9

INTERNATIONAL JOURNAL OF RESEARCH ARTICLE
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031

81 | P a g e
Volume 3, Issue 5, September October 2013 http://www.ijpi.org

Formulation Development & Optimization of Reconstitution
Solvent for Lyophilized Omeprazole Injection
1
Patel Mitesh*, Patel Amit
2

1
Department of Pharmaceutical Science, JJT University, Jhunjhunu, Rajasthan
2
B M Shah College of Pharmaceutical Education and Research, Modasa, Gujarat

ABSTRACT
For development of Lyophilized injection Omeprazole sodium salt used as active ingredients,
Edetate disodium used as chelating agent, Sodium hydroxide for pH adjustment were used
with water for injection as aqueous vehicle into 10 ml tubular glass vials with half bunging.
The filled vials were loaded into Lyophilizer and lyophilized them as per standard cycle and
for development of Solvent for reconstitution, propylene glycol used as Solubilizer as well as
vehicle for reconstitution, Citric acid monohydrate as buffer, Sodium hydroxide for pH
adjustment and water for injection as aqueous vehicle into 10ml Clear glass ampoules.
Different concentration of additives was used and different pH concentrations of 3.5, 4.0, 4.5
and 5.0 were adjusted with 1.0 N Sodium hydroxide solution were tried to formulate the
Solvent for reconstitution. The objective of this experiment is to formulate the Reconstitution
Solvent for Lyophilized Omeprazole injection for same solvent used for intravenous bolos as
well as intravenous infusion administration and better stability of formulation. Description,
pH, Particulate matter and Refractive index were checked according to Pharmacopoeial
method. The formulation F (7) was one of the well optimized Compositions; it was used for
reconstitution stability. The obtained results suggested that a stable formulation of Propylene
Glycol 40% w/v based Solvent was developed.
Keywords: Parenteral, Lyophilization, Propylene Glycol, Citric acid monohydrate,
Omeprazole sodium

INTRODUCTION
Proton pump inhibitors (PPIs), such as
Omeprazole, lansoprazole and rabeprazole,
are considered to have stronger gastric
acid-suppressive effects than histamine H2
receptor antagonists
[14]
, and are widely
used in initial and maintenance therapy for
gastro-oesophageal reflux disease
(GERD).Recently, it has been found that
cytochrome P450 2C19(CYP2C19), which
is a major enzyme involved in PPI
metabolism
[5]
, has three hereditary
genotypes: homozy-gous extensive
metabolisers with higher enzymatic
activity, heterozygous extensive
metabolisers with moderate enzymatic
activity and poor metabolisers with
markedly impaired enzyme activity
[69]
.
Therefore, a subjects CYP2C19genotype

*Corresponding Author
Patel Mitesh

82 | P a g e
affects the acid-suppressive effects of
PPIs, and differences in its effects among
the three genotypic groups are significant
[1015]
. As a result, the acid-suppressive
effect of PPIs should be studied in relation
to CYP2C19 genotype status.
In Japan, as well as in many other
countries, in an effort to reduce medical
expenditure, the authorities have recently
been promoting the use of generic drugs
which contain the same active ingredients
as the original products, and this may
involve verifying the stability, quality and
effects of the generic drugs. However, in
terms of volume of all prescriptions,
generic products accounted for only 11%
in Japan, but54% in the United States,
52% in the United Kingdom and54% in
Germany in 2001
[16]
.Since 2004, an
increasing number of generic Omeprazole
containing products have been in the
market in Japan.
[1719]

Omeprazole is a substituted benzimidazole
that selectively inhibits the gastric proton
pump of the parietal cells. It is used for the
treatment of peptic ulcers, reflux
esophagitis and the Zollinger-Ellison
syndrome. In some cases an intravenous
omeprazole formulation is needed,
especially for the treatment of patients in
intensive care. Normally these patients
receive a freshly prepared aqueous
omeprazole solution via perfusion. Due to
their chemical instability, available
formulations should be used within 6 h.
Omeprazole is a lipophilic, weak base with
pKa1 4.2 andpKa2 9.0; it is chemo-
and thermo labile and rapidly degraded
and discolored when exposed to acidic
media and warm temperature
[20]
. The free
base is only poorly soluble in water (82.3
mg/l)
[21]
.

