Accelerating drug discovery with analytical R&D solutions

insights from industryMike Bradley, Sudhir Dahal, Patrick BrownFTIR Product Manager, Raman Product Manager, UV-Vis/NMR Product ManagerThermo Fisher Scientific

In this interview, Thermo Fisher Scientific discusses how to accelerate drug discovery through analytical R&D.

Please can you introduce yourselves and tell us about the analytical techniques you work with at Thermo Fisher Scientific that can aid drug discovery?

Mike Bradley:

My name is Mike Bradley. I am the product manager for the FTIR and FTIR microscopy products at Thermo Fisher Scientific. I will give a brief overview of FTIR in pharmaceutical processes, from drug discovery to forensics and other applications.

Sudhir Dahal:

I am Sudhir Dahal, the product manager for research Raman products at Thermo Fisher Scientific. I will focus on Raman spectroscopy as a valuable tool in drug development and the pharmaceutical industry in general.

Patrick Brown:

My name is Patrick Brown, and I am the product manager for Thermo Fisher’s UV-Vis, NanoDrop, and NMR spectroscopy instruments. I will discuss the uses of UV-Vis spectroscopy for quantification and sample qualification.

What are the advantages of Fourier-transform infrared spectroscopy (FTIR)?

Mike Bradley:

The primary reason you use FTIR is because it gives answers quickly. It answers the main question, which is: what is it?

This particularly applies to organic materials, such as polymers and organics. It can also, if properly calibrated, give you an answer as to how much there is.

But primarily, it is used to identify materials. For example, if you had a small amount of contamination in a tablet or a small amount of powder you found somewhere, we would consider FTIR the ultimate triage technique. You present the sample, get an answer, and act on it, which you want to do in a triage situation.

The sampling can be very flexible in FTIR. We can look at gases, liquids, or solids. One of the other huge advantages of the technique is that it is non-destructive and in most cases, even non-contact, so you can use that sample for further analysis later.

You can extend it to microscopy, meaning you can go from bulk to micron-sized samples.

When you are looking at FTIR, you need to define what it is you want to do. Is it something you are going to do one time? You could be conducting a forensics investigation which is a sequence of one-time events where you will be looking at a contaminant in a tablet. Or you could be conducting something repetitive, like quality control. Are you looking for contaminants, or are you looking for bulk quality assurance?

Several factors define how you configure your FTIR depending on your problem.

Can you give us some examples of applications of FTIR?

Mike Bradley:

I am going to discuss a forensic example from an actual crime case. When looking at a tablet or a powder, these can often be mixtures. In this case, a drug had been issued to someone, and we took an FTIR spectrum of it.

When searched against the library, it did not give a high-quality search result. The reason is that this material was a mixture. We have algorithms called multicomponent search or multicomponent mixture analysis algorithms that allow us to deconvolute that spectrum.

They do something like chromatography from a vibrational spectroscopy point of view. This substance was a nasty mixture of ketamine, methamphetamine, procaine, and caffeine. You can look at the spectrums of these substances individually and then the composite spectrum.

The algorithm goes through and matches the peaks. Within about a minute of placing the sample on the accessory, we had the deconvoluted spectrum and four different answers. It was like doing chromatography in a hurry. These results were subsequently verified by using GC-MS spec. It is very quick if the concentrations are within range of the device.

In another interesting case, we used a RaptIR FTIR Microscope to examine an oxycodone tablet. If you are familiar with oxycodone and other drugs like that, the active pharmaceutical ingredient (API), is present at a very low concentration. In this case, it was only five milligrams out of the full 325.

This means that when looking for the oxycodone in the tablet, we are looking for a needle in a haystack. That is precisely what we did. We found four different components.

The largest one was acetaminophen spread throughout the tablet. The spectra also showed a low presence of oxycodone. The spectrum we pulled out was very clean for oxycodone. Even though it was just a tiny little trace, we got very good data on it.

We could also see other major additives: cellulose and stearic acid. But the main point here is that we could show the homogeneity of the tablet, show the distribution of the oxycodone, and find the oxycodone even in low concentration points. That is a major benefit for pharmaceutical analysis.

How is near-infrared spectroscopy (NIR) used in pharmaceuticals and what advantages does it have?

