FORM-2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION Sec 10-Rule 13
A STABLE SPILL RESISTANT SYRUP
INDOCO REMEDIES LIMITED
Indian
R-92-93, T.T.C Industrial Area, Thane Belapur Road, Rabale MIDC
Navi Mumbai-400701
The following complete specification describes the invention and the manner in which it is to be performed.

Field of Invention:
This invention relates to a stable spill resistant syrup. More specifically, the patent invention relates to a spill free oral dosage form for administration of combination of drugs i.e. paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate. The spill resistant oral syrup is stable at pH value between range 4.5-5.5. The invention further provides a process for preparation, packaging and uses of spill resistant oral dosage form. Background of Invention:
Almost all the time physicians prefer oral dosage form over the other forms. The oral drug delivery is preferred by patient too because of noninvasiveness and ease of administration. Traditional oral dosage form includes tablet, capsule, pill, syrup etc whereas non-traditional dosage form includes wafer drug delivery, orally disintegrated films and controlled drug delivery systems etc. Among these, a liquid dosage form is easy to swallow and palatable; therefore comfortable for administration of drug to pediatric or elderly patients. The liquid dosage form examples include but not limited to syrup, suspension, emulsion and drop etc. Though the liquid dosage form confirms some advantages to the patient, it also has some disadvantages too, foremost disadvantage of the same is spillage from the spoon which in turn increases treatment time, cost and challenge for patient compliance.
A combination of paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate is indicated for nasal and sinus congestion, headache and upper respiratory allergies. This triple combination is available as traditional syrup for pediatric use. During measurement of dosage form or at the time administration through mouth, chances of spillage are very high. And to avoid this under fill quantity of dosage form is administered to patient. This practice could increases duration, cost of treatment and leads to patient non compliance as well.
US patent applications 20030235618 and 20050143471 discloses spill resistant composition comprising drug, neutralized carbomer and polyethylene glycol. A

neutralized carbomer may be selected from carbomer 934P or carbopol 974P which
imparts viscosity to composition. A number of polyethylene glycol derivatives eg.
PEG 600, 800, 900 and 1000 are suitable for. spill resistant composition. Both
applications disclose spill resistant composition for acetaminophen and
diphenhydramine respectively with pH over about 6.
US7758877 reveals spill resistant loratadine suspension comprising butylparaben as
preservative and other acceptable excipients, This invention solves problem related to
oxidative degradation and increases storage stability as compared to ordinary
solutions of loratidine.
US6355258 disclose methods for manufacturing and examination of the spill resistant
composition. Patent also focuses on storage stability of spill resistant composition.
Furthermore '258 offers improvement in packaging of dosage form by providing
receptacle with package. A spill resistant formulation disclosed by patent has
improved rheological characteristics.
US6102254 discloses a packaging system for spill resistant formulation. The
packaging system comprises a squeezable container with outlet of flow channel and a
closure for opening, a closing flow channel and a receptacle to collect dose squeezed
from package.
US6656482 discloses a ready to use and squeezable system for delivery of semi solid
dosage form for patient. The said semi solid dosage form contains thickening agent
which is combination of cellulose derivatives and carboxyvinyl polymer to impart
suitable properties to the formulation.
WO 2015137829 teaches necessity of pH adjustment to stabilize oral formulation
comprising combination of phenylephrine hydrochloride and maleate salt of
antihistaminic drugs. Above pH 5.5, phenylephrine hydrochloride significantly
degrades in presence of maleate salts and responsible to decrease in therapeutic value
of dosage form.

Phenylephrine hydrochloride degrades above pH 7 by losing secondary amine function where phenol group remains unchanged. (Pg no 441, Ansel's Pharmaceutical dosage forms and drug delivery systems).
Polymeric excipients are backbone of various pharmaceutical dosage forms. This polymer may function as viscosity builder, solubilizer, thickener, coating agent, or taste masking agent.
A polymer with good thixotropic properties is best candidate for the spill resistant dosage forms and commonly employed polymers for spill resistant oral dosage form includes, e.g. - carbopol, sodium carboxymethyl cellulose, carrageenan etc. Due to shear stress, polymer converts to less viscous solution on shaking; however after few seconds regains its original gel state, once the shear stress on account of shaking is removed.
Carbopol is a synthetic polymeric gelling agent, consist subunits of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. It is pH dependent viscosity modifier and exhibits maximum viscosity at neutral pH, where the viscosity plateaus between pH values 6.3 to7.0. The carbopol swells in water up to 1000 times of original volume to form gel when exposed to pH environment above 6. Carrageenan is polysaccharide, contains hydrocolloid extracted from red sea-weed. It is located in the cell wall and intercellular matrix of the sea-weed plant tissue. The carrageenan mainly categorized as follows - 1) Lambda 2) Iot and 3) Kappa. The , highest apparent viscosity was observed at pH 7. Sodium carboxymethyl cellulose is cellulose based polymer and relatively gel out at pH between range 7 to 9.
Many times, liquid dosage form is difficult to administer to pediatric patients, due to two major reasons viz. high chances of spill at time of administration or patient may spit if taste is bitter.
Thus there is unmet need, to develop a stable spill resistant syrup comprising of combination of phenylephrine hydrochloride, chlorpheniramine maleate and /or

