Post on 01-Mar-2018
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DOSAGE FORM CONSIDERATION:
PREFORMULATION
By: LOUJESSA D. ARCELO
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DOSAGE FORM CONSIDERATION
The need for dosage forms
General considerations in dosage
form designPreformulation Studies
Drug and Drug Product StabilityPharmaceutical ingredients and
excipients
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Dosage Form Design
PHARMACEUTICS
• study on the: formulation, manufacture, stability, andeffectiveness of pharmaceutical dosage forms
Pharmaceutical ingredients or
excipients• solubilize thicken stabilize flavor
• suspend dilute preserve efficacious
• suspend emulsify color appealing closure forms.
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Requirements of a proper design &
formulation of dosage form
Considerationof drug
substances:
compatible with oneanother - stable,
efficacious,attractive, easy toadminister & safe
*manufacturedunder appropriate
measures of qualitycontrol & packaged
in containers to
make product stable *labeled to promotecorrect use & storedunder conditions tomaximize shell life
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THE NEED FOR DOSAGE
FORMS
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Mechanism for safeand convenientdelivery of
accurate dosage
Protection ofdrug from
atmosphere (CT)
Protection ofdrug from
gastric acid(EC)
Conceal bitter,salty, or
offensive taste
or odor
Provide liquidpreparations ofinsoluble drugs
THE NEED FOR DOSAGE FORMS
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Provide clearliquid dosage
forms
Provide rate-
controlled drugaction
Provide topicaldrug action
Provide for
insertion intobody cavity
Provide forplacement intobloodstream
Provide for
inhalationtherapy
THE NEED FOR DOSAGE FORMS
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GENERAL CONSIDERATIONS
IN DOSAGE FORM DESIGN
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General Considerations in Dosage
Form Design
Determine desired product type
• framework for product development.
Develop and examine initial formulations ofthe product:
• desired features: drug release profile, bioavailability,
clinical effectiveness• pilot plant studies and production scale-up.
MASTER FORMULA
- formulation that best meets the goals of the product
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General Considerations in Dosage
Form Design
Factors to consider before formulationof a medicinal agent in one or more
dosage forms
• Therapeutic matters (nature of the illness)
• manner it is treated (locally or throughsystemic action)
• age and anticipated condition of the
patient.
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Design
of DrugProducts
Effectiveness
Safety
Reliability Stability
Pharma-ceutical
elegance
Convenience
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PREFORMULATION
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PREFORMULATION
Is branch of Pharmaceutical science that utilizes
biopharmaceutical principles in the determination of
physicochemical properties of the drug substance.
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Safe handlingof ingredients
andequipments
Propersequence of
addition ofingredients
Optimumenvironmental
conditions
Precautions tobe observed
Expectedinteraction
Need foroverages
PREFORMULATION
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Preformulation Studies1. Physical Description
• Description, particlesize, crystalline
structure, meltingpoint, solubility
• Ability to get tosite of action andelicit a response
• Structure,form,reactivity
• Liquid drugsare used to amuch lesserextent thansolid drug Solids,
liquids,gases
ChemicalProperties
PhysicalProperties
BiologicalProperties
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COLOR ODOUR TASTE
OFF-WHITE PUNGENT ACIDIC
CREAM-YELLOW SULFUROUS BITTER
SHINY FRUITY SWEET
AROMATIC TASTELESS
ODOURLESS TASTELESS
Preformulation Studies1. Physical Description: ORGANOLEPTIC PROPERTIES
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Particle size
Particle size
range
Crystal
structure
Particle
shape
Preformulation Studies2. Microscopic Examination
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Preformulation Studies3. Heat of Vaporization
Vapor pressure
Volatile drugscan migratewithin a soliddosage form
Personnelexposure
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Puritydetermination
Identity
Preformulation Studies4. Melting point depression
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Phase diagrams constructed determines:
existence & extent of the presence of solid and liquid
phases in binary, ternary & other mixtures
Preformulation Studies5. Phase Rule
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affects : physical – chemical properties of drug
substances:
*dissolution rate bioavailability content uniformity
stability taste texture
flow properties absorption sedimentation rate
Preformulation Studies6. Particle Size
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Preformulation Studies7. Polymorphism
substances can existin more than onecrystalline form
Polymorphic forms –
diff. physical-chemicalproperties (melting pt.
