M1 LESSON 2: DOSAGE FORM DESIGN Flashcards
THE GENERAL AREA OF STUDY CONCERNED WITH THE FOLLOWING AREAS OF PHARMACEUTICAL DOSAGE FORM DESIGN
PHARMACEUTICS
PHARMACEUTICS FORM DESIGN
⦿Formulation
⦿Manufacture
⦿Stability
⦿Effectiveness
THE NEED FOR DOSAGE FORM
PRIMARY REASON
FOR THE SAFE AND CONVENIENT DELIVERY OF ACCURATE DOSAGE
To provide liquid preparation of substances that are either insoluble or unstable in the desired vehicle _________ or clear preparation ____________
Suspension and Solution
Why is there a need for dosage forms?
To protect drug substances from the destructive influences of atmospheric oxygen or humidity
- Coated Tablets
- Sealed Ampules
To protect drug substances from the destructive influence of gastric acid after oral administration
Enteric Coated Tablets
The formulation that best meets the goal of the product is the
“MASTER FORMULA”
to provide for insertion of drug into one of the body’s orifices
Rectal
Vaginal Suppositories
To provide placement of drug directly in the bloodstream or body tissues
Injection
To conceal bitter, offensive or salty taste or odor of a drug substance
Capsule, Coated Tablets, Syrups
To provide rate - controlled drug action
Controlled Release Tablet, Capsule, Suspension
PRE-FORMULATION CONSIDERATIONS
- Physical Description
- Microscopic examination
- Heat vaporization
- Melting point depression
- Phase rule
- Particle size
- Polymorphism
- Solubility
- Dissolution
- Membrane permeability
- Partition Coefficient
- Dissociation Constant
to provide optimal drug action from topical administration sites
Ointment
Creams
Transdermal Patch
Opthalmic Preparation
Ear Preparation
Nasal Preparation
(patched and its contents go through the layers of the skin)
Transdermal Patch
ability to get to a site of action and elicit response
◼biological property
Through Inhalation therapy
Inhalants, Inhalation Aerosols
THERAPEUTIC CONSIDERATIONS
- The nature of the illness
- The manner in which it is treated
- The age and the anticipated condition of the
patient
GENERAL CONSIDERATIONS In
DOSAGE FORM DESIGNS
- PHYSICAL AND CHEMICAL
PROPERTIES OF THE DRUG SUBSTANCE - THERAPEUTIC CONSIDERATIONS
physical description, particle size, crystalline structure, melting point and solubility
◼physical property
● The amount of heat absorbed when 1 g of liquid vaporizes
● Operation of implantable pumps delivering medicine
● Aerosol dosage forms
● Nasal inhalants for treating nasal decongestion
● Particle size affects vapor pressure; the smaller the particle size the greater the vapor pressure
HEAT VAPORIZATION
( structure, form, and reactivity
◼chemical property
◼the purity of the chemical substance is essential for its identification and for evaluation of its chemical, physical, and biological properties
PHYSICAL DESCRIPTION
HYDRATES AND SOLVATES
- Hygroscopic powder
- Deliquescent powder
- Efflorescent powder
- Organic Salt Consideration
- Organic Ester Consideration
Kinds of Solubility
Very Soluble
Freely Soluble
Soluble
Sparingly Soluble
Slightly Soluble
Very Slight Soluble
the smaller the particle size the greater the?
vapor pressure
● Gives an indication of particle size and size range of the raw materials along with the crystal structure
● Spherical and oval powders flow more easily than needle shaped powders
MICROSCOPIC EXAMINATION
● Used to determine the purity of the substance
● Change in melting point means the product is not pure
MELTING POINT DEPRESSION
- Crystal or amorphous
- Affects melting point and solubility
POLYMORPHISM
To produce biological response, the drug molecules must first cross the biologic membrane (acts as lipid barrier) permits absorption of lipid soluble substance by passive diffusion
MEMBRANE PERMEABILITY
is frequently added to increase solubility
Salt and ester forms
a useful device for relating the effect of the least number of independent variables (e.g., temperature, pressure, and concentration) upon the various phases (solid, liquid, and gaseous)that can exist in an equilibrium system containing a number of components.
