Introduction Polymorphism arises when a solid compound present in two or more crystal forms. If polymorphic impurities or anything else other than the predicted crystalline forms are 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 substance, 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 presence of crystal polymorphs.

1. Polymorphic Impurities: Risk Assessment & Investigation
Introduction
Polymorphism arises when a solid compound present in two or more crystal forms. If
polymorphic impurities or anything else other than the predicted crystalline forms are 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 substance, 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 presence of crystal polymorphs.
Crystallisation 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

2. 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 analyse different
crystalline or amorphous form of drug substance. XRD is 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 form 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.
Conclusion:
Presence of polymorphic impurities may result into dissimilarity in pharmacological
properties, such as stability, solubility and, subsequently, safety, efficacy and bioavailability
of drug products. XRPD is the most appropriate technique used for detection of polymorphs.
Polymorphism to be checked in drug substance, during manufacturing and finished products
over the shelf life to ensure that there is no change into polymorphic form.

3. References:
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: http://www.fda.gov/downloads/Drugs/Guidances/UCM281764.pdf.
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,
4. J. Bauer et al., “Ritonavir: An Extraordinary Example of Conformational
Polymorphism,” Pharm. Res.,
5. U. Griesser, “Relevance and Analysis of Polymorphism in Drug Development,”
presented at 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.
To know more about Impurities and Pharmaceutical Drug substance read our blogs or to buy
them visit Our website https://veeprho.com/