PHARMACEUTICAL MANUFACTURING WITH REGULATORY PHARMACY College Of Pharmacy 2024

CHAPTER 3 • Nontoxic, adequately soluble, compatible, acceptable

FORMULATION OF LIQUIDS AND SUSPENSION taste and odor
PRESERVATION
INTRODUCTION
Advantage of Liquid  combination of two or more preservatives are needed to
 Ease of administration for patients who have difficulty of achieve the desired antimicrobial effect
swallowing solid dosage forms  effective designed preservative system must retain its
 A drug must be in solution in order to be absorbed antimicrobial activity for the shelf-life of the product
• Immediate, rapid, efficient - evaluate by microbial evaluation
Disadvantages of Liquid  Phenol – oldest and best known but not used in oral
 Instability of drugs in liquid form pharmaceutical preservatives due to characteristic odor and
 Required pharmaceutical elegance instability when exposed to oxygen
SOLUBILITY  Neutral, mercurial and quaternary ammonium compounds is
 Depends on used in ophthalmic, nasal &parenteral
• Nature and intensity of forces present in the solute PHARMACEUTICAL PRESERVATIVES
• Resultant solute-solvent interaction
 Equilibrium solubility
• one in the final product
• Fixed temperature
 Solubility of the solute is not exceeded even at temperatures
as low as 4oC
Role of pH
 pH environment for adequate solubility
• Must not be in conflict with other product
requirements
- Stability, physiologic compatibility
• Adequately buffered
- Adequate capacity in the pH range
- Biologically safe
- Little or no deleterious effect on the stability of the final SUBJECTIVE PRODUCT CHARACTERISTICS
product 1. Sweetening Agents
- Permit acceptable flavor and color 2. Viscosity Control
Effective ph Ranges of Pharmaceutical Buffers 3. Flavors
4. Appearance
SWEETENING AGENTS
 Major portion of the formula
1. Sucrose
• available in highly purified form at reasonable cost
• stable at pH 4-8
• disadvantage: Caplocking
2. Liquid glucose (corn syrup)
• imparts body and sweetness
• prepared by partial hydrolysis of starch with strong acid
3. Artificial sweeteners
• soluble in water. alcohol, polyols
Role of Co-Solvency • desired sweetness at low concentration
 Co-solvents increase the water solubility of the solute • Aspartame – 200x
• Ethanol, sorbitol, glycerin, propylene glycol • Saccharin – 250 – 500 x; bitter aftertaste
 works by reducing interfacial tension between predominantly • Cyclamate – 15-30
aqueous solutions and the hydrophobic solute VISCOSITY CONTROL
 Also used to improve the solubility of volatile constituents  Purpose of increasing viscosity:
used as flavor and aroma • Improve pourability
Role of Complexation  can be achieved by:
 Addition of complexing agent to promote solubility of the • Increase sugar concentration
drug • Incorporate viscosity-adding agents
 Solubility of the drug in a complex is limited by the solubility  Polyvinylpyrrolidone (PVP), methyl cellulose, sodium
of the complex or in some cases, the solubility of the carboxymethylcellulose (NaCMC)
complexing agent  May form molecular complexes and affect the activity of the
• EDTA parent drug
 Microbial contamination  May impede drug release and absorption by resisting dilution
• Health hazard by gastrointestinal fluids
• Product stability FLAVORS
 Sources of microbial contamination: Raw materials,  Process of choosing flavor:
processing containers and equipment, manufacturing a. Selection – flavor guide
environment, operators, packaging materials, user b. Evaluation – taste test (trial and error)
 Criteria:  Effective masking of taste sensations
• Effective against a broad spectrum of microorganisms • salty, bitter, sweet, sour
• Physically, chemically and microbiologically stable  Desensitizing agents

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PHARMACEUTICAL MANUFACTURING WITH REGULATORY PHARMACY College Of Pharmacy 2024