Omeprazole, 5-methoxy-2-h [(4-methoxy-
3,5-dimethyl-2- pyridinyl)
lmethyl]sulphinylj-1H-benzimidazole (Fig.
1), is a proton pump inhibitor in the gastric
parietal cells, effectively suppressing the
gastric acid secretion
22-24
. Omeprazole, due
to its mode of action may be considered as
a pro-drug. Omeprazole is converted into
its sulphonamide form by protonation but
the drug is very unstable below pH 6.5 and
is inactivated by gastric acid. It is in the
active protonated form that the drug
produces an irreversible linkage bond with
the H /K ATPase enzyme, also known as
the proton pump
22
.

Lyophilization (freeze-drying) is often
used to prepare dry pharmaceutical
formulations to achieve commercially
viable shelf lives. The process comprises
three steps: freezing, primary drying, and
secondary drying. As water freezes in the
first step, the dissolved components in the
formulation remain in the residual liquid, a
phase termed the freeze-concentrate. At
the point of maximal ice formation, the
freeze concentrate solidifies between the
ice crystals that make up the lattice. Under
appropriate Lyophilization conditions, the
ice is removed by sublimation during
primary drying, leaving the remaining
freeze-concentrate in the same physical

83 | P a g e
and chemical structure as when the ice was
present. Residual water in the freeze-
concentrate is removed in the secondary
drying step.

Lyophilization cycle development
typically focuses on optimizing the
primary drying step. That is the most time
consuming of the three steps, and the
primary drying parameters are easily
adjustable. They can affect both the time
involved and the quality of the resulting
cake. Extensive investigation of primary
drying has demonstrated that two
important parameters are chamber pressure
and shelf temperature
[25-33]
.They are
usually adjusted to maximize the rate of
heat transfer to each vial (speeding ice
sublimation) without causing cake
collapse. Less attention has been paid to
the freezing conditions and their potential
effect on the primary and secondary drying
processes and on the characteristics of the
final product. Kochs et al. reported the
effects of freezing conditions on primary
drying in a specially designed aluminium
and plastic sample cell
[34]
. They observed
variations in vapour diffusion coefficients
(a measure of the ease of water-vapor
flow) as a function of position and cooling
rate. The variations appeared to be largely
due to variations in sample morphology.
Searles et al. reported some effects of
freezing on the rate of primary drying in
vials
[35]
.

MATERIALS AND METHODS
MATERIALS
Omeprazole Sodium is an active
ingredient, Edetate disodium as Chelating
agent, Sodium hydroxide for pH
adjustment, water for injection as a vehicle
for solubility were used for Lyophilized
formulation and for Solvent preparation
Propylene glycol as Solubilizern as well as
vehicle for reconstitution, Citric acid
monohydrate as buffer, Sodium hydroxide
for pH adjustment and water for injection
as a vehicle were used for formulation.
Active ingredient was procured from Gufic
Biosciences Ltd. and all other ingredients
used were AR grade.
EQUIPMENTS
Lyophilizer 20 Kg- Lyodrier 3S,
Lyophilization system India Pvt. Ltd.
HPLC Series 1200, Agilent
UV-visible spectrophotometer- UV 1601
PC, Shimadzu, Japan
Vial Filling Machine- Single Head,
Ambica Industries
Ampule Filling Machine- Single Head,
Ambica Industries
Weighing balance- Model FB-200 of
EssaeTeraoka Ltd
PH Meter-CL46+, Toshcon industries
Pvt.Ltd
Refractometer-Rajdhani
Stirrer-RQ-124, Remi motors

METHODOLOGY:
Formulation of Lyophilized Omeprazole
Injection
Standard formulation of Omeprazole
Injection has been used for the experiment
which was placed in table-1. 600 ml WFI
was collected in a beaker, weighed
quantity of Edetate disodium was added
and dissolved by stirring until a clear
solution was formed. Then Omeprazole
Sodium was weighed and transferred to the
above solution and dissolved by stirring
for minimum duration of 5 min below

84 | P a g e
25C. The pH of the solution was checked
and adjusted the pH with 1 N Sodium
Hydroxide solution slowly below 25C.
The solution was diluted and made up to
750 ml, by WFI below 25C&pH was
checked. The final solution was filtered by
using 0.22m membrane filter. The
solution was filled into 10ml tubular vials
(20 mm neck) and half bunging the vials
with 20 mm grey bromobutyl full slotted
rubber stopper. The filled vials were
loaded into lyophilizer and lyophilized
them as per standard cycle. After
completion of Lyophilization cycle,
stoppering the vials without breakage of
vacuum using hydraulic system. Now
break the vacuum of the plant with help of
the sterile nitrogen. Unload the vials for
sealing and seal the vials. Temperature of
room should be below 25
o
C and humidity
below 40%.

