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Buffers and pH Adjusting Agents

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18
Buffers and pH
Adjusting Agents
Melgardt de Villiers, PhD

Definitions
CHAPTER
OUTLINE Uses of Buffers and pH Adjusting Agents
Buffer Capacity
Selecting a Buffer System or a Compound to Adjust pH
Acidifying, Alkalizing, and Buffering Agents

I. DEFINITIONS
A. An acid may be defined as
1. A substance that, when dissolved in water, yields hydrogen ions, H+ (Arrhenius theory).
2. A species that yields protons, H+ (Bronsted-Lowry theory).
3. An electron pair acceptor (Lewis theory).
B. A base may be defined as
1. A substance that, when dissolved in water, gives hydroxide ions, OH (Arrhenius theory).
2. A species that can accept a proton (Bronsted-Lowry theory).
3. An electron pair donor (Lewis theory).
In pharmaceutical systems, we usually are dealing with solutions that contain water; therefore, the
Arrhenius and Bronsted-Lowry definitions are most suitable for our purposes.
C. A buffer is a compound or a mixture of compounds that, when present in a solution, resists
changes in the pH of the solution when small quantities of acid or base are added to the solution.
D. Buffer capacity is a measure of the resistance to change in the pH of a solution when acids or
bases are added to the solution.
E. Many useful equations have been derived to deal with the subject of acid-base chemistry.A list of
those equations most useful in pharmaceutical systems is given in Table 18.1. Example calculations
using these equations are also given.

II. USES OF BUFFERS AND pH ADJUSTING AGENTS

Buffers or agents to adjust the pH of solutions may be added to manufactured pharmaceutical prod-
ucts or to extemporaneously compounded preparations for any of the following reasons:

224
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Chapter 18 Buffers and pH Adjusting Agents 225

A. For preparations that are intended to be applied to the sensitive membranes of the eye or nasal
passages or that may be injected into muscles, blood vessels, organs, tissue, or lesions, it is desirable
to adjust the pH of the preparation to a level that is close to the physiologic pH of the tissue.This
is done to minimize tissue damage and pain or discomfort experienced by the patient.
B. The absorption, and therefore the therapeutic effectiveness, of certain drugs may be improved
when they are present either in an ionized or nonionized state.This state may be manipulated and
maintained by adjusting the pH of the medium.
C. The chemical stability of many drugs in solution may be improved by maintaining the pH of the
solution in a particular range.
D. The aqueous solubility of many organic drugs depends on the degree to which these weak elec-
trolytes are present in ionic form.This, in turn, may depend on the pH of the solution.

III. BUFFER CAPACITY

A. Buffer capacity, , is defined by the formula:
¢B

¢pH
where B is the gram equivalents per liter of strong acid or strong base added to the buffer solu-
tion and pH is the resulting pH change. The larger  is, the greater the buffer capacity of the
system (that is, its ability to resist a pH change).
B. While buffer capacity can be determined for a system by using the formula just given, it is not
often calculated in compounding situations. Because of the limited beyond-use datings needed for
compounded drug preparations, exact buffer capacities are not required. For a detailed treatment
of the subject of buffer capacity, refer to a book on physical pharmacy (1).
C. Even though we rarely calculate buffer capacity, it is helpful to understand the concept in princi-
ple and to understand the circumstances under which buffer capacity is maximized.
1. Solutions of strong acids such as HCl will resist a change in pH at or below pH 3. In fact, the
standard buffer solution identified by the USP for the pH range 1.2 to 2.2 is a 0.2 M solution
of HCl to which KCl has been added as a neutral salt for proper electrolyte concentration (2).
2. Similarly, strong bases such as NaOH give good buffer capacity at pH 11 or higher.
3. The most common buffer systems consist of a combination of a weak acid and its salt (i.e., its
conjugate base) or a weak base and its salt (i.e., its conjugate acid).
a. The Henderson-Hasselbalch equation, also known as the buffer equation, relates the pH of a
solution, which contains an acid-base conjugate pair, to the pair’s dissociation constant and
the concentrations of the species in the solution. This equation and sample problems are
shown in Table 18.1.
b. Acid-base conjugate pairs have their greatest buffer capacity when the pH of the solution is
equal to their pKa, and buffer capacity of an acid-base pair is effective in the range pH 
pKa  1.
4. Buffer capacity is related to the concentration of the buffer; the greater the concentration of
the buffer, the greater the resistance to a change in pH.
5. High buffer capacity is sometimes undesirable. For example, when a drug is most stable at a
pH that differs considerably from the physiologic pH at the site of administration, a compro-
mise must be found. One possible solution is to use a buffer that maintains the pH at the desir-
able level for stability but has a relatively low buffer capacity, so that on administration, the
body’s natural buffering systems will rapidly alter the pH of the solution to a more comfort-
able level.