Paracetamol at pH between range 4.5 to 5.5 which retain therapeutic potency of each
drug and delivers accurate quantity of dosage to patient.
Surprisingly, the inventors of present invention have arrived at a novel spill resistant
syrup composition that doesn't alter therapeutic effectiveness of drugs at pH 4.5 to
5.5 with better palatable properties.
Objects of Invention:
An object of the invention is to provide a stable spill resistant syrup comprising of
combination of paracetamol, phenylephrine hydrochloride and chlorpheniramine
maleate; which is stable between range of pH 4.5 to 5.5.
Another object of present invention is to provide spill resistant syrup with taste
masking property for administration of two or more drugs to a patient.
One another object of present invention is to provide optimum concentration of
hydroxyethyl cellulose to formulate stable spill resistant syrup which on shaking
converts to less viscous liquid.
Yet another object of present invention is to provide a stable taste masked spill
resistant viscous syrup.
Further object of the present invention is to provide a suitable composition to
manufacture without any specialized equipment or requirement and/or specific drug
delivery system.
Still further object of the present invention is to provide a process for preparation of
spill resistant dosage form.
Yet another object of the present invention is to provide a novel spill resistant
composition packed in user friendly container or other acceptable packaging material.
Still further object of present invention is to provide the spill resistant composition
for treating nasal and sinus congestion, sinus pain, headache etc in patients.
Summary of the Invention:
The present invention relates to a spill resistant oral syrup combination composition
comprising bitter drugs like paracetamol, phenylephrine hydrochloride,
chlorpheniramine maleate and pharmaceutically acceptable excipients and a process

for preparing such formulation. Further, the present invention relates to uses of syrup.
A viscosity modifier i.e. Hydroxyethyl cellulose in concentration between 1.5 to
1.8%, produce spill resistant syrup which on shaking converts to less viscous liquid
and becomes easily pourable on spoon, spatula etc and eventually converts to gel
which does not spill from it, upon holding the same for a short duration.
Detailed Description of Invention:
In one aspect, the present invention relates to the stable spill resistant oral syrup, with
satisfactory palatability properties.
In other aspect, the present invention relates to a spill resistant pharmaceutical
composition with optimum pH value; makes solution stable and restrains degradation
of active drugs.
In another aspect, the invention relates to a stable spill resistant taste masked syrup
composition for accurate delivery of drug to patient.
The present invention also relates to a spill resistant syrup comprising of single or
combination following drugs -
1) Paracetamol 2) Phenylephrine hydrochloride 3) Chlorpheniramine maleate. The API which can be used for present invention is selected from paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate or combination thereof. In one embodiment, the pharmaceutical composition of present invention comprises any one drug selected from paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate.
In another embodiment, the pharmaceutical composition of present invention comprises combination of paracetamol and phenylephrine hydrochloride. In another one embodiment, the pharmaceutical composition of present invention comprises combination of phenylephrine hydrochloride and chlorpheniramine maleate.
Still in one embodiment, the pharmaceutical composition of present invention comprises combination of paracetamol and chlorpheniramine maleate.

Yet in one embodiment, the pharmaceutical composition of present invention
comprises triple combination of paracetamol, phenylephrine hydrochloride and
chlorpheniramine maleate.
Yet in another embodiment, the pharmaceutical composition of present invention
comprises combination of paracetamol, phenylephrine hydrochloride or
chlorpheniramine maleate.
According to one embodiment, the invention relates to a process for preparing orally
administrable spill resistant syrup comprises single or combination of drug in
therapeutically effective amount with bitter taste; and drugs are selected from
paracetamol, phenylephrine hydrochloride and chlorpheniramine maleate.
Yet in one embodiment, the present invention relates to a use of buffering agents to
maintain final pH of composition is between 4.5 to 5.5. This forbids conversion of
actives in to inactive derivatives by inhibiting degradation of phenylephrine
hydrochloride as well as by preventing formation of adducts of phenylephrine
hydrochloride and maleate salt.
Hydroxyethyl cellulose is non-ionic water soluble polymer, derived from cellulose
and widely used in pharmaceutical formulation. It is made by reacting ethylene oxide
with alkali-cellulose under rigidly controlled conditions. It dissolved quickly in hot or
cold water which forms clear, smooth and uniform solution. Aqueous solution of
hydroxyethyl cellulose is relatively stable at pH between range 2 to 12. Hydroxyethyl
cellulose containing solution are psuedoplastic and non-newtonian in nature means
fluid whose viscosity decreases under shear strain.
In further embodiment, the current invention relates to a use of viscosity modifier i.e
hydroxyethyl cellulose which forms gels at pH below 6. This forbids conversion of
actives in to inactive derivatives by inhibiting degradation of phenylephrine
hydrochloride as well as by preventing formation of adducts of phenylephrine
hydrochloride and maleate salt.
According to one embodiment, the concentration of hydroxyethyl cellulose is in the
range of 1.5% to 1.8%.

