Claims:We claim:
1. An extended release granules of drug comprises 25.00-40.00 %w/w drug as an active ingredient, 3.00-10.00 %w/w hydroxyploymethly cellulose, 1.50-3.50 %w/w polyvinylpyrrolidone K30, 10.00-15.00 %w/w purified water, 1.25-4.25 %w/w co-polymer-1 of methacrylic acid, 1.25-4.25 %w/w co-polymer-2 of methacrylic acid, 0.10-0.25 %w/w dibutyl phthalate, 1.25-4.25 %w/w talc, 20.00-30.00 %w/w isopropyl alcohol, 12.00-22.00 %w/w acetone and pharmaceutically acceptable excipients to form extended release granules of a drug.
2. The extended release granules of drug as claimed in claim 1, where-in the active ingredient may be selected from group consisting of paracetamol / acetaminophen.

3. The extended release granules of drug as claimed in claim 1, where-in the polymers may be selected from group consisting of methyl cellulose based polymer and methacrylic acid based co-polymers.

4. The extended release granules of drug as claimed in claim 3, where-in the methyl cellulose based polymer may be selected from group consisting of hydroxypropyl methyl cellulose, xanthan gum, hydroxyl ethyl cellulose based polymers, ethyl cellulose and hydroxyl poly methyl celluloses of other molecular weights and viscosity.

5. The extended release granules of drug as claimed in claim 3, where-in the methacrylic acid based co-polymers are selected but not limited to eu-dragit RS100, eudragit L100, poly acrylic acid based polymers, polyvinyl al-cohol based polymers, other methacrylates of different molecular weights and viscosity.

6. The extended release granules of drug as claimed in claim 1, where-in the solvents may be selected from group consisting of purified water, iso-propyl alcohol and acetone.

7. The extended release granules of drug as claimed in claim 1, where-in the binders may be selected from group consisting of polyvinylpyrrolidone (PVP K30), gelatin, cellulose derivatives, starch, sucrose and polyethylene glycol.

8. The extended release granules of drug as claimed in claim 1, where-in the plasticizers may be selected from group consisting of dibutyl phthalate, dibutyl sebacate, acetyltributylcitrate, diisonyl phthalate, diisobutyl phtha-late, diisodecyl phthalate.

9. The extended release granules of drug as claimed in claim 1, where-in the anticaking agents may be selected from group consisting of talc, magnesium silicate, tricalcium phosphate, magnesium stearate, calcium silicate, bentonite and aluminium silicate.

10. A method for preparation of extended release granules of drug comprises following steps:
(a) dispensing all the raw materials through a stainless steel scoop and weigh-ing / measuring them accurately;
(b) transferring hydroxypropyl methyl cellulose K200 (HPMC K200) from dispensing area to sifting area where the paracetamol is passed through 12(#) sieve and hydroxypropyl methyl cellulose K200 (HPMC K200) is passed through 100 (#) sieve;
(c) mixing paracetamol and hydroxypropyl methyl cellulose K200 (HPMC K200) properly in a mass mixer at a speed of 1440 rpm for about 5 minutes;
(d) taking purified water in a clean and dried vessel and dissolving polyvi-nylpyrrolidone k30 (PVP K30) into the above dispensed purified water with continuous stirring using a stirrer machine until polyvinylpyrrolidone gets fully dissolved and preparing binder solution properly and pouring the above prepared binding solution slowly into dry mix in mass mixer and mix-ing the solution well till the cohesive wet mass is obtained;
(f) transferring the cohesive wet mass to multi-mill and passing the above prepared wet mass using 12 (#) screen and collecting the prepared granules in bowl for drying and drying the above prepared granules in fluidized bed dryer until moisture content is 1% and the temperature of 60 - 80 °C should be maintained in the fluidized bed dryer ;
(h) sifting the dried granules through 14 (#) sieve and the granules retained below 14 (#) sieve are again placed over 20 (#) sieve and also the granules re-tained above 20 (#) sieve are taken for next process further rest fine granules below 20(#) sieve are kept aside and the specific quantity of dried granules are taken further for coating procedure;
(i) dispensing dried granules, eudragit RS100, eudragit L100, dibutyl phtha-late and talc properly with the use of weighing balance and preparing mix-ture of isopropyl alcohol, acetone and water and dissolving the coating poly-mers in this solution pouring the prepared coating solution into a spraying gun;
(k) placing the above dried granules into coating pan which are passed through 14(#) and 20 (#) sieves and setting the speed of coating pan at about 12 to 14 rpm where the coating solution is sprayed through the spraying gun in which about 5-10 ml solution is sprayed per minute through the spraying gun;
(m) drying of the coated granules with a blower or a dryer by providing hot air to the coating pan after 18.75-25% of coating solution is sprayed over the granules and repeating the process of coating until the entire coating solution is applied over the granules and are dried again with the blower or the dryer and collecting the dried and coated granules from the coating pan and weigh-ing the granules with weighing balance machine.

