Title of Invention

IMPROVED PROCESS FOR THE PREPARATION OF PHARMACEUTICAL GRADE TANNATES

Abstract

The invention disclosed in this application relates to an improved process for the preparation of pharmaceutical grade having residual solvent within permissible limits which comprises preparing and aqueous solution of tannic acid using distilled water or USP grade water or dematerialized water, adding antihistamine base to the resulting solution stirring, applying the vacuum to remove water and unloading the material & breaking the lumps and further vacuum drying

Full Text

Field of the invention The invention relates to an improved process for the preparation of pharmaceutical grade tannates, Particulars the invention relates to an improved process for the preparation of pharmaceutical grade Ephedrine, Pseudoephedrine and Phenylephrine tannates. The tannates prepared by the process of the present invention are useful as antihistamines Background of invention Antihistamines are available in the form of free bases as well as salts such as hydrochloride, maleate, tonnage etc. Usually tannates are preferred because of safety and stability. Tannic acid is a well known naturally occurring substance and is also commercially available. The commercially available tannic acid contains about 5 % water and has a mol weight of about 1700 Commercially available antihistamine tannates, presently manufactured are relatively impure. These are prepared by the reaction of the base with tannic acid using a volatile solvent usually ispropanol (I PA) The yield is only fair about 70% and contains impurities such as decomposition products about 2-5 % along with significant amount of the volatile solvent used in the process, Many antihistamine tannates such as Ephedrine. Pseudoephedrine and Phenylephrine tannates are heat sensitive and therefore undergo decomposition readily upon prolonged exposures to temperatures .It is not possible to reduce the solvent content less than 6.0% based on the weight of antihistamine tannates even at reduced pressure and very mild elevated temperatures. Further from the environmental point of view and ecology, it would be highly desirable if antihistamine tannates are manufactured without using volatile organic solvents. us patent no 5663415 (of Chopdekar V.M et al. Jame fine chemicals, inc),describes a method of preparing antihistamine tannate which comprises the steps (a) contacting an antihistamine in the form of its free base with tannic acid in the presence of water at a maximum temperature which will not cause decomposition of the antihistamine tannate to an extent greater than about 5 wt % based on the weight of the antihistamine tannate ( b) allowing the tannate to remain in contact with the tannic acid in the presence of water for a period in the range of about 5 minutes to 4 hrs at said maximum temperature and ( c ) freeze drying the tannate at a temperature and at a reduced pressure and for such period of time that (i) at least about 90 % wt of the water is removed from the antihistamine tannate and (ii) decomposition of the tannate will be limited to a maximum of about 5 Wt % Though the process utilizes water, the main purpose is for reducing the impurity and to get minimum purity level of at least 90 % usually at least 95% and often at 98% . There is no mention in this patent about the reducing the content of solvent in the final tannate prepared by the process Further the process requires freeze drying which is very well known in Biological processes to handle small scale levels but not in chemical processes because of its economical viability in the commercial scale . It is also very time consuming and needs very large and special equipment to dry the material The process also needs temperatures in the range of -60c to -20c which is difficult to achieve in bigger scales continuously and is very expensive. Similarly, in US Patent no 5599846(of Chopdekar VM etal Jame fine chemicals, inc) describes a- tannates composition using isopropanol . The resulting antihistamine tannate composition has 8% and 2% respectively isopropanol content and degradation product. As per the ICH Guidelines for phannaceutical agents, the residual solvent isopropanol should be less than 0.5 % or 5000PPM . The guideline recommends use of less toxic solvents and describe levels considered to be toxicologically acceptable for some residual solvents. Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality based requirements. They have classified the solvents in to three categories. Glass-1 Solvents that are known to cause unacceptable toxicities, should be avoided in the production of drug substances unless their use can be strongly justified in the risk benefit assessment. Ex: Benzene, carbon tetrachloride. 1,2-Dichloroethane....etc Class-2 Solvents associated with less severe toxicity, should be limited In order to protect patients from potential adverse effects. Ex:Chloroform, dichloromethane....etc Class-3 Solvents that are less toxic.should be used where practical Ex. Acetone, Butanol Ethyl acetate....etc The complete list of solvents with permissible limiting drug substances are mentioned In ICH harmonized tripartite guideline under the heading IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS." In the POT application no WO 02/ 05747 dated 24^^ Jan 2002 of Cadila Pharmaceuticals, a process for the manufacture of pharmaceutical grade tannates has been disclosed. In this process the main finding is the use of compatible solvents like halogenated alkanes or alkanoic esters ( see lines 3 & 4 in page 4) . In other words the process does not use the usually employed isopropanol as the solvent. The examples given in the patent substantiating their findings uses only such solvents thereby confirming that only such solvents are envisaged within the scope of the said invention The objectives of that invention as stated in the description (last para in page 2 ) "The yield is only fair (around 70%) and decomposition products eg. 2-5% along with significant amount of volatile solvent isopropanol ( 6-10%) remains with the product which cannot be removed . In another PCT application no WO 02/ 05745 dated 24 Jan 2002 of the same applicants namely Cadila Pharmaceuticals, another process for the manufacture of phaimaceutical grade tanates has been disclosed. In this process the main finding is the use of hexane as the solvent (see lines 4 in page 3). In this process the use of hexane reduces the content of isopropanol to around 3% in the end product The objective of the invention seems to be to reduce the content if isopropanol to the minimum even though it has not been stated specifically. They could achieve to reduce the content of isopropanol only to around 3 % as compared to the requirement of 0.5% stipulated by ICH guidelines. In yet another PCT application no WO 02/ 05746 dated 24*^ Jan 2002 also of the same applicants namely Cadila Phannaceuticals , yet another process for the manufacture of pharmaceutical grade tannates has been disclosed. In this process the main finding is the use of water as the solvent ( see lines 4 in page 3) . In this process the use of hexane reduces the content of isopropanol to around 3% in the end product The objective of the invention seems to be to reduce the content if isopropanol to the minimum even though it has not been stated specifcally. They could achieve to reduce the content of isopropanol only to around 3 % as compared to the requirement of 0.5% stipulated by ICH guidelines. In the US Patent application no2003/0114392 A1 a process for the preparation of tannates has been disclosed shish comprises reacting pseudo ephedrine free base with tannic acid at a temperature in the range of about 50 to about 150 deg C and thereafter recovering the resultant tannate .The process envisages use of water in the reaction The process is also require elaborate steps requiring freeze drying From the description of the patent application ( US2003/0114392A1) it can be observed that the objectives of the invention is to achieve a product having extended release properties . It has been stated in the patent that though the antihistamine now available are quickly absorbed within the body. Though such products are efficient to get the required relief, there is a disadvantage of using large doses which may be harmful for the body on long use To our knowledge there has been no process hitherto known to produce an tannate having less than 0.5% of isopropanol in the end product as per the requirement of the above stated ICH guide lines. Objectives of the invention The main objective of the present invention is to provide an improved process for the preparation of pharmaceutical grade tannates having residual solvent within permissible limits of ICH guidelines. Another objective to the present invention is to provide an improved process tor the preparation of pharmaceutical grade tannates without the use of organic solvents especially isopropanol. Still another objective of the present invention is to provide an improved process for the preparation of pharmaceutical grade tannates using aqueous medium