Transcript Buffered and Isotonic Solutions

Buffered and
Isotonic Solutions
1
Contents
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
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Introduction
Buffered Solutions ?
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Buffered Solutions
0.1N HCl 1ml
H 2O
NaCl
HAc,NaAc
pH7
pH7
pH4.7
3
3
4.58
buffer action
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Buffered Solutions
• Combination of a weak acid and its conjugate base
HA + OH-
A- + H2O
• Combination of a weak base and its conjugate acid
A-
+
H3O+
HA
+
OH5
Contents
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
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The Buffer Equation
• A Weak Acid and Its Salt
HAc + H2O
H3O+ + Ac-
K1[HAc][H2O] = K2[H3O+][Ac-]
Ka =
[H3O+][Ac-]
[HAc]
salt
acid
-log[H3O+]= - logKa - log[acid] + log[salt]
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The Buffer Equation
• A Weak Acid and Its Salt
pH= pKa+log
Dissociation
exponent
[salt]
[acid]
Buffer equation or
Henderson-Hasselbalch
equation
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Common ion effect
* when Sod. acetate is added to acetic acid…
[H3O+][Ac-]
Ka =
[HAc]
is momentarily disturbed since the acetate ion supplied
by the salt increases the [Ac-]
HAc + H2O
H3O+ + Ac-
The ionization of HAc is repressed upon the addition
of the common ion [Ac-]
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The Buffer Equation
• A Weak Base and Its Salt
OH- + BH+
B + H2O
Kb =
[OH-][BH+]
[B]
salt
base
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The Buffer Equation
• A weak base and its salt
[OH-] = Kb
[base]
[salt]
[H3O+] • [OH-] = Kw
-log[H3O+]= - logKw – log1/Kb - log[salt]/[base]
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The Buffer Equation
• A Weak Acid and Its Salt
pH= pKw- pKb + log
[base]
[salt]
* Buffers are not ordinarily prepared from weak
bases because of the volatility & instability of the
bases and because of the dependence of their pH
on pKw, which is often affected by temp. changes.
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Activity coefficients
HAc + H2O
Ka =
[H3O+][Ac-]
[HAc]
Conc.
H3O+ + Acactivity
aH3O+ •aAc=
aHAc
activity
Molar conc.
(γH3O+•cH3O+)•(γAc-• CAc-)
=
(γHAc•CHAc)
Activity coefficients
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Activity coefficients
- log[a
+
H3O ]
= - log Ka + log
aAcaHAc
* activity coefficient of the undissociated acid γHAc is
essentially 1 and may be dropped.
pH = pKa + log
[salt]
[acid]
+ log γAc-
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pH 에 영향 주는 인자
1. Altering the ionic strength
① Addition of neutral salts
② Dilution (alter activity coefficients)
2. Temperature
The pH of the most basic buffer was found
to change more markedly with temp. than
that of acid buffers, owing to Kw.
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pH indicator
• Acid indicator의 경우
HIn + H2O
H3O+ + In-
Acid color
KIn =
Alkaline color
[H3O+ ][ In-]
[HIn]
base
acid
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PH indicator
• pH = pKIn + log
[base]
[acid]
1/10~10/1
* From experience, one cannot discern a change from the
acid color to the salt color the ratio of [base] to [acid] is
about 1 to 10
* The effective range of the indicator is…
pH =pKIn + 1
base
10/1
1/10
acid
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pH indicator
• Characteristics of colorimetric method
① less accurate
② less convenient but less expensive than
electrometric method
③ difficult to apply for the unbuffered
pharmaceutical preparation (change the pH indicator itself is acids or base)
④ error may be introduced by the presence of
salts & proteins
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Contents
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
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Buffer capacity
• …the magnitude of the resistance of a buffer to pH
changes
β=
buffer capacity
= buffer efficiency
= buffer index
= buffer value
B
pH
ΔB : small increment in gram equivalents/Liter
of strong(or acid) added to the buffer
soln. to produce a pH change of ΔpH
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Buffer capacity (근사식 이용)
HAc + NaOH
(0.1- 0.01)
0.01
NaAC
+ H2 O
(0.1+ 0.01)
• Before the addition of NaOH
[salt]
pH=pKa + log
[acid] = 4.76
• After the addition of NaOH
pH=pKa + log [salt] + [base] = 4.85
[acid] - [base]
β=
B
0.01
=
= 0.11
pH
0.09
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Buffer capacity
• A more exact equation for buffer capacity (1914, 1922)
β = 2.3 • C •
Ka • [H3O+]
(Ka + [H3O+])2
c : total buffer conc.(sum of the molar conc. of
the acid & the salt)
.