& solubility)
Crystalline andAmorphous
Evaluation of:*crystal structure(microscopy, IRspectroscopy, thermal
analysis, x-ray diffraction)
POLYMORPHS
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If solubility is
<1mg/ml
Solubility:4°C and 37°C.
Preformulation Studies8. Solubility
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Preformulation Studies8. Solubility
Description Parts of solvent required for
one part of solute
Very soluble < 1
Freely soluble 1 - 10
Soluble 10 - 30
Sparingly soluble 30 - 100Slightly soluble 100 - 1000
Very slightly soluble 1000 - 10,000
Insoluble > 10,000
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SOLUBILITY
Some aqueoussolubility
required fortherapeuticefficacy
Chemicalnature and
type of drug;chemical
modification
SOLUBILITYand PARTICLE
SIZE
SOLUBILITY
and pH
Preformulation Studies8. Solubility
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Points to consider:
• Salts prepared from strong acids orbases• Salts prepared from weaker acid or
base• Injections should ideally lie in the pH
range 3-9• Oral syrups should not be too acidic
Preformulation Studies8. Solubility: SALTS
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SURFACTANT
low
concentration?
Very high
concentration?
Preformulation Studies8. Solubility: SURFACTANT
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Endothermicreaction
Exothermicreaction
Preformulation Studies8. Solubility: EFFECT OF TEMPERATURE
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PARTICLESIZE
Very coarse(#8)
Coarse(#20)
Moderatelycoarse(#40)
Fine (#60)
Very fine(#80)
Preformulation Studies8. Solubility: PARTICLE SIZE
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Dissolution
rate Suspendability
Uniform
distribution
Penetrability Lack ofgrittiness
Preformulation Studies8. Solubility: PARTICLE SIZE
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Preformulation Studies8. Solubility and pH
adjustment ofpH of solventwhere drug is
dissolved toadjustsolubility
Weak acidic
or basic drugs
pH onsolubility and
stability
cosolvents ,complexation,micronization,
or soliddispersion
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Addition ofco-solvent
pH changemethod
Reduction ofparticle size
Temperaturechange
method
Addition ofSurfactant
Complexation
Preformulation Studies8. Solubility: INCREASE SOLUBILITY
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Preformulation Studies8. Solubility: INCREASE SOLUBILITY
PG, ehtanol,
glycerin, sorbitol,PEG, Glyceryl
formal, glycofurol,
ethyl carbamate,ethyl lactate and
dimethyl
acetamide.
For weak acidic
drug? For weak base
drug?
CO-SOLVENT pH CHANGE METHOD
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Preformulation Studies8. Solubility: CO-SOLVENT
It must be non-toxic. Non-
irritating.
It should be
able tosolubilize thedrug in given
solvent.
It should be
able to crossthe
membrane.
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Preformulation Studies8. Solubility: INCREASE SOLUBILITY
ENDOTHERMICREACTION?
EXOTHERMICREACTION?
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Preformulation Studies8. Solubility: INCREASE SOLUBILITY
SURFACTANT
IONIC
Cationic
Anionic
ZwitterionicNON-IONIC
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Preformulation Studies8. Solubility: INCREASE SOLUBILITY
CATIONIC
Cetyl TrimethylAmmoniumBromide (CTAB)HexadecylTrimethylAmmonium
Bromide, andotherAlkyltrimethylAmmoniumSalts,CetylpyridiniumChloride (cpc)
ANIONIC
Sodium DodecylSulphate (SDS),AmmoniumLauryl Sulphateand other alkylsulfate salts,
SodiumLaurethSulphate, alsoknown asSodium LaurylEther Sulphate
(SLES).
