The Halogens Are Coming

Four elements—fluorine, cholorine, bromine, and iodine—play multiple roles in existing pharmaceuticals and hold promise for more to come.

By Agustin L. Gonzalez, OD

Included in many topical ophthalmic formulations that our patients use daily, the halogens are some of the friendliest elements employed in infection control and pharmaceutical drug design, with special importance in eye care. Molecule design and halogenation play central roles in achieving the varied broad spectrum activity and antiinflammatory potency in many of our medications.1

Since the discovery in the first halogens in the 1700s, these elements have revolutionized the manner in which drugs are designed and have given shape to many distinctive therapeutic modalities. These molecules are used in a wide variety of products, from simple antiseptics and disinfectants to more complex topical ophthalmic formulations.1-3

The common characteristic of the five halogens—fluorine, chlorine, bromine, iodine, and astatine—is their oxidation state. Compared with other element groups in the periodic table, this group contains the best oxidizing agents, bar none. This unique oxidizing property serves to disrupt the activity of proteins and enzymes, causing microbial cell death.4 The variations in density among each element of the family give them unique abilities for drug design, with the exception of astatine, a radioactive element that has not been used for drug-design purposes.1

With their different oxidizing traits modifying both activity and valence in formulations, the four other molecules in this group are widely used in pharmaceutical drug design in a variety of ways, from the compounding of active ingredients (AIs) to forming crystals or salts. Halogenation can render the AI in a pharmaceutical formulation stable, making the crystalline form of the AI more favorable than the amorphous form, even if the latter might demonstrate greater potency and action.5-7

The discovery of these molecules has run the spectrum from intentional to serendipitous. The first were accidentally discovered in the early 1700s, others in the 1800s, and astatine in the 1900s.2,5-7

BECOMING CRYSTAL CLEAR

Halogenation was originally used as a method for stabilizing AIs. Many AIs, in their free form, are relatively unstable under normal conditions, with changes in temperature and humidity affecting the AI’s structure and efficacy. Halogens are used to form salts, which are relatively stable under normal conditions because they are crystalline structures.8

TO THE POINT

Halogens, used by drug manufacturers to stabilize inactive ingredients or enhance antibiotic activity, may play a role in new drug development.

The crystalline form of a drug can be important in both design and use, especially for drug delivery, as this characteristic renders the drug more bioavailable. Halogenation also improves solubility, allowing increased dissolution into various forms, which can be useful in increasing the concentration of an AI in its target tissue. In some cases, this can permit manufacturers to formulate multiple dosage forms from a crystallized AI.1,4

A RANGE OF ACTIVITIES

The antimicrobial activity of halogens is based on their ability to create disruption of DNA synthesis. The structure of DNA can be a sensitive target for halogens in compounds classified as halogen-releasing agents due to their formation of halogenated nucleotides. Another characteristic of halogens is the ability to penetrate spore coats, resulting in sporicidal and biofilm-disruptive activity. This effect is shown particularly by hypochlorous acid, a form of dissolved chlorine.9

Iodine is well known in surgical settings, often employed during preparation in formulations, such as povidone-iodine, an iodophor consisting of a solubilizing agent (povidone) and a halogen (iodine) reservoir. This structure allows increased availability of the iodine and penetration of iodine into bacterial cell walls. The effects of iodine are the same as those of other halogens, but iodine mainly targets sulfur-containing amino acids, such as methionine and cysteine. It has the added action of targeting nucleotides and fatty acids, adding to its bactericidal effect.2,9

Florine was instrumental in the transformation of the quinolones into the more powerful fluoroquinolones, potent antibiotics in widespread use in ophthalmology. Quinolone was discovered by the formation of nalidixic acid from chloroquine, a chlorinated quinine drug originally used as an antimalarial. The addition of fluorine to chloroquine gave this new drug enhanced activity against DNA gyrase and topoisomerase IV, enhancing its bacterial kill rate by preventing bacterial cell division. In short, halogenation of the molecule enhanced the mechanism of action, allowing the fluoroquinolones to have a broad spectrum of activity against both gram-positive and gram-negative bacteria. It was also discovered that halogens tend to disrupt oxidative phosphorylation, depleting energy stores in bacterial cells, causing death to the bacteria.9-11

CONCLUSION

From simple hypochlorous formulations used in the management of external lid disease, to steroids, to nonsteroidal antiinflammatory agents with bromine, to the double-halogenated steroids, to the fluoroquinolones, there is no doubt that halogens influence a wide range of drug efficacy factors from AI penetration to bacterial kill rate. These agents allow greater penetration, a wider spectrum of microbial activity, and enhanced antiinflammatory potency.

With rising concerns regarding bacterial resistance, and with surveillance of resistance of particular importance in empirical treatments, it is vital for clinicians to recognize the many roles of halogens in their arsenal of medications.12 With little activity ongoing in the development of novel antibiotics, we may look for halogens to play prominent roles in the development of new antimicrobial formulations and products in the future, based simply on their oxidative properties.

1. Datta S, Grant DJ. Crystal structures of drugs: advances in determination, prediction and engineering. Nat Rev Drug Discov. 2004;3(1):42-57.

2. Wisniak J. The history of iodine–from discovery to commodity. Indian Journal of Chemical Technology. 2001;8:518-526.

3. Brooks G, Carroll KC, Butel J, et al. Jawetz, Melnick & Adelberg’s Medical Microbiology. 26th ed. New York: McGraw-Hill; 2013: 64.

4. Frizzo CP, Gindri IM, Tier AZ, et al. Pharmaceutical salts: solids to liquids by using ionic liquid design, ionic liquids–new aspects for the future. Kadokawa J-I, ed. Rijeka, Croatia: InTech; 2013. doi: 10.5772/51655.

5. Wisniak J. The history of fluorine–from discovery to commodity. Indian Journal of Chemical Technology. 2002;9:363-372.

6. Wisniak J. The history of chlorine–from discovery to commodity. Indian Journal of Chemical Technology. 2002;9:450-463.

7. Wisniak J. The history of bromine–from discovery to commodity. Indian Journal of Chemical Technology. 2002;9:263-271.

8. McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev. 1999;12(1):147-179.

9. Sharma PC, Jain A, Jain S. Fluoroquinolone antibacterials: a review on chemistry, microbiology and therapeutic prospects. Acta Pol Pharm. 2009;66(6):587-604.

10. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev. 1989;2(4):378-424.

11. Morden N, Berke E. Topical fluoroquinolones for eye and ear. Am Fam Physician. 2000;62(8):1870-1876.

12. Asbell PA, Sanfilippo CM, Sahm DF, Decory HH. Antibiotic resistance among ocular pathogens–results from the ARMOR surveillance study 2013-present. Poster presented at: The Annual Meeting of the Association for Research in Vision and Ophthalmology; May 6, 2015; Denver, CO.

Agustin L. Gonzalez, OD, FAAO
• optometric glaucoma specialist and therapeutic optometrist, Eye & Vision, Richardson, Texas
• financial disclosure: consultant and speaker, Bausch+Lomb, Shire Ophthalmics, Sun Ophthalmics
ag@txeyedr.com