Natural Products and Their Crystal Polymorphs

For the ongoing discovery of natural products, their structural characterization remains a critical activity with an array of increasingly sophisticated spectroscopic methods routinely employed. ¹ However, there does appear to be a rapidly growing area of important organic structural elucidation which the natural products field has not yet fully explored and exploited. That opportunity is the intriguing phenomenon of crystal polymorphism and the subject of this letter.

Crystal polymorphism (unrelated to genomic polymorphism) can be succinctly described as the presence of separate crystal structures for the same compound. However, a Reviewer has raised the valuable point that there is still literature debate ² about the appropriate use of the term “pseudopolymorph,” often applied to polymorph hydrates or solvates. Consensus is that crystal polymorphism was initially discovered by German chemist Eilhard Mitscherlich in the early 1820's based on his examination of several inorganic salt crystals. Soon afterward, the simple organic substance benzamide was also observed to display different crystal forms, demonstrating that molecular complexity was not required for such polymorphism. Then, for nearly 150 years these remarkable early efforts were largely forgotten until the publication of a comprehensive review of crystal polymorphism by Walter McCrone in 1969. ³ In that timely paper, McCrone not only described state-of-the-art crystal polymorph detection and characterization but also the profound effect that a crystal polymorph could have on the physical and biological properties of a substance. In doing so, McCrone elevated the status of crystal polymorphism from a mere chemical curiosity to a property-impacting attribute which could be practically leveraged.

Since this seminal publication, research into crystal polymorphism has greatly accelerated, especially in the pharmaceutical sector. A SciFinder^® chemistry database search indicated that there are now over 25,000 articles in the literature regarding crystal polymorphism. Curiously, reviewing this vast database reveals that very few of these many publications pertain to natural products. It would seem there is still a large opportunity in natural products research to more fully explore crystal polymorphism as an important descriptor in chemical space.

Two recent examples are useful to consider. Mangiferin is a glycosylated xanthone first isolated from the mango tree. Mangiferin's promising bioactivity prompted a recent systematic search for its potential crystal polymorphs with five of them being discovered and exhaustively characterized by differential scanning calorimetry, powder x-ray diffraction and thermogravimetry among other techniques. This thorough investigation identified one specific crystal polymorph (Form V) as the one best suited for further pharmaceutical development. ⁴ This selection was largely based on the fact that Form V, the more amorphous polymorph, had the fastest dissolution rate in both (pH 1) hydrochloric acid as well as (pH 7) pure water, valuable properties for pharmaceutical effectiveness. In a related paper, the hunt for crystal polymorphs of the shrub alkaloid (-)-monophyllidin was undertaken with six of them being identified. ⁵ This careful study clearly demonstrated that the method of natural product isolation (and solvent exposure) often had a critical effect on the crystal polymorph outcome. All the (-)-monophyllidin polymorphs were found to contain guest molecules, especially water. This tendency of (-)-monophyllidin to form hydrates suggested that it might function botanically as a “water-preserving reservoir” for plants. Both examples also well-illustrated the abundance of crystal polymorphs which can be associated with a single natural product.

Natural products research has always been at the leading edge of solving some of the most challenging chemical structures. Crystal polymorph characterization is clearly the next important step in fully understanding the molecular spatial arrangements of natural product structures and their resulting properties.