ZWITTERIONIC
DodeclyBetamineand Dodecly
Dimethylamine Oxide
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Preformulation Studies8. Solubility: SURFACTANT (HLB SCALE)
Most antifoaming agents
W/O Emulsifying agents
Wetting and Spreading agents
O/W Emulsifying agents
Detergents and Solubilizing agents
0
3
6
9
12
15
18
TWEEN(polyoxyethylen
ederivative of
span)
sorbitan
ester
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Time for the drug to dissolve in the fluids atthe absorption site
• (rate-limiting step in absorption)• Can affect onset, intensity, and duration of response and
control overall bioavailability of the drug from the dosageform
Increasing dissolution rate:
• decreasing the particle size.
• use a highly water soluble salt of the parent substance.
Preformulation Studies9. Dissolution Rate
f l i S di
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• 1st law: relates to a steady stateflow
• 2nd law: relates to a change in conc.of drug with time, at any distance,or a nonsteady state of flow
Fick’s law(law of
diffusion)
• Describes the relationship between
particle size, diffusion layercoefficient, and drug saturatedsolubility (Dissolution)
Noyes-WhitneyEquation
Preformulation Studies9. Dissolution Rate
P f l i S di
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MembranePermeability
early assessmentof passage ofdrug moleculesacross biologic
membranes
drug molecule
must cross abiologic
membrane
The biologicmembrane (lipid
barrier) pKa, solubility, anddissolution rate
data can provide anindication ofabsorption.
EVERTEDINTESTINAL
SAC
Preformulation Studies10. Membrane Permealibility
P f l i S di
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Preformulation Studies11. Partition Coefficient
octanol – water
partitioncoefficient
P f l i S di
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Preformulation Studies12. pKa / Dissociation Constants
Extent ofdissociation or
ionization
Dependenton pH ofmedium
Can affect
absorption,distribution,
andelimination
P f l i S di
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Can be calculated by Henderson Hasselbach
equation-
For acidic drugs….pH= pKa+ log [ionized drug]
[unionized drug]
For basic drugs….pH= pKa+ log[unionized drug]
[ionized drug]
Preformulation Studies12. pKa / Dissociation Constants
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DRUG AND DRUG PRODUCT STABILITYStability is 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 its manufacture.
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INSTABILITY
Undesired
change inperformance
Substantialchanges in
physicalappearance ofthe dosage form
Cause product
failures
Drug Stability: Mechanisms
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Drug Stability: Mechanisms
of Degradation
Hydrolysis(solvolysisprocess)
(drug) moleculesinteract with watermolecule to yield
breakdown product.
esters, substitutedamides, lactones,
and lactams
Oxidation
loss of electronsfrom an atom or
molecule; involvesfree radicals
aldehydes, alcohols,phenols, sugars,
alkaloids &unsaturated fats &
oils
Photolysis
decompositionby light
1. suitable packing in
amber-coloured
bottles
2. cardboard outers
3. aluminium foil over
wraps
D d D P d t St bilit
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Drug and Drug Product Stability:
A. Kinetics and Shelf Life
• active ingredient retains chemical integrityand labeled potency within the specifiedlimits.
CHEMICAL STABILITY
• original physical properties, appearance,palatability, uniformity, dissolution and
suspendability are retained.
PHYSICAL STABILITY
• sterility/resistance to microbial growthMICROBIOLOGICAL
STABILITY
• therapeutic effect remains unchangedTHERAPEUTIC
STABILITY
• no significant increase in toxicity occurs.TOXICOLOGIC
STABILIY
D d D P d t St bilit
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Drug and Drug Product Stability:
B. Rate Reactions
description of the drugconcentration with respect to time
ZERO ORDERKINETICS
(NONLINEARPHARMACOKINETICS)
FIRST ORDERKINETICS
(LINEARPHARMACOKINETICS)
D d D P d t St bilit
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Drug and Drug Product Stability:
C. Q10 METHOD
Q10
METHOD
AcceleratedStabilityStudies
estimate the shelflife of a product thathas been stored or
to be stored under adifferent set of
conditions.
