WO2007017890A2 - Procede de preparation de sesquihydrate de sodium de pantoprazole et produit obtenu a l'aide dudit - Google Patents

Procede de preparation de sesquihydrate de sodium de pantoprazole et produit obtenu a l'aide dudit Download PDF

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WO2007017890A2
WO2007017890A2 PCT/IN2006/000150 IN2006000150W WO2007017890A2 WO 2007017890 A2 WO2007017890 A2 WO 2007017890A2 IN 2006000150 W IN2006000150 W IN 2006000150W WO 2007017890 A2 WO2007017890 A2 WO 2007017890A2
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pantoprazole sodium
sodium sesquihydrate
ether
pantoprazole
sesquihydrate form
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PCT/IN2006/000150
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English (en)
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WO2007017890A3 (fr
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Ranjan Prasad Srivastava
Vinodkumar Deonayak Mishra
Ajit Arjun Kadam
Rajiv Ramchandra Dalvi
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Rpg Life Sciences Limited
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Publication of WO2007017890A3 publication Critical patent/WO2007017890A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for preparation of pantoprazole sodium sesquihydrate and product prepared thereby and to pharmaceutical compositions containing the same. Particularly, it relates to a process for preparation of pantoprazole sodium sesquihydrate, which has been designated as Form I and Form I of pantoprazole sodium sesquihydrate produced thereby and to pharmaceutical compositions containing the same.
  • Pantoprazole sodium sesquihydrate is chemically known as 5- (Difluoromethoxy)-2-[[(3,4-di-methoxy-2-pyridinyl)methyl]sulfinyl]-lH- benzimidazole sodium sesquihydrate and has been found to be more suitable pharmaceutically active gastric acid secretion inhibitor.
  • Pantoprazole sodium sesquihydrate Form - I has following Formula-I
  • pantoprazole sodium sesquihydrate Form - I finds its application as an active ingredient of pharmaceutical product, which is in solid state and more of crystalline Form having unique physical properties, so that it can be used for pharmaceutical composition meant for gastroesophageal reflux disease. Therefore, a constant research is going on to find out more and more economical and environment friendly method for its preparation.
  • pantoprazole sodium sesquihydrate has been prepared from pantoprazole free base by drop wise addition of sodium hydroxide in a solution of pantoprazole free base in the mixture of ethanol and dichloromethane followed by addition of diisopropryl ether as an anti solvent (hereinafter referred to as first known method) [J. Medicinal Chemistry, 1992, Vol. 35, page 1049-1057, No.6].
  • first known method a solution of pantoprazole free base in the mixture of ethanol and dichloromethane followed by addition of diisopropryl ether as an anti solvent
  • pantoprazole sodium sesquihydrate is problematic, but even its yield is low.
  • this first known method employs dichloromethane, which is known to cause carcinogenicity, hazard and toxic pollution in the environment being chlorinated solvent [National Institute for Occupational Safety and Health Doc. No. 76-138 (1976)]. Therefore, the above first known method is highly uneconomical not only on small scale production, but also on large scale production and is also more time consuming and less environment friendly.
  • pantoprazole sodium sesquihydrate from pantoprazole free base
  • This method [hereinafter referred to as second known method) comprises dissolving pantoprazole free base in sodium hydroxide solution in a suitable solvent followed by filtration to have a clear solution and then followed by adding an anti solvent to the filtrate produced thereby to isolate pantoprazole sodium sesquihydrate.
  • the suitable solvent to dissolve pantoprazole free base to have a clear solution is selected from C1-C4 straight or branched chain alcohols, tetrahydrofuran and ethyl acetate, and the suitable anti-solvent employed in this process is selected from petroleum ether, hexane, n-heptane, cyclohexane, cycloheptane or chlorinated solvents such as dichloromethane or chloroform or ethereal solvents, such as diisopropryl ether [DIPE] or methyl-tertiary butyl ether [MTBE].
  • DIPE diisopropryl ether
  • MTBE methyl-tertiary butyl ether
  • the main object of the above second known method was to overcome disadvantages, drawbacks and limitations of the above first known method by avoiding use of excess volumes of the solvents and to avoid large number of solvents to have cost-effective, substantially pure, easily scalable and environment friendly process.
