pH value Determination Procedure as per IP, BP & USP

Explore comprehensive guidelines for pH value determination in pharmaceuticals, following the protocols set by IP, BP, and USP pharmacopoeia

Procedure for pH value Determination

1.0     Objective

    • The objective of this General Test Procedure (GTP) is to describe the procedure to be used for performing pH value of the sample.

2.0     Principle/Reaction

    • The pH value conventionally represents the acidity or alkalinity of an aqueous solution.
    • In the Pharmacopoeia, standards and limits of pH have been provided for those Pharmacopoeial substances in which pH value as a measure of the hydrogen-ion activity is important from the standpoint of stability or physiological suitability.
    • The determination i’s carried out at a temperature of 25° 2°, unless otherwise specified in the individual STP.

3.0     Requirements:

    • As per IP
      1. pH meter with electrodes
      2. Potassium tetraoxalate
      3. Potassium dihydrogen tartrate
      4. Potassium dihydrogen citrate
      5. Potassium hydrogen phthalate
      6. Potassium dihydrogen phosphate
      7. Anhydrous Disodium hydrogen phosphate
      8. Sodium tetraborate
      9. Sodium carbonate
      10. Sodium bicarbonate
    • As per USP
      1. pH meter with electrodes
      2. Potassium tetraoxalate
      3. Potassium Biphthalate
      4. Anhydrous Disodium hydrogen phosphate
      5. Potassium dihydrogen phosphate
      6. Sodium tetraborate
      7. Calcium Hydroxide
    • As per BP/Ph.Eur.
      1. pH meter with electrodes
      2. Potassium tetraoxalate
      3. Potassium dihydrogen tartrate
      4. Potassium dihydrogen citrate
      5. Potassium hydrogen phthalate
      6. Potassium dihydrogen phosphate
      7. Anhydrous Disodium hydrogen phosphate
      8. Sodium tetraborate
      9. Sodium carbonate
      10. Sodium bicarbonate
      11. Calcium Hydroxide

4.0     Procedure for determination of pH value as per Indian Pharmacopoeia (IP)

  • Apparatus

    • The pH value of a solution is determined potentiometrically by means of a glass electrode, a reference electrode and a pH meter either of the digital or analogue type.
    • Calibrate the apparatus as per Calibration SOP using Buffers for pH value given in Table 1, corresponding to the temperature of the solution.

    • Reference Buffer Solutions

    • Prepare the following buffer solutions using carbon dioxide free water.
    • Buffer solutions should be stored in bottles made of alkali-free glass, and must not be used later than 3 months after preparation.

Note : Commercially available buffers may be used for calibration.

      • 271% w/v solution of potassium tetraoxalate.
      • A freshly prepared solution, saturated at 25°, of potassium dihydrogen tartrate.
      • A freshly prepared 1.151% w/v solution of potassium dihydrogen citrate.
      • A 1.021 % w/v solution of potassium hydrogen phthalate previously dried at 110° to 135° for 2 hours.
      • A mixture containing 0.348% w/v of potassium dihydrogen phosphate and 0.355% w/v of anhydrous Disodium hydrogen phosphate, both previously dried at 110° to 130° for 2 hours.
      • A mixture containing 0.1184% w/v of potassium dihydrogen phosphate and 0.4303% w/v of anhydrous Disodium hydrogen phosphate, both previously dried at 110° to 130° for 2 hours.
      • A 0.3814% w/v solution of sodium tetraborate stored protected from carbon dioxide.
      • A mixture containing 0.2649% w/v of sodium carbonate and 0.210% w/v of sodium bicarbonate.
      • Shake on excess of calcium hydroxide with carbon dioxide free water and decant at 25°C.

    • Method of Determination of pH value

    • Immerse the electrodes in the solution being examined and measure the pH at the same temperature as for the standard solutions.
    • At the end of a set of measurements, record the pH of the solution used to standardise the meter and electrodes.
    • If the difference between this reading and the original value is greater than 0.05, the set of measurements must be repeated.
    • When measuring pH values above 10.0 ensure that the glass electrode is suitable for use under alkaline conditions and apply any correction that is necessary.
    • All solutions and suspension of substances being examined must be prepared using carbon dioxide-free water.

