11b-r_burnett.indd

PRACTICE REPORTS Omeprazole
Stability and viscosity of a fl avored omeprazole
oral suspension for pediatric use
JANE E. BURNETT AND ETHAN R. BALKIN
Purpose. The stability and viscosity of
tration dependent. After one week, the Proton-pump inhibitors (PPIs)
are substituted pyridylmeth- preparations of a commercially available, 0.6- and 1.2-mg/mL suspensions retained ylsulfi nyl benzimidazole com- fl avored, immediate-release powder for 87.2% and 93.1% of their respective initial pounds that act to inhibit gastric acid oral suspension (omeprazole–sodium bi- omeprazole concentrations, whereas the secretion by selectively and irrevers- carbonate) during refrigerator and room 2-, 3-, and 4-mg/mL suspensions retained ibly inhibiting the stomach's parietal temperature storage were investigated. >97% of their initial omeprazole concentra- cells' H+,K+-ATPase.1 Since fi rst in- tions. Suspension viscosities varied 10-fold troduced in the late 1980s, PPIs have ate 20-mg packets were suspended to ini- over the concentrations studied, but all tial omeprazole concentrations of 0.6 and were within the viscosity ranges of other become the medications of choice 2 mg/mL, and omeprazole–sodium bicar- commercially available oral suspensions. in the treatment of acid-related dis- bonate 40-mg packets were suspended to Prolonged refrigeration did not increase orders, including gastroesophageal initial omeprazole concentrations of 1.2, 2, the suspensions' viscosities.
refl ux disease (GERD), duodenal and 3, and 4 mg/mL. Suspensions were stored at gastric ulcers, and Zollinger–Ellison 4 °C in darkness (refrigerated) or 22–25 °C ate suspensions of 0.6–4 mg/mL omepra- syndrome. Of five PPIs currently (room temperature) in light for one week. A zole were stored at 4 °C in darkness for up approved for use in treating these third set of suspensions was stored refriger- to 28 days. The viscosities of refrigerated sus- ated for one month. Omeprazole's stability pensions did not increase over 7 days. Except disorders, lansoprazole and omepra- was quantifi ed after 0, 6, 12, 24, 48, and 168 for the 0.6 mg/mL preparations, suspensions zole are approved for use in children hours in one-week samples and after 0, 7, stored at room temperature in the light re- older than one and two years of age, 14, 21, and 28 days in one-month samples tained >90% of their initial omeprazole con- using high-pressure liquid chromatogra- tent after 7 days, despite turning yel ow.
The activity of PPIs is dependent phy. Viscosities of refrigerated suspensions on the weakly basic nature of the were measured after 0, 1, and 7 days.
Index terms: Antacids; Color; Concentra-
pyridyl nitrogen, which has a pK Results. Refrigerated suspensions retained
tion; Gastrointestinal drugs; Omeprazole; >98% and >96% of their initial omepra- Pediatrics; Photodecomposition; Sodium near <4.1,4 At neutral pH, PPIs are zole concentrations after one week and bicarbonate; Stability; Storage; Suspen- inactive, remaining as lipophilic one month, respectively. Stability of room sions; Temperature; Viscosity prodrugs that can freely cross cell temperature suspensions was concen- Am J Health-Syst Pharm. 2006; 63:2240-7
membranes. At pH <4, the pyridyl nitrogen becomes protonated, which initiates a structural rearrangement to form a reactive cyclic sulfenamide, active also render them unstable and coated granules. The enteric coatings the pharmacologically active form of subject to degradation. For this rea- protect the PPIs from degradation by son, most oral PPI dosage forms are stomach acid.1 The structural features of PPIs enteric-coated tablets or extended- Administration of enteric-coated that make them pharmacologically release capsules containing enteric- PPIs is problematic in pediatric, JANE E. BURNETT, B.S., is Senior Research Specialist, Department Sciences Building DC096.00, Columbia, MO 65212 (burnettj@health.
of Surgery, University of Missouri Hospital and Clinics (UMHC), Columbia. ETHAN R. BALKIN, B.A., is Graduate Research Assistant, Santarus, Inc., provided an unrestricted grant for this study, which Area of Pathobiology, Harry S. Truman Memorial Veterans' Hospital, included the authors' salaries. The authors acknowledge Jeffrey O. Columbia; at the time of the study he was Senior Research Labora- Phillips, Pharm.D., who served as a consultant during this study, and tory Technician, Department of Surgery, UMHC.