IV. SELECTING A BUFFER SYSTEM OR A COMPOUND TO ADJUST pH

A. First, consider the route of administration for the dosage form.
1. Ingredients to buffer or adjust pH must be nontoxic for the intended route of administration.
This is an important factor to consider. For example, boric acid and sodium borate are com-
mon ingredients for ophthalmic solutions; these would not be satisfactory for systemic drug
preparations because borate is toxic systemically.
2. Agents for any route of administration should be nonirritating at the needed concentration.
3. For oral liquid preparations, buffer compounds should not have a disagreeable odor or taste.
4. Agents used for parenteral preparations must be in sterile form or must be rendered sterile.
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Table 18.1 EQUATIONS USEFUL IN ACID-BASE AND BUFFER CALCULATIONS

GENERAL EQUATIONS DEFINING pH AND pK

pH  log [H3O] Ka is the dissociation constant for a weak acid.

pOH  log [OH] For: HA  H2O Δ H3O  A
pH  pOH  pKw  14 [H3O][A]
Ka 
pKa  log Ka [HA]
pKb  log Kb Kb is the dissociation constant for a weak base
pKa  pKb  pKw  14 For: B  H2O Δ BH  OH
[BH][OH]
Kb 
[B]
Generally K values for all drugs, both acids and
bases, are now reported as Kas.

SPECIFIC EQUATIONS EXAMPLES

For a strong acid: 0.1 N HCl

pH  log [Ca]  log [H] pH  log [Ca]  log [0.1]  1
For a strong base: 0.1 N NaOH
pOH  log [OH]  log [Cb] pH  pKw  log [Cb]  14  log [0.1]
or pH  pKw  log [Cb]  14  1  13
For a weak acid: 0.1 N acetic acid HOAc; pKa  4.76
pH  1⁄2 pKa  1⁄2 log [Ca] pH  1⁄2 (4.76)  1⁄2 log [0.1]
 2.38  (0.5)  2.88

