energy barrier
minimizing interparticulate attraction and ultimate deflocculation.
The general choice includes protective colloids surfactants,
viscosity builders and dispersing agents. Some of the
suspending agents used largely in the formulation are:
a. Modified cellulose polymers such a SCMC methocel,
methoce hydroxyl methycellulose
b. Proteins such as gelatin
c. Totally synthetic polymers such as carbapol (polyacrylic
acid) mostly such as hydrated aluminum and/or a high
degree to foam colloidal dispersions having high viscosity.

Formulation of Adjuvants
Suspension adjuvants the preservatives colorants flavorants and perfume.
These may affect suspension characteristics. The final adjuvant is the package. The
main concern of these adjuvants is compatibility with the vehicle and the active
ingredient.