Mike Bradley:

For one thing, you can analyze through containers like glass or plastic bags. When raw materials come in at the loading dock in their drums, they are contained within plastic bags inside the drums. You do not want to have to open those plastic bags to analyze because of contamination or the possibility of making someone at the loading dock sick.

We can use near-infrared to analyze right through that package. That gives us the ability to do the raw material identification. We can look at the uniformity of a tablet and the coatings.

One of the big ones for near-infrared is also moisture. Typically, moisture is done using Karl Fischer titrations, which are very dependent on the user's skill and require solvents that must be thrown out.

Near-infrared carries out that analysis much quicker and easier without requiring any chemicals. It allows you to monitor online processes, hot melt extrusion, fermentation, and cell culture.

The primary benefit is the labor-saving and the need for a lower skill level. You do not need somebody who knows how to do titrations.

Overall, FTIR and near IR allow you to triage things and work quickly to get an answer. This answer is usually qualitative, but it can also be calibrated to give you quantitative information, especially in the case of near IR.

What is Raman spectroscopy?

Sudhir Dahal:

Raman spectroscopy is an optical technique in which a sample is excited with a laser and the energy scatter from the sample is analyzed. It looks at the interaction between the excision laser light and covalent bonds within the molecules in the sample.

Raman can provide detailed molecular information and the bonds that are best represented tend to be the highly symmetric bonds most commonly found in the backbone of molecules or crystal lattices. Raman is also very sensitive to even the slightest changes in bond angle or strength, making it an excellent means for distinguishing between similar compounds, including polymorphs.

These characteristics make Raman an excellent means of characterizing molecules, drugs, and various chemicals used in the pharmaceutical industry.

What information can be obtained using Raman spectroscopy?

Sudhir Dahal:

Raman is used for understanding molecular structures, changes in molecular structure and chemical environments. Raman spectroscopy is an excellent technique for distinguishing between very similar materials. It can also identify and differentiate polymorphs where the sample comprises the same compounds; the only difference is their crystalline forms.

Raman spectroscopy is also a great tool in drug development as it can monitor reactions and processes, reaction intermediates, products and contaminants in real time. Finally, Raman images can be created using spectra data to visualize spatial distribution, impurities, and defects.

Imagine you have the Raman spectra of two common medicines, ibuprofen and acetaminophen. Since there will be so many peaks with distinct shapes and sizes, Raman spectroscopy makes identifying samples very easy, even when more than one species are mixed together.

With modern-day advanced software, data analysis capabilities, and libraries of compounds to search from, such identification and differences are even more accurate and easy to carry out.

What capabilities does Raman imaging provide?

Sudhir Dahal:

Take a sample which is a powder mixture primarily containing caffeine, acetaminophen, and aspirin spread on a glass slide. To our eyes, the color of this mixture would be white. However, when Raman spectra are obtained from individual points in a given area, this spectra collection can be combined to visualize the components and the distribution. Different-colored areas would represent aspirin, acetaminophen, and caffeine.

This is a simple example to show the capability of Raman imaging in helping to visualize components, uniformity, degradation, impurities, and defects in products. This is applicable to both R&D and quality control.

A very high-resolution image could show that the three-component tablet is actually composed of much more than aspirin, acetaminophen, and caffeine. There could also be starch, cellulose, and sodium lauryl sulfate present.

The ability to analyze at such a high resolution makes it possible to analyze for any type of compound present, such as active ingredients, binders, and contaminants. The example I just discussed is a mixture we prepare in our lab for demonstration purposes to show the distribution of components.

Can you give us a real-world example of Raman in the pharmaceutical industry?

Sudhir Dahal:

I will discuss a real pharmaceutical tablet with a very low concentration of active pharmaceutical ingredient.

Tibolone is a synthetic hormone which is used in some parts of the world to treat endometriosis and is also used for hormone replacement therapy in menopausal women. An entire tablet of tibolone was analyzed with our imaging Raman microscope. The surface area of the tablet was six by six millimeters.

From an image of a multivariate curve resolution (MCR) analysis of the surface of the tibolone tablet, different-colored areas showed starch and lactose. Harder-to-see areas showed a fluorescent compound that is likely used to enhance the tablet's appearance.

