Simple by Design

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Studying how a drug dissolves and disintegrates is crucial to understanding how it will perform in the body. The US Pharmacopeial Convention (USP) has established guidelines for testing dissolution in most commercial dosage forms.

However, especially for pharmaceutical tablets and capsules, the seven traditional test methods and equipment recognized by USP (1) are variations on a single theme: tablet holder, bath, and paddles. They can seem worlds away from the complexities of the human body. 

As William E. Brown, senior scientific liaison for general chapters with USP explains, the dissolution test distills all the information that is known about the performance of a pharmaceutical in a laboratory setting. “It is highly simplified and intentionally so,” he says. “For manufacturing, you want a test that passes or fails.” 

To delve deeper into studying bioavailability, complex systems are available that mimic closely the digestive systems in a mammal or a human (2,3). Ishai Nir, small-molecule product manager at Distek, a manufacturer of dissolution test equipment and ancillary products, recalls the TNO gastro Intestinal Model (TIM), a simulator developed by researchers at the Netherlands-based Organization for Applied Scientific Research (abbreviated TNO in Dutch) in the early 1990s. 

As Nir explains, TIM includes a stomach model with simulated contractions, as well as simulated mouths and intestine, all modeled with the correct pH, flow time of materials, and simulated gastric fluids. Other advanced models include the Institute for Food Research’s dynamic gastric model (DGM), France’s National Institute for Agricultural Research’s (INRA in French) In-Vitro, and Canada’s Laval and Guelph. 

These models, however, are costly, complicated, and take a long time to use because they involve so many variables, says Nir. “Of necessity, the industry has replaced bioavailability testing with dissolution testing as a simpler QC test for manufacturing,” he says. Companies pick the formulation that showed efficacy in clinical trials and put it through conventional dissolution testing so that it becomes a benchmark for future manufacturing QC. 

“It’s like goodness by association. We know that this formulation with this property performed well in the clinic trials, so if we keep making tab- lets that have the same dissolution and disintegration characteristics, we can assume they will continue to work well in vivo,” adds Nir. 

“In fact, in many ways dissolution is largely a reproducibility test that asks whether the last batch is the same as the current one, and whether or not it behaves the same in vitro as it did in the clinical study where the formulation was shown to work,” he elaborates. 

But, as formulations become more complex, will that be enough for the future? Researchers are working to improve the correlation between in-vivo and in-vitro testing and to come up with better methods that are more representative of bioavailability and give more information about functionality, says Nir. “For some,” he says, “this effort has become a holy grail.” 

It began, he says, with using simulated gastric media instead of running tests using simple media such as water or 0.1 Normal hydrochloric acid. Tests would emulate the stomach when full or fasted, and simulate a much broader array of variables than simply pH, he adds. In addition, Nir notes, some innovator companies are examining the properties of compression and its impact on dissolution more closely. Because the stomach works based on muscular contraction, researchers are simulating that (although, perhaps, not to the extent seen in TNO’s TIM), to identify key parameters. 

A 2016 article (4) coauthored by experts from Bristol-Myers Squibb and AstraZeneca discussed some of the ways that dissolution testing could be made more biorelevant. At this point, however, the industry isn’t exactly clamoring for more biorelevance in dissolution testing. “The test is well understood and well constrained, and makes it easy to compare between batches and between facilities, and to do scaleup without a tremendous amount of work,” says Nir. 

Little change in test methods 

Dissolution testing has remained largely unchanged for the past few years, says Nir. However, USP continues to update its information. The organization recently drafted a new general chapter on performance testing for mucosal routes, has a new chapter on testing for topical routes, and plans to re-evaluate testing for injectable pharmaceuticals, says Brown. 

At the same time, draft guidance from FDA may bring some changes. For readily soluble biopharmaceuticals in the biopharmaceutics classification system (BCS) 1 and 3, says Brown, regulators have said that traditional basket/paddle test methods should suffice. “New products in BCS 1 and 3 won’t need new exotic dissolution test methods,” he says. 

