VOLUME 17 NUMBER 3

Current & Practical Compounding

Information for the Pharmacist
provided for by a grant from
Perrigo Pharmaceuticals
Stability Of Extemporaneously Prepared
Oral Liquid Formulations Part X
Goal: To provide information from the peer-reviewed literature on stability studies of oral liquids.
Objectives: After reading and studying the article, the reader will be able to:
1. Explain the difference between potency and stability-indicating assay methods.
2. Determine the beyond-use date of each of the ten preparations discussed.
3. Determine the appropriate storage temperature to ensure the stability of the preparations.
4. Discuss the methods of preparation of selected drugs using modified release dosage forms.

INTRODUCTION
Potency vs Stability Testing
Potency tests are designed to determine how much
of an active drug is in a sample. Stability tests are Table 1: Concentrations of the various drugs
used to determine an expiration date of a prod- in the studies reported in this paper.
uct or a beyond-use date of a preparation. Being
able to employ the proper method to determine Drug Concentration (mg/mL)
potency or stability is the key to understanding Ciprofloxacin hydrochloride 50
the difference between potency testing versus
stability testing. In order to determine potency, a Diclofenac sodium 10
method may or may not be stability-indicating. Famotidine 8
When determining stability, the method must
Gabapentin 100
be stability-indicating. When using a stability-
indicating method, both potency and stability can Itraconazole 20
be determined. Quality assurance programs are Mycophenolate mofetil 100
essential to establishing standards for compounded
preparations. It is important that compounding Ondansetron hydrochloride 0.8
pharmacists understand the differences between Oxandrolone 1
potency and stability tests and that these tests are Thalidomide 20
made an integral part of the quality assurance
program. Venlafaxine hydrochloride 15
The extemporaneous preparations presented in this
paper, many of which use commercial products,
include those listed in Table 1.

Loyd V. Allen, Jr., Ph.D., R.Ph. Quest Educational Services Inc. is on probation as an accredited provider
Professor Emeritus, University of Oklahoma College of Pharmacy of continuing pharmacy education by the Accreditation Council for
Editor in Chief, International Journal of Pharmaceutical Compounding Pharmacy Education. Next scheduled review: October 1, 2013
ACPE Number 0748-0000-13-001-H04-P (0.1CEU)
Dr. Allen is not affiliated with Perrigo Pharmaceuticals
The initial release for this lesson is 5/31/13.
This lesson is no longer valid for CE credit after 5/31/16.

