Natural Products as Cocrystal Constituents

The adverse physical aspects of some lipophilic natural products can be troublesome and limit their utility. Perhaps nowhere is this dilemma more evident than with the phytocannabinoid class of natural products. Recognizing this difficulty, Uchida and Hamada recently published an elegant communication in this journal ¹ describing a helpful aqueous nanoparticle dispersion for the well-known hydrophobic phytocannabinoid cannabidiol (CBD). The purpose of this letter is twofold: first, to showcase cocrystallization as an alternate strategy for efficiently adjusting the properties of CBD. More importantly, the primary objective of this letter is to promote cocrystallization as relevant to even more substances than CBD, representing an invaluable yet unrealized opportunity for similar natural products.

Recently, we reviewed the latest progress in utilizing the powerful technology of cocrystallization for the phytocannabinoids and particularly for CBD. ² First chanced upon many decades ago but substantially unexplored until now, the novel methodology of cocrystallization has been reconsidered and is being rapidly leveraged to enhance the physical attributes of countless organic substances. Although the principal crystal of a compound incorporates just a solitary molecule within its unit cell, a cocrystal is defined ³ as “…two or more components in the same crystal lattice, generally in a stoichiometric ratio…” In this way, the essential pharmacology of the key chemical is preserved while its tangible qualities can be fine-tuned by selecting an appropriate cocrystal “coformer” companion molecule. The modular construction of cocrystal partners is secured by well-described noncovalent forces like hydrogen bonding and π-π ring systems stacking. With respect to CBD, patent applications for CBD cocrystals have already been filed with apparently one patent being granted.

Remarkably, although cocrystallization is rapidly becoming a versatile tool in the drug industry, this technique has only been slowly assimilated into the natural products field. According to the SciFinder^® chemistry database, there have been over 13 500 journal articles and patents utilizing cocrystal technology. However, in filtering this expansive cocrystal literature, only about 1% of it relates in some way to natural products. Intriguingly, one natural product family that has more quickly exploited the power of cocrystallization are the flavonoids. Besides enhanced biological availability, cocrystal methodology has also recently assisted in the separation of the flavonoids baicalein, quercetin, and myricetin from each other ⁴ as well as facilitating the first x-ray crystal characterization of syringic acid. ⁵ Furthermore, the dextrose cocrystal of curcumin not only improved its solubility but also its stability in water. ⁶

As a cautionary note, there is one potential complication of cocrystal science to mention and that is the possible formation of cocrystal polymorphs with different physical properties. ⁷ However, if this problem were to happen, it would simply prompt the substitution of the original cocrystal coformer for another one not displaying this undesirable behavior. Very likely, with the ever-expanding selection of varied coformers as well as continued progress in innovative cocrystal design and synthesis, many other natural products would greatly profit from this exciting and revitalized crystal paradigm.