DEVELOPMENT OF DRY SYRUP FORMULATION

www.wjpr.net Vol 6, Issue 9, 2017.

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Jaiswal et al. World Journal of Pharmaceutical Research

DEVELOPMENT OF DRY SYRUP FORMULATION

Ankita Jaiswal, Arun Patel, Shailendra Patel, Neeraj Kaurav and Neelesh Devedi

Shri Ram Group of Institution, Faculty of Pharmacy, Jabalpur 487001 (M.P.) INDIA.

ABSTRACT

The objective of present work was to explore the novel application

mixed solvency mixed solvency technique in the formulation of dry

dosage forms of poorly soluble drug and to minimize the toxic effects

of solubilizers by reducing the concentration of individual solubilizer

(used for solubility enhancement). In the present study, poorly water

insoluble drug cefixime was selected. Cefixime was tried to solubilize

by using solubilizers which were physiologically compatible in an

attempt to prepare its oral liquid formulation (dry syrup).

KEYWORDS: mixed solvency, dry syrup, Cefixime.

INTRODUCTION

Mixed Solvency[1,2]

As per the mixed solvency concept each and every substance present in the universe has got

solubilizing property i.e. all the liquids, gases and solids possess solubilizing power. As per

his statement each substance is solubilizer. A concentrated aqueous solution containing

various water soluble substances may act as good solvent for poorly water soluble drugs.

Such concentrated solutions may show synergistic or additive solubilizing actions of

solubilizers present in the solution.

The concept of mixed solvency has been show’s the enhancement of aqueous solubility of

indomethacin (a poorly water soluble drug). He has employed aqueous mixed blends of

sodium benzoate, sodium citrate, PEG200, PEG 400 and PEG 600. The observed solubility of

indomethacin in distilled water was 0.21 mg/ml, while at the room temperature solubility of

indomethacin ranged from 130 to 138 mg/ml in blends. The solubility of a large number of

poorly soluble drugs has been enhanced by mixed solvency concept[3-18]

World Journal of Pharmaceutical Research SJIF Impact Factor 7.523

Volume 6, Issue 9, 512-523. Research Article ISSN 2277– 7105

Article Received on

27 June 2017,

Revised on 17 July 2017,

Accepted on 07 Aug. 2017

DOI: 10.20959/wjpr20179-9163

*Corresponding Author

Arun patel

Shri Ram Group of

Institution, Faculty of

Pharmacy, Jabalpur

487001(M.P.) INDIA.


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ADVANTAGES

Each and every weaker solvent (for a solute) can be made a strong solvent by proper selection

of solubilizers. For example oil soluble excipients (PVP, vanillin, BHA, BHT, propyl gallate,

benzoic acid, methyl paraben, propyl parabenetc) in proper concentrations, may enhance the

oil solubility of an oil insoluble drug, hence assisting in the development of an oily injection,

oily topical solution, multiple emulsion having higher drug loading in oily phase, SEDDS

having higher drug loading etc. Combination of such excipients (solubilizers) in safe

concentrations, solves the problem of toxicity issue (in comparison to the large concentration

of single excipient). Likewise, propylene glycol based solutions of propylene glycol insoluble

drugs can be made by the use of proper concentrations of propylene glycol soluble excipients

(e.g. benzoic acid, niacinamide, sodium benzoate, PVP, methyl parabenetc).

1. Solid dispersions of poorly water soluble drugs may be developed using combination of

proper concentrations (in safe limits) of water soluble solid excipients precluding the use

of organic solvents. (Drawbacks of organic solvents include high cost, pollution and

toxicity due to residual solvent).

2. By combining various excipients, additives and synergistic solvent actions are expected

which has advantage of reducing the toxicities. For a desired solubility enhancement, a

single solubilizer may prove toxic for human being but the combination of different

excipients in safe concentrations solves the problem of toxicity for same desired solubility

of drug.

3. Mixed solvency concept can also be employed in titrimetric analysis of poorly water

soluble drugs.