the rate constantincreases for a
100C temp.increase
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E N H
A N C I N
G D
R U
G
S T A B I
L I T Y
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HYDROLYSIS OXIDATION
ENHANCING STABILITY
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ENHANCING STABILITY
HYDROLYSIS
Reduction orelimination of
water
Tablet:
waterproofprotective
coating
pH: pH 5 & 6
Buffer ing
agent
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ENHANCING STABILITY
HYDROLYSIS
unstable antibioticdrugs (aq. prepn
desired)
Tightly closedcontainers
l iqu id
formulat ion:
water replacedby substitute
liquids.
in jectable
produc ts :
anhydrous
vegetable oilsmay be used assolvent
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ENHANCING STABILITY
OXIDATION
prepared indry state
packaged insealed
containers withair replaced by
inert gas
addantioxidants
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alpha tocopherol,butylhydroxyanisole &
ascorbylparmitate
AQUEOUS PREPARATIONOLEAGINOUS/UNCTOUSPREPNS:
Na2SO3, NaHSO3,Na2S2O5, ascorbic
acid
ENHANCING STABILITY
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OXIDATION
TRACE METALS
purification ofsource of
contaminant
complexing or
binding metal(chelating agents)
Ca disod edetate
& EDTA)
LIGHTlight-resistant or
opaquecontainers
TEMPE-RATURE
Cool place
pH Buffering agent
ENHANCING STABILITY
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Conditions Temperature
Freezer -20°C – (-10°C)
Refrigerator 2°C - 8°C
Cold Not exceeding 8°C
Cool 8°C – 15°C
Warm 30°C – 40°C
Excessive Heat Above 40°C
NOTE: Article for storage in cool place – stored in refrigerator.
Article for storage in a controlled room temperature may be stored
in a cool place.
STORAGE TEMPERATURE
Other destructive process in
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Other destructive process inpharmaceutical preparations
Reaction between
two or moreidentical molecules
with resultant
formation of new &
generally larger
molecule
(formaldhyde)
Decarboxylation
decomposition ofRCOOH & release of
CO2
Deamination
removal of nitrogencontaining group from
organic amine (ex.
Insulin)
POLYMERIZATION OTHER PROCESSES
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Enumerate 3 The instability possibilities in
different formulations: (1 whole yellow paper)
1. Oral Solutions
2. Parenteral Preparations
3. Suspension
4. Emulsion
5. Semi-solid Preparations
6. Capsule and Tablets
ASSIGNMENT.
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STABILITY TESTING
Requisite data to demonstrate and
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Before approval for marketing, a product’s stability must
be assessed with regard to its formulation;
the influence of its pharmaceutical ingredients;
the influence of the container and closure;
the manufacturing and processing conditions (e.g., heat);
packaging components;
conditions of storage;
anticipated conditions of shipping, temperature, light, andhumidity;
and anticipated duration and conditions of pharmacy shelf
life and patient use
q
document the product’s stability
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Expiration Date
The date placed on the immediate container
label of a drug product that designates thedate through which the product is expected
to remain within specifications
STABILITY TESTING
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Duration Storage
Condition
Humidity
Long Term 12 mos. 25°C±2 60±5% RH
Intermediate 6 mos. 30°C±2 60±5% RH
Short Term 6 mos. 40°C±2 75% RH
STABILITY TESTING
Scientific data pertaining to the stability
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Scientific data pertaining to the stability
of a formulation
leads to:
*prediction of the expected shelf-life of the
proposed product
*redesign of the drug (to more stable salt or
ester form)
*reformulation of the dosage form.
