Polymorphism Characterization of Excipients

Particle size, particle morphology, density, moisture content and polymorphism of excipients used to produce solid dosage forms can have a profound impact on the critical quality attributes (CQAs) of the product. Polymorphs are characterized by different arrangements of the same chemical molecules within the crystals in the solid state. Different polymorphs of the same molecule may exhibit different properties such as bioavailability, melting point, stability, solubility, and hygroscopicity. The physical functional properties of excipients are determined by a series of factors such as particle size, shape, density, and surface area in the crystal lattice. Therefore, the improvement of excipients focuses on the optimization of these characteristics, and identification of the polymorphs formed at different stages of the manufacturing process is crucial to obtain the most acceptable form of excipients.

BOC Sciences' in-house laboratory offers a wide range of analytical methods such as X-ray and laser diffraction, vibrational and nuclear magnetic resonance (NMR) spectroscopy, microscopy, as well as thermogravimetric and differential scanning calorimetry (DSC) for the polymorphism characterization of excipients.

Figure 1. Schematic representation of the structural relationship between polymorphs, solvates, co-crystals, salts and the amorphous phase. (Veith, H.; et al. 2011)

Significance of Polymorphism Studies

• Determine the ease and results of excipient processing
• Improve the drug performance by controlling the polymorphs
• Understand the polymorph-related state changes of the excipients plays an important role in determining the purity of the excipients
• Discovery and design of new formulations

Analytical Techniques of Polymorphisms

The discovery of novel excipients is developed based on the various physicochemical properties of polycrystalline. The polymorphic transition is a kinetic process; therefore, it is important to characterize polymorphic excipients. BOC Sciences has introduced several analytical methods such as DSC, scanning electron microscopy (SEM), X-ray powder diffraction (XPRD), and Raman spectroscopy, which are commonly used to characterize different types of polymorphic excipients.

Figure 2. Pictorial representation (a) Amorphous form (b) Crystalline form (c) Hydrates and Solvates (d) Clathrates O Drug molecule. (Raza, K.; et al. 2014)

DSC - Determination of the Thermodynamic Stability

Thermal analysis shows the thermal behavior of different forms of an excipient (glass transition, melting and crystallization). In addition, it provides information about the potential transformation properties between two or more forms. Therefore, DSC is a useful tool to distinguish between different polymorphic forms, and has become one of the most common techniques used to characterize excipients in drug development. We employ DSC technique for the thermodynamic stability of excipients and determine the difference in their morphology by determining the melting point of the excipients obtained by DSC. In order to understand and characterize the thermal behavior of polymorphs as accurately as possible, we use DSC technique to test whether phase transitions occur in the excipients and thus identify polymorphs.

X-Ray Diffraction (XRD) - Confirmation of the Crystalline or Amorphous Form

XRD can be used to confirm the crystalline or amorphous nature of the target compound. For crystalline excipients, our experts use XRD technique for the characterization of excipient polymorphs.

SEM - Identification of the Polymorphic Form

SEM is an effective tool for the identification of polymorphic forms, which present different morphologies and particle sizes. Combining optical microscopy and SEM images, we are able to identify the differences in crystal structure and polymorphic forms of different polycrystalline excipients.

Infrared (IR) - Identification of Short-range Structure of Polymorphs

The fundamental molecular vibrations of each polymorph are different, providing a unique "fingerprint" in the form of a spectrum. Spectroscopic techniques such as IR can be employed to offer short-range structural information of polymorphs. Our experts use FTIR to distinguish different polymorphs of excipients.

Raman Spectroscopy- Identification of Polymorphism

Some excipients can exist as amorphous or as different crystalline solids (polycrystals). Since polycrystals have different lattice vibrations which can be detected by Raman spectroscopy, the Raman spectra of amorphous and different crystalline forms are quite different. Therefore, different Raman spectra polymorph screening is of utmost importance for the pharmaceutical industry. Polymorph screening of excipients is essential during the pharmaceutical manufacturing process, as the physical and chemical properties (as well as processability, bioavailability, etc.) of polymorphs can vary considerably. At BOC Sciences, we have applied Raman spectroscopy in the identification of pharmaceutical excipient polymorphism.