  • pantoprazole sodium sesquihydrate from pantoprazole free base has not been successful to overcome disadvantages, drawbacks and limitations of the first known method, because second known method also involves more than one solvent in-addition to employing sodium hydroxide solution, and also requires formation of a clear solution before isolating pantoprazole sodium sesquihydrate from reaction mixture meaning thereby the second known method is also a two step process.
  • disadvantage of the second known method is that it not only involves two solvents in-addition to sodium hydroxide, but it also employs the solvents in sufficiently large quantities.
  • the second known method could not overcome main drawbacks of the first known method to prepare pantoprazole sodium sesquihydrate from pantoprazole free base, that is, it could not be successful in avoiding use of excess number of solvents and anti-solvents, and excess volume of solvents and anti-solvents, and could not overcome problem of two step process, that is, the problems of time consuming, poor yield and poor purity.
  • the another object of the second known method was to avoid use of large amounts of ethanol to have better yield and better purity of pantoprazole sodium sesquihydrate and ease of isolation.
  • the suitable solvent to dissolve pantoprazole free base includes alcohols, including ethanol. Accordingly, this method might have been successful to avoid excess volume of ethanol as solvent, but it could not avoid use of ethanol to have better yield and better purity of pantoprazole sodium sesquihydrate and ease of isolation. Further, as stated hereinabove, even the second known method is also two steps process. It is well known that processes involving more than one process step are known to give poor yield and low purity of the end product, particularly during the large scale production. To have a process commercially successful, it is most desirable to have minimum number of process steps and minimum number of solvent mediums, because this will result in minimum amount of efforts for removal of solvents and isolation of the desired end product.
  • pantoprazole sodium sesquihydrate cannot be considered, at least, to be cost-effective, less time consuming, less hazardous and environment friendly process.
  • the above processes - the first known method and the second known method require in first step to react with or to dissolve pantoprazole free base in solution of sodium hydroxide in a solvent or mixture of solvents to give a clear solution, and in second step the clear solution of pantoprazole free base in solution of sodium hydroxide in a solvent or mixture of solvents is then treated with an anti-solvent to precipitate pantoprazole sodium sesquihydrate from such clear solution thereby making the overall process two step process.
  • the above known processes are not only more time consuming but also more energy consuming thereby making the overall processes further uneconomical, less productive, more time consuming, particularly on large scale production.
  • Yet another known method for preparation of pantoprazole sodium sesquihydrate from pantoprazole free base comprises reacting pantoprazole free base with solution of sodium hydroxide in a selected diluent (US 2004/0177804A1).
  • the diluent is selected from 2-propanol, tetrahydrofuran, acetonitrile, methanol, ethanol, water, mixtures of sec-butanol and dichloromethane and ethyl acetate.
  • the main drawback of the above third known method is that in accordance with this method also the resulted mixture of pantoprazole free base in solution of sodium hydroxide in a selected diluent is treated to obtain clear solution which is then subjected to a step of crystallization to produce pantoprazole sodium sesquihydrate either by cessation of heating or by adding an anti-solvent selected from MTBE and heptane.
  • Still another drawback of the above third known method is that it requires a step of heating to reflux the solution of pantoprazole free base in sodium hydroxide in a selected diluent to obtain clear solution before the pantoprazole sodium sesquihydrate is precipitated and isolated, and hence, it is also more time consuming and more energy consuming.
  • the above third known method also teaches that first the pantoprazole free base is dissolved in a solution of sodium hydroxide in suitable solvent to have a clear solution, even if required, by heating to reflux to have a clear solution. The clear solution is then subjected to treatment with another solvent to precipitate pantoprazole sodium sesquihydrate, which in- turn is isolated from the reaction mixture. For all practical purposes this process is also two steps process in-addition to requiring a step of heating.
