Transcript Parenteral Products - Queen's University

Parenteral Products
administration by injection.
 i.v., i.m., s.c., i.d.
B. Amsden
CHEE 440
Solution Formulation
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solvents must meet purity standards
restricted number and kind of added substances
no coloring agents permitted
products are always sterilized
products are pyrogen-free
products prepared in environmentally controlled areas under
sanitary conditions
 volumes used are specific to application
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CHEE 440
Components
water
 water for injection
 sterile water for injection
active agent
 need to consider solubility
anti-oxidants
 ex. ascorbic acid, sodium bisulfite
buffers
 e.g. citric acid, sodium phosphate, sodium acetate, dipotassium
hydrogen phosphate
chelating agents
 inactivate metals which catalyze degradation
co-solvents
 e.g. ethanol, PEG, glycerin
tonicity agents
 related to semi-permeable nature of cell membranes and osmotic
pressure of solution
preservatives
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CHEE 440
Preservatives
Criteria
 effective
 soluble
 sufficiently non-ionized in solution
 nonirritating, nonsensitizing, nontoxic
 chemically stable
 compatible with other ingredients
Types
 antifungals
• benzoic acid, parabens, sodium benzoate, sodium propionate
 antimicrobials
• benzyl alcohol, phenol, chlorobutanol, cetylpryidinium chloride
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CHEE 440
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
Osmotic activity is a colligative property
• depends on number of molecules present
• freezing point depression
• boiling pt elevation
• osmotic pressure
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CHEE 440
Osmotic Pressure, P
water moves across a semi-permeabl membrane due to DmL to R
at equilibrium mw,R = mw,L
nonideal solutions :
RT
P 
lna 1
V1
ideal solutions :
RT
P 
lnX1
V1
P  m2 RT
ideally dilute solutions :
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CHEE 440
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
DTb 
X2
DH v
 for very dilute solutions :
RTb2 M1
DTb 
m2  K bm2
1000DHv
• Kb = ebullioscopic constant (Tables)
• Kb water = 0.51 K kg/mol
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CHEE 440
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)
 isotonic = same P (isoosmotic)
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CHEE 440
Freezing Point Depression
assume solvent freezes as pure solvent
RTf2
DTf 
X2
DHf
RTf2 M1
DTf 
m 2  Kf m 2
1000DHf
 Kf = cryoscopic constant (Tables)
 Kf water = 1.86 K kg/mol
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CHEE 440
Electrolyte Solutions
Van’t Hoff Factor, i
 accounts for nonideality, increased number of moles
produced
ideally
dilute
P  imRT
DTb  iKb m
DTf  iK f m
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CHEE 440
Methods of Adjusting Tonicity
DTf 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)
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CHEE 440
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)
B. Amsden
CHEE 440
Methods of Adjusting Tonicity
Freezing Point Depression
 freezing point depressions of 1w/v% drug solutions
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(DTf1%) have been tabulated (p 622-627 Remington)
choose appropriate solute for adjusting tonicity
• using DTf,ref1% determine required amount (wref) to
cover remaining DTf
w re f
0.52 CDTf1% 

Vre q
1%


 DTf, re f

• Vreq = volume of water required
• C = drug concentration (w/v%)
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CHEE 440
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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CHEE 440
Buffers
compounds or mixtures which resist changes in their pH
typically a combination of a weak acid and its conjugate base (salt)
or a weak base and its conjugate acid
 ex. acetic acid and sodium acetate
to determine pH of buffer solution
 weak acid + salt
salt 

pH pKa  l og
acid
 weak base + salt
valid for 4 < pH < 10
base

pH pKw  pKb  l og
 salt 
Buffers
buffer capacity, b
 the amount of resistance to change in pH


b  2.3buffer
K  H O 
K a H3O 

a
3
 maximum capacity
• when pH = pKa
buffer   acid   salt
bmax  0.576buffer
 
2
Buffers : clinical significance
drugs
 many exert some buffering action
biological buffers
 blood
• pH ≈ 7.4 (7.0-7.8)
• bblood ≈ 0.031
 lacrimal fluid
• pH ≈ 7.4 (7-8)
• large b (15 x dilution)
reaction with tissue
 want pH formulation ≈ pH body fluid
 don’t want a strong capacity
Buffers
preparation
 select weak acid with a pKa near desired pH
 use buffer capacity eqn to calculate [acid]:[salt]
ratio
 a suitable buffer has a [salt] + [acid] = 0.05 - 0.5 M
and a capacity of 0.01 - 0.1
 check tonicity
Containers
B. Amsden
CHEE 440
Freeze Drying
used to dry heat-sensitive materials
liquid
P
solid
vapor
T
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CHEE 440
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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CHEE 440