(2) PHARMACEUTICS: Dosage Form Design (Pharmaceutical and Formulation Considerations)

pharmaceutics

- study on the formulation, manufacture, stability, and effectiveness of pharmaceutical dosage forms

pharmaceutical ingredients or excipients

- selective use of these non medicinal agents

- uses: solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, color, flavor, efficacious, appealing closure forms

labeled

_____ to promote correct use and stored under conditions to maximize shell life

manufactured

______ under appropriate measures of quality control and packaged in containers to make product stable

coated tablets

- dosage form that protect the drug substance from the destructive influences of atmospheric oxygen or humidity

enteric coated

- dosage form that protect the drug substance from the destructive influence of gastric acid after oral administration

capsules, flavored syrups

- dosage form that conceal the bitter, salty, or offensive taste or odor of a drug substance

suspension

- dosage form that provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle

syrups, solutions

- dosage form that provide clear liquid dosage forms of substances

controlled-release tablets

- dosage form that provide rate-controlled drug action

ointments, creams, transdermal patches

- dosage form that provide optimal drug action from topical administration sites

suppositories

- dosage form that provide for insertion of a drug into one of the body's orifices

injections

- dosage form that provide placement of drugs directly in the bloodstream or body tissues

inhalants, inhalation aerosols

- dosage form that provide for optimal drug action through inhalation therapy

master formula

- formulation that best meets the goals of the product

preformulation studies

- drug be chemically and physically characterized

- define the nature of the drug substance

physical description, chemical properties, purity

- preformulation studies

- physicochemical description

physical description

- particle size, crystalline structure, melting point solubility

chemical properties

- structure form reactivity

purity

- property of a chemical substance for identification and for evaluation of its chemical, physical, and biologic properties

preformulation studies microscopic examination

- indication of particle size and size range of the raw material along with the crystal structure

- information generated in formulation processing attributable to changes in particle or crystal characteristic changes of the drug molecules or particles

preformulation studies melting point depression

- determines the purity of the substance

- compatibility of various substance before inclusion in the dosage form

- pure substance: sharp MP

- impure substance: depressed MP

phase diagrams

- determines the existence and extent of the presence of solid and liquid phases in binary, ternary, and other mixtures

preformulation studies phase rule

- phase diagrams is constructed to determine the existence and extent of the presence of solid and liquid phases in binary, ternary, and other mixtures

- particle size affects the physical-chemical properties of drug substances dissolution rate, stability, flow properties, bioavailability, taste, absorption, content uniformity, texture, sedimentation rate

particle size

- affects the physical-chemical properties of drug substances dissolution rate, stability, flow properties, bioavailability, taste, absorption, content uniformity, texture, sedimentation rate

preformulation studies polymorphism

- substances can exist in more than one crystalline form

- evaluation of crystal structure, IR spectroscopy, solvate form

equilibrium solubility method

- excess amount of drug + solvent = shaken at constant temperature over a prolonged period of time until equilibrium is obtained

preformulation studies solubility

- determined by equilibrium solubility method

- drug possess aqueous solubility (for therapeutic efficacy)

- insoluble compounds: incomplete/erratic absoprtion

- solubility, particle size, and pH

- drug formulated to liquid product: adjustment of pH of solvent where drug is dissolved to adjust solubility

weak acidic or basic drugs

- requires extremes in pH outside or accepted physiologic limits or that may cause stability problems with formulation ingredients

preformulation studies dissolution rate

- time of drug to dissolve in the fluids at the absoprtion site (rate-limiting step in absoprtion)

- it is increased by decreasing particle size

- to increase, use a highly water soluble salt of the parent substance

constant surface method

- determines dissolution rate

- intrinsic dissolution rate of the agent

- characteristic of compound and solvent under fixed experimental conditions

- mg dissolved/min/cm square

particulate dissolution

- determines dissolution rate

- 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

fick's law (law of diffusion)

- describes the relationship of diffusion and dissolution of the active drug in the dosage form and when administered in the body

- 1st law: relates to a steady state flow

- 2nd law: relates to a change in concentration of drug with time, at any distance, or a nonsteady state of flow

everted intestinal sac

- determines the degree and rate of passage of drug through the membrane sac by passive and active transport

biologic membrane (lipid barrier)

