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Dosage Form Design: Pharmaceutical
and Formulation Considerations
Chapter 4
Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
Objectives
After reading this chapter, the student will be able to:
1. List reasons drugs are incorporated into various dosage forms.
2. Compare and contrast the advantages/disadvantages of various
drug dosage forms.
3. Describe the information needed in preformulation studies to
characterize a drug substance for possible inclusion into a dosage
form.
4. Describe the mechanisms of drug degradation and provide
examples of each.
5. Describe the five types of drug instability of concern to the
practicing pharmacist.
6. Summarize approaches employed to stabilize drugs in
pharmaceutical dosage forms.
7. Calculate rate reactions for various liquid dosage forms.
8. Categorize various pharmaceutical ingredients and excipients.
Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
Dosage Form Design: Pharmaceutical and
Formulation Considerations
• The need for dosage forms
• General considerations in dosage form design
• Pharmaceutical ingredients and excipients
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General Considerations in Dosage Form
Design
• Preformulation Studies
– Physical Description
– Microscopic Examination
– Heat of Vaporization
– Melting Point Depression
– The Phase Rule
– Particle Size
– Polymorphism
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General Considerations in Dosage Form
Design (cont’d)
• Preformulation Studies (cont’d)
– Solubility
– Solubility and Particle Size
– Solubility and pH
– Dissolution
– Membrane Permeability
– Partition Coefficient
– pKa/Dissociation Constants
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General Considerations in Dosage Form
Design (cont’d)
• Drug and Drug Product Stability
– Drug Stability: Mechanisms of Degradation
– Drug and Drug Product Stability: Kinetics and Shelf
Life
– Rate Reactions
– Q10 Method of Shelf Life Estimation
– Enhancing Stability of Drug Products
– Stability Testing
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Pharmaceutical Ingredients and
Excipients
• Definitions and Types
• Handbook of Pharmaceutical Excipients
• Harmonization of Standards
• Appearance and Palatability
– Flavoring Pharmaceuticals
– Sweetening Pharmaceuticals
– Coloring Pharmaceuticals
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Pharmaceutical Ingredients and
Excipients (cont’d)
• Preservatives
– Sterilization and Preservation
– Preservative Selection
– General Preservative Considerations
– Mode of Action
– Preservative Utilization
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The Need for Dosage Forms
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The Need for Dosage Forms
• Mechanism for safe and convenient delivery of accurate
dosage
• Protection of drug from atmosphere
• Protection of drug from gastric acid (EC)
• Conceal bitter, salty, or offensive taste or odor
• Provide liquid preparations of insoluble drugs
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The Need for Dosage Forms (cont’d)
• Provide clear liquid dosage forms (solutions)
• Provide rate-controlled drug action
• Provide topical drug action (ointments, creams, patches,
ophthalmic, otic, nasal)
• Provide for insertion into body cavity
• Provide for placement into bloodstream
• Provide for inhalation therapy
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General Considerations in
Dosage Form Design
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Physiological States Altering Response to
Drugs
• Age (infants)
• Body weight
• Age (elderly)
• Time of administration
• Diurnal variation
• Tolerance
• Pregnancy
• Temperature
• Sex
• Physiological reserve
• Menopause
• Milieu
• Race
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Factors Affecting Drug Presentation to the
Body
• Portal of drug entry into the body
• Physical form of the drug product
• Design and formulation of the product
• Method of manufacture of the product
• Physicochemical properties of the drug and excipients
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Factors Affecting Drug Presentation to the
Body (cont’d)
• Physicochemical properties of the drug product
• Control and maintenance of location of drug at the
absorption site
• Control of the release rate of the drug from the drug
product
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Design of Drug Products
• Effectiveness
• Safety
• Reliability
• Stability
– Physical
– Chemical
– Microbiological
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Design of Drug Products (cont’d)
• Pharmaceutical elegance
– Appearance
– Organoleptic properties
• Convenience
– Ease of use
– Dosing frequency
– Consumer acceptance
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General Considerations in Dosage Form
Design
• Preformulation Studies
• Drug and Drug Product Stability
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Preformulation Studies
• Chemical characterization
• Physical characterization
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Physical Description
• Solids, liquids, gases
• Chemical Properties
– Structure, form, reactivity
• Physical Properties
– Description, particle size, crystalline structure,