PHASE RULE
◼ Should possess aqueous solubility for therapeutic effect
SOLUBILITY
Measure of drug’s lipophilic character
PARTITION COEFFICIENT
◼ Adjustment in __________ and ________ can increase solubility
particle size and pH
Rate-limiting step in the absorption process
DISSOLUTION
Certain physical and chemical properties of drug substances, including dissolution rate, bioavailability, content uniformity, taste, texture, color and stability are affected by the particle size distribution
Flow characteristics and sedimentation rates
Particle size influences oral absorption
PARTICLE SIZE
Change in melting point means the product is not?
pure
The extent of dissociation and ionization of the drug.
Extent of ionization has strong effect on drugs absorption, distribution, and elimination
pKa / DISSOCIATION CONSTANT
the time it takes for the drug to dissolved in the fluids at the absorption site.
Dissolution rate
absorb moisture from air then liquefy
Deliquescent powder
tends to absorb moisture from air
Hygroscopic powder
give up water of crystallization and may even become damp and pasty
Efflorescent powder
drugs are either weak acids or weak bases and have limited water solubility, often used the salts of the product to increase the aqueous solubility
ORGANIC SALT CONSIDERATION
Prepared for increase solubility, stability, and resistance to degradation after administration, use of prodrug
ORGANIC ESTER CONSIDERATION
PREFORMULATION STABILITY STUDIES
- Solid state stability of the drug alone
- Solution phase stability
- Stability in the presence of expected excipients
A solvolysis process in which drug interact with water to yield breakdown products of different chemical constitution
HYDROLYSIS
Amides, lactones, and lactams are also prone to hydrolytic decomposition
HYDROLYSIS
Example: Acetylsalicylic acid + water → salicylic
acid + acetic acid
HYDROLYSIS
Common to aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats and oils
OXIDATION
prone to hydrolytic decomposition
Amides, lactones, and lactams
MECHANISMS OF DEGRADATION
⦿ HYDROLYSIS
⦿ OXIDATION
Involves the loss of electrons from an atom or a molecule
OXIDATION
The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability are retained
PHYSICAL
Each active ingredient retain its chemical integrity and labeled potency, within specified limits.
CHEMICAL
Chemical stability is important for;
- Selecting storage condition (temperature,
light, humidity) - Selecting the proper container (glass vs plastic; clear vs amber)
- Anticipating interactions when mixing drugs
FIVE TYPES OF STABILITY
- CHEMICAL
- PHYSICAL
- MICROBIOLOGIC
- THERAPEUTIC
- TOXICOLOGIC
Is defined as the extent to which a product retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its manufacture
STABILITY
❑ Sterility or resistance to microbial growth is retained
❑ Antimicrobial agents that are present retain effective within specified limits
MICROBIOLOGIC
The therapeutic effect remain unchanged
THERAPEUTIC
No significant increase in toxicity occur
TOXICOLOGIC
Intermediate pH
sodium bi sulfite
Aqueous Prep
In liquid preparations, water can be frequently replaced or reduced through the use of substitute liquids such as;
◼Glycerin, propylene glycol, and alcohol
⦿ Use of buffering agents
◼For most hydrolyzable drugs, optimum stability is
on the acid side (pH 5 and 6)
High pH
sodium sulfite
Aqueous Prep
Ascorbyl palmitate
Oleagenous Prep
Low pH
hypophosphorous acid
Ascorbic acid
Aqueous Prep
Alpha-tocopherol
Oleagenous Prep
butyl hydroxy anisole
Oleagenous Prep
Factors that affects oxidation
- oxygen present as airspace within the container-nitrogen
- trace elements in drugs, solvent, container, and stopper- chelating agent eg. EDTA
(ethylenediaminetetraacetic acid) and calcium
disodium edetate - light- light resistance or opaque plastic
- temperature- cool place
- ph of the preparation- maintain solution in pH most favorable to its stability
APPEARANCE AND PALATABILITY
FLAVOR, FRAGRANCE AND ODOR
☺ low MW salts- salty ; high MW salts-bitter
🗉 Increase hydroxyl group, increase sweetness
🗉 Aldehyde is pleasant to taste
🗉 Nitrogen compound- (plant alkaloids)bitter /
(aspartame) sweet
FLAVORING
Organic esters, alcohols, and aldehydes are
pleasant to taste
salty
low MW salts
high MW salts
bitter
Increase hydroxyl group