Pamela S. Cooper, Ph.D., who prepared the manuscript.
Address correspondence to Ms. Burnett at the Department of Sur- gery, University of Missouri Hospital and Clinics, NW301 Medical DOI 10.2146/ajhp060026 Am J Health-Syst Pharm—Vol 63 Nov 15, 2006 PRACTICE REPORTS Omeprazole
elderly, or critically ill patients who zole powder for oral suspension,a from 40-mg packets were suspended may be unable to swallow solid became commercially available; it to initial omeprazole concentrations dosage forms. Recommendations contains sweeteners and additional of 1.2, 2, 3, and 4 mg/mL. Volumes for administration in these patients flavorings to improve palatability.7,8 of water used for omeprazole– involve opening capsules and mix- Omeprazole–sodium bicarbonate sodium bicarbonate suspensions are ing the enteric-coated granules into is dispensed as single, ready-to-use indicated in Table 1. For short-term soft acidic foods or flushing gran- packets that, with the addition of stability determinations, six tubes of ules through nasogastric tubes with 30 mL of water, provide either 20 or each omeprazole–sodium bicarbon-liquids. Such methods have signifi- 40 mg of omeprazole homogeneous ate suspension concentration were cant drawbacks. Flushing granules suspension buffered with sodium bi- prepared. Three tubes were stored through nasogastric tubes is time- carbonate (20 meq per packet).8 Sus- for one week at 4 °C in darkness, consuming and may lead to clogging pensions have a peach–mint flavor.
and three were stored at room tem- Previous studies have investigated perature (22–25 °C) in continuous Oral administration of enteric- the stability of omeprazole in extem- light. For extended storage stabil- coated granules to pediatric patients poraneously prepared, unflavored ity determinations, tubes of each is fraught with problems. Children omeprazole–bicarbonate suspen- omeprazole–sodium bicarbonate may be too young to swallow even sions.6, 9,10 However, no data are avail- suspension concentration were pre- soft foods, or they may chew the able on the stability of omeprazole pared in triplicate and stored at 4 °C granules, which compromises the in flavored suspensions. This study in darkness for 28 days. enteric coating and leads to drug in- reveals the effects of refrigerated To assess the stability of omepra- activation.5 Also, adjusting pediatric and ambient storage of omeprazole– zole during suspension storage, dosages of granule-containing PPI sodium bicarbonate suspensions pre- aliquots of approximately 80 µL were formulations by weight is difficult pared to final omeprazole concentra- removed from all tubes immediately and not recommended.
tions ranging from 0.6 to 4 mg/mL. after preparation (time 0) and at Homogeneous liquid suspensions The study also shows the effect of specific times throughout the stor- of PPIs permit greater ease of ad- refrigerated storage on omeprazole– age period. For preparations stored ministration orally or via nasogastric sodium bicarbonate fluidity as a func- for one week, aliquots were removed tube, and they also simplify dosage tion of suspension concentration.
at 6, 12, 24, 48, and 168 hours (7 adjustments for children. Homog- days). For extended storage experi- enous suspensions of omeprazole Methods
ments, aliquots were removed at 7, and lansoprazole can be prepared by Sample preparation. Individual 14, 21, and 28 days. Before remov-
dissolving enteric-coated granules in packets of omeprazole–sodium bicar- ing aliquots, tubes were mixed well a solution of 8.4% sodium bicarbon- bonate powder containing either 20b to ensure uniform resuspension of ate. However, these preparations are or 40b mg omeprazole were dissolved insoluble materials that had settled intensely salty and bitter and unde- in tap water in clear plastic 50-mL during storage. sirable as orally administered formu- conical polypropylene tubes.c Powders Because of the potential for volume lations, especially in children. from 20-mg packets were suspended error due to difficulty in pipetting In 2004, omeprazole–sodium bicar- to initial omeprazole concentrations thicker, more concentrated suspen- bonate, an immediate-release omepra- of 0.6 and 2 mg/mL, and powders sions, the exact volume of an aliquot Table 1.