In one embodiment, the concentration of hydroxyethyl cellulose is in the range of
1.6% to 1.8%.
In another embodiment, the concentration of hydroxyethyl cellulose is in the range of
1.7% to 1.8%.
According to one embodiment, the pharmaceutical composition comprises 2.5 to
7.5% paracetamol, from 0.1 to 0.2% about phenylephrine hydrochloride, from 0.02 to
0.06% about chlorpheniramine maleate, from 0.8 to 5% about buffering agent, from
0.01 to 0.5% about chelating agent, from about 0.010% to 0.2% preservative, from
about 0.01-0.4% antioxidant, from about 10% to 30% cosolvent, from about 1.5 to
1.8 % viscosity modifier, and suitable amount of sweetener, coolant, flavour and
colourant.
One embodiment, the pharmaceutical composition comprises 2.5 to 7.5%
paracetamol, from 0.1 to 0.2% about phenylephrine hydrochloride, from 0.02 to
0.06% about chlorpheniramine maleate, from 0.3 to 5% about buffering agent, from
0.01 to 0.5% about chelating agent, from about 0.010% to 0.2% preservative, from
about 0.01-0.4% antioxidant, from about 10% to 30% cosolvent, from about 1.5 to
1.8 % viscosity modifier, and suitable amount of sugar, sweetener, coolant, flavour
and colourant.
In another embodiment, the existing invention relates to a pharmaceutical
composition comprises paracetamol, phenylephrine hydrochloride, chlorpheniramine
maleate, sodium citrate, sugar, disodium edetate, sodium methylparaben, sodium
propylparaben, citric acid monohydrate, sodium metabisulfite, propylene glycol,
sodium saccharin, menthol, essence rose and hydroxyethyl cellulose.
According to one embodiment, the pharmaceutical composition comprises 2.5 to
7.5% paracetamol, from 0.1 to 0.2% about phenylephrine hydrochloride, from 0.02 to
0.06% about chlorpheniramine maleate, from 0.8 to 5% about combination of sodium
citrate and citric acid monohydrate, from 0.01 to 0.5% about disodium EDTA, from
about 0.015%) to 0.2% combination of sodium methylparaben and sodium
propylparaben, from about 0.01-0.4% sodium metabisulfite, from about 10% to 30%

propylene glycol, from about 1.5 to 1.8 % hydroxyethyl cellulose, and suitable amount of sugar, sweetener, coolant, flavour and colourant.
In one embodiment, the pharmaceutical composition comprises 2.5 to 7.5% paracetamol, from 0.1 to 0.2% about phenylephrine hydrochloride, from 0.02 to 0.06% about chlorpheniramine maleate, from 0.3 to 5% about sodium citrate, from 0.01 to 0.5% about disodium EDTA, from about 0.015% to 0.2% combination of sodium methylparaben and sodium propylparaben, from about 0.01-0.4% sodium metabisulflte, from about 10% to 30% propylene glycol, from about 1.5 to 1.8 % hydroxyethyl cellulose, and suitable amount of citric acid monohydrate, sugar, sweetener, coolant, flavour and colourant.
According to another embodiment, the pharmaceutical composition comprises 2.5 to 7.5% paracetamol, from 0.1 to 0.2% about phenylephrine hydrochloride, from 0.02 to 0.06% about chlorpheniramine maleate, from 0.8 to 5% about combination of sodium citrate and citric acid monohydrate, from 0.01 to 0.5% about disodium EDTA, from about 0.015% to 0.2% combination of sodium methylparaben and sodium propylparaben, from about 0.01-0.4% sodium metabisulflte, from about 10% to 30% propylene glycol, from about 1.5 to 1.8 % hydroxyethyl cellulose, and suitable amount of sugar, sweetener, coolant, flavour and colourant, wherein pH of composition is between 4.5 to 5.5.
Yet in one embodiment, the pharmaceutical composition comprises 2.5 to 7.5% paracetamol, from 0.1 to 0.2% about phenylephrine hydrochloride, from 0.02 to 0.06% about chlorpheniramine maleate, from 0.8 to 5% about combination of sodium citrate and citric acid monohydrate, from 0.01 to 0.5% about disodium EDTA, from about 0.015% to 0.2% combination of sodium methylparaben and sodium propylparaben, from about 0.01-0.4% sodium metabisulflte, from about 10% to 30% propylene glycol, from about 1.5 to 1.8 % hydroxyethyl cellulose, and suitable amount of sweetener, coolant, flavour and colourant, wherein pH of composition is between 4.5-5.5, or any specific value within said range.

Still in one embodiment, the pharmaceutical composition comprises 2.5 to 7.5% paracetamol, from 0.1 to 0.2% about phenylephrine hydrochloride, from 0.02 to 0.06% about chlorpheniramine maleate, from 0.8 to 5% about combination of sodium citrate and citric acid monohydrate, from 0.01 to 0.5% about disodium EDTA, from about 0.015% to 0.2% combination of sodium methylparaben and sodium propylparaben, from about 0.01-0.4%) sodium metabisulfite, from about 10% tq 30% propylene glycol, from about 1.5 to 1.8 % hydroxyethyl cellulose, and suitable amount of sugar, sweetener, coolant, flavour and colourant, wherein pH of composition is between 4.5-5.5, or any specific value within said range. According to another embodiment, the pharmaceutical composition comprises, the pharmaceutical composition comprises 2.5% paracetamol, 0.1% phenylephrine hydrochloride, 0.02% chlorpheniramine maleate, 0.30% sodium citrate, 30%) sugar, 0.05% disodium EDTA, 0.20% sodium methylparaben, 0.04% sodium propylparaben, 0.01% sodium metabisulfite, 20%) propylene glycol, 0.20% sodium saccharin, 0.02% menthol, 0.12% essence rose, 1.5% hydroxyethyl cellulose and suitable amount of citric acid monohydrate.
According to one embodiment, the pharmaceutical composition comprises, the pharmaceutical composition comprises 2.5% paracetamol, 0.1% phenylephrine hydrochloride, 0.02%) chlorpheniramine maleate, 030% sodium citrate, 30%o sugar, 0.05% disodium EDTA, 0.20% sodium methylparaben, 0.04% sodium propylparaben, 0.01 % sodium metabisulfite, 20% propylene glycol, 0.20% sodium saccharin, 0.02% menthol, 0.12% essence rose, 1.5% hydroxyethyl cellulose and suitable amount of citric acid monohydrate, wherein pH of composition is between 4.5 to 5.5.
Another embodiment, the pharmaceutical composition comprises, the pharmaceutical composition comprises 2.5%) paracetamol, 0.1%o phenylephrine hydrochloride, 0.02% chlorpheniramine maleate, 0.30% sodium citrate, 30% sugar, 0.05%) disodium EDTA, 0.20%) sodium methylparaben, 0.04%) sodium propylparaben, 0.01%) sodium metabisulfite, 20%) propylene glycol, 0.20%) sodium saccharin, 0.02% menthol,