TABLE 1 — pH of reference buffer solutions at various temperature

Temp.

t°

 Reference Buffer Solution
A B C D E F G H I
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 6.87 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
ΔpH/Δt +0.001 -0.0014 -0.0022 +0.0012 —0.0028 -0 0028 -0.0082 —0.0096 -0.034

5.0     Procedure for determination of pH value as per United States Pharmacopoeia (USP)

    • For compendial purposes, pH is defined as the value given by a suitable, properly standardized, potentiometric instrument (pH meter) capable of reproducing pH values to 0.02 pH unit using an indicator electrode sensitive to hydrogen-ion  activity, the glass electrode,   and a suitable reference electrode.
    • The instrument should be capable of sensing the potential across the electrode pair and, for pH standardization purposes, applying as adjustable potential to the circuit by manipulation of ‘standardization, “zero,” “asymmetry,” or “calibration” control, and should be able to control the change in millivolts per unit change in pH reading through a “temperature’ and/or “slope” control. Measurements are made at 25 + 2°, unless otherwise specified in the individual STP or herein.

    • The pH scale is defined by the equation: pH = pHs + (E — E S) / k,

    • in which E and E S are the measured potentials where the galvanic cell contains the solution under test, represented by pH, and the appropriate Buffer Solution for Standardization, represented by pHs, respectively.
    • The value of k is the change in potential per unit change in pH and is theoretically [0.05916 + 0.000198(t – 25°)] volts at any temperature.
    • It should be emphasized that the definitions of pH, the pH scale, and the values assigned to the Buffer Solutions for Standardization are for the purpose of establishing a practical, operational system so that results may be compared between laboratories.
    • The pH values thus measured do not correspond exactly to those obtained by the definition, pH = – log a H +. So long as the solution being measured is sufficiently similar in composition to the buffer used for standardization, the operational pH corresponds fairly closely to the theoretical pH.
    • Although no claim is made with respect to the suitability of the system for measuring hydrogen-ion activity or concentration, the values obtained are closely related to the activity of the hydrogen ion in aqueous solutions.
    • Where a pH meter is standardized by use of an aqueous buffer and then used to measure the “pH“ of a non aqueous solution or suspension, 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 Standardization of the pH Meter —

    • Buffer Solutions for Standardization are to be prepared as directed in the accompanying table.
    • * Buffer salts of requisite purity can be obtained from the National Institute of Science and Technology.
    • Solutions may be stored in chemically resistant, tight containers; such as hard glass bottles or polyethylene bottles fitted with tight closure or carbon dioxide absorbing tube (soda lime).

    • Fresh solutions should be prepared at intervals not to exceed 3 months.

    • The table indicates the pH of the buffer solutions as a function of temperature.
    • The instructions presented here are for the preparation of solutions having the designated molal (m) concentrations. for convenience, and to facilitate their preparation, however, instructions are given in terms of dilution to a 1000-mL volume rather than specifying the use of 1000 g of solvent, which is the basis of the molality system of solution concentration.
    • The indicated quantities cannot be computed simply without additional information.
    • Potassium Tetraoxalate, 0.05 m—Dissolve 12.61 g of KH3(C2O4)2-2H2O in water to make 1000 mL.
    • Potassium Biphthalate, 0.05 m—Dissolve 10.12 g of KHC8H4O4, previously dried at llO° for 1 hour, in water to make 1000 mL.
    • Equimolal Phosphate, 0.05 m—Dissolve 3.53 g of Na2HPO4 and 3.39 g of KH2PO4, each previously dried at 120° for 2 hours, in water to make 1000 mL.
    • Sodium Tetraborate, 0.01 m—Dissolve 3.80 g of Na2B407 I0H2O in water to make 1000 mL. Protect from absorption of carbon dioxide
    • Calcium Hydroxide, saturated at 25°—Shake an excess of calcium hydroxide with water, and decant at 25° before use. Protect from absorption of carbon dioxide.
    • Because of variations in the nature arid operation of the available pH meters, it is not practicable to give universally applicable directions for the potentiometric determinations of pH.
    • The general principles to be followed in carrying out the instructions provided for each instrument by its manufacturer are set forth in the following paragraphs.