Table 1: Formulation of Lyophilized Omeprazole injection

Batch No Ingredients Quantity Per
vial
Quantity per 300 vials
Standard
Batch
Omeprazole Sodium
equivalent to Omeprazole
(5% Overages)
40 mg 14.7 gm*
Edetate disodium 1 mg 300 mg
Sodium Hydroxide
(For pH adjustment)
Q.S Q.S
Water for Injection Q.S to 2.5 ml Q.S to 750 ml

*Quantity of Omeprazole calculated on water content and assay.

Formulation of Solvent for Lyophilized
Omeprazole Injection
Different composition and concentration of
additives has been used for the experiment
which was placed in table-2. 1500 ml WFI
of was collected in a S.S vessel, weighed
quantity of Propylene glycol was added
and mixed by stirring until a clear solution
was formed. Stirring for minimum
duration of 10 min below 25C. Dissolve
weighed quantity of citric acid
Monohydrate in separate beaker containing
100 ml Water for Injection. Transfer citric
acid solution in Propylene glycol solution.
Starrierd until a clear solution was formed
at below 25C for 10 min. The pH of the
solution was checked and adjusted the pH
with 1 N Sodium Hydroxide solution
slowly below 25C. The solution was
diluted and made up to 3.0 Litre, by WFI
below 25C &pH was checked. The final
solution was filtered by using 0.22m
membrane filter. The solution was filled
into 10ml Clear glass Ampoules and seal.
Temperature of room should be below
25
o
C and humidity below 40%


85 | P a g e
Table2: Formulation of Solvent for Lyophilized Omeprazole injection of Various
Batches
Batch
No .
Propylene Glycol

Citric acid
Monohydrate
1 N Sodium
Hydroxide solution
Water for injection
Gm/
Ampoule
Qty./3.0
litre
Mg/
Ampoule
Qty./3.0
litre
Mg/
Ampoule
Qty./3.0
litre
ml/
Ampoule
Qty./3.0
litre
F1 3.0 900 gm 5 1.5 gm q.s. to
pH 3.5
q.s. to
pH 3.5
q.s. to
10
q.s. to
3.0 litre
F2 3.0 900 gm 5 1.5 gm q.s. to
pH 4.0
q.s. to
pH 4.0
q.s. to
10
q.s. to
3.0 litre
F3 3.0 900 gm 5 1.5 gm q.s. to
pH 4.5
q.s. to
pH 4.5
q.s. to
10
q.s. to
3.0 litre
F4 3.0 900 gm 5 1.5 gm q.s. to
pH 5.0
q.s. to
pH 5.0
q.s. to
10
q.s. to
3.0 litre
F5 4.0 1200 gm 5 1.5 gm q.s. to
pH 3.5
q.s. to
pH 3.5
q.s. to
10
q.s. to
3.0 litre
F6 4.0 1200 gm 5 1.5 gm q.s. to
pH 4.0
q.s. to
pH 4.0
q.s. to
10
q.s. to
3.0 litre
F7 4.0 1200 gm 5 1.5 gm q.s. to
pH 4.5
q.s. to
pH 4.5
q.s. to
10
q.s. to
3.0 litre
F8 4.0 1200 gm 5 1.5 gm q.s. to
pH 5.0
q.s. to
pH 5.0
q.s. to
10
q.s. to
3.0 litre

