Does Your Drug Expertise Include Clinical Pharmaceutics?

David W. Newton, BS Pharm, PhD, FAPhA, Professor
Department of Biopharmaceutical Sciences
Bernard J. Dunn School of Pharmacy
Shenandoah University
Winchester, Virginia

Member of the Editorial Board of the
Science and Technology for the Hospital Pharmacist Newsletter

Are You Your Patients' Last Chance for Safe and Effective Drug Therapy?

A "yes," obviously, requires broad and deep drug and health knowledge and that includes clinical pharmaceutics such as drug stability and compatibility/incompatibility chemistry (C/I). Starting with the May 2000 inaugural graduating class, Shenandoah University's traditional program PharmD Degree students culminate their 3-year, 8 month-long curriculum with pledging the Oath of a Pharmacist.^1,a My one-minute preamble to annually leading that one-minute recital features the following excerpt:

Living the Oath earns pharmacists our unique status as the public's most accessible source for correct drug and health information, and patients' last chance for safe and effective drug therapy.

To be patients' last chance requires terminal control by pharmacists over identification, retrieval, preparation, labeling, and counseling or instruction of drug therapy. An additional hospital (and home infusion) criterion is insertion of pharmacist knowledge and control before intravenous (i.v.) drug and nutrient administration by nurses and physicians (and patients). This was corroborated (for the countless times) in a June 2014 letter reporting precipitation when a nurse injected furosemide into a patient's central line infusion of esmolol hydrochloride; the non-mention of patient harm hopefully meant none occurred.²

Question 1:
If consulted in advance by a nurse, could you have identified and; thus, prevented that incompatibility?

Question 2:
If reported to you subsequently, as in reference 2, could you have chemically explained, and not merely cited the incompatibility from Trissel's Handbook on Injectable Drugs?^b A "yes" answer requires the following knowledge:

• The -ide in esmolol hydrochloride identifies esmolol as an organic cation (i.e., acid).^3-5
• Furosemide is an organic anion (i.e., base, in its alkaline injection).^3-5,c
• Organic cations (acids) and anions (bases) are likely to precipitate in concentrated mixtures.^3-5

Question 3:
Do you know that a —COOH group on furosemide (or any other drug) becomes a —COO^- ion at the alkaline pH of furosemide (or any other drug) injection?^3-5

Pharmacists who answer "no" to any of these questions cannot be patients' last chance for safe and effective i.v. drug therapy (i.e., they are not whole as drug experts).

Trissel's Reflection on Pharmacists' Drug Incompatibility and Instability Knowledge

On accepting the Institute for Safe Medication Practices (ISMP) Lifetime Achievement Award in December 2011, long-time pharmacist colleague, Lawrence A. Trissel,^d reflected on his nearly 40 years of contributing 17 editions of the Handbook on Injectable Drugs and scores of related research papers with the following poignant remarks:

We should all applaud the increased clinical roles that pharmacists are now playing, and the positive impact on patient safety that it can represent. But...New pharmacy graduates have been shortchanged regarding needed traditional skills in...clinical pharmaceutics as well as with their application to direct patient care. The changes envisioned while moving pharmacy into a more clinical role were not intended to eliminate drug stability and compatibility research, but, in the U.S., that has indeed been one outcome. At the December 2011 American Society of Health-System Pharmacists Midyear Clinical Meeting, the largest pharmacy meeting in the world, there were only three poster presentations on drug stability and compatibility. Clinical pharmaceutics research is viewed by much of the present day pharmacy profession as an activity outside of the profession.

• Whose job is it to protect patients from harm from drug instabilities and incompatibilities and other aspects of clinical pharmaceutics?
• Nurses and physicians? Not likely.
• Drug companies or the FDA? Even less likely.
• If not pharmacists, the self-declared drug experts, then who?⁶

It is notable that Larry Trissel's career ISMP Award was conferred not for contributing and tallying results of thousands of drug-drug and drug-diluent stability and C/I specimens, but for the increased patient safety and health that resulted from all that clinically applied chemistry (i.e., clinical pharmaceutics). Two months after and before reading Trissel's ISMP speech, I expressed a similar worry in this then nine-month old publication.⁷

Clinical Pharmaceutics Case 1: -ium Salts Mixed with -ate or -ide Salts

Despite passion for pharmacists' C/I expertise, my first paper on the topic was in a nursing journal.⁸ Furthermore, to ensure its publication I convinced a hospital-director-of-nursing friend to be the first author. Those simple 1975 guidelines to avoid precipitation in concentrated mixtures of salts of organic drugs containing -ium name ending nondrug ions with those containing -ate or -ide name ending nondrug ions were targeted to nurses because (a) U.S. hospital pharmacy i.v. admixture services, although nationally increasing, were not the norm in the 1970's, and (b) Trissel's Handbook did not debut until January 1977, after which it rapidly became hospital pharmacists' preferred C/I resource for advising nurses and compounding their own i.v. admixtures. Application of those 1975 guidelines to three randomly selected 2008-2009 C/I reports resulted in 89% to 100% accurate predictability for multiple drug-drug mixtures.⁴

Specimens I and C below quickly and clearly illustrate the vital C/I aspect of clinical pharmaceutics. I have used them successfully for 17 years with first-year PharmD students.

