SOP Guide for Pharma

Elixir Department: SOP for pKa Determination – V 2.0

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Elixir Department: SOP for pKa Determination – V 2.0

Standard Operating Procedure for pKa Determination of Active Ingredients in Elixir Formulations

Department Elixir Department
SOP No. SOP/ELX/231/2025
Supersedes SOP/ELX/231/2022
Page No. Page 1 of 8
Issue Date 11/04/2025
Effective Date 15/04/2025
Review Date 11/04/2026

1. Purpose

To describe the procedure for determining the acid dissociation constant (pKa) of active pharmaceutical ingredients (APIs) used in elixir formulations using potentiometric titration or spectrophotometric methods to support formulation design and stability evaluation.

2. Scope

This SOP applies to the Quality Control and Formulation Development Departments for determining the pKa of APIs intended for use in oral liquid (elixir) dosage forms during pre-formulation studies and analytical method validation.

3. Responsibilities

  • Analytical Chemist:
    • Prepare solutions, perform titration/spectral analysis, and calculate pKa values.
  • Formulation Scientist:
    • Interpret results for buffering range and solubility profile adjustment.
  • QA Officer:
    • Review analytical data for compliance with documentation and research protocols.

4. Accountability

The Head of QC is accountable for correct determination and documentation of pKa values. The Formulation Head is responsible for ensuring this data supports the development of stable elixir products.

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5. Procedure

5.1 Methods for Determination

  1. Potentiometric Titration: Primary method using a calibrated pH meter and titrant.
  2. Spectrophotometric Method: Alternative method using UV absorption changes at varying pH (when applicable).

5.2 Reagents and Equipment

  • pH meter (calibrated with pH 4.0, 7.0, and 10.0 buffers)
  • Standardized titrant (e.g., NaOH 0.1 N or HCl 0.1 N)
  • API sample (pure substance)
  • Deionized water
  • UV spectrophotometer (for spectrophotometric method)

5.3 Sample Preparation (Potentiometric)

  1. Dissolve an accurately weighed quantity of API (typically 50 mg) in deionized water (100 mL) or suitable non-interfering solvent.
  2. Place the solution in a clean beaker under constant stirring.
  3. Immerse the pH electrode and begin titration with acid or base depending on the API’s nature.

5.4 Titration and Calculation

  1. Record the pH after each incremental addition of titrant (e.g., 0.1 mL).
  2. Plot the titration curve (pH vs. volume of titrant).
  3. The pKa is identified as the midpoint of the steepest slope or where pH = pKa (buffering region).
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5.5 Spectrophotometric Method (Alternative)

  1. Prepare a series of buffered solutions with varying pH values (e.g., pH 2–12).
  2. Dissolve the same amount of API in each solution.
  3. Measure absorbance at a specific λmax for the ionized and unionized forms.
  4. Plot absorbance vs. pH and determine the pKa at the inflection point or using the Henderson-Hasselbalch equation.

5.6 Acceptance Criteria

  1. Repeatability: pKa value should not differ by more than ±0.1 between runs.
  2. Validation: pKa value must be consistent with literature or used as baseline for new API.

5.7 Documentation

  1. Record all titration data, pH values, volumes added, and plots in the pKa Determination Logbook (Annexure-1).
  2. Attach raw data, calibration logs, and summary sheets to the method development report.

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6. Abbreviations

  • SOP: Standard Operating Procedure
  • pKa: Acid Dissociation Constant
  • API: Active Pharmaceutical Ingredient
  • QC: Quality Control
  • QA: Quality Assurance

7. Documents

  1. pKa Determination Logbook (Annexure-1)
  2. pH Meter Calibration Log
  3. Method Development Summary Report

8. References

  • USP Chapter <791> – pH
  • ICH Q2(R1) – Validation of Analytical Procedures
  • Remington: The Science and Practice of Pharmacy

9. SOP Version

Version: 2.0

10. Approval Section

Prepared By Checked By Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: pKa Determination Logbook

Date API Name Method Run 1 pKa Run 2 pKa Average Tested By Verified By
11/04/2025 Diphenhydramine HCl Potentiometric 9.17 9.19 9.18 Rajesh Kumar Sunita Reddy

Revision History:

Revision Date Revision No. Revision Details Reason for Revision Approved By
01/01/2024 1.0 Initial SOP Release New SOP Creation QA Head
11/04/2025 2.0 Added spectrophotometric method and acceptance criteria Scientific Expansion QA Head
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