DESCRIPTION :

The present invention provides a process for the removal of residue on ignition by the use of nanofiltration technique during the process of preparation of active pharmaceutical ingredient (API). The active pharmaceutical ingredient (API) includes of ropinirole, trauxrutin, fexofenadine, ioversol and iohexol and its pharmaceutically acceptable salts.

US patent No 6,068,705 discloses a process for producing a low DE starch hydrolysate, involves fractionating a starch hydrolysate.

US patent No 6,187,195 relates to inhibition and delay of deposit formation in membrane processes.

US patent No 5,308492 relate to process for the purification of industrial waste-waters by nanofiltration.

US patent Nos 5,342,521 and 5,266,207 relate to a reverse osmosis or nanofiltration membrane and to its production process.

Processes for the preparation of active pharmaceutical ingredient (API) require removal of residue on ignition (ROI) to desirable limits. Residue on ignition may comprise undesirable inorganic constituents. The pharmaceutically active ingredient comprising the residue on ignition formed as a result of a reaction in its process of preparation. The presence of residue on ignition resulted the lowering the assay of active pharmaceutical ingredient (API) and also makes them unsuitable to use.

Removal process for the reduction of ROI to desirable limits requires performing series of unit operations of the filtrate comprising the active pharmaceutically ingredient, sometimes performing more than once the series of unit operations or any one of them. The time requirement for each of the unit operations or series of unit operations may be several hours. For example the unit operations may be any one or more of the following; crystallization, filtration, drying, evaporation, condensation, gas absorption and adsorption and acid base transformation.

The present inventors while developing processes for the preparation of preparation of active pharmaceutical ingredient (API) encounter problem in reduction of residue on ignition to desirable pharmaceutically acceptable limit. The inventors have developed a process of removal of residue on ignition using nano filtration technology. The process includes of use of membrane separation process to reduce the overall process time by several hours and makes the process free from use of many unit operation equipments and release of the capacity of several unit such as crystallizers, dryers, filtration equipments. The nanofiltration technique reduces the residue on ignition to a desired value which other wise would not be possible to achieve by the use of conventional unit operations and be economical and less laborious.

In one of the aspects of the invention the solution of the active pharmaceutical ingredient (API) comprising the residue on ignition (ROI) constituents above the desirable limit may be subjected to removal by the use of a membrane separation process such as nanofiltration to reduce the residue on ignition (ROI) below the desirable limit.

The membrane separation process may comprise circulating the solvent washed filtrate through the cartridge comprising the chosen membrane material. The reaction mixture where final isolation of the active pharmaceutical ingredient is to be performed may also be used to pass through the membrane to get the active pharmaceutical ingredient directly from reaction mixture free from residue on ignition. In case where isolated active ingredient has residue on ignition more than the desirable limit may also be dissolved in a suitable solvent to form a solution and prepared solution may undergo filtration through membrane i.e. nanofilteration. Periodic check of the conductivity of the permeate liquid followed by solvent washing of the filtrate till permeate liquid conductivity is of desired value may ensure retain liquid is of adequate purity for further processing to obtain the pharmaceutically active ingredient of less than or equal to the desired residue on ignition (ROI). The desired value of the conductivity of the permeate liquid may vary from 0.05 to 100 µs/cm.

The membrane separation process known as nanofiltration is essentially a liquid phase one because it separates a range of inorganic and organic substances from a solution in a liquid. The mass transfer mechanism in nanofiltration is diffusion. Membrane allows the diffusion of certain ionic solutes (such as sodium and chloride), predominantly monovalent ions, as well as water. Larger ionic species, including divalent and multivalent ions and more complex molecules are highly retained.

The nanofiltration membrane for the removal of active pharmaceutical ingredient (API) may be selected from the group having a molecular weight cut-off of less than 1000 daltons.

The desirable limit of residue on reduction (ROI) may be less than or equal to 0.1% in the pharmaceutically active ingredient.

Permeate liquid is the liquid which passes through the membrane. Retain liquid is the liquid which does not pass through the membrane.

Molecular weight cut offs (MWCOs) can be defined as the molecular weight at which 50 -90% of the analytes (or solutes) are prohibited from membrane diffusion.

The process of removal of residue on ignition from the active pharmaceutical ingredient ropinirole comprising residue on ignition 1% or more may be subjected to removal by the use of a membrane separation process such as nanofiltration to reduce the ROI to below 0.1%.

The removal of residue on ignition process includes, making solution of active pharmaceutical ingredients in suitable solvent and includes circulating the solution through the cartridge comprising the chosen membrane material. Periodic check of the conductivity of the permeate liquid followed by solvent washing of the filtrate till the desired conductivity of permeate i.e. 50 µs/cm may ensure retain liquid is of adequate purity for further processing to obtain the pharmaceutically active ingredient of less than or equal to the desired ROI. Solvent may be recovered at atmosphere pressure as well as under reduced pressure. The pure active pharmaceutical ingredient may be isolated by the concentration of the solvent or by addition of anti-solvent to get product with residue on ignition 0.1% or less.

The active pharmaceutical ingredients include but not limited to ropinirole, trauxrutin, fexofenadine, ioversol and iohexol and its pharmaceutically acceptable salts.

The term suitable solvent used herein the solvent that are capable of dissolving API, includes of polar protic as well as aprotic solvent those may be hydrocarbons, esters, ether and halogenated solvents.

The examples of these solvents include of dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide, formic acid, n-butanol, isopropyl alcohol, n-propanol, ethanol, methanol, acetic acid and water.

