REPORTS Lisinopril
`
`Characterization of an extemporaneous liquid
`formulation of lisinopril
`KAREN C. THOMPSON, ZHONGXI ZHAO, JESSICA M. MAZAKAS,
`CHRISTOPHER A. BEASLEY, ROBERT A. REED, AND CHERYL L. MOSER
`Lisinopril is an orally active angio-
`
`course of one month, with multiple
`doses taken from a single bottle, so
`preservation of the vehicle was neces-
`sary to minimize microbial growth
`over the shelf life of the suspension.
`Vehicles preserved with sodium ben-
`zoate increased the risk of adverse
`
`events for pediatric patients and were
`not considered for use in this suspen-
`sion.3 Compounding vehicles pre-
`served with parabens and potassium
`sorbate were pursued as they provid-
`ed less risk to low-birth-weight in-
`fants and term infants with signifi-
`
`KAREN C. THOMPSON, PH.D., is Senior Research Fellow, Formula-
`tion Design and Characterization; ZHONGXI ZHAO, PH.D., is Re-
`search Fellow; JESSICA M. MAZAKAS, B.S., is Staff Chemist; CHRIS-
`TOPHER A. BEASLEY, B.S., is Chemist; ROBERT A. REED, PH.D., is
`Director; and CHERYL L. MOSER, M.S., is Senior Research Associate,
`Pharmaceutical Analysis and Control, Merck Research Laborato-
`ries, West Point, PA.
`
`Address correspondence to Dr. Thompson at Merck Research
`Laboratories, P.O. Box 4, WP78-302, West Point, PA 19486
`(karen_thompson@merck.com).
`Supported in part by AstraZeneca Pharmaceuticals LP.
`Copyright © 2003, American Society of Health-System Pharma-
`cists, Inc. All rights reserved. 1079-2082/03/0101-0069$06.00.
`
`Am J Health-Syst Pharm—Vol 60 Jan 1, 2003
`
`69
`
`Abstract: The stability of lisinopril in an ex-
`temporaneously prepared suspension
`stored at or below 25 °C for 28 days under
`ambient light exposure was studied.
`A formulation of 1-mg/mL oral suspen-
`sion was prepared from commercially avail-
`able 20-mg lisinopril tablets, using Bicitra
`and Ora-Sweet SF as the compounding ve-
`hicles to make a final volume of 200 mL.
`Individual samples, stored in 8-oz amber
`polyethylene terephthalate bottles, were
`used for each test performed. All samples
`were stored at 25 °C. Appropriateness of
`the extemporaneous preparation method
`was performed by shaking three lots of
`each suspension for 30, 60, and 90 seconds.
`To test the robustness and reproducibility
`of the method, two chemists prepared the
`suspensions from the same three lots of lis-
`inopril tablets. Chemical and physical sta-
`bility were established by analyzing dupli-
`cate samples at time zero and after one,
`two, four, and six weeks. The solubility of
`lisinopril was tested from suspensions
`stored for four weeks. In-use stability was
`also examined over four weeks. Photo-
`chemical stability was examined by expos-
`
`ing three batches of the suspension to
`maximum light stress in accordance with
`the International Conference on Harmoni-
`zation. Antimicrobial-effectiveness testing
`was also conducted with freshly prepared
`suspensions and suspensions stored for six
`weeks.
`The preparation method used was ap-
`propriate and effective. Lisinopril is fully
`dissolved in the suspension matrix. Satis-
`factory chemical, physical, and microbio-
`logical results were obtained after the sus-
`pensions were stored for six weeks at 25 °C
`and 35% relative humidity.
`Lisinopril suspensions extemporaneous-
`ly prepared from tablets are stable for at
`least four weeks when stored at or below
`25 °C under ambient light exposure.