Preparation of Immediate-Release Omeprazole–Sodium Bicarbonate Suspension
Omeprazole
Omeprazole
Volume of
Final Volume
Packet Size
Tap Water
of Solution,
Sodium Bicarbonate
Added (mL)
aMolarity indicated in parentheses.
bVolume recommended by manufacturer.
Am J Health-Syst Pharm—Vol 63 Nov 15, 2006 PRACTICE REPORTS Omeprazole
was calculated from the weight of the HPLC system,g a 50-µL aliquot of determine if storage time at 4 °C the aliquot (determined on a tared the supernatant was diluted 1:10 with had an effect on the viscosity of electronic balance) and the density methanol/15 mM sodium phosphate omeprazole–sodium bicarbonate of the suspension from which it was buffer, pH 7:4 (40:60, v/v). Injection suspensions, they were subjected to taken. The densities of suspensions volumes ranged from 30 to 100 µL.
shear stress in a rotational viscom- were determined by weighing them The HPLC column confi guration eter. Viscosity, which is the inverse and dividing by the fi nal suspension consisted of a C silica columnh fi t- of fl uidity, is measured in units of ted with a C silica precolumn.i Mo- Omeprazole extraction and anal-
bile phase was methanol/acetonitrile/ Omeprazole–sodium bicarbonate ysis. For determination of omepra-
15 mM sodium phosphate buffer was prepared by the same method zole concentrations in aliquots, a (40:10:50 v/v/v, pH 7.4). The fl ow that was used for the stability de-method of omeprazole extraction rate was 1 mL/min and the detector terminations (Table 1). Samples and assay by reverse-phase high- wavelength was 300 nm.
were prepared in duplicate 300-mL performance liquid chromatography Calibration standards were pre- batches by combining the contents (HPLC) was developed on the basis pared by using the mobile phase of multiple packets and bringing to of previously published methods.9,11 to dilute a 1-mg/mL stock solution volume with tap water prechilled to 4 Extraction of omeprazole from of pure omeprazolej (dissolved in °C. Suspensions were stored in glass suspension aliquots was a two-step 100% methanol) to 1 and 10 µg/mL. jars at 4 °C in darkness.
process, begun when aliquots were Volumes of these working standards Viscosity measurements of 60-mL collected and completed on the equivalent to 0.02, 0.05, 0.1, and 0.2 aliquots of each suspension were day of HPLC injection. For the fi rst µg of omeprazole were injected to taken immediately after suspension step of the extraction, 9 volumes obtain calibration curves. The stock (time 0) and after one and seven of methanold/15 mM sodium phos- solution and aliquots of the working days of storage using a rotational phate buffere (1:1, v/v, pH 7.4) were standards were stored at –80 °C.
viscometer.l Samples were subjected added to the aliquots, and the sam- Standard curves were produced to a constant shear rate of 110/sec ples were mixed by inversion and agi- by the software included in the for 120 seconds at 4 °C. Preliminary tation using a benchtop vortex mixer. HPLC system. Standard curves were experiments had shown that viscos-The methanol/phosphate-containing linear and highly reproducible, with ity became constant for preparations aliquots were immediately placed at r2 values always greater than 0.999. analyzed in this study 80 seconds –80 °C, where they remained until The coeffi cient of variation for the into the run. Therefore, viscosities the day of HPLC analysis. The addi- slope of the standard curves over a reported here are those recorded at tion of methanol before freezing was six-month period was 1.5% (n = 18 80 seconds.