β ---- at any [H3O+]
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Maximum Buffer capacity
• βmax occurs where pH = pKa ([H3O+] = Ka)
[H3O+]
2
2.303
βmax = 2.303 • C •
•C
=
+
2
4
(2 [H3O ])
βmax = 0.576 • C
( pH = pKa )
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Characteristics of Buffer Capacity
• …is not a fixed value, but rather depend on the amount
of base added
• …depends on the value of the ratio [salt]/[acid] and
magnitude of the individual concentrations of the
buffer components
• The greatest capacity(βmax) occurs where
[salt]/[acid] = 1 and pH = pKa
• Because of interionic effects, buffer capacities do not in
general exceed a value of 0.2
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Universal Buffer
• Total buffer capacity of a universal buffer
(combination of several buffers)
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Contents
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
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In Vivo biologic buffer systems
• Blood
① Primary buffers : Plasma ;
NaHCO3-- H2CO3, NaHPO4--NaH2PO4, protein
② Secondary buffers : Erythrocytes ;
hemoglobin-oxyhemoglobin, K2Hpo4--KH2PO4
• Lacriminal fluid
- pH: 7.4 (range 7 – 8 or slightly higher)
• Urine
- pH: 6.0 (range 4.5 – 7.8)
- below normal…hydrogen ions are excreted by the kidney.
- above pH 7.4…hydrogen ions are retained by action of the kidney.
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Pharmaceutical buffers
• ophthalmic soln.
• colormetric determination of pH
• research studies in which pH must be
held constant
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Pharmaceutical buffers
• Clark-Lubs mixtures and pH
(a) HCl & KCl, pH 1.2 - 2.2
(b) HCl & potassium biphthalate, pH 2.2 - 4.0
(C) NaOH & potassium biphthalate, pH 4.2 - 5.8
(d) NaOH & KH2PO4 , pH 5.8 - 8.0
(e) H3BO3, NaOH & KCl, pH 8.0 - 10.0
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Preparation of pharmaceutical buffer solutions
• Steps for development of a new buffer
① Select a weak acid having a pKa approximately equal
to the pH at which the buffer is to be used.
② Calculate the ratio of salt & weak acid required to
obtain the desired pH.
③ Consider the individual conc. Of the buffer salt & acid
needed to obtain a suitable buffer capacity
* Individual conc. : 0.05 ~ 0.5M
* buffer capacity : 0.01 ~ 0.1
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Preparation of pharmaceutical buffer solutions
• Steps for development of a new buffer
④ Availability of chemicals, sterility of the final soln, stability
of the drug & buffer, cost of materials, freedom from
toxicity
ex) borate buffer – toxic effect – not be used for oral or
parenteral products.
⑤ Determine the pH and buffer capacity
using a reliable pH meter
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Buffer in
pharmaceutical and biologic systems
• Influence of buffer capacity and pH on tissue
irritation
* Tissue irritation will be minimal when…
(a) Buffer solution – β , Volume
(b) Physiologic fluid - β , Volume
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Buffer in
pharmaceutical and biologic systems
• Stability vs. optium therapeutic response
* Undissociated form of a weakly acidic or basic drug has a
higher therapeutic activity than the dissociated salt form.
* Molecular form is lipid soluble & can penetrate body
membranes readily, where the ionic form, not being lipid
soluble, can penetrate membranes only with greater
difficulty.
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Buffer in
pharmaceutical and biologic systems
• pH and solubility
* Influence of buffering on the solubility of base
- At a low pH : base is in the ionic form & usually very
soluble in aqueous media
- As the pH is raised : more undissociated base is formed
when the amount of base exceeds the limited water
solubility of this form, free base precipitates from soln.
Base soln. should be buffered at a sufficiently low pH
for stabilization against precipitation.
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Buffer in
pharmaceutical and biologic systems
(Example)
GOAL: Compute the mole percent of
free base present on 25℃ and at a
pH of 7.4. The pKb of pilocarpine
is 7.15 at 25℃.