Disclaimer: The content and opinions of this article are those of the author and are for educational purposes only. Although the material is based on review of multiple sources of information,
it is not all inclusive of information available. Readers should review and consider other publications and materials on this topic and not rely solely upon the information in this article.
STABILITY OF EXTEMPORANEOUS
FORMULATIONS
Ciprofloxacin hydrochloride
(C17H18FN3O3.HCl.H2O, MW 385.82) occurs as faintly
yellowish to light yellow crystals. It is sparingly soluble
in water and very slightly soluble in dehydrated alcohol.
Ciprofloxacin hydrochloride 50 mg/mL was prepared
by gradually adding equal amounts of ORA-Plus and
Simple Syrup NF to the contents of crushed 750 mg
ciprofloxacin hydrochloride tablets in a glass mortar to
final volume. Six identical suspensions were prepared
and packaged in plastic, two-ounce amber prescription
bottles with child-resistant caps; three were stored at
room temperature and three under refrigeration. The
samples were analyzed for content, color, taste, odor
and pH; microbiological testing was not performed.
Results showed no detectable change in color or odor
and no visible microbiological grown in any sample.
There was no appreciable change in pH (4.48 +/- 0.1) in
any of the samples. The results in Table 2 show that the
preparations were stable for at least 56 days in amber,
plastic prescription bottles at room or refrigerated
temperature.1,2
Table 2: Stability of ciprofloxacin hcl 50 mg/mL
in a 1:1 mixture of ORA-Plus and Syrup NF
stored at both room and refrigerated temperatures.
% of Initial Concentration Remaining
Storage
Temp Day 0 Day 7 Day 14 Day 28 Day 56
23-25 C 51.6 (1.3)a 100.0 (3.0) 99.8 (1.0) 100.4 (3.4)
3-5 C 50.9 (2.0)a 99.9 (2.6) 99.8 (3.0) 99.4 (3.4)
a Mean (S.D.) initial concentration (mg/mL)
Diclofenac sodium
(C14H10C12NNaO2, MW 318.13) occurs as a white to
off-white, hygroscopic crystalline powder. It melts
about 284 C and is sparingly soluble in water. Diclof-
enac sodium 10 mg/mL was prepared from commer-
cially available diclofenac sodium enteric coated
tablets. The tablets were ground to a powder and then
combined with ORA-Blend to create a 10 mg/mL
suspension. The suspension was placed in 60 mL
amber PVC prescription bottles and stored at either 5
C or at 23 C for 93 days; all bottles were protected
from light. The pH of the suspensions did not change
more than 0.07 units during storage and remained at
about pH 6.0 (6.04 to 6.11) for the duration of the study.
All suspensions were deemed stable for at least 93 days
using both storage conditions, as shown in Table 3.1,3
Table 3: Stability of diclofenac sodium 10 mg/mL
suspension in ORA-Blend.
% of Initial Concentration Remaining
Storage
Temp Day 0 Day 14 Day 27 Day 56 Day 93
23-25 C 9.0 (0.28)a 101.2 (1.1) 102.6 (0.9) 100.6 (1.2) 101.2 (0.9)
3-5 C 8.9 (0.13)a 99.5 (1.4) 99.8 (1.8) 105.4 (1.7) 99.8 (1.1)
a Mean (S.D.) initial concentration (mg/mL)
Famotidine
(C8H15N7O2 S3, MW 337.43) occurs as a white to pale
yellowish-white, crystalline powder. It is sensitive to
light and very slightly soluble in water. Famotidine 8
mg/mL suspension was prepared using famotidine
tablets in equal volumes of ORA-Plus and ORA-Sweet.
Samples were packaged in 2 ounce amber polyethylene
terephthalate bottles with child-resistant caps at room
temperature for up to 95 days. The pH of the suspensions
was 5.8 initially and remained unchanged throughout
the study; there was no detectable change in color or
odor and no visible microbial growth in any sample.
The suspension retained more than 90% of its initial
famotidine concentrations for 95 days at 23-25 C.1,4
Gabapentin
(C9H17NO2, MW 171.24) occurs as a white to off-white
crystalline solid that is freely soluble in water at both
alkaline and acidic pH. Gabapentin 100 mg/mL oral
suspensions were prepared using gabapentin capsules.
100.5 (3.5)
Two vehicles were prepared; one in 1% methylcellulose
99.6 (2.8)
in syrup (1:1) and another in equal volumes of ORA-
Plus:ORA-Sweet. The suspensions were stored in two
ounce plastic prescription bottles and stored at either
4 or 25 C for up to 91 days after preparation. Results,
as shown in Table 4, demonstrated that gabapentin
100 mg/mL was stable in ORA-Plus and ORA-Sweet
1:1 for at least 56 days at 25 C and 91 days at 4 C.
There were no substantial changes in pH, physical
appearance, or odor during the 91 day study period.1,5
Table 4: Stability of gabapentin 100 mg/mL in
ORA-Plus:ORA-Sweet.
% of Initial Concentration Remaining
Storage
Temp Day 0 Day 14 Day 28 Day 56 Day 91
23-25 C 102.21 (1.93)a 99.03 (1.89) 97.17 (2.03) 93.81 (3.19) 91.32 (3.37)
3-5 C 102.96 (1.67)a 99.93 (1.98) 98.07 (2.07) 97.04 (2.11) 95.02 (2.73)
a Mean (S.D.) initial concentration (mg/mL)
pH 5.58 (0.005) room temperature; pH 5.48 (0.008) refrigerated temperature
Stability of Extemporaneously Prepared Page 2
Oral Liquid Formulations Part X
Itraconazole
(C35H38C12N8O4, MW 705.63) occurs as a white or
almost white powder that is practically insoluble in Table 6: Stability of ondansetron hcl 0.8 mg/mL in
water. Itraconazole 20 mg/mL suspension was pre- ORA-Plus:ORA-Sweet or ORA-Plus:ORA-Sweet SF
pared from the capsules in a 1:1 mixture of ORA-Sweet stored at 4 C.
and ORA-Plus. The suspension was packaged in two
% of Initial Concentration Remaining
ounce amber plastic prescription bottles and stored
at either 25 or 4 C and sampled for up to 91 days. Day 0 Day 10 Day 21 Day 35 Day 42
Results showed no appreciable changes in color, odor ORA-Plus:ORA-Sweet
or pH (5.23). Itraconazole was stable for up to 56 days 0.896 (0.026)a 102.9 (4.9) 98.1 (6.7) 96.5 (2.9) 101.4 (7.3)
at both storage conditions, as shown in Table 5.1,6 ORA-Plus:ORA-Sweet SF
0.808 (0.024)a 101.6 (2.2) 100.5 (3.6) 99.5 (2.3) 97.1 (4.9)
Table 5: Stability of itraconazole 20 mg/mL in a Mean (S.D.) initial concentration (mg/mL)
1:1 ORA-Sweet and ORA-Plus.