• Impart own flavor and odor  Water is the most important constituent in a liquid product
• Ex: Menthol and chloroform • distillation or ion-exchange treatment
Flavor Selection  RMQC
 Additional processing
EQUIPMENT
 Mixing tanks equipped with:
• a means of agitation
• measuring devices for large and small amounts of solids
and liquids
• filtration system for the final polishing
• and/or sterilization of the solution
 Bulk handling: Tote Bins
 Thoroughly cleaned and sanitized (or sterilized if possible)
before use
EQUIPMENT
 sterilized by: alcohol, boiling water, autoclaving, steam or dry
heat
APPEARANCE
 liquid is transported to the filling line either manually or by
 Color and clarity
pumping (gravity flow)
 Color should be consistent with flavor
• distance the product travels between the holding tank and
 Purification step achieves clarity
filling line should be held to
 Particulate matter
• a minimum to reduce the chance of
• Lint and fibers from the solvent
• microbial contamination
• Trace quantities of insoluble contaminants
• all lines should be easy to disassemble, clean and sanitize
 Polishing, filtration, clarification
• portable laminar flow units
• Extraction of biologically active material from the filter pad
COMPOUNDING PROCEDURE
Filtration System
 Dilute solutions with rapidly dissolving materials
 Classes of Filter Media
• Charging the solute into the solvent
 Concentrated solutions or solutions with slowly dissolving
materials
• Application of heat
 Metering of purified water into the mixing tank
• To check malfunctioning metering devices
• volumetric (laboratory) vs gravimetric (large scale)
 Solutes present in small concentrations
• Predissolved prior to mixing with main portion
• complete solution should be confirmed at every stage
 Amount and type of filter aid
• Generally <0.5 g/L
PACKAGING
 Specific method for filling depends on
• Liquid characteristics (viscosity, surface tension, foam
STABILITY
• producing qualities, compatibility)
1. Chemical Stability
• Type of package
2. Physical Stability
• Production output
Chemical Stability
 Filling methods:
 Magnified in solutions
• Gravimetric, volumetric, constant level methods
 How fast the drug degrades and what are the consequences
Gravimetric
of degradation?
 filling the containers to a given weight disadv: large
 Important factors
containers and highly viscous
• pH
Volumetric
• Solvents
 positive displacement piston action
• Exposure to light and heat
 highly viscous liquid may cause piston to seize, resulting in
 Consequences
line breakdown or loss of fill accuracy
• Suboptimal blood levels
 thin liquids may flow past the piston causing uncontrollable
• Products of degradation may be toxic
dripping
Physical Stability
Constant Level Methods
 Viscosity, color, clarity, taste, odor
 controlling the fill of each unit
 Packaging
 fill amount is varied by adjusting the height to which the
• May decrease bioavailability
container is filled
MANUFACTURING CONSIDERATIONS
1. Raw Materials
2. Equipment
3. Compounding Procedure
4. Packaging
RAW MATERIALS
 Conform to specifications
• Identity, purity, uniformity, microbial contamination

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PHARMACEUTICAL MANUFACTURING WITH REGULATORY PHARMACY College Of Pharmacy 2024