4. The mixed solvency concept may also be employed to carry out UV spectrophotometric

analysis of poorly soluble drugs without the use of organic solvents. Drawbacks of

organic solvents include toxicity of organic solvents, inaccuracy due to volatility,

pollution, higher cost etc.


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Applications

1. In Pharmaceutical Analysis

In titrimetric analysis

S.N. Drug

Organic solvent

used in official

method

Blend of solubilizers

(Mixed solvency)

Solubility

enhancement

1.

Ibuprofen[2]

(Bulk Drug) Ethanol

PEG 400+ PEG 300+ urea + sodium

citrate

(10% w/v each)

More than 40 fold

2. Salicylic Acid

[23]

(Bulk Drug) Ethanol

Glycerine+PEG 300+PEG

400+ Sodium citrate (10% w/v each) More than 54 fold

3. Furosemide24

(Bulk Drug)

Dimethyl

formamide

15%w/v Niacinamide

solution in ethanol More than 3 fold

In uvspectrophotometric analysis

S. N. Drug Blend of solubilizers(Mixed solvency) Solubility

enhancement

1. Ornidazole20(tab.) Eutectic liquid of phenol and niacinamide More than 15 fold

2. Tinidazole21(tab.) Melted phenol More than 220 fold

3. Nalidixicacid22 (tab.) Eutectic liquid of phenol and niacinamide More than 600 fold

4. Indomethacin19(tab.)

10% sodium benzoate + 5% sodium

citrate + 25% cosolvent (PEG200, PEG400,

PEG 600)

More than 400 fold

MATERIAL AND METHODS

Drug - Cefixime.

Excipients

Sodium citrate - Solubilizing agent.

Sodium acetate - Solubilizing agent.

β cyclodextrin - Solubilizing agent.

Sodium benzoate – Preservative.

Sucrose - Sweetning agent.

Distilled water.

Development of Dry Syrup formulation

The oral liquid dosage form of poorly water-soluble drugs available in market are mostly in

the form of solid dosage form like tablets, capsules etc. Liquid oral solutions (syrups) show

better availability and quick onset of action in comparison to the tablet dosage form. In the

present investigation, the poorly water-soluble drug cefixime has been selected for

formulating its dry syrup with the help of β cyclodextrin, sodium citrate and sodium acetate


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as solubilizing agents. As of now, cefixime is available in the market in the form of

suspension (after reconstitution). In the present study, the use of mixed solvency has been

explored to develop syrup of poorly water-soluble drug (in solution form after

reconstitution) by employing the combination of physiologically compatible solubilizing

agents at reduced concentrations to provide quick onset of action and better availability (in

comparison to its suspension form).

On the basis of the results obtained from the solubilization studies, both dry and readymade

syrup of poorly water-soluble drug cefixime have been developed.

Syrup formula: The formula for the formulation of syrup is as follows.

Table: Formula of cefixime oral liquid formulation (Syrup).

S. No. Ingredients Amount taken

1. Cefixime 2 g

2. Sodium citrate 2.5 g

3. Sodium acetate 5 g

4. β cyclodextrin 3.5 g

5. Sodium benzoate 0.5 g

6. Sucrose 40 g

7. Distilled water (q.s.) 100

Formulation of Dry Syrup Formulation

The syrup was formulated according to the formulation details given in table, following the

procedure given below.

All the ingredients were weighed appropriately and were mixed by geometric dilution method

for proper mixing in a pestle mortar. The resultant mixture was mixed thoroughly in a pestle

mortar for uniform mixing.

The prepared formulation was then transferred to vials and vials were stoppered and sealed

immediately.

Formulation of Readymade Syrup Formulation

The syrup was formulated according to the formulation details given in table, following the

procedure given below.


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All the ingredients were weighed appropriately and were mixed by geometric dilution method

for proper mixing in a pestle mortar. The resultant mixture was mixed thoroughly in a pestle

mortar for uniform mixing. The resultant powder mixture was transferred into appropriate

container and 15ml demineralised water was added to dissolve the content and later volume

was made upto 30ml with demineralised water. The prepared formulation was then

transferred to vials and vials were stoppered and sealed immediately.

