|Title of Invention||
AN IMPROVED SINGLE STAGE PROCEDURE FOR THE SYNTHESIS OF CROSS-LINKED POLYALLYLAMINE HYDROCHLORIDE
|Abstract||The invention describe the method for production of a polymerized cross linked poly allyl amine hydrochloride polymer which comprises a first step of polymerizing a allyl amine hydrochloride and a second step of cross linking the said polymer, wherein the said method charaterized in the continuous production of a cross linked poly allyl amine hydrochloride polymer which carries out continuously the said two steps.|
|Full Text||FIELD OF INVENTION
Cross-linked polyallyl amine hydrochloride polymer, also known as Sevelamer hydrochloride, is a commercially important polymer. It is completely insoluble in water and many organic solvents. In water it is known to form a viscous gel. Being an ionic polymer it is capable of functioning as an ion-exchange polymer. It has been shown to be a good phosphate binder. Commercially it is used as a drug to remove excess phosphate from the human body, especially in renal patient (patients with kidney disorders).
Sevelamer is a phosphate binding drug to prevent hyper phosphataemia with renal failure. When taken with meals, sevelamer binds to diatary phosphate & prevents its absorption. It is sold by Genzyme under the name Renagel® and many other companies also sell sevelamer as a drug.
Sevelamer is a copolymer of 2-(Chloromethyl)oxirane(epichloro hydrin) and prop-2-en-i-amine (allyl amine). The sevelamer hydrochlride is a partial hydrochloride salt being present as approximately 40% amine hydrochloride and 60% sevelamer base. The amine groups of sevelamer become partially protonated in the intestine and interact with phosphorus molecules through ionic and hydrogen bondings.
The reported method for the production of sevelamer hydrochloride involves two stages. In the first stage allyl amine hydrochloride is polymerized and polyall amine hydrochloride is isolated and purified. In the second stage polyallyamine hydrochloride is cross - linked with various cross - linking agents to get a gel-like polymer which is purified and dried. The steps involved in this two-stage process are given in the following flow charts(Chart 1 and 2).
There are many methods known in prior art for preparation of sevelamer. The compound and its preparation and use are covered in US 5496545, US 5667775 and WO 95/05184. The preparation is also covered in US 5487888, US4605701 and US5428347, US5496545, US5667775, WO 95/05184, US5487888, US4605701, US 4528347, US 6423754, US 6926912 and US 6600011 all describe the process, but none have addressed the core problematic issue relating to the unnecessary difficult intermediate step between the polymerization and cross linking.
There are many problems and disadvantages in the two stage process as practiced in prior art, which are described herein. Sevelamer Hydrochloride is a commercially important polymer, used in many applications. Simplification of the procedure for its synthesis in terms of cutting down the number of stages, usage of large quantities of solvents in its synthesis is a desirable goal. The present methodology involves a two - stage process. The product obtained in the first stage, namely polyallyl amine hydrochloride, is very deliquescent and difficult to hand under atmospheric conditions. It is also highly corrosive. Large quantities of toxic solvents such as methanol are used in the purification of the first stage product. Upon storage product of the first stage turns into a viscous liquid (due to its deliquescent nature). Due to its finite solubility there is loss of material during the purification process of this product.
In known art for e.g., the allyl amine hydrochloride is firstly polymerized, secondly purified and finally cross linked in the presence of cross linking agent. Disadvantages of such a process are that the intermediately product is very deliquescent and difficult to handle under atomosphreic condition and due to its corrosive nature it is difficult handle.
This has been discussed in many articles including Reference : Holmes Farley and others, Phosphate binding polymer for oral administration, US patent 5,496,545 (1996), PCT Int.appl. 1996, W O 9621454.
The prior art has been defined by flow charts herein. The flow charts l and 2, illustrate the stage 1 and stage 2 of prior art respectively, above described.
OBJECTS OF INVENTION:
The first object is simple single pot process is aimed at and achieved, which involves reacting allyl amine hydrochloride with conventional polymerization agent, immediately thereafter cross linking it with conventional cross linking agent to obtain pure sevelamer hydrochloride polymer.
The second object of the present invention is the process be preferably carried out continuously in all its steps in one pot. However, it is also possible for the polymerization step and /or more or all of these steps of the process to be non-continuous.
DESCRIPTION OF INVENTION WITH DRAWINGS:
The present invention is illustrated in chart 3. The invention and the claims of the present invention is self explanatory as illustrated in the form of flow chart(chart 3).
DESCRIPTION OF INVENTION:
This invention relates to overcoming various degradation and disadvantages during the intermediate process of drying and purifying between the polymerization and cross linking, and thereby eliminating the use of organic solvents etc., and to achieve a method which is a rapid continuous preparation involving cross linking immediately after polymerization process.