Storage
% of Initial Concentration Remaining Oxandrolone
Temp Day 0 Day 7 Day 28 Day 56 Day 91 (C19H30O3, MW 306.44) occurs as a white, odorless,
crystalline powder that is stable in air but darkens on
23-25 C 16 (0.85)a 104.6 (1.5) 95.3 (2.7) 91.9 (1.6) 85.9 (1.5) exposure to light. It melts at about 225 C and is spar-
3-5 C 15.9 (0.86)a 93.7 (4.0) 93.7 (3.7) 95.0 (2.9) 89.8 (2.8)
ingly soluble in alcohol and practically insoluble in
a Mean (S.D.) initial concentration (mg/mL)
water. Oxandrolone 1 mg/mL oral suspension was
prepared using oxandrolone tablets and 1:1 ORA-Plus:
ORA-Sweet or ORA-Plus:ORA-Sweet SF. The preparation
Mycophenolate mofetil was packaged in 2 ounce amber plastic bottles at room
(C23H31NO7, MW 433.49) occurs as a white to off- temperature and sampled up to 90 days. At least 98%
white crystalline powder. It is soluble, 43 g/mL in of the original oxandrolone concentration was retained
water at pH 7.4 and 4.27 mg/mL at pH 3.6. Mycophe- at the end of the 90 day study period as shown in
nolate mofetil 100 mg/mL was prepared using the Table 7; there was no appreciable change in odor, taste,
capsules and a vehicle of ORA-Plus with artificial cherry color or pH (4.35 and 4.31 for the ORA-Plus:ORA-
flavoring, FD&C Red No. 40 and aspartame. At room Sweet and ORA-Plus:ORA-Sweet SF, respectively).1,9
temperature, the cherry flavor often disappeared on
storage leaving a strong musty odor; the authors Table 7: Stability of oxandrolone in ORA-Plus:
recommended the preparation be stored at refriger- ORA-Sweet and ORA-Plus:ORA-Sweet SF
ated temperature to retain the cherry flavor. The pH stored at 23-25 C.
(5.9) remained unchanged throughout the study. The
initial concentration was 96.8 (1.9) mg/mL. After 30 % of Initial Concentration Remaining
days, the percent remaining was 103.8 (1.5) and after Day 0 Day 7 Day 35 Day 60 Day 90
120 days, was 100.3 (1.7).1,7
ORA-Plus:ORA-Sweet
1.01 (0.02)a 100.18 (1.61) 100.97 (1.43) 100.05 (1.65) 98.17 (1.75)
Ondansetron hydrochloride
ORA-Plus:ORA-Sweet SF
(C18H19N3O.HCl.2H20, MW 365.85) occurs as a white
0.99 (0.02)a 100.46 (0.88) 100.44 (1.22) 99.73 (1.62) 98.96 (2.21)
to off-white powder that is sparingly soluble in water
a Mean (S.D.) initial concentration (mg/mL)
and in alcohol. Ondansetron hydrochloride 0.8 mg/mL
was prepared from the tablets in a 1:1 mixture of either
ORA-Plus:ORA-Sweet or ORA-Plus:ORA-Sweet SF.
The preparations were packaged in amber plastic vials
and stored at 4 C for up to 42 days. Results showed
that all the ORA-Plus:ORA-Sweet and ORA-Plus:
ORA-Sweet SF preparations remained greater than
90% of the initial concentration throughout the 42 day
study period, as shown in Table 6. The pH of these
preparations was 4.1.1,8