`
`Index terms: Angiotensin converting en-
`zyme inhibitors; Compounding; Contain-
`ers; Contamination; Formulations; Lisino-
`pril; Photodecomposition; Polyethylene
`terephthalate; Solubility; Stability; Storage;
`Suspensions
`
`Am J Health-Syst Pharm. 2003; 60:69-74
`
`tensin-converting enzyme (ACE)
`inhibitor used for the treatment of
`hypertension, heart failure, and acute
`myocardial infarction. It is currently
`supplied as 2.5-, 5-, 10-, and 20-mg
`tablets in two brand-name products,
`Prinivil (Merck Research Laborato-
`ries, West Point, PA) and Zestril (As-
`traZeneca UK Ltd., London, En-
`gland). Recent clinical studies have
`been completed with pediatric pa-
`tients using a suspension of lisinopril
`prepared from 20-mg Zestril or Prin-
`ivil tablets.1 An extemporaneously
`compounded oral suspension allows
`physicians to adjust the dose for pe-
`diatric patients and provides easier
`administration for patients who have
`difficulty swallowing tablets. Phar-
`macokinetic studies have demon-
`strated the bioequivalence between
`lisinopril suspension and 20-mg
`Prinivil tablets in adults.2 This article
`describes the development of a lisi-
`nopril 1-mg/mL oral suspension.
`The vehicle used for the lisinopril
`suspension was selected with several
`specific objectives. First, only vehi-
`cles readily available to pharmacies
`for pharmaceutical compounding
`were considered. Second, the desired
`product would be used over the
`
`Flat Line Capital Exhibit 1016
`Page 1
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`KVK-Tech, Flat Line Capital Exhibit 1016
`Page 1
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`

`

`REPORTS Lisinopril
`cant hyperbilirubinemia.4 Ora-Sweet
`and Ora-Sweet SF were considered as
`compounding vehicles on the basis
`of their preservatives. Of the two,
`Ora-Sweet SF was chosen as the pri-
`mary vehicle for long-term adminis-
`tration in pediatric patients because
`it is sugar free.
`The extemporaneous formulation
`was prepared from 20-mg Prinivil or
`Zestril tablets. Although these tablets
`contain calcium phosphate, after
`preparing the suspension the pH was
`high enough to decrease the antimi-
`crobial effectiveness of potassium
`sorbate.5 Bicitra (Alza Corporation,
`Mountain View, CA), an oral solution
`containing sodium citrate and citric
`acid, was used to control the pH and
`effectively adjust the calcium phos-
`phate. This vehicle was added to the
`Ora-Sweet SF and the stability of the
`resulting suspension was analyzed.
`
`Methods
`
`For every test performed and de-
`scribed below, separate bottles were
`freshly made and discarded immedi-
`ately after high-performance liquid
`chromatography (HPLC) analysis,
`except for the in-use stability test.
`For that test, bottles of lisinopril sus-
`pension were repeatedly sampled
`and returned to storage.
`Preparation of samples. Each oral
`suspension of lisinopril 1 mg/mL was
`prepared by placing 10 20-mg lisino-
`pril (Prinivila or Zestrilb) tablets and
`10 mL of purified water into an 8-oz
`amber polyethylene terephthalate
`(PET) bottle,c shaking by hand, and
`gradually adding the compounding
`vehicles (Bicitra solutiond and Ora-
`Sweet SFe), shaking the bottle after
`each addition, to achieve a final vol-
`ume of 200 mL. The suspensions
`were shaken before each use and
`stored at or below 25 °C for 28 days.
`The detailed procedure for this ex-
`temporaneous compounding is pro-
`vided in the appendix.
`Assay of lisinopril suspension. A
`gradient HPLC method was developed
`to assay lisinopril, its degradation
`
`product diketopiperazine, methylpar-
`aben and propylparaben, and the
`chromatographically rich matrix of
`Bicitra and Ora-Sweet SF. Commercial
`HPLC instrumentsf equipped with a
`photodiode array detector were used
`for sample assay analyses. A C-8 col-
`umng was used because of its extended
`polar selectivity to separate hydro-
`philic species around lisinopril and
`diketopiperazine. Column tempera-
`ture was maintained at 40 °C. Two
`reservoirs contained the mobile
`phases of (A) 91% 30-mM phosphate
`bufferh with a pH of 2.2 and 9% ace-
`tonitrilei and (B) acetonitrilei, which
`were pumped through the column at
`a flow rate of 1.0 mL/min. The gradi-
`ent conditions were isocratic, with
`100% mobile phase A for 16 minutes,
`followed by a linear gradient from 0
`to 45% mobile phase B over the next
`9 minutes, and remained at 45% mo-
`bile phase B over the next 15 min-
`utes. The injection volume was 50
`µL, and the detection wavelength was
`215 nm.
