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USP 41 Physical Tests / á791ñ 6543

á791ñ pH

INTRODUCTION

For compendial purposes, pH is defined as the value given by a suitable, properly calibrated, potentiometric sensor and
measuring system. [NOTE—The measuring system has traditionally been referred to as the “pH meter.” While the pH meter is
still in common use, the measuring system can also be embedded inside the pH sensor, and the pH signal can be transmitted
digitally to an external device such as a computer, Programmable Logic Controller (PLC), Distributed Control System (DCS),
data acquisition system, terminal, or other microprocessor-controlled device.] By definition, pH is equal to −log10[aH+] where
aH+ is the activity of the hydrogen (H+) or hydronium ion (H3O+), and the hydrogen ion activity very closely approximates the
hydrogen ion concentration.
The practical pH scale is defined:
pH = pHS + [(E − ES)/k]

E = measured potential where the galvanic cell contains the solution under test (pH)
ES = measured potential where the galvanic cell contains the appropriate buffer solution for calibration (pHS)
k = change in potential/unit change in pH and is derived from the Nernst equation (as follows)
k = loge(10) × (RT/nF)

R = 8.314 J/mole/°K
T = temperature (°K)
n = moles/half-reaction
F = Faraday constant, 96485 C/mole
The resulting equation is [0.05916 + 0.0001984(T − 25°)] volts at temperature T. Values of k from 15°–35° are provided in
Table 1.
Table 1. Values of k for Various Temperatures
Temperature k
(°C) (V)
15.00 0.05718
20.00 0.05817
25.00 0.05916
30.00 0.06016
35.00 0.06115

Values of k at other temperatures can be determined from the equation above. For practical purposes, values of k are deter-
mined from pH sensor calibration.

PH MEASUREMENT SYSTEM

The measurement system consists of: (1) a measuring electrode sensitive to hydrogen-ion activity, typically a glass electrode,

General Chapters
though other electrode types are possible, (2) a suitable reference electrode, for example, a silver–silver chloride electrode, and
(3) a voltage measurement system with an input resistance capable of measuring at a high input impedance of the pH sensor.
The measuring and reference electrode may be separated or combined. The voltage measurement system may be separated
from the pH sensor or integrated into the sensor. For most applications, a temperature measurement will be necessary for
compensation of the Nernst temperature influence described above. A temperature device may be embedded into the pH sen-
sor, or an external temperature device may be used.

INSTRUMENT REQUIREMENTS

The measurement system shall be capable of performing a two-point (or more) pH calibration (see below). The accuracy of
the pH measurement system is described in the Calibration section. The resolution of the pH measurement system shall be at
least 0.01 pH. The instrument shall be capable of temperature-compensating the pH sensor measurement to convert the milli-
volt signal to pH units at any temperature, either automatically using a temperature device built into the sensor system or by
manual entry of the sample temperature into the measurement system. The accuracy of the temperature measurement system
shall be ±1°. The resolution of the temperature measurement system shall be at least 0.1°. Lab-based pH measurements are
typically performed at 25 ± 2° unless otherwise specified in the individual monograph or herein. However, temperatures out-
side this range are acceptable if samples are more conveniently prepared at alternative temperatures. Examples of non-lab-
based measurements include test samples inside process pipes, vessels, tanks, and other non-standard processing conditions.

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6544 á791ñ / Physical Tests USP 41

[NOTE—The definitions of pH, the pH scale, and the values assigned to the buffer solutions for calibration are for the purpose
of establishing a practical, operational system so that results may be compared between laboratories. The measured pH values
do not necessarily correspond exactly to those obtained by the definition, pH = −log aH+, rather the values obtained are closely
related to the activity of the hydrogen-ion in aqueous solutions.] [NOTE—Where a pH measurement system is calibrated by use
of an aqueous buffer and then used to measure the “pH” of nonaqueous systems, the ionization constant of the acid or base,
the dielectric constant of the medium, the liquid-junction potential (which may give rise to errors of approximately 1 pH unit),
and the hydrogen-ion response of the glass electrode are all changed. For these reasons, the values so obtained with solutions
that are only partially aqueous in character can be regarded only as apparent pH values.]

