FORM2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION: 'An improved process for preparation of Glucosamine:! buprofcn complex"

2. APPLICANT (S)
(a) NAME: Centaur Chemicals Pvt. Ltd
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Centaur Chemicals Pvt. ltd. Centaur House, shanti Nagar,Vakola, Santacruz (e) Mumbai 400055. Tel No. 022- 66499144 Fax No. 022-66499108/112.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to
be performed.



An improved process for preparation of Glucosamine:Ibuprofen complex.
Field of Invention:
The novel process mainly directed to the commercially feasible preparation of Glucosamine:Ibuprofen complex and other NSAIDs. The formula of Glucosamine:Ibuprofen complex (formula-I) is represented below.

Background of Invention:
The salt or mixture of glucosamine or glucosamine sulphate and therapeutic drugs such as Aspirin (US 3, 008874), Ketoprofen (US 6,291,527 Bl), Acetaminophen (US2001/0046971A1), Ibuprofen, Diclofenac sodium, Sodium valporate (WO2006/119844) are reported in the literature. The complex of glucosamine with acidic
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drug are either reported as a solid form or in liquid form. The usefulness of these complexes as controlled release dosage is given in WIPO application WO2006/119844.
As per United state application US2001/0046971 patent, the glucosamine salt is mixed mechanically with analgesic drug.The resulting physical mixture is used for the osteoarthritis.
The drawback of the process is that, it is not feasible industrially to manufacture such complex on large scale, moreover the physical complex of glucosamine salt with analgesic drug does not have uniformity as a drug substance.
The preparation of ketoprofen: glucosamine salt in aqueous solution is described in United States patent US 629I527B1. In this patent, the use of glucosamine and ketoprofen in aqueous solution is described after adjusting the pH of solution to 7.
The main disadvantage of such aqueous solution of the glucosamine and acidic drug is stability of the preparation. Also on large scale the addition of preservative or maintaining aseptic condition could be a limiting factor.


The WIPO application WO2006/119844, describes the complex formation of glucosamine and sodium or potassium salt of acidic drug .The aqueous solution of such ionic complexes are undesirable due to presence of sodium and potassium.
As per US 2007/0249735A1 patent, the halide free glucosamine base is mixed with ibuprofen in methanol. The complex is isolated by stripping out methanol under vacuum at low temperature. In another example,the glucosamine base is reacted with acidic drug in water at 35~45°C, followed by freeze drying of the sample to obtain glucosamine-drug complex.
According to above prior art, there is still need of a cost effective and commercial process for preparation of Glucosamine: Ibuprofen complex. In our embodiment glucosamine base which is free from any salt forms the complex with acidic drug such as ibuprofen or (S)-ibuprofen in water.The isolated complex by such method is free from any ibuprofen as indicated by Differntial Scanning Calorimetry.(DSC). Also the process of the preparation does not involve costly unit operation such as freeze drying. From above advantages the process is more acceptable for large scale preparation.
In another embodiment the complex formation of glucosamine base and analgesic drug such as ibuprofen or (S)-ibuprofen is much more convenient due to ease of preparation. Due to precipitation of complex from aqueous solution and uniformity of drug substance in complex is superior as compared to physical mixing. Also glucosamine base drug complex is isolated from water found to have better solubility in water as that of complex isolated from organic solvent.
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Object of Invention:
The main object of present invention is to provide an improved, industrially applicable
and commercially feasible process along with ease of operation over the existing prior
art.
Summary of invention:
This invention mainly directed to the noveI,industrially applicable and commercially
feasible process for the preparation of Glucosamine:Ibuprofen and Glucosamine:(S)
Ibuprofen complex.The invented process is carried out under mild condition is without
usage of costly unit operation like freeze drying.
This method further provides benefits relative to previously used or suggested preparation of methods. For example, the isolation of complex in solid form, absence of moisture in complex, absence of sodium or potassium in complex, improved solubility of the complex in water and ease of preparation. Importantly the present method is industrially feasible and cost efficient.
According to present invention, the preparation of Glucosamine: Ibuprofen complex involves following steps:
Step-I
The halide free glucosamine prepared by reacting lithium hydroxide with glucosamine hydrochloride at reflux temperature in methanol, furthermore reacted with ibuprofen at 30-40 °C in water for 10 minutes furthermore cool the reaction mass to 0-5 °C for 48 hrs and isolate the complex by filtration.


Step-II
The isolated solid from step-I is resuspended in water cooled and filtered. The solid isolated were dried under vacuum at 30-40 °C. The obtained solids is sludged in cyclohexane and dried under vacuum 30-40 °C .This invention encompasses an improved method of preparation of Glucosamine:Ibuprofen complex which has been well illustrated in forgoing examples.
Detailed Description of Invention:
While the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. This improved process for preparation of Glucosamine: Ibuprofen complex carried out in two steps which have been well illustrated as follows:
Step-I:
The halide free glucosamine (1.0 to 2.0 moles) is stirred with ibuprofen (0.8 to 1.2 moles) in purified water at 30-40 °C for 10 to 60 minutes solid start separating out after the complexation.The reaction mixture is cooled to 0-5 °C for 35 to 50 hrs.The solids obtained are filtered.


