ramipril ( see scheme 1 ) contains not less than 
 98.0% of c23h32n2o5 ; ( 2s,3as,6as)-1-[(2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-3,3a,4,5,6,6a - hexahydro-2h - cyclopenta[d]pyrrole-2 
 carboxylic acid . it belongs in a class of drugs 
 called angiotensin converting enzyme ( ace ) inhibitors which are used for 
 treating high blood 
 pressure and heart failure and for 
 preventing kidney 
 failure due to high blood pressure and 
 diabetes . angiotensin ii contracts the muscles of most 
 arteries in the body , including the heart , thereby 
 narrowing the arteries and elevating the blood pressure . in the kidney , the narrowing 
 caused by angiotensin ii also increases blood pressure and decreases the flow 
 of blood . ace inhibitors such as ramipril lower blood pressure by reducing the 
 production of angiotensin ii , thereby relaxing the arterial muscles and 
 enlarging the arteries . the enlargement of the arteries throughout the body 
 reduces the blood pressure against which the heart must pump blood , and it 
 becomes easier for the heart to pump blood . this increases the flow of blood and oxygen to the 
 heart , and this improves further the ability of the heart to pump blood . the 
 effects of ace inhibitors are particularly beneficial to people with congestive 
 heart failure . in the kidneys , the 
 enlargement of the arteries also reduces blood pressure and increases blood 
 flow . methods in current use for the assay of ramipril , 
 in pharmaceutical preparation , are based on spectrophotometry [ 16 ] , liquid 
 chromatography [ 712 ] , gas chromatography [ 13 , 14 ] , enatioselective biosensors 
 , enatioselective membrane , voltammetry , amperometric biosensor 
 , and mass spectrometry . however , most of these methods are 
 sophisticated , tedious , and required many manipulation steps . on the other hand , although , ion - selective electrodes and potentiometric sensors are much simpler , 
 fast , and inexpensive , only one ion - selective electrode has been reported for 
 the determination of ramipril drug as anionic species . in this paper , the preparation , 
 characterization , and analytical application of new two ramipril cationic ion - selective electrodes based on phosphomolibdate and tetraphenylborate - ramipril 
 ion - pair complexes have been reported . the merits offered by the proposed 
 electrodes include the high cationic sensitivity of the drug in the acid media 
 with fast response time ( < 30  seconds ) and long life span ( 2 months ) . the 
 potentiometric measurements were made at 25  1c , using an orin ( model 
 a720 ) digital ph / mv meter and orion ross combination ph electrode ( model 81 - 02 ) 
 for all ph measurements . the suggested ramipril pvc membrane - based electrode 
 was used for all potentiometric measurements in conjunction with a double 
 junction reference electrode ( orion model 90 - 02 ) containing kno3 ( 10%  w / v ) in the outer compartment . 1430 ratio recording ir 
 spectrophotometer was used for structure elucidation of the ion - pair complexes . all chemicals were of analytical reagent 
 grade unless otherwise stated and doubly distilled water was used throughout . poly ( vinyl chloride ) powder ( pvc ) of high molecular weight ( 10  000 ) and dioctyl 
 phthalate plasticizer of purity 98% were obtained from aldrich chemical company , 
 inc . ( milwaukee , wis , usa ) . 
 tetrahydrofuran ( thf ) with a purity of 99% containing 0.025% 
 butylatedhydroxytoluene inhibitor was used as solvent . ramipril 
 stock solution ( 10  mol  l ) was prepared by dissolving 0.4165  g in a minimal 
 volume of acetic acid with continuous stirring and then diluted to 100  mllwith 
 distilled water . the resulting clear solution of ph 3 was obtained by the addition 
 of small aliquots of 10  mol  l hcl . ( 0.2  mol  l ) were individually prepared 
 by dissolving appropriate weight of sodium phosphomolibdate and tetraphenylborate , 