DESCRIPTIVE TERMS OF SOLUBILITY  Solutions used to treat conditions of the mouth and differ
with gargles by swishing the liquid in the oral cavity
Types
• Therapeutic Mouthwashes
- Used for the treatment of oral cavity problems like
gingivitis and stomatitis
• Cosmetic Mouthwashes
- Used for their deodorant, refreshing or antiseptic effect for
halitosis
AURAL OR OTIC SOLUTIONS
 Also known as “ear drops”
 Solutions of one or more active ingredients which exert a
local effect in the ear
- Treatment of otitis media/externa
- Removal of cerumen
FACTORS AFFECTING SOLUBILITY NASAL SOLUTIONS
• Temperature- An important factor in determining the  Aqueous solutions administered in nasal passages for the
solubility of a drug and in preparing its solution. management of nasal conditions [decongestant]
• Pressure- The solubility of a pure chemical substance at a  They are isotonic and slightly buffered at pH 5.5 to 6.5
given temperature and pressure is constant. [similar to nasal secretions]
• Particle size- The finer the powder, the greater the surface IRRIGATION SOLUTIONS
area that comes in contact with the solvent and the more  Are solutions used to bathe or wash surgical wounds,
rapid the dissolving process. incisions or body tissues
METHODS OF PREPARATION OF SOLUTIONS  They must pass the USP requirements regarding sterility,
Solution by Chemical Reaction total solids present and bacterial endotoxin tests
• Prepared by reacting two or more solutes with each other Examples:
in a suitable solvent - NaCl irrigation for wounds
Solution by Distillation SWEET/VISCID SOLUTIONS
• Dissolving the volatile principles from a drug inside a SYRUPS
copper wire cage which allows the free passage of vapors  Are concentrated aqueous solutions of sugar/sucrose or
and boiling water other sugar-substitutes
Solution by Extraction Types
• Maceration – soaking or steeping • Medicated Syrups
• Percolation – sieving - Syrups with therapeutic use
• Digestion – maceration with gentle heat • Nonmedicated Syrups
• Infusion – maceration with cold or boiling water - Utilized as flavored vehicles
• Decoction – boiling in water for 15 minutes Methods of Preparations
CLASSES OF SOLUTION • Simple solution or solution with agitation
1. Aqueous solution • Solution with the aid of heat
2. Aromatic Waters - Generally used or perfuming and/or • Percolation
flavoring agents • Addition of sucrose to an already prepared flavored or
AQUEOUS SOLUTIONS medicated liquid
ENEMAS HONEYS
Types  Are thick liquid preparations similar to syrups in terms of
• Evacuation Enema active constituent [invert sugar]
- Usually administered 1 to 2 pints  Most common sweetening agent before sugar was available
- Barium sulfate enema MUCILAGES
- Fleet enema  Are thick, viscid, adhesive aqueous solutions which can be
• Retention Enema prepared by:
- Usually administered <150 mL Aminophylline [for - Dispersion of gum and water
asthma] - Extraction of the mucilaginous principles from vegetable
- Hydrocortisone [for steroid therapy] drugs
DOUCHES  Prone to decomposition
 Solutions directed against a part or body cavity for cleansing  Used primarily in suspending insoluble substances in liquids
or antiseptic effect JELLIES
Types  Class of gels in which the structural coherent matrix
- Eye douche  contains a high portion of liquid usually water
- Pharyngeal douche  Used as a lubricant for surgical gloves, catheters and rectal
- Vaginal douche thermometers
- Nasal douche NON AQUEOUS SOLUTIONS
 They are introduced into appropriate body cavity by the use SPIRITS
of a bulb syringe  Also known as “essences”
GARGLES
 Are alcoholic or hydroalcoholic solutions of volatile oils or
 Solutions used to treat the pharynx and the nasopharynx by other aromatic substances
forcing air from the lungs through the gargle that is held in
 Usually contain 60% ethanol
the throat and subsequently expectorated
 They are used as flavoring agent and some for their medicinal
valve
MOUTHWASHES
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PHARMACEUTICAL MANUFACTURING WITH REGULATORY PHARMACY College Of Pharmacy 2024