The term anti-solvent used herein defined as the solvents, which have low polarity, and in those active pharmaceutical ingredient is practically insoluble as defined in US pharmacopoeia.

The antisolvent may be from the group of alcohols, ether, ketone and hydrocarbons for example isopropyl alcohol, isopropyl ether, methyl ethyl ketone, methyl isobutyl ketone, hexane, pentane and the like.

The nanofiltration membrane for the removal of residue on reduction of ropinirole HCl may be selected from the group having a molecular weight cut-off of less than 300 daltons.

The nanofiltration membranes are the key to the performance of nanofiltration systems. They are produced in plate and frame form, spiral wound, tubular, capillary and hollow fiber formats, from a range of materials, including cellulose derivatives and synthetic polymers, from inorganic materials, ceramics especially, and from organic/inorganic hybrids. Nanofiltration membrane made of organic material may be polysulphone, cellulose acetate, polyamide or PVDF. Nanofiltration membrane made of inorganic materials may be such as TiO2, ZrO2 or Al2O3. Nanofiltration membranes may be selected from the commercially available group consisting of ASP40 and ASP50 (manufactured by Advanced Membrane Technology), and GH and GE, (manufactured by Osmonics/Desal) or other known brands.

Nanofiltration membranes allow to a greater or lesser extent, the passage of low molecular weight, water-soluble inorganic substances, especially salts, while low molecular weight organic substances with a molecular weight of more than 1000 Daltons are more or less totally retained. The retention coefficient of these membranes also depends on hydrophilic/hydrophobic properties of the substances to be filtered. Usually hydrophobic substances are preferably retained. Such membranes are generally characterized by a retention coefficient e.g. for NaCl of almost 0% and for Na2 SO4 of about 20%.

Nanofiltration membranes have extended their capabilities in very high or low pH environments and their application to non-aqueous liquids. The plastic media are highly cross-linked, to give long-term stability and a practical lifetime in more aggressive environments. Membranes tend to have a slightly charged surface, with a negative charge at neutral pH. This surface charge plays an important role in the transportation mechanism and separation properties of the membrane.

As with any other membrane process, nanofiltration is susceptible to fouling, and so nanofiltration systems must be designed to minimize its likelihood – with proper pretreatment, with the right membrane material, with adequate cross-flow velocities to scour the membrane surface clear of accumulated slime, and by use of rotating or vibrating membrane holders.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example: Removal of residue on ignition of form isolated ropinirole HCl

Dissolved Ropinirole (ROI 9.0%) (50 gm) in methanol (900ml) and charged the filtrate in nanofiltration equipment having cartridge 150 Dalton. Circulated the filtrate through the cartridge and permeate liquid was collected. The collected liquid was concentrated under reduced pressure at around 500C. In the residue isopropyl alcohol was added under stirring and mixture was cooed to 25 - 300C and further stirred for 2 hours. The product was filtered washed with isopropyl alcohol and dried.
Yield: 45 gm
Residue on ignition (w/w): 0.1%
Assay: 99.3% (HPLC)

Example: Removal of residue on ignition of ropinirole HCl from reaction mixture
Charged [2-Nitro-6-2- (N, N-di-n-propylamino) ethyl) phenyl] acetic acid hydrochloride (100 g) in methanol (2.0 L) in hydro generator. Added palladium catalyst (12.5 g) and water (50 ml) and hydrogenate under hydrogen pressure of 4.0-5.0 kg/cm2 at 45-500C for 3-4 hours. After completion of the reaction cool to room temperature, Filtered and used the filtrate for nanofiltration in nanofiltration equipment having cartridge 150 Dalton. Pumped the filtrate through the cartridge and collected permeate liquid in a separate vessel. Retained liquid was circulated through the cartridge, washed with water. Retained liquid is collected and subjected to removal of solvent under reduced pressure at around 550C. In the residue isopropyl alcohol was added under stirring and mixture was cooed to 25 - 300C and further stirred for 2 hours. The product was filtered washed with isopropyl alcohol and dried.
Yield: 39.0 g
ROI : 0.07%
Assay : 99.43% (HPLC)

We Claim:

1 A process for the removal of residue on ignition from the active pharmaceutical ingredient comprising the steps of;
(a) solution of the active pharmaceutical ingredient in a suitable solvent
(b) filtering (a) by membrane separation process comprising permeate and retain liquid,
(c) isolating retain liquid of (b) when the conductivity value of the permeate liquid is in the range of 0.05 to 100 µs/cm..
2 The process of claim 1, wherein the pharmaceutically active ingredient is ropinirole, trauxrutin, fexofenadine, ioversol, iohexol and its pharmaceutically acceptable salt.
3 The process of claim 1 wherein, suitable solvents are polar protic, aprotic solvent and those are hydrocarbons, esters, ether and halogenated solvents.
4 The process of claim 1 wherein, membrane separation process is nanofiltration.
5 The process of claim 1 wherein, isolation of active pharmaceutical ingredient after membrane separation process is by removal of solvent or by addition of anti-solvent.
6 The process of claim 5 wherein, antisolvent is one or more mixture of isopropyl alcohol, isopropyl ether, methyl ethyl ketone, methyl isobutyl ketone, hexane and pentane.
7 The process of claim 1 wherein, reduction of residue on ignition is less than or equal to 0.1% in the pharmaceutically active ingredient.
8 The process of claim 1 wherein the residue on ignition comprises inorganic substances.
9 The process of claim 1 wherein the membrane material is made of either organic material or inorganic material.
10 The process of claim 9 wherein the organic material is polysulphone or cellulose acetate or polyamide or PVDF and inorganic material is TiO2, ZrO2 or Al2O3.