In the recent past, FDA guidance had focused on validation, with the agency advocating the use of mechanical validation alone in validating dissolution test apparatus, without USP’s prednisone “tester tablets.” The argument against using the tablets was that they themselves could be subject to variability, and thus inject more variability into a process that can already be affected by environmental and equipment factors and technician training and experience.

As Nir says, FDA’s guidance led some companies, particularly some of the larger name-brand companies, to change their approach, and to move to mechanical calibration for validation. However, many manufacturers, and particularly those in developing nations, continue to use the tablet testers for validation, he says.

“If a manufacturer looks at its own dissolution numbers quite frequently, its products are much more likely to be consistent and to have tighter dissolution profiles, but that doesn’t make a very good diagnostic. The USP intentionally makes its calibrator tablets sensitive to multiple parameters. This way, if there is too much vibration, if component concentricity is off, or problems with other parameters, then this will be indicated by the testing” says Nir.

Sometimes product batches will fail because of other factors. “From what we have seen, the single biggest parameter that people tend to get wrong is degassing. Not only are the tester tab- lets sensitive to physical factors, such as vibration, concentricity, and centration, they are also very sensitive to degassing,” says Nir. This can cause perfectly good batches of product tablets to fail dissolution tests.

“When we respond to calls about test failures, and measure dissolved oxygen in the vessel, we often find that the level is too high. Even if the manufacturer has degassed properly, by the time they get the material into the vessel, they may have inadvertently re-aerated it, and there will be problems with the batch test,” says Nir.

To get around this problem, Distek offers EZFill, a degasser that degasses and dispenses the media at the same time, providing better uniformity of degassing in the vessel itself to help prevent false alarms.

Despite FDA’s guidance, USP’s position on calibration is that enhanced mechanical calibration alone is not enough to ensure quality. “Our standards already incorporate mechanical calibration, but we do not agree with the use of mechanical calibration alone,” says William (Jay) Pearson, project director, portfolio and program management at USP.

Mechanical calibration or tester tablets?

“We suggest use of performance verification tablets because mechanical calibration alone may not be able to address some things that might be intrinsic to the setup of a given dissolution test in a given lab. The tester tablets have been designed to speak to these issues,” he says.

Brown agrees: “It’s not sufficient to just look at speed and operation of the stirring element and the dimensions of vessel. If we really want to control performance, and variability due to the testing apparatus, we need to put a probe right where the apparatus is working. That is difficult to do by any means, but using a tester tablet is a good way to evaluate performance.”

Dissolution test methods have been adapted for new formulations such as slow-release tablets. One technology that is becoming more prominent for longer dissolution tests (i.e., those lasting 24 hours or longer) is fiber optics, which, Nir says, can address problems such as evaporation and the need to replace media for sampling.

The biggest problem with dissolution testing for extended release is that, if you’re running a fairly large number of sample points, you have to control evaporation but still have a way to get liquid in and out. “It’s very difficult to have a sealed environment because you need to run probes and have access points,” says Nir. “Fiber optics is a completely sealed measurement tool and lets you take as many measurements as you want without having to extract and replace media,” he adds.

Distek purchased fiber optic testing technology from Leap Technologies in 2012. Use of the technology was first published by AstraZeneca in Sweden in 1988 (5), Nir notes.

PAT and modeling

A number of companies are also work- ing with process analytical technologies (PAT) for dissolution testing (6). “There have always been projects that use fluorescence, near-infrared (NIR), and Raman spectroscopy. But NIR tends to be very sensitive to physical parameters, which is one of the challenges in implementing NIR for content uniformity. The models work very well until people change the manufacturing site, the compaction, physical parameters, or excipients. Then they have to develop a new model,” says Nir. Raman is great for selectivity, but that’s not a problem with dissolution, he says.

Between ultraviolet (UV) and high-performance liquid chromatography (HPLC), virtually all bases are covered for dissolution testing, says Nir. One notable exception, however, is in processing nanoparticles, whether they are encapsulated or deposited on nanospheres. “These exotic dosage forms are giving people fits, not because HPLC or UV don’t work but because filters stop working, so the question then becomes: how do you arrest dissolution after you’ve pulled a sample if you cannot filter out all the existing remnant particles in that sample? That’s another area where fiber optics has become the go-to technique because it allows measurements in-situ in real time, eliminating the need for filtration,” he says.