Freeze drying procedure:
Standard freeze drying process was taken
for the formulation development of
omeprazole Lyophilized injection. Freeze
drying cycle includes freezing of the
product under the lyophilizer at -28C for
two hours. Then Primary drying at -25C
for seven hours along with vacuum 100 to
150 mtor & then at -10C for twelve hours
along with vacuum 100 to 150 mtor, then
+10C for five hours along with vacuum
100 to 150 mtor. Secondary drying was
carried out at +30C for 2 hours along with
vacuum 10 to 50 mtor.
Method of Analysis:
HPLC analysis was carried out with a
column 4.6 mm x 25 cm column that
contains packing C18, 5 micron, flow rate
was 1.0ml/min, detector was UV detector

at 280 nm and injection volume was 20l,
with the runtime of 8min.
Mobile phase: Prepare a filtered and
degassed mixture of acetronitrile and
buffer in the ratio of 50: 45. Do not filter
mobile phase after mixing.
Buffer: Dissolve 2.725 g of potassium
dihydrogen orthophosphate and 0.525 g of
Dipotassium hydrogen orthophosphate in
1000 ml of distilled water. Adjust pH to
7.0 with 1 N potassium hydroxide
solution. Filter and degassed.
Standard preparation: Weigh accurately
about 40 mg of Omeprazole working
standard into a 50 ml volumetric flask.
Add sufficient amount of diluents
(methanol: acetonitrile 1:1). Sonicate to
dissolve, cool at ambient temperature and

86 | P a g e
dilute up to the mark with same. Further
dilute 5 ml from this to 20 ml with water.
Sample preparation: Reconstitute the
sample of 5Lyophilized vials. Each vial
reconstituted with 10 ml propylene glycol
solvent. Mix all the reconstituted solution
in 1000 ml volumetric flask. Add
sufficient amount of distilled water.
Sonicate in cold water for 5-7 minutes and
dilute up to the mark to 1000 ml with
distilled water.
(If necessary make adjustment in the
mobile phase)
Procedure: Separately inject equal volumes
(20 l) of the blank, standard and sample
preparation into the chromatograph.
Record the chromatograms and measure
the responses for the major peaks. The
relative standard deviation of 5 replicate
injections of standard preparation should
not be more than 2.0%. Limit for assay is
within 90.0% to 110.0%.
Analysis for Propylene glycol solvent:
Description, pH, Particulate matter and
Refractive index was checked according to
Pharmacopeia method.
Stability studies:
Accelerated stability study as well as
Reconstituted stability study were
conducted for the standard batch of
Omeprazole and Optimized batch of
solvent under various temperature and
humidity conditions. The water content,
assay and pH were determined and
compared with marketed formulation.

RESULTS AND DISCUSSION
Standard process for Lyophilization of
Omeprazole Injection was taken for
standard batch of Omeprazole injection as
given under table no 1. The moisture
content of the lyophilized vial was within
the acceptance limit (Max. 6.0%) and the
formation of good cake was observed in
the vials.
Date:
Table 3: Observation of Omeprazole lyophilized Injection

For optimization of formulation of solvent,
batches (F1-F8) were planned to observe
the effect of pH by adjusting with 1 N
Sodium Hydroxide solution and different
concentration of Propylene glycol,
obtained results were summarized in table-
4. Description, pH, Particulate matter and
Refractive index were checked according
to Pharmacopoeial method.

Batch No Description of cake Water content Assay
Standard Batch White lyophilized cake 4.23% 104.17%

87 | P a g e
Table 4: Observation of reconstitution solvent for Omeprazole lyophilized injection

The optimization of solvent was finalized
based on reconstitution study with
lyophilized Omeprazole injection 40 mg.
The acceptance limit for pH of
reconstituted solution of Omeprazole
injection is 8.8 to 9.2 and the assay limit is
90.0% to 110.0%.

Table 5: Observation of Reconstituted Omeprazole Injection

Based on reconstitution study, F7 batch
has shown clear colourless solution
without any sign of turbidity & its pH &
assay were within limits.
The accelerated stability study was
conducted for the optimized batch of
solvent (F7) with standard batch of
Omeprazole for 6 months at 40C
2C/75% RH 5% RH. The results were
depicted in Table-6& 7.
The reconstituted lyophilization
omeprazole injection stability for 12 hours
at 25C for I.V. Bolus administration and
12 hour at 25C for I.V Infusion
administration. The results have been
depicted in Table-8& 9 respectively.