Dated this 11th day of September 2019 , Description:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
“EXTENDED RELEASE GRANULES OF A DRUG AND METHOD FOR PROCESSING THEREOF”
2. APPLICANT:

1. (A) CHEMOSYN LIMITED.
(B) Indian
(C) 405 Abhishilp, Premchand Nagar Road,
Opp. Keshav Baug Party Plot,
Vastrapur, Ahmedabad-380015
3. PREMABLE TO THE DESCRIPTION:
PROVISIONAL
SPECIFICATION
(See section 10 and rule 13)
The following specification describes the invention. ? COMPLETE
SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to extended release granules of a drug and method for processing thereof for treatment more particularly in pediat-ric and geriatric age groups wherein it has proven efficacy and unmatched safety in these age groups. More particularly, the present invention relates to a method for preparation of extended release granules of a drug exhibiting pharmacological effectiveness of the drug followed by which the pharmacol-ogical effects persists over the desired dosing interval of the said drug.
BACKGROUND OF THE INVENTION
The majority of oral extended release systems rely on dissolution, dif-fusion and/or erosion or a combination of these mechanisms, to generate slower release of drug to the gastrointestinal milieu. Theoretically and desira-bly an extended release delivery device would result in a blood-level time profile similar to that after intravenous constant rate infusion.
Pharmaceutical invention and research are increasingly focusing on delivery systems which enhance desirable therapeutic objectives while mini-mizing the side effects. Modifications by retarding / controlling drug release in oral drug delivery system represent one of the frontier areas of controlled drug delivery system. Such a dosage form offers the major advantage of pa-tient compliance. Extended release dosage forms are designed to retard the release of a drug at a suitable rate in order to maintain plasma drug concen-tration at/above desired levels for an extended or specific period of time whilst minimizing side effects.
Extended Release drug delivery system is also providing a promising way to decrease the side effects of the drug by preventing the fluctuation of the therapeutic concentration of the drug in body and / or reducing the total daily intake of the drug.
On consideration of an example i.e. paracetamol (PCM) which has a short plasma half-life between 2 to 4 hours. Consequently, for ensuring that the plasma levels remain above the targeted level, paracetamol has to be ad-ministered at intervals of every 4 to 6 hours, which makes it inconvenient or impractical since a dosing period will invariably fall during nighttime. Fur-thermore, most standard textbooks recommend a total daily dose of 40 to 60 mg / kg of body weight but to be administered not more than 4 times / day, making it impractical to administer the 60 mg / kg dosing. Even with a 4 time dosing per day which is commonly followed there will be periods between two successive doses where the plasma level will fall below the target which is not desirable.
Considering the plasma drug concentration - profile for a conventional paracetamol tablet or liquid oral formulation, an extended release formula-tion is always desired. The major target of pharmaceutical science is to design a successful and suitable dosage form for effective therapy, considering pa-tient’s needs and compliance.
As mentioned above, extended release dosage forms are designed to retard the release of a drug at a suitable rate in order to maintain plasma drug concentration at/above desired levels for an extended or specific period of time whilst minimizing side effects. Extended release tablets and liquid orals are commonly taken in lower number of doses per day compared with coun-terpart conventional forms that have to be taken in more number of doses per day daily to achieve the desired therapeutic effect. The advantage of adminis-tering an extended release dose of a drug is that it is released over an ex-tended period of time to maintain blood level of the drug at / over the level necessary for therapeutic effects which often translates into better patient compliance, as well as enhanced clinical efficacy of the drug for its intended use.
One such document for determination of a sustained release dry sus-pension of a drug and method for processing thereof which has been dis-closed in patent document EP A 305051 that determines the preparation of a sustained release bilayer tablet containing either 650 or 667mg of paraceta-mol. The sustained release layer is provided by a matrix comprising a mixture of hydroxyethylcellulose and polyvinylpyrrolidone. The potential disadvan-tage of the said document relates to a formulation of a tablet, which cannot be administered to paediatric age group and is also inconvenient to swallow in the geriatric age group. It would therefore be preferble if the dosage form was such that it could be easily and conveniently administered to the paediatric and geriatric age group and yet provide the benefits of desired therapeutic effects throughout the interval between successive dosing and lower number of doses per day.
