Download Buffered and Isotonic Solutions

SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
2 SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
3 SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
0.1N HCl 1ml
H 2O
NaCl
HAc, NaAc
pH 7
pH 7
pH 4.7
3
3
4.58
4 SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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 SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
6 SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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]
7 SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• A Weak Acid and Its Salt
pH= pKa+log
Dissociation
exponent
[salt]
[acid]
Buffer equation or
Henderson-Hasselbalch
equation
8 SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
* 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-]
9 SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• A Weak Base and Its Salt
OH- + BH+
B + H2O
Kb =
[OH-][BH+]
[B]
salt
base
10SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• A weak base and its salt
[OH-] = Kb
[base]
[salt]
[H3O+] • [OH-] = Kw
-log[H3O+]= - logKw – log1/Kb - log[salt]/[base]
11SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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.
12SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
HAc + H2O
Ka =
[H3O+][Ac-]
[HAc]
H3O+ + Acactivity
aH3O+ •aAc=
aHAc
Molar conc.
(γH3O+•cH3O+)•(γAc-• CAc-)
=
(γHAc•CHAc)
Activity coefficients
13SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
* activity coefficient of the undissociated acid γHAc is
essentially 1 and may be dropped.
- log[aH3O+] = - log Ka + log
pH = pKa + log
[salt]
[acid]
aAcaHAc
+ log γAc-
14SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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.
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• Acid indicator의 경우
HIn + H2O
H3O+ + In-
Acid color
KIn =
Alkaline color
[H3O+ ][ In-]
[HIn]
base
acid
16SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
•
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
17SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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
18SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
19SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• …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 base (or acid) added to the buffer
soln. to produce a pH change of ΔpH
20SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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
21SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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+]
22SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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 )
23SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• …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
24SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• Total buffer capacity of a universal buffer
(combination of several buffers)
25SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
26SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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.
27SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• ophthalmic soln.
• colormetric determination of pH
• research studies in which pH must be
held constant
28SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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
29SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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
30SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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
31SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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
32SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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.
33SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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.
34SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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℃.
35
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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]
Mole percent of base =
3.56 / (1 + 3.56) • 100 =
78%
[base]
4.0 = 14 – 7.15 + log [salt]
[base] = 0.0014 / 1
[salt]
Mole percent of base =
0.0014 / (1 + 0.0014) • 100 =
0.13%
36
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
37
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Red blood
cell
NaCl solution
0.9 %
2.0 %
Hypertonic, Isotonic
Shrink
0.2 %
Hypotonic,
Hemolysis
38
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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)
39
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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)
40
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• The Van’t Hoff expression
Tf = L · c
Liso =
(Chapter 6)
Molal freezing
point depression
of water
Tf / c
0.52 °
Conc. that is
isotonic with
body fluids
41
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
Calculating Tonicity Using Liso values
42
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• The Buffer Equation
• Buffer Capacity
• Buffers in
pharmaceutical and Biologic Systems
• Buffered Isotonic Solutions
• Methods of Adjusting Tonicity and pH
43
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
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
44
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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
45
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• Sodium chloride equivalent(E) method (염화
나트륨당량법) 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
46
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• White-Vincent method
(Example)
GOAL: make 30mL of a 1% soln. of procaine
HCl isotonic with body fluid
47
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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
48
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• 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.
49
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실
• Sprowls method
w
E
V
0.9 g
=
100 ml
W = 0.3 g
(1% solution)
TABLE
?
50
SKKU Physical Pharmacy Laboratory
성균관대학교 물리약학연구실