ceutics parenterals 2

what is a pyrogen

bacterial endotoxins; large molecules of lipoglycans; cause fever in excessive amounts

t/f: parenterals are sterile and considered pyrogen free if under the endotoxin limit (EU)

true

what is an endotoxin limit

endotoxin concentration that must not be exceeded in parenterals

parenterals must be packaged in __________ containers

hermetically sealed (airtight; protected from environment)

what does "pyrogen free" imply in parenterals

there may be pyrogens present but they do not exceed the endotoxin limit

can coloring agents be used in parenteral preparations

no

why are parenteral preparations used over other dosage forms?

1. rapid action

2. patient is unconscious/uncooperative/ cant take it orally

3. drug is ineffective orally (unstable in GI, poor absorption)

R= rapid action

U= unconcious

G= GI unstable

what are the 5 official USP injectable products

1. injection (liquid drug solution)

2. for injection (solid drug for vehicle)

3. injectable emulsion (drug dispersed in emulsion)

4, injectable suspension (drug dispersed in medium)

5. for injectable suspension (solid drug for suspension)

referring to the 5 types of USP injectable products, what does "for" mean

this is a solid that must be dissolved or suspended before injecting. it is not immediately mixed with the solvent because of stability and shelf life

IV route advantages and disadvantages

adv:

1. rapid action= no need for absorption

2. optimum blood levels in short time

dis:

1. non-removable

2. possible thrombus/embolus

thrombus vs embolus

Thrombus- blood clot

Embolus- a thrombus that is not stationary and travels

causes of thrombus/embolus

1. IV needles or catheters damaging walls of vein

2. irritation of the vein by the drug/ foreign particles

3 things required prior to injection

1. sterile product

2. sterile syringe

3. disinfected injection site

3 injection methods

1. manual

2. infusion pump (hospitals)

3. patient controlled devices

t/f: injectable solutions are preferred to be aqueous to mix readily with blood

true

IM advantages and disadvantages

adv:

1. less rapid than IV

2. longer duration of action than IV

3. can be aqueous, oil, solution[fastest absorption], or suspension

dis:

1. cannot be removed

if a drug requires a longer duration of action and later onset, would you give it IV or IM?

IM; less rapid and longer duration

t/f: both IV and IM can be given as aqueous, oil, solution, or suspension

false. IV is preferred to be aqueous so that it mixes with blood. IM can be any of them

what cannot be given SQ

-volume >2mL

-irritating drugs/ thick suspensions

potential side effects of giving irritating drug SQ

1. induration: skin hardening

2. sloughing: skin depression

3. abscess: pus

4. pain

does the physical form of the product (ex: suspension vs solution) have effect on drug onset and duration?

yes.

aqueous= fast acting

non-aqueous= long action

which physical form of a preparation has the fastest action

solution

WFI

-purified by:

-requirements:

-Purified by distillation or by reverse osmosis

-MUST be pyrogen free (not required to be sterile)

-Should be stored in tight, STERILE, pyrogen free containers

T/F: WFI does not have to be sterile nor stored in sterile containers

false. it does not have to be sterile, but it must be stored in sterile containers

Sterile WFI

-pyrogen free (like WFI)

-for SMALL volume parenterals

t/f: WFI can be used for small volume parenterals

false. must be sterile or bacteriostatic WFI

bacteriostatic WFI

-WFI+ antimicrobial

-NOT STERILE

- small volume parenterals

-NOT FOR NEONATES

USP labeling "not for neonates" is placed on which injection vehicles? why?

-toxicity due to benzoyl alcohol

bacteriostatic WFI, bacteriostatic NaCl

NaCl injection

STERILE NaCl in WFI

-for sterile solutions/susps an IV line flush

bacteriostatic NaCl injection packages at ___mL or less

30

what is bacteriostatic NaCl used for

IV line flush

t/f: bacteriostatic NaCl injection can be used as IV line flush in neonates

false. contains benzoyl alcohol which is toxic to neonates due to limited liver detoxification

as little as ___mL/kg of benzoyl alcohol could kill a neonate

11mL/kg/d

Ringer's Solution

-sterility?

