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  • Polymorphic Impurities: Risk Assessment & Investigation

    Polymorphism arises when a solid compound is present in two or more crystal forms. If polymorphic impurities or anything else other than the predicted crystalline forms is present in a drug substance of a pharmaceutical product, it may impact the performance, quality, safety, efficacy, and stability of the drug product. Different polymorphic forms can have different melting points, spectral properties, and thermodynamic stability. Amorphous

    Assessment of Risk to the Quality of Drug Substance and Drug Product

    Polymorphs are one type of solid form. Other solid form types include solvates, hydrates, and amorphous forms. Many organic and inorganic compounds, including drug substances, can exist in multiple solid forms. In the manufacturing of drug substances, polymorphism of crystals must be strictly controlled, because it significantly affects the bio-availability of a drug Impurity is one of the important aspects in control of crystal polymorphism.

    Polymorphism is regularly affected by a trace amount of impurities. Many drug substances are synthesized through many reactions. It is significant to know the impact of the impurities in the presence of crystal polymorphs.

    Crystallization from different solvents may give rise to different crystal forms or solvates. Excessive humidity or heat are the most visible cause of polymorphism. Changes in polymorphism can also be induced as a significance of numerous common stages of drug substance processing such as granulation, melting, spray drying, compression, and milling that are required to produce the final dosage form.

    Investigation of Polymorphic Impurities

    Powder X-ray diffractometry is a powerful analysis technique to detect trace impurities of ≤1%. X-ray diffraction patterns provide an influential technique to analyze the different crystalline or amorphous forms of the drug substance.  XRD is a perfect technique for the estimation of polymorphic impurities due to its simple sample preparation and non-destructive technique. XRD diffractogram characterizes a crystalline drug substance “fingerprint” required for patent descriptions, and to classify different lots of drug substances. Following are the usages of XRD techniques:

    1. Detection of different forms of impurities,
    2. Excipient compatibility study,
    3. Crystal morphology of drug substance,
    4. Drug substance and drug product stability or dosage uniformity of different batches,
    5. Optimization of process parameters.

    Other than XRD following are the useful techniques for solid-state characterization:

    1. Melting point,
    2. Differential Scanning Calorimetry (DSC),
    3. Thermal Gravimetric Analysis (TGA),
    4. Dynamic Vapour Sorption (DVS)
    5. Hot-Stage Microscopy (HSM),
    6. Optical microscopy,
    7. Solid-state Nuclear Magnetic Resonance,
    8. Fourier-Transform Infrared Spectroscopy,
    9. Raman spectroscopy.


    1. Guidance for Industry ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information, U.S. Department of Health and Human Services Food and Drug Administration Centre for Drug Evaluation and Research (CDER) July 2007 OGD,
    2. FDA. U.S. Food and Drug Administration. Guidance for Industry – Regulatory Classification of Pharmaceutical Co-Crystals, 2013. Available at:
    3. GRANT, D.J.W.; BYRN, S.R. A timely re-examination on drug polymorphism in pharmaceutical development and regulation. Adv. Drug Delivery Rev., v.56,
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    5. U. Griesser, “Relevance and Analysis of Polymorphism in Drug Development,” presented at the British Association of Crystal Growth Spring Meeting. Lancaster, UK, Apr,
    6. S.R. Byrn, “Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations,” Pharm. Res,
    7. J.M. Miller et al., “Identifying the Stable Polymorph Early in the Drug Discovery-Development Process,” Pharm. Dev. Technol. 10. 

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