Another such document for determination of a sustained release dry suspension of a drug and method for processing thereof which has been dis-closed in patent document WO 2016042570 that discloses an extended release formulation of acetaminophen comprising the ready to use formulation In-stamodel with acetaminophen. The invention relates to a preparation process of the said extended release acetaminophen in combination of the ready to use formulation with the basic manufacturing steps of a compressed tablet. The problem associated in the prepared composition of the extended release formulation of acetaminophen involves high costing due to the ready to use formulation and time consuming in context with the constant monitoring of the steps being conducted during the manufacturing process.
Hence, to overcome the above mentioned problems it is desperately needed to invent an effective and an efficient composition and method for preparation of extended release granules of drug which is not subjected to above mentioned problems so that the finally obtained extended release gra-nules of any dug has the desired properties, is lower in cost, user friendly, ef-ficacious and yet which is suitable for treatment.
OBJECT OF THE INVENTION
The principle object of the present invention is to provide extended re-lease granules of drug and method for processing thereof.
Further object of the present invention is to provide extended release granules of drug and method for processing thereof with improved, user friendly, more economical, stable and convenient treatment especially in pe-diatric and geriatric age group.
Another object of the present invention is to provide extended release granules of drug and method for processing thereof which maintains plasma levels above the target level for the entire period or interval between two suc-cessive doses of administration of the drug.
Another object of the present invention is to provide extended release granules of drug and method for processing thereof exhibiting pharmacologi-cal effectiveness of the drug followed by which the pharmacological effects persist over the desired dosing interval of the drug.
Another object of the present invention is to provide extended release granules of the drug and method for processing thereof which prospects that the administered dose of drug that is released over an extended period of time to maintain blood level of the drug at / over level necessary for desired therapeutic effect which often translates into better patient compliance, as well as enhanced clinical efficacy of the drug for its intended use.
Yet another object of the present invention is to provide extended re-lease granules of the drug and method for processing thereof which is to be administered only 3 times a day unlike the available conventional prepara-tions which are to be administered 4 to 6 times a day for an effective relief.
SUMMARY OF THE INVENTION
The present invention relates to extended release granules of the drug and method for processing thereof for the treatment of fever and pain espe-cially in pediatric and geriatric age group. More particularly, it comprises an effective amount of an active ingredient in combination with several other pharmaceutically acceptable excipients. A process for preparation of ex-tended release granules of the drug comprises a wet granulation process to obtain granules which are dried and are sifted to obtain granules of the de-sired size. The granules are then coated through a spray coating process re-sulting to extended release granules of the desired drug. The method perco-lates that the prepared extended release granules of the drug exhibits phar-macological effectiveness of the drug followed by which the pharmacological effects persist over the desired dosing interval of the said drug. The extended release granules of the drug prospects that the administered dose of drug is released over an extended period of time to maintain blood level of the drug at / over level necessary for desired therapeutic effect which often translates into better patient compliance, as well as enhanced clinical efficacy of the drug for its intended use.
BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 illustrates a graph of % drug release versus time with respect to sam-ples collected at Trial-1.
Fig. 2 illustrates a graph of % drug release versus time with respect to sam-ples collected at Trial-2
Fig. 3 illustrates a graph of % drug release versus time with respect to sam-ples collected at Trial-3
Fig. 4 illustrates a graph of % drug release versus time with respect to sam-ples collected at Trial 3 at t6 months.