`The analytical standard was pre-
`pared in mobile phase A. An analytical
`standard consisting of lisinopril,j
`diketopiperazine,k methylparaben,l
`and propylparabenm was prepared at
`concentrations of 31, 0.3, 12, and 3.2
`µg/mL, respectively. Satisfactory chro-
`matographic resolution was obtained
`for all four species in the standard so-
`lution. Lisinopril, methylparaben,
`diketopiperazine, and propylparaben
`eluted at 7.4, 13.1, 17.8, and 26.0
`minutes, respectively. Analytical sam-
`ple solutions were prepared by pipet-
`ting 5 mL of the lisinopril suspension
`into 200-mL flasks and diluting to vol-
`ume with mobile phase A.
`Method validation was performed
`for specificity, recovery, linearity,
`limits of detection and quantitation,
`solution stability, and method preci-
`sion. For lisinopril, the mean ± S.D.
`recovery for samples with concentra-
`tions ranging from 50% to 150% of
`the testing concentration (0.025 mg/
`mL) was 99.1% ± 0.3% (n = 10) and
`the correlation coefficient for lineari-
`
`ty was 0.9999. The mean ± S.D. re-
`covery for diketopiperazine samples
`with concentrations ranging from
`0.1% to 1.5% of the nomimal lisino-
`pril concentration (0.025 mg/mL)
`was 105.6% ± 2.6% (n = 10) and the
`correlation coefficient for linearity
`was 0.999.
`The linear response of methyl-
`paraben and propylparaben was ex-
`amined by diluting appropriate
`amounts of Ora-Sweet SF, which
`contained both parabens from 50%
`to 150% of the final target composi-
`tion and yielded a correlation coeffi-
`cient greater than 0.99. The precision
`of measurement was examined using
`multiple injections of a standard so-
`lution, resulting in acceptable values
`for lisinopril, diketopiperazine,
`methylparaben, and propylparaben
`with standard deviations of 0.2%,
`0.6%, 0.2%, and 0.4%, respectively
`(n = 10). The precision of the meth-
`od was examined by preparing 10 lis-
`inopril suspension samples, yielding
`standard deviations of 0.6%, 0.4%,
`and 2.0% for lisinopril, methylpara-
`ben, and propylparaben, respective-
`ly. Diketopiperazine levels in all sam-
`ples were below quantitation limits.
`The method’s limits of detection and
`quantitation were 0.03% and 0.1%,
`with a minimum signal-to-noise ra-
`tio of 3 and 13, respectively. Both
`sample and standard solutions were
`stable for one week under ambient
`temperature and light conditions.
`Formulation appropriateness.
`Shaking time. Initial studies were per-
`formed to examine the sensitivity of
`the extemporaneous sample prepara-
`tion to the recommended one
`minute of shaking time. Three sam-
`ple preparations were independently
`made from different lots of Prinivil
`tablets.a Bottles were shaken for 30,
`60, and 90 seconds to disperse the
`tablets. The sample preparations
`were completed as previously de-
`scribed and assayed by HPLC.
`Robustness. Three different lots
`of Prinivil tabletsa were used by two
`different chemists to prepare oral
`
`70
`
`Am J Health-Syst Pharm—Vol 60 Jan 1, 2003
`
`Flat Line Capital Exhibit 1016
`Page 2
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`KVK-Tech, Flat Line Capital Exhibit 1016
`Page 2
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`

`

`maximum light stress, in accordance
`with the International Conference on
`Harmonization (ICH) (a minimum
`of 1.2 million lux-hours of visible
`light, followed by a minimum of 200
`W-hours/m2 of ultraviolet light), in a
`photostability chambern at 25 °C.
