Poster J6 - Controlling Acetaminophen Polymorphism: Environmental Conditions - Naomi Malone

Thursday, October 24, 2024

10:00 AM - 11:00 AM EST

Location: Exhibit Hall E, F & G

Presenting Author(s)

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Naomi Malone

Student (Undergraduate)
Bucknell University
Severn, Maryland, United States

Co-Author(s)

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Madeleine Whitsitt

Student (Undergraduate)
Bucknell University, United States
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Elizabeth Xia

Student (Undergraduate)
Bucknell University, United States

Last Author(s)

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Eleanor Lowe

Student (Graduate)
Bucknell University, United States

Primary Investigator(s)

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Brian Smith

Professor & Research Mentor
Bucknell University, United States

Introduction: Polymorphism occurs when molecules can crystalize in more than one structure. Properties vary in solubility, bioavailability, compressibility, and chemical/physical stability. Controlling polymorph selectivity is a fundamental challenge, especially in the pharmaceutical industry.

During our research, we focused on identifying the environmental conditions that favor the crystallization of Form III. Form III refers to the third polymorph of acetaminophen, the active ingredient in Tylenol. Acetaminophen has three polymorphic forms. Form I is the most stable form, while Form II and Form III are the metastable forms, with Form III being the least stable and least understood form. Acetaminophen is the model polymorphic system used because the compound is not overly complex and there is a sufficient amount of information known about the compound and its polymorphs, while still having space for further research. While the difference in forms for acetaminophen does not drastically change in terms of effectiveness from a pharmaceutical standpoint, other compounds used in medicine may have one form that proves to be effective in the body while another form does not, which is why understanding the conditions in which specific forms recrystallize is important.

This research aims to identify environmental conditions that favor Form III. In addition, the goal is to engineer a headspace-controlled chamber for future surface functionalization and sample upscaling.

Materials and

Methods: Melt-recrystallization employs a heat/cool cycling of the pure compound. The first heat cycle fully melts all acetaminophen crystals, erasing the polymorphic history and generating an amorphous melt upon rapid cooling. The second heat cycle recrystallizes different forms depending on the conditions.

Once both heat/cool cycles are complete the Powder X-ray Diffraction (PXRD) can be utilized to identify the acetaminophen crystal formed. The polymorph is identified by peak patterns based on its 3D packing structure. Using unique characteristic peaks, both pure samples and mixtures can be analyzed.

The crystallization of Form III occurs when acetaminophen recrystallizes in completely dry conditions. To explore the sensitivity to humid exposure, mixtures of forms II and III were prepared and analyzed by PXRD for calibration.

Recrystallizations of acetaminophen were performed under dry N2 with variable exposure to the room atmosphere for the duration of the process (~ 1 hour).

When engineering the headspace-controlled chamber several factors were incorporated to allow proper data collection. These included the chamber being purgeable, having an air-tight seal, and being transparent to verify that reached its amorphous phase after the first heat/cool cycle. Additionally, the chamber had to have the capacity to hold 1 to 2 glass slides, withstand temperatures of up to 200℃, and have proper heat transfer rates throughout the entire chamber.

Results, Conclusions, and Discussions: Acetaminophen is very sensitive to humidity while in its amorphous phase and a small amount of exposure to humidity leads to a change in polymorph formation.

In designing the chamber, O-rings proved essential in creating an air-tight seal and eliminating oxidation due to air exposure. Through the construction of the chamber, parts were created to modify the heat transfer and to aid in sample preparation.

While comparing the new chamber to the small Schlenk-tube recrystallization, used in previous research, different polymorphs were generated despite identical atmospheres. A temperature difference was observed, with the Schlenk tube being ~15-20 degrees cooler than the chamber.

The challenges with the recrystallization of Form III in the chamber are likely due to overheating the sample beyond the 120˚C Form III to II transition, caused by differences in heat transfer rate. Furthermore, the temperature and hold time of the 2nd heat is thought to be the deciding factor in the recrystallization of Form III.

In conclusion, humidity is a critical factor in whether Form III of acetaminophen can properly crystallize. To mitigate this issue a newly designed headspace-controlled chamber was designed and can control atmospheric conditions. However, further work is needed to optimize heating rates with scale-up heat transfer rates.

Acknowledgements (Optional): Perrin, M.-A., et al., Chem. Commun., 2009, (22), 3181–3183.
Telford, R., et al., Chem. Commun., 2016, 52 (81), 12028-12031.
Gaisford, S., et al., J. Pharm. Biomed. Anal., 2010, 53 (3), 366-370.
Burley, J. C., et al., Eur. J. Pharm. Sci., 2007, 31 (5), 271-276.
For further information: smithchemistry.com