melting point, solubility
• Biological Properties
– Ability to get to site of action and elicit a response
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Microscopic Examination
• Particle size
• Particle size range
• Crystal structure
• Particle shape
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Heat of Vaporization
• Vapor pressure
• Volatile drugs can migrate within a solid dosage form
• Personnel exposure
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Melting Point Depression
• Purity determination
• Identity
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The Phase Rule
• Phase diagrams
• Visual picture of presence of solid and liquid phases in
binary, ternary, and other mixtures
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Particle Size
• Dissolution rate
• Bioavailability
• Content uniformity
• Taste
• Texture
• Color
• Stability
• Flow characteristics
• Sedimentation rates
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Polymorphism
• Crystalline
• Amorphous
• Melting point variation
• Solubility differences
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Solubility
• Some aqueous solubility required for therapeutic efficacy
• Equilibrium solubility
• Solubility in different solvents
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Solubility and Particle Size
• Small increases in solubility can be achieved by particle
size reduction.
• Decreases in particle size may enhance dissolution rates.
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Solubility and pH
• pH:solubility profiles are important.
• pH can affect solubility.
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Dissolution
• Dissolution may be rate-limiting step in the absorption of
poorly soluble drugs.
• Can affect onset, intensity, and duration of response and
control overall bioavailability of the drug from the dosage
form
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Membrane Permeability
• pKa, solubility, and dissolution rate data can provide an
indication of absorption.
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Partition Coefficient
• Octanol:water partition coefficient often used in
formulation development
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pKa/Dissociation Constants
• Extent of dissociation or ionization
• Dependent on pH of medium
• Can affect absorption, distribution, and elimination
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Drug and Drug Product Stability
• Physical stability
• Chemical stability
• Shelf life of 2-3 years is generally desired
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Drug Stability: Mechanisms of
Degradation
• Hydrolysis, solvolysis
• Oxidation
• Other processes
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Drug and Drug Product Stability: Kinetics
and Shelf Life
• Chemical stability
• Physical stability
• Microbiological stability
• Therapeutic stability
• Toxicologic stability
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Rate Reactions
• Change of drug concentration with respect to time
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Q10 Method of Shelf Life Estimation
• Shelf life estimation
• Q10 = e{(Ea/R)[(1/T + 10) – (1/T)]}
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Enhancing Stability of Drug Products
• Excipients may be added to protect the drug
– Antioxidants
– Preservatives
– Chelating agents
– Buffering agents
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Stability Testing
• Done at each stage of product development
• Product containers and closures must be considered
• Temperature and humidity studies
• Light studies
• Changes in physical appearance, color, odor, taste, texture
• Chemical changes of drug degradation
• Pharmacist is last professional to check for quality and stability
prior to dispensing
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Kinetics and Drug Stability
Kinetics is important in all phases of the drug
development process as well as in quality control,
stability, bioavailability, and therapeutic drug
monitoring.
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Kinetics
• The study of the rate of chemical change and the way
this rate is influenced by conditions of concentration of
reactants, products, and other chemical species that may
be present and by factors such as solvent, pressure, and
temperature
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Importance of Kinetics
1. Selection of proper storage temperature
– Temperature
– Light
– Advising patient on storage conditions
2. Selection of proper container for dispensing
– Glass vs. plastic
– Clear vs. amber vs. opaque
– Cap liner selection
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Importance of Kinetics (cont’d)
3. Anticipation of interactions when mixing drugs and
dosage forms (incompatibilities)
– Active drugs
– Excipients
4. Dissolution determinations
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Importance of Kinetics (cont’d)
5. ADME Processes in pharmacokinetics
– A = Absorption
– D = Distribution
– M = Metabolism/Biotransformation
– E = Excretion
6. Drug action at the molecular level
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Responsibility of the Pharmacist
• Dispense oldest stock first and observe expiration dates.