to minimize omeprazole degrada- Microbiological analysis. Ali-
tion that might occur as a result of The stability-indicating capacity quots from omeprazole–sodium bi- freezing and thawing or subsequent of the HPLC assay was assessed by carbonate 40-mg suspensions stored sample handling.
forced degradation of omeprazole in for one week under light and room Frozen omeprazole–sodium bi- acid. A 40-mg packet was prepared to temperature conditions were plated carbonate suspension aliquots were 1.2 mg/mL omeprazole. From each on chocolate, MacConkey, and blood thawed at room temperature in dark- of duplicate 2-mL samples, 100-µL agar plates. Plates were incubated for ness. The thawed tubes were then aliquots were removed to determine fi ve days at 35 °C under 6% carbon maintained in darkness at 4 °C until the time 0 omeprazole concentra- dioxide and examined daily for mi- they could be processed. All samples tion in each tube. To the remaining crobial growth.
were thawed and processed as rapidly 1.9 mL in each tube, 140 µL of either Statistical analysis. Effects of
as possible after removal from the 12 N hydrochloric acid (HCl)k or storage time on omeprazole concen-–80 °C freezer.
tap water was added, and additional tration and viscosity were determined Thawed samples were remixed 100-µL aliquots were removed after by one-way repeated-measures anal- and then centrifuged for one min- 15 and 30 minutes of incubation at ysis of variance for each sample and ute in a microcentrifuge to pellet room temperature. All aliquots were storage condition. For main effects, insoluble materials. The fi nal extrac- extracted and analyzed by HPLC as statistical signifi cance was set a priori tion step was completed by adding described above.
at p < 0.05. When a signifi cant main 9 volumes of 100% acetonitrilef to All reagents used for extraction, effect was detected, paired t tests the supernatant and centrifuging for dilution and separation were HPLC were conducted to identify values three minutes to remove precipitated or analytical grade.
signifi cantly different from values at excipient materials. For injection into Viscosity determinations. To time 0. All statistical analyses were
Am J Health-Syst Pharm—Vol 63 Nov 15, 2006 PRACTICE REPORTS Omeprazole
conducted with SPSS version 11.0.2 pensions made with powders from All freshly prepared suspensions (SPSS Inc., Chicago, IL). To control 20-mg packets had omeprazole con- were white in color. Refrigerated for Type I errors, significance levels centrations that averaged 97.5% and samples did not change color even for post hoc tests were determined 97.7% of the initial concentrations, after one month of storage. Samples using Holm's sequential Bonferroni respectively. The 1.2-mg/mL suspen- stored at room temperature in the sion made with powders from 40- light began to turn yellow after 24 mg packets had 96.2% of the mean hours, and color intensity increased starting concentration. However, with duration of storage. The 0.6- and The HPLC assay for omeprazole none of these decreases in omepra- 1.2-mg/mL samples exhibited a more was stability indicating. The addition zole concentration were statistically intense color change than the 2-, 3-, of 140 µL of concentrated HCl to a significant.
and 4-mg/mL samples. No colonies 2-mL aliquot of omeprazole–sodium Storage at room temperature in or other evidence of bacterial or bicarbonate suspended to 1.2 mg/mL the light resulted in omeprazole deg- fungal growth were detected on any omeprazole resulted in most of the radation in the 0.6- and 1.2-mg/mL of the culture media for any of the omeprazole being degraded within suspensions (Table 2). After 48 hours, suspensions tested.
15 minutes (Figure 1). Degradation the mean omeprazole concentration Across the range of suspension products that appeared with acid of the 0.6-mg/mL suspensions made concentrations analyzed, viscosities treatment did not interfere with the with powders from 20-mg packets varied 10-fold from 0.02 to 0.21 Pa-ability to detect remaining intact was 96.6% of the mean starting con- sec. Storage for up to one week in the omeprazole. Control samples in centration. After one week, the mean cold did not result in any increase which water was added instead of omeprazole concentration in the 0.6- of viscosity in any of the suspensions acid showed no significant loss of mg/mL suspensions had declined to (Table 4). In fact, viscosity appeared to omeprazole over the 30-minute incu- 87.2% of the starting concentration, slightly decrease during storage for all bation period (data not shown).
statistically significant for this sample but the two most dilute suspensions.
