INTERNATIONAL JOURNAL OF RESEARCH ARTICLE

PHARMACEUTICAL INNOVATIONS ISSN 2249-1031

Formulation Development & Optimization of Reconstitution

Solvent for Lyophilized Omeprazole Injection
1Patel Mitesh*, Patel Amit2
1Department 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 metabolism [5], has three hereditary

Proton pump inhibitors (PPIs), such as genotypes: homozy-gous extensive
Omeprazole, lansoprazole and rabeprazole, metabolisers with higher enzymatic
are considered to have stronger gastric activity, heterozygous extensive
acid-suppressive effects than histamine H2 metabolisers with moderate enzymatic
receptor antagonists [1–4], and are widely activity and poor metabolisers with
used in initial and maintenance therapy for markedly impaired enzyme activity [6–9].
gastro-oesophageal reflux disease Therefore, a subject’s CYP2C19genotype
(GERD).Recently, it has been found that
cytochrome P450 2C19(CYP2C19), which *Corresponding Author
is a major enzyme involved in PPI Patel Mitesh
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affects the acid-suppressive effects of base is only poorly soluble in water (82.3
PPIs, and differences in its effects among mg/l) [21].
the three genotypic groups are significant
[10–15]
. As a result, the acid-suppressive Omeprazole, 5-methoxy-2-h [(4-methoxy-
effect of PPIs should be studied in relation 3,5-dimethyl-2- pyridinyl)
to CYP2C19 genotype status. lmethyl]sulphinylj-1H-benzimidazole (Fig.
In Japan, as well as in many other 1), is a proton pump inhibitor in the gastric
countries, in an effort to reduce medical parietal cells, effectively suppressing the
expenditure, the authorities have recently gastric acid secretion22-24. Omeprazole, due
been promoting the use of generic drugs to its mode of action may be considered as
which contain the same active ingredients a pro-drug. Omeprazole is converted into
as the original products, and this may its sulphonamide form by protonation but
involve verifying the stability, quality and the drug is very unstable below pH 6.5 and
effects of the generic drugs. However, in is inactivated by gastric acid. It is in the
terms of volume of all prescriptions, active protonated form that the drug
generic products accounted for only 11% produces an irreversible linkage bond with
in Japan, but54% in the United States, the H /K ATPase enzyme, also known as
52% in the United Kingdom and54% in the proton pump22.
Germany in 2001 [16].Since 2004, an
increasing number of generic Omeprazole
containing products have been in the
market in Japan. [17–19]

Omeprazole is a substituted benzimidazole

that selectively inhibits the gastric proton Lyophilization (freeze-drying) is often
pump of the parietal cells. It is used for the used to prepare dry pharmaceutical
treatment of peptic ulcers, reflux formulations to achieve commercially
esophagitis and the Zollinger-Ellison viable shelf lives. The process comprises
syndrome. In some cases an intravenous three steps: freezing, primary drying, and
omeprazole formulation is needed, secondary drying. As water freezes in the
especially for the treatment of patients in first step, the dissolved components in the
intensive care. Normally these patients formulation remain in the residual liquid, a
receive a freshly prepared aqueous phase termed the freeze-concentrate. At
omeprazole solution via perfusion. Due to the point of maximal ice formation, the
their chemical instability, available freeze concentrate solidifies between the
formulations should be used within 6 h. ice crystals that make up the lattice. Under
Omeprazole is a lipophilic, weak base with appropriate Lyophilization conditions, the
pKa1 ¼ 4.2 andpKa2 ¼ 9.0; it is chemo- ice is removed by sublimation during
and thermo labile and rapidly degraded primary drying, leaving the remaining
and discolored when exposed to acidic freeze-concentrate in the same physical
media and warm temperature [20]. The free
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and chemical structure as when the ice was adjustment, water for injection as a vehicle
present. Residual water in the freeze- for solubility were used for Lyophilized
concentrate is removed in the secondary formulation and for Solvent preparation
drying step. Propylene glycol as Solubilizern as well as
vehicle for reconstitution, Citric acid
Lyophilization cycle development monohydrate as buffer, Sodium hydroxide
typically focuses on optimizing the for pH adjustment and water for injection
primary drying step. That is the most time as a vehicle were used for formulation.
consuming of the three steps, and the Active ingredient was procured from Gufic
primary drying parameters are easily Biosciences Ltd. and all other ingredients
adjustable. They can affect both the time used were AR grade.
involved and the quality of the resulting EQUIPMENTS
cake. Extensive investigation of primary Lyophilizer 20 Kg- Lyodrier 3S,
drying has demonstrated that two Lyophilization system India Pvt. Ltd.
important parameters are chamber pressure HPLC –Series 1200, Agilent
and shelf temperature [25-33].They are UV-visible spectrophotometer- UV 1601
usually adjusted to maximize the rate of PC, Shimadzu, Japan
heat transfer to each vial (speeding ice Vial Filling Machine- Single Head,
sublimation) without causing cake Ambica Industries
collapse. Less attention has been paid to Ampule Filling Machine- Single Head,
the freezing conditions and their potential Ambica Industries
effect on the primary and secondary drying Weighing balance- Model FB-200 of
processes and on the characteristics of the EssaeTeraoka Ltd
final product. Kochs et al. reported the PH Meter-CL46+, Toshcon industries
effects of freezing conditions on primary Pvt.Ltd
drying in a specially designed aluminium Refractometer-Rajdhani
and plastic sample cell [34]. They observed Stirrer-RQ-124, Remi motors
variations in vapour diffusion coefficients
(a measure of the ease of water-vapor METHODOLOGY:
flow) as a function of position and cooling Formulation of Lyophilized Omeprazole
rate. The variations appeared to be largely Injection
due to variations in sample morphology. Standard formulation of Omeprazole
Searles et al. reported some effects of Injection has been used for the experiment
freezing on the rate of primary drying in which was placed in table-1. 600 ml WFI
vials [35]. was collected in a beaker, weighed
quantity of Edetate disodium was added
MATERIALS AND METHODS and dissolved by stirring until a clear
MATERIALS solution was formed. Then Omeprazole
Omeprazole Sodium is an active Sodium was weighed and transferred to the
ingredient, Edetate disodium as Chelating above solution and dissolved by stirring
agent, Sodium hydroxide for pH for minimum duration of 5 min below
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25°C. The pH of the solution was checked loaded into lyophilizer and lyophilized
and adjusted the pH with 1 N Sodium them as per standard cycle. After
Hydroxide solution slowly below 25°C. completion of Lyophilization cycle,
The solution was diluted and made up to stoppering the vials without breakage of
750 ml, by WFI below 25°C&pH was vacuum using hydraulic system. Now
checked. The final solution was filtered by break the vacuum of the plant with help of
using 0.22μm membrane filter. The the sterile nitrogen. Unload the vials for
solution was filled into 10ml tubular vials sealing and seal the vials. Temperature of
(20 mm neck) and half bunging the vials room should be below 25oC and humidity
with 20 mm grey bromobutyl full slotted below 40%.
rubber stopper. The filled vials were

