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4.14.14  |  VOL 4  |  ISSUE 2

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QUALITY CONTROL: Refractive Index III: Controlled Drug Substances

Loyd V. Allen, Jr., PhD, RPh

This is the third in the series on the use of refractometry in pharmacy; the application portion in this newsletter is a little different than the previous two articles, as it concerns the determination of whether or not a controlled drug substance (CDS) has been tampered with or altered.

The Basics: Part III

Variables in refractometry include the wavelength of light used, temperature, and pressure. Temperature influences the refractive index (RI) of a substance primarily because of any accompanying change in density. Therefore, most measurements are done at a controlled temperature (commonly 25°C). For the average liquid, temperature should be maintained within +/- 0.2°C for four-place accuracy. The index of refraction of some liquids is also given at 20°C. A notation should be made at which temperature is used. The temperature is usually a part of the symbol for RI; nD20, nD25.

Quantitative Analysis
When used for quantitative analysis, various concentrations of the substance in a liquid, such as water, can be prepared in grams of solute per 100 mL of solution. When working with mixtures of organic liquids, greater linearity is obtained when solutions are prepared on a volume percent basis. Once the standard curve is developed, an unknown can be easily compared. This is a relatively simple method of checking actual concentrations of simple solutions.

Qualitative Analysis
At the same drug concentration, different prepared samples should have the same RI value. However, if the RI value is different, there is a reasonable probability that the drug or concentration is different. The Bardas study discussed below shows an example where morphine was actually given instead of meperidine.1

The Application
In 1990, Gill and others used RI to determine how accurately the refractometer could identify and distinguish solutions of controlled drug injections and vehicles, by studying the following2:

  • Atropine sulfate injection
  • Edrophonium chloride injection
  • Fentanyl citrate injection
  • Lactated Ringer's injection
  • 5% dextrose and lactated Ringer's injection
  • Midazolam hydrochloride injection
  • Morphine sulfate injection
  • 0.9% sodium chloride injection with and without preservatives
  • Sodium thiopental injection
  • Sterile water for injection with and without preservatives

RI successfully distinguished all 60 samples except for fentanyl citrate and sterile water, which had the same RI due to the very low dose/concentration of fentanyl citrate. Next, they analyzed more than 1100 samples of CDSs returned by physicians to an operating room satellite pharmacy on Monday, Wednesday, and Friday, screening 30 samples per week in 1988. Their conclusions were that it is viable to utilize a refractometer for a first screen and as a deterrent to determine whether or not tampering has occurred.

In 1991, Cheung and associates used RI on a survey of 83 CDS solutions returned to the hospital pharmacy. They demonstrated that the procedure is capable of identifying a solution of unexpected concentration. They experienced the same result with fentanyl citrate injection as the Gill study did and also found that injections with organic cosolvents (diazepam injection, phenobarbital sodium injection) caused higher RI values and required dilution prior to measurement. They concluded that RI is a rapid, simple, reproducible, and inexpensive method applicable to a wide array of CDSs.3

In 1992, Bardas and associates used RI to analyze the contents of opened containers and syringes of CDSs. They screened more than 5,000 samples during a two-year period. They found one instance in which morphine was given in place of meperidine. Also, they used RI to monitor the activity of an anesthesiologist that was known to have been chemically impaired. They found some instances of non-homogeneity of a solution resulting from inadequate mixing possibly due to cosolvents such as propylene glycol, and a clear line of demarcation on the RI scale was not obtained. They concluded that RI screening is an effective and well-received means of monitoring health professionals handling CDSs.1


  1. Bardas SL, Ferraresi VF, Lieberman SF. Refractometric screening of controlled substances used in operating rooms. Am J Hosp Pharm 1992; 49(11): 2779-2781.
  2. Gill DL Jr., Goodwin SR, Knudsen AK et al. Refractometer screening of controlled substances in an operating room satellite pharmacy. Am J Hosp Pharm 1990; 47(4): 817-818.
  3. Cheung JF. Use of refractometers to detect controlled-substance tampering. Am J Hosp Pharm 1991; 48(7): 1488-1492.

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Loyd V. Allen, Jr.; International Journal of Pharmaceutical Compounding, Edmond, OK

Lisa D. Ashworth; Children's Medical Center Dallas, Dallas TX

Ron Donnelly; Ottawa Hospital, Ottawa, Canada

Mark Klang; Sloan-Kettering Institute, New York, NY

Ken Latta; Duke University Hospital, Durham, NC

Linda McElhiney; Indiana University Health, Indianapolis, IN

Dave Newton; Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA

Richard Osteen; Vanderbilt University Medical Center, Nashville, TN

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