  • the above third known method is also a two steps process requiring the reaction mixture of pantoprazole free base in solution of sodium hydroxide in a selected diluent to be heated to reflux to obtain a clear solution which is then subjected to a step of crystallization to obtain pantoprazole sodium sesquihydrate, and hence, the overall process still suffers from drawbacks of two step process, and being more time consuming and more energy consuming thereby making the overall process further uneconomical and less productive, particularly on large scale production
  • the above three known methods involve use of solution of sodium hydroxide if pantoprazole sodium sesquihydrate is prepared from pantoprazole free base, and of solvents like ethanol and chlorinated solvents, and require formation of a clear solution as pre-condition before precipitating pantoprazole
  • the other known method for preparing pentoprazole sodium sesquihydrate (US 2004/0177804A1) comprises forming heterogeneous mixture of pantoprazole sodium Form II identified by PXRD shown in accompanying Figure-I with a diluent selected from ethyl acetate, dichloromethane, water, dimethylcarbonate and 2-propanol.
  • the above fourth known method does overcome problem of large volume of solvents.
  • this process results in very poor mixing, particularly on large scale production thereby rendering the process more or less solid ageing process which is not advisable in the pharma production which requires homogeneous mixing and not the heterogeneous mixing for better yield and better purity of the end product. Therefore, the reaction mixture is required to have proper slurry in the solvent medium for getting homogeneous mixture to obtain better yield and better purity of the end product.
  • the solid ageing process that is a process comprising heterogeneous mixing does not result in completion of a reaction, and hence, the end product may comprise un- reacted pantoprazole sodium thereby rendering the end product unsuitable for pharmaceutical applications.
  • the another drawback of above fourth known method is that in accordance with some preferred embodiments, it employs 2-propanol as a solvent, which, as per International Conference of Harmonization [ICH] guidelines, is Class 3 solvent and its permissible limit is 5000 ppm, that is 0.5% w/w.
  • the 2-propanol is used in an amount of about 4% w/v, which is equivalent to 3.16% w/w which is obviously very higher than the permissible limit of 0.5% w/w. Accordingly, the above fourth process is not acceptable for the production of a pharmaceutical substance. Further, if no drying is involved, the end product may very likely fail in residual solvent content at production scale. Still further, the process may also fail with respect to the odour because 2- propanol has a peculiar and irritant smell, and hence, is not advisable as a solvent in pharmaceutical productions.
  • pantoprazole sodium sequihydrate from said pantoprazole sodium, in case the diluent is 2- propanol or tetrahydrofuran or acetonitrile or ethanol or water or ethyl acetate, requires that said pantoprazole sodium is first dissolved in the diluent by heating to reflux to obtain clear solution followed by either evaporating the diluent or concentrating the reaction mixture to obtain pantoprazole sodium sesquihydrate. Accordingly, these processes are also two steps processes, and require heating to reflux and hence, are highly time consuming as the reaction is carried out for about two or more nights and highly energy consuming as the reaction mixture is heated to obtain the clear solution.
  • pantoprazole sodium employed in the present invention is distinctively different from pantoprazole sodium employed in above fourth known method as can be visualized from PXRD shown in Figures I and II, which respectively show PXRD of pantoprazole sodium employed in US 2004/0177804A1 as starting material and PXRD of pantoprazole sodium employed in present invention as starting material for preparing pantoprazole sodium sesquihydrate of Form I. NEED OF THE INVENTION
  • pantoprazole sodium sesquihydrate Form I from pantoprazole sodium, which is not only economical, but can also be scaled up for commercial production on large scales, and can also avoid use of hazardous solvents to make the developed process more environment friendly, and at the same time, the developed process should be simple and fast, that is one step process and less time consuming and less energy consuming, and should result in higher yields of pantoprazole sodium sesquihydrate Form I having higher purity.
  • the main object of the present invention is to provide an improved process for preparation of pantoprazole sodium sesquihydrate Form I employing pantoprazole sodium as a starting material.
  • the another main object of the present invention is to provide an improved process for preparation of pantoprazole sodium sesquihydrate Form I employing pantoprazole sodium as a starting material, and still being less time consuming and less energy consuming, that is which neither requires preparation of a clear solution as a pre-condition for isolation of pantoprazole sodium sesquihydrate Form I thereby resulting the process one step process and less time consuming process nor requires a step of heating to reflux thereby resulting the process energy saving process.