Table 1: Formulation of Lyophilized Omeprazole injection

Batch No Ingredients Quantity Per Quantity per 300 vials

vial
Omeprazole Sodium
equivalent to Omeprazole 40 mg 14.7 gm*
(5% Overages)
Standard
Edetate disodium 1 mg 300 mg
Batch
Sodium Hydroxide
Q.S Q.S
(For pH adjustment)
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 acid solution in Propylene glycol solution.

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

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Table2: Formulation of Solvent for Lyophilized Omeprazole injection of Various

Batches
Batch Propylene Glycol Citric acid 1 N Sodium Water for injection
No . Monohydrate Hydroxide solution
Gm/ Qty./3.0 Mg/ Qty./3.0 Mg/ Qty./3.0 ml/ Qty./3.0
Ampoule litre Ampoule litre Ampoule litre Ampoule litre
F1 3.0 900 gm 5 1.5 gm q.s. to q.s. to q.s. to q.s. to
pH 3.5 pH 3.5 10 3.0 litre
F2 3.0 900 gm 5 1.5 gm q.s. to q.s. to q.s. to q.s. to
pH 4.0 pH 4.0 10 3.0 litre
F3 3.0 900 gm 5 1.5 gm q.s. to q.s. to q.s. to q.s. to
pH 4.5 pH 4.5 10 3.0 litre
F4 3.0 900 gm 5 1.5 gm q.s. to q.s. to q.s. to q.s. to
pH 5.0 pH 5.0 10 3.0 litre
F5 4.0 1200 gm 5 1.5 gm q.s. to q.s. to q.s. to q.s. to
pH 3.5 pH 3.5 10 3.0 litre
F6 4.0 1200 gm 5 1.5 gm q.s. to q.s. to q.s. to q.s. to
pH 4.0 pH 4.0 10 3.0 litre
F7 4.0 1200 gm 5 1.5 gm q.s. to q.s. to q.s. to q.s. to
pH 4.5 pH 4.5 10 3.0 litre
F8 4.0 1200 gm 5 1.5 gm q.s. to q.s. to q.s. to q.s. to
pH 5.0 pH 5.0 10 3.0 litre

Freeze drying procedure:

Standard freeze drying process was taken at 280 nm and injection volume was 20μl,
for the formulation development of with the runtime of 8min.
omeprazole Lyophilized injection. Freeze Mobile phase: Prepare a filtered and
drying cycle includes freezing of the degassed mixture of acetronitrile and
product under the lyophilizer at -28C for buffer in the ratio of 50: 45. Do not filter
two hours. Then Primary drying at -25C mobile phase after mixing.
for seven hours along with vacuum 100 to Buffer: Dissolve 2.725 g of potassium
150 mtor & then at -10C for twelve hours dihydrogen orthophosphate and 0.525 g of
along with vacuum 100 to 150 mtor, then Dipotassium hydrogen orthophosphate in
+10C for five hours along with vacuum 1000 ml of distilled water. Adjust pH to
100 to 150 mtor. Secondary drying was 7.0 with 1 N potassium hydroxide
carried out at +30C for 2 hours along with solution. Filter and degassed.
vacuum 10 to 50 mtor. Standard preparation: Weigh accurately
Method of Analysis: about 40 mg of Omeprazole working
HPLC analysis was carried out with a standard into a 50 ml volumetric flask.
column 4.6 mm x 25 cm column that Add sufficient amount of diluents
contains packing C18, 5 micron, flow rate (methanol: acetonitrile 1:1). Sonicate to
was 1.0ml/min, detector was UV detector dissolve, cool at ambient temperature and