`One bottle from each preparation lot
`was wrapped in aluminum foil and
`placed in the light chamber to act as a
`control. All samples were then ana-
`lyzed by HPLC.
`Antimicrobial-effectiveness test-
`ing. Antimicrobial-effectiveness
`testing was performed on lisinopril
`suspensions in accordance with USP
`requirements6 at Lancaster Laborato-
`ries (Lancaster, PA) and the Pharma-
`ceutical Analysis and Control Division
`at Merck Research Laboratories
`(West Point, PA). Testing was con-
`ducted on freshly prepared suspen-
`sions and suspensions stored for six
`weeks at 25 °C and 35% relative hu-
`midity in an 8-oz PET bottle.
`
`Results and discussion
`
`Appropriateness of extempora-
`neous preparation. After the suspen-
`sion was prepared, the bottles were
`shaken individually for 30, 60, or 90
`seconds. Table 1 summarizes the ef-
`fect of shaking time on the solubility of
`
`REPORTS Lisinopril
`lisinopril. The entire content of lisi-
`nopril in Prinivil tablets dissolved
`into water after 30 seconds of shak-
`ing; therefore, the recommended
`shaking time of one minute is more
`than adequate.
`The reproducibility and robust-
`ness of the extemporaneous prepara-
`tion are illustrated in Table 2. Lisi-
`nopril dissolved completely after 60
`seconds of shaking. Low standard
`deviations were obtained by both
`chemists for each suspension. The
`developed extemporaneous prepara-
`tion for Prinivil tablets can also be
`easily applied to Zestril tablets, as
`shown in Table 3, and yields similar
`reproducibility and robustness re-
`sults to those suspensions prepared
`with Prinivil tablets.
`Stability. Table 4 summarizes the
`chemical and physical results of lisino-
`pril, methylparaben, propylparaben,
`and diketopiperazine. Methylparaben
`and propylparaben contents were
`monitored to assess their chemical
`stability. Lisinopril, methylparaben,
`and propylparaben concentrations;
`pH; and appearance were unchanged
`throughout the six-week period for all
`three suspensions. A 0.1% increase in
`the levels of diketopiperazine was ob-
`served and considered inconsequen-
`
`Table 1.
`Lisinopril Concentrations in Oral Suspensions Prepared from Prinivil
`Tablets with Different Shaking Times
`% Nominal Concentration (1 mg/mL)
`30-sec Shake
`60-sec Shake
`90-sec Shake
`101.7
`103.1
`101.7
`99.7
`103.1
`102.2
`101.3
`100.5
`101.2
`
`123
`
`Lot
`
`Table 2.
`Lisinopril Concentrations in Oral Suspensions Prepared from Prinivil
`Tablets by Different Chemists
`
`% Nominal Concentration (1 mg/mL)
`Mean (% RDS)a
`Chemist 1
`Chemist 2
`103.8
`101.6
`102.6 (1.9)
`104.5
`100.3
` 99.6
`100.8
`100.6
`100.7
`101.6
`100.0
`101.5
`100.5
`n = 4. % RSD = % relative standard deviation.
`
`Lot
`
`1 2 3
`
`100.4 (0.6)
`
`100.9 (0.8)
`
`a
`
`Am J Health-Syst Pharm—Vol 60 Jan 1, 2003
`
`71
`
`suspensions to demonstrate the re-
`producibility and robustness of the
`extemporaneous preparation. The
`robustness of the preparation meth-
`od for lisinopril pediatric suspension
`using Zestril tablets was also estab-
`lished by using three different lots of
`Zestril tablets.b All samples were ana-
`lyzed by HPLC.
