PHARMACEUTICAL MANUFACTURING WITH REGULATORY PHARMACY College Of Pharmacy 2024

- obtained from petroleum by collection of a particular

CHAPTER 5 viscosity-controlled fraction
FORMULATIONOF MEDICATED APPLICATIONS HYDROCARBON WAXES
INTRODUCTION  help increase the viscosity of hydrocarbons
 Pharmaceutical preparations for the treatment of  “stiffening agents”
conditions such as rashes, skin irritation, insect sting, fungal - Ozokerite – mined wax with MP 65-75ºC
infections, etc. - Paraffin wax – obtained from petroleum with MP of 35-
 normally supplied in the form of cream or ointment, as this 75ºC
provides an effective means of delivering the active/s - Cerezin – mixture of ozokerite and paraffin wax
directly to the affected area  Synthetic waxes from vegetable oils and naturally occurring
OINTMENTS waxes involving C18-C36 HC chains
 composed of fluid HC meshed in a matrix of higher melting  They exhibits thermoplasticity
solid hydrocarbons OLEAGINOUS SUBSTANCES
prepared by:  provides lubricating, softening effect to the skin
- melting the components together  fixed oils of vegetable origin
- drugs or other components are added in the fluidized state - peanut oil, almond oil, sesame oil, olive oil
- if solids are insoluble, a milling process may be done so that FATTY ACIDS AND ALCOHOLS
solids are fully dispersed (colloid mill, homogenizer,  acts as auxiliary emulsifiers
ultrasonic mixer)  Stearic acid – used in water-removable creams as an
PASTES emulsifier to develop a certain consistency in the cream and
 ointments with higher percentage of insoluble solids has to give a matt effect on the skin
been added - when used, enough KOH or triethanolamine is added to
 used as protective barriers on the skin react with about 8-20% of the stearic acid, unreacted fatty
prepared by : acid increases the consistency of the cream
- incorporating a solid directly into a congealed system by - cream are soft and develop a sheen or luster upon aging;
levigation with a portion of the base to form a paste-like much firmer in consistency
mass  Stearyl alcohol and cetyl alcohol– also used in creams as
- remainder of the base is added with continued levigation emollient produces a firm cream that may be softened with
until the solids are uniformly dispersed in the vehicle cetyl alcohol
CREAMS EMULSIFIERS
 semisolid emulsions systems with opaque appearance  water-soluble soaps were among the first emulsifiers used
compared with translucent ointments for semisolid oil-in-water emulsions
 consistency and rheologic character depends whether  Viscosity of the cream or ointment prevents coalescence of
emulsion is o/w or w/o type and on the nature of the solids the emulsified phase and helps stabilize the emulsion
in the internal phase  “mixed emulsifier system” – combination of surfactant with
GELS oil-soluble auxiliary emulsifier
 semisolid systems in which the liquid phase is constrained - triethanolamine stearate soap + cetyl alcohol
within three-dimensional polymeric matrix (natural or POLYOLS
synthetic gums)  as humectant
- Natural: tragacanth, pectin, carrageen, agar, alginic acid - prevent the formation of “crust” on top of ointments and
- Synthetic and semisynthetic: methylcellulose, creams contained in jars
hydroxyethylcellulose, CMC, carbopols - Glycerine, propylene glycol, sorbitol 70% and the lower
Prepared by: molecular weight polyethylene glycols
- fusion process INSOLUBLE POWDERS
- special procedure necessitated by gelling characteristic of  must be uniformly dispersed throughout the vehicle to
the gellant ensure homogeneity of the product
USES  solid must be impalpable to the touch (not gritty)
• Applied to the skin: - 74 microns (equivalent to 200 mesh)
- as emollient - Milling to a finely divided states provides more surface area
- as protective or occlusive dressings for contract with the dermal site and increases the rate of
- as vehicles for topically applied drugs dissolution of poorly soluble substances
RAW MATERIALS IN THE FORMULATION OF MEDICATED TYPES OF NONMEDICATED SEMISOLID BASES/VEHICLES (USP)
APPLICATIONS  Hydrocarbon/ Oleaginous bases
 Hydrocarbons  Adsorption/ Emulsifiable bases
 Hydrocarbon Waxes  Water-removable bases
 Oleaginous substances  Water-soluble bases
 Fatty acids and Alcohols HYDROCARBON/ OLEAGINOUS BASES
 Emulsifiers Polyols  acts as occlusive dressings, producing a warm sensation,
 Insoluble powders since normal evaporation of insensible perspiration is
HYDROCARBONS inhibited
 includes petrolatum and mineral oil  Petrolatum and white ointment, which is petrolatum with 5%
Petrolatum beeswax
- complex mixture of semisolids HCs, containing ABSORPTION/ EMULSIFIABLE BASES
aliphatic, cyclic, saturated, unsaturated, branched  hydrophilic mixtures formed by the addition of substances
and unbranchedsubstances in varying proportions miscible with HCs, possess polar groupings suck as alkyls,
sulfates, carboxyl, hydroxyl and ether linkages

