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3.12.14  |  VOL 3  |  ISSUE 11

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QUALITY CONTROL: Refractive Index I: Parenteral Nutrition Solution

Loyd V. Allen, Jr., PhD, RPh

We are beginning a 4-part series on the use of refractive index (RI) by pharmacists in quality checks of pharmaceuticals. We will discuss the following topics:

1.  Refractive index and parenteral nutrition solutions

2.  Refractive index and osmolarity

3.  Refractive index and controlled drug substances

4.  Implementing a refractive index quality program

Each part in this series will cover two topics: (1) some aspect of the characteristics and use of RI, and (2) an application discussion from published articles. First, we will discuss the use of RI in parenteral nutrition solutions.

The Basics: Part I
Refractometry is important in pharmacy because it can be used as an aid in (1) identifying a pure substance, (2) establishing the purity of some substances, (3) determining the concentrations of some simple solutions (i.e., alcohol solutions, sugar solutions [percent of sugar in syrup]), and (4) quickly determining the uniformity of final compounded preparations, once a refractometric standard has been established. RI (refractometry) is also used as a general, nonspecific, method of detection in high-performance liquid chromatography (HPLC). Refractometry is a basic and simple technique that can be used for both qualitative and quantitative analysis.

The index of refraction, or RI, of a substance is a physical constant and is routinely used in the pharmaceutical sciences. RI is a physical property of a substance, like density, melting point, boiling point, etc.; therefore, it us useful as a means of assisting in identifying a substance and in establishing its purity. Even though it is a nonspecific property, relatively few substances have identical RIs at a given temperature and wavelength. It is a physical constant for many substances, such as fats, fatty oils, waxes, sugars, organic solvents, etc.

The Application
Parenteral nutrition (PN) solutions may consist of up to 37 different compounds.1 This medium-risk preparation compounded from commercial products is quite complex and a complete analysis is expensive and impractical. Most PN solutions are prepared using automated compounding devices. Also, over 40% of pharmacies routinely measure large volume ingredients using the weight method. This study measured the RI of each manufacturer's ingredient by measuring the RI at various concentrations. The authors found the concentration of each ingredient to have a linear relationship with respect to the RI ( i.e., doubling the concentration doubled the RI) and that the RI for each product was additive, allowing for the determination of a calculated RI for the final nutrient solution.1

The RI contribution of each ingredient was calculated as follows:

RIconcentrate= (volume of concentrate (mL))/(total volume of PN solution (mL))

All the contributions were added together, and the sum was then added to the RI of water (1.3330). This sum was then compared with the experimental value and was found to be a very good predictor of the measured RI. Due to the linear predictive value of the RI, the final RI of a multicomponent preparation can be calculated by summing the RI contribution for each ingredient.

The contribution of dextrose and amino acid concentrations to the RI of the final preparation can be calculated and then compared to the actual experimental value. Most studies show that the concentrations of electrolytes, vitamins, and trace elements do not affect the RI. This study developed an equation for calculating the RI of PN solutions by analyzing 154 pediatric PN solutions. This equation was then validated using 1057 pediatric PN samples. The calculated RI value correlated well with the measured RI value (R2 = 0.94, ;>0.0001). Using two standard deviations, 99.8% of the samples fell within this range. The authors concluded that this method of QC can be used to confirm the compounding accuracy of dextrose and amino acid concentrations in the final compounded PN preparation.1

Another study consisted of comparing the measured RI of 500 clinical PN solutions to their predicted RI values. Only two of the 500 prepared solutions (0.4%) had less than the predicted RI. They concluded that RI can be used as a reliable quality-assurance tool for monitoring PN preparations.2

An earlier study used RI measurements to assure accurate formulation of pediatric PN base solutions. The actual RI for 300 pediatric PN solutions was compared with a calculated theoretical reading. The actual RI for all solutions was consistently predicted by their derived equation. They concluded that the use of RI measurements is a valuable quality-assurance tool for pediatric PN base formulations.3

Finally, the effect of dextrose and amino acid composition on the RI values of PN solutions was reported with the development of three different equations, based on the data they generated with different concentrations of the substances.4

A RI measurement is often the simplest, most convenient, and most rapid procedure for evaluating the composition of a binary liquid or a gaseous mixture. A straight-line calibration curve is often obtained if the concentrations of aqueous solutions are expressed in grams of solute per 100 mL of solution. Linearity is not an absolute requirement for quantitative work since a suitable calibration curve can be prepared.

Refractive Index II in this series will discuss Refractometry and Osmolarity.


  1. Nelson S, Barrows J, Haftmann R et al. Calculating the refractive index for pediatric parenteral nutrient solutions. Am J Health Syst Pharm 2013; 70(4): 350-355.
  2. Chang WK, Chao YC, Yeh MK. Application of refractometry to quality assurance monitoring of parenteral nutrition solutions. Asia Pac J Clin Nutr 2008; 17(1):116-122.
  3. Meyer GE, Novielli KA, Smith JE. Use of refractive index measurement for quality assurance of pediatric parenteral nutrient solutions. Am J Hosp Pharm 1987; 44(7): 1617-1620.
  4. Kitzen JM, Halberstadt DJ, Nguyen H et al. The effect of dextrose and amino acid composition on the refractive indices of parenteral nutrition solutions. Hosp Pharm 1996; 31(7): 817-822.


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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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International Journal of Pharmaceutical Compounding, Inc.
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