Dosage Form Design: Pharmaceutical And Formulation Considerations Flashcards
Study on formation, manufacture, stability, and effectiveness of pharmaceutical dosage forms
Pharmaceutics
Selective use of these non medicinal agents
Pharmaceutical ingredients
Uses of pharmaceutical ingredients
solubilize
thicken
stabilize
flavor
suspend
dilute
preserve
efficacious
suspend
emulsify
color
appealing
closure forms.
THE NEED FOR DOSAGE FORM DESIGN
- To protect the drug substance from the destructive influences of atmospheric oxygen or humidity. (Coated tablets)
- To protect the drug substance from the destructive influence of gastric acid after oral administration. (Enteric-coated)
- To conceal the bitter, salty or offensive taste or odor of a drug substance. (Capsules, Flavored syrups)
- To provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle. (Suspension
- To provide clear liquid dosage forms of substances. (Syrups, Solutions)
- To provide rate-controlled drug action.
(Controlled-release tablets) - To provide optimal drug action from topical administration sites. (Ointments,Creams, Transdermal patches)
- To provide for insertion of a drug into one of the body’s orifices (Suppositories)
- To provide placement of drugs directly in the bloodstream or body tissues (Injections)
- To provide for optimal drug action through inhalation therapy (Inhalants, Inhalation aerosols)
GENERAL CONSIDERATIONS IN
DOSAGE FORM DESIGN
Determine desired product type
Develop and examine initial formulations master formula
Factors to consider before formulation of a medicinal agent in one or more dosage forms
- Therapeutic matters
- manner it is treated
- age and anticipated condition of the patient.
PREFORMULATION STUDIES
- PHYSICAL DESCRIPTION
- MICROSCOPIC EXAMINATION
- MELTING POINT DEPRESSION
- PHASE RULE
- PARTICLE SIZE DISTRIBUTION
- EVALUATION OF POLYMORPHISM
- SOLUBILITY
- DISSOLUTION RATE
- MEMBRANE PERMEABILITY
- BASIS OF PH-PARTITION COEFFICIENT
- PKA / DISSOCIATION CONSTANTS
- STABILITY
Three properties of Physical Description
- Physical Property
- Chemical Property
- Biologic Property
What are under the Physical Properties?
- Crystalline structure
- particle size
- melting point solubility
What are under the Chemical Properties?
- Structure
- Form
- Reactivity
Its ability to get to site of action and elicit a biologic response
Biologic Property
What is under the Microscopic Examination?
particle size
size range
crystal structure
Determines the: purity of the substance compatibility of various subs before inclusion in the dosage form
MELTING POINT DEPRESSION
Two Types of Substances
Pure subs: sharp melting point
Impure subs: depressed melting point
Phase diagrams constructed determines:
- existence & extent of the presence of solid and liquid phases in binary, ternary & other mixtures
PHASE RULE
- PARTICLE SIZE DISTRIBUTION
affects : physical–chemical properties of drug sub’s:
- dissolution rate
- bioavailability
- content uniformity
- stability taste
- texture
- flow properties
- absorption
- sedimentation rate
substances can exist in more than one crystalline form
- EVALUATION OF POLYMORPHISM
Different physical-chemical properties (incl. melting pt. & solubility)
Polymorphic forms
- Determined by equlibrium solubility method
Drug possess aqueous solubility - for therapeutic efficacy.
- Insoluble compounds: incomplete/erratic absorption
- Solubility & particle size
- Solubility & pH
SOLUBILITY
time for the drug to dissolve in the fluids at the absorption site (rate-limiting step in absorption).
DISSOLUTION RATE
increased by decreasing the particle size
Dissolution rate of drugs
use a highly water soluble salt of the parent Substance.