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PHARMACEUTICAL INGREDIENTS
(EXCIPIENTS)
PHARMACEUTICAL INGREDIENTS &
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PHARMACEUTICAL INGREDIENTS &
EXCIPIENTS
Stabilizers (antioxidants and
chelating agents) – prevent
decomposition Solvents – used to dissolve the
drug substance
Flavors and Sweeteners – make
product more palatable
Colorants – enhance appeal
Preservatives – prevent
microbial growth
Diluents or fillers – to increase
bulk of the formulation
Binders – adhesion of thepowdered drug and
pharmaceutical substances
Antiadherents or lubricants –
assist smooth tablet formation
Disintegrating agents –
promote tablet breakup after
administration
FOR SOLUTIONS FOR TABLETS
PHARMACEUTICAL INGREDIENTS &
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HARMONIZATION OF STANDARDS
United States Pharmacopeia – National
Formulary (USP-NF)
British Pharmacopeia
European Pharmacopeia
Japanese Pharmacopeia
PHARMACEUTICAL INGREDIENTS &
EXCIPIENTS
A d P l bili
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Appearance and Palatability
Flavoring PharmaceuticalsColor, odor, texture, and taste must coincide/balance
In general, LMW salts are salty while HMW salts are bitter.
In organic chemistry, the more hydroxyl group present,
increase sweetness.
Different types of flavors: Natural, Artificial, Spice
Delaney Clause
Flavor Type of Drug
Cocoa Bitter drugs
Fruit or citrus Sour and acid-tasting drugs
Cinnamon, Orange, Raspberry &
others
Salty drugs
D l Cl
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Delaney Clause
"No additive shall be deemed to besafe if it is found to induce cancer
when ingested by man or laboratoryanimals or if it is found, after tests
which are appropriate for theevaluation of the safety of food
additives, to induce cancer in man oranimals."
Fl S l i G id
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Salty Butterscotch/Maple
Bitter Wild Cherry/Licorice
Chocolate Mint
Acrid/Sour Raspberry/Fruit
Berry/Acacia Syrup
Oily Peppermint/Anise
Wintergreen
Sweet Fruit/Berry/Vanilla
Acid Citrus
Flavor Selection Guide
S i Ph i l
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Sweetening Pharmaceuticals
Dextrose
Mannitol
SaccharinSorbitol
Sucrose
S t i Ph ti l
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Aspartame – - 1st artificial sweetener (1958 amendment)
w/ requirement for pre-marketing proof of safety.
- Aspartame breaks down in the body into three basic components:
phenylalanine, aspartic acid, and methanol.- Acesulfame potassium (nonnutritive sweetener)
- structurally similar to saccharin (USP approved)
-180 – 200 times as sweet as sucrose, excreted unchanged in
the urine;- more stable than aspartame
- Stevia (Stevia rebaudiana bertoni)
– new sweetening agent: natural, nontoxic, safe,
30x sweeter than cane sugar/sucrose
Sweetening Pharmaceuticals
S t i Ph ti l
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Saccharin & cyclamate - used in foods
-“generally recognized as safe” (before the
amendment’s passage)- use on rats: developed incidence of bladder
tumors (cancer)
- continued availability but warning labels be used
-cyclamates (banned) - possible carcinogenicity,
genetic damage, testicular atrophy
Sweetening Pharmaceuticals
C l i Ph ti l
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Coloring PharmaceuticalsUsed in pharmaceutical preparations for esthetics
Certain agents that are not pharmaceutical
colorantsSulfur (Yellow)
Riboflavin (Yellow)
Cupric sulfate (Blue)
Ferrous sulfate (Bluish green)
Cyanocobalamin (Red)
Red Mercuric iodide (Vivid Red)
Aniline dyes
Coloring Pharmaceuticals
C l i Ph ti l
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Coloring Pharmaceuticals
Coal tar (pix carbonis)
- thick black viscid liquid
- by product of destructive distillation of coal.- source of synthetic coloring agents in pharm.
products in the middle of the 19th century
Dyes – added to pharmaceutical preps. in the
form of diluted solutions
Lakes - commonly used in the form of fine
dispersions or suspensions.