DETAILED DESCRIPTION
Before explaining the present invention in detail, it is to be understood that the invention is not limited in its application to the details. The invention is capable of other embodiment and of being practiced or carried out in a va-riety of ways. It is to be understood that the phraseology and terminology employed herein is for the purpose of description and not of limitation.
It is to be understood that the extended release granules of the drug is aimed to achieve more predictability and reproducibility to control the drug release, drug concentration in the blood and optimization of the therapeutic effect of the drug by controlling its release in the body with less frequent dos-ing. The sustained drug delivery system reduces the frequency of the dosing and / or increases effectiveness of the drug by maintaining blood level above that required for desired therapeutic effect, reducing the number of doses re-quired per day or maintaining therapeutic effects for the entire duration be-tween dosing intervals.
The extended drug release dosage form is a dosage form that releases one or more drugs continuously over an extended period of time as com-pared to the immediate release counterpart, either systemically or to a speci-fied target organ. Extended release dosage forms provide a better control of plasma drug levels, less dosage frequency, less side effects, increased efficacy and constant drug delivery.
The extended drug delivery system also provides a slower release of drug over an extended period of time which also provides some control, whether this is of a temporal or spatial nature, or both, of drug release in the body, or in other words, the system is successful at maintaining drug level at / above the level required for desired therapeutic effect in the blood or target tissue or cells.
The present invention describes the preparation of extended release granules of drug through a wet granulation process involving a release re-tarding polymer, a binder, purified water, and certain other pharmaceutically acceptable excipients to obtain the granules which were dried, sifted to obtain granules of the desired size and then coated through a spray coating method resulting in extended release of the said drug through the coated granules.
The active ingredient of the present invention is selected but not lim-ited to paracetamol also known as acetaminophen.
Polymers of the present invention are selected but not limited to me-thyl cellulose based polymer and methacrylic acid based polymer. More pref-erably the methyl cellulose based polymer is selected but not limited to hy-droxypropyl methyl cellulose (HPMC), xanthan gum, hydroxyl ethyl cellu-lose based polymers, ethyl cellulose and hydroxyl poly methyl celluloses of other molecular weights and viscosity whereas the methacrylic based pol-mers are selected but not limited to co-polymer of ethyl acrylate , co-polymer of amino methacrylate, poly acrylic acid based polymers, polyvinyl alcohol based polymers, other methacrylates of different molecular weights and vis-cosity. More preferably, HPMC K200 is used as the release retardant polymer in the granulation stage and mix of eudragit RS100 and eudragit L100 are used as release retarding coating co-polymers.
Solvents for dissolution of the coating co-polymers of the present in-vention are selected but not limited to purified water, isopropyl alcohol and acetone.
Binders of the present invention is selected but not limited to polyvi-nylpyrrolidone (PVP), gelatin, cellulose derivatives, starch, sucrose and poly-ethylene glycol. More preferably polyvinylpyrrolidone K30 is used as a binder.
Plasticizers of the present invention is selected but not limited to dibu-tyl phthalate, dibutyl sebacate, acetyltributylcitrate, diisonyl phthalate, diiso-butyl phthalate, diisodecyl phthalate. More preferably dibutyl phthalate is used as a plasticizer.
Anticaking agent / glidant of the present invention is selected but not limited to talc, magnesium silicate, tricalcium phosphate, magnesium stea-rate, calcium silicate, bentonite and aluminium silicate. More preferably talc is used as an anticaking agent / glidant.
It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classi-fied differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in composition of the present invention. One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden.
The present invention provides a method for processing of extended release granules of drug which comprises following stages and steps:

