formulation development & optimization of reconstitution … · formulation development &...

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 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

Proton pump inhibitors (PPIs), such as

Omeprazole, lansoprazole and rabeprazole,

are considered to have stronger gastric

acid-suppressive effects than histamine H2

receptor antagonists [1–4]

, 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 [6–9]

.

Therefore, a subject’s CYP2C19genotype

*Corresponding Author

Patel Mitesh



affects the acid-suppressive effects of

PPIs, and differences in its effects among

the three genotypic groups are significant [10–15]

. 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. [17–19]

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 ¼ 4.2 andpKa2 ¼ 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 secretion22-24

. 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 pump22

.

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



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



25°C. The pH of the solution was checked

and adjusted the pH with 1 N Sodium

Hydroxide solution slowly below 25°C.

The solution was diluted and made up to

750 ml, by WFI below 25°C&pH was

checked. The final solution was filtered by

using 0.22μm 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 25oC 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 25°C. 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 25°C for 10 min. The pH of the

solution was checked and adjusted the pH

with 1 N Sodium Hydroxide solution

slowly below 25°C. The solution was

diluted and made up to 3.0 Litre, by WFI

below 25°C &pH was checked. The final

solution was filtered by using 0.22μm

membrane filter. The solution was filled

into 10ml Clear glass Ampoules and seal.

Temperature of room should be below

25oC and humidity below 40%



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 20μl,

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



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 µl) 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%



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 40°C±

2°C/75% RH ± 5% RH. The results were

depicted in Table-6& 7.

The reconstituted lyophilization

omeprazole injection stability for 12 hours

at 25°C for I.V. Bolus administration and

12 hour at 25°C 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 -



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 25°C. (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%



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

solution stability at 25°C. (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 25°C. 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.

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