`Stability studies. Chemical and
`physical stability. Bottles of suspen-
`sion were prepared from three differ-
`ent lots of Prinivil tablets,a stored in a
`stability chamber at 25 °C and 35%
`relative humidity, and analyzed in
`duplicate at time zero (preparation)
`and after one, two, four, and six
`weeks. Each bottle was sampled only
`once, and the bottles were discarded
`after sampling.
`Solubility. Lisinopril solubility in
`the suspensions was evaluated by
`studying four-week samples made
`from Prinivil tabletsa both before and
`after shaking the sample for 30 sec-
`onds. Four weeks after the suspen-
`sions were prepared, samples were
`carefully removed from the stability
`chambers to avoid further mixing the
`suspension. A 5-mL sample was pi-
`petted from the clear upper portion
`of the solution. The same bottle was
`then shaken for about 30 seconds to
`resuspend the insoluble portion of
`the formulation to yield a uniform
`suspension. Another 5-mL sample of
`the suspension was taken. Both 5-mL
`samples were assayed.
`In-use stability. To test the formu-
`lation’s in-use stability, lisinopril
`suspensions generated from Prinivil
`tabletsa from three different lots were
`tested immediately after preparation.
`Subsequently, one bottle from each
`lot was stored at 25 °C and 60% rela-
`tive humidity. The same bottles were
`repeatedly sampled and returned to
`the chamber after one, two, and four
`weeks of storage. All samples were
`assayed by HPLC.
`Photochemical stability. Three
`batches of lisinopril suspensions gen-
`erated from each of the Prinivil tablet
`lotsa were prepared and exposed to
`
`Flat Line Capital Exhibit 1016
`Page 3
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`KVK-Tech, Flat Line Capital Exhibit 1016
`Page 3
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`

`

`porting the multidose use of this
`extemporaneously compounded
`product (Table 6).
`Duplicate samples of extempora-
`neous preparations from each lot
`were exposed to 1.2 million lux of
`visible light and 200 W/m2 of ultravi-
`olet light and agreed within experi-
`mental error (Table 7). Further, no
`significant differences between the
`control samples and the full ICH
`light-stressed samples were observed.
`Therefore, precautions against expo-
`sure to ambient light are not neces-
`sary for lisinopril oral suspensions
`prepared and stored in PET bottles.
`Antimicrobial effectiveness.
`Microorganisms, including Sta-
`phylococcus aureus, Pseudomonas
`aeruginosa, Escherichia coli, Candida
`albicans, and Aspergillus niger, were
`monitored in the samples, and the
`resulting data are summarized in Ta-
`ble 8. Both initial and six-week sam-
`ples passed the USP antimicrobial-
`effectiveness test for a category-1C
`product.
`
`Conclusion
`
`Lisinopril suspensions extempo-
`raneously prepared from tablets are
`stable for at least four weeks when
`stored at or below 25 °C under ambi-
`ent light exposure.
`
`REPORTS Lisinopril
`tial to the safety and efficacy of lisi-
`nopril. This formulation can be
`stored for up to six weeks at 25 °C
`and 35% relative humidity.
`Because the suspended solid parti-
`cles precipitate over time, a clear su-
`pernatant forms that was sampled to
`determine the amount of lisinopril in
`the supernatant solution. The same
`bottle was then shaken to resuspend
`the solids, a second sample was tak-
`en, and both samples were analyzed
`by HPLC. The data clearly show that
`the soluble drug does not settle out
`with insoluble excipients after sitting
`undisturbed for four weeks and that
`lisinopril remains quantitatively fully
`dissolved in the extemporaneous
`
`preparations (Table 5). These data
`were expected because Bicitra and
`Ora-Sweet SF are water-based dilu-
`ents and because lisinopril has an
`aqueous solubility almost 100 times
`higher than the targeted 1-mg/mL
`concentration in the targeted pH
`range (4–5).
`The in-use stability study simu-
`lated actual usage by patients. Each
`suspension was removed from the
`stability chamber, sampled, and re-
`turned to the chamber at each time
`point. The suspension’s chemical
`and physical integrity were then
`monitored after each repeated sam-
`pling. The properties of these sus-
`pensions remained unchanged, sup-
`
`Table 3.