Stage I: Dispensing
Before starting the operation ensure that the manufacturing area should be maintained with the temperature less than 25°C and humidity not more than 55%. Record the temperature and humidity at each stage of manufacturing area at specified time.
The present invention includes a composition of extended release gra-nules of a drug which comprises 25.00-40.00 %w/w drug as an active ingredi-ent, 3.00-10.00 %w/w HPMC K200, 1.50-3.50 %w/w PVP K30, 10.00-15.00 %w/w purified water, 1.25-4.25 %w/w eudragit RS100, 1.25-4.25 %w/w eu-dragit L100, 0.10-0.25 %w/w dibutyl phthalate, 1.25-4.25 %w/w talc, 20.00-30.00 %w/w isopropyl alcohol and 12.00-22.00 %w/w acetone.
Accurately dispense the active ingredient, HPMC K200 and PVP K30 through a stainless steel scoop and weigh them through a weighing balance accurately.
Stage II: Sieving
(i) Transfer the active ingredient and HPMC K200 from the dispens-ing area to the sifting area where the active ingredient is passed through a 12(#) sieve and HPMC K200 is passed through a 100(#) sieve.
(iii) The active ingredient and HPMC K200 are mixed properly in a mass mixer at a speed of 1440 rpm for about 5 minutes.
Stage III: Binding
(iv) Dispense purified water in a clean, dry vessel.
(v) Dissolve PVP K30 into the above dispensed purified water with continuous stirring using a stirrer machine until PVP K30 gets fully dissolved and prepare the binding solution properly.
(vi) Pour the above prepared binding solution slowly into the dry mix in a mass mixer. Mix the solution well till the cohesive mass is obtained.
Stage IV: Wet Milling
(vii) Transfer the cohesive mass to a multi-mill. Pass the above pre-pared wet mass using 12 (#) screen and then collect the granules in the bowl for drying.
Stage V: Drying of granules
(viii) Dry the above prepared granules in a fluidized bed dryer until the moisture content is 1% and the temperature of 60 - 80°C should be maintained in the fluidized bed dryer.
Stage VI: Sifting of dried granules
(ix) The above dried granules after achieving the moisture content of 1% the dried granules are sifted through 14 (#) sieve.
(x) The granules which are below 14 (#) sieve are again placed over 20 (#) sieve for sifting and the granules which are above 20 (#) sieve are taken for the next process and rest fine granules below 20 (#) sieve are kept aside.
(xi) The above dried granules between 14 (#) sieve to 20 (#) sieve are taken further for the coating procedure.

Stage VII: Coating of the dry granules between 14(#) - 20(#)
(xii) Dispense dried granules, eudragit RS100, eudragit L100, dibutyl phthalate and talc properly with the use of a weighing balance.
Stage VIII: Preparation of a coating solution
(xiii) Prepare the coating solution by dissolving the coating polymers in mixture of isopropyl alcohol, acetone and water and pour the prepared coating solution into a spraying gun.
(xiv) The above dried granules which are of the size between 14 (#) and 20 (#) sieves are placed into a coating pan.
(xv) Set the speed of the coating pan with 12 to 14 rpm where the coat-ing solution is sprayed through a spraying gun over the lubri-cated granules gradually until about 5-10 ml solution is sprayed per minute through the spraying gun.
(xvi) After the first coating the granules become wet wherein after some specified quantity of coating solution (about 18.75-25.00% of the total volume of the coating solution) is applied over the granules and then granules are dried with a blower or a dryer by giving a hot air to the coating pan over the prepared granules.
(xvii) Repeat the process for second, third coating and so on until the total coating solution (100%) has been applied over the prepared granules.
(xviii) Further, the above prepared granules are again dried through the blower or the dryer to achieve appropriate drying of the gran-ules.
(xix) The dried granules are taken out from the coating pan and weighed using the weighing balance machine after the comple-tion of the said coating procedure.
The invention is illustrated more in detail in the following example. The example describes and demonstrates embodiment within the scope of the present invention. This example is given solely for the purpose of illustration and is not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope.
Example 1:
One accomplishment of the present invention may be illustrated by preparation of extended release granules of a drug and its preferred excipi-ents ratios are described in Table 1 below:
Composition of the extended release granules of drug i.e. Paracetamol
Table 1: Ingredients utilized in the paracetamol extended release granules
Sr. No. Ingredients Qty taken (%w/w)
1. Paracetamol 33.54
2. Methyl cellulose based polymer (HPMC K200) (15%) 5.03
3. PVP K30 (5%) 1.68
4. Purified water 11.74
Coating materials
5. Methacrylic Acid based co polymer-1
(eudragit RS100) 1.19
6. Methacrylic Acid based co polymer-2
(eudragit L100) 1.19
7. Dibutyl phthalate 0.18
8. Talc 1.19
Coating solution
9. Isopropyl alcohol 25.30
10. Acetone 16.87
11. Purified water 2.11