Since tibolone is present at a very low concentration, less than 3%, it is not well characterized by MCR analysis. To see the distribution of the active ingredient tibolone, all we needed to do was to analyze the data that was already obtained a bit further.

We looked at the spectrum of pure tibolone. The peak height intensity at 2,102, which is a bit unique to tibolone, was then used to generate a profile image to demonstrate the location of tibolone. Two different colors of spots, red and orange, then denoted the distribution of tibolone in the tablet.

Taking the analysis of tibolone one step further, we can look for evidence of both polymorphs of tibolone. Again, the spectra and relatively low concentration differences were insufficient to clearly allow routine MCR to distinguish between this polymorph.

However, by using peak height profiles, it was possible to distinguish between two different polymorphs of tibolone. Subtle differences in peak heights and profiles can also be used to distinguish pit polymorphs.

How could you use Raman if you were analyzing a multilayer tablet?

Sudhir Dahal:

Multilayer tablets are designed for the systematic release of drugs. They are manufactured with layers that help systematic release after ingesting.

We could image the layers after the tablet is cross-sectioned with a layer opt-in from a Raman imaging microscope. Then we could obtain a Raman spectrograph compound in each layer. The layers are clearly distinguished. Another obvious advantage is that even if two layers could look the same to our eyes due to having the same color, Raman imaging will show them distinctly.

If the sample is transparent, confocal depth profiling capability can help get information from different layers without cross-sectioning. To elaborate on that fundamental a bit further, here are a couple of slides.

The excitation and collection of optics of the Thermo Scientific DXR Raman microscope are confocal, meaning they focus tightly on the same point in space. Since the Raman signal is predominantly from the focal point, you can actually see the depth of transparent materials.

In Raman scattering, the scatter is controlled at the focal point. By moving the sample up and down, you can depth profile the sample. We can measure from the different layers. This is a very powerful application that helps measure through the sample without actually having to cut the sample.

Tell us about ultraviolet–visible (UV-Vis) spectroscopy. What are the critical parts of a UV spectrophotometer?

Patrick Brown:

Generally, a UV-Vis instrument can be broken down into simple pieces.

The starting point is always a light source. That light is shown through your sample, and then there is a mechanism to discriminate that light into individual nanometer wavelengths. At the end of your measurements, you have an idea of how much light is absorbed at different wavelengths in the visible spectrum and in the ultraviolet spectrum.

We make an absorbance measurement by comparing the light transmitted through a blank or reference sample to the amount of light that gets through your sample.

When light is blocked by your sample, that is absorbance. Using the amount of light that is blocked, the absorbance of your sample, the light path length (the distance through which light passes through your sample), and an extinction coefficient, we can calculate a sample concentration.

An extinction coefficient is a factor specific to a particular wavelength, as well as a molecule, and that is something that would need to be empirically derived, but it allows researchers to calculate in a concentration based on absorbance.

Please can you tell us about the NanoDrop spectrophotometers and when they are useful?

Patrick Brown:

The NanoDrop instruments are ideal for scientists measuring either highly absorbing samples that block a lot of light, or in situations where the scientist only has a small sample volume, maybe 20 to 50 microliters.

The sample bridges two different steel pedestals within which fiber optic cables are set. The light shines through the sample from one pedestal to the other and collects light within the instrument to measure absorbance. Researchers and scientists interested in this instrument frequently use it to measure biological samples like DNA, RNA, protein, and other samples such as bacterial cell culture.

This software can comply with 21 CFR Part 11 regulations.

Can you walk us through an application of the NanoDrop?

Patrick Brown:

This is more focused on a molecular biologist. You might use a quantitative polymerase chain reaction workflow to elucidate the mechanism of action of a drug, trying to understand its gene targets to validate, for example, if it is working properly on the genes of interest. The challenge here is that it will take days, potentially weeks, to run this full experiment.

You will frequently start with a source material, whether a primary tissue source like a mouse model or cells in culture. You will run your experimental protocol, extract RNA, convert that to cDNA, and finally run your qPCR experiment.

Sometimes, that qPCR experiment can fail, and you have to go back and troubleshoot where the problems were introduced into the workflow. That is where our NanoDrop instruments can help.