    • Examine the electrodes and, if present, the salt bridge prior to use.

    • If necessary, replenish the salt bridge solution, and observe other precautions indicated by the instrument or electrode manufacturer.
    • To standardize the pH meter as per SOP, (selecting two Buffer Solutions for Standardization whose difference in pH does not exceed 4 units and such that the expected pH of the material under test falls between them.
    • Standardize at the same temperature as the material to be measured. The pH of the second buffer solution is within +0.07 pH unit of the tabulated value.
    • If a larger deviation is noted, examine the, electrodes and, if they are faulty, replace them.
    • Adjust the “slope“ or “temperature“ control to make the observed pH value identical with that tabulated.
    • Repeat the standardization until both Buffer Solutions for Standardization give observed pH values within 0.02 pH unit of the tabulated value without further adjustment of the controls.
    • When the system is functioning satisfactorily, rinse the electrodes and cell several times with a few portions of the test material, fill the cell with the test material, and read the pH value.
    • Use carbon dioxide-free water for solution or dilution of test material in pH determinations.

    • In all pH measurements, allow a sufficient time for stabilization.

    • Where approximate pH values suffice, indicators and test papers may be suitable.
    • 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 Reagents, Indicators, and Solutions.

pH Values of Buffer Solutions for Standardization

Temperature,

°C

Potassium Tetraoxalate 0.05m

Potassium Biphthalate 0.05m

Equimolal Phosphate 0.05m

Sodium tetrabcate 0.O1m

 Calcium Hydroxxide Saturated at 25°
10 1.67 4.00 6.92 9.33 13.00
15 1.67 4.00 6.90 9.28 12.81
20 1.68 4.00 6.88 9.23 12.63
25 1.68 4.01 6.86 9.18 12.45
30 1.68 4.02 6.85 9.14 12.29
35 1.69 4.02 6.84 9.10 12.13
40 1.69 4.04 6.84 9.07 11.98
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 1145

6.0     Procedure for determination of pH value as per BP / Ph. Eu.

    • The pH is a number, which represents conventionally the hydrogen ion concentration of an aqueous solution. For practical purposes, its definition is an experimental one.
    • The pH of a solution to be examined is related to that of a reference solution (pH ) by the following equation:

pH = pHs – E – Eg

                   K

    • in which E is the potential, expressed in volts, of the cell containing the solution to be examined and
    • Es is the potential, expressed in volts, of the cell containing the solution of known pH {pHs ),
    • k is the change in potential per unit change in pH expressed in volts, and calculated from the Nernst equation.

Table: Values of k at different temperatures

Sr. No Temperature (°C) X(V)
1 15 0.0572
2 20 0.0582
3 25 0.0592
4 30 0.0601
5 35 0.0611
    • The potentiometric determination of pH is made by measuring the potential difference between 2 appropriate electrodes immersed in the solution to be examined: one of these electrodes is sensitive to hydrogen ions (usually a glass electrode) and the other is the reference electrode (for example, a saturated calomel electrode).

  • Apparatus

    • The measuring apparatus is a voltmeter with an input resistance at least 100 times that of the electrodes used.
    • It is normally graduated in pH units and has sensitivity such that discrimination of at least 0.05-pH unit or at least 0.003 V may be achieved.  [Suitable glass electrodes and pH meters of both the analogue and digital type are described in British Standards 2586:1979 and 3145:1978.]
Temp. t° pH of Reference Buffer Solution at various temperature
A B C D E F G H 1
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 6.87 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
ΔpH*/Δt +0.001 -0.00 l4 -0.0012 +0.0012 -0.0028 -0.0082 -0.0082 -0.0096 -0.034

(*) pH variation per degree Celsius.