Specimen I

1. Add 0.4 mL of 50-mg/mL diphenhydramine hydrochloride injection to 10 mL of water in a small, clear, colorless container and mix well.
2. Add 0.4 mL of 50-mg/mL phenytoin sodium injection to create a dense, white precipitate. The precipitate (↓) could consist of (a) nonionized diphenhydramine base, (b) nonionized phenytoin acid, and (c) ion pairs of cationic diphenhydramine acid and anionic phenytoin base held by induced dipole-induced dipole or London dispersion intermolecular forces between carbon atoms in the closely aligned benzene rings of those drug molecules, which cannot be dissociated by water.³

diphenhydramineH⁺ + Cl^- + phenytoin- + Na⁺ → (a) diphenhydramine↓ + (b) phenytoin↓ + (c) [diphenhydramineH⁺-phenytoin]↓ + Cl^- + Na⁺

Specimen C

1. Add 0.4 mL of 50-mg/mL diphenhydramine hydrochloride injection to 100 mL of water in a small, clear, colorless container and mix well.
2. Add 0.4 mL of 50-mg/mL phenytoin sodium injection, and observe the lack of precipitation. The oppositely charged aromatic diphenhydramine cations and phenytoin anions were separated too far in this 10-fold dilution of specimen I for London dispersion forces to occur.

   diphenhydramineH⁺ + Cl^- + phenytoin^- + Na⁺ → diphenhydramineH⁺ + Cl^- + phenytoin^- + Na⁺

Clinical Pharmaceutics Case 2: Refrigerated Injection Stability

In July 2012, when a patient opened a package of Aranesp (darbepoetin alfa) injection syringes on the day of delivery from out of state, he felt the freezer gel packs were thawed, but they and the syringes were still cool. He immediately placed the syringes in his refrigerator. The next day he asked me if the drug was still good, or should he request a replacement from the hospital pharmacy. The syringes should be refrigerated at 2°C to 8°C or 36°F to 46°F in the absence of light and not frozen or shaken.⁹ I asked for the expiration date on the syringes, which was June 2013. The United States Pharmacopeia (USP) defines "refrigerator" as maintaining 2°C to 8°C or 36°F to 6°F, "cold" as not exceeding 8°C or 46°F, and "cool" as 8°C to 15°C or 46°F to 59°F.¹⁰

Question 4:
Would you have consulted the manufacturer (Amgen Inc.) and repeated that information to the patient without making any further deliberation of stability?

Question 5:
What would you have advised based solely on the patient describing the cool, but not cold, feel of syringes with 11 months of stability remaining under refrigeration?

Question 6:
What would you have advised if provided different information from which you deduced those syringes had been exposed to an average temperature of 105°F or 41°C for 7 hours in a closed vehicle before the patient refrigerated them (i.e., how much of the remaining 11-month expiration date [July 2012 to June 2013] at 2°C to 8°C was expended by 7 hours at 41°C)?

The conservative answer to Question 6 is obtained by an adaptation of the Arrhenius equation,¹¹ in which t90 is the time when a clinical minimum of 90% of original drug activity or strength remains and the mean refrigeration temperature is 5°C. Assume that the highest exposure temperature of the syringes exceeded 105°F or 41°C, but it only increased drug degradation rate without causing a new reaction that instantaneously destroyed all drug activity.

• t90 at 41°C = 11 months at 5°C/4^([41-5]/10) = 11 months/4^3.6 = 11 months/147.03 = 0.075 month
• Time remaining until t90 at 41°C = {0.075 month - (7 hours × [month/720 hours])} = 0.065 month
• 11 months at 5°C/0.075 month at 41°C) = (X/0.065 month), X = 9.5 months remaining until t90 at 5°C
• 7 hours at 41°C consumed an equivalent of 1.5 months of stability at 5°C

Question 7:
When answering questions 4 through 6, are you considering replacement costs (to patient and/or pharmacy) and drug supply shortage decisions?