- permits absorption of lipid soluble substance by passive diffusion

molecules' lipophilic character

- measured by the oil-water coefficient

preformulation studies partition coefficient

- selection of appropriate extraction solvents, drug stability use of salting-out additives and environmental concerns

preformulation studies pKa/dissociation constants

- extent of ionization of drug

- strong effect on formulation and pharmacokinetic parameters of the drug

- determined by potentiometric titration

- predicts precipitation in admixtures

- used to calculate solubility of drugs at certain pH values

stability

- extent a product retains within specified limits and through its period of storage and use

- conducted in the preformulation phase: solid-state of the drug alone, solution phase, with the expected excipients

solid-state of the drug alone, solution phase, with the expected excipients

- stability studies conducted in the preformulation phase

alcohols, phenols, aldehydes, ketones, esters, ethers, acids, salts, alkaloids, glycosides, and others

- chemically drug substances with different susceptibilities toward chemical instability

hydrolysis (solvolysis process)

- destructive process

- (drug) molecules interact with water molecule to yield breakdown product

- susceptible to this process: esters, substituted amides, lactones, and lactams

oxidation

- destructive process

- loss of electrons from an atom or molecule

-involves free radicals (molecules or atoms containing one or more unpaired electrons)

- destructive to: aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats and oils

chemical stability

- active ingredient retains chemical integrity and labeled potency within the specified limits

- must know reaction order and rate

- important for selecting:

- storage conditions (temp., light, humidity)

- proper container for dispensing

- anticipating interactions when mixing drugs and dosage forms

physical stability

- original physical properties, appearance, palatability, uniformity, dissolution and suspendability are retained

microbiologic stability

- sterility/resistance to microbial growth

therapeutic stability

- therapeutic effects remains unchaged

Toxicologic Stability

- no significant increase in toxicity occurs

rate reactions

- description of the drug concentration with respect to time

Q10 method

- estimate the shelf life of a product that has been stored or to be stored under a different set of conditions

5 and 6

pH for optimum stability

trace metals

- when present in drug, solvent, container or stopper, becomes source of difficulty in preparing stable solutions of oxidizable drugs

- eliminated by:

- purification of source of contaminant

- complexing or binding metal by using specialized agents (chelating agents - Ca disod edatate and EDTA)

polymerization

- destructive process

- reaction between two or more identical molecules with resultant formation of new and generally larger molecule (formaldehyde)

chemical decarboxylation and deamination

- process where one or more active chemical groups removed

decarboxylation

- decomposition of RCOOH and release of CO2

deamination

- removal of nitrogen containing group from organic amine

- ex. insulin

accelerated stability testing

- use of exaggerated conditions of temperature, humidity, light and others

- accelerated temperature

- 6 months study at 40 deg celsius with 75% relative humidity

short term accelerated studies

- determines most stable of the proposed formulations for a drug product

- lesser temperature and humidity

- 30 deg celsius and 60% humidity

stress testing

- temperature elevations in 10 deg celsius increments higher than used in accelerated studies

- employed until chemical or physical degradation

long term stability studies

- product is subjected to different climatic zones (temperature and humidity) nationally and internationally

- predicted from the data generated from continuing stability studies

- 12 months minimum and conducted at 25 deg celsius +/- 2 deg celsius and at a relative humidity of 60% +/- 5%

labelling

- essential for product stability and efficacious use

containers

- standards for packaging of pharmaceuticals by manufacturers are contained in the CGMP

light-transmission test

- test of glass or plastic

vapor-transmission test

- test for plastics, moisture barrier tests, toxicity studies for plastics

sterility and permeation test

- test for parenteral containers

drug stability

- test for all packaging

container

- holds the article and is or may be in direct contact with the article

immediate container

- in direct contact with the article at all times

closure and container

- part of the container

- clean and dry prior to its being filled with the drug

well-closed container

- protects the contents from extraneous solids and from the loss of the article under ordinary conditions of handling, shipment, storage, and distribution

tight container

- protects the contents from contamination by extraneous liquids, solids, or vapors from loss of the articles, and from efflorescence, deliquescence, or evaporation under the ordinary or customary conditions of handling, shipment, storage and distribution and is capable of tight re-closure