Where

A   = Potassium tetraoxalate 0.05M

B  = Potassium Hydrogen Tartrate saturated at 25°C

C  = Potassium Dihydrogen Citrate 0.05M

D  = Potassium Hydrogen Phthalate 0.05M

E          = Potassium Dihydrogen Phosphate 0.025M + Disodium Hydrogen Phosphate 0.025M

F   = Potassium Dihydrogen Phosphate 0.0087M + Disodium Hydrogen Phosphate 0.0303M

G  = Disodium Tetraborate 0.0lM

H  = Sodium Carbonate0.025M + Sodium Bicarbonate 0.025M I    = Calcium

  • Method for Determination of pH value

    • Unless otherwise prescribed in the STP, all measurements are made at the same temperature (20-25 °C).
    • Above Table shows the variation of pH with respect to temperature of a number of reference buffer solutions used for calibration.
    • For the temperature correction, when necessary, follow the manufacturer’s instructions.
    • Calibrate the instrument as per SOP.
    • The pH of a third buffer solution of intermediate pH read off on the scale must not differ by more than 0.05 pH unit from the value corresponding to this solution.
    • Immerse the electrodes in the solution to be examined and take the reading in the same conditions as for the buffer solutions.
    • When the apparatus is in frequent use, checks must be carried out regularly. If not, such checks should be carried out before each measurement.
    • All solutions to be examined and the reference buffer solutions must be prepared using carbon dioxide-free water R.

    • Preparation of reference buffer solutions

    • Potassium Tetraoxalate 0.05 M 
    • Dissolve 12.61 g of C‹H3KO82H2Oin carbon dioxide-free water R and dilute to 1000.0 m1 with the same solvent.
    • Potassium Hydrogen Tartrate, Saturated at 25 °C Shake an excess of C4HsKOc vigorously with carbon dioxide-free water R at 25 °C. Filter or decant. Prepare immediately before use.

    • Potassium Dihydrogen Citrate 0.05M

    • Dissolve 11.41 g of CbH7KO7in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent. Prepare immediately before use.
    • Potassium Hydrogen Phthalate 0.05M
    • Dissolve 10.13 g of CgHsKO , previously dried for 1 h at 110 + 2 °C, in carbon dioxide-free water R and dilute to 10O0.0 ml with the same solvent.
    • Potassium Dihydrogen Phosphate 0.025M + Disodium Hydrogen Phosphate 0.025M Dissolve 3.39 g of KH2PO and 3.53 g of NacHPO , both previously dried for 2 h at 120 2 °C, in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent.
    • Potassium Dihydrogen Phosphate 0.0087M + Disodium Hydrogen Phosphate 0.0303M  Dissolve 1.18 g of KH2PO4 and 4.30 g of NasHPOi, both previously dried  for 2 h at 120 + 2 ‘C, in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent.
    • Disodium Tetraborate 0.0 lM Dissolve 3.80 g of NauB Oz lOHzO in carbon dioxide-free water R and dilute to 1000.0 m1 with the same solvent. Store protected from atmospheric carbon dioxide.
    • Sodium Carbonate 0.025M + Sodium Hydrogen Carbonate 0.025M  Dissolve 2.64 g of NacCO3 and 2.09 g of NaHCO3 in carbon dioxide-free water R and dilute to 1000.0 m1 with the same solvent. Store protected from atmospheric carbon dioxide.
    • Calcium Hydroxide Saturated at 25 °C  Shake an excess of calcium hydroxide R with carbon dioxide-free water R and decant at 25 ‘C. Store protected from atmospheric carbon dioxide.

  • Storage of pH Buffer Solutions

    • Store buffer solutions in suitable chemically resistant, tight containers, such as type I glass bottles or plastic containers suitable for aqueous solutions.