The present invention relates to an improved but simpler process for preparing sevelamer hydrochloride..
As per the present invention, it is attempted to achieve a method for preparing a sevelamer hydrochloride, the method comprising:-
a. Polymerization with conventional polymerizing agent, and
b. Cross linking with a conventional cross linking agent.
The reasons for eliminating the intermediate steps are many Polymeric hydrogels experience a cohesive phase at certain levels of moisture content ; wherein the polymer particle adhere to each other and equipment surfaces. So drying the hydrogel is challenging. So if it is a mechanical agitator, it has to be robust. Drying and purifying of polymer is complicated as hydrogels are sensitive to atomosphere and wet polymer hydrogel are subject to undesired oxidation upon thermal treatment also. Controlling the drying atmosphere can add to the cost of manufacturing. The process which avoids the need to control drying and purifying atmosphere is desired by many commercial manufacturers of sevelamer hydrochloride.
The polymer is rendered water-insoluble by cross-linking. A preferred cross-linking agent is epichlorohydrin because of its high availability and low cost. Epichlorohydrin is also advantageous because of its low molecular weight and hydrophilic nature, maintaining the water swellability of the polyamine gel. The level of cross-linking makes the polymer insoluble and substantially resistant to absorption and degradation thereby limiting the activity of the polymer to the gastro intestinal track when it is administers orally as a drug. Thus the compositions are non-systemic in their activity and will lead to reduced side effects in the patient.
Polymers are characterized in part by their ability to absorb water and retain it under pressure. The hydrophilic nature of these materials complicates their purification and drying and consequently increases manufacturing expenses.
Typically polymer hydrogels are isolated from manufacture as wet gels containing impurities from manufacture such as initiator residues, solvents & soluble oligomers. Depending upon their intended application, the polymers
are purified and dried to the extent required. Drying is necessary for transportation and packaging. It also conditions the polymers to absorb large quantity of liquid.
Pharmaceutical applications demand the control of soluble oligomer content and are expected to be insoluble. Soluble components are contaminants or undesired components. Polymer hydrogels are shear sensitive and/or subject to thermal degradation. Purification and drying process can break high molecular weight polymer chains, increasing oligomer concentrations in the product.
It is attempted to simplify existing manufacturing technique to reduce the production costs. It is also desired that the process does not use organic solvents or unnecessary additives, but the end products has high purity standards and also maintains the desired physical and chemical polymer characteristics.
The proposed single stage process eliminates the handling of highly deliquescent and corrosive product produced at the end of the first stage in prior art and also eliminates the usage of large quantities of toxic solvents such as methanol for its purification. The use of solvent, do create by-products or contaminants
The term contaminants as used herein refer to undesired particles present in the hydrogel as a result of chemical reaction in which the hydrogel is produced. Eg. Unreacted chemical reactants, partially reacted chemical reactants, chemical reactions byproducts and these in general are water-soluble and can be removed by wash water medium. The quantity of water is sufficient to atleast remove 95% of contaminants. Repeated washing is necessary to achieve required product purity. There is no specific need for the chemical wash, hitherto followed in prior art.
Sevelamer hydrochloride is manufactured in a batch process. A single-stage process as envisaged in the invention will be more economical and time saving compared to a two-stage process. The proposed method may also be a one-pot process.
Continuous processes generally have, among other advantages, higher thoroughput capabilities, lower capital equipment costs and lower labour costs. An advantage of the present invention is that the method comprising purifying and drying the polymer hydrogel is well suited to continuous processing.
The purification process after polymerization suffers from the inability to exclude the inclusion of by-products created during the washing process. This limitation results in the structured deficiencies in the gel and the purified solid. In order to retain the properties of the gel, it is attempted to regulate and reduce the formation of by-products during the process.
The characteristics described in polymer which is the end product, may not always be the result of multiple steps or sequences followed as per prior art in the preparation. When considered in aggregate the multiple steps, efforts and risks the result reached may not be at satisfactory level as desired against the investment of cost, risk and time factors. It is therefore desirable to prepare a polymer having same characteristic but involving lesser steps and safer steps.
The intermediate wash may lead to dropping of molecular weight as well as generate by-product residues. These changes in the characteristics of polymer are detrimental. There are commercial incentive in deleting the intermediate purifying step since this leads to better economics for production of these polymers. If the physical attributes of the polymers could meet or exceed the
properties now achieved in prior art, the invention provides an effective process with reduced steps and easy steps.
Commercially available sevelamer hydrochloride polymer generally have atleast two steps and improvement in efficiency of the process of preparing the same would be achieved if a single step could be used to achieve a preparation, without loss of required characteristics. This is not only reducing cost directly, but also time which again is cost effective.