`Lisinopril Concentrations in Oral Suspensions Prepared from Zestril
`Tablets by Different Chemists
`
`% Nominal Concentration (1 mg/mL)
`Chemist 1
`Chemist 2
`Mean (% RSD)a
`101.6
`103.1
`102.3 (0.7)
`102.0
`101.4
`101.8
`102.8
`102.0
`102.2
`101.3
`102.2
`100.7
`100.5
`n = 4. % RSD = % relative standard deviation.
`
`Lot
`
`1 2 3
`
`102.5 (0.4)
`
`101.4 (0.8)
`
`a
`
`Table 4.
`Stability of Lisinopril 1-mg/mL Oral Suspensions and Content of Degradation Product and Preservatives
`
`Time
`
`Lisinopril
`
`Diketopiperazine Methylparaben
`
`Propylparaben
`
`pH (n = 1)
`
`Appearance
`
`% Initial Concentration Remaininga
`
`Lot 1
`Initial
`Week 1
`Week 2
`Week 4
`Week 6
`Lot 2
`Initial
`Week 1
`Week 2
`Week 4
`Week 6
`Lot 3
`Initial
` 100 (0.32)
` 100 (1.1)
`Week 1
`98.1 (1.2)
`101.6 (1.0)
`Week 2
` 99.2 (0.51)
`101.4 (1.3)
`Week 4
` 99.2 (0.22)
` 101.4 (0.67)
`Week 6
` 96.0 (0.22)
` 98.5 (0.77)
`aData reported as mean (% relative standard deviation). All samples tested in duplicate, except for initial concentrations, which were measured in triplicate.
`
`4.4
`4.3
`4.3
`4.3
`4.4
`
`4.3
`4.4
`4.3
`4.4
`4.4
`
`4.4
`4.4
`4.3
`4.4
`4.4
`
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`
` 100 (0.15)
` 98.5 (0.36)
` 98.2 (0.07)
`98.0 (2.6)
` 96.1 (0.74)
`
` 100 (0.76)
` 98.8 (0.43)
` 97.6 (0.07)
` 97.7 (0.73)
` 94.9 (0.22)
`
` 100 (0.63)
`101.2 (1.4)
` 100.5 (0.08)
`100.9 (1.1)
` 98.8 (1.8)
`
` 100 (1.5)
` 101.2 (0.60)
` 99.7 (0.15)
` 100.6 (0.45)
` 96.6 (0.31)
`
` 100 (0.72)
` 99.9 (0.98)
` 100 (0.21)
` 99.9 (0.42)
` 98.4 (0.78)
`
` 100 (0.40)
`99.7 (0.57)
` 100 (0.78)
`100.5 (0.21)
` 99.6 (0.14)
`
` 100 (0.51)
`100.3 (0.70)
` 99.8 (0.14)
`100.6 (0.49)
` 99.4 (0.21)
`
`<0.1
`<0.1
`<0.1
`<0.1
` 0.1 (141)
`
`<0.1
`<0.1
`<0.1
`<0.1
` 0.1 (141)
`
` 0.1 (14.0)
`0.2 (3.9)
` 0.2 (18.6)
` 0.2 (141)
` 0.2 (141)
`
`72
`
`Am J Health-Syst Pharm—Vol 60 Jan 1, 2003
`
`Flat Line Capital Exhibit 1016
`Page 4
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`KVK-Tech, Flat Line Capital Exhibit 1016
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`

`

`REPORTS Lisinopril
`
`Table 5.
`Lisinopril Concentrations in Oral Suspensions with and without
`Shaking
`
`Lot
`
`Unshakena (n = 2)
`
`Shaken (n = 1)
`
`% Nominal Concentration (1 mg/mL)
`
`99.9
`99.3
`99.5
`
`123
`
`100.8 (0.07)
`100.0 (0.28)
`100.8 (0.35)
`aData reported as mean (% relative standard deviation).