7.0  Procedure of pH Value Determination as per United States Pharmacopoeia (USP)

    • Conduct the determination on 1 or 2 g if the test specimen is in the form of large crystals, reduce the particle size to about 2 mm by quickly been dried for 30 minutes under the same conditions to be employed in the determination.
    • Put the test specimen in the bottle, replace the cover, and accurately weigh the bottle and the contents.
    • By gentle sidewise shaking, distribute the tests specimen as evenly as practicable to a depth of about 5 mm generally and not more than 10 mm in the case of bulky material.
    • Place the loaded bottle in the drying chamber, removing the stopper and leave it also in the chamber.
    • Dry the test specimen at the temperature and for the time specified in the standard test procedure.
    • The temperature specified in the monograph is to be regarded as being within the range of ±2ºC of the stated value. Upon opening the chamber, close bottle promptly, and allow it to come to room temperature in a desiccator before weighing.
    • If the substance melts at a lower temperature, maintain the bottle with its contents for 1 to 2 hours at a temperature 5ºC to 10ºC below the melting temperature, then dry at the specified temperature.

    • For capsules: Use a portion of the mixed contents of not fewer than 4 capsules.

    • For Tablets: Use powder from not fewer than 4 tablets ground to a fine powder.
    • Where drying in vacuum over a desiccant is directed in the standard test procedure, a vacuum desiccator or a vacuum drying pistol, or other suitable vacuum drying apparatus, is to be used. 
    • Where drying in a desiccator is specified, exercise particular care to ensure that the desiccant is fully effective by frequent replacement/regeneration.
    • Where drying in capillary-stoppered bottle in vacuum is directed in the standard test procedure, use a bottle or tube fitted with a stopper having a 225 ± 25 µm diameter capillary and maintain the heating chamber at a pressure of 5 mm or less of mercury. At the end of the heating period, admit dry air to the heating chamber, remove the bottle, and with the capillary stopper still in place allow it to cool in a desiccator before weighing

8.0     pH Value determination Procedure as per British Pharmacopoeia/Ph. Eur.

    • Place the prescribed quantity of the substance to be examined in a weighing bottle previously dried under the conditions prescribed for the substance to be examined.
    • Dry the substance to constant mass or for the prescribed time by one of the following procedures.
    • Where the drying temperature is indicated by a single value rather than a range, drying is carried out at the prescribed temperature ± 2ºC.
      1. “In a desiccator”: the drying is carried out over Diphosphorus Pentoxide R at atmospheric pressure and at room temperature.
      2. “In vacuo”: the drying is carried out over Diphosphorus Pentoxide R, at a pressure of 1.5 kPa to 2.5 kPa at room temperature.
      3. “In an oven within a specified temperature range”: the drying is carried out in an oven within the temperature range prescribed in the standard test procedure.
      4. “Under high vacuum”: the drying is carried out over Diphosphorus Pentoxide R at a pressure not exceeding 0.1 kPa, at the temperature prescribed in the standard test procedure.
    • If other conditions are prescribed, the procedure to be used is described in full in the standard test procedure.

9.0     pH Value Determination Procedure as per Indian Pharmacopoeia (IP)

    •  Place the prescribed quantity of the substance to be examined in a weighing bottle previously dried under the conditions prescribed for the substance to be examined.
    • Transfer to he bottle the quantity of the sample specified in the individual monograph, cover it and accurately weigh the bottle and the contents.   
    • Distribute the sample as evenly as practicable by gentle sidewise shaking to a depth not exceeding 10mm.
    • Place the loaded bottle in the drying chamber (oven or desiccator) as directed in the monograph, remove the stopper and leave it also I the chamber.
    • Dry the sample to constant weight or for the specified time and at the temperature indicated in the monograph.
    • After drying is completed, open the drying chamber, close the bottle promptly and allow it to cool to room temperature (where applicable) in a desiccator before weighing.
    • Weigh the bottle and the contents.

NOTE – Where drying in a desiccator is specified, care must be taken to keep the desiccant fully effective by frequent replacement. (2) Where the drying temperature is indicating by a single value, dry at a prescribed temperature ±2ºC.  

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