Step-II:
The filtered solid from step-I is resuspended in water (3 to 5 parts) at room temperature
and stirred for 1-2 hrs at 20-30 °C .The solids are filtered and washed with water and
sucked dry. The obtained solids are dried at 30-40 °C under vacuum (l-10mm) till
moisture level comes down to 0.5% w/w.
The dried solids are resuspended in 5-10 parts of cyclohexane at 25-35 °C.The suspension
is stirred for 30-45 minutes at same temperature .The solids are filtered and washed with
2 parts of cyclohexane and dried at 30-40 ° C under vacuum.
The Glucosamine: Ibuprofen complex obtained is characterized by DSC and XRD.
The melting point of Glucosamine:Ibuprofen complex is 140.99 °C The diffential scanning calorimetry showed only one endotherm mark at 142 °C that indicates the pure Glucosamine: Ibuprofen complex (Figure-I)
The use of different proportion of glucosamine in the formation of Glucosamine: Ibuprofen complex is also studied, it is seen that the equimolar proportion of glucosamine and ibuprofen when used in complex formation, the isolated complex invariably shows un-reacted free ibuprofen in isolated Glucosamine: Ibuprofen complex (Figure-II). The r increased molar proportion of glucosamine base when used with comparison to ibuprofen, the isolated Glucosamine: Ibuprofen complex shows decrease amount of free ibuprofen The optimum result is obtained when 1.6:1 molar proportion of glucosamine base is used as compared to ibuprofen in the complex formation .Further increments in


molar ratio of glucosamine in complex formation led to decrease in the yield of final product.
The (S) ibuprofen is also reacted with halide free glucosamine in purified water at 30-40 °C to 1-12 hrs .The Glucosamine:(S)-Ibuprofen complex is isolated by filtration at low temperature .The final complex obtained by re-suspending the above solid in water followed by filtration and drying of the product. The dried product was again suspended in 5-10 parts of cyclohexane at room temperature and stirred for 30-45 minutes. The solids obtained by filtration are dried at room temperature under vacuum. The complex of Glucosamine: (S) Ibuprofen is characterized by DSC and XRD .A single endotherm at 141.47 °C in DSC indicated the formation of complex without free ibuprofen.
Without further description, it is believed that one of ordinary skill in the art can use the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following examples are given to illustrate the present invention. It should be understood that the invention is not to be limited to the specific conditions or details described in this examples.
Example: 1
Preparation of halide free glucosamine base
Charged glucosamine hydrochloride (50.0gms) and methanol (500ml) in 1 lit RB. Flask The reaction mixture stirred at room temperature for 10 min. The reaction mixture is cooled to 15-20 °C in an ice water bath. Lithium hydroxide monohydrate (10.7 gms) is added to the above slurry over a period of 10 min. at 18-20 °C .The clear solution obtained was stirred at 15-20 °C for further 2 hrs. The solid product obtained was filtered


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and sludged in methanol (105 ml) at room temperature for 1 hr. The glucosamine base thus formed was filtered and dried under vacuum at room temperature. Yield = 33.3 gms
Example-II
Charged glucosamine base (29.6 gms) and water (280 ml in 500 ml RB flask .The reaction mixture (clear solution) was heated to 35-37 °C. Pulverised ibuprofen (20 gms) is added in small lots over a period of 10 min. The clear solution is stirred at 35-37 °C for further 10 min.The reaction mixture was filtered and clear filtrate cooled to 0-5 °C for 48 hrs. The reaction mass is filtered and suck dried. Glucosamine: Ibuprofen complex was sludged in water (110 ml) and stirred for 1-2 hrs at 20-30 0C- Filtered and suck dried, the complex was dried under vacuum at room temperature. Furthermore, the dried solids were resuspended in 5-10 parts of cyclohexane at 25-35 0C.The suspension is stirred for 30-45 minutes at same temperature.The solid were filtered and washed with 2 parts of cyclohexane and dried at room temperature under vacuum-
The Glucosamine: Ibuprofen complex obtained was characterized by DSC and XRD. Yield: 14.00 gms.


Claims:
1) An improved process for preparation of Glucosamine: Ibuprofen complex of formula-I

Comprising steps:
a) Forming a clear solution of Glucosamine base in water at 35-37 °C.
b) Furthermore, forming a solid complex with Ibuprofen by lot wise addition of pulverized ibuprofen to glucosamine solution at temperature 35-37°C and continues for 48 hrs to get complete precipitate of Glucosamine: Ibuprofen complex.
c) Filtering the resultant Glucosamine:Ibuprofen complex at 0-5°C and re-suspending in water, followed by sludging in cyclohexane to obtain stable, water free Glucosamine:Ibuprofen complex in solid form which is characterized by DSC (Differential Scanning Calorimetry) and XRD (X-ray diffraction)
2) The process of claim 1(b), wherein mole ratio for Glucosamine and ibuprofen is 1.6:1 to exert complete formation of ibuprofen:glucosamine complex .


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3) The process of claim 1(c), wherein Glucosamine: Ibuprofen complex mentioned in above said process is in solid form, which has moisture content below 0.5 % w/w and having good stability.
4) The process of claim 1, where (S)-Ibuprofen can form a complex with glucosamine by using the above same method of manufacturing.