0.12% essence rose, 1.6% hydroxyethyl cellulose and suitable amount of citric acid monohydrate.
Yet in one embodiment, the pharmaceutical composition comprises, the pharmaceutical composition comprises 2.5% paracetamol, 0.1% phenylephrine hydrochloride, 0.02% chlorpheniramine maleate, 0.30% sodium citrate, 30% sugar, 0.05%) disodium EDTA, 0.20% sodium methylparaben, 0.04% sodium propylparaben, 0.01% sodium metabisulfite, 20%) propylene glycol, 0.20% sodium saccharin, 0.02% menthol, 0.12% essence rose, 1.6% hydroxyethyl cellulose and suitable amount of citric acid monohydrate, wherein pH of composition is between 4.5 to 5.5.
Yet in one embodiment, the pharmaceutical composition comprises, the pharmaceutical composition comprises 2.5% paracetamol, 0.1% phenylephrine hydrochloride, 0.02% chlorpheniramine maleate, 0,30% sodium citrate, 30% sugar, 0.05%o disodium EDTA, 0.20% sodium methylparaben, 0.04%o sodium propylparaben, 0.01%o sodium metabisulfite, 20% propylene glycol, 0.20%) sodium saccharin, 0.02%) menthol, 0.12% essence rose, 1.7% hydroxyethyl cellulose and suitable amount of citric acid monohydrate.
According to an embodiment, the pharmaceutical composition comprises, the pharmaceutical composition comprises 2.5%> paracetamol, 0.1%o phenylephrine hydrochloride, 0.02% chlorpheniramine maleate, 0.30%) sodium citrate, 30%o sugar, 0.05% disodium EDTA, 0.20% sodium methylparaben, 0.04% sodium propylparaben, 0.01% sodium metabisulfite, 20%o propylene glycol, 0.20% sodium saccharin, 0.02%) menthol, 0.12% essence rose, 1.7%) hydroxyethyl cellulose and suitable amount of citric acid monohydrate, wherein pH of composition is between 4.5 to 5.5.
Yet in another embodiment, the pharmaceutical composition comprises, 2.5%o paracetamol, 0.1% phenylephrine hydrochloride, 0.02%o chlorpheniramine maleate, 0.30%o sodium citrate, 30% sugar, 0.05%o disodium EDTA, 0.20% sodium methylparaben, 0.04%o sodium propylparaben, 0.01%o sodium metabisulfite, 20%o

propylene glycol, 0.20% sodium saccharin, 0.02% menthol, 0.12% essence rose,
1.8% hydroxyethyl cellulose and suitable amount of citric acid monohydrate.
Yet in another embodiment, the pharmaceutical composition comprises, 2.5%
paracetamol, 0.1 % phenylephrine hydrochloride, 0.02% chlorpheniramine maleate,
0.30% sodium citrate, 30% sugar, 0.05% disodium EDTA, 0.20% sodium
methylparaben, 0.04% sodium propylparaben, 0.01%) sodium metabisulfite, 20%
propylene glycol, 0.20% sodium saccharin, 0.02% menthol, 0.12% essence rose,
1.8%) hydroxyethyl cellulose and suitable amount of citric acid monohydrate, wherein
pH of composition is between 4.5 to 5.5.
Chelating agents and buffering agents include, but not limited to Sodium citrate, citric
acid monohydrate, and disodium EDTA. Sodium citrate and citric acid monohydrate
in combination increases palatability in addition to maintaining pH of said
formulation.
Sugar or sweetener includes, but not limited to sucrose, fructose, sorbitol, xylitol,
glycerol, liquid glucose and artificial sweeteners like sodium saccharin, ammonium
and sodium glycyrrhizinate, sucralose and aspartame.
Viscosity modifier includes, but not limited to methyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline
cellulose, sodium carboxymethyl cellulose, and combination thereof.
Preservative includes, but not limited to paraben, benzoic acid and its salts, sorbic
acid and its salts, potassium sorbate and combination thereof.
Antioxidant includes, but not limited to ascorbic acid, sodium sulfite, butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), beta-carotene, alpha-
tocopherol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite
and combination thereof.
Cosolvent includes, but not limited to propylene glycol, glycerine, polyethylene
glycol and combination thereof.
Flavouring agent includes, but not limited to butterscotch, vanilla, essence rose,
cherry, mint, citrus flavours and combination thereof.