increase sweetness
pleasant to taste
Aldehyde
plant alkaloids
bitter
aspartame
sweet
mask the bitter taste of drugs (Alkaloids,
Epsom salt)
Cocoa
mask salty taste of drugs (Chlorides of Na, K, and Ammonium)
Cinnamon, raspberry and orange flavors
combat acid or sour taste of drugs
Fruit or citrus flavors
prefer sweet, candy-like preparations with fruity flavors
Children
CONSIDERATIONS IN SELECTING A FLAVORANT
- TASTE OF THE DRUG SUBSTANCES
- AGE OF THE INTENDED PATIENT
prefer less sweet with tart rather than a fruit flavor pharmaceutical
Adult
180 to 200 times sweeter than sucrose;
contraindicated to phenylketonuria
ASPARTAME
SWEETENING AGENTS
- Sucrose
- Glycerin
- Saccharin
- Aspartame
- Cyclamate
- Acesulfame Potassium
- Stevia Powder
has carcinogenic potential; artificial sweetener
CYCLAMATE
Commonly used sweetener; from sugar cane/sugar beet
SUCROSE
less sweet than sucrose
GLYCERIN
300 times as sweet as sucrose; has a bitter after taste; carcinogenic in animal
SACCHARIN
COLORING PHARMACEUTICALS
⦿Plant dyes
⦿Minerals
⦿Synthetic
Achuete
Plant dyes
130 times as sweet as sucrose
ACESULFAME POTASSIUM
natural, non-toxic, safe and about 30 times sweeter than sucrose
STEVIA POWDER
Ferric Oxide (red); it is mixed in small portion with Zinc oxide imparting a characteristic pink color in Calamine powder
Minerals
natural, non-toxic, safe and about 30 times sweeter than sucrose
ACESULFAME POTASSIUM
can cause allergic reactions to patient who has sensitivity reaction to aspirin;
FDA requires the listing of this dye on the labels of food and ingested drugs containing the substance
FD & C Yellow No. 5 (tartrazine)
used in food, drugs, and cosmetics
FD & C
Coal tar dyes, anthracene dyes, aniline dyes
Synthetic
approved for use in drugs, some in cosmetics, and some in medical devices
D & C
changes of colorant according to toxicological findings
a) withdrawal of certification
b) the transfer of colorant from one certification category to another
c) the addition of new color to the list
the use of which is restricted to external parts of the body, not including the lips or any body surface covered by mucous membrane
External D & C
DRUG PRODUCTS REQUIRING COLORANTS
⦿ Capsules
⦿ Compressed tablets
⦿ Sugar-coated tablets
⦿ Suspension
DRUG PRODUCTS THAT DO NOT CONTAIN COLOR ADDITIVES
● Ophthalmic products
● Parenteral products
● Ointments
● Suppositories
Products requiring preservatives
- Syrups
- Emulsions
- Semisolid preparations
- Ophthalmic products
- Parenterals (multiple-dose package)
⦿ Chlorobutanol, benzalkonium chloride and phenyl
mercuric nitrate are the frequently used
preservatives in ophthalmic preparations because of
their low degree of irritant qualities
PRESERVATIVES
⦿ Acidic preservatives are more effective in acid media, while
alkaline preservatives are less effective in acid or neutral media
but more effective in alkaline media
⦿ Examples:
1. Benzoic acid and sodium benzoate
2. Alcohol
3. Cresol and Phenol
4. Chlorobutanol, Benzalkonium chloride and phenyl mercuric
acetate
5. Paraben
Products NOT requiring preservatives
- Alcoholic and hydroalcoholic solutions
● 15-20% alcohol in solution will prevent microbial contamination
● Elixirs, tinctures, and spirits are self-preserving - Large Volume Parenterals
the amount added to liquid preparations ranges from 0.0005 to 0.001% depending upon the colorant and the depth of color desired.
LIQUID DYES
FD and C lake is a pigment consisting of a substratum of alumina hydrate on which the dye is adsorbed or precipitated.
Suitable for coloring products in which the moisture levels are low.
LAKE PIGMENTS
Parenterals and Ophthalmic preparations are
sterilized by
, however may still require additional preservatives
AUTOCLAVING, BACTERIAL FILTRATION
and DRY HEAT
are the frequently used preservatives in ophthalmic preparations because of their low degree of irritant qualities
Chlorobutanol
Benzalkonium chloride
Phenyl mercuric nitrate
are less effective in acid or neutral media but more effective in alkaline media
alkaline preservatives
are more effective in acid media
Acidic preservatives
- Benzoic acid and sodium benzoate
- Alcohol
- Cresol and Phenol
- Chlorobutanol, Benzalkonium chloride and phenyl mercuric acetate
- Parabens (Methyl- and propylparaben) - antifungal
PRESERVATIVES