-composition?

-use?

sterile WFI

NaCl, KCl, CaCl2

drug vehicle, electrolyte replenisher, fluid extender

lactated ringer's solution

-composition

-use?

same as ringer's + sodium lactate

-fluid, electrolyte replenisher, alkalizer (acts as buffer in acidosis)

examples of non-aqueous vehicles

vegetable oils, glycerin, PEGs, alcohol

properties of non-aqueous vehicles

1. non-irritating, nontoxic

2. pharmacologically inert

3. HIGH bp

4. LOW vapor pressure

5. constant purity

describe boiling point and vapor pressure of non-aqueous vehicles

high boiling point to withstand sterilization and low vapor pressure

added substances in parenterals must have

NO THERAPEUTIC EFFECT and harmless

why does USP require a preservative in multidose containers

to prevent microbial contamination during repeat drug removals

why is air in vials sometimes replaced with inert gas

to reduce oxidation rate of drug by removing the air (with O2) and adding inert gas like N or He

sterilization is defined as

destruction or removal of all living organisms and their spores

what are the 5 methods of sterilization

Steam/moist heat

Dry heat/hot air

sterile filtration

gas

radiation

sterilization method of choice for thermostable products

steam sterilization or dry heat

steam sterilization

-temps?cycles?

15 psi steam, 121C, 20 min

*lag times(small=5-10mins, large 20+mins)

lag times for steam sterilization

small: 5-10mins

large: 20+mins

t/f: steam sterilization has a higher temp than dry heat

false. steam=121C, dry heat=170C

dry heat requirements

160-170C for >2 hours

-thermostable materials

-for materials not fit for moisture (oils, glycerin, glassware)

examples of products for dry heat sterilization

oil, glycerin, heat stable powders, glassware, surgical instruments

describe sterile filtration

bacterial removal by adsorption on filter or retention due to small pore size

sterile filtration is affected by

1. electrical charge (of filter and/or bacteria)

2. pH

3. temp

4. pressure/vaccuum

filter pore size for sterile filtration

0.2 micrometers

RBC size? bacteria size? cornoa virus size? which one of these does not pass sterile filtration

RBC: 6.5 micrometer

bacteria: 0.2 micrometer

corona virus: 0.1 micrometers

-> virus will pass bc filter is 0.2 micrometers

advantages and disadvantages of sterile filtration

adv:

-quick, inexpensive

- good for thermolabile materials (cant use heat)

-removes BOTH living and dead

- can be used on line during filling

dis:

-fragile membranes

-possible drug adsorption onto filter

what is gas sterilization used for

medical/surgical supplies; thermolabile drugs

which forms of sterilization cannot be used for thermolabile drugs

steam and dry heat

gas sterilization uses

ethylene oxide diluted with CO2 or freons

gas sterilization disadvantages

1. highly flammable

2. more variable than steam (temp, gas concentration, humidity)

3. assure absence of chemical rxn btwn drug and gas

4. must have low amounts of gas in final product

radiation sterilization

-via gamma rays

-need highly specialized personnel; expensive

biological indicator for sterility parameter

adding microorganisms resistant to a particular sterilization process used to monitor a sterilization cycle

main forms of biological indicators for sterilization

1. spores on a carrier (permeable membrane)

2. spores in bulk

bacillus stearothermophilus

biological indicator of sterilization for moist heat or EtO (bc highly resistant)

bacillus subtilis

biological indicator for dry heat (bc resistant to dry heat)

effectiveness of thermal sterilization is determined by

F value= time of thermal death=time required to kill a particular organism

in ALL sterilization processes, microorganisms will die according to a __________ relationship between concentration of LIVING microbes and _____

logarithmic; time of exposure to treatment

D-value

amount of time required to kill 90% (or 1 log) of microorganisms present

interpret a d value of 6

takes 6 minutes to kill 90% (or 1 log = 10) of microbes

equation used to relate F0 (time to kill organism) to D (time to kill 90%)

F= D (logA-logB)

A= initial population

B= final population

what temp does the d value refer to

121C

if D=1 min, A=10^6 and B=10^-6, what is F0?