`
`Table 6.
`Stability of Lisinopril 1-mg/mL Oral Suspension with Multiple Usage
`
`% Initial Concentration Remaining
`
`Time
`
`Lot 1
`Initial
`Week 1
`Week 2
`Week 4
`Lot 2
`Initial
`Week 1
`Week 2
`Week 4
`Lot 3
`Initial
`Week 1
`Week 2
`Week 4
`
`Lisinopril
`
`Diketopiperazine Methylparaben
`
`Propylparaben
`
`pH
`
`Appearance
`
` 100
` 99.6
` 100.3
` 98.8
`
` 100
` 98.6
` 99.4
` 97.8
`
` 100
` 99.9
` 100
` 98.8
`
` <0.1
`<0.1
` 0.1
` 0.1
`
`<0.1
`<0.1
`<0.1
` 0.1
`
` 0.1
` 0.1
` 0.2
` 0.2
`
` 100
` 98.9
` 100.5
` 100.2
`
` 100
` 98.8
` 100
` 98.8
`
` 100
` 100.2
` 100.1
` 100.1
`
`100
` 98.9
` 106.1
` 103.2
`
`100
` 100.4
` 106.2
` 103
`
`100
` 99.8
` 102.9
` 101.8
`
`4.4
`4.5
`4.5
`4.4
`
`4.4
`4.5
`4.5
`4.4
`
`4.4
`4.5
`4.4
`4.4
`
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`
`Unchanged
`Unchanged
`Unchanged
`Unchanged
`
`aData reported as mean±S.D. All samples tested in duplicate, except for initial concentrations, which were measured in triplicate.
`
`Table 7.
`Photochemical Stability of Lisinopril 1-mg/mL Oral Suspension Prepared with Prinivil Tablets
`
`Sample
`
`Lisinopril
`
`Diketopiperazine Methylparaben
`
`Propylparaben
`
`pH
`
`Appearance
`
`% Nominal Concentration Remaininga
`
`100
`98.6 (0.93)
`
`100
`99.8 (0.07)
`
` <0.1
` <0.1
`
` <0.1
` <0.1
`
`100
` 99.2 (0.50)
`
`100
`100.2 (0.58)
`
`100
` 99.5 (0.30)
`
`100
`100.3 (1.2)
`
`Lot 1
`Control
`Full light-stress
`Lot 2
`Control
`Full light-stress
`Lot 3
`Control
`100
` <0.1
`100
`100
`Full light-stress
`99.3 (0.28)
` <0.1
` 98.8 (0.43)
` 96.9 (0.75)
`aData reported as mean (% relative standard deviation) for light-stressed samples, which were tested in duplicate. Full light-stressed = exposure to 1.2 million lux of
`visible light and 200 W/m2 of ultraviolet light.
`
`4.4
`4.4
`
`4.4
`4.4
`
`4.4
`4.4
`
`Unchanged
`Unchanged
`
`Unchanged
`Unchanged
`
`Unchanged
`Unchanged
`
` aPrinivil 20-mg tablets, Merck & Co., West
`Point, PA, lots HBB738, HBB754, and J8227.
`bZestril 20-mg tablets, AstraZeneca Phar-
`maceuticals LP, Wilmington, DE, lots
`CSH871, CSJ151, and CSJ281.
`cPolyethylene terephthalate 8-oz bottles,
`Owens Brockway, Brookville, PA.
`dBicitra, Alza Corporation, Mountain
`View, CA, lots 9A008 and 8B131.
`eOra-Sweet SF, Paddock Laboratories,
`
`Minneapolis, MN, lots 0D6302, 9F6726, and
`8K6273.
`fHPLC, model HP 1100, Agilent Technolo-
`gies, Palo Alto, CA.
`gAlltech Platinum EPS C-8 column, 250-
`mm × 4.6-mm inner diameter, 5-µm packing,
`Alltech Associates, Deerfield, IL.