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

RESULTS AND DISCUSSION

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

Table 3: Observation of Omeprazole lyophilized Injection

Batch No Description of cake Water content Assay

Standard Batch White lyophilized cake 4.23% 104.17%

For optimization of formulation of solvent, obtained results were summarized in table-

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

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Table 4: Observation of reconstitution solvent for Omeprazole lyophilized injection

Batch No Description of Solution pH Particulate matter Refractive Index
F1 Clear, colourless solution 3.49 Complies as per IP 1.385
F2 Clear, colourless solution 4.05 Complies as per IP 1.384
F3 Clear, colourless solution 4.51 Complies as per IP 1.386
F4 Clear, colourless solution 5.07 Complies as per IP 1.388
F5 Clear, colourless solution 3.52 Complies as per IP 1.386
F6 Clear, colourless solution 4.10 Complies as per IP 1.384
F7 Clear, colourless solution 4.50 Complies as per IP 1.384
F8 Clear, colourless solution 5.09 Complies as per IP 1.385

The optimization of solvent was finalized reconstituted solution of Omeprazole

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

Table 5: Observation of Reconstituted Omeprazole Injection

Batch No Batch No of Description of Reconstituted pH Assay
Solvent usedfor solution
Reconstitution
F1 Slightly turbid solution 8.50 -
F2 Slightly turbid solution 8.61 -
F3 Clear, yellowish solution 8.83 99.68%
Standard F4 Slightly turbid yellowish solution 9.42 -
batch F5 Slightly turbid solution 8.54 -
F6 Slightly turbid solution 8.67 -
F7 Clear, colourless solution 8.90 104.12%
F8 Slightly turbid yellowish solution 9.51 -

Based on reconstitution study, F7 batch 2°C/75% RH ± 5% RH. The results were

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

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Table6: Evaluation of Reconstitution solvent for lyophilized Omeprazole injection 40

mg by Accelerated study
Batch Description of pH Particulate matter Refractive Index
No Solution
3 Months 6 Months 3 6 3 Months 6 Months 3 6
Months Months Months Months
F7 Clear, Clear, 4.51 4.50 Complies Complies 1.384 1.384
colourless colourless as per IP as per IP
solution solution

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

Batch No Description of cake Water content Assay

3 Months 6 Months 3 6 3 Months 6 Months
Months Months
Standard White White 4.59% 5.37% 103.12% 101.39%
batch lyophilized lyophilized
cake cake

Table 8: Evaluation of Reconstituted lyophilized Omeprazole injection 40 mg by

optimized solvent stability at 25°C. (For I.V Bolus administration)

Batch No Batch No of Time Description of pH Assay Total

of Solvent used period Reconstituted Impurities
lyphillized for solution
Omeprazole Reconstitution
Injection
Initial Clear, colourless 8.90 104.12% 1.89%
solution
Standard 8 Hours Clear, colourless 8.94 103.49% 2.41%
F7
batch solution
12 Clear, Light 9.02 100.64% 2.83%
Hours yellowish solution

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%

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Table – 9: Evaluation of lyophilized Omeprazole injection 40 mg by reconstitution

solution stability at 25°C. (For I.V Infusion)

Reconstituted Infusion Time Description of pH Assay Total

vial solvent period Reconstituted Impurities
solution
Lyophilized Initial Clear, colourless 9.87 104.57% 1.63%
Omeprazole solution
vial with 10 8 Hours Clear, colourless 9.95 103.51% 2.17%
100 ml saline
ml Propylene solution
glycol 12 Hours Clear, colourless 9.98 103.11% 2.68%
solvent solution

The acceptance limit for pH of closure. The formulation was stable for 6
reconstituted solution of Omeprazole months on accelerated stability studies and
injection in infusion solvent is 9.3 to 10.3 reconstituted formulation was stable for 12
and the assay limit is 90.0% to 110.0% and hours at 25°C. In conclusion a stable
total impurities not more than 3.0% formulation batch no F7 of reconstitution
Finally based on stability studies, batch F7 solvent Propylene glycol 40 % w/v for
was considered as optimized batch of Lyophilized Omeprazole Injection was
reconstitution solvent for Lyophilized developed& which is suitable both
Omeprazole Injection. Intravenous bolus & infusion
administration.
CONCLUSION ACKNOWLEDGEMENT
Current Marketed formulation of We thank Gufic Biosciences Ltd for
Omeprazole for injection available in two material donation. We thank Dr. Amit for
different formulations like Losec 40 mg valuable guidance and suggestions on the
powder with suitable solvent which is used manuscript.
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 INTERNATIONAL JOURNAL OF RESEARCH ARTICLE
PHARMACEUTICAL INNOVATIONS ISSN 2249-1031

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