A process for preparation of extended release granules of a drug i.e. pa-racetamol
Stage I: Dispensing
(i) 33.54 %w/w paracetamol, 5.03 %w/w ,HPMC K200, 1.68 %w/w PVP K30, 13.85 %w/w purified water, 1.19 %w/w eudragit RS100, 1.19 %w/w eudragit L100, 0.18 %w/w dibutyl phthalate, 1.19 %w/w talc, 25.3 %w/w isopropyl alcohol and 16.87 %w/w acetone were dispensed and weighed / measured.
Stage II: Sieving
(ii) The above dispensed 33.54 %w/w paracetamol and 5.03 %w/w HPMC K200 were transferred from the dispensing area to the sifting area where the 33.54 %w/w paracetamol was passed through a 12(#) sieve and 5.03 %w/w HPMC K200 was passed through a 100(#) sieve.
(iii) The above dispensed 33.54 %w/w paracetamol and 5.03 %w/w HPMC K200 were mixed properly in a mass mixer at a speed of 1440 rpm for about 5 minutes.
Stage III: Binding
(iv) 11.74 %w/w purified water IP was taken in a clean, dry vessel.
(v) The binder was dissolved into the above dispensed purified water with continuous stirring using a stirrer machine until 1.68 %w/w PVP K30 gets fully dissolved.
(vi) The above prepared binding solution was poured slowly into the dry mix in the mass mixer. The contents were mixed well till the cohesive wet mass was obtained.
Stage IV: Wet Milling
(vii) The above prepared cohesive mass was transferred to a multi-mill. The above prepared wet mass was passed using 12 (#) screen and then the granules were collected in the bowl for dry-ing.
Stage V: Drying of granules
(viii) The above prepared granules were dried within the temperature range 60 - 80 °C in a fluidized bed dryer until the moisture con-tent is 1% and the temperature of 60 - 80 °C was maintained in the fluidized bed dryer.
Stage VI: Sifting of dried granules
(ix) The above dried granules after achieving the moisture content of 1% the dried granules were sifted through 14 (#) sieve.
(x) The granules which were below 14 (#) sieve were again placed over 20 (#) sieve for sifting, and the granules which were above 20 (#) sieve were taken for the next process and rest fine granules below 20 (#) sieve were kept aside.
(xi) The specified quantity of dried granules between 14 (#) sieve to 20 (#) sieve were taken further for the coating procedure.
Stage VII: Coating of the dried granules between 14 (#) - 20 (#)
(xii) 1.19 %w/w eudragit RS100, 1.19 %w/w eudragit L100, 0.18 %w/w dibutyl phthalate and 1.19 %w/w talc were dispensed properly with the use of a weighing balance.
Stage VIII: Preparation of a coating solution
(xiii) A mixture of 25.3 %w/w isopropyl alcohol,16.87 %w/w acetone and 2.11 %w/w water was prepared and the coating co-polymers were dissolved in this mixture and further the prepared coating solution was poured into a spraying gun.
(xiv) The above prepared dried granules which were passed through a 14 (#) and 20 (#) sieves were placed in a coating pan.
(xv) The speed of the coating pan was set within 12 to 14 rpm where the coating solution was sprayed through a spraying gun over the granules gradually at the rate of about 5-10 ml per minute.
(xvi) After the first coating the granules became wet wherein after some specified quantity of coating solution (about 18-25 % of to-tal volume of coating solution) was applied over the granules and then granules were dried with a blower or a dryer by giving a hot air to the coating pan over the prepared granules.
(xvii) The process was repeated for second, third coating and so on un-til the total coating solution (100%) had been applied over the prepared granules.
(xviii) Further, the above prepared granules were again dried through the blower or the dryer to achieve appropriate drying of the coated granules.
(xix) The dried coated granules were taken out from the coating pan and weighed using the weighing balance machine after the com-pletion of the said coating procedure.

Evaluation study:
The final product was evaluated through various parameters. The final prod-uct i.e. paracetamol extended release granules was used as a sample and was evaluated through various parameters. The parameters for evaluation study are as follows:
i) Description:
The visual examination of sample paracetamol extended release granules was done. The prepared paracetamol extended release granules was white/ odor-less free flowing granules.
ii) Solubility:
The solubility of sample paracetamol extended release granules was checked in water and other common solvents. The sample paracetamol extended re-lease granules were insoluble in water, alcohol and acetone.
iii) Characterization based on flow properties of granules:
A) Bulk density (BD):
Bulk density of a powder is the ratio of the mass of an untapped powder sample and its volume indicating the contribution of the inter-particulate void volume. The bulk density is expressed in grams per ml (g/ml). Bulk den-sity is determined by weighing powder into a dry graduated 250 ml cylinder. The powder was carefully levelled without compacting, volume (VO) was re-corded & bulk density g/ml was calculated using the following formula:
Bulk density = Mass / Volume (Vo)
OBSERVATION:
Table 2: Bulk density of coated granules
No. of trials Bulk density
(g/cc)
1 0.5005
2 0.5010