Omeprazole–sodium bicarbonate (p = 0.018). In the 1.2-mg/mL suspen- To determine how the viscosity of suspensions refrigerated in darkness sions made with powders from 40- the omeprazole–sodium bicarbonate showed no appreciable degradation mg packets, the mean concentration suspensions compared to other com-of omeprazole during either short- after 48 hours was 97.2% of the start- mercially available oral suspensions, term or long-term storage. Samples ing concentration; after one week, viscosity determinations were also stored for a week showed less than the mean concentration had declined made on a pediatric acetaminophen 2% loss of omeprazole (Table 2). Af- to 93.1% of the starting concentra- suspensionm and on a buffered, ter 28 days of refrigerated dark storage, tion. Suspensions prepared to 2, 3, chocolate-flavored product for use losses of 2–4% were noted for three and 4 mg/mL showed no more than in preparing oral suspensions of suspensions (Table 3). Specifically, after 2.5% degradation after one week of enteric-coated PPI granules.n The 28 days, the 0.6- and 2-mg/mL sus- storage at room temperature.
acetaminophen suspension had a Figure 1. Chromatograms showing the time course of omeprazole degradation by acid. Omeprazole was quantified in 100-µL portions of a
2-mL omeprazole–sodium bicarbonate suspension (1.2 mg/mL omeprazole prepared using omeprazole–sodium bicarbonate 40-mg pack-
ets) taken before and after addition of 140 µL 12 N hydrochloric acid. Horizontal axes show retention time in minutes. Omeprazole retention
time = 8.1 minutes. Arrows indicate omeprazole peaks.
t = 0
t = 15 min acid
t = 30 min acid
Am J Health-Syst Pharm—Vol 63 Nov 15, 2006 PRACTICE REPORTS Omeprazole
viscosity of 0.349 Pa-sec, whereas demonstrated that PPIs dissolved in in the refrigerator and for two weeks the fl avored buffer product had an 8.4% (1 M) sodium bicarbonate are at room temperature when stored in initial viscosity of 0.157 Pa-sec that stable6,9,10,16-18 and bioavailable.18-20 glass vials. Phillips et al.10 determined increased slightly over time. Vis- The United States Pharmacopeia that such suspensions could be stored cosities of the omeprazole–sodium (USP) criterion for omeprazole in clear glass containers for up to six bicarbonate suspensions were less delayed-release capsules is that months in the refrigerator and for than or similar to these other oral omeprazole content must be be- one week at room temperature with- tween 90% and 110% of the labeled out signifi cant loss of omeprazole. amount.21 A 90% cutoff has been DiGiacinto et al.6 concluded that the criterion used in previously pub- unfl avored omeprazole–bicarbonate A drawback of liquid suspensions lished reports that assessed the stabil- suspensions stored in plastic amber of omeprazole and other PPIs is the ity of unfl avored omeprazole suspen- syringes were stable for 45 days in potential for degradation due to the sions prepared to 2 mg/mL in 8.4% the refrigerator and for two weeks at acid lability of the compounds. The sodium bicarbonate.6,9,10 Quercia et room temperature.
stability of PPIs is increased at alka- al.9 concluded that these unfl avored This study was undertaken to de- line pH,14,15 and previous studies have suspensions were stable for 30 days termine the stability of omeprazole Table 2.
Stability of Omeprazole in Immediate-Release Omeprazole–Sodium Bicarbonate Suspension
% ± S.D. Omeprazole Remaininga
Size (mg)
an = 3.
bRT = room temperature, 22–25 °C.
cp = 0.018 from the concentration at time 0.
