A Survey of Material Science and Physical Characterization Techniques and Equipment for Small Molecules – Part I

January 22, 2024 Bob Brousseau

Material science and physical characterization are crucial to ensure drug products’ or drug substances’ identities with measurements and analysis. There are many types of techniques and equipment to do this, each with its own features and qualities. In this blog, the first part of a series, we will review the advantages of a range of techniques and equipment.

We’ll begin with X-Ray Powder Diffraction (XRPD) or XRD analysis. It is a powerful, non-destructive, and rapid technique for analyzing a wide range of materials (1 µm to 100 mm), including metals, polymers, catalysts, plastics, pharmaceuticals, and other materials. It is used for identification, crystal form characterization, and crystalline content in amorphous products.

Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) is useful for the detection of elemental content and elemental impurities. ICP-MS is also

efficient as it is a multi-element technique. Ions are directly detected by an MS detector rather than by emission of light, as in the case of ICP-OES (Inductively Coupled Plasma-Optical Emission Spectroscopy). The ions are separated by a Quadrupole based on the mass-to-charge ratio. The best detection limits are available for most of the elements in ICP-MS as the number of ions produced is high, and although some spectral interference is seen, these are defined and limited.

Dynamic Vapor Sorption (DVS) is a gravimetric technique used to measure the change in

mass of a material in response to changes to surrounding conditions such as temperature or humidity. DVS is primarily used with water vapor but can be applied to other organic solvents as well for the physicochemical characterization of solids. Some of the most common uses of DVS include:

To determine the sorption isotherm;
To evaluate the hygroscopicity of an API powder;
To compare the hygroscopicity of different solid-state forms: solvates, polymorphs, salts, amorphicity, and cocrystals;
To determine the deliquescence point of a material;
To quantify and qualify the amorphous content in drug substance or excipient, and
To evaluate the efficacy of packaging materials.

We will wrap up with Differential Scanning Calorimetry (DSC). It is one of the most used thermoanalytical techniques for determining freezing and melting points and phase transitions. Specifically, it measures the heat flow produced by a sample when it is either heated, cooled, or held isothermally at an unchanging temperature. Crystallization behavior and chemical reactions are some other characteristics that can be measured by this technique.

Our next entry will conclude with a look at Thermogravimetric Analysis (TGA), Fourier-Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR), and, of course, the definitive analytical technique, Mass Spectroscopy (both GCMS and LCMS).

Resources

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Chiral Purity Analysis – The Need to Know What Both Hands Are Doing

October 10, 2023 Bob Brousseau

Background on Chiral Purity
Chirality refers to the phenomenon that occurs when a mirror image cannot be superimposed. It is sometimes called “optical rotation”.

The origin is from the late 19th-century Greek word kheir (‘hand’) and is one of the easiest demonstrations of the concept. Although a person’s hands may appear virtually identical, if they were switched, the outcome would be very different. Amino acids and sugars are the chiral building blocks of larger molecules such as peptides, proteins, and nucleic acids. Therefore, those polymers, in turn, are chiral as well.¹ Molecules with chiral centers may have a different therapeutic impact, and this guides the need to test and control chiral purity. The effects of chiral impurities can result in horrific outcomes, as evidenced by the infamous birth defects associated with Thalidomide² or as benign as Aspartame and sugars (the D/L sugars) that, when superimposed, can create different taste sensations (sweet versus sour, etc.) or metabolic activity. Each chiral center can generate two enantiomers. “Enantiomers or optical isomers are chiral molecules which are non-superimposable mirror images of each other,”³ and multiple chiral centers can generate diastereomers (non-mirror image isomers).

Determining Purity
HPLC has been the primary technique for determining chiral purity, with gas chromatography used occasionally. Measurement of optical rotation is a legacy technique that is fast but not as accurate. Historically, HPLC methods used under normal phase conditions could limit the type of molecules that could be analyzed. However, now modern chiral columns are compatible with reverse phase conditions.

Simulated Moving Bed (SMB) Chromatography as an Option for Chiral Purity Analysis
Do you have a partner for chiral separations? AMPAC Analytical has the expertise in performing chiral purity testing, along with the equipment and techniques. Additionally, our parent company, AMPAC Fine Chemicals, has decades of experience conducting chromatographic separations at a commercial scale in a highly regulated environment. Our services include SMB screening, method development, proof-of-concept demonstration, and production. We operate the largest CGMP Simulated Moving Bed (SMB) chromatography unit in the United States. These technologies and expertise are part of a one-stop shop (from 10-millimeter columns up to 1000mm). Our SMB processes can be developed in a few weeks and are easily scalable. In many cases, scale-up from gram to multi-ton quantities can be achieved in fewer than six months. Our facilities include kilo-scale and pilot-scale units to support smaller quantities, also under CGMP conditions. The SMB facilities have been inspected and approved by the FDA for the manufacturing of APIs. AFC has registered four products with regulatory authorities (FDA/EMA) using SMB technology. Along with chiral separations, we can also perform the separation of diastereomers & regioisomers.

Contact us today for information on how we can assist with your raw material, amino acid, drug product, and API chiral purity testing or to learn more about our SMB processes.

References

Ampac Analytical

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A Survey of Material Science and Physical Characterization Techniques and Equipment for Small Molecules – Part I

Chiral Purity Analysis – The Need to Know What Both Hands Are Doing