The use of spectroscopy, however, points to the potential to use principles of PAT and quality by design (QbD) for real-time release (RTR) testing. Recently, notes Nir, the industry has been abuzz since news came that Vertex Pharmaceuticals received approval to release an existing product using a model, rather than traditional dissolution testing (6). “It’s a very specific case, but points out what might be possible in the future,” Nir says. Vertex is doing online monitoring, he says, and applying PAT/QbD, instead of doing dissolution testing. However, Nir notes, the company did a tremendous amount of dissolution testing using fiber optics to get the data needed to develop the models.

“Of course, one can correlate NIR to dissolution, but part of the reason the company could do this is because the product had been manufactured for many years so there was a tremendous amount of data to work with. It’s not like attempting RTR testing with a brand-new product,” says Nir.

Innopharma Labs is developing predictive methods that model dissolution to optimize tablet coating for real-time release, as a way to ensure consistent coating despite variability in raw materials and other factors (7). In this approach, an NIR analyzer measures initial particle size at the start of processing. Initial size data are automatically fed to a dynamic process-control algorithm, which defines what is needed to add the correct amount of material per minute to achieve the coating thickness for optimal dissolution, and stops the process once it has reached a predefined growth level.

Predictive methods hold promise

USP is evaluating the use of PAT and predictive dissolution methods, although nothing has been incorporated into any specific standards or guidance yet. Nir sees the idea of doing this as very promising. “It’s nondestructive, and allows manufacturers to modify and improve the process. Someday it may even be possible, for example, that if a given formulation develops a problem that it could be fixed in real-time by adjusting some parameter like the compaction, allowing the manufacturer to save the batch,” he says. The question is how sensitive the models will be to future changes and differences in the excipients or manufacturing equipment used.

Recently, multiple component analysis (MCA), a chemometric technique, was used with UV fiber optics to allow UV dissolution testing to be done on formulations containing two active ingredients (8). Normally, UV spectrophotometry would not be able to provide clear results for formulations that contain more than one active.

The benefits of this particular form of MCA stem from the fact that it is a closed, rather than an iterative technique, says Nir. “You solve a series of equations and develop the model. Because these are well defined, it makes it easy to validate,” he explains.

While efforts continue to improve the way the industry approaches dissolution testing, many pharmaceutical manufacturers take an ‘if it ain’t broke don’t fix it’ approach. “Those in the industry who are focused on making product are very happy with the dissolution test as it is,” says Nir.

References

1. A. Siew, PharmTech, 40 (16), pp 56,64,.
2. A.Mackie,“Simulating Digestion: In-Vitroand In-SilicoModeling,” Infogest training school, infogest.com.
3. M. McAllister, Pharmaceutics, 7(5), pp 1374-1381, 2010.
4. X. Lu et al., AAPS News Magazine, September 2017
5. M.Josefson,E.Johansson,A.Torstensson, Anal. Chem.60 (1988) 2666–2671.
6. I. Colon and J. Medendorp, “Novel Approaches and Challenges in Dissolution Testing of Pharmaceutical Solid Oral Dosage Beyond Commercialization,” americanpharmaceuticalreview. com, March 25, 2018
7. A. Shanley, “Innopharma Labs Bets on Manufacturing 4.0,” PharmTech.com, March 21, 2018.
8. A. Kielt, I. Nir, et al., “Analysis of Two APIs...Using UV Spectrophotometry with Multiple Component Analysis with a Fiber Optic Dissolution Analyzer,” white paper, American Pharmaceutical Review, September-October 2016.

Article Details

Pharmaceutical Technology
Vol. 42, No. 6
June 2018
Pages: 42–45

Citation

When referring to this article, please cite it as A. Shanley, "Simple by Design," Pharmaceutical Technology 42 (6) 2018.