Standard Operating Procedure for Polymorph Screening Method in API Manufacturing

Department	API Manufacturing
SOP No.	SOP/API/063/2025
Supersedes	SOP/API/063/2022
Page No.	Page 1 of 10
Issue Date	13/04/2025
Effective Date	15/04/2025
Review Date	13/04/2026

1. Purpose

To establish a standard and scientifically robust procedure for polymorph screening in API development and manufacturing to ensure the identification and control of solid-state forms of active pharmaceutical ingredients.

2. Scope

This SOP applies to all new and existing API compounds undergoing development, scale-up, or process optimization phases, where polymorphic behavior may impact stability, solubility, bioavailability, or regulatory requirements.

3. Responsibilities

• R&D Scientists: Conduct polymorph screening experiments and interpret analytical data.
• QC Department: Perform XRPD, DSC, and microscopy for solid-state characterization.
• QA Department: Review reports and support documentation for regulatory submissions.
• Technology Transfer Team: Ensure screened polymorph is consistently reproduced in plant batches.

4. Accountability

The R&D Head is accountable for execution and documentation of polymorph screening. The QA Head is responsible for review and archival of polymorph data.

5. Procedure

5.1 Selection of Solvents and Conditions

1. Select a panel of solvents based on polarity (e.g., water, methanol, acetone, toluene, ethyl acetate, hexane).
2. Include binary/ternary solvent mixtures to expand screening coverage.
3. Study cooling, evaporation, and slurry equilibration as crystallization techniques.

5.2 Experimental Execution

1. Prepare saturated or near-saturated solutions of the API in selected solvents.
2. Initiate crystallization using:
   • Cooling (e.g., from 60°C to 5°C)
   • Evaporation (at ambient or reduced pressure)
   • Slurry equilibration (for conversion studies)
3. Maintain each experiment for a minimum of 24–72 hours for complete crystallization or transformation.
4. Collect solid samples, filter, and dry at controlled temperature (e.g., 40°C for 6 hours).

5.3 Analytical Evaluation

1. Perform the following analyses:
   • XRPD: X-ray Powder Diffraction for crystal form identification
   • DSC: Differential Scanning Calorimetry for melting behavior
   • TGA: Thermogravimetric Analysis if solvates/hydrates are expected
   • Microscopy: Crystal morphology under polarizing microscope
   • FTIR: To detect conformational polymorphs (if applicable)
2. Compare all results with reference standards or previously established polymorphic forms.

5.4 Documentation and Interpretation

1. Document all data in “Polymorph Screening Summary Log” (Annexure-1).
2. Summarize key findings in a “Polymorph Screening Report” including:
   • Polymorph form(s) obtained
   • Stability observation (if tested)
   • Preferred crystallization conditions
3. Route the selected polymorph and its control strategy into process development.

6. Abbreviations

• XRPD: X-Ray Powder Diffraction
• DSC: Differential Scanning Calorimetry
• TGA: Thermogravimetric Analysis
• SOP: Standard Operating Procedure
• API: Active Pharmaceutical Ingredient
• QC: Quality Control
• QA: Quality Assurance

7. Documents

1. Polymorph Screening Summary Log (Annexure-1)
2. Polymorph Screening Report
3. Analytical Raw Data (XRPD, DSC, etc.)

8. References

• ICH Q6A – Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and Products
• FDA Guidance on ANDAs: Pharmaceutical Solid Polymorphism
• Internal Polymorph Study Guidelines

9. SOP Version

Version: 2.0

10. Approval Section

	Prepared By	Checked By	Approved By
Signature
Date
Name
Designation
Department

11. Annexures

Annexure-1: Polymorph Screening Summary Log

Date	API Name	Solvent	Method	Polymorph Observed	Remarks
13/04/2025	API-A	Acetone	Cooling	Form I	Matched with Reference

Revision History:

Revision Date	Revision No.	Details	Reason	Approved By
01/01/2022	1.0	Initial SOP Release	New Polymorph Control Program	QA Head
13/04/2025	2.0	Added Binary Solvent System Screening	Project Expansion	QA Head