Coolant includes, but not limited to menthol, eucalyptus oil, camphor, clove bud oil,
peppermint oil and combination thereof.
Colourant includes, but not limited to quinolone yellow, sunset yellow, erythrosine,
brilliant blue or combination thereof.
According to another aspect, the present invention provides uses of spill resistant
syrup for treating nasal and sinus congestion, sinus pain, headache, nose or throat
allergies caused due to upper respiratory tract allergies, minor aches and pains, runny
nose and sneezing, itchy and watery eyes, etc in patients.
In one embodiment, invention relates to a treatment of conditions like nasal and sinus
congestion, sinus pain, headache, nose or throat allergies caused due to upper
respiratory tract allergies, minor aches and pains, runny nose and sneezing, itchy and
watery eyes, etc by administering spill resistant syrup to patient via oral route.
In another aspect, the present invention provides a novel spill resistant composition
packed in user friendly container or other acceptable packaging material.
In one embodiment, invention relates to a packaging of unit dose of syrup in small
pouch which able to deliver unit dosage form at single time. The unit dose packed in
small pouch has advantages such as easy to carry, no necessity of dose measurement
and hygienic administration of dose.
In one embodiment, invention relates to a novel spill resistant composition packaged
in squeezable container or pouch, glass or plastic bottles, tetra pack, small pack filled
with unit dose.
In one embodiment, invention relates to packaging of unit dose in bowl of spoon,
where packaging material is wrapped on bowl up to the neck of spoon.
In one embodiment, invention relates to packaging of spill resistant syrup in an
aluminum squeeze pouch with nozzle.
In another aspect, the present invention provides a process for preparation of spill
resistant dosage form contains simple steps without specialized manufacturing
equipment.

According to one embodiment, invention provides manufacturing process which requires simple, routine equipment and vessel.
In one embodiment, invention relates to a process for preparation of spill resistant dosage form comprising of following steps -
1) Preparing solution by mixing of at least one preservative and at least one chelating agent in water,
2) Preparing sugar syrup by adding at least one sugar to the mixture of step 1 and filtering syrup with suitable filtration techniques.
3) Dissolving at least one buffering agent and at least antioxidant in water. Transferring this mixture to syrup of step 2.
4) Dissolving the paracetamol with heated cosolvent. Adding paracetamol solution to syrup of step 3.
5) Separately dissolving chlorpheniramine maleate and phenylephrine hydrochloride in water. Adding of individual solutions to syrup of step 4.
6) Dissolving the sodium saccharine in water and adding to syrup of step 5.
7) Adding coolant in cosolvent. Mixing this solution to syrup of step 6.
8) Adding flavouring agent to syrup of step 7.
9) Checking the pH of solution and making the volume with water,
10) Adding hydroxyethyl cellulose under stirring to above solution.
In another embodiment, invention relates to a process for preparation of spill resistant dosage form comprising of following steps -
1) Preparing solution by mixing of at least one preservative and at least one chelating agent in water.
2) Preparing sugar syrup by adding at least one sugar to the mixture of step 1 and filtering syrup with suitable filtration techniques.
3) Separately dissolving chlorpheniramine maleate and phenylephrine hydrochloride in water. Adding of individual solutions to syrup of step 2.
4) Dissolving at least one buffering agent, at least one sweetener and at least one antioxidant in water. Transferring this mixture to syrup of step 3.

5) Dissolving at least one buffering agent in water and adding to syrup of step 4.
6) Dissolving the paracetamol with heated cosolvent. Adding paracetamol solution to syrup of step 5.
7) Adding coolant in cosolvent. Mixing this solution to syrup of step 6
8) Adding flavouring agent to syrup of step 7.
9) Adding colouring agent to syrup of step 8.
10) Checking the pH of syrup of step 9.
11) Adding hydroxyethyl cellulose under stirring to solution of step 10.
In another aspect of the present invention, a spill resistant syrup is evaluated to assert
quality and stability of dosage form.
In one embodiment, spill resistant syrup is evaluated for organoleptic properties and
spill resistant properties.
A number of polymers are disclosed in prior art to modify viscosity of formulation
such as carbopol, carboxymethyl cellulose sodium, dextrin, xanthan gum etc.
Example 1 shows composition for spill resistant syrup where different polymers were
evaluated to achieve spill resistant viscosities.
Experiment No 1
As shown in Table 1, we have tested same composition with different viscosity
modifiers and surprisingly found that hydroxyethyl cellulose shows better viscosity
than other viscosity modifiers. All formulations had low viscosities except
hydroxyethyl cellulose containing formulation that shown viscous fluid. This
experiment fosters the use hydroxyethyl cellulose for Spill resistant syrup.

Table 1:

Sr. No. Batches lor evaluation of candidate viscosity modifiers Experimental Batch A Experimental Batch B Experimental Batch C Experimental Batch D Experimental Batch E Experimental Batch F