• Store products under conditions stated in USP monographs
and/or labeling.
• Observe products for evidence of instability.
• Properly treat/label products that are repackaged, diluted,
or mixed with other products.
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Responsibility of the Pharmacist (cont’d)
• Dispensing in proper container with proper closure
• Informing/educating patients concerning proper storage
and use of products, including the disposition of outdated
or excessively aged prescriptions
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Why Do We Need Shelf Life Estimates?
• Expiration date given at room temperature:
– What is the expiration extension if refrigerated?
• Expiration date for refrig temperature given:
– How long if left at room temperature?
• Expiration date for room temperature given and it is
desired to heat (autoclave):
– What is the % decomposition?
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Why Do We Need Shelf Life Estimates?
(cont’d)
• Expiration date for refrigerated temperature given;
product stored at room temperature and then returned to
refrigerator:
– What is the new expiration date?
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Stability: USP
• The extent to which a product retains, within specified
limits, and throughout its period of storage and use (i.e.,
its shelf life), the same properties and characteristics
that it possessed at the time of manufacture
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Definitions
• Accelerated Testing
– Studies designed to increase the rate of chemical or
physical degradation by using exaggerated storage
conditions
• Bulk Drug Substance
– Active drug before formulation
• Drug Product
– Finished dosage form
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Definitions (cont’d)
• Expiration Date
– The date placed on the immediate container label of
a drug product that designates the date through
which the product is expected to remain within
specifications
• Expiration Dating Period
– The interval that a drug product is expected to
remain within the approved specifications after
manufacture
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Definitions (cont’d)
• Primary Stability Data
– Data on the drug product stored in the proposed
container-closure for marketing under storage
conditions that support the proposed expiration date
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Definitions (cont’d)
• Stability-Indicating Methodology
– Quantitative analytical methods based on the
characteristic structural, chemical, or biological
properties of each active ingredient of a drug
product, and that will distinguish each active
ingredient from its degradation products so that the
active ingredient content can be accurately measured
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Definitions (cont’d)
• Stability
– The capacity of a drug product to remain within
specifications established to ensure its identity, strength,
quality, and purity
• Strength
– A quantitative measure of active ingredient, as well as
other ingredients requiring quantitation
• Supportive Stability Data
– Data other than primary stability data
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Physical Paths of Instability
• 1. Polymorphs
– Cocoa butter, Cortisone Acetate
• 2. Crystallization
– Solutions, suspensions
• 3. Vaporization
– Flavoring agents, cosolvents, nitroglycerin
• 4. Particle sedimentation
– Suspensions
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Observing Products for Evidence of
Instability
• Solid Dosage Forms
– Hard/soft gelatin capsules
– Uncoated tablets
– Coated tablets
– Dry powders and granules
– Powders/granules for solution/suspension
– Effervescent tablets/granules/powders
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Observing Products for Evidence of
Instability (cont’d)
• Liquid Dosage Forms
–
Solutions/elixirs/syrups
–
Emulsions
–
Suspensions
–
Tinctures/fluid extracts
–
Sterile liquids
• Semisolids
–
Creams
–
Ointments
–
Suppositories
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Reaction Kinetics
• Want two things from kinetic data:
– Reaction order
– Reaction rate
• In considering the chemical stability of a pharmaceutical,
we need to know the REACTION ORDER, which is obtained
experimentally by measuring the REACTION RATE as a
function of concentration of the degrading drug.
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Reaction Kinetics
• The overall ORDER of a reaction is the SUM of the
EXPONENTS of the CONCENTRATION terms of the RATE
EXPRESSION.
• The ORDER with respect to EACH REACTANT is the
EXPONENT of the INDIVIDUAL CONCENTRATION terms in
the RATE EXPRESSION.
