Identification and quantification techniques of polymorphic forms - A review

Area of Science:

• Pharmaceutical Science
• Solid-State Chemistry
• Analytical Chemistry

Background:

• Polymorphism in Active Pharmaceutical Ingredients (APIs) can significantly affect therapeutic efficacy.
• Accurate qualitative and quantitative monitoring of pharmaceutical solid forms is crucial for quality control.
• Detecting and quantifying crystalline forms, including polymorphs, at low levels is essential.

Purpose of the Study:

• To review and emphasize the importance of selecting appropriate solid-state techniques for API polymorphism detection and quantification.
• To evaluate techniques based on limits of detection (LOD) and quantification (LOQ), pharmacopeial specifications, and international guidelines.
• To provide a comprehensive analysis of various solid-state techniques for pharmaceutical solid form analysis.

Main Methods:

• Analysis of powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Infrared and Raman spectroscopies, and solid-state nuclear magnetic resonance (NMR).
• Review of major pharmacopeias (Argentine, Brazilian, British, European, International, Japanese, Mexican, USA).
• Comparison of techniques regarding advantages, disadvantages, LOD, and LOQ values for APIs.

Main Results:

• PXRD offers an advantage using calculated diffraction patterns from Crystallographic Information Frameworks (CIFs) as reference patterns.
• The Rietveld method combined with PXRD allows for lower LOD values for minority phases without calibration curves.
• Raman spectroscopy detects polymorphs in small particles; solid-state NMR excels in quantifying crystalline and crystalline-amorphous mixtures.

Conclusions:

• The selection of appropriate solid-state techniques is vital for accurate and efficient control of API polymorphism.
• Reference materials must be pre-identified with their corresponding polymorphs for accurate identification analyses.
• This review serves as a guide for controlling API polymorphism in pharmaceutical compounds with efficiency and accuracy.