METHODS OF PREPARATIONS Powdered Extracts

• Simple Solution  These are dry extracts or powders used in compounding
- Example: Aromatic Spirit of Ammonia powders, capsules and tablets
• Solution with Maceration TINCTURES
- Example: Peppermint Spirit  Are alcoholic or hydroalcoholic solutions prepared from
• Solution by Chemical Reaction animal or vegetable sources
- Example: Ethyl Nitrite Spirit  They have a 1:10 ratio or 10% w/v concentration
- Chemical Reaction: NaNO2 + EtOH –H2SO4 Ethyl nitrite Methods of Preparations
• Distillation • Process M
• Brandy - Example: Sweet orange peel tincture
- Spirit vini vitis • Process P
- Fermented wine from juice of ripe grapes - Example: Belladonna tincture
• Whiskey • Simple Solution
- Spiritus frumentii - Example: Iodine tincture
- Fermented cereals and malted grains FLUIDEXTRACTS
Storage  Are liquid preparations of vegetable drugs usually prepared
• Tight, light-resistant containers by percolation
• Cool place and away from flame Types of Percolation
ELIXIRS • A – uses an alcoholic menstruum
 Clear, sweetened, pleasantly-flavored hydroalcoholic • B – uses two menstruum
solutions intended for oral use • C – fractional or divided percolation
 Are usually less sweet and less viscous and they have the less • D – uses boiling water as menstruum
ability to mask the offensive taste of drugs compared to • E– alternative to A, uses a percolator that is loner/greater
syrups diameter to increase the concentration of drugs
COLLODIONS SUSPENSION
 Are non-aqueous preparations that contain “pyroxillin” in a  Are preparations containing finely divided drugs/solid
mixture of ethyl ether and ethanol [3:1] particles [suspensoids] distributed
 Commonly employed as protectives and are applied to the  throughout a vehicle in which the drug exhibits a minimum
skin with a fine camel’s hair brush or a glass applicator degree of solubility
LINIMENTS COMPONENTS OF SUSPENSION
 Also known as “embrocations” • Suspensoid – dispersed phase
 They are applied externally with friction and rubbing • Solvent – dispersing medium
Types • Suspending agent – a third component added to stabilize
- Oily liniments are used when massaging is desired the suspension
- Alcoholic liniments are used for their penetrating effects CLASSES OF SUSPENDING AGENTS
TOOTHACHE DROPS • Natural Polysaccharides
 Also known as “odontalgicum” - Tragacanth
 Are preparations intended for the temporary relief of - Acacia
toothache - Agar
 It usually contains eugenol from clove oil, benzocaine and - Starch
alcohol - Guar gum
OLEOVITAMINS - Carrageenan
 Are composed of vegetable oils or fish liver oils and vitamin - Sodium alginate
concentrates • Semisynthetic Polysaccharides
 Source of vitamins A and D - Methylcellulose
EXTRACTIVES/GALENICALS - Microcrystalline cellulose
 Are preparations obtained from plant and animal tissues with - Hydroxyethylcellulose
the aid of solvents and extraction procedures - Sodium carboxymethylcellulose
Classes of Extractives • Clays
- Extracts - Bentonite
- Tinctures - Talc
- Fluidextracts - Kaolin
EXTRACTS • Synthetic Thickeners
 Are concentrated preparations or vegetable and animal drugs - Carbomer
obtained by the removal of the active ingredient of the - Colloidal silicon dioxide
respective drugs with suitable menstrual, evaporation of all - Polyvinyl alcohol
or nearly all of the solvent and adjustments of the residual • Miscellaneous
masses to the prescribed standards - Gelatin
Forms of Extracts TYPES OF SUSPENSIONS
Semiliquid Extracts Ready-to-Use Form
 These are liquid of syrupy consistency used as - Suspensions that are already distributed through a liquid
concentrates in the manufacture or pharmaceuticals vehicle with or without stabilizers and other additives
Pillular or Solid Extracts Dry Powders/Mixtures for Reconstitution
 These are soft extracts with plastic-like consistency
preferred when compounding ointments and preparation - Suspensions that generally contain a powder mixture of drug
of pill masses and other ingredients to be diluted and agitated with a
specified quantity of vehicle at the time of dispensing

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PHARMACEUTICAL MANUFACTURING WITH REGULATORY PHARMACY College Of Pharmacy 2024