BUFFER SOLUTIONS FOR CALIBRATION OF THE PH MEASUREMENT SYSTEM

Buffer solutions for calibration are prepared as directed in Table 2.1 Buffer salts of requisite purity can be obtained from the
National Institute of Standards and Technology, other national authorities, or other suppliers. Buffer solutions should be stored
in appropriate containers that ensure stability of the pH through the expiry date, and fitted with a tight closure. For buffer
solutions greater than 11, the storage should be in containers that are resistant to or reduce carbon dioxide intrusion which
would lower the pH of the buffer. For buffer solutions lower than 11, they should typically be prepared at intervals not to ex-
ceed 3 months. For buffer solutions greater than 11, they should typically be prepared and used fresh unless carbon dioxide
ingress is restricted. All buffer solutions should be prepared using Purified Water. Table 2 indicates the pH of the buffer solutions
as a function of temperature. The instructions presented here are intended for the preparation of solutions having the designa-
ted molal (m) concentrations. However, in order to facilitate their preparation, the instructions are given in molarity. The dif-
ference in concentration between molality and molarity preparations for these buffer solutions is less than 1%, and the pH
difference is negligible. Calibration using buffer solutions shall be done in the temperature range of the buffers listed in Table
2. [NOTE—The Nernst temperature compensation corrects only for the electrode millivolt output change with temperature,
not the actual pH change of the buffer solution with temperature which is unique for each buffer.] Features such as automatic
buffer recognition or buffer pH–temperature correction are available for convenience in accommodating the temperature influ-
ence on buffer solutions. The pH–temperature response can be determined from the values in Table 2.
Table 2. pH Values of Buffer Solutions for Calibration
Potassium Sodium
Dihydrogen Carbo-
Phosphate, nate,
0.0087 M, 0.025 M, Calcium
Potassium Potassium and and Hydrox-
Potassium Hydrogen Dihydro- Potassium Equimolal Disodium Sodium Sodium ide,
Temper- Tetra- Tartrate gen Biphtha- Phos- Hydrogen Tetra- Bicarb- Satura-
ature oxalate, Saturated Citrate, late, phate, Phosphate, borate, onate, ted at
(°C) 0.05 m at 25° 0.05 M 0.05 m 0.05 m 0.0303 M 0.01 m 0.025 M 25°
10 1.67 — — 4.00 6.92 — 9.33 — 13.00
15 1.67 — 3.80 4.00 6.90 7.45 9.28 10.12 12.81
20 1.68 — 3.79 4.00 6.88 7.43 9.23 10.06 12.63
25 1.68 3.56 3.78 4.01 6.86 7.41 9.18 10.01 12.45
30 1.68 3.55 3.77 4.02 6.85 7.40 9.14 9.97 12.29
35 1.69 3.55 3.76 4.02 6.84 7.39 9.10 9.93 12.13
40 1.69 — — 4.04 6.84 — 9.07 — 11.98
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45 1.70 — — 4.05 6.83 — 9.04 — 11.84

50 1.71 — — 4.06 6.83 — 9.01 — 11.71
55 1.72 — — 4.08 6.83 — 8.99 — 11.57
60 1.72 — — 4.09 6.84 — 8.96 — 11.45
DpH/D°C 0.0010 −0.0014 −0.0022 0.0018 −0.0016 −0.0028 −0.0074 −0.0096 −0.0310

Preparation of alternative volumes at the same concentrations to those indicated below is acceptable.
Potassium tetraoxalate, 0.05 m: Dissolve 12.61 g of KH3(C2O4)2 · 2H2O, and dilute with water to make 1000.0 mL.
Potassium hydrogen tartrate, saturated at 25°: Add C4H5KO6 to water until saturation is exceeded at 25°. Then filter or
decant.
Potassium dihydrogen citrate, 0.05 M: Dissolve 11.41 g of C6H7KO4, and dilute with water to make 1000.0 mL.

1 Commercially available buffer solutions for pH measurement system, calibrated by methods traceable to the National Institute of Standards and Technology

(NIST) or other national authorities, labeled with a pH value accurate to 0.02 pH unit may be used. Solutions prepared from ACS reagent grade materials or other
suitable materials, may be used provided the pH of the resultant solution is the same as that of the solution prepared from the NIST (or other national authorities)
certified material. Buffer solutions that are greater than 12 should be used immediately, or should be prepared using freshly boiled water, and stored under condi-
tions to minimize carbon dioxide absorption and ingress.