INGREDIENTS Qty/5 ml
(mg) % w/w Qty/5 ml
(mg) % w/w Qty/5 ml
(mg) % w/w Qty/5
ml
(mg) % w/w Qty/5 ml
(mg) % w/w Qty/5
ml
(mg) % w/w
I Paracetamol 125 2.5 125 2.5 125 2.5 125 2.5 125 2.5 125 2.5
2 Phenylephrine HCL 5 0.1 5 0.1 5 0.1 5 0.1 5 0.1 5 0.1
3 Chlorpheniramine Maleate 1 0.02 1 0.02 1 0.02 1 0.02 I 0.02 1 0.02
4 Sodium citrate 15 0.3 15 0.3 15 0.3 15 0.3 15 0.3 15 0.3
5 Sugar (Food Grade) 1500 30 1500 30 1500 30 1500 30 1500 30 1500 30
6 Disodium Edetate 2.5 0.05 2.5 0.05 2.5 0.05 2.5 0.05 2.5 0.05 2.5 0.05
7 Sodium methyl paraben 10 0.2 10 0.2 10 0.2 JO 0.2 10 0.2 10 0.2
8 Sodium Propyl Paraben 2 0.04 2 0.04 2 0.04 2 0.04 2 0.04 2 0.04
9 Citric acid monohydrate q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
10 Sodium metabisuliite 0.5 0.01 0.5 0.01 0.5 0.01 0.5 0.01 0.5 0.01 0.5 0.01
11 Propylene Glycol 1000 20 1000 20 1000 20 1000 20 1000 20 1000 20
12 Sodium Saccharin 10 0.2 10 0.2 10 0.2 10 0.2 10 0.2 10 0.2
13 Menthol 1 0.02 1 0.02 1 0.02 1 0.02 1.5 0.02 1 0.02
14 Essence rose 6 0.12 6 0.12 6 0.12 6 0.12 6 0.12 6 0.12
16 Microcrystalline Cellulose and Carboxymethylcellulose Sodium 150 3 0 0 0 0 0 0 0 0 0 0
17 Dextrin 0 0 75 1.5 0 0 0 0 0 0 0 0
18 Sodium carboxymethyl cellulose 0 0 0 0 25 0.5 30 0.6 0 0 0 0
19 Xanthan Gum 0 0 0 0 20 0.4 0 0 0 0 0 0
20 Cartage nan 0 o 0 0 0 0 25 0.5 0 0 0 0
21 Carbopol 0 0 0 0 0 0 0 0 25 0.5 0 0
22 Hydroxy ethyl cellulose 0 0 0 0 0 0 0 0 0 0 60 1.2
23 Purified Water q.s, q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s, q.s. q.s. q.s.
Experiment No 2
Table 2 shows, compositions with different concentration of hydroxyethyl cellulose to evaluate suitable concentration for spill resistant syrup. Last row of Table 2 provides observation of various trials.

Table 2:

Batches to study concentration of Hydroxyethyl cellulose Experimental Batch F Experimental Batch G Experimental Batch H Experimental Batch I
Sr. No. INGREDIENTS Qty/5ml
(mg) % w/w Qty/5ml (mg) % w/w Qty/5ml
(mg) % w/w Qty/5ml (mg) % w/w
I Paracetamol 125 2.5 125 2.5 125 2.5 125 2.5
2 Phenylephrine HCL 5 0.1 5 0.1 5 0.1 5 0.1
3 Chlorpheniramine Maleate 1 0.02 1 0.02 1 0.02 1 0.02
4 Sodium citrate 15 0.3 15 0.3 15 0.3 15 0.3
5 Sugar (Food Grade) 1500 30 1500 30 1500 30 1500 30
6 Disodium Edetate 2.5 0.05 2.5 0.05 2.5 0.05 2.5 0.05
7 Sodium methylparaben 10 0.2 10 0.2 10 0.2 10 0.2
8 Sodium propylparaben 2 0.04 2 0.04 2 0.04 2 0.04
9 Citric acid monohydrate q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
10 Sodium metabisulfite 0.5 0.01 0.5 0.01 0.5 0.01 0.5 0.01
11 Propylene Glycol 1000 20 1000 20 1000 20 1000 20
12 Sodium Saccharin 10 0.2 10 0.2 10 0.2 10 0.2
13 Menthol 1 0.02 1 0.02 1 0.02 1 0.02
14 Essence rose 6 0.12 6 0.12 6 0.12 6 0.12
15 Hydroxyethyl cellulose 60 1.2 75 1.5 90 1.8 100 2
16 Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Observation Viscosity of formulation was very low which is not suitable for spill free formulation. Viscosity of formulation was found to be satisfactory Viscosity of formulation was found to be
satisfactory Viscosity of formulation was very high. Lump was observed.

On comparison, it has been observed that concentration of 1.5% - 1.8% of hydroxyehthyl cellulose produces viscous syrup with satisfactory viscosity whereas the compositions with other than said concentration of hydroxyehtyl cellulose show unacceptable viscosity. The formulation with 1.2% of hydroxyethyl cellulose had very less viscosity in contrast to formulation with 2% of hydroxyethyl cellulose which shows lump with stiff viscosity. The presence of 1.5-1.8% hydroxyethyl cellulose in formulation builds viscous formulation which on shaking converts to less viscous syrup. That means hydroxyethyl cellulose in quantity 75mg - 90mg produces spill resistant syrup which on shaking reduces viscosity and provide easiness to pour composition on spoon.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description. It is therefore contemplated that such modification can be made without departing from the spirit or scope of the present invention as defined. The following examples are given by way of illustration of the present disclosure and should not be construed to limit the scope of present disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the subject matter. Example 1 Table 3

Sr. No. Ingredients Qty/5ml (mg) % w/w
1 Paracetamol 125 2.5
2 Phenylephrine hydrochloride 5.00 0.10
3 Chlorpheniramine Maleate 1.00 0.02
4 Sodium citrate 15.00 0.30

5 Sugar 1500.00 30.00
6 Disodium Edetate 2.50 0.05
7 Sodium methylparaben 10.00 0.20
8 Sodium propylparaben 2.00 0.04
9 Citric acid monohydrate q.s. q.s.
10 Sodium metabisulfite 0.50 0.01
11 Propylene glycol 1000 20
12 Sodium saccharin 10.00 0.20
13 Menthol 1.00 0.02
14 Essence rose 6 0.12
15 Hydroxyethyl cellulose 90 1.8
16 Purified Water q.s q.s.
Table 3 shows, spill resistant syrup composition comprising 90 mg of viscosity
modifier i.e. Hydroxyethyl cellulose.
Procedure:
1) In S.S tank, sodium methylparaben, sodium propylparaben and disodium edetate were mixed in water.
2) Sugar was added to solution of step 1 under stirring and stir to dissolve it completely.
3) Sugar solution of step 2 was passed through nylon cloth.
4) Citric acid monohydrate, sodium citrate and sodium metabisulfite were dissolved in water and added in syrup of step 3.
5) Paracetamol was dissolved in hot propylene glycol under stirring and added in syrup from step 4.
6) Chlorpheniramine maleate was dissolved in water and added in syrup of step 5.
7) Phenylephrine hydrochloride was dissolved in water and added in syrup of step
6,
8) Sodium saccharine was dissolved in water and added in syrup of step 7.