Mineral oil
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WATER-REMOVABLE BASES
 oil in water emulsions, referred to as creams
 best applied to skin lesions, since oil in water vehicle tend to
absorb serous charges
WATER-SOLUBLE BASES
 prepared from mixtures of high and low molecular weight
PEG
 “greaseless” ointment bases, since no additional water is
required in its preparation
PASTES, GELS, JELLIES AND OPHTHALMIC OINTMENTS
PASTES
 dispersions of high concentrations of insoluble powdered
substances in a fatty or aqueous base
 fatty base are less greasy as well as stiffer in consistency than
ointments
 adhere well to the skin and are of benefit in the treatment of
chronic lesions
 provide protective layer and when covered with suitable
dressings, prevent excoriation of the patient’s skin by
scratching
JELLIES
– water-soluble bases prepared from natural gums (tragacanth,
pectin, alginates, etc.) or from synthetic derivatives
(methylcellulose and NaCMC)
GELS
 transparent semisolids containing the solubilized active
substance formed with cellulose
Ex: benzoyl peroxide gel
OPHTHALMIC OINTMENT
 contains:
- soft petrolatum, bland absorption base, watersoluble base
- water-soluble base prepared with polyethyleneglycols or
with a water-soluble gum
- all materials used should be impalpable to avoid eye
irritation or discomfort, must be sterile
GENERAL CONSIDERATION IN THE CHOICE OF PRESERVATIVES
 Plastic containers may absorb preservative and thereby
decrease the quantity available
 some may sting or irritate the mucous tissues of the eye or
nasal passages
- methylparaben and propylparaben more irritating
- when applied to the nose than quaternaryammonium
compounds or the phenylmercuricsalts
- boric acids used in the ophthalmic preparations but
omitted from products used in the nose due to possible
toxic effects
INDUSTRIAL PROCESSING
1. Preparations of the Oil Phase
- flake/powder ingredients, sometimes dry are blended in
advance, and are dispersed into mineral oil or silicone oil
- heating may be required to melt some ingredients (fusion
method)
2. Hydration of the aqueous phase ingredients
- emulsifiers, stabilizers, thickeners are dispersed into
water in a separate vessel
- heating may be required to accelerate hydration
Use of antioxidants
• added whenever oxidative deterioration is anticipated
• acids like citric, maleic, phosphoric or tartaric may be
added to the combination to chelate trace quantities of
metals
3. Foaming the Emulsion
- two phases are blended under vigorous agitation to
form the emulsion
4. Dispersion of the active/s
- the active/s makes up only a small proportion of the
formulation
College Of Pharmacy 2024
- must be efficiently dispersed to maximize yield and
product effectiveness
Manufacture by Fusion Method
Factors to be controlled during manufacture of semi-solids
1. temperature of mixing
2. time of mixing
3. mechanical works – rate of agitation
Steps of Fusion Method
Preparation of the oil and aqueous phase
 components of the oil or fat mixture are placed into a
stainless steel steam jacketed kettle, melted and mixed
 petrolatum is melted at 60-62ºC
- transferred to the mixing kettle by metering pump
- strained through layers of cheese cloth to remove
foreign matter
- ophthalmic prep: pass through filter medium
 components of the aqueous phase are dissolved in water
and filtered
- soluble drug may be added (provided the drug is not
heat sensitive, otherwise add the soluble drug after the
emulsion is formed and cooled
- if perfume is to be added:
- mixing temp 43-45ºC to avoid chilling the emulsion and
facilitate dissolution of the perfume oil in still
incompletely congealed oil phase
COOLING THE SEMI-SOLID EMULSION
 rate of cooling is slow to allow for adequate mixing while the
emulsion is still liquid
- temp of cooling medium in the kettle jacket must be
decreased gradually at a rate consistent with stirring and
scraping the walls to prevent formation of congealed
masses
- if perfume is to be added:
- mixing temp 43-45ºC to avoid chilling the emulsion and
facilitate dissolution of the perfume oil in still incompletely
congealed oil phase
STORAGE OF SEMI-SOLIDS WHILE AWAITING QC TESTS
 considered to be “in-process” until it has been packaged
- time-consuming and delay the packaging process
- active substance in cream or ointment may react with the
storage container unless a highly resistant #316 stainless
steel
- placing non-reactive plastic sheeting in direct contact with
the cream and covering the container with tight-fitting
stainless steel lidprevent evaporation of water from cream
TRANSFER OF PRODUCT FOR FILLING AND PACKAGING
 can be done by:
- gravity fed
- pumped to the filling equipment
 homogenizers, pumps and filling equipment wherein pockets
of water or product may accumulate must be disassembles,
cleaned, sanitized and dried before reassembly
 manufacturing and packaging equipment should be sanitized
- chlorinated water, formalin or other suitable sterilant
followed by a bacteria-free water rinse
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- water and swab samples should be taken to verify

microbial elimination

Quality Control Assessment of Semisolid

A. USP requirements
 Storage and Labeling
 Microbial Limit Test
- screening S. aureusand P. aeruginosa
 Minimum fill
- assessment of content uniformity
 Assay of API
 Sterility Test
 In vivo
- Dermatopharmacokinetic studies
B. Non-USP requirements
 pH
 Water content assay by Karl Fischer method
 Foreign substances
 Metal particles detection tests
- ophthalmic oint only
 Leaker test
- ophthalmic ointment only

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