  • the another object of this invention is to provide a process for preparation of pantoprazole sodium sesquihydrate Form I employing pantoprazole sodium as a starting material, wherein the pantoprazole sodium sesquihydrate Form I is directly produced from pantoprazole sodium.
  • Still another object of this invention is to provide a process for preparation of pantoprazole sodium sesquihydrate Form I which neither employs undesirable and hazardous solvents, like alcohols and chlorinated solvents nor sodium hydroxide nor demands anhydrous conditions and is simple, convenient and safe even on large scale productions.
  • Yet another object of this invention is to provide a process for preparation of pantoprazole sodium sesquihydrate Form I which neither employs large number of solvents nor employs large amount of solvents and still results in higher yield of pantoprazole sodium sesquihydrate Form I.
  • pantoprazole sodium sesquihydrate Form I which is suitable to produce pantoprazole sodium sesquihydrate Form I having moisture content varying within the permissible limits, that is between about 6.2 to about 7.1%.
  • pantoprazole sodium sesquihydrate primarily suffer from the problem of requirement of preparation of clear solution of pantoprazole free base or of pantoprazole sodium, as the case may be, as a pre-condition for isolating pantoprazole sodium sesquihydrate and the requirement of heating to reflux to obtain a clear solution of pantoprazole free base or of pantoprazole sodium, as the case may be, because the selection of starting material, that is pantoprazole free base or pantoprazole sodium and of solvent medium is such that it cannot result in direct preparation of pantoprazole sodium sesquihydrate. Therefore, the main object of the inventors of the present invention is to provide a method which is not only one step process, but also avoids heating to reflux, that is which does not require formation of a clear solution as a precondition.
  • pantoprazole sodium is treated with a solvent mixture of water and ether taken in such a ratio so as to have water content varying from about 0.3% to about 1.2% v/v of the volume of ether it directly results in preparation of pantoprazole sodium sesquihydrate thereby avoiding preparation of a clear solution of pantoprazole sodium and solvent mixture as a precondition, and hence, provides a one step process which is less time consuming.
  • pantoprazole sodium is treated with above solvent mixture of water and ether taken in above ratio so as to have water content varying from about 0.3% to about 1.2% v/v of the volume of ether at room temperature it still results in direct preparation of pantoprazole sodium sesquihydrate thereby avoiding a step of heating to reflux to obtain a clear solution of pantoprazole sodium and solvent mixture as a precondition, and hence, provides a one step process which is less energy consuming.
  • the present process in-addition to avoiding pre-condition of preparation of a clear solution of pantoprazole sodium and solvent, and avoiding a step of heating to reflux to obtain clear solution of pantoprazole sodium and solvent as a pre-condition before isolation of pantoprazole sodium sesquihydrate, has also been observed to avoid chances of formation of side products thereby making the process more productive to produce pantoprazole sodium sesquihydrate in higher yield having higher purity.
  • the pantoprazole sodium and solvent mixture are taken in a ratio varying from about 1 :8 to about 1 : 12 w/v which has been surprisingly observed to allow very good mixing of pantoprazole sodium and solvent mixture even on large scale production thereby making the process a wet blending process which is more desirable in the pharma production which produces required homogeneous mixing for better yield and better purity of the end product, that is of pantoprazole sodium sesquihydrate.
  • the reaction mixture produced in accordance with present method has also been observed to have proper slurry in the solvent medium which results in formation of a homogeneous mixture to obtain better yield and better purity of the end product, that is of pantoprazole sodium sesquihydrate, and hence, it has been observed to result in completion of a reaction by converting pantoprazole sodium to pantoprazole sodium sesquihydrate. It has been observed that the end product does not comprise un-reacted pantoprazole sodium thereby makes the end product more suitable for pharmaceutical applications, and the present method still avoids preparation of clear solution and/ or heating to reflux to obtain clear solution as a pre-condition to isolate pantoprazole sodium sesquihydrate.
  • the above solvent mixture of water and ether used in above ratio of the present invention has also been observed to be safer solvent medium thereby making the present process more environment friendly and less hazardous.