Solvents are traditionally used for washing and purifying the poly allyl amine hydrochloride salt in solution as a viscous liquid obtained after the process of polymerization which results in an increase in the number of process steps required to prepare the polymer. There is a need therefore to simplify and improve the efficiency of the preparation process.
The yield of the final product obtained in the single stage process as per invention is higher than that of the two stage process, and The phosphate binding property of the final product from the single stage process is better or equal to that of the two stage process. This is based on the experimental and trial values.
It is evident that sevelamer hydrochloride is a commercially important . product. The prior art manufacturing this material involves two stages. The present application deals with a single stage procedure that is significantly novel and improved from the point of view of manufacturing. Experimental synthesis using single stage procedure reported herein, in 150-220 grams scale reaction have been successful with consistent results.
Experimental procedure for the synthesis of cross-linked polyallylamine hydrochloride by a single-stage process as per the invention: Synthesis of polyallylamine epichlorohydrin cross-linked polymer:
In a three necked flash fitted with a mechanical stirrer, condenser, nitrogen inlet and a thermometer, cooled to + 5°C in an ice bath, was added 155ml of concentrated hydrochloric acid (35% by weight). 100 grams (131.5ml) of Allylamine was taken in the dropping funnel and was added dropwise with vigorous stirring, maintaining the temperature at 5-10 °C. After the addition of allylamine was complete nitrogen was bubbled through the solution for 15-20 minutes to degas the solution. A suspension of 2 grams of 2,2’ - azobis (2-methylproprionamidine) dihydrochloride(initiator) in 5ml water was added and the mixture was heated in an oil bath for 24 h at 5O°C with continuous stirring under nitrogen atmosphere. Another 2 grams of initiator in 5ml of water was added and heating and stirring was continued for another 24 h. once again 2 grams of the initiator in 5ml of water was added and heating and stirring was continued for another 20 h. Thus three aliquot of the initiator was added and the total reaction time was 68h. After this time a thick viscous liquid was obtained. The liquid was transferred to a plastic bucket and diluted with 250ml of distilled water to make up a total volume of 500ml. The pH of the solution was measured to be 1.5. A solution of NaOH was added to adjust the pH of the solution to 10.0. The solution was allowed to stand for 30 min to ensure that the pH remained at 10.0. 14.8 grams (12.5ml) of Epichlorohydrin was added all at once with stirring using a glass rod. The reaction mixture was allowed to stand at room temperature (30-32°C). After 1 h formation of gel was observed. The reaction mixture was left undisturbed for addition 18 h upon which it had turned into a thick transparent gel. The gel was added to 400ml of isopropyl alcohol and mixed well with a mechanical stirrer for 15 minutes until the product precipitated as coarse white particles. It was filtered using a suction pump and the solid thus obtained was suspended in 450ml of distilled water and vigorously stirred for 15 minutes using a mechanical stirrer. Swelling of the product was observed. The initially coarse white solid turned into a transparent thick gel. It was filtered and the process of washing with distilled water was repeated 4 times with addition 450ml of distilled water each time. Finally, the transparent gel
obtained from the above process was suspended in 1.5L of isopropyl alcohol and stirred for 15 min upon which the gel turned into coarse white solid. The solid was filtered using a suction pump and it was dried to constant weight in a vacuum (approximately 5- 10 mm Hg) over at 65-7O°C for 12 hours to obtain 146 grams of white solid product. The yield of the sevelamer hydrochloride is nearly quantitative.
Phosphate uptake studies have been conducted:-
1 grams of sevelamer hydrochloride obtained in the above method was suspended in 100ml of lM solution of sodium dihydrogen phosphate in distilled water. The mixture was stirred using a magnetic stirrer for 18 h at room temperature. Phosphate concentration before and after exchange was estimated using standard EDTA titrimetric method. From the difference in the concentration the phosphate uptake was calculated to be 5.0 milliequivalent per gram of the sevelamer hydrochloride. The literature reported value of phosphate uptake is 3.3 mill equivalents.
The said polymer may be the purpose of at oral administration. Further the pharmaceutical composition are prepared with the said polymers along with carrier for the purpose of administration. The carrier may be solid, semi solid, liquid powder, etc. The administration may be in the form of tablets, capsules, powder for sprinkling on edible, liquids etc, as prepared in conventional pharmaceutical preparation processes practiced in prior art.
|Indian Patent Application Number||263/CHE/2006|
|PG Journal Number||2/2010|
|Date of Filing||20-Feb-2006|
|Name of Patentee||INDIAN INSTITUTE OF TECHNOLOGY|
|Applicant Address||IIT P.O, CHENNAI 600 036|
|PCT International Classification Number||A61K 31/785|
|PCT International Application Number||N/A|
|PCT International Filing date|