B) Tapped density (TD):
Tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing a powder sample. After observing the initial powder volume to weight, the measuring cylinder or vessel is mechanically tapped, and volume readings are taken until little (less than1%) further vol-ume change is observed. The mechanical tapping is achieved by raising the cylinder or vessel and allowing it to drop under its own weight at specified distance. Secure the cylinder in the holder of the apparatus with weighed powder sample. Measure 100-200 taps and observe the corresponding vol-umes to the nearest graduated unit
Tapped density = Mass/ Tapped volume
OBSERVATION:
Table 3: Tapped density of coated granules
No. of trials Tapped density
(g/cc)
1 0.5269
2 0.5280

C) Carr’s Index:
The Carr’s Index and Hausner’s ratio are measures of the porosity of a pow-der to be compressed. They measure the relative importance of interparticulate interactions. For poor flow materials, there are frequently greater interparticulate interactions and a greater difference between the bulk and tapped densities. These differences are reflected in the Compressibility Index and Hausner’s Ratio.
Carr’s Index was calculated using the following formula:
Carr’s Index= 100x (TD-BD)/TD
OBSERVATION:
Table 4: Carr’s index of coated granules
No. of trials Carr’s index
(%)
1 5.01
2 5.11

D) Hausner’sRatio:
The Hausner’s Ratio is a number that is correlated to the flow ability of a powder or granular material. Hausner’s ratio is calculated using following formula:
Hausner’s ratio = TD/BD
OBSERVATION:
Table 5: Characterization of the coated granules
Carr’s index (%) Flow character Hausner’s Ratio
< 10 Excellent 1.00-1.11
11-15 Good 1.12-1.18
16-20 Fair 1.19-1.25
21-25 Passable 1.26-1.34
26-31 Poor 1.35-1.45
32-37 Very poor 1.46-1.59
>38 Very, very poor >1.60

Table 6: Hausner’s ratio of coated granules
No. of trials Hausner’s ratio
1 1.0527
2 1.0538

RESULT:
Hausner’s ratio, Carr’s Index, Bulk density, Tapped density were determined to predict flowability. A higher value indicates greater cohesion between par-ticles with higher Carr’s Index is indication of the tendency to form bridges. For both the trials the tapped, bulk density were comparable. Hausner’s ratio and Carr’s Index was little more for trial 2 as compared to trial 1. Results showed that both trials were found to possess good flow characteristic based on these parameters.

iv) Assay:
The UV spectrophotometric assay was performed on Jasco UV Spectropho-tometer using the following method.
Label claim: 0.325 gm of paracetamol/sachet
REAGENTS:
i) 0.1 M Sodium Hydroxide: Dissolve 0.42 g of sodium hydroxide in wa-ter and finally make the volume to 100 ml with water.

GLASSWARES:
i) 100 ml volumetric flask
ii) 200 ml volumetric flask

METHOD:
Test solution: Take 5.0 g coated granules and crush it in a mortar pestle up to fine powder. Weigh accurately 0.2 gm of powder (equivalent to about 0.15g paracetamol) and transfer in a 200 ml volumetric flask, add 50 ml of 0.1M so-dium hydroxide followed by 50 ml of water, shake for 15 minutes, add suffi-cient water to produce 200 ml. Mix and filter the solution with 20-25 µm filter paper. Dilute 10 ml of the clear filtrate to 100 ml with water. Further take 10 ml of this solution in to a 100 ml volumetric flask, add 10 ml of 0.1M sodium hydroxide, and dilute to 100 ml with water. Measure the absorbance of the test solution at the maximum at 257 nm, with blank solution in a reference cell.

Blank solution: Dilute 10 ml of 0.1M sodium hydroxide, to 100 ml with wa-ter.

Calculate the content of paracetamol taking 715 as the specific absorbance at 257 nm.

Spl taken:…………………..gm (0.17g) Test Abs at 257nm :……………….