Stability of Extemporaneously Prepared Page 3

Oral Liquid Formulations Part X
Thalidomide
(C13H10N2O4, MW 258.23) occurs as a white to
off-white powder that is sparingly soluble in water.
Thalidomide 20 mg/mL suspension was prepared
using the capsules and ORA-Plus:ORA-Sweet 1:1.
The preparation was placed in 2 ounce amber plastic
bottles with child-resistant caps and stored in a refrig-
erator. Samples were withdrawn and analyzed for up
to 35 days. At least 92% of the initial concentration was
retained throughout the 35 day study period as
shown in Table 8 with no detectable changes in color,
odor or pH (4.32) and no visible microbial growth in a
sample.1,10
Table 8: Stability of thalidomide 20 mg/mL in
ORA-Plus:ORA-Sweet stored at 4 C.
% of Initial Concentration Remaining
Day 0 Day 7 Day 14 Day 21
20.00 (0.08)a 100.03 (0.84) 100.41 (1.38) 99.75 (1.82)
a Mean (S.D.) initial concentration (mg/mL)
Venlafaxine hydrochloride
(C17H27NO2.HCl, MW 313.86) occurs as a white to
off-white crystalline powder that is soluble in water.
Venlafaxine 15 mg/mL was prepared from extended-
release microspheres that were reduced to a powder
and suspended in ORA-Plus:ORA-Sweet 1:1. Samples
were placed in 120 mL plastic, amber oral liquid bottles
and stored at either room or refrigerated temperatures
for up to 28 days. As shown in Table 9, there was no loss
of venlafaxine over the duration of the study period.
There was no change in color and only a slight change
in pH from 6.21 to 6.03.1,11
Table 9: Stability of venlafaxine hcl 15 mg/mL in
ORA-Plus:ORA-Sweet 1:1.
% of Initial Concentration Remaining
Storage
Temp Day 0 Day 7 Day 14 Day 21 Day 28
23 C 12.4 (0.46)a 97.1 (2.5) 99.6 (2.3) 101.8 (1.1)
5 C 12.2 (0.22)a 101.8 (0.9) 97.9 (2.0) 101.5 (1.4)
a Mean (S.D.) initial concentration (mg/mL)
REFERENCES
1. USP Pharmacopeia, 35/National Formulary 30.,
U.S. Pharmacopeial Convention, Inc., Rockville MD,
2012, pp 344-350, 1110, 1114, 1118, 1119, 1125, 1131,
1133, 1149, 1152.
2. Johnson CE et al. Stability of ciprofloxacin in an
extemporaneous oral liquid dosage form.
IJPC 1998;2(4):314-317.
3. Donnelly RF et al. Stability of diclofenac sodium
oral suspensions packaged in amber polyvinyl
chloride bottles. Can J Hosp Pharm.
2010;63(1):25-30.
4. Dentinger PJ, Swenson CF, Anaizi NH.
Stability of famotidine in an extemporaneously
compounded oral liquid. Am J Health-Syst
Pharm. 2000;57:1340-2.
Day 35 5. Nahata MC. Development of two stable oral
suspensions for gabapentin. Pediatr Neurol.
93.38 (0.74)
1999;20(3):195-197.
6. Abdel-Rahman SM, Nahata MC. Stability of
itraconazole in an extemporaneous suspension.
J Ped Pharm Prac. 1998;3(2):115-118.
7. Swenson CF, Dentinger PJ, Anaizi NH. Stability
of mycophenolate mofetil in an extemporaneously
compounded sugar-free oral liquid.
Am J Health-Syst Pharm. 1999;56:2224-6.
8. Williams CL et al. Stability of ondansetron
hydrochloride in syrups compounded from tablets.
Am J Hosp Pharm. 1994;51:806-9.
9. Johnson CE et al. Stability of extemporaneously
prepared oxandrolone oral suspensions.
Am J Health-Syst Pharm. 2011;68:519-21.
10. Kraft S, Johnson CE, Tyler RP. Stability of an
extemporaneously prepared thalidomide suspension.
Am J Health-Syst Pharm. 2012;69:56-8.
11. Donnelly RF et al. Stability of venlafaxine
immediate-release suspensions.
IJPC 2011;15(1):81-84.
99.9 (0.8)
100.5 (1.4)
Stability of Extemporaneously Prepared Page 4
Oral Liquid Formulations Part X