C l i Ph ti l
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Coloring Pharmaceuticals
90% of the dyes used in the products - synthesized from
derivative of benzene (aniline)
FDA - regulates use color additives in foods, drugs, and
cosmetics (Federal Food, Drug, and Cosmetic Act of 1938)- FD&C color additives - foods, drugs, and cosmetics
- D&C color additives - drugs, some in cosmetics &
medical devices
- external D&C color additives - restricted to external parts
of the body (not including the lips and other parts that
are covered by mucous membrane)
F t i l ti d
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Factors in selecting dyes
Solubility ofprospective dye
pH & pH stabilityof the preparation
to be colored
Dyes must bephotostable
PRESERVATIVES
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PRESERVATIVES
liquid and semisolid preparations
- must be preserved against microbialcontamination.
St ili ti d P ti
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Sterilization and Preservation
some types of pharmaceutical products
(ex. Ophthalmic and injectable
preparations)
- sterilized by physical methods :
*autoclaving (20min at 15 lb. press. &121°C, dry heat at 180°C for 1 hr)
*bacterial filtration.
Sterili ation and Preser ation
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Preparations that provide excellent growth
media for microbes
- aqueous preparations: syrups, emulsions,
suspensions
- semi solid preparations particularly creams.
- hydro-alcoholic & most alcoholic preparation
*may not require addition of chemical
preservative
Sterilization and Preservation
Sterilization and Preservation
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prevent microbial growth:
*15% alcohol in acid media
*18% alcohol in alkaline media.
Alcohol-containing pharmaceuticals (elixirs, spirits,
and tinctures) - self sterilizing and do not require
additional preservation.
Sterilization and Preservation
Preservative Selection
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Preservative Selection
Considerations in selecting preservative inpharmaceutical preparations:
1. Prevents the growth of the type ofmicroorganisms ( contaminants of the
preparations)2. Soluble enough in water to achieve adequate
concentrations in aqueous phase with two or morephase systems
3. Proportion of preservative remainingundissociated at the pH of preparation (canpenetrate the microorganism & destroy itsintegrity).
Preservative Selection
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Preservative Selection
4. Concentration of the preservative does not
affect the safety/comfort of the patient
5. With adequate stability and not reduced in
concentration by chemical decomposition/volatilization
6. Compatible with all other formulative
ingredients and does not interfere with them7. Does not adversely affect the preparation’s
container or closure.
Preservative Selection
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Preservative Selection
Dosage formRoute of
administration
Compatibilitywith
excipients
Container andclosure
compatibility
General Preservative Considerations
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Range of
activity
Concentration
required
pHrequirements
Compatibility
General Preservative Considerations
Mode of action: Mechanisms preservative interfere
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with microbial growth, multiplications, and metabolism:
1. Modifications of cell membranepermeability & leakage of cell constituents(partial lysis)
2. Lysis and cytoplasmic leakage
3. Irreversible coagulation of cytoplasmicconstituents
4. Inhibition of cellular metabolism byinterfering with enzyme systems/inhibition ofcell wall synthesis
5. Oxidation of cellular constituents andHydrolysis
PRESERVATIVES
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PRESERVATIVES
Benzoic acid/sodium benzoateAlcohol Phenylmercuric nitrate/acetate
PhenolCresolChlorobutanol Benzalkonium chlorideMethylparaben/propylparabenOthers
PRESERVATIVES
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PRESERVATIVE PROBABLE MODE OF ACTION
Benzoic acid, Boric acid, p-
hydroxybenzoates
Denaturation of proteins
Phenols and chlorinated phenoliccompounds
Lytic & denaturation action on cytoplasmicmembranes and for chlorinated preservatives,
also by oxidation of enzymes
Alcohols Lytic & denaturation action on membranes
Quaternary compounds Lytic action on mebranes
Mercurials Denaturation of enzymes by combining withthiol (-SH groups)
PRESERVATIVES
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