Table 3.
Stability of Omeprazole in Immediate-Release Omeprazole–Sodium Bicarbonate Suspension
in Darkness at 4 °C
% ± S.D. Omeprazole Remaininga
Size (mg)
an = 3.
Am J Health-Syst Pharm—Vol 63 Nov 15, 2006 PRACTICE REPORTS Omeprazole
tain 8.4–16.8% sodium bicarbonate Viscosity of Immediate-Release Omeprazole–Sodium
In this study, all omeprazole– Bicarbonate Suspension in Darkness at 4 °C
sodium bicarbonate suspensions Omeprazole
stored at room temperature in the ± S.D. Viscositya (Pa-sec)
light began to turn yellow after 24 Size (mg)
hours, with the two most dilute sus- pensions exhibiting the most intense color change over the course of a week. Previous studies have also not- ed that omeprazole–bicarbonate sus- pensions change color upon storage at room temperature in the light.6,9,10 Discolorations appear to be largely due to acid-induced decomposition of omeprazole.14,22 Upon addition of n = 2.
bPrepared according to manufacturer's instructions but without omeprazole.
acid, omeprazole suspensions imme- cSingle sample measured at 25 °C.
diately turn pale yellow and become dark yellow to brown with heating.14 Omeprazole solutions that degrade in a commercially available omepra- be influenced by the concentration of completely without alkaline stabiliz- zole powder for suspension that, un- the omeprazole–sodium bicarbonate ing agents typically turn purple upon like extemporaneous suspensions suspension. For the first 24 hours of prolonged storage.22examined in earlier studies, con- storage, all samples were relatively While light may also contribute tains flavorings and other excipi- stable. After 24 hours of storage, how- to omeprazole degradation, the ent materials. The study examined ever, the 0.6- and 1.2-mg/mL samples extent of that contribution is not omeprazole–sodium bicarbonate exhibited degradation that increased clear. DiGiacinto et al.6 observed that suspensions prepared over final with increasing storage time. While 2-mg/mL suspensions stored in am-omeprazole concentrations ranging degradation was accelerated in the ber syringes exhibited slight yellowing from 0.6 to 4 mg/mL. When prepared 1.2-mg/mL samples, these suspen- after one week at room temperature; according to package instructions, sions still retained 93.1% of their in that study, samples could be stored final omeprazole concentrations for initial omeprazole concentration at room temperature for up to 14 days the 20- and 40-mg packets are 0.6 after one week of storage. However, without significant (>10%) loss of and 1.2 mg/mL. Higher concentra- the 0.6-mg/mL samples retained only omeprazole. However, Quercia et al.9 tions than 1.2 mg/mL were also 87.2% of the mean starting concen- found that suspensions in glass vials investigated because they are more tration after one week, a statistically were stable for the same amount of useful for pediatric use because the significant difference.
time, noting that under these condi- volume per dose is reduced.
A possible explanation for reduced tions, suspensions gradually turned No significant omeprazole deg- stability of the more dilute suspen- from white to brown.