  • the present invention provides an economical and easily scalable to large scale production, and environment friendly, and one step, one pot, simple, convenient and safe process for preparation of pantoprazole sodium sesquihydrate Form-I from pantoprazole sodium by forming a suspension of pantoprazole sodium in a mixture of selected solvents and directly recovering the pantoprazole sodium sesquihydrate Form - I by filtration in better yield and high purity, thereby avoiding not only use of undesirable and hazardous solvents and anhydrous conditions, but also avoiding the step of forming a clear solution as a pre-condition to isolate pantoprazole sesquihydrate Form I or avoiding the step of heating to reflux to form a clear solution as a pre-condition to isolate pantoprazole sesquihydrate Form I, and at the same time being less time consuming and less energy consuming.
  • pantoprazole sodium sesquihydrate Form-I is recovered directly from the suspension by way of filtration, thereby making its isolation easier. Accordingly, the present invention relates to a process for preparation of pantoprazole sodium sesquihydrate having following Formula-I.
  • pantoprazole sodium comprising formation of a suspension of pantoprazole sodium in a solvent mixture and directly recovering the pantoprazole sodium sesquihydrate Form - 1 by filtration.
  • the present invention provides a pantoprazole sodium sesquihydrate Form-I which has been characterized by PXRD, IR, DSC, and C, H, N analysis and moisture content (MC).
  • the present invention also provides pharmaceutical compositions comprising pantoprazole sodium sesquihydrate Form-I produced by the present process.
  • the present invention also provides a method for treatment of stomach disorder or gastroesophageal reflux disease by way of administration of pantoprazole sodium sesquihydrate Form-I produced by the present process.
  • the present invention also provides use of pantoprazole sodium sesquihydrate Form-I produced by the present process as suitable pharmaceutically active gastric acid secretion inhibitor.
  • Figure - I shows PXRD of pantoprazole sodium employed as starting material in the prior art.
  • Figure - II shows PXRD of pantoprazole sodium employed as starting material in the present invention.
  • Figure - III shows DSC scan of pantoprazole sodium employed as starting material in the present invention.
  • FIG. IV shows PXRD of pantoprazole sodium sesquihydrate Form I prepared in accordance with one embodiment of the present invention.
  • FIG - V shows DSC scan of pantoprazole sodium sesquihydrate Form I prepared in accordance with one embodiment of the present invention the PXRD of which has been shown in Figure IV.
  • FIG. - VI shows IR of pantoprazole sodium sesquihydrate Form I prepared in accordance with one embodiment of the present invention the PXRD of which has been shown in Figure IV.
  • the present invention provides an economical and easily scalable to large scale production, and environment friendly, and one step, one pot, simple, convenient and safe process for preparation of pantoprazole sodium sesquihydrate Form-I having a following Formula -I
  • the solvent mixture is mixture of water and ether.
  • the ether is selected from diisopropyl ether [DIPE], diethyl ether and methyl tert-butyl ether [MBTE], preferably the ether is diisopropryl ether.
  • the water content in the solvent mixture is varied from about 0.3 to about 1.2% (V/V) of the volume of ether, preferably varied from about 0.6 to about 1.2% (V/V) of the volume of ether, more preferably varied from about 0.6 to about 0.8% (V/V) of the volume of ether.
  • pantoprazole sodium forms a clear solution thereby making recovery of pantoprazole sodium sesquihydrate Form I very difficult.
  • pantoprazole sodium does not form clear solution and gets completely converted to pantoprazole sodium sesquihydrate Form-I thereby making the recovery of pantoprazole sodium sesquihydrate Form-I not only easier, but also in higher yield having higher purity.
  • pantoprazole sodium forms heterogeneous mixture and such heterogeneous mixture has been observed to result in incomplete conversion of pantoprazole sodium to pantoprazole sodium sesquihydrate. Further, it has been observed that the end product from the heterogeneous mixture comprises un-reacted pantoprazole sodium thereby renders the end product unsuitable for pharmaceutical applications.
  • pantoprazole sodium and the solvent mixture are taken in a ratio varying from about 1:8 to about 1: 12, preferably varying from about 1 :9 to about 1 : 1 1, more preferably in a ratio of about 1: 10 (W/ V).