Conclusion

Question 8:
Do you agree that clinical pharmaceutics—as Trissel so aptly named it—is "an activity outside of the profession?"

Question 9:
Do pharmacists need any more justification than preventable deaths and injuries from calcium phosphate precipitation that C/I expertise is required to be a complete drug expert?¹²

"No" to Questions 1 through 3 and "yes" to Questions 8 through 9 have been and shall be detrimental to the health of patients and reputations of pharmacists and pharmacy. Lacking manufacturers' reasonable answers to Questions 4 through 6 and acknowledging the non-ignorable dilemmas of Question 7 justify why pharmacists must be competent in clinical pharmaceutics. No healthcare professionals other than pharmacists are nicknamed drug experts or are better formally educated to master drug chemistry in the bottle^e (i.e., injection stability and C/I clinical pharmaceutics) as a prerequisite for drug administration to cause safe and effective drug chemistry in the body (i.e., clinical pharmacokinetics and pharmacology).

Footnotes
^aThe original 1994-2008 Oath by the American Association of Colleges of Pharmacy (AACP) and American Pharmacists Association (APhA) was revised in 2007 for use beginning 2009. An important addition for 2009 was commitment to prepare future pharmacists.

^bPharmacists' reliance on Trissel's Handbook and similar resources alone will fail in cases of unlisted drug-drug and drug-diluent combinations, which is when fundamental, drug nonspecific C/I knowledge to rapidly provide safe decisions is critical.

^cFurosemide Injection USP for human administration is prepared from nonionized furosemide acid dissolved with adequate sodium hydroxide to create an in situ furosemide sodium salt. Because it is not made by initially dissolving furosemide sodium salt, it cannot be named furosemide sodium injection.³

^dDuring 2000-2010, Larry Trissel and I were leaders on two 5-year USP committees that developed the original version and first revision of USP General Chapter <797> Pharmaceutical Compounding—Sterile Preparations, and I authored the introductions to the 1980 Second Edition and 1983 Third Edition of his Handbook on Injectable Drugs.

^ePharmacists are better educated via multiple required general and organic chemistry prerequisite and professional curricula medicinal chemistry and pharmaceutics courses.

References

1. American Association of Colleges of Pharmacy. Oath of a Pharmacist. [AACP Website.] 2008-2009. Available at: www.aacp.org/resources/studentaffairspersonnel/studentaffairspolicies/
   Documents/OATHOFAPHARMACIST2008-09.pdf. Accessed August 4, 2014.
2. Zhao B, Sun W. Incompatibility of esmolol hydrochloride and furosemide in a central venous access port. Am J Health Syst Pharm 2014; 71(11): 901-902.
3. Newton DW. Drug incompatibility chemistry. Am J Health Syst Pharm 2010; 66(4): 348-357, 1431.
4. Newton DW. Crux of drug compatibility and incompatibility. Am J Health Syst Pharm 2010; 67(2): 108, 112.
5. Newton DW. General Guidelines/Summary for Compatibility (Solubility) and Chemical Stability. Science & Technology for the Hospital Pharmacist 2012 (Mar. 19); 2: 2. Available at: http://compoundingtoday.com/Newsletter/
   Science_and_Tech_1203.cfm. Accessed August 4, 2014.
6. Trissel LA. Institute for Safe Medication Practices Lifetime Achievement Award 2011. IJPC 2012; 16(1): 54-56.
7. Newton DW. The ps in Therapeutics. Science & Technology for the Hospital Pharmacist 2012 (Feb. 8); 2: 1. Available at: http://compoundingtoday.com/Newsletter/Science_and_Tech_1202.cfm. Accessed August 4, 2014.
8. Kozma MT, Newton DW. Nursing guidelines for in-syringe mixtures. Superv Nurse 1975; 6(8): 26, 27, 31, 33.
9. Aranesp (darbepoetin alfa) [product package insert]. Revised December 2013. Thousand Oaks, CA: Amgen, Inc. Available at: http://pi.amgen.com/united_states/aranesp/ckd/aranesp_pi_hcp_
   english.pdf. Accessed August 4, 2014.
10. U.S. Pharmacopeial Convention, Inc. United States Pharmacopeia 37-National Formulary 32. Rockville, MD: US Pharmacopeial Convention, Inc.; 2014: General Chapter <659> Packaging and Storage Requirements.
11. Allen LV Jr., Popovich NG, Ansel HC. Ansel's Pharmaceutical Dosage Forms and Delivery Systems. 9th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2011: 114-116.
12. Newton DW, Driscoll DF. Calcium and phosphate compatibility: Revisited again. Am J Health Syst Pharm 2008; 65(1): 73-80.

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