Yet another objective of the present invention is to provide an improved process for the preparation of pharmaceutical grade tannates having improved quality of the pharmaceutical grade tannates. We have due to the sustained R&D conducted have found out that it is possible to avoid the use of organic solvents in the preparation of pharmaceutical grade tannates. By avoiding the solvent the presence of additional residual solvent in the final tannate does not arise thereby strictly complying the above mentioned mandatory requirement. This has been made possible by our finding that by the combination of employing water as the sole solvent medium instead of using any other organic / inorganic solvents and using vacuum drying avoiding freeze drying .Such a process has the benefit of utilizing it for commercial production without any problems To the best of our knowledge there is no such process known any where in the world for the preparation of tannates wherein the end product having residual solvent within the above mentioned mandatory requirements DESCRIPTION OF THE INVENTION Accordingly the present invention provides an improved process for the preparation of pharmaceutical grade having no residual solvent which comprises (i) preparing an aqueous solution of Tannic acid using Distilled water or USP grade water or Demineralised water. (ii_) adding antihistamine base to the resulting solution in 15min to 2hrs at 20 °C to 55 X (iii)stirring the resulting solution for a period in the range of 15min to 2hrs at a temperature in the range of 20 to (iv) Applying the vacuum to the flask at the temperature to 75 to remove water v)removing the material from the flask ,breaking the lumps and further vacuum drying . The tannate base used may be selected from the group consisting of Phenylephrine, cartetapentane, protamine, chlorpheniramine, ephedrine, pseudo ephedrine, bromppheniramine, bromodiphenhydramlne, diphenhydramine, phenylamines, phenyltoxamine, clandestine, tripelennamine, cyproheptadine, phenindamine and phenyltoloxamine as a single ingredient or a combination of more than one. preferably pseudoephedeine. The water added may range from 0.5 to 3 times to that of tannic acid preferably 1time. The addition of antihistamine base in step(ii) may be effected during a period of 15min to 2hrs preferably Samantha stirring in step {iii ) may be done for a period in the range of 15min to 2hrs preferably for 30 minutes or till material becomes sufficiently uniform. The temperature used in step( ii & iii ) may be in the range of 20 "C to 55 °C preferably 25 - 30" C The vacuum to the flask may be applied at temperature 30 - 75 'C preferably 60 remove water. The details of the invention are provided in the Examples given below which are provided to illustrate the invention only and therefore cannot be construed to limit the scope of the invention Example -1 Preparation of Ephedrine tannate: l-Ephedrine base 50g Tannic acid (m/c 10%) : 100g Demineralised Water : loam The above mentioned quantities of water and tannic acid are charged into a flask and stirred for one hour. The specified quantity of l-ephedrine base was charged to the flask slowly in 30min at a temperature in the range of 25' to . The reaction mass was stirred for 30 mins. High Vacuum (1mm-5mm)is applied first to the receiver at GO '-GSC and then directly to the flask 24 hours at the same temperature. Lumps formed are broken and unloaded from the flask. The lumps are further vacuum dried till the moisture content of the product (tannate) attains less then 2%. The tannate prepared reveals the following 1. Description: yellowish tan. fine powder 2. water content: 4.0%wAw 3. residue on Ignition : 0.30% w/w 4. heavy metals: less than 5 ppm 5. tannic acid : 64.01 % w/w 6. ephedrine base : 32.11 % w/w 7. assay: 101.88%w/w 8. residual solvents : Toluene: 85 ppm , Acetone:40ppm Though the solvents are not used in the manufacture ,when product was checked for residual solvents the product tannate contain small traces of toluene and acetone which are carried in to the product from prior step, that is from the Ephedrine base . Dry weight; 120g to 125 g EXAMPLE -2 PREPARATION OF d-PSEUDOEPHEDRINE TANNATE d-Pseudoephedrine base: 50g Tannic acid (m/c 10%) : lOOg Demineralised Water : lOOmL The above mentioned quantities of water and tannic acid are charged into a flask and stirred for one hour . The specified quantity of d-Pseudoephedrine base was charged to the flask slowly in 30min at a temperature in the range of 25°C to sec. The reaction mass was stirred for 30 