Hermetic container

- impervious/resistant to air or any other gas under the ordinary or customary conditions of handling, shipment, storage, and distribution

- those sterile are generally used to hold preparations intended for injection or parenteral administration

Single dose container

- quantity of drug contained is intended as a single dose and when opened cannot be resealed with assurance that sterility has been maintained

- includes fusion-sealed ampules, pre-filled syringes and cartridges

Single dose container

- designed to hold a quantity of drug intended for administration as a single dose promptly after the container is opened

- single unit package is termed a unit dose package when dispensed to a patient

- may be performed on a large scale by a manufacturer or distributor or on a smaller scale by the pharmacy dispensing the medication

Multiple dose container

- hermetic container that permits withdrawal of successive portions of the contents without changing the strength or endangering the quality or purity of the remaining portion

- referred as vitals

- contain more than a single unit or dose of the medication

Tablets, capsules, and oral liquids

- packaged in single unit or multiple unit containers

Packaging materials

- may be combinations of paper, foil, plastics, or cellophane

Solid dosage forms

- packaged in clear plastic or aluminum blister wells

- most popular method of single unit packaging

clear plastic or aluminum blister wells

The most popular method of single-unit packaging

Oral liquids

- may be single unit dispensed in: plastic, foil cups, pre-packaged and dispensed in glass

- with threaded caps or crimped aluminum caps

Light resistant containers

- required by many pharmaceutical products to protect them from photochemical deterioration

- this reduce light transmission sufficiently to protect a light sensitive pharmaceutical

- UV absorbers may be added to plastic to decrease the transmission of short UV rays

- must meet the USP standards with define the acceptable limits of light transmission at any wavelength of light between 290 and 450 nm

Type 1

- highly resistant borosilicate glass

- for parenteral products

Type 2

- treated soda lime glass

- for parenteral products

Type 3

- soda lime glass

- for parenteral products

Type NP

- glass for non parenteral

Polyethylene Terephthalate

- newer plastic PET

Amorphous polyethylene terephthalate

- newer plastic APET

Polyethylene terephthalate glycol

- newer plastic PETG

APET and PETG

- newer plastic material

- excellent transparency, luster and can be sterilized with gamma radiation

Leaching

- movement of components of a container into the contents

- occurs when liquid or semi solid dosage forms are packaged in plastic

- influenced by: temperature, excessive agitation of the filled container, solubilizing effect of liquid contents on one or more of the polymer additives

Soft walled plastic containers of PVC - polyvinyl Cl

- used to package IV solutions and blood for transfusion

Sorption

- binding of molecules to polymer materials

- absorption and adsorption are considered

- occurs through chemical or physical means due to: chemical structure of the solute molecules, physical and chemical properties of the polymer

- occurs with active pharmacologic agents or with pharmaceutical excipients thus, ingredients must be examined in the proposed plastic packaging to determine its tendency

Child resistant container

- significantly difficult for children under 5 years of age to open or to obtain a harmful amount of its contents within a reasonable time

- not difficult for normal adults to use properly

Child proof closures

- initial regulations called for its use for

- aspirin products, certain household chemical products

- shown to have a significant potential for causing accidental poisoning in youngsters

1998

- the year the regulations that require that child resistant containers must be capable of being readily opened by senior adults was amended

Storage

- must be under proper conditions

- to ensure the stability of a pharmaceutical preparation for the period of its intended shelf life

Cold

- any temperature not exceeding 8 degrees celsius (46 deg fahrenheit)

- ex. Refrigerator (temperature is maintained between 2 degrees celsius and 8 degrees celsius (36 and 46 fahrenheit)

Cool

- any temperature between 8 degrees celsius and 15 degrees celsius (46 and 59 fahrenheit)

Room temperature

- temperature prevailing in a working area

- 20 degrees celsius ro 25 degrees celsius (68 to 77 degrees Fahrenheit) buy also allows for temperature variations between 15 degrees and 30 degrees celsius (59 and 86 Fahrenheit) experienced in pharmacies, hospitals, and drug warehouses

Warm

- any temperature between 30 and 40 degrees Celsius (86 and 104 degrees Fahrenheit)