Our NanoDrop One solution is a great tool for a quality control check for that sample in a couple of different places: after the extraction and after the RT-PCR step. Our software can predict the concentration of a sample even in the presence of a co-purified contaminant, which can happen in some of these extractions and some of the post-extraction processing. This software can help you to have more successful PCR experiments.

We can show this by looking at the control cycle count, a measure you would get from your qPCR experiment. When we purposefully spiked a sample with RNA, we saw that the cycle count increased by one value, indicative of a single log unit. However, when we use our software analysis to identify the sample contaminant, we can use a correct value and that concentration to build our qPCR experiment.

That value becomes much more aligned with the control when we do that. This is one way our NanoDrop instruments can help prevent failed experiments in the qPCR workflow.

How can your spectrophotometers be used in the pharmaceutical industry?

Patrick Brown:

Our spectrophotometer can identify drugs, such as an ibuprofen molecule, and calculate a concentration.

If you are in R&D, you may be developing your sample identification and quantification method that you could then push to the manufacturing side.

In this case, the software can determine the identification of ibuprofen through the absorbance spectral shape. By looking at different concentrations of ibuprofen through different preparations, we can identify three essential parts of the UV-visible spectrum for ibuprofen.

By developing this assay, we found the parameters for developing an acceptable range for the spectral shape.

Looking at a sample concentration, we can use the absorbance at a particular wavelength, say at 264, and the path length of a cuvette in which the sample is suspended as the absorption coefficients. Then, by rearranging for concentration, we can calculate how much ibuprofen is in the sample based on those parameters.

UV-Vis is a helpful technology because it can make quick measurements and does not destroy the sample. It can be used on samples of very low or large volume, and several accessories are available to access features, such as controlling temperature, measuring multiple cells at once, and enabling autosamplers.

About the interviewees

Dr. Michael Bradley taught graduate and undergraduate chemistry for 15 years before becoming a field applications scientist with Thermo Fisher Scientific. He helped develop and launch the Thermo Scientific Nicolet iN10 FTIR Microscope and the Nicolet iS10 FTIR Spectrometer. He then led the development team for the Nicolet iS50 FTIR Spectrometer and most recently the Nicolet RaptIR FTIR Microscope.

Dr. Bradley is now the Product Manager for FTIR spectrometers and microscopes. He’s involved in product development and helps teach customers to better utilize spectroscopy tools. He ensures that customer feedback is incorporated into the development of next-generation hardware and software tools. Mike also sits on the Advisory Board for Spectroscopy Magazine.

Sudhir Dahal is Product Manager of research Raman products at Thermo Fisher Scientific. The products include Raman microscopes and benchtop Raman spectrometers. He has worked with several spectroscopy techniques in the industry and has over 7 years of experience. He has a PhD from University of Maryland Baltimore County (UMBC), where he researched and collaborated on developing novel spectroscopy-based technique for brain tumor cell detection. 

Patrick Brown is the Product Manager for NanoDrop spectrophotometers, cuvette-based spectrophotometers, and NMR instruments at Thermo Fisher Scientific. Patrick collects user feedback, integrates feedback into software and hardware updates, and works with marketing teams to communicate these benefits to end users. Thermo Fisher Scientific spectrophotometers are used by scientists around the world to quantify and qualify a variety of analytes from life science to materials science. Before joining Thermo Fisher Scientific in 2015, Patrick earned a master's degree in biomedical sciences from Pennsylvania State University.

About Thermo Fisher Scientific – Materials & Structural Analysis

Thermo Fisher Materials and Structural Analysis products give you outstanding capabilities in materials science research and development. Driving innovation and productivity, our portfolio of scientific instruments enable the design, characterization and lab-to-production scale of materials used throughout industry.

X-ray fluorescence spectrometers, FTIR spectrometers and X-ray photoelectron spectrometers enable researchers and material analysts to probe the chemical composition of materials ranging from ultra thin-films to bulk powders used in product development and materials troubleshooting. We offer a line of rheometry and viscometry instruments, as well as single- and twin-screw extruders, for laboratory benches that enable you to measure the physical property of semi-solids and liquids for shear flow and yield stress.

No other company offers the breadth of products and the depth of analytical capabilities for materials science and engineering.


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