mins. High Vacuum (1mm-5mm)is applied first to the receiver at SO^C -65°C and then directly to the flask 24 hours at the same temperature. Lumps formed are broken and unloaded from the flask. The lumps are further vacuum dried till the moisture content of the product (tannate) attains less then 2%. The tannate prepared reveals the following 1. Description : Ceramist brown tan, fine powder 2. Water: 3.45%w/w 3. Residue on Ignition: 0.1%w/w 4. Heavy metals: Less than 5 ppm 5. Tannic acid: 66.19%W/W 6. Pseudo ephedrine base: 33.24% w/w 7. Assay: 101.74% w/w 8. Residual solvent Toluene: 25ppm Though the solvents are not used in the manufacture .when product was checked for residual solvents the product tannate contain small traces of toluene which is carried in to the product from prior step, that is from the Pseudo Ephedrine base - Dry weight; 120g to 125 g EXAMPLE -3 PREPARATION OF I- PHENYLEPHRINE TANNATE l-Phenylephrine base Tannic acid (M/C: 10%) Demineralised Water 100g 170g 255 mL The above mentioned quantities of water and tannic acid are charged into a flask and stirred for one hour , The specified quantity of l-Phenylephrine base was charged to the flask slowly in Semen at a temperature in the range of 25 to 30 . The reaction mass was stirred for 30 mins. High Vacuum (1mm-5mm) is applied first to the receiver at SO -650 and then directly to the flask 24 hours at the same temperature. Lumps formed are broken and unloaded from the flask. The lumps are further vacuum dried till the moisture content of the product (tannate) attains less then 2%, The tannate prepared reveals the following 1. Description : 2. Water: 3. Residue on Ignition: 4. Heavy metals: 5. Tannic acid: 6. i-Phenylephrine base: 7. Assay: 8. Residual solvent: light brownish tan, fine powder 1.52%w/w 0.08%w/w Less than 5 ppm 64.0%W/W 35.97% w/w 100.96 %w/w Isopropyl alcohol: 52.7 methanol: 78.8ppm Dry weight: 200g to 210 g Though the solvents are not used in the manufacture, when product was checked for residual solvents the product tannate contain small traces of Isopropyl alcohol and methanol which are carried in to the product from prior step, that is from the Phenylephrine base . Advantages of the invention 1. The process avoids the use of any organic solvents 2. The process results in producing phaimaceutical grade tannates having residual solvent within permissible limits below lOO ppm .the solvent(s) are those used in the preparation of the starting base used 3. The process is economical as it uses only water as the solvent 4. The process does not use freeze drying and therefore simple , environmentally safe and commercially applicable 5. The process is useful for commercial production We claim: 1. An improved process for the preparation of pharmaceutical grade tannates which comprises (i) preparing an aqueous solution of Tannic acid using Distilled water or USP grade water or Demineralised water. (ii) adding antihistamine base to the resulting solution in 15 min to 2 hrs at 20 "C - 55 °C (iii)stirring the resulting solution for a period in the range of 15 min to 2 hrs at 20 X-55 X (iv)applying vacuum at a temperature in the range of 30"* to 75*^0 , (v) removing the material from the flask .breaking the lumps and further vacuum drying. 2. An improved process as claimed in claim 1 wherein the ternate base used is selected from the group consisting of Phenylephrine, carbetapentane, parliament, chlorpheniramine, ephedrine, pseudo ephedrine. bromppheniramine, bromodiphenhydramine, diphenhydramine, pheniramine, phenyltoxamine, clematises, tripelennamine, cyproheptadine, phenindamine and phenyltoloxamine as a single ingredient or a combinations of more than one, .preferably pseudoephedeine. 3. An improved process as claimed in claims 1& 2 wherein the stirring in step (iii) is done for 30 minutes. 4. An improved process as claimed in claims 1 to 3 wherein the temperature used in step( iii ) is in the range of 25° - 30 °C 5. An improved process as claimed In claims 1 to 4 wherein the material is dried by applying the vacuum directly to the flask at temperature 60 - 65 "^C in step (iv ) 6. An improved process for the preparation of pharmaceutical grade tannates substantially as herein described with reference to Examples 1 to 3.

Documents:

129-che-2004-abstract.pdf

129-che-2004-claims filed.pdf

129-che-2004-claims granted.pdf

129-che-2004-correspondnece-others.pdf

129-che-2004-correspondnece-po.pdf

129-che-2004-description(complete) filed.pdf

129-che-2004-description(complete) granted.pdf

129-che-2004-form 1.pdf

129-che-2004-form 19.pdf