  • pantoprazole sodium of the present invention when pantoprazole sodium of the present invention is mixed in accordance with present invention in a solvent mixture consisting of water and ether present in above ratio, it forms a homogenous suspension and not a clear solution, which on stirring just for few hours directly results in formation of crystalline form of pantoprazole sodium sesquihydrate Form I in higher yield having better purity thereby making the present process one step process which has been observed to be highly economical and environment friendly, and highly time saving and energy saving process due to avoidance of formation of a clear solution as precondition and avoidance of step of heating to reflux to obtain a clear solution as a precondition.
  • pantoprazole sodium employed in the present invention can be prepared by any known method or obtained from the commercially available pantoprazole sodium. However, it should be characterized by the PXRD shown in accompanying Figure II, which is significantly different from the pantoprazole sodium employed in US 2004/0177804A1 having PXRD shown in accompanying Figure I.
  • the process comprises formation of a suspension of pantoprazole sodium having a PXRD shown in Figure II and DSC scan shown in Figure III in a solvent mixture consisting of water and ether, wherein ether is selected from diisopropyl ether [DIPE], diethyl ether and methyl fert-butyl ether [MBTE], preferably the ether is diisopropryl ether, and water and ether are taken in such a ratio so as to have water content in the solvent mixture varying from about 0.3 to about 1.2% (V/V) of the volume of ether, preferably varying from about 0.6 to about 1.2% (V/V) of the volume of ether, more preferably varying from about 0.6 to about 0.8% (V/V) of the volume of ether, and the pantoprazole sodium and the solvent mixture are taken in a ratio varying from about 1:8 to about 1: 12 (W/V), preferably varying from about 1:9 to about 1 :11 (W
  • the present invention uses benefit of formation of suspension of pantoprazole sodium in the solvent mixture of water and ether when present in ratio disclosed in present invention. It has been surprisingly observed that solvent mixture of water and ether in above ratio, when taken in above- described ratio with respect to pantoprazole sodium, not only provides the adequate volume to pantoprazole sodium to form homogeneous suspension under stirring but also results in higher yield of pantoprazole sodium sesquihydrate Form I of higher purity, that is there is no loss of overall yield due to completion of desired reaction and there is no loss of purity due to no formation of side products.
  • the present invention discloses a process which neither employs large number of solvents nor large amount of solvents. Further, the disclosed process has been observed to be safe, eco-friendly, economical, simple and convenient process even on large scale productions, because it neither demands any anhydrous medium nor requires use of any undesired or hazardous or expensive reagents or solvents like, alcohols, chlorinated solvents, sodium hydroxide, methylene dichloride, chloroform, carbon tetrachloride etc.
  • the still another advantage of the present process is that it is carried out at room temperature neither requiring step of heating to reflux nor a pre-condition to form a clear solution of pantoprazole sodium in solvent mixture. This not only results in savings of energy, but also results in end product in higher yield having higher purity even on prolonged reaction time, which in present invention varies up to 12 hrs. Accordingly, the present process has also been observed to be commercially feasible on industrial scale productions.
  • the present invention provides a pantoprazole sodium sesquihydrate Form-I which has been characterized by PXRD, IR, DSC, and C, H, N analysis and moisture content (MC).
  • the present invention also provides pharmaceutical compositions comprising pantoprazole sodium sesquihydrate Form-I produced by the present process.
  • the present invention also provides a method for treatment of stomach disorder or gastroesophageal reflux disease by way of administration of pantoprazole sodium sesquihydrate Form-I produced by the present process.
  • the present invention also provides use of pantoprazole sodium sesquihydrate Form-I produced by the present process as suitable pharmaceutically active gastric acid secretion inhibitor.
  • pantoprazole sodium used as starting material for preparation of pantoprazole sodium sesquihydrate Form-I has been characterized by Powder X-ray diffractogram
  • pantoprazole sodium sesquihydrate Form-I prepared in accordance with the present invention has been characterized by Powder X- ray diffractogram (PXRD) [ Figure-IV], Differential Scanning Calorimetry thermogram (DSC) [ Figure-V], Infrared spectrum (IR) [ Figure-VI], and C,H,N analysis and moisture content (MC).