F0= D (logA-logB)

F0= 1 (6--6)= 12 minutes

what is the time for a 12-D process to occur if the D-value is 0.21 minutes

12-D means reduced by 12 logs

F0= 0.21 (12)= 2.52 minutes

lipopolysaccharides can be classified as

pyrogens/endotoxins

t/f: pyrogens are organic and could therefore be oxidized

true

how can pyrogens be removed

fractional distillation

describe USP pyrogen test

1. healthy rabbits-> control and test

2. pyrogen free needles, glassware

3. warm product to 37C

4. inject 10mL/kg/10min into ear vein of 3 rabbits

5. record temp at 30 minute intervals, 1-3 hours

PASS: no rabbits temp raises more than 0.5C

-if temp rises, continue test with 5 more rabbits

PASS-> if LESS THAN 3 of 8 rabbits show temp rise

PASS-> sum of temps are NOT >3.3C

LAL test

limulus amebocyte lysate; blood cells derived from the horseshoe crab used to detect and quantify bacterial endotoxins

-has enzymes that coagulate with lipopolysaccharides

which endotoxin test is most sensitive

LAL test (compared to rabbit test)

t/f: because the LAL test is the most sensitive, it is used for all parenteral testing

false. some parenterals cannot be used with LAL because the active ingredient interferes with the outcome

(ex: oxacillin sodium and vancomycin HCl)

examples of drugs tested with LAL

diphenhydramine HCl, ephedrine HCl, thiamine HCl

how is the following prepared for parenteral sterilization:

1. aseptic suites

2. sanitized equipment

3. sterilized items

1. aseptic suites= UV lights, filtered air

2. sanitized equipment= equipment lyophilizers

3. sterilized items

describe validation methods for sterility

=evaluation of 3 consecutive production batches

= extensive sampling-> beginning`, middle, end

which department reviews routine production monitoring for sterile products

quality control department

air quality of 1) compounding room and 2) aseptic filling rooms

1) compounding room= class 10,000

2) aseptic filling room= class 100 (stricter, sterile, no more than 100 particles)

ideal vs normal manufacturing sequence

ideal: (drug and additive)-sterile filtration-aseptic fill- terminally sterilize

normal= same as above but no terminal sterilization

examples of drugs requiring isolated manufacturing facilities

penicillins, cephalosporins, cancer agents

t/f: osmotic pressure is a colligative property of drugs

true

osmotic pressure

pressure that must be applied to prevent osmotic movement across a selectively permeable membrane

lyophilized products

products that have been freeze dried. Lyophilization removes water from a product, which stabilizes it and extends its shelf life

filling area for injections is supplied with.... to control for particulates

1. HEPA filter

2. direct laminar airflow

3. glass washed 3x with WFI and dry heat sterilized

4. garbing

why is control for particulates in injections important?

may cause thrombi or vessel blockage

volume of single dose injectables

0.5 to 2.0 mL

multiple dose containers usually contain _______________. volume?

antibacterial preservatives; 30-50mL

why would tubing length be reduced for an adsorbent small dose drug

sometimes drugs adsorb onto tubing. lowering the SA/reducing length makes it less likely for drug to adsorb

(ex: nitroglycerin and PVC)

USP labeling: "sterile" was eliminated from all labels except _____

sterile WFI

USP labeling guidelines for sterile products

1.name

2. liquid product drug %

3. dry product amount of API

4. route of administration

5. storage conditions

6. expiration date

7. manufacturer/distributor

8. lot#

large volume parenterals are >___

100mL

large volume parenterals examples

water, electrolytes, caloric requirements

who are large volume parenterals for

1. unconscious

2. unable to take fluids orally

3, severe loss of fluid/electrolytes

replacement therapy

administration of a naturally occurring substance that the body is not able to produce in adequate amounts to maintain normal function (ex: water, electrolytes)

=uses large volume parenterals

maintenance therapy

few days: water, dextrose, Na, K

weeks: total parenteral nutrition