For a weak base: 0.1 N sodium acetate (the conjugate base of acetic acid) NaOAc
pOH  1⁄2 pKb  1⁄2 log [Cb] or pH  7  2.38  1⁄2 log [0.1]  8.88
pH  1⁄2 pKw  1⁄2 pKa  1⁄2 log [Cb]
For a diprotic (H2A) acid: 0.1 M carbonic acid H2CO3; pKa1  6.37; pKa2  10.33
Solution with only the acid pH  1⁄2 (6.37)  1⁄2 log [0.1]
pH  1⁄2 pKa1  1⁄2 log [Ca]  3.185  (0.5)  3.685
Notice that this is the same equation as for a
weak acid.
For a diprotic (H2A) acid: 0.1 M sodium bicarbonate NaHCO3
Solution with only the ampholyte HA pH  1⁄2 (6.37)  1⁄2 (10.33)
pH  1⁄2 pKa1  1⁄2 pKa2  3.185  5.165  8.35
For a diprotic (H2A) acid: 0.1 M sodium carbonate Na2CO3
Solution with only the diacidic base, A2 pH  1⁄2 (14)  1⁄2 10.33)  1⁄2 log (0.1)
pH  1⁄2 pKw  1⁄2 pKa2  1⁄2 log [Cb]  7  5.165  (0.5)  11.67
For conjugate acid-base pairs: Ex. #1: 0.1 M HOAc and 0.1 M NaOAc
[conjugate base] [0.1]
pH  pKa  log pH  4.76  log  4.76  log 1
[conjugate acid] [0.1]
 4.76  0  4.76
For acids this is often written: Ex. #2:0.1 M HOAc and 0.2 M NaOAc
[salt] [0.2]
pH  pKa  log pH  4.76  log  4.76  0.30
[acid] [0.1]
 5.06
For bases this is often written: Ex. #3:0.1 M ammonia NH4OH and 0.1 M ammonium chloride NH4Cl
[base]
pH  pKa  log pKb  4.76 pKa (for conjugate acid)  9.24
[salt]
[0.1]
pH  9.24  log  9.24
[0.1]
These are all equivalent forms of the Henderson. Ex. #4: 0.1 M NH4OH and 0.2 M NH4Cl
[0.1]
Hasselbalch equation. pH  9.24  log  9.24  0.30  8.94
[0.2]

Note: You may recall from previous coursework that the equations presented in this table are simplified versions of more complex
(and more accurate) equations. They are based on assumptions that do not hold in all cases. (For example, pKw  14 only at 25C.)
They do give the sort of approximations that are helpful in the practical situations encountered in compounding. For a detailed treat-
ment of this subject, the reader may wish to review chapters on ionic equilibria and buffered and isotonic solutions in a book on phys-
ical pharmacy (1) or an equivalent text.
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Chapter 18 Buffers and pH Adjusting Agents 227

Table 18.2 MODIFIED WALPOLE ACETATE BUFFER

ACETIC ACID 99% SODIUM ACETATE SODIUM CHLORIDE TO

pH (mL/100 mL) ANHYDROUS (g/100 mL) MAKE ISOTONIC (g/100 mL)

3.6 1.11 0.123 0.28

3.8 1.06 0.197 0.28
4.0 0.98 0.295 0.27
4.2 0.88 0.435 0.26
4.4 0.76 0.607 0.24
4.6 0.61 0.804 0.22
4.8 0.48 0.984 0.21
5.0 0.35 1.156 0.19
5.2 0.25 1.296 0.18
5.4 0.17 1.402 0.17
5.6 0.11 1.484 0.16
Note: This buffer is suitable for internal, external, or ophthalmic use.
Source: Reprinted with permission from Schumacher GE. Buffer formulations. Am J Hosp Pharm 1966; 23: 629.