for higher dissolution rate
2 methods in determining dissolution rates of chemical compounds
1.Constant surface method
2.Particulate dissolution
- intrinsic dissolution rate of the agent
- Characteristic of compound & solvent under fixed experimental conditions mg dissolved/min/cm square
Constant surface method
- Weighed amount of powdered sample + dissolution medium in constant agitation system
- to study the influence of particle size, surface area, and excipients upon the active agent
Particulate dissolution
- describes the: relationship of diffusion & dissolution of the active drug in the dosage form & when administered in the body
FICK’S LAW (LAW OF DIFFUSION)
relates to a steady state flow
1st Law of Fick’s
relates to a change in conc. of drug with time, at any distance, or a nonsteady state of flow
2nd Law of Fick’s
Everted intestinal sac
- determines degree & rate of passage of drug through the membrane sac by passive & active transport
- early assessment of passage of drug molecules across biologic membranes
To produce a biologic response______
drug molecule must first cross a biologic membrane
measured by the oil-water coefficient
Molecules’ lipophilic character
Interrelationship at the absorption site & absorption characteristics of various drugs:
- Dissociation constant
- lipid solubility
- pH
BASIS OF PH-PARTITION COEFFICIENT
Indication of absorption expectations:
Data from basic physicochemical studies: pKa, solubility & dissolution rate
Interrelationship at the absorption site & absorption characteristics of various drugs:
- Dissociation constant
- lipid solubility
- pH
strong effect on formulation & pharmacokinetic parameters of the drug
extent of ionization of drug
- for the pharmacist important:
*predicting precipitation in admixtures
*calculating solubility of drugs at certain pH values
determined by potentiometric titration
extent a product retains within specified limits and through its period of storage and use
STABILITY
Stability studies conducted in the
preformulation phase:
- Solid-state of the drug alone
- Solution phase with the expected excipients
Evaluation of physical and chemical stability of pure drug substances - important for preformulation.
DRUG AND DRUG PRODUCT STABILITY
Chemically drug substances with different susceptibilities toward chemical instability:
-alcohols
-phenols
-aldehydes
-ketones
-esters
-ethers
-acids
-salts
-alkaloids
-glycosides
-others.
Drug Stability : Mechanisms of Degradation
MOST FREQUENTLY ENCOUNTERED DESTRUCTIVE PROCESS:
-Hydrolysis (solvolysis process)
-Oxidation
- (drug) molecules interact with water molecule to yield breakdown product.
- susceptible to the hydrolytic process: esters, substituted amides, lactones, and lactams
Hydrolysis (solvolysis process)
Oxidation
-loss of electrons from an atom or molecule;
-involves free radicals (free radicals (molecules or atoms containing one or more unpaired electrons).
-destructive to: aldehydes, alcohols, phenols, sugars, alkaloids & unsaturated fats & oils
OTHER DESTRUCTIVE PROCESS IN PHARMACEUTICAL PREPARATIONS
Polymerization
reaction between two or more identical molecules with resultant formation of new & generally larger molecule
Polymerization
Process where one or more active chemical groups is removed:
- Chemical decarboxylation
- Deamination
Decarboxylation decomposition of RCOOH & release of CO2
Chemical decarboxylation
Removal of nitrogen containing group from organic amine (ex. Insulin)
Deamination
DRUG AND DRUG PRODUCT STABILITY:
- KINETICS AND SHELF LIFE
- RATE REACTIONS
- Q10 METHOD
A. KINETICS AND SHELF LIFE
(FIVE TYPES OF STABILITY)
CHEMICAL AI
PHYSICAL
MICROBIOLOGIC
THERAPEUTIC
TOXICOLOGIC
retains chemical integrity and labelled potency w/in the specified limits
CHEMICAL AI
original physical properties, appearance, palatability, uniformity, dissolution and suspendability are retained.
PHYSICAL
sterility/resistance to microbial growth
MICROBIOLOGIC
therapeutic effect remains unchanged
THERAPEUTIC
no significant increase in toxicity occurs.
TOXICOLOGIC
description of the drug concentration with respect to time.
RATE REACTIONS
estimate the shelf life of a product that has been stored or to be stored under a different set of conditions.
Q10 METHOD
IMPORTANCE OF DRUG STABILITY
in preclinical testing and in clinical (human) trials
- for a true and accurate assessment of the drug/drug prod evaluated
marketed drug product
- for the safety and effectiveness when distributed and during the entire course of its shelf-life and use
water reduced or eliminated from the system
ENHANCING STABILITY (DRUGS SUBJECTED TO HYDROLYSIS)
waterproof protective coating applied in the tablet.
water-liable drugs
major determinant in stability
pH
optimum stability
pH 5 & 6
increases stability
buffering agents
- catalyst to oxidation reactions
- preparations packaged in light resistant or opaque containers
LIGHT