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Order of a Reaction
• An experimental quantity; merely provides information
about the way in which the rate depends on
concentration
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Factors Affecting Reaction Rates
• Temperature
• Dielectric Constant
• Ionic Strength
• Solvent Effect
• Catalysis
• Light
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Chemical Kinetics vs. Chemical Stability
• KINETICS
• STABILITY
• Several half-lives
• Down to about 85% of drug
remaining
• Involves complete dosage
form
• Pure systems
• Goal is to elucidate reaction
mechanisms.
• Goal is to establish an
expiration date.
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First-Order Rate Reaction
–dt
dC
= kC
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Half-Life
• Is meaningless to attempt to describe the time required
for ALL material to decompose (i.e., infinity)
• Therefore, reaction rate can be described by K or halflife, t1/2
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Zero-Order Rate Reaction
–dC\dt = k0
C = –k0t + C0
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Arrhenius Equation
log = k2\k1 = Ea (t2 – T1)\2.3 RT1T2
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Arrhenius Equation (cont’d)
• Energy of activation calculations
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Energy of Activation and Reaction Types
• 2-3 kcal/mole----------
• Diffusion or photolysis
• <10 kcal/mole---------
• Fast reactions stability
problems in development
• 10-30 kcal/mole-------
• Solvolytic process; most
drug degradation
• 50-70 kcal/mole-------
• Pyrolytic reactions
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Shelf Life Estimates
• Q10 = [K(T+10)]/KT
• =e[-(Ea/R) ({1/T+10} - {1/T}]
• Q10 =2
Lower limit
• Q10 = 3
Average, best estimate
• Q10 = 4
Upper limit
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t90 Equation for Shelf Life Estimates
• t90(T2) = t90(T1)/Q10(Delta T/10)
• Note: A “+” Delta T decreases shelf life and a “-” Delta T
increases shelf life
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Pharmaceutical Ingredients and
Excipients
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Definitions and Types
• Active pharmaceutical ingredients
• Pharmaceutical ingredients added to prepare a dosage
form
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Components of Drug Delivery Systems
• Drug
• Route of administration
• Suitable physical dosage form
• Use of chemical derivatives of the drug
• Control of certain physicochemical and/or biochemical
processes that alter the rate and extent of response
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Excipients
• Coloring agents
• Thickening agents
• Sweetening agents
• Suspending agents
• Flavoring agents
• Binding agents
• Surfactants
• Solvents
• Solubilizing agents
• Lubricants
• Antioxidants
• Perfumes
• Preservatives
• Fats and oils
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Handbook of Pharmaceutical Excipients
• Monographs on more than 250 excipients used in dosage
form preparation
• Additional excipients listed in Food Chemicals Codex and
National Formulary
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Harmonization of Standards
• International harmonization of excipients
• Pharmaceutical industry is multinational
• Uniform standards needed
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Appearance and Palatability
• Compliance issues
• Odor, color, and taste
• Important for all age groups, especially pediatrics and
geriatrics
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Flavoring Pharmaceuticals
• Complex area
• Important for compliance
• Color and taste should generally match
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Flavor
• Taste
• Touch
• Smell
• Sight
• Sound
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Four Primary Tastes
• Sweet
• Bitter
• Sour
• Salty
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Four Primary Tastes (cont’d)
• TASTE
SLIGHT
MOD
STRG
• Sweet/Sucrose
5%
10%
15%
• Sour/Citric Acid 0.05
0.10
0.20
• Salty/NaCl
0.4
0.7
1.0
• Bitter/Caffeine
0.05
0.10
0.20
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Causative Factors for Taste
• Hot
Mild, counterirritant
• Astringent
Tannins, acids
• Coarseness/Grittiness
Texture
• Coolness
Neg heat of solution
• Greater sensitivity to odors than to tastes
• Females have greater sensitivity to odors than males