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USP 41 Physical Tests / á791ñ 6545

Potassium biphthalate, 0.05 m: Dissolve 10.12 g of KHC8H4O4, previously dried at 110° for 1 h, and dilute with water to
make 1000.0 mL.
Equimolal phosphate, 0.05 m: Dissolve 3.53 g of disodium hydrogen phosphate (Na2HPO4) and 3.39 g of potassium di-
hydrogen phosphate (KH2PO4), each previously dried at 120° for 2 h, and dilute with water to make 1000.0 mL.
Potassium dihydrogen phosphate, 0.0087 M, and disodium hydrogen phosphate, 0.0303 M: Dissolve 1.18 g of
KH2PO4 and 4.30 g Na2HPO4, both dried for 2 h at 120 ± 2°, and dilute with water to make 1000.0 mL.
Sodium tetraborate, 0.01 m: Dissolve 3.80 g of Na2B4O7 · 10H2O, and dilute with water to make 1000.0 mL. Protect
from absorption of carbon dioxide.
Sodium carbonate, 0.025 M, and sodium bicarbonate, 0.025 M: Dissolve 2.64 g of sodium carbonate (Na2CO3) and
2.09 g of sodium bicarbonate (NaHCO3), and dilute with water to make 1000.0 mL.
Calcium hydroxide, saturated at 25°: Add Ca(OH)2 to water until saturation is exceeded at 25°. Use water that has been
recently boiled and protected from the atmosphere to limit carbon dioxide absorption. Then filter or decant.

CALIBRATION

Because of variations in the nature and operation of the available pH measurement systems, it is not practical to provide
universal directions for the calibration of the measurement system. However, the general principles to be followed are set forth
in the following paragraphs. Examine the electrodes, especially the reference electrode and electrolyte level, if a liquid electro-
lyte is used. If necessary, replenish electrolyte supply, and observe other precautions indicated by the instrument and electrode
manufacturers.
The calibration or verification of the pH measurement system should be periodically executed. The historical performance of
the measurement system, the criticality of the pH measurement, the maintenance of the pH sensor, and the frequency of
measurement operation is used to determine the frequency of the calibration/verification. In addition to the two-point calibra-
tion process described below, other multipoint methods may be available for use. These are acceptable if the pH sensor slope
and the offset criteria (see step 10) as well as the calibration accuracy (see step 14) are met.
If the pH of the buffer is sensitive to ambient carbon dioxide, then use Purified Water that has been recently boiled, and
subsequently stored in a container designed to minimize ingress of carbon dioxide.
1. To calibrate the pH measurement system, select three buffer solutions for calibration, preferably from those given in Table
2, such that the expected pH of the material under test falls within their range. Two of the buffers are used for the calibra-
tion process, and the third buffer is used for verification. The value of the verification buffer shall be between two of the
calibration buffers. If the operational range of the pH sensor is beyond the pH range of the buffer solutions in Table 2,
then either 1) select two nearby pH buffers from Table 2 or 2) select one from Table 2 and another documented prepared
buffer that is outside the range.
2. Rinse the pH sensor several times with water, then with the first buffer solution.
3. Immerse the pH sensor in the first buffer solution at a temperature within the range of Table 2.
4. If automatic temperature measurement and compensation is not included in the measuring system, manually enter the
temperature of the buffer and pH value of the buffer solution at that temperature into the instrument. For temperatures
not listed in Table 2, use linear interpolation to determine the pH value as a function of temperature.
5. Initiate the two-point calibration sequence with the first buffer according to the manufacturer’s instructions.
6. Remove the pH sensor from the first buffer and rinse the electrode(s) with water, and then with the second buffer solu-
tion.
7. Immerse the pH sensor in the second buffer at a temperature within the range of Table 2.
8. If automatic temperature measurement and compensation is not included in the measuring system, manually enter the

