Multistep Thermal Characterization of Liquid-Filled Capsules and Medication Packaging Using GC/MS

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The development of pharmaceuticals brought with it a great change in human health. However, these pharmaceuticals are only helpful if they are free of impurities and administered safely. Packaging must also keep drugs free from contamination, slow microbe growth, ensure the product is safe, and not contaminate the pharmaceutical. Chemical analysis of drugs, supplements, and packaging can also aid in competitive analyses, or determine why a drug was ineffective. It can be important in forensic studies, product development, and regulation.

Various instrumental methods are used to analyze pharmaceuticals, including titrimetric, spectroscopic, and chromatographic. Of the chromatographic techniques, gas chromatography is used for the detection of volatile and semivolatile organic compounds.

High-molecular-weight products such as polypeptides, or other polymers associated with the drug, limit the scope of gas chromatography. Adding pyrolysis to a gas chromatograph can facilitate the study of larger polymeric materials. Using high temperatures to break molecular bonds, polymers are broken apart into volatile fragments and sent to a gas chromatograph for analysis. Additionally, multistep thermal sampling¹ permits the analysis of both volatile and nonvolatile constituents directly to the gas chromatograph. The sample is heated quickly to progressively higher temperatures, delivering different compounds for each GC run. By using a sequence of temperatures, different classes of compounds can be separated for easier analysis.

Experimental

A Pyroprobe interfaced to a GC/MS was used to perform thermal analysis on products from the pharmaceutical and supplement industry. All samples were analyzed using a Pyroprobe 6000 Series Autosampler (CDS Analytical, Oxford, PA) interfaced to a GC/MS. Samples of about 100 μg were placed into a quartz tube, which was then dropped into the chamber of the autosampler and heated to the desired temperature. Multiple runs on the same sample could be performed sequentially by programming the Pyroprobe to keep the sample tube in the pyrolysis chamber between runs, then discharge it at the end of the sampling sequence.

Capsule coatings, their encapsulated ingredients, and medication blister packaging were all analyzed using a multistep temperature program: 150 °C, 300 °C, and 700 °C.

Pyrolysis

Valve oven: 300 °C; transfer line: 300 °C; pyrolysis setpoints: 150 °C for 1 minute, 300 °C for 1 minute, and 700 °C for 30 seconds.

GC/MS

Oven: 40 °C for 2 minutes, then 10 °C/min to 300 °C; injector: 320 °C; carrier: helium, flow: 1 mL/min; split: 75:1; column: 30 × .25 mm, .25 µm film thickness, 5% phenyl methyl silicone; mass range: 35–600 amu.

Results and discussion

Each shell of two different liquid-filled capsule types (a caprylic acid supplement and a pain relief medication) was analyzed and compared to a standard of gelatin. Gelatin, made from collagen, is a protein found in the connective tissues of animals. When it pyrolyzes, it produces aromatics and nitrogen-containing rings such as pyrroles and indoles. These same compounds, with the same relative amounts, are also seen in the two different shells of the capsules. This ensures that the main polymer component of each capsule is gelatin (Figure 1).

Figure 1 – Multitemperature chromatograms of gelatin (left), caprylic acid supplement capsule shell (middle), and pain relief capsule shell (right).

There are, however, a few differences regarding other ingredients: a caprylic acid supplement capsule coating has a peak for glycerin at 150 °C and 300 °C. This is a desorption product, often used as a lubricant in pharmaceuticals and supplements, and is a listed ingredient on the supplement label. The pain relief capsule has a peak for ibuprofen, the active pain-relief ingredient. A large peak for isosorbide is also present. This is the dehydration product of both sorbitan, an emulsifier, and sorbitol, a humectant.

When the liquid inside the caprylic acid supplement was subjected to the same multitemperature sequence, it produced a series of peaks at 150 °C and 300 °C, and at 700 °C, nothing was left to pyrolyze. Each of the peaks represents a different triglyceride from medium chain triglyceride oil, frequently derived from coconuts (Figure 2).

Figure 2 – Liquid inside caprylic acid supplement at 150 °C (top) and 300 °C (bottom).

As expected, the ingredients inside the pain relief capsules are different from the caprylic acid supplement. Ibuprofen is present at the lower temperatures. At 700 °C, the remaining ibuprofen decomposes, along with polyethylene glycol, the polymer matrix (Figure 3). As polyethylene glycol pyrolyzes, it produces a repeating pattern of polyethylene oxide oligomers, each subsequent peak representing a longer chain length.

Figure 3 – Liquid inside pain relief capsule at 150 °C (top), 300 °C (center), and 700 °C (bottom); NIST library search match for polyethylene glycol for the circled peaks (right).

In addition, a name-brand drug and a store-brand drug differ slightly. If the region between 15 and 30 minutes in the 150 °C run is expanded and magnified, the name-brand drug has the same medium chain triglycerides previously seen in the caprylic acid supplement. This is from coconut oil, one of the ingredients on the label of the name-brand drug, but not the store-brand drug (Figure 4).

Figure 4 – Name-brand (top) and store-brand pain relief (bottom) capsule liquid at 150 °C, between 15 and 30 minutes.

Just as supplements and pharmaceuticals can be analyzed thermally, medication packaging can be analyzed this way as well. Blister packaging consists of layers of multiple materials: a backing, often paper and foil, hard clear plastic cover, and then glue to hold everything together. Performing multistep pyrolysis on medication packaging² can help an analyst uncover all of these components, which may prove useful in failure or competitive analyses. Therefore, the same multistep heating analysis was performed on blister packaging from allergy relief medication. At 150 °C, very little evolved, but at 300 °C, the packaging started to degrade. Pyrolysis products of PVC (HCl, benzene, and naphthalene) from the cover, paper from the backing (furan and levoglucosan), and polyurethane adhesive (toluene diisocyanate) were revealed. At 700 °C, the package continued to pyrolyze, producing methyl methacrylate, and benzoic acid from polyester (Figure 5).

Figure 5 – Medication blister packaging at 150 °C (top), 300 °C (center), and 700 °C (bottom). Pyrolysis products for corresponding polymers: polyvinyl chloride (blue), paper (orange), polyurethane (black), acrylic (green), and polyester (red).

Conclusion

Multistep thermal sampling allowed the analysis of both volatile and nonvolatile constituents directly to the gas chromatograph. As an alternative to solvent extraction, it can be an integral part of pharmaceutical and supplement product analysis. Differences in semivolatile ingredients were found in supplements and medications, and blister packaging can also be thermally separated and studied.

References

1. Wampler, T. Multistep thermal characterization of polymers using GC-MS. Am. Lab. March 2007, 39.
2. Wampler, T. Tri-step Analysis of Food Packaging. Application note #146a, CDS Analytical LLC.

Karen D. Sam is an applications chemist, CDS Analytical LLC, 465 Limestone Rd., Oxford, PA 19363, U.S.A.; tel.: 610-932-3636; e-mail: [email protected]; www.cdsanalytical.com