  • PXRD Powder X- ray diffractogram
  • DSC Differential Scanning Calorimetry thermogram
  • IR Infrared spectrum
  • Figure-VI C,H,N analysis and moisture content
  • the X-ray powder diffractogram of the crystalline Form-I of pantoprazole sodium sesquihydrate Form I is measured on a Philips X' pert CUU3040/60 advance powder X-ray Diffractometer with Cu k alpha- 1 Radiation source and the diffractogram has been shown accompanying in Figure-IV.
  • a PXRD pattern shown in Figure-IV having significant two-theta values shows following peaks:
  • pantoprazole sodium sesquihydrate Form - I has also been characterized by Differential Scanning Calorimetry thermogram (DSC) which exhibits a significant endo peak about 138.38°C, the thermogram of which has been shown in Figure-V.
  • DSC Differential Scanning Calorimetry thermogram
  • pantoprazole sodium sesquihydrate Form - I has further been characterized by the infrared (IR) spectrum, which is measured by KBr transmission method and shown in Figure - VI. It shows following significant I. R. bands:
  • pantoprazole sodium sesquihydrate Form I The C, H, N analysis of above crystalline form of pantoprazole sodium sesquihydrate Form I has further established that the present invention results in formation of crystalline form of pantoprazole sodium sesquihydrate Form I.
  • the moisture content (MC) of above crystalline form of pantoprazole sodium sesquihydrate Form I has been found to be in the range of about 6.2 to about 7.1% further establishing that the present invention results in formation of crystalline form of pantoprazole sodium sesquihydrate Form I.
  • pantoprazole sodium and pantoprazole sodium sesquihydrate Form I As evident from above Table 1 and Table 2 and accompanied PXRDs shown in figures II and IV for pantoprazole sodium and pantoprazole sodium sesquihydrate Form I respectively, the characteristic peak at about 22.204 [2-theta (2 ⁇ ) angle] for pantoprazole sodium sesquihydrate Form I is absent in PXRD of pantoprazole sodium, and the characteristic peak at about 21.722 [2-theta (2 ⁇ )] for pantoprazole sodium is absent in PXRD of pantoprazole sodium sesquihydrate Form I confirming thereby conversion of pantoprazole sodium to pantoprazole sodium sesquihydrate Form I when the same is prepared in accordance with method of the present invention.
  • pantoprazole sodium is characterized by a significant endothermic peak at about 153.15 0 C
  • the DSC scan of pantoprazole sodium sesquihydrate Form I is characterized by a significant endothermic peak at about 138.38 0 C [ Figure- V] confirming thereby conversion of pantoprazole sodium to pantoprazole sodium sesquihydrate Form I when the same is prepared in accordance with method of the present invention.
  • pantoprazole sodium sesquihydrate Form I is pantoprazole sodium sesquihydrate Form I and not pantoprazole sodium meaning thereby the pantoprazole sodium sesquihydrate Form I is obtained in higher yield and having higher purity.
  • Pantoprazole sodium (0.02K) was added Pantoprazole sodium (0.02K) in one lot at room temperature.
  • the suspension was stirred at room temperature (25-30 0 C) for lhr to directly result in preparation of pantoprazole sodium sesquihydrate Form-I.
  • the white solid was Filtered and dried at 40-45°C for 3 to 3.5hrs. under 700mm vacuum to directly furnish pantoprazole sodium sesquihydrate Form-I which has been observed to have PXRD, DSC scan and IR spectra shown in Figures IV, V and VI respectively, and expected C,
  • pantoprazole sodium 0.5k
  • distilled water distilled water (0.03L) in one lot at room temperature.
  • the suspension was stirred at room temperature (25-30 0 C) for 12hrs to directly result in preparation of pantoprazole sodium sesquihydrate Form-I.
  • the white solid was filtered and dried at 40-45 0 C under 700mm vacuum for 3 to 3.5hrs to directly furnish pantoprazole sodium sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 93% and MC 6.59%.