Batch No Description of Solution pH Particulate matter Refractive Index
F1 Clear, colourless solution 3.49 Complies as per IP 1.385
Batch No Batch No of
Solvent usedfor
Reconstitution
Description of Reconstituted
solution
pH Assay
Standard
batch
F1 Slightly turbid solution 8.50 -
F3 Clear, yellowish solution 8.83 99.68%
F4 Slightly turbid yellowish solution 9.42 -
F7 Clear, colourless solution 8.90 104.12%
F8 Slightly turbid yellowish solution 9.51 -

88 | P a g e
Table6: Evaluation of Reconstitution solvent for lyophilized Omeprazole injection 40
mg by Accelerated study

Table 7: Evaluation of lyophilized Omeprazole injection 40 mg by Accelerated study

Table 8: Evaluation of Reconstituted lyophilized Omeprazole injection 40 mg by
optimized solvent stability at 25C. (For I.V Bolus administration)

The acceptance limit for pH of reconstituted solution of Omeprazole injection is 8.8 to 9.2
and the assay limit is 90.0% to 110.0% and total impurities not more than 3.0%

Batch
No
Description of
Solution
pH Particulate matter Refractive Index
3 Months 6 Months 3
Months
6
Months
3 Months 6 Months 3
Months
6
Months
F7 Clear,
colourless
solution
Clear,
colourless
solution
4.51 4.50 Complies
as per IP
Complies
as per IP
1.384 1.384
Batch No Description of cake Water content Assay
3 Months 6 Months 3
Months
6
Months
3 Months 6 Months
Standard
batch
White
lyophilized
cake
White
lyophilized
cake
4.59% 5.37% 103.12% 101.39%
Batch No
of
lyphillized
Omeprazole
Injection
Batch No of
Solvent used
for
Reconstitution
Time
period
Description of
Reconstituted
solution
pH Assay Total
Impurities
Standard
batch
F7
Initial Clear, colourless
solution
8.90 104.12% 1.89%
8 Hours Clear, colourless
solution
8.94 103.49% 2.41%
12
Hours
Clear, Light
yellowish solution
9.02 100.64% 2.83%

89 | P a g e
Table 9: Evaluation of lyophilized Omeprazole injection 40 mg by reconstitution
solution stability at 25C. (For I.V Infusion)

The acceptance limit for pH of
reconstituted solution of Omeprazole
injection in infusion solvent is 9.3 to 10.3
and the assay limit is 90.0% to 110.0% and
total impurities not more than 3.0%
Finally based on stability studies, batch F7
was considered as optimized batch of
reconstitution solvent for Lyophilized
Omeprazole Injection.

CONCLUSION
Current Marketed formulation of
Omeprazole for injection available in two
different formulations like Losec 40 mg
powder with suitable solvent which is used
only for Intravenous Bolous route and
Losec 40 mg powder which is used only
for intravenous infusion route. Therefore,
it was developed same reconstitution
solvent used for both intravenous bolous
as well as intravenous infusion
administration and gives better stability of
formulation. As well as, Lyophilized
Omeprazole Injection 40 mg and solvent
Propylene Glycol 40% w/v was
compatible with 10mL clear glass USP
Type I vial and Grey bromobutyl rubber
closure. The formulation was stable for 6
months on accelerated stability studies and
reconstituted formulation was stable for 12
hours at 25C. In conclusion a stable
formulation batch no F7 of reconstitution
solvent Propylene glycol 40 % w/v for
Lyophilized Omeprazole Injection was
developed& which is suitable both
Intravenous bolus & infusion
administration.
ACKNOWLEDGEMENT
We thank Gufic Biosciences Ltd for
material donation. We thank Dr. Amit for
valuable guidance and suggestions on the
manuscript.
REFERENCE
1. Hallerback B, Unge P, Carling L,
Edwin B, Glise H, Havu N, et
al.Omeprazole or ranitidine in
long-term treatment of reflux
esophagitis.Gastroenterology
1994;107:130511.
2. Sontag SJ, Kogut DG, Fleischmann
R, Campbell DR, RichterJ, Haber
M. Lansoprazole prevents
recurrence of erosive
refluxesophagitis previously
Reconstituted
vial
Infusion
solvent
Time
period
Description of
Reconstituted
solution
pH Assay Total
Impurities
Lyophilized
Omeprazole
vial with 10
ml Propylene
glycol
solvent
100 ml saline
Initial Clear, colourless
solution
9.87 104.57% 1.63%
solution
9.95 103.51% 2.17%
solution
9.98 103.11% 2.68%

