Method Development (AMD) department and covers the use of gravimetric and volumetric techniques that rely on insoluble product formation, followed by separation and quantification.

3. Responsibilities

• Analytical Chemist: Executes method development trials, prepares reagents, and records data.
• Reviewer: Verifies method calculations and checks precision, reproducibility, and robustness data.
• QA Officer: Ensures GMP compliance, documentation accuracy, and procedural adherence.
• Head – AMD: Reviews and approves validated methods for routine implementation or regulatory submission.

4. Accountability

The Head of AMD is accountable for ensuring the scientific integrity and regulatory compliance of precipitation-based analytical methods developed in the department.

5. Procedure

5.1 Method Selection

1. Review pharmacopoeial monographs and scientific literature for analytes that react with suitable reagents to form insoluble precipitates.
2. Common examples:
   • Chloride with silver nitrate → AgCl (white precipitate)
   • Sulfate with barium chloride → BaSO₄ (white precipitate)
   • Calcium with oxalate → CaC₂O₄ (white precipitate)
3. Document method basis in Annexure-1: Method Selection Justification Log.

5.2 Reagent Preparation

1. Prepare precipitation reagents in freshly distilled or deionized water.
2. Ensure stoichiometric accuracy and stability of solutions (e.g., 0.1 N AgNO₃ for chloride).
3. Filter or clarify if needed to avoid seed crystallization.
4. Record reagent preparation in Annexure-2: Reagent Log.

5.3 Sample Preparation

1. Weigh test material accurately and dissolve in specified solvent (e.g., water, dilute acid).
2. Ensure pH adjustment if required (e.g., sulfate determination at pH 4–5).
3. Filter insoluble residues to avoid interference with precipitation.
4. Document sample prep in Annexure-3: Sample Solution Log.

5.4 Execution of Precipitation Reaction

1. Transfer known volume of test solution to reaction vessel.
2. Add precipitation reagent dropwise with continuous stirring.
3. Maintain optimal conditions:
   • Temperature (25–60°C depending on analyte)
   • Stirring time (usually 10–30 minutes)
   • pH control
4. Allow precipitate to settle or age for 1–2 hours to improve crystallinity.
5. Proceed with filtration, washing (to remove excess reagent), and drying if using gravimetric endpoint.
6. For titrimetric endpoints, use indicators or redox titration after precipitation (e.g., Volhard’s method).
7. Document reaction and separation steps in Annexure-4: Precipitation Method Log.

5.5 Calculation

1. Gravimetric Method:

   % Assay = (Mass of dried precipitate × Gravimetric factor × 100) / Weight of sample

2. Volumetric (Back Titration):

   % Assay = (V × N × Eq. Wt × 100) / W × 1000

3. Include dilution factors and stoichiometry corrections where applicable.
4. Use Annexure-5: Assay Calculation Sheet for all derived results.

5.6 Method Optimization

1. Assess:
   • Reaction time, reagent excess, precipitation pH, and stability
   • Washing efficiency (tested by checking filtrate with original reagent)
   • Drying temperature and consistency of weight (gravimetric methods)
2. Run trials in duplicate to triplicate to ensure precision.
3. Optimize for minimal co-precipitation or colloidal interference.
4. Document trials in Annexure-6: Optimization Log.

5.7 Method Validation

1. Specificity: Confirm absence of interfering ions or compounds.
2. Accuracy: Spike recovery within 98–102% across 80%, 100%, and 120% levels.
3. Precision: RSD ≤ 2.0% across replicates (repeatability and intermediate precision).
4. Linearity: If applicable, vary analyte concentration and observe linearity of weight or titrant volume.
5. Robustness: Vary pH, stirring time, reagent volume slightly and assess impact on recovery.
6. Summarize all outcomes in Annexure-7: Validation Summary Report.

6. Abbreviations

• SOP: Standard Operating Procedure
• AMD: Analytical Method Development
• RSD: Relative Standard Deviation
• API: Active Pharmaceutical Ingredient

7. Documents

1. Method Selection Justification Log – Annexure-1
2. Reagent Log – Annexure-2
3. Sample Solution Log – Annexure-3
4. Precipitation Method Log – Annexure-4
5. Assay Calculation Sheet – Annexure-5
6. Optimization Log – Annexure-6
7. Validation Summary Report – Annexure-7

8. References

• USP <231>, <221> – Limit and Assay Tests
• Ph. Eur. 2.2.1 – Gravimetric Analysis
• IP Appendix – Quantitative Classical Analysis
• ICH Q2(R1) – Validation of Analytical Procedures

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Method Selection Justification Log

Analyte	Reaction Chosen	Rationale	Analyst
Chloride	AgNO₃ precipitation	Quantitative white precipitate of AgCl	Sunita Reddy

Annexure-2: Reagent Log

Reagent	Strength	Prepared On	Used By
AgNO₃	0.1 N	10/05/2025	Ajay Mehra

Annexure-3: Sample Solution Log

Sample	Weight	Solvent	Prepared By
NaCl Tablet	250 mg	Water	Rajesh Kumar

Annexure-4: Precipitation Method Log

Reaction Time	Temperature	Filtration Method	Yield (mg)
15 min	25°C	Vacuum	123.5 mg

Annexure-5: Assay Calculation Sheet

Trial	Weight of Precipitate	% Assay
1	123.5 mg	99.2%

Annexure-6: Optimization Log

Parameter	Change Applied	Observation	Conclusion
pH	Adjusted to 4.5	Stable precipitate	Accepted

Annexure-7: Validation Summary Report

Parameter	Criteria	Result	Status
Accuracy	98–102%	99.4%	Pass
Precision	RSD ≤ 2%	1.1%	Pass
Specificity	No interference	Confirmed	Pass

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
04/05/2025	2.0	Integrated validation section and annexures for gravimetric methods	Annual SOP Update