  • pantoprazole sodium (0.01k) in one lot at room temperature.
  • the suspension was stirred at room temperature (25-30 0 C) for
  • pantoprazole sodium sesquihydrate Form-I 12hrs to directly result in preparation of pantoprazole sodium sesquihydrate Form-I.
  • the white solid was filtered and dried at 40-45 0 C for 3 to 3.5hrs under 700mm vacuum to directly furnish pantoprazole sodium sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 91.93% and MC 6.65%.
  • pantoprazole sodium (0.01k) in one lot at room temperature.
  • the suspension was stirred at room temperature (25-30 0 C) for 12hrs to directly result in preparation of pantoprazole sodium sesquihydrate Form-I.
  • the white solid was filtered and dried at 40-45 0 C for 3 to 3.5hrs under 700mm vacuum to directly furnish pantoprazole sodium sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 91.93% and MC 6.75%.
  • pantoprazole sodium (0.01k) in one lot at room temperature. The suspension was stirred at room temperature (25-30 0 C) for 12hrs to directly result in preparation of pantoprazole sodium sesquihydrate
  • Form-I The white solid was filtered and dried at 40-45 0 C for 3 to 3.5hrs under 700mm vacuum to directly furnish pantoprazole sodium sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 92.4% and MC 6.69%.
  • range of a parameter includes both values of the range, for example range "about 90 to about 95%” includes both values 90 and 95.

Abstract

L'invention concerne un procédé permettant de préparer du sesquihydrate de sodium de pantoprazole de forme I, de formule (I), à partir de sodium de pantoprazole, selon lequel il est prévu de former une suspension de sodium de pantoprazole dans un mélange de solvants et de récupérer directement le sesquihydrate de sodium de pantoprazole par filtration. L'invention concerne également le sesquihydrate de sodium de pantoprazole de forme I, obtenu au moyen dudit procédé.
PCT/IN2006/000150 2005-05-04 2006-04-28 Procede de preparation de sesquihydrate de sodium de pantoprazole et produit obtenu a l'aide dudit WO2007017890A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009010937A1 (fr) 2007-07-17 2009-01-22 Ranbaxy Laboratories Limited Procédé de préparation de pantoprazole sodique.
KR100939216B1 (ko) * 2007-12-11 2010-01-28 동우신테크 주식회사 판토프라졸 나트륨 쎄스키히드레이트의 제조방법
CN113461664A (zh) * 2020-03-30 2021-10-01 北京新领先医药科技发展有限公司 一种制备泮托拉唑钠倍半水合物的方法

Citations (1)

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Publication number Priority date Publication date Assignee Title
US20040186139A1 (en) * 2002-09-02 2004-09-23 Dr. Reddy's Laboratories Limited Process for preparation of crystalline form-1 of pantoprazole sodium sesquihydrate

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US20040186139A1 (en) * 2002-09-02 2004-09-23 Dr. Reddy's Laboratories Limited Process for preparation of crystalline form-1 of pantoprazole sodium sesquihydrate

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KOHL B. ET AL.: '(H+,K+)-ATPase Inhibiting 2[(2-Pyridylmethyl)sulfinyl]benzimidazoles. 4. A Novel Series of Dimethoxypyridyl-Substituted Inhibitors with Enhanced Selectivity. The Selection of Pantoprazole as a Clinical Candidate' J. MED. CHEM. vol. 35, 1992, pages 1049 - 1057 *
ZUPANCIC V. ET AL.: 'Physical characterization of pantoprazole sodium hydrates' INTERNATIONAL JOURNAL OF PHARMACEUTICS vol. 291, 29 December 2004, pages 59 - 68 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009010937A1 (fr) 2007-07-17 2009-01-22 Ranbaxy Laboratories Limited Procédé de préparation de pantoprazole sodique.
KR100939216B1 (ko) * 2007-12-11 2010-01-28 동우신테크 주식회사 판토프라졸 나트륨 쎄스키히드레이트의 제조방법
CN113461664A (zh) * 2020-03-30 2021-10-01 北京新领先医药科技发展有限公司 一种制备泮托拉唑钠倍半水合物的方法

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