5. Ophthalmic solutions are ordinarily buffered at the pH of maximum stability for the drugs they
contain, but if this pH is more than 1 pH unit from neutrality (i.e., outside the range of 6.5 to
8.5), a system with a low buffer capacity should be used (3) so that when the ophthalmic solu-
tion is dropped into the eye, the buffer system of the tears will quickly bring the pH of the
solution back to that of the tears. Generally, a buffer capacity less than 0.05 is desired with a
pH in the range of 4 to 8 (4,5). See Chapter 33 for more details on pH and buffering consid-
erations for ophthalmic solutions.
B. Consider the easiest systems first.
1. If a formula merely calls for the adjustment of pH to a given level, usually a dilute solution (0.1
to 0.2 N) of HCl or NaOH may be used. Be aware of possible compatibility considerations with
the chloride ion in HCl. For example, if a drug is available as a salt with an uncommon anion,
such as mesylate, the chloride may cause precipitation because the hydrochloride salt of that drug
is less soluble; the preservatives phenylmercuric acetate and nitrate precipitate with halides, etc.
2. Sodium Bicarbonate Injection is often used to raise the pH of some parenteral preparations. It
is sterile and nontoxic, but it too may have compatibility issues. Always check for compatibil-
ity with all formulation components.
3. For oral or topical liquids, consider using a preformulated vehicle. Many of the available fla-
vored syrups and liquid vehicles contain buffers or ingredients that function as buffers. See
Chapter 22,Vehicles for Liquid Preparations, for descriptions and specifications, and examples
in Sample Prescriptions 28.5 and 28.6 in Chapter 28 and 30.7 in Chapter 30 of this book.
4. For an easily made buffer in the low- to mid-pH range (3.6 to 5.6), the Acetate Buffer given
in Table 18.2 is useful (6). It may be used for systemic, topical, or ophthalmic drug preparations.
If isotonicity is needed, the appropriate quantities of sodium chloride are also given; if any of
the preparation ingredients are incompatible with halides, sodium nitrate or dextrose in equal
osmolar quantities (see Chapter 11) can be substituted for the sodium chloride.
5. For preparations to be buffered between pH 6 and 8, Sorensen’s Phosphate Buffer is a useful
system. It can be used for systemic, topical, or ophthalmic preparations. Its formula is shown in
Table 18.3 (7,8). It has a relatively high buffer capacity. If an isotonic solution is needed, sodium
chloride in the amounts given in the table can be added; if any of the preparation ingredients
are incompatible with halides, sodium nitrate or dextrose in equal osmolar quantities (see
Chapter 11) can be substituted for the sodium chloride.The use of this buffer in an ophthalmic
solution is illustrated in Sample Prescription 33.2 in Chapter 33.
6. If a concentrated multi-purpose buffer solution is desired in the low- to mid-pH range (2.5
to 6.5), the Citrate Buffer in Table 18.4 can be used.When combined in the ratios given, the
resulting solution has a molarity of 0.33 M. This buffer can be diluted 10-fold and still have
adequate buffer capacity (6).
7. For ophthalmic solutions that require buffering in the mid-acid range (~5), an aqueous solu-
tion of Boric Acid 1.9% is isotonic, easy to make, and has an appropriately low buffer capacity
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228 Part 4 Pharmaceutical Excipients

Table 18.3 SORENSEN’S MODIFIED PHOSPHATE BUFFER

ACID STOCK SOLUTION, ALKALINE STOCK SOLUTION,

M/15 SODIUM BIPHOSPHATE M/15 SODIUM PHOSPHATE

*Sodium Biphosphate, 8.006 g Sodium Phosphate, 9.473 g

Anhydrous Anhydrous
Purified Water, qs ad 1,000 mL Purified Water, qs ad 1,000 mL

mL OF M/15 mL OF M/15 SODIUM CHLORIDE

SODIUM SODIUM REQUIRED
BIPHOSPHATE SOLUTION PHOSPHATE SOLUTION pH FOR ISOTONICITY (g/100 mL)

90 10 5.9 0.52
80 20 6.2 0.51
70 30 6.5 0.50
60 40 6.6 0.49
50 50 6.8 0.48
40 60 7.0 0.46
30 70 7.2 0.45
20 80 7.4 0.44
10 90 7.7 0.43
5 95 8.0 0.42
*Sodium biphosphate, monohydrated 9.208 g may be used.
This buffer is suitable for internal, external, or ophthalmic use.
Source: Deardorff DL. Ophthalmic solutions. In: Hoover JE, ed. Remington’s pharmaceutical sciences, 14th ed.
Easton, PA: Mack Publishing Co., 1970; 1553–1555. Sörensen SL. Enzyme studies. II. The measurement and
importance of the hydrogen ion concentration in enzyme reactions. Biochem Z 1909; 21: 131 and 22: 352.