radation was detected in samples sions is that they may not have suf- Although additional studies are refrigerated for up to one month, ficient buffering capacity to permit necessary to determine the precise irrespective of suspension concen- prolonged room temperature stor- relationship between omeprazole loss tration. All omeprazole–sodium age. Each omeprazole–sodium bicar- and light-induced or temperature- bicarbonate suspensions showed 2% bonate packet provides 20 meq (1.68 induced color changes, it appears or less degradation after one week, g) of sodium bicarbonate, which is that the color change to yellow is and no more than 2–4% degradation intended to protect the drug from not necessarily an indicator that the after one month, which fulfilled the acid degradation in an adult stomach suspension can no longer be used, USP criterion. For samples stored at when taken as a single dose. When especially if the preparation has room temperature in the light, all but prepared in 30 mL water according been at room temperature for only the 0.6-mg/mL suspension fulfilled to the manufacturer's instructions, a few days. While yellowing may the USP criterion for up to one week the 0.6- and 1.2-mg/mL suspensions indicate the beginning of acid- of storage. therefore contain 5.0% sodium bi- induced degradation, HPLC analysis The rate of degradation at room carbonate. Suspensions prepared to of omeprazole–sodium bicarbonate temperature in the light appeared to 2, 3, and 4 mg/mL omeprazole con- suspensions showed that, with the Am J Health-Syst Pharm—Vol 63 Nov 15, 2006 PRACTICE REPORTS Omeprazole
exception of the 0.6-mg/mL suspen- When administering omeprazole– provide at least 7 meq of sodium bi- sion, omeprazole content was still sodium bicarbonate suspensions that carbonate in a dose from packets pre-greater than 90% of the preparations' have been prepared to concentrations pared to 2 mg/mL, the administered starting concentrations after one higher than those recommended by volume of suspension prepared from week at room temperature. More- the manufacturer, suffi cient sodium 40-mg packets can be no less than over, room temperature storage does bicarbonate must be present in the 7 mL; when prepared from 20-mg not appear to promote any microbial dose to protect the omeprazole from packets, the administered volume growth in suspensions.
degradation by stomach acid. An es- can be no less than 3.5 mL. Refrigeration did not cause the timate of this minimum requirement Because of the minimum sodium viscosity of omeprazole–sodium was obtained by calculation using a bicarbonate/volume requirement, bicarbonate suspensions to increase previously published maximal rate the decision to prescribe either the over time, regardless of concentra- of acid production measured in a 20- or 40-mg packet size is best de- tion. While a 5-fold decrease in the pediatric population, 0.24 meq/kg/ termined by the amount of omepra- amount of water added did result hr.23 Assuming a gastric transit time zole a patient is to receive per dose. in a 10-fold increase in viscosity, the of 2.25 hours (children with GERD For pediatric patients requiring ≥14 viscosities of the most concentrated often have reduced gastrointestinal mg omeprazole per dose, the 40-mg omeprazole–sodium bicarbonate motility24) and a 13-kg patient (one- packet should be prescribed. For pa- suspensions were still comparable to year-old child at the 97th percentile tients requiring <14 mg per dose, the those of other commercially available of growth25), the extent of acid 20-mg packet should be prescribed suspensions. Therefore, concentrated exposure will be 0.24 × 13 × 2.25 = (Table 5). suspensions stored for up to a week 7 meq; therefore, 7 meq of sodium Preparation of omeprazole– are still fl uid enough to be poured or bicarbonate is necessary to neutralize sodium bicarbonate to allow multiple drawn into a syringe. this quantity of acid.
doses from a single preparation in- Homogeneous buffered suspen- At the University of Missouri volves combining several packets. At sions of PPIs prepared to concen- Hospital and Clinics, this bicarbon- the University of Missouri Hospital trations of 2 mg/mL and above are ate requirement is followed when and Clinics, children between one useful for treating acid-related dis- prescribing omeprazole–sodium bi- and two years of age who are di- orders in pediatric patients because carbonate to pediatric patients. Pedi- agnosed with acid refl ux disorders they permit ease of dose adjustment. atric patients are typically prescribed are typically prescribed omeprazole Suspensions prepared to higher PPI age-adjusted or weight-adjusted at 1 mg/kg three times a day using concentrations also permit admin- dosages of omeprazole–sodium bi- suspensions prepared to 2 mg/mL.26 istration in the smaller volumes carbonate suspensions prepared to 2 For example, a one-year-old child more readily tolerated by infants mg/mL of omeprazole.26 Because the weighing 10 kg would receive 10 mg and young children. This study dem- 20- and 40-mg omeprazole–sodium of omeprazole per dose (i.e., 5 mL onstrates that omeprazole–sodium bicarbonate packet sizes both con- of a 2-mg/mL omeprazole–sodium bicarbonate prepared to 2 mg/mL or tain 20 meq of sodium bicarbonate, bicarbonate suspension) three times higher omeprazole concentrations is a 2 mg/mL omeprazole suspension a day. To provide an amount of sus-suffi ciently stable and fl uid to allow prepared with the 20-mg packet will pension suffi cient for two days' worth a single packet to provide multiple contain 2 meq/mL sodium bicar- of dosage for that child, three 20-mg doses, resulting in potential cost and bonate, whereas one prepared with packets could be combined and water time savings for caregivers of pediat- the 40-mg packet will contain only added to a fi nal volume of 30 mL. ric patients.