`hPotassium bisphosphate and phosphoric
`acid 85%, HPLC grade, Fisher Scientific, Fair
`Lawn, NJ.
`
`iAcetonitrile, Optima grade, Fisher Scientific.
`jLisinopril standard, Merck & Co., Rahway,
`NJ, lot L-154, 826-000T.
`kDiketopiperazine, Merck & Co., lot L-659,
`199-000L.
`lMethylparaben, Aldrich, Milwaukee, WI,
`lot L-474, 898-000V.
`mPropylparaben, Aldrich, lot L-510, 208-000V.
`nPhotostability chamber, model ES 2000,
`Environmental Specialties, Raleigh, NC.
`
`Am J Health-Syst Pharm—Vol 60 Jan 1, 2003
`
`73
`
`Flat Line Capital Exhibit 1016
`Page 5
`
`KVK-Tech, Flat Line Capital Exhibit 1016
`Page 5
`
`

`

`REPORTS Lisinopril
`
`Table 8.
`Antimicrobial Effectiveness of Lisinopril 1-mg/mL Oral Suspensions
`
`Initial Preparation (CFU/mL)a
`Inoculum
`Concentration
`
`14 Days
`
`28 Days
`
`Stored for 6 Weeks (CFU/mL)
`Inoculum
`Concentration
`
`14 Days
`
`28 Days
`
`Organism
`Staphylococcus aureus
`(ATCCb No. 6538)
`Pseudomonas
`aeruginosa
`(ATCC No. 9027)
`Escherichia coli
`(ATCC No. 8739)
`Candida
`albicans
`(ATCC No. 10231)
`Aspergillus niger
`(ATCC No. 16404)
`aCFU = colony-forming unit.
`bATCC = American Type Culture Collection.
`
`5.7
`
`5.8
`
`6.0
`
`6.1
`
`5.7
`
` 1.0
`
` 2.9
`
`<1.0
`
` 2.2
`
` 3.3
`
`<1.0
`
` 2.2
`
`<1.0
`
` 2.0
`
` 2.7
`
`5.5
`
`5.4
`
`5.5
`
`5.4
`
`5.6
`
`<1.0
`
`<1.0
`
`<1.0
`
`<1.0
`
` 4.2
`
`<1.0
`
`<1.0
`
`<1.0
`
`<1.0
`
` 4.1
`
`References
`1. Supplemental new drug application 19-
`558 for Prinivil (lisinopril). 2001 Sep 24.
`2. FDA report study 209000/0058, 1988 Feb
`9.
`3. Smolinske SC. Handbook of food, drug,
`and cosmetic excipients. Boca Raton, FL:
`CRC Press; 1992:351-7.
`4. Hindmarsh KM, John E, Asali LA et al.
`Urinary excretion of methylparaben and
`its metabolites in preterm infants. J Pharm
`
`Sci. 1983; 72:1039-41.
`5. Arthur Kibbe, ed. Handbook of pharma-
`ceutical excipients. Washington, DC:
`American Pharmaceutical Association;
`1986.
`6. Antimicrobial effectiveness testing (errata
`to general information chapter 51). In:
`The United States pharmacopeia, 23rd
`rev., and The national formulary, 18th ed.
`Suppl 8. Rockville, MD: United States
`Pharmacopeial Convention; 1998:4293-5.
`
`Appendix—Procedure for preparing
`lisinopril suspension
`1. Place 10 20-mg lisinopril tablets and 10 mL
`of purified water into an 8-oz amber polyeth-
`ylene terephthalate bottle.
`2. Place cap on bottle and shake for one minute.
`3. Add 30 mL of Bicitra. Shake bottle again.
`4. Add 160 mL of Ora-Sweet SF and shake to
`disperse contents.
`5. Shake bottle before withdrawing sample.
`
`74
`
`Am J Health-Syst Pharm—Vol 60 Jan 1, 2003
`
`Flat Line Capital Exhibit 1016
`Page 6
`
`KVK-Tech, Flat Line Capital Exhibit 1016
`Page 6
`
`