P E E R R E V I E W E D
`
`The Stability of Lisinopril
`as an Extemporaneous Syrup
`
`Abstract
`The stability of lisinopril as an extemporaneous syrup com-
`pounded from powder was studied. The lisinopril syrup (2
`mg/mL) was prepared by incorporating lisinopril powder dis-
`solved in water into simple syrup. Samples of the syrup were
`stored in amber-colored plastic bottles at 5 and 23°C. At var-
`ious times during the 30-day study period, the concentration
`of lisinopril was determined by a stability-indicating high per-
`formance liquid chromatography assay procedure. Samples
`were also visually inspected for color and clarity. Over the 30-
`day study period, the percentage of the initial concentration
`remained between 97.46% and 100.54% for the 23°C samples
`and 98.15% and 100.74% for the 5°C samples.
`
`Introduction
`The angiotensin-converting enzyme (ACE) inhibitors appear
`to act primarily through the suppression of the renin-angiotensin-
`aldosterone system. Inhibition of ACE leads to a reduction of
`peripheral arterial resistance in hypertensive patients, along with
`an increase in sodium and fluid loss. Additionally, a number of these
`agents are used in adjunctive therapy in the management of con-
`gestive heart failure in patients not responding adequately to
`diuretics and digitalis. The ACE inhibitor lisinopril is currently
`only available as a tablet. An alternative dosage form is not an
`option for patients unable to swallow tablets (ie, infants and
`patients with carcinoma of the throat or cachexia).1 The purpose
`of this study was to investigate the stability of lisinopril in an oral-
`liquid dosage form at a concentration useful in clinical practice.
`Materials
`All chemicals used were of reagent grade or better and used
`without further purification. All water used was distilled and
`further purified by filtration (Norganic® Filtration Cartridges,
`Millipore Corporation, Bedford, MA). All solvents were of high-
`performance liquid chromatography (HPLC) grade. Lisinopril
`was purchased from Sigma Chemical Co., St. Louis, MO (Lot
`73H0893). Syrup was prepared according to a method described
`elsewhere.2
`Methods
`Preparation and Storage of Solutions
`Lisinopril (1 g) was dissolved in distilled water (30 mL). The
`resultant solution was incorporated into syrup using geometric
`dilution to a final volume of 500 mL (2 mg/mL). The syrup was
`divided between six amber plastic prescription bottles. Three
`sample bottles were stored at 5°C and three at 23°C. Aliquots of
`
`Corresponding author: Andrew A. Webster, PhD, Pharmacokinetics
`Center, McWhorter School of Pharmacy, Samford University, 800
`Lakeshore Drive, Birmingham, AL 35229
`
`352 International Journal of Pharmaceutical Compounding
`Vol. 1 No. 5 September/October 1997
`
`Andrew A. Webster, PhD
`Brett A. English
`Deidra J. Rose
`Pharmacokinetics Center, McWhorter School of Pharmacy,
`Samford University, Birmingham, AL
`
`each sample bottle were diluted to appropriate concentrations
`and analyzed in duplicate at time zero, and at 1,2,4,8,12 and 24
`hours and on days 2,3,7,14, 21 and 30. Additionally, aliquots of each
`sample bottle were visually assessed for color and clarity at each
`sampling time.
`High-Performance Liquid Chromatograph
`A fully automated, computer-controlled, HPLC system
`consisting of the following, from Waters Corporation, Milford, MA:
`solvent-delivery pump (model 510), refrigerated autosampler
`(model 712 WISP™), programmable multiple-wavelength detec-
`tor (model 490E Programmable Multiwavelength Detector)
`set at 215 nm; and C8 analytical column (Supelcosil® LC-8 HPLC
`Column 25 cm x 4.6 mm, 5 mm, Supelco, Inc., Supelco Park,
`Bellefonte, PA) heated to 40°C was used for the analyses.
`Lisinopril concentrations were determined by a modification of
`a previously published method.2 The mobile phase consisted of potas-
`sium phosphate monobasic (0.03 M) adjusted to pH 4.1 with phos-
`phoric acid and acetonitrile (80:20) with 1-octanesulfonic acid
`sodium salt (0.004 M). The flow rate was set at 1.5 mL per minute.
`The bottles were shaken well prior to sampling. Each sample was
`
`Ta b l e 1 . S t a b i l i t y o f L i s i n o p r i l 2 m g / m L a
`i n S y r u p a t 2 3 a n d 5 ° C .