Determination of pH of Developed Liquid Syrup

The pH of formulated syrups was determined using digital pH meter.

pH values of reconstituted syrup formulations.

Formulation code pH

DSB-6 4.18

RSB-6 4.23

Result: The pH of the formulations DSB-6was found to be 4.18 and that of the readymade

syrup RSB-6 was found to be 4.23 respectively.

Determination of Reconstitution Time

For reconstitution of developed dry syrup, 1 ml of demineralised water was injected into the

vial through the rubber closure. The vial was then vigorously shaken for proper mixing of the

contents. The reconstitution times were recorded in table.

Table: Reconstitution time of formulation.

Formulation code Reconstitution time (min.)

DSB-6 4min 32 sec

Physical &chemical stability testing of Formulated Syrups

The formulated syrups were subjected to physical and chemical stability testing at three

different temperatures (ambient, moderate and relatively higher temperature).

Physical stability testing of formulated syrups

The dry powder for syrups were filled in 5ml glass vials and vials were plugged and sealed.

The vials were kept at room temperature, 40°C/75% RH and 50°C. For physical stability

studies, the syrups were observed at definite time intervals for colour change and clarity (to

observe any turbidity or precipitation). Observations are recorded in table.


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Physical stability testing data for syrup formulation DSB-6.

Conditions Time (days) Physical parameters

Colour Clarity Precipitation

RTD 0 Slight yellow Clear solution No precipitation

RTD 15 Slight yellow Clear solution No precipitation

RTD 30 Slight yellow Turbid Precipitation

40°C/75% RH 0 Slight yellow Clear solution No precipitation

40°C/75% RH 15 Slight yellow Clear solution No precipitation

40°C/75% RH 30 Slight yellow Turbid Precipitation

50°C 0 Slight yellow Clear solution No precipitation

50°C 15 Slight yellow Turbid Precipitation

50°C 30 Slight yellow Turbid Precipitation

Result and Discussion

It was found that the batch DSB-6, showed no significant color change or precipitate

formation.

Similarly, RSB-6 showed little opalescence upon storage. The opalescence was found due to

the precipitation of β-cyclodextrin.

Freeze Thaw cycling

In case of products that are susceptible to phase separation, loss of viscosity, precipitation and

aggregation an extra investigation involving thermal cycling is carried out to establish the

influence of temperature variation during distribution. Under this, the packaged product is

cycled through temperature conditions that simulate the changes likely to be encountered

once the drug product is in distribution.

Procedure for Freeze Thaw cycling testing of syrups

The vials were kept alternately at 40±1°C and 4±1°C for 24 hour each, and shaken everyday

for 5 minutes on a touch type vortex mixer. Two vials of formulation were taken, one of

which was kept at 40±1°C and the other at 4±1°C for first day, followed by subsequent

temperature cycling and shaking as described. Fter 7-7 such cycles at 4±1°C and 40±1°C

(alternately), the vials were observed to check turbidity and precipitation, if any.


There was no precipitation and no turbidity in syrup DSB-6 formulation upon reconstitution

at the end of testing. Little opalescence was found in RSB-6 formulation at the end of this

testing.


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Chemical stability testing of dry syrup

In order to study the chemical stability of syrups, the samples were collected at seven days

interval upto one month and analyzed by UV Visible spectrophotometer to calculate the

residual drug content of the syrups. The initial drug content for each formulation was taken as

100%. The values of percent residual drug for the formulation at different time intervals as

well as at different temperatures are noted in table.

Chemical stability testing data for syrup formulations DSB6.

Conditions Time (days) Percent residual drug in formulation

DSB-6

Room temperature 0 100

Room temperature 7 96.12






40±2°C/75% RH 0 100

40±2°C/75% RH 7 96.01

40±2°C/75% RH 14 91.37

40±2°C/75% RH 21 90.17

40±2°C/75% RH 28 87.52

40±2°C/75% RH 35 81.63

40±2°C/75% RH 42 79.52

50°C 0 100

50°C 7 95.48

0°C 14 89.62

50°C 21 83.79

50°C 28 78.12

50°C 35 72.84

50°C 42 65.39

Fig: Degradation curve of cefixime in DSB-6.