1 meq/mL. Therefore, in order to The preparation can be stored in the Table 5.
Guide for Preparation of Immediate-Release Omeprazole–Sodium Bicarbonate Suspension (2 mg/mL
Omeprazole)
Packet Size
Final Volume
Water To Add
(mg/dose)
(meq/mL)
aMinimum volume per dose to provide 7 meq of sodium bicarbonate.
Am J Health-Syst Pharm—Vol 63 Nov 15, 2006 PRACTICE REPORTS Omeprazole
refrigerator between doses, and care- 2. Prevacid (lanzoprazole) package insert. 15. Shin JM, Cho YM, Sachs G. Chemistry givers should be instructed to shake Chicago, IL: TAP Pharmaceuticals; 2006 of covalent inhibition of the gastric (H+, K+)-ATPase by proton pump inhibitors. J the stored preparations before use to 3. Prilosec (omeprazole) package insert. Am Chem Soc. 2004; 126:7800-11.
ensure a uniform suspension. Wilmington, DE: AstraZeneca Pharma- 16. Phillips JO, Metzler M, Olsen K. The stabil- ceuticals LP; 2005 Jul.
ity of simplified lansoprazole suspension 4. Lorentzon P, Bayati A, Andersson K. (SLS). Gastroenterology. 1999; 116:122. Selective inhibition of the gastric H+, K+-ATPase by omeprazole and related 17. Dentinger PJ, Swenson CF, Anaizi NH. ate suspensions of 0.6–4 mg/mL compounds. Ann N Y Acad Sci. 1997; 834: Stability of pantoprazole in an extempo- raneously compounded oral liquid. Am J omeprazole were stored at 4 °C in 5. Israel DM, Hassall E. Omeprazole and Health-Syst Pharm. 2002; 59:953-6.
darkness for up to 28 days. The vis- other proton pump inhibitors: pharma- 18. Ferron GM, Ku S, Abell M et al. Oral bio- cosities of refrigerated suspensions cology, efficacy, and safety, with special availability of pantoprazole suspended reference to use in children. J Pediatr in sodium bicarbonate solution. Am J did not increase over 7 days. Except Gastroenterol Nutr. 1998; 27:568-79.
Health-Syst Pharm. 2003; 60:1324-9.
for the 0.6 mg/mL preparations, sus- 6. DiGiacinto JL, Olsen KM, Bergman K et 19. Phillips JO, Metzler MH, Palmieri TL pensions stored at room temperature al. Stability of suspension formulations et al. A prospective study of simplified of lansoprazole and omeprazole stored in omeprazole suspension for the prophy- in the light retained >90% of their amber-colored plastic oral syringes. Ann laxis of stress-related mucosal damage. initial omeprazole content after 7 Pharmacother. 2000; 34:600-5.
Crit Care Med. 1996; 24:1793-1800.
days, despite turning yellow. 7. Food and Drug Administration. 20. Sharma VK. Comparison of 24-hour Zegerid, omeprazole; sodium bicarbon- intragastric pH using four liquid formu- ate. NDA #021636. www.accessdata.
lations of lansoprazole and omeprazole. aZegerid omeprazole powder for oral sus- Am J Health-Syst Pharm. 1999; 56(suppl): pension, Santarus, San Diego, CA.
b20-mg packets, lot C4I00351; 40-mg pack- Name=ZEGERID (accessed 2005 Jul 25).
21. Omeprazole delayed-release capsules ets, lot C5A0065.
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