General Chapters
temperature of the buffer and pH value of the buffer solution at that temperature into the instrument.
9. Continue the two-point calibration sequence with the second buffer according to the manufacturer¢s instructions.
10. After completion of the two-point calibration process, verify that the pH slope and offset are within acceptable parame-
ters. Typical acceptable parameters are a slope of 90%–105% and an offset of 0 ± 30 mV (0.5 pH units at 25° C). Depend-
ing on the pH instrumentation, the pH slope and offset may be determined in software or by manual methods. If using
manual methods, follow supplier instructions to calculate the pH sensor slope/offset. If these parameters are not within
acceptable parameters, the sensor should be properly cleaned, replenished, serviced, or replaced, and the two-point cali-
bration process shall be repeated.
11. Remove the pH sensor from the second buffer, and rinse thoroughly with water, and then the verification buffer.
12. Immerse the pH sensor in the verification buffer at a temperature within the range of Table 2.
13. If automatic temperature measurement and compensation are not included in the measuring system, manually enter the
temperature of the buffer and pH value of the buffer solution at that temperature into the instrument.
14. The pH reading shall be within ±0.05 pH of the value in Table 2 at the buffer solution temperature.

OPERATION

All test samples should be prepared using Purified Water, unless otherwise specified in the monograph. All test measurements
should use manual or automated Nernst temperature compensation.

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6546 á791ñ / Physical Tests USP 41

1. Prepare the test material according to requirements in the monograph or according to specific procedures. If the pH of
the test sample is sensitive to ambient carbon dioxide, then use Purified Water that has been recently boiled, and subse-
quently stored in a container designed to minimize ingress of carbon dioxide.
2. Rinse the pH sensor with water, then with a few portions of the test material.
3. Immerse the pH sensor into the test material and record the pH value and temperature.
In all pH measurements, allow sufficient time for stabilization of the temperature and pH measurement.
Diagnostic functions such as glass or reference electrode resistance measurement may be available to determine equipment
deficiencies. Refer to the electrode supplier for diagnostic tools to assure proper electrode function.
Where approximate pH values suffice, indicators and test papers (see Indicators and Indicator and Test Papers) may be suita-
ble.
For a discussion of buffers, and for the composition of standard buffer solutions called for in compendial tests and assays, see
Buffer Solutions in the section Solutions. This referenced section is not intended to replace the use of the pH calibration buffers
in Table 2.

á795ñ PHARMACEUTICAL COMPOUNDING—NONSTERILE

PREPARATIONS

INTRODUCTION

The purpose of this chapter is to provide compounders with guidance on applying good compounding practices for the
preparation of nonsterile compounded formulations for dispensing and/or administration to humans or animals. Compound-
ing is an integral part of pharmacy practice and is essential to the provision of healthcare. This chapter and applicable mono-
graphs on formulation help define good compounding practices. Furthermore, this chapter provides general information to
enhance the compounder's ability in the compounding facility to extemporaneously compound preparations that are of ac-
ceptable strength, quality, and purity. Pharmacists, other healthcare professionals, and others engaged in the compounding of
drug preparations should comply with applicable state and federal compounding laws, regulations, and guidelines.

CATEGORIES OF COMPOUNDING

In the three general categories of nonsterile compounding described in this section, different levels of experience, training,
and physical facilities are associated with each category.
Criteria used to determine overall classification include:
• degree of difficulty or complexity of the compounding process
• stability information and warnings
• packaging and storage requirements
• dosage forms
• complexity of calculations
• local versus systemic biological disposition
• level of risk to the compounder
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• potential for risk of harm to the patient.

See Pharmaceutical Compounding—Sterile Preparations á797ñ for risk levels associated with sterile preparations. Specialty areas
such as radiopharmaceuticals require special training and are beyond the scope of this chapter. Compounders shall acquire
and maintain knowledge and skills in all areas (e.g., dosage form, patient population, and medical specialty) for which they
compound.

Description of Categories

SIMPLE

Making a preparation that has a United States Pharmacopeia (USP) compounding monograph or that appears in a peer-re-
viewed journal article that contains specific quantities of all components, compounding procedure and equipment, and stabili-
ty data for that formulation with appropriate BUDs; or reconstituting or manipulating commercial products that may require
the addition of one or more ingredients as directed by the manufacturer. Examples include Captopril Oral Solution, Indometha-
cin Topical Gel, and Potassium Bromide Oral Solution, Veterinary.

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