`
`Initial Concentration
`1 hour
`2 hours
`4 hours
`8 hours
`12 hours
`24 hours
`2 days
`3 days
`7 days
`14 days
`21 days
`30 days
`
`23°C
`2.09 ± 0.44
`99.1 ± 1.09b,c
`98.67 ± .75
`98.54 ± .84
`98.27 ± .82
`97.88 ± .45
`99.18 ± 2.5
`99.32 ± .55
`98.41 ± .81
`99.82 ± .45
`97.46 ± .41
`100.2 ± .65
`100.54 ± .22
`
`5°C
`2.09 ± 0.44
`99.15 ± .60
`99.19 ± 1.23
`98.48 ± .83
`98.19 ± .45
`98.15 ± .28
`98.73 ± .76
`98.58 ± .53
`100.12 ± 1.32
`99.92 ± .33
`98.44 ± .46
`98.15 ± .68
`100.74 ± .71
`
`a. Nominal concentration
`b. Triplicate samples were prepared and analyzed with duplicate
`determinations for each (n=6).
`c. Percent initial concentration
`
`Flat Line Capital Exhibit 1033
`Page 1
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`P E E R R E V I E W E D
`
`A
`
`A
`
`0.02
`
`0.00
`
`AU
`
`2.00
`
`4.00
`
`6.00
`
`8.00
`
`10.00
`
`0.00
`
`2.00
`
`4.00
`
`6.00
`
`8.00
`
`10.00
`
`0.40
`
`0.20
`
`AU
`
`0.00
`
`0.00
`
`MINUTES
`
`MINUTES
`
`Fig. 1. Representative chromatogram of time-zero injection of
`lisinopril (A).
`
`Fig. 2. Representative chromatogram of lisinopril (A) after one hour
`reflux with concentrated acid.
`
`diluted with water:methanol (4:1) to 0.2
`mg/mL, a concentration for which the de-
`tector signal was established to respond
`linearly (Fig. 1). A five-point standard curve
`was constructed daily using drug concen-
`trations of 0.05 to 0.4 mg/mL, which demon-
`strated linearity (r 2 = 0.998). Sample
`concentrations were determined by in-
`serting the computer-integrated peak areas
`for the samples into the regression equation
`generated by the standard curve. The stan-
`dard error of the mean for replicate injec-
`tions of the same sample or standard solution
`was less than 4%.
`Evidence of noninterference by degra-
`dation products with the sample peaks was
`obtained. Aqueous solutions of lisinopril (2
`mg/mL) and lisinopril in syrup (2 mg/mL)
`were prepared. One milliliter of each solution
`was diluted 1:5 with 0.1 M sodium hydrox-
`ide solution, and a second milliliter of each
`was diluted 1:5 with 0.05 M sulfuric acid. Each
`of the resultant solutions was heated under
`reflux conditions for one hour, and 20-mL
`samples of each were then assayed. In all
`cases there appeared to be no interfering
`peaks from degradation products (Fig. 2).
`Data Analysis
`Individual determinations for each drug
`after time zero were reported as percent-
`ages of the initial mean concentration. Sta-
`bility was defined as the retention of >95%
`of the initial concentration of the drug.
`Results
`None of the samples formed a visible pre-
`cipitate or changed in color or clarity. Over
`the 30-day study period, the percentage of
`the initial concentration remained between
`97.46% and 100.54% for the room tem-
`perature samples and 98.15% and 100.74%
`for the refrigerated samples (Table 1).
`
`Conclusions
`Lisinopril when incorporated into syrup
`(2 mg/mL) is stable at both 23 and 5°C for
`30 days. It is the recommendation of the au-
`thors that, even though no microbial growth
`was observed, the product should be stored
`at 5°C to inhibit microbial growth.
`
`References
`1. Kaplan S. New drug approaches to the
`treatment of heart failure in infants and
`children, Drugs 1990; 39:388-393.
`2. United States Pharmacopeia XXIII/National
`Formulary 18. United States Pharma-
`copeial Convention, Inc., Rockville,
`MD, 1995 pp 895-896, 2314.
`
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`International Journal of Pharmaceutical Compounding
`Vol. 1 No. 5 September/October 1997
`
`353
`
`Flat Line Capital Exhibit 1033
`Page 2
`
`KVK-Tech, Flat Line Capital Exhibit 1033
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`
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