 These are wetting agents containing both hydrophilic and

FEATURES OF A GOOD SUSPENSION lipophilic groups
 Slow sedimentation rate and resuspendable Examples
 Constant particle size • Anionic Emulsifying Agents [pH of >8]
 Pourability - Triethanolamine oleate [soap]
- Sodium lauryl sulfate [sulfonate]
KINDS OF PHARMACEUTICAL SUSPENSIONS • Cationic Emulsifying Agents [pH of 3 to 7]
LOTIONS - Benzalkonium chloride
 Are liquid suspensions or dispersions intended for external • Nonionic Emulsifying Agents [pH of 3 to 10]
application to the body - Spans [a polyoxyethylene derivative]
 They are prepared by: - Tweens [a polyoxyethylene derivative]
- Trituration FINELY DIVIDED SOLIDS
- Precipitation  These include the colloidal clays
MAGMAS AND MILKS Examples
 Are aqueous suspensions of insoluble inorganic drugs that • Bentonite [aluminum silicate]
differ from gels in that the suspended particles are usually • Veegum [magnesium aluminum silicate]
larger TYPES OF EMULSIONS
GELS O/W Emulsions
 Are defined as semisolid systems consisting of dispersions  Emulsions with an oleaginous internal phase and an
made up of either small inorganic particles or large organic aqueous external phase
molecules enclosing and interpenetrated by a liquid  Can be diluted with water
Terminologies Related to Gels  Usually intended for oral use or preparations and also for
• Imbibition external preparations if it is desired to have a preparation
- Is the taking up of a certain amount of liquid without a that is easily removed from the skin with water
measureable increase in volume W/O Emulsions
• Swelling  Emulsions with an aqueous internal phase and an
- Is the taking up of a liquid with an increase in volume oleaginous external phase
• Syneresis  Can be diluted with oleaginous solutions
- Gel shrinking due to separation of dispersion medium  Used for external preparations that can be applied evenly
• Thixotrophy on the skin and if emollient effect is desired
- Is a reversible gel-sol formation THEORIES OF EMULSIFICATION
EMULSIONS Surface Tension Theory
 A heterogeneous system of two immiscible liquids  Emulsifiers tend to lower the interfacial tension of the two
COMPONENTS immiscible liquids, reducing the repellent force between
• Internal or Discontinuous Phase the liquids and diminishing each liquid’s attraction for its
- The dispersed phase [solute] usually in globule form own molecules.
• External or Continuous Phase  Thus the surfactants facilitate the breaking up of large
- The dispersing medium [solvent] usually serving as a globules into smaller ones, which then have a lesser
vehicle for the internal phase tendency to reunite or coalesce
• Emulsifying Agent Oriented-Wedge Theory
- Emulsifier or the third component necessary in preparing  Emulsifiers orient themselves in a liquid in a manner
stable emulsions reflective of their solubility.
- MOA: Lowering of interfacial tension between the two  The phase in which the emulsifier is more soluble
immiscible liquids becomes the external phase.
CLASSES OF EMULSIFIERS  Generally, if the emulsifying agent is hydrophilic it will
NATURAL EMULSIFIERS promote an o/w emulsion and if it is hydrophobic it will
Plant-Derived favor a w/o emulsion.
 They are usually carbohydrate materials that form Plastic or Interfacial Film Theory
hydrophilic colloids when added to water and generally  Emulsifiers surround the droplets of the internal phase
produce o/w emulsions  as a thin layer of film adsorb on the surface of the drops,
Examples the film prevents the contact and coalescence of the
- Acacia – frequently used, 35% dispersion in water dispersed phase leading to a more stable emulsion.
- Tragacanth – thickener for acacia-emulsified products, METHODS OF PREPARATION
6% dispersion in water Continental or Dry Gum method
- Agar – thickener for acacia-emulsified products  It is also referred to as 4:2:1 method
- Pectin  It involves the preparation of a “primary emulsion”, then
- Chondrus add water all at once and the mixture is triturated
Animal-Derived immediately, rapidly and continuously until the primary
 They are usually protein materials and favor the formation emulsion is creamy white and produces a crackling sound.
of o/w emulsions English or Wet Gum method
Examples:  4:2:1 ratio of oil, water and gum
- Gelatin [makes the emulsion too fluid]  It involves the preparation of a “mucilage”, then the oil is
- Egg yolk slowly added in portions and the mixture is triturated to
- Casein emulsify the oils.
- Wool fat Bottle or Forbes Bottle method
- Cholesterol  2:2:1 or 3:2:1 ratio of oil, water and gum
SYNTHETIC EMULSIFIERS

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 Useful for the extemporaneous preparation of emulsions

from volatile oils or oleaginous substances of low viscosities
 Prepare a primary emulsion, then water is added in
portions and thoroughly shaken after each addition.
In Situ Soap or Nascent Soap method
 A method that has lead to the preparation of soaps acting
as the emulsifying agents
 It is prepared by mixing diluted alkaline solution with a fatty
acid resulting to the formation of soap
Examples
- Soft soaps
PROBLEMS IN EMULSIONS
Creaming or Flocculation
 Refers to the aggregation of oil
 globules that rise to the top of the
 emulsion
Sedimentation
 Refers to the aggregation of oil globules that fall to the
bottom of the emulsion
Cracking or Breaking or Coalescence
 Refers to the complete separation of internal andexternal
phases of the emulsion
Phase Inversion
 A process where the emulsion changes from o/w to w/o or
vice versa

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