90 | P a g e
resistant to H2-RA therapy. The
LansoprazoleMaintenance Study
Group. Am J Gastroenterol
1996;91:175865.
3. Gough AL, Long RG, Cooper BT,
Fosters CS, Garrett AD,
LangworthyCH. Lansoprazole
versus ranitidine in the
maintenance treatmentof reflux
oesophagitis. Aliment Pharmacol
Ther 1996; 10:52939.
4. Harris RA, Kuppermann M,
Richter JE. Proton pump inhibitors
orhistamine-2 receptor antagonists
for the prevention of recurrencesof
erosive reflux esophagitis: a cost-
effectiveness analysis. Am
JGastroenterol 997;92:217987.
5. Andersson T, Miners JO, Veronese
ME, Tassaneeyakul W,
TassaneeyakulW, Meyer UA, et al.
Identification of human
livercytochrome P450 isoforms
mediating omeprazole metabolism.
BrJ Clin Pharmacol 1993;36:521
30.
6. Chang M, Dahl ML, Tybring G,
Gotharson E, Bertilsson L. Use
ofomeprazole as a probe drug for
CYP2C19 phenotype in
SwedishCaucasians: comparison
with S-mephenytoin hydroxylation
phenotypeand CYP2C19 genotype.
Pharmacogenetics 1995;5:35863.
7. Chang M, Tybring G, Dahl ML,
Gotharson E, Sagar M, SeensaluR,
et al. Interphenotype differences in
disposition and effect on
gastrinlevels of omeprazole
suitability of omeprazole as a probe
forCYP2C19. Br J Clin Pharmacol
1995;39:5118.
8. Kubota T, Chiba K, Ishizaki T.
Genotyping of S-mephenytoin 4_-
hydroxylation in an extended
Japanese population. Clin
PharmacolTher 1996;60:6616.
9. Ishizaki T, Horai Y. Cytochrome
P450 and the metabolism of
protonpump inhibitorsemphasis
on rabeprazole. Aliment Pharmacol
Ther1999;13(Suppl. 3):2736.
10. Furuta T, Ohashi K, Kosuge K,
Zhao XJ, Takashima M, KimuraM,
et al. CYP2C19 genotype status
and effect of omeprazole
onintragastric pH in humans. Clin
Pharmacol Ther 1999;65:55261.
11. Adachi K, Katsube T, Kawamura
A, Takashima T, Yuki M,
AmanoK, et al. CYP2C19
genotype status and intragastric pH
duringdosing with lansoprazole or
rabeprazole. Aliment Pharmacol
Ther2000;14:125966.
12. Shirai N, Furuta T, Moriyama Y,
Okochi H, Kobayashi K,
TakashimaM, et al. Effects of
CYP2C19 genotypic differences in
themetabolism of omeprazole and
rabeprazole on intragastric pH.
AlimentPharmacol Ther
2001;15:192937.
13. Shirai N, Furuta T, Xiao F,
Kajimura M, Hanai H, Ohashi K, et
al.Comparison of lansoprazole and
famotidine for gastric acid
inhibitionduring the daytime and
night-time in different CYP2C19
genotypegroups. Aliment

