(M1230-04-19) Guaifenesin: Discovery and Attributes of Novel Racemic Compound

Purpose: Guaifenesin, a well-known drug used to treat the common cold, cough and respiratory infections is commercially available (e.g., as Mucinex ®) as a racemic conglomerate (“G-CON”).¹ The medicinal properties of guaifenesin have been known for a long time, as demonstrated by its use by Native Americans and chemical syntheses dating from the early 1900s.² Despite the relative maturity of this molecule and a range of dosage forms (e.g., oral solid and oral liquid, individual and combination products), it is surprising that a systematic solid-form screening study has not been conducted and reported. Because the different crystalline forms (e.g., polymorphs, hydrates, chiral modifications) often exhibit dramatic differences in physicochemical properties, the discovery of alternative forms provides an opportunity to understand the risks and benefits associated with any potential new form in the context of the performance (e.g., stability and bioavailability) and quality of the drug product.³ This study details the systematic solid-form screening of guaifenesin, which resulted in the discovery and characterization of an alternative, racemic compound modification, referred to as “G‑RAC”.

Methods: Approximately 200 crystallization experiments were conducted to explore different ways in which guaifenesin can pack into a crystal structure. Four crystallization modes were employed: i) slurry-ripening (5-40 °C), ii) cooling (ambient-5°C), iii) slow solvent evaporation, iv) and fast solvent evaporation (~10 mbar and ~35 °C). 32 screening solvents were utilized for each mode. Solvents were chosen based on their diverse attributes (polarity, polarizability, density, dielectric constant, and boiling point) and the collected upfront solubility profile of G-CON. To create high water activity in a low-solubility solvent, several acetates were saturated with water (“wet”) overnight prior to use in the screen. All products of the screen were isolated and analyzed by powder X-ray diffraction (PXRD; Bruker D8 Advance). Representative unique samples were further analyzed by additional techniques: differential scanning calorimetry (DSC; TA Instruments 2500), thermogravimetric analysis (TGA; TA Instruments 5500), and single-crystal X-ray diffraction (SCXRD; Bruker D8 Venture Photon III). The select data were compared with those of commercial G-CON. The relative thermodynamic stabilities of G-CON and G-RAC were determined at 5 °C and room temperature via slurry ripening in di-isopropyl ether

Results: The screen produced single polymorphs of G-CON (predominant) and G-RAC, in addition to several amorphous products (Table 1). No hydrates or solvates were detected of any of the chiral modifications. The new G-RAC modification was observed only from fast evaporation, where the solvent was rapidly removed by applying elevated temperature and low pressure. Therefore, the G-RAC crystallizes under highly kinetic conditions favoring high supersaturation. Thermal characterization (Figure 1 and Figure 2) of G-RAC confirmed a non-solvated crystal form with a lower melting onset (72 °C) and enthalpy of fusion (185 J/g) than those of G-CON (79 °C; 210 J/g), indicative a higher thermodynamic stability of the conglomerate. The relative thermodynamic stability results (Table 2) confirmed that G-CON is the more stable than G-RAC between 5-20 °C and that the solvent-mediated interconversion is very fast (hours). Monitoring the G-RAC material stored at -20 °C by PXRD confirmed that it is physically stable for at least five months. Single crystals of the metastable G-RAC were successfully grown by creating a highly supersaturated solution and using crystallization inhibitors that allowed the particle to grow slowly without converting to G-CON. The single X-ray crystal structure showed a centrosymmetric (C2/c) space group, confirming the presence of both enantiomers and therefore racemic nature of the compound (Table 3). The comparison of the calculated and experimental PXRD patterns (Figure 4) indicates that the prepared bulk G-RAC material for this study was phase-pure.

Conclusion: A systematic solid-form screening resulted in a new racemic compound of the very well-known drug guaifenesin. Carefully selected conditions were applied to detect and isolate the G-RAC in the screening, as well as to growing single crystals, which subsequently allowed elucidation of its chiral nature. G-RAC was shown to be thermodynamically metastable with respect to the commercial G-CON between 5-20 °C; however, it is kinetically stable in the solid state at sub-ambient temperatures for months. The racemic compound of guaifenesin may be further studied in the context of risks and opportunities posed to the currently present on the market conglomerate form.

References: 1. Albrecht, H. H.; Dicpinigaitis, P. V.; Guenin, E. P. Role of guaifenesin in management of chronic bronchitis and upper respiratory tract infections. Multidiscip. Respir. Med. 2017, 12, 31.
2. Wiegand, J. T. Guaifenesin. In Encyclopedia of Toxicology; Wexler, P., Ed.; Academic Press, 2023; pp 93–97.
3. Byrn, R. S.; Pfeiffer, R. R.; Stowell, G. J. Solid-state Chemistry of Drugs, 2nd ed.; SSCI Inc. 1999.

Acknowledgements: The authors thank Alcami Corporation for financial support.


Figure 2. PXRD Patterns of G-RAC (Top) and G-CON (Bottom)


Figure 3. Single-Crystal Structure of G-RAC


Figure 4. Comparison of the Calculated PXRD Pattern (Bottom) and Experimental PXRD Pattern (Top) of G-RAC.