1 buffered and isotonic solutions. 2 contents the buffer equation buffer capacity buffers in...
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Buffered and Isotonic Solutions
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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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Introduction
Buffered Solutions ?
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Buffered Solutions
0.1N HCl 1ml
pH4.7
H2O NaCl HAc,NaAc
pH7 pH7
3 3 4.58buffer action
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Buffered Solutions
HA + OH- A- + H2O
A- + H3O+ HA + OH-
• Combination of a weak acid and its conjugate base
• Combination of a weak base and its conjugate acid
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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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The Buffer Equation • A Weak Acid and Its Salt
H3O+ + Ac-HAc + H2O
-log[H3O+]= - logKa - log[acid] + log[salt]
salt
acid Ka =
[H3O+][Ac-]
[HAc]
K1[HAc][H2O] = K2[H3O+][Ac-]
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The Buffer Equation
• A Weak Acid and Its Salt
pH= pKa+log [salt] [acid]
Buffer equation orHenderson-Hasselbalch equation
Dissociation exponent
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Common ion effect
H3O+ + Ac-HAc + H2O
* when Sod. acetate is added to acetic acid…
is momentarily disturbed since the acetate ion supplied by the salt increases the [Ac-]
Ka =[H3O+][Ac-]
[HAc]
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
Kb =[OH-][BH+]
[B]
OH- + BH+B + H2O
salt
base
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The Buffer Equation
• A weak base and its salt
[H3O+] • [OH-] = Kw
[OH-] = Kb [base][salt]
-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
H3O+ + Ac-HAc + H2O
aH3O+ •aAc-
aHAc
Ka =[H3O+][Ac-]
[HAc] =
(γH3O+•cH3O+)•(γAc-• CAc-)
(γHAc•CHAc)=
Molar conc.
Activity coeffi-cients
Conc. activ-ity
activity
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Activity coefficients
aAc-
aHAc
- log[aH3O+] = - log Ka + log
* activity coefficient of the undissociated acid γHAc is essentially 1 and may be dropped.
[salt][acid]
pH = pKa + log + 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)
The pH of the most basic buffer was found to change more markedly with temp. than that of acid buffers, owing to Kw.
2. Temperature
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pH indicator
• Acid indicator 의 경우
HIn + H2O H3O+ + In-
Alkaline colorAcid color
KIn = [H3O+ ][ In-]
[HIn]
base
acid
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PH indicator
• pH = pKIn + log [base][acid]
1/10~10/1
pH =pKIn + 1
base acid10/1 1/10
* 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…
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pH indicator
• Characteristics of colorimetric method
① less accurate
② less convenient but less expensive than elec-trometric method
③ difficult to apply for the unbuffered pharma-ceutical 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
β= 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
buffer capacity= buffer efficiency
= buffer index= buffer value
• …the magnitude of the resistance of a buffer to pH changes
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Buffer capacity ( 근사식 이용 )HAc
(0.1- 0.01)
NaAC(0.1+ 0.01)0.01
+ NaOH + H2O
pH=pKa + log [salt] + [base][acid] - [base]
= 4.85
pH=pKa + log[salt][acid] = 4.76
=0.01
0.09= 0.11=
pH β
B
• Before the addition of NaOH
• After the addition of NaOH
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• A more exact equation for buffer capacity (1914, 1922)
Buffer capacity
β ---- at any [H3O+].
Ka • [H3O+]β = 2.3 • C •
(Ka + [H3O+])2
c : total buffer conc.(sum of the molar conc. of
the acid & the salt)
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• βmax occurs where pH = pKa ([H3O+] = Ka)
Maximum Buffer capacity
( pH = pKa )
βmax = 0.576 • C
42.303
• C[H3O+]2
βmax = 2.303 • C • (2 [H3O+])2
=
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Characteristics of Buffer Ca-pacity
• …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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• Total buffer capacity of a universal buffer (combination of several buffers)
Universal Buffer
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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 kid-ney.
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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 so-lutions
• 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 ob-tain 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 so-lutions
• Steps for development of a new buffer
④ Availability of chemicals, sterility of the final soln, stabil-ity 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 sys-tems
• Influence of buffer capacity and pH on tissue ir-ritation
* 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 sys-tems
• 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 dif-ficulty.
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Buffer in pharmaceutical and biologic sys-tems• pH and solubility
* Influence of buffering on the solubility of base
- At a low pH : base is in the ionic form & usually very sol-uble in aqueous media
- As the pH is raised : more undissociated base is formed when the amount of base exceeds the limited water solubil-ity 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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(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 .℃
Buffer in pharmaceutical and biologic sys-tems
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Buffer in pharmaceutical and biologic sys-tems• Example
At pH 7.4
C11H16N2O2 + H2O C11H16N2O2H+ + OH-
(Pilocarpine base)
(Pilocarpine ion)
pH= pKw- pKb + log
[base] [salt]
At pH 4.0
7.4 = 14 – 7.15 + log [base] [salt]
[base] [salt] = 3.56 / 1
Mole percent of base =
3.56 / (1 + 3.56) • 100 = 78%
4.0 = 14 – 7.15 + log
[base] [salt] = 0.0014 / 1
Mole percent of base =
0.0014 / (1 + 0.0014) • 100 = 0.13%
[base] [salt]
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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 solu-tion
Red blood cell
NaCl solution 2.0 %Hypertonic,
Shrink
0.9 %Isotonic
0.2 %Hypotonic,Hemolysis
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Buffered isotonic solu-tion• 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 col-ligative 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 sam-ples 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
Tf = L · c
(Chapter 6)
Conc. that is isotonic with body fluids
Liso = Tf / c
0.52 °
Molal freezing point depression
of water
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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
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Method of adjusting tonicity and pHClass I …add Sod. Chloride to lower the
freezing point of soln. to -0.52°
① White-Vincent method
② Sprowls method
① Cryoscopic method ② Sodium chloride equivalent method
Class II …add Water to form an isotonic soln.
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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
ΔTf = Liso · c
ΔTf = Liso · 1g/MWc = 1 g / molec-
ular weight
3.4
58.45
E
E : weight of NaCl with the same freezing point depression as 1g of the drug.
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 method① 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 0.9 g/100mL = 0.063 g / V③ V = 0.063 • 100/0.9④ V = 7.0 mL⑤ Add isotonic-buffered diluting soln. to complete
V = w • E • 111.1
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Class II methods
•White vincent method
0.3g drug(E=0.21) 7ml
add 0.9%NaCl
or
Isotonic buffered sol.
30ml
water
0.9%NaCl
isotonic
GOAL: make 30mL of 1% soln.
of procaine HCl iso-tonic with body fluid
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Class II methods
• Sprowls method
w EV
=0.9 g100 ml
W = 0.3 g (1% solution)
?
TABLE
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Thank you for your attention