91 | P a g e
14. Shimatani T, Inoue M, Kuroiwa T,
Horikawa Y, Mieno H,
NakamuraM. Effect of omeprazole
10 mg on intragastric pH in three
differentCYP2C19 genotypes,
compared with omeprazole 20 mg
and lafutidine20 mg, a new H2-
receptor antagonist. Aliment
Pharmacol Ther2003;18:114957.
15. Shimatani T, Inoue M, Kuroiwa T,
Horikawa Y. Rabeprazole 10
mgtwice daily is superior to 20 mg
once daily for night-time
gastricacid suppression. Aliment
16. Peny JM. How bright is the future
for generics? Scrip Mag2003:137.
17. Mikami H, Ikemoto M, Yoshiyama
I, Tatsuki H. Bioequivalence
evaluationof omeprazole 10 mg
and 20 mg tablet in healthy
volunteer.J Med Pharm Sci
2004;51:891901 (in Japanese).
18. http://www.taiyo-
yakuhin.com/dinet/file/data/1/1/01/
1101OVULANZE tab P.I.pdf (in
Japanese).
19. http://www.nichiiko.co.jp/medicine
/be/be pdf/o p/omerap10 be.pdf(in
Japanese).
20. D. Castro, M.A. Moreno, S.
Torrado, J.L. Lastres, Comparison
ofderivative spectrophotometric
and liquid chromatograpic methods
forthe determination of omeprazole
in aqueous solutions during
stabilitystudies, J. Pharm. Biomed.
Anal. 21 (1999) 291298.
21. SRC PhysProp Database, Internet
available.
22. Howden, C.W., 1991. Clinical
pharmacology of omeprazole. Clin.
Pharmacokinet.20, 3849.
23. Howden, C.W., Menedith, P.A.,
Forrest, J.A.H., Reid, J.L., 1984.
Oral pharmacokinetics of
omeprazole. Eur. J. Clin.
Pharmacol. 26, 641 643.
24. Kobayashi, K., Chiba, K., Sohn,
D.-R., Kato, Y., Ishizaki, T., 1992.
Simultaneous determination of
omeprazole and its metabolites in
plasma and urine by reversed-phase
high-performance liquid chroma
tography with alkaline-resistant
polymer-coated C column. J. Chro
matogr. 579, 299305.
25. Watanabe, K., Furuno, K., Eto, K.,
Oishi, R., Gomita, Y., 1994. First-
pass metabolism of omeprazole in
rats. J. Pharm. Sci. 83, 11311134.
26. S.L. Nail, The Effect of Chamber
Pressure on HeatTransfer in the
Freeze Drying of
ParenteralSolutions, PDA J.
Pharm. Sci. Technol. 34,358368
(1980).
27. M.J. Pikal et al., Physical
Chemistry of Freeze-Drying:
Measurement of Sublimation Rates
forFrozen Aqueous Solutions by a
MicrobalanceTechnique, J.
Pharm. Sci. 72, 635650 (1983).
28. M.J. Pikal, M.L. Roy, and S. Shah,
Mass andHeat Transfer in Vial
Freeze-Drying ofPharmaceuticals:
Role of the Vial, J. Pharm.Sci. 73,
12241237 (1984).
29. M.J. Pikal, Use of Laboratory
Data in FreezeDrying Process
Design: Heat and MassTransfer

92 | P a g e
Coefficients and the
ComputerSimulation of Freeze
Drying, PDA J.Parenteral Sci.
Technol. 39, 115139 (1985).
30. R.G. Livesey and T.W.G. Rowe,
ADiscussion of the Effect of
Chamber Pressureon Heat and
Mass Transfer in Freeze-Drying,J.
Parenteral Sci. Technol. 41, 169
171(1987).
31. M.J. Pikal and S. Shah, The
CollapseTemperature in Freeze
Drying: Dependence
onMeasurement Methodology and
Rate of WaterRemoval from the
Glassy Phase,Int. J. Pharm. 62,
165186 (1990).
32. M.J. Pikal, Freeze-Drying of
Proteins, Part 1:Process Design,
BioPharm 3(8), 1827 (1990).(8)
B.S. Chang and N.L. Fischer,
Developmentof an Efficient
Single-Step Freeze-DryingCycle
for Protein Formulations, Pharm.
Res.12, 831837 (1995).
33. D.E. Overcashier, T.W. Patapoff,
and C.C. Hsu,Lyophilization of
Protein Formulations inVials:
Investigation of the Relationship
BetweenResistance to Vapor Flow
During PrimaryDrying and Small-
Scale Product Collapse, J.Pharm.
Sci., 88, 688695 (1999).
34. M. Kochs et al., The Influence of
theFreezing Process on Vapour
Transport DuringSublimation in
Vacuum-Freeze-Drying
ofMacroscopic Samples, Int. J.
Heat MassTransfer, 36, 17271738
(1993).
35. J.A. Searles, J.F. Carpenter, and
T.W.Randolph, The Ice
Nucleation Temperature
Determines the Primary Drying
Rate ofLyophilization for Samples
Frozen on aTemperature-
Controlled Shelf,J. Pharm. Sci.,
90(7), 860871 (2001).

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INTERNATIONAL JOURNAL OF RESEARCH ARTICLE

PHARMACEUTICAL INNOVATIONS ISSN 2249-1031

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