Transcript No Slide Title

Parenteral Products
 administration

CHEE 440
by injection.
i.v., i.m., s.c., i.d.
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Parenterals
 advantages




rapid onset of action
predictable, nearly complete bioavailability
avoidance of problems associated with GIT
reliable admin. to very ill and comatose
 disadvantages


cost (professional care)
patient compliance
 formulations
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
CHEE 440
solutions
suspensions
emulsions
colloidal dispersions
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Solution Formulation
 solvents
must meet purity standards
 restricted number and kind of added
substances

no coloring agents permitted
 products



are :
always sterilized
pyrogen-free
prepared in environmentally controlled
areas under sanitary conditions
 volumes
used are specific to
application
CHEE 440
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Composition

active agent


anti-oxidants
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
CHEE 440
e.g. ethanol, PEG, glycerin
tonicity agents


inactivate metals which catalyze degradation
co-solvents


e.g. citric acid, sodium phosphate, sodium
acetate, dipotassium hydrogen phosphate
chelating agents


ex. ascorbic acid, sodium bisulfite
buffers (pH)


Need to consider solubility
related to semi-permeable nature of cell
membranes and osmotic pressure of solution
preservatives
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Preservatives

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for preps that can’t be sterilized easily
required for multiple-dose formulations
good growth media include
» most aqueous preps (esp. syrups),
emulsions, suspensions, creams
preps which contain alcohol do not
require sterilization or preservation
Criteria
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CHEE 440
effective
soluble
sufficiently non-ionized in solution
nonirritating, nonsensitizing, nontoxic
chemically stable
compatible with other ingredients
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Preservatives
Modes of Action
 modification of cell membrane
permeability
 lysis and cytoplasmic leakage
 protein denaturation
 inhibition of cellular metabolism
 oxidation and/or hydrolysis of cellular
components (enzymes)
CHEE 440

antifungals
» benzoic acid, parabens, sodium benzoate,
sodium propionate

antimicrobials
» benzyl alcohol, phenol, chlorobutanol,
cetylpryidinium chloride
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Types of Water
 water
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source water typically contaminated
purified by distillation or reverse
osmosis
not required to be sterile, but pyrogenfree
intended to be used within 24 hours
 sterile
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
CHEE 440
for injection
water for injection
as above but sterilized
intended for use in reconstituting
powders
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Osmotic Pressure :
Clinical Relevance
 whole
blood, plasma, serum are
complex mixtures of proteins,
glucose, non-protein nitrogenous
compounds, and electrolytes (Na,
Ca, K, Mg, Cl, CO3 )
 electrolytes determine osmotic
pressure
 must formulate with osmotic
pressure in mind
 is a colligative property
CHEE 440
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Boiling Point Elevation
 boiling
pt of solution is higher than
that of pure solvent

consider a vapor in equilibrium with a
solution at constant pressure
RTb2
Tb 
X2
H v

for very dilute solutions :
RTb2 M1
Tb 
m2  K bm2
1000Hv
» Kb = ebullioscopic constant (Tables)
» Kb water = 0.51 K kg/mol
CHEE 440
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Freezing Point Depression
 assume
solvent freezes as pure
solvent
RTf2
Tf 
X2
Hf
RTf2 M1
Tf 
m 2  Kf m 2
1000Hf


CHEE 440
Kf = cryoscopic constant (Tables)
Kf water = 1.86 K kg/mol
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Osmotic Pressure, P
at t = 0
sucrose
solution
water
semipermeable membrane
at equilibrium
h
P  gh
CHEE 440
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Osmotic Pressure, P
 water
moves across membrane due
to mL to R
 at equilibrium mw,R = mw,L
nonideal solutions :
RT
P 
lna 1
V1
ideal solutions :
RT
P 
lnX1
V1
ideally dilute solutions : P  m2 RT
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Electrolyte Solutions :
Colligative Properties
that P can be determined from
 Tb and  Tf measurements
 note
 Van’t

accounts for nonideality, increased
number of moles produced
ideally
dilute
CHEE 440
Hoff Factor, i
P  imRT
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Tonicity
 extent
of swelling or contraction of
biological membrane (cells, mucous
membranes)
 cell membranes are semipermeable
 hypertonic = higher P than cells

causes cells to crenate or shrink
 hypotonic

= lower P than cells
causes cells to rupture (lyse)
= same P (isoosmotic)
 isoosmotic doesn’t necessarily mean
isotonic
 isotonic
CHEE 440
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Methods of Adjusting
Tonicity


Tf blood and tears = - 0.52˚C
add appropriate amount of compound (ex.
NaCl) to drug solution or add water to
drug solution
NaCl Equivalent Method
E = amount of NaCl equivalent in P to 1 g of
drug
NaCl (w/v%) = 0.90 - E*[drug] (w/v%)
values for E found in Tables (p 622-7
Remington)
CHEE 440
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Methods of Adjusting
Tonicity
White-Vincent Method
(USP Method)
calculates volume (V) in ml of isotonic
solution that can be prepared by mixing
drug with water/isotonic buffered solution
V = w * E *111.1
w = wt. of drug (g)
CHEE 440
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Methods of Adjusting
Tonicity
Freezing Point Depression


freezing point depressions of 1w/v% drug
solutions (Tf1%) have been tabulated (p
622-627 Remington)
choose appropriate solute for adjusting
tonicity
» using Tf,ref1% determine required
amount (wref) to cover remaining Tf
w re f
0.52 CTf1% 

Vre q
1%


 Tf, re f

» Vreq = volume of water required
» C = drug concentration (w/v%)
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Example :
1. Make a 25 ml isotonic solution of
2.5 w/v % epinephrine bitartrate.
2. Do the same but now add 0.5w/v %
phenol.
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Containers
CHEE 440
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Freeze Drying
 used
to dry heat-sensitive materials
liquid
P
solid
vapor
T
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Freeze Drying
 advantages
degradation of product is
minimized
 light, porous product
 no concentration of product
during drying

 disadvantages
product is very hygroscopic
 slow and expensive process

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