Send this completed form in for CE credit today!
Please circle the most appropriate answer for each of the following questions. There is only ONE correct answer per question.
1. Potency tests are designed to: 7. Using commercial products as the drug source may result in a
I. Determine how much of an active drug is in a sample compounded preparation inadvertently being outside the 90.0-110.0%
II. Estimate the beyond-use date of a preparation requirement for the active drug. This is due to allowable variations in
III. Determine the presence of degraded substances commercial drug products. Which of the following preparations was
outside the allowable limits at the initial time-zero period at any
A. I only D. II and III only temperature of these three?
B. III only E. I, II and III
C. I and II only I. Mycophenolate mofetil
II. Ondansetron hydrochloride
2. Stability tests are used to: III. Venlafaxine hydrochloride
I. Determine how much of an active drug is in a sample A. I only D. II and III only
II. Help determine an expiration date B. III only E. I, II and III
III. Help determine a beyond-use date C. I and II only
A. I only D. II and III only
B. III only E. I, II and III 8. Which preparation demonstrated a change in taste during the study at
C. I and II only room temperature?
A. Diclofenac sodium D. Mycophenolate mofetil
3. Which of the following preparations were compounded using modified B. Gabapentin E. Ondansetron hydrochloride
release dosage forms? C. Itraconazole
I. Diclofenac sodium
II. Venlafaxine hydrochloride 9. Which drug had the largest deviation at the final sampling point for 25 C
III. Thalidomide for these five preparations?
A. I only D. II and III only A. Ciprofloxacin hydrochloride D. Oxandrolone
B. III only E. I, II and III B. Diclofenac sodium E. Venlafaxine hydrochloride
C. I and II only C. Gabapentin
4. Which of the following presented data justifying the longest beyond-use 10. Which drug had the largest deviation at the final sampling point for 5 C
date, regardless of temperature? for these five preparations?
A. Ciprofloxacin hydrochloride D. Oxandrolone A. Diclofenac sodium D. Ondansetron hydrochloride
B. Diclofenac sodium E. Venlafaxine hydrochloride B. Gabapentin E. Thalidomide
C. Mycophenolate mofetil C. Itraconazole
5. Which preparation had the highest initial pH in the studies? 11. The quality of the information presented in this article was:
A. Ciprofloxacin hydrochloride D. Ondansetron hydrochloride A. Excellent B. Good C. Fair D. Poor
B. Famotidine E. Venlafaxine hydrochloride
C. Gabapentin 12. Did the ACPE activity meet the participants educational needs?
6. Using commercial products as the drug source may result in a A. Yes B. No
compounded preparation inadvertently being outside the 90.0-110.0%
requirement for the active drug. This is due to allowable variations in 13. Approximately how long did it take you to read the Secundum Artem article
commercial drug products. Which of the following preparations was AND respond to the test questions?
outside the allowable limits at the initial time-zero period at any 14. What topics would you like to see in future issues of Secundum Artem?
temperature of these three?
I. Ciprofloxacin hydrochloride
II. Diclofenac sodium 15. Were the objectives of the article met? If not, please describe.
III. Itraconazole
A. I only D. II and III only
B. III only E. I, II and III
C. I and II only

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