Table 18.4 CONCENTRATED MULTI-PURPOSE BUFFER SOLUTION (CITRATE

BUFFER)

ACID STOCK SOLUTION, ALKALINE STOCK SOLUTION,

M/3 CITRIC ACID M/3 SODIUM CITRATE

*Citric Acid 70 g Sodium Citrate 98 g

Monohyrate Dihydrate
Purified Water, qs ad 1,000 mL Purified Water, qs ad 1,000 mL
*Citric Acid Anhydrous 64 g
may be substituted

mL OF M/3 CITRIC ACID SOLUTION mL OF M/3 SODIUM CITRATE SOLUTION pH

92 8 2.5
82 18 3.0
68 32 3.5
58 42 4.0
44 56 4.5
28 72 5.0
14 86 5.5
6 94 6.0
2 98 6.5
Both compounds combined yield a concentration of 0.33 M.
This buffer is suitable for internal, external, or ophthalmic use.
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Chapter 18 Buffers and pH Adjusting Agents 229

Table 18.5 PALITZSCH OPHTHALMIC BUFFER

ACID STOCK SOLUTION ALKALINE STOCK SOLUTION

Boric Acid 12.404 g Sodium Borate 19.108 g

Decahydrate
Purified Water, q.s. ad 1,000 mL Purified Water, q.s. ad 1,000 mL

mL OF 0.2 M BORIC ACID SOLUTION mL OF 0.05 M SODIUM BORATE SOLUTION pH

97 3 6.8
94 6 7.1
90 10 7.4
85 15 7.6
80 20 7.8
75 25 7.9
70 30 8.1
65 35 8.2
55 45 8.4
45 55 8.6
40 60 8.7
30 70 8.8
20 80 9.0
10 90 9.1
Source: Palitzsch S. Use of borax and boric acid solutions in the colorimetric measurement of the hydrogen
ion concentration of sea water. Biochem Z 1915; 70: 333.

for this situation. Its use is illustrated in Sample Prescription 33.1 in Chapter 33. An example
of a borate buffer system at higher pH, the Palitzsch buffer, is given in Table 18.5 (9). Numer-
ous other borate buffers are reported in the literature (7,10–12).
C. If a customized buffer solution must be made, follow these steps:
1. Select a compound or combination of compounds that can give you a pH in the range you desire.
a. As discussed earlier, this may be a strong acid, a strong base, or a conjugate pair. If using a con-
jugate pair, the pKa of the conjugate acid should be within one pH unit of the desired pH.
b. For possible conjugate pairs, you may want to consult the table in the appendix section of
the CD that accompanies this book. This table gives the pKas of a large number of drugs
and reference compounds.
c. Be sure that your choice is chemically stable, is sufficiently soluble, is compatible with the
other ingredients in the formulation, is free from odor and color, and is nonsensitizing and
nontoxic by the route of administration being used.
d. Examples of some possible choices are given in Table 18.6.

Table 18.6 BUFFER CHOICES FOR SPECIFIC pH RANGES

pH RANGE BUFFER

pH 1–3 HCl
pH 2.5–6.5 Citrate Buffer
pH 3.6–5.6 Acetate Buffer
pH 6–8 Sorenson’s Phosphate Buffer
pH 8–9 Sodium Bicarbonate
pH 9–11 Sodium Bicarbonate/Sodium Carbonate
pH 11–13 NaOH
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230 Part 4 Pharmaceutical Excipients

