Imaging Spectroscopy Sheds New Light on Pill Production

Tablet-based medical therapy dates back to about 1500 BCE, with the earliest pills apparently being made from bread dough, honey, or grease, with active ingredients (such as ground up medicinal plants) mixed in before being formed into little balls that could be swallowed. Today, "pills" have evolved into a sophisticated component of the medical therapeutics tool kit. They come in various types including tablets, capsules, and caplets. Tablets uniquely comprise a diverse set of categories including coated/uncoated tablets, modified and time-release tablets, and soluble, dispersible, chewable, and effervescent tablets. Mass-production of pills has grown into a significant global undertaking, with pharmaceutical giants like AstraZeneca of Cambridge, United Kingdom, producing more than 10 billion tablets and capsules annually.

While it may not be obvious to the outsider, photonics plays a major role in the production of all those tablets. Spectroscopy-based analytical quality control is a critical aspect of tablet manufacturing and is one of the key factors that ensures each unit is safe and effective by the time it reaches the consumer.

There are many analytical tools available to probe pharmaceuticals before, during, and after their manufacture. Most of them are spectroscopic in nature and the choice of method depends on the substances involved and the type of measurement desired. Raman spectroscopy generally outperforms near-IR with inorganic compounds, for instance, while near-IR spectroscopy easily differentiates cellulose and sugar-like compounds that can be difficult to differentiate using Raman spectroscopy.

Conventional pharmaceutical production is generally accomplished using batch processing with laboratory-based analytical testing conducted on samples taken from the production line to evaluate product quality. The testing technologies are often destructive: though tablets taken from a production line may be probed using spectroscopy, destructive testing, such as dropping, cutting, and dissolving the tablet is also involved.

Even for homogeneous tablets (as opposed to time-release or coated tablets), manufacturers must assess whether the correct amount of the active ingredient is present in a specific tablet, and that it is not only uniformly distributed within a tablet but also consistently across multiple tablets in a batch. Further, since most active pharmaceutical ingredients (APIs) are produced by crystallization, the phenomenon of polymorphism, whereby an organic molecule can adopt more than one crystalline form, is also an important aspect of product quality that must be monitored during the manufacture of tablets. The uncontrolled occurrence of multiple physical forms (polymorphs, solvates, salts, co-crystals, or amorphous) of an API can have significant effects on the performance of the medicine.

Several years ago, the US Federal Drug Administration (FDA) noted that the opportunity existed to improve pharmaceutical development and manufacture and released its Process Analytical Technology (PAT) guidance framework for industry. The guidance was intended to encourage the voluntary development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance.

"The FDA has challenged companies to explore innovating and developing more efficient and more effective continuous manufacturing processes and implementing those with various types of looped, online systems where you can employ continuous process control and continuous sensing," explains Doug Kiehl, a Research Advisor at Eli Lilly and Company in Indianapolis, Indiana.

Two relatively recent additions to the spectroscopy toolset are hyperspectral imaging, and terahertz imaging and spectroscopy. These can provide inline information such as spatial distribution and architecture of active ingredients that complements the compositional, quantitation, and structural determination available from other methods.

Terahertz technology, like hyperspectral imaging, is nondestructive—a key element of inline testing—and can estimate critical quality attributes in pharmaceutical products such as crystalline structure, thickness, and chemical composition. Terahertz systems maker TeraView of Cambridge, United Kingdom, is a leading manufacturer of systems for this market. The company has also produced 3D coating thickness maps for multiple coating layers and structural features models that allow better understanding and control of product scale up and manufacture.

There is, however, no silver bullet, explains TeraView CEO Dr. Don Arnone. "All these techniques are very complementary. What we have discovered with terahertz, or hyperspectral imaging, or Raman, or infrared is that there will be a class of APIs and/or excipients that work well with a certain technology but don't work well with others."

"Hyperspectral imaging is a very powerful technique," he says, "but one of the advantages that [terahertz has] over hyperspectral is that we can see through a complete tablet with a very negligible scattering from an imaging perspective, but from the spectroscopy perspective, that also enables us to get very clear spectra."

"Hyperspectral imaging can do a similar thing, but there will be some materials where it doesn't work well, due to absorption or scattering, and terahertz does work well," he says. There will be other applications where hyperspectral or infrared or indeed Raman techniques actually give you very accurate information, whereas terahertz is more limited."

In the pharmaceutical industry, Kiehl agrees that the physical and chemical attributes of the materials dictate what may work for some processes and might not work for others. "You still may need to implement a separate batch manufacturing process for some steps," he says. "It's case by case. Ideally, whatever is going to be simplest and whatever is going to address the immediate need most economically and most directly while maximizing attention on safety and quality is what's going to be employed," he says.

Arnone highlights two areas of current interest around terahertz spectroscopy. "One is in using terahertz spectroscopy, not to do polymorph detection, but actually to look at the amount of amorphous versus crystalline materials and drugs, and things like drug and API stability."

"If a certain polymorphic form is absorbed by the body—has high bioavailability—if that changes into an amorphous state, or indeed, if it changes into another polymorphic form, another crystalline state, then that actually affects the bioavailability," he explains.

The other area of current interest is tablet disintegration. "If you pass terahertz [radiation] through a tablet and look at the refractive index of the tablet, that refractive index actually correlates with the propensity of the tablet to disintegrate. So what we've got is a potentially very interesting technique for doing inline monitoring of the quality of tablets ... whether they will stay intact as they make their way from a blister pack, or whatever the dispensing mechanism is, to the body," Arnone explains.

Looking to the future, it's clear that both hyperspectral and terahertz techniques will remain part of the overall landscape of tablet testing. "The key for terahertz," says Arnone, "is to move from being a development technique or tool, to more on the QA side of things."

Both Kiehl and Arnone also note the growing importance of portable and handheld technologies. "They are of very high interest in the pharmaceutical environment," said Kiehl, "because of the convenience and accessibility, especially in places like warehouses and loading docks."

So, while medicinal tablets may be "as old as the hills," the processes involved in making them continue to evolve are, in fact, very modern. As tablet production moves to inline processing to the extent possible, quality assurance protocols are continuously improving. They will likely involve photonics for the foreseeable future as evolving techniques like imaging spectroscopy shed new light on the quality of the end products.

-Stephen G. Anderson is the SPIE Director of Industry Development.