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Buffer in
pharmaceutical and biologic systems
• Example
C11H16N2O2 + H2O
(Pilocarpine base)
+
-
C11H16N2O2H + OH
(Pilocarpine ion)
[base]
pH= pKw- pKb + log [salt]
At pH 7.4
At pH 4.0
7.4 = 14 – 7.15 + log [base]
[salt]
[base] = 3.56 / 1
[salt]
[base]
4.0 = 14 – 7.15 + log [salt]
[base] = 0.0014 / 1
[salt]
Mole percent of base =
3.56 / (1 + 3.56) • 100 =
Mole percent of base =
0.0014 / (1 + 0.0014) • 100 =
78%
0.13%
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Contents
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
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Buffered isotonic solution
Red blood
cell
NaCl solution
0.9 %
2.0 %
Hypertonic, Isotonic
Shrink
0.2 %
Hypotonic,
Hemolysis
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Buffered isotonic solution
• The term Isotonic should be restricted to
solutions having equal osmotic pressures
which respect to a particular membrane
(Husa)
• Isotonicity value…the concentration of an
aqueous NaCl soln. having the same
colligative properties as soln. (Goyan &
Reck)
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Measurement of tonicity
• Hemolytic method
…apply red blood cells
…based on the fact that a hypotonic soln. liberates oxyhemoglobin
in direct proportion to the number of cells hemolyzed
• determine colligative properties (chapter 5)
…modifications of the Hill-Blades Technique
…based on a measurement of the slight temp. differences arising
from differences in the vapor pressure of thermally insulated
samples contained in constant-humidity chambers
Tf = 0.52 ºC (Freezing point lowering of
human blood & lacrimal fluid)
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Calculating Tonicity Using Liso values
• The Van’t Hoff expression (Chapter 6)
Tf = L · c
Liso =
Molal freezing
point depression
of water
Tf / c
0.52 °
Conc. that is
isotonic with
body fluids
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Calculating Tonicity Using Liso values
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Contents
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
43
Method of adjusting tonicity and pH
Class I …add Sod. Chloride to lower the
freezing point of soln. to -0.52°
① Cryoscopic method
② Sodium chloride equivalent method
Class II …add Water to form an isotonic soln.
① White-Vincent method
② Sprowls method
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Class I methods
• Cryoscopic method (빙점강하도법)
(Example)
How much NaCl is required to render 100mL of a 1% soln. of
apomorphine HCl isotonic with blood serum?
Δ Tf0.9% of NaCl soln : 0.52°(Isotonic with blood)
Δ Tf1% of apomorphine HCl soln : 0.08° (from table)
to reduce the freezing point by an additional 0.44°(0.52-0.08)
Δ Tf1% of NaCl soln : 0.58°
1(%)/X = 0.58/0.44 ; X = 0.76 (%)
Dissolve 1 g apomorphine HCl + 0.76g NaCl make 100mL
soln. with water
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Class I methods
• Sodium chloride equivalent(E) method
(염화나트륨당량법) by Mellen & Seltzer
1g drug tonicity = Eg NaCl tonicity
E : weight of NaCl with the same freezing point depression
as 1g of the drug.
ΔTf = Liso · c
ΔTf = Liso · 1g/MW
3.4
E
c = 1 g / molecular
weight
58.45
E ≈ 17 · Liso / MW
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Class II methods
• White-Vincent method
(Example)
GOAL: make 30mL of a 1% soln. of procaine
HCl isotonic with body fluid
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Class II methods
• Steps for White-Vincent method
① Weight in grams of drug(0.3 g) • Sod. Chloride
equivalent E(0.21..from table) = quantity of sod.
Chloride equivalent to w of drug(0.063 g)
②
③
④
⑤
0.9 g/100mL = 0.063 g / V
V = 0.063 • 100/0.9
V = 7.0 mL
Add isotonic-buffered diluting soln. to complete
V = w • E • 111.1
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Class II methods
• White vincent method
GOAL:
make 30mL of 1% soln.
of procaine HCl
isotonic with body
fluid
water
add 0.9%NaCl
0.9%NaCl
isotonic
0.3g drug
(E=0.21)
or
30ml
7ml
Isotonic buffered sol.
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Class II methods
• Sprowls method
w
E
V
0.9 g
=
100 ml
W = 0.3 g
(1% solution)
TABLE
?
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Thank you for your attention
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