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Flavor/Odor Correlations with Chemical
Structure
• Sour taste
H+
• Saltiness
Anions & cations
• Bitter
High-MW salts
• Sweet
Polyhydroxyl cmpds,
polyhalogenated cmpds,
alpha amino acids
• Sharp, biting
Unsaturation
• Camphoraceous odor
Tertiary “C” atom
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Flavor/Odor Correlations with Chemical
Structure (cont’d)
• Pleasant odor
Ketones
• Methylparaben
Floral, gauze-pad
• Propyl/butyl paraben
Numbing mouthfeel
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Flavor Selection
• Immediate flavor identity
• Rapid full flavor development
• Acceptable mouthfeel
• Short aftertaste
• No undesirable sensations
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Flavoring Techniques
• Blending
– Fruit===========Sour
– Salty/Sweet/Sour===Bitter
– Salty===========Decreases sourness
– Salty===========Increases sweetness
• Overshadowing
– Methylsalicylate====Glycyrrhiza
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Flavoring Techniques (cont’d)
• Physical
– Formation of insoluble compounds
– Emulsification of oils
– Effervescence
– High-viscosity fluids
– Coating tablets
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Flavoring Techniques (cont’d)
• Chemical
– Adsorption-silica gel
– Complexation
• Physiological
– Anesthetic effect====Menthol (mint)
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Raspberry Concentrate Imitation
• Vanillin
0.180 g
• Indol
0.004 g
• Aldehyde C16
0.240 mL
• Diacetyl
0.060 mL
• Phenylethyl alcohol
240 mL
• Aldehyde C14
0.015 mL
• Aldehyde C18
0.015 mL
• Aldehyde C20
0.400 mL
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Raspberry Concentrate Imitation (cont’d)
• Orange flower oil
0.005 mL
• Ethyl butyrate
0.120 mL
• Benzyl acetate
0.075 mL
• Alpha novoviol
0.400 mL
• Beta novoviol
0.200 mL
• Lemon oil
0.060 mL
• Propylene glycol qs
100 mL
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Flavor Selection Guide
• Salty
Butterscotch/Maple
• Bitter
Wild Cherry/Licorice
Chocolate Mint
• Acrid/Sour
Raspberry/Fruit
Berry/Acacia Syrup
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Flavor Selection Guide (cont’d)
• Oily
Peppermint/Anise
Wintergreen
• Sweet
Fruit/Berry/Vanilla
• Acid
Citrus
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Sweetening Pharmaceuticals
• Complex area
• Natural vs. synthetic
• Heat stability
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Sweetening Agents
• Dextrose
• Mannitol
• Saccharin
• Sorbitol
• Sucrose
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Coloring Pharmaceuticals
• Lighter shades preferred
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Coloring Agents
• Dyes: FD&C, D&C, Ext D&C
• Lakes: Calcium and aluminum salts
• Liquids: 0.001% to 0.0005%
• Powders: 0.1%
• Caramel
• Ferric oxide: Red/yellow
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Coloring Agents (cont’d)
• Red No. 1, Ponceau 3R, Cherry Red
– 9.8/5
• Blue No. 1, Brilliant Blue, Blue-Green
– 20/20
• Yellow No. 5, Tartrazine, Lemon Yellow
– 20/18
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Preservatives
• Sterilization and Preservation
• Preservative Selection
• General Preservative Considerations
• Mode of Action
• Preservative Utilization
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Sterilization and Preservation
• Some products must be sterile
– Injectables
– Ophthalmics
• Sterilization
– Autoclave
– Filtration
– Dry heat
– Irradiation
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Preservative Selection
• Dosage form
• Route of administration
• Compatibility with excipients
• Container and closure compatibility
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General Preservative Considerations
• Range of activity
• Concentration required
• pH requirements
• Compatibility
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Mode of Action
• Modification of cell membrane permeability
• Lysis and cytoplasmic leakage
• Irreversible coagulation of cytoplasmic constituents
• Inhibition of cellular metabolism
• Oxidation of cellular constituents
• Hydrolysis
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Preservative Utilization
• Benzoic acid/sodium benzoate
• Alcohol
• Phenylmercuric nitrate/acetate
• Phenol
• Cresol
• Chlorobutanol
• Benzalkonium chloride
• Methylparaben/propylparaben
• Others
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