Formula for Calculation:

%w/w = Test abs x 100 x 100 x 200
715 x 10 x 10 x Sample wt

= x 100 x 100 x 200
715 x 10 x 10 x

= ……….……%w/w

OBSERVATION:
The method for Assay followed is as per the assay of paracetamol tab-lets mentioned in the Indian Pharmacopoeia. Hence it is not necessary to va-lidate the method with respect to precision, accuracy stability, specificity, li-nearity, Limit of Detecting, Limit of Quantification, ruggedness and robust-ness according to ICH guidelines.
The method, being the official pharmacopoeal method, is specific for the quantitative determination of paracetamol in oral solid formulations. Sample solution was analyzed in triplicate after preparation of the drug solu-tion as mentioned above is experimental section. The amount of paracetamol sample was found to be within the range of 95 - 105 % of the labelled amount. None of the excipients were found to interfere with the absorbance of parace-tamol and the results.

v) Dissolution Profile:
The dissolution test was performed through U.S.P. Type- 1 (Basket), 6 Paddle Apparatus.
Label claim: 0.325 gm of paracetamol/sachet
Dissolution Condition:
0.1 M HCL: Mix 8.5 ml of concentrated HCL with 500 ml of distilled water and finally make the volume to 1000 ml with distilled water.
Dissolution Medium: 900 ml 0.1 M HCL
Diluents: 0.1 M HCL
Apparatus: Paddle type
Speed: 50 rpm
Temperature: 37°C ± 0.5°C
UV Wavelength: 280 nm
Procedure:
Maintain the above said condition during the dissolution time (up to 4 hours). After completion of 15 minutes filter 10 ml the dissolution medium from each bowl with 0.45 µm filter paper. Replace 10 ml dissolution medium to each bowl and run the apparatus up to further specified time. Transfer 1 ml of the filtered dissolution medium to 50 ml volumetric flask and finally make the volume to 50 ml with diluents. Measure the absorbance of sample solution at 280 nm using 0.1 M HCL as blank. Repeat the procedure for sample solution after 30 mins / 1 hr / 2 hr / 3 hr / 4 hr / 5 hr (if required). Similarly make the concentration of paracetamol standard solution with same diluents and measure the absorbance at 280 nm.
CALCULATION:
Calculate the percentage of paracetamol content per sachet by below men-tioned formula for said time interval:

% of Paracetamol per sachet =
Absorbance sample x weight of standard x 900 x 50 x % purity of std x100 -% LOD
Absorbance of standard x100 x 0.325 x 1 x 100 x 100

OBSERVATION:
Table 8: Amount dissolved with respect to time
Sr.No. Time interval Amount dis-solved (%) (Lim-its)
1. 30 minutes 15 to 35
2. 60 minutes 35 to 55
3. 3 hour NLT 80%

Table 9: In-vitro data trials with detailed sampling
Time
(minutes) Dissolution (Average) of 6 baskets (%)
T1 T2 T3 T3 180 days (6 month stability)
0 0 0 0 0
15 16.62 13.46 11.38 13.77
30 25.81 30.37 24.65 27.83
60 47.57 37.7 41.61 45.44
120 78.64 67.51 72.01 72.73
180 97.44 84.85 86.33 87.64
240 103.09 94.94 99.32 99.45
300 -- 98.95 -- --

It was observed that the data was found to be similar even after 6 months on conducting the stability study of the prepared paracetamol extended release granules.
RESULT:
The developed and characterized extended release granules of parace-tamol, after oral administration could prolong the therapeutic action and in-crease the bioavailability of the drug. In order to provide the extended release of the drug paracetamol for providing therapeutic effects for the entire dura-tion between doses and to minimize the dose dependent side effects as well as to improve patient compliance the said extended release granules was formulated. As compared to immediate release formulation of paracetamol, the extended release granules will have the desired therapeutic effect in a sus-tained manner with constant fashion over extended period of time i.e. for the entire dutration between successive doses. Therefore, the prepared paraceta-mol formulation i.e. extended release granules of paracetamol were found to have characteristics of an optimized formulation.

Although the example as well as the process of preparation and use that has been specifically described, it should be understood that variations in the preferred embodiment could be achieved by a person skilled in the art without departing from the spirit of the invention. It is also to be understood that the present invention is given with the understanding that this invention is intended only to be an illustration without serving as a limitation on the scope of the invention as defined in the claims.