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Chemical stability testing data for syrup formulations RSB6.

Conditions Time (days) Percent residual drug

RSB-6

Room temperature 1 100



40±2°C/75% RH 1 100

40±2°C/75% RH 7 96.87

40±2°C/75% RH 14 93.49

50°C 1 100

50°C 7 95.52

50°C 14 91.23

Fig: Degradation curve of cefixime RSB- 6.

Result and discussion

The results of chemical stability studies showed that the residual drug content at the end of 42

days was found to be 85.21% in DSB-6. The residual drug content at 42 day time period in

the formulation DSB-6 is 91.59% at 40°C and 65.39% at 50°C.

The results for the chemical stability of the readymade syrup at the end of 14 days for RSB- 6

formulation was found to be 92.35%. The residual drug content at the end of 14 days in the

formulation RSB- 6 was 93.49% at 40º C and 91.23% at 50ºC.

Evaluation of Formulation[25]

1. Sedimentation behavior

Redispersibility

The redispersibility was determined was determined by studying number of strokes to

redisperse the formed sediment at the end of 7 days of storage of the formulations (not more

than 100 strokes=Redispersibility).


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Sedimentation Volume Ratio (SVR)

During the seventh day study sedimentation behavior of formulations was studied for

sedimentation volume (F) and degree of flocculation (β).

2. Determination of pH

10ml of the sample was placed in a 100ml beaker. A calibrated glass electrode was dipped

into the sample solution and pH of each formulation was found out.

3. Liquid flow rate

Pipette out 10ml of the dry syrup sample using 10ml pipette. Now release the sample solution

from the pipette and start the stopwatch. The time required for each suspension sample toflow

through a 10 ml pipette was determined and the apparent viscosity (ηα in mls-1) was

calculated using the equation:

Volume of pipette (ml)

Flow rate ηα =

Flow time (s)

4. Drug content

1ml of reconstituted dry syrup equivalent to 0.200g Cefixime was pipette into 100 ml

volumetric flask. 50ml distilled water was added to this & mixed well for 15 min & volume

was made up to 100ml by adding sufficient distilled water (Table ). The solution was

analyzed at 275nm and 230nm for Cefixime respectively.

RESULTS AND DISCUSSION

Table: Micromeritic study of powder mixture of various formulations.

Formulation

Code F1 F2 F3 F4 F5 F6 F7 F8

Bulk Density

(gm/ml) 0.4878 0.524 0.505 0.4869 0.4869 0.530 0.529 0.4875

Tap Density

(gm/ml) 0.5692 0.5806 0.5804 0.5659 0.5809 0.5693 0.5692 0.5806

Angle of Repose (º) 17.10 17.52 17.52 17.10 17.53 17.52 17.10 17.53


The dry syrup for reconstitution of cefixime was also formulated. From the solubility data

obtained, the blends selected was and B-6 and both readymade and dry syrup formulation

were formulated. The prepared formulation was also subjected to clarity testing physical

stability studies and chemical stability studies. The prepared dry syrup formulations, DSB-6


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when subjected to accelerated stability studies showed good stability. Also the readymade

syrup of cefixime was also formulated and when subjected to accelerated stability studies the

maximum stability shown by RSB-6 is 92.35% drug as compared to initially 100% at room

temperature at end of 14 days). The prepared DSB-6 formulation did not showed any

precipitation whereas the RSB-6 formulation showed little opalascence at the end of freeze

thaw cycling.

Thus, above findings supports that by employing novel concept of mixed solvency the

required solubility can be achieved, also solubilizers can be selected in safer range and

dosage forms of good stability can also be developed. Also from the syrup formulation, it can

also be concluded that cefixime can also be formulated in the form of syrup instead of

formulating it as a suspension and as a result better bioavailability of the drug can be

obtained.

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DEVELOPMENT OF DRY SYRUP FORMULATION

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