9) Menthol was dissolved in propylene glycol and added in syrup of step 8.
10) Essence rose white was added in syrup of step 9.
11) Volume of solution 10 was made up with water.
12) Hydroxyethyl cellulose was added to syrup of step 11 under stirring.
Example 2 Table 4

Sr. No. Ingredients Qty/5ml (mg) %w/w
1 Paracetamol 125 2.5
2 Phenylephrine hydrochloride 5.00 0.1
3 Chlorpheniramine Maleate 1.00 0.02
4 Sodium citrate 15.00 0.3
5 Sugar 1500.00 30
6 Disodium Edetate 2.50 0.05
7 Sodium methyl paraben 10.00 0.2
8 Sodium propylparaben 2.00 0.04
9 Citric acid monohydrate q.s. q.s
10 Sodium metabisulfite 0.50 0.01
11 Propylene Glycol 1000 20
12 Sodium Saccharin 10.00 0.2
13 Menthol 1.00 0.02
14 Essence rose 6 0.12
15 Hydroxyethyl cellulose 75 1.5
16 Purified Water q.s q.s
Table 4 shows, spill resistant syrup composition comprising 75 mg of viscosity modifier i.e. Hydroxyethyl cellulose.

Procedure:
1) In S.S tank, sodium methylparaben, sodium propylparaben and disodium edetate were mixed in water.
2) Sugar was added to solution of step 1 under stirring and stir to dissolve it completely.
3) Sugar solution of step 3 was passed through nylon cloth.
4) Citric acid monohydrate, sodium citrate and sodium metabisulfite were dissolved in water and added in syrup of step 3.
5) Paracetamol was dissolved in hot propylene glycol under stirring and added in syrup from step 4.
6) Chlorpheniramine maleate was dissolved in water and added in syrup of step 5.
7) Phenylephrine hydrochloride was dissolved in water and added in syrup of step 6.
8) Sodium saccharine was dissolved in water and added in syrup of step 1,
9) Menthol was dissolved in propylene glycol and added in syrup of step 8.
10) Essence rose white was added in syrup of step 9.
11) Volume of solution 10 was made up with water.
12) Hydroxyethyl cellulose was added to syrup of step 11 under stirring.
Example 3 Table 5

Sr. No. Ingredients Qty/5ml (mg) % w/w
1 Paracetamol 125 2.5
2 Phenylephrine hydrochloride 5.00 0.1
3 Chlorpheniramine Maleate 1.00 0.02
4 Sodium citrate 15.00 0.3
5 Sugar 1500.00 30

6 Disodium Edetate 2.50 0.05
7 Sodium methyl paraben 10.00 0.2
8 Sodium propylparaben 2.00 0.04
9 Citric acid monohydrate q.s. q.s
10 Sodium metabisulfite 0.50 0.01
11 Propylene Glycol 1000 20
12 Sodium Saccharin 10.00 2
13 Menthol 1.00 0.2
14 Essence rose 6 1.2
15 Hydroxyethyl cellulose 75 15
16 Quinoline yellow 0.2 0.004
17 Purified Water q.s q.s.
Table 5 shows, spill resistant syrup composition comprising 75 mg of viscosity modifier i.e. Hydroxyethyl cellulose. The composition also contains colourant that is quinoline yellow. Procedure:
1) In S.S tank, sodium methylparaben, sodium propylparaben and disodium edetate were mixed in water.
2) Sugar was added to solution of step 1 under stirring and stir to dissolve it completely.
3) Sugar solution of step 3 was passed through nylon cloth.
4) Chlorpheniramine maleate was dissolved in water and added in syrup of step 3.
5) Phenylephrine hydrochloride was dissolved in water and added in syrup of step 4.
6) Sodium saccharine, sodium citrate and sodium metabisulfite were dissolved in water and added in syrup of step 5.
7) Citric acid monohydrate was dissolved in water and added in syrup of step 6.

8) Paracetamol was dissolved in hot propylene glycol under stirring and added in syrup from step 7,
9) Menthol was dissolved in propylene glycol and added in syrup of step 8.
10) Essence rose white was added in syrup of step 9.
11)Quinoline yellow was added in syrup of step 10.
12) Check the pH of syrup of step 11.
13)Hydroxyethyl cellulose was added to syrup of step 12 under stirring.
The said spill resistant formulation is evaluated by performing various tests as follows-
Viscosity:
Viscosity is measured using a Brookfield Viscometer with S-96 Spindle with helipath
movement at 20 RPM and 20-25°C.
Shaking:
A lab shaker was used to demonstrate the test. The test was performed on lab shaker
for 5 minutes and then spillage was measured by tilting the spoon at a 90° angle.
Tilting:
Measurements were made to determine the time at which the products tend to come
off the spoon. The test was carried out by tilting spoon at a 90° angle and monitor the
product slidding off the spoon.
Inversion:
The test was carried out for measurement of comparative spilling of the product from
a spoon, when inverted (turned upside down). The test was performed by inverting
spoon at a 180° angle.
The spill resistant properties of the formulation are represented in Table 6.

Table 6

Spill resistant/ Resistant Properties
pH Value Viscosity (cps) (S-96, 20RPM) Inversion
(sec) Shaking
(sec) Tilting (sec) Non spill characteristic
4.0-5.0 20433-21792 cps 4min 20sec 2min 30sec 4min 40sec Yes
Following table represents results for stability studies performed at different set of temperature & relative humidity.
Table7

Parameters to be Monitored Initial 40°C/75%RH 3 Months 25°C/60%RH 3 Months 30°C/65%RH 3 Months
Appearance Clear transparent gel Complies Complies Complies
pH Value 4.51 4.51 4.5 4.48
Assay
Paracetamol 97.40% 98.90% 98.60% 98.30%
Phenylephrine hydrochloride 99.10% 90.60% 97.80% 98.30%
Chlorpheniramin e Maleate 99.80% 105% 96.90% 98.10%
The above table assures stability of formulation, which remains constant over the period of time at different storage conditions.

We Claim:
1) A stable spill resistant syrup composition comprising :
2.5 to 7.5% paracetamol or its salt, 0.1 to 0.2% phenylephrine
hydrochloride, 0.02 to 0.06% chlorpheniramine maleate;
1.5 to 1.8% viscosity modifier selected from hydroxyethyl cellulose, methyl
cellulose, hydroxyl propyl cellulose and microcrystalline cellulose;
0.8 to 5%> buffering agent selected from sodium citrate and citric acid
monohydrate;
0.1 to 0.5% chelating agent selected from sodium citrate, citric acid
monohydrate and disodium edetate;
0.01 to 0.2% preservative selected from sodium methyl paraben, sodium
propyl paraben, benzoic acid, sorbic acid and potassium sorbate;
0.01 to 0.4% antioxidant selected from sodium metabisulfite, sodium
sulfate, butylated hydroxyanisole, butylated hydroxytoluene, beta carotene,
alpha tocopherol, propyl gallate, sodium ascorbate, sodium bisulfite and
ascorbic acid; and,
10 to 30% co-solvent; selected from propylene glycol, glycerine and
polyethylene glycol.
2) The stable spill resistant syrup composition of claim 1, further contains sugar, sweetener, coolant, flavouring agent and colorant.
3) The stable spill resistant syrup composition of claim 1 and claim 2, wherein sugar is selected from sucrose, fructose, sorbitol, xylitol, glycerol, liquid glucose and artificial sweeteners like sodium saccharin, ammonium and sodium glycyrrhizinate, sucralose and aspartame.
4) The stable spill resistant syrup composition of claim 1 and claim 2, wherein sweetener is selected from sucrose, fructose, sorbitol, xylitol, glycerol, liquid glucose, sodium saccharine, sucralose, ammonium and sodium glycyrrhizinate and aspartame.
5) The stable spill resistant syrup composition of claim 1 and claim 2, wherein coolant is selected from menthol, eucalyptus oil, camphor, clove bud oil and peppermint oil

6) The stable spill resistant syrup composition of claim 1 and claim 2, wherein flavouring agent is selected from butterscotch, vanilla, essence rose, cherry, mint and citrus.
7) The stable spill resistant syrup composition of claim 1 and 2 wherein colouring agent is selected from quinolone yellow, sunset yellow, erythrosine, and brilliant blue.
8) The stable spill resistant syrup composition of claim 1, wherein the pH of composition is between 4 to 5.5.
9) The process to prepare pharmaceutical composition of claim 1, comprises of following steps:

a) Preparing solution by mixing of at least one preservative and at least one chelating agent in water.
b) Preparing sugar syrup by adding at least one sugar to the mixture of step a) and filtering syrup with suitable filtration techniques.
c) Dissolving at least one buffering agent and at least one antioxidant in water. Transferring this mixture to syrup of step b).
d) Dissolving the paracetamol with heated cosolvent. Adding paracetamol solution to syrup of step c).
e) Separately dissolving chlorpheniramine maleate and phenylephrine hydrochloride in water. Adding of individual solutions to syrup of step d).
f) Dissolving the at least one sweetener in water and adding to syrup of step
e).
g) Adding coolant in cosolvent. Mixing this solution to syrup of step f),
h) Adding flavouring agent to syrup of step g).
i) Checking the pH of solution and making the volume with water. j) Adding hydroxyethyl cellulose under stirring to syrup of step i)
9) The process to prepare pharmaceutical composition of claim 1, comprises of following steps:
a) Preparing solution by mixing of at least one preservative and at least one chelating agent in water.

b) Preparing sugar syrup by adding at least one sugar to the mixture of step a) and filtering syrup with suitable filtration techniques.
c) Separately dissolving chlorpheniramine maleate and phenylephrine hydrochloride in water. Adding of individual solutions to syrup of step b).
d) Dissolving at least one buffering agent, at least one sweetener and at least one antioxidant in water. Transferring this mixture to syrup of step c).
e) Dissolving at least one buffering agent in water and adding to syrup of step d).
f) Dissolving the paracetamol with heated cosolvent. Adding paracetamol solution to syrup of step e).
g) Adding coolant in cosolvent. Mixing this solution to syrup of step f).
h) Adding flavouring agent to syrup of step g).
i) Adding colouring agent to syrup of step h).
j) Checking the pH of syrup of step i).
k) Adding hydroxyethyl cellulose under stirring to syrup of step j).