USP 30/NF 25 ARTICLES CATEGORIZED AS ACIDIFYING, ALKALIZING, OR BUFFERING

Table 18.7 AGENTS

ACIDIFYING AGENT ALKALIZING AGENT BUFFERING AGENT

Acetic Acid Ammonia Solution, Strong Acetic Acid

Acetic Acid, Glacial Ammonium Carbonate Adipic Acid
Citric Acid, Anhydrous Diethanolamine Ammonium Carbonate
Citric Acid Monohydrate Potassium Hydroxide Ammonium Phosphate
Fumaric Acid Sodium Bicarbonate Boric Acid
Hydrochloric Acid Sodium Borate Citric Acid, Anhydrous
Hydrochloric Acid, Diluted Sodium Carbonate Citric Acid Monohydrate
Malic Acid Sodium Hydroxide Lactic Acid
Nitric Acid Trolamine Phosphoric Acid
Phosphoric Acid Potassium Citrate
Phosphoric Acid, Diluted Potassium Metaphosphate
Propionic Acid Potassium Phosphate, Dibasic
Sulfuric Acid Potassium Phosphate, Monobasic
Tartaric Acid Sodium Acetate
Sodium Citrate
Sodium Lactate Solution
Sodium Phosphate, Dibasic
Sodium Phosphate, Monobasic
Succinic Acid
Source: The United States Pharmacopeial Convention Inc. 2007 USP 30/NF 25. Front matter—NF: excipients. Rockville, MD: Author, 2006.

2. Calculate the concentration of each compound needed.

a. You may use the appropriate equation from Table 18.1 (remembering that these equations
can only give approximations) or one of the buffer formulas from Tables 18.2 through 18.5.
b. If an acid-base conjugate pair is selected, recall that the Henderson-Hasselbalch equation
gives you just the ratio of concentrations. From the calculated ratio, select the specific con-
centrations for the ingredients based on the fact that adequate buffer capacity can be had
with final concentrations of 0.05 to 0.5 M (1).
3. After the solution is made, use pH paper or a pH meter to measure the pH of the solution and
make adjustments as needed.

V. ACIDIFYING, ALKALIZING, AND BUFFERING AGENTS

Table 18.7 shows compounds that are official articles in the USP30/NF25 and that are categorized
by USP–NF as excipients used as acidifying, alkalizing, and buffering agents (13).

REFERENCES
1. Sinko PJ. Martin’s physical pharmacy and pharmaceutical sci-
ences, 5th ed. Baltimore, MD: Lippincott Williams & Wilkins,
2006.
2. The United States Pharmacopeial Convention Inc. Reagents:
buffer solutions. 2007 USP 30/NF 25. Rockville, MD: Author,
2006.
3. Gonnering R, et al. The pH tolerance of rabbit and human
corneal epithelium. Invest Ophthalmol Vis Sci 1979; 18: 3373–
3390.
4. Allen LV. Compounding ophthalmic liquids. Secundum Artem,
volume 6, number 4 (http://www.paddocklabs.com/images/
PadSec_v6n4.pdf).
5. Anonymous. Buffer solutions for ophthalmic preparations. Int J
Pharm Compound 1998; 2(3): 190–191.
6. Schumacher GE. Buffer formulations. Am J Hosp Pharm 1966;
23: 629.
7. Deardorff DL. Ophthalmic solutions. In: Hoover JE, ed. Rem-
ington’s pharmaceutical sciences, 14th ed. Easton, PA: Mack
Publishing Co., 1970; 1553–1555.
8. Sörensen SL. Enzyme studies. II. The measurement and impor-
tance of the hydrogen ion concentration in enzyme reactions.
Biochem Z 1909; 21: 131 and 22: 352.
9. Palitzsch S. Use of borax and boric acid solutions in the colori-
metric measurement of the hydrogen ion concentration of sea
water. Biochem Z 1915; 70: 333.
10. Gifford SR. Reaction of buffer solution and of ophthalmic
drugs. Arch Ophthalmol 1935; 13: 78.
11. Neuwald F, et al. Galenical and pharmacological research on the
composition of aqueous ophthalmic pharmaceuticals. I. Stability
of some compounds used as ophthalmic pharmaceuticals. II. A
generally useful buffer. Pharm Ztg Ver Apotheker-Ztg 1957; 102:
40, 51–52 and 1958; 103: 12.
12. Atkins WR, Pantin GF. Buffer mixture for the alkaline range of
hydrogen-ion concentration determinations. Biochem J 1926;
20: 102.
13. The United States Pharmacopeial Convention Inc. Front matter-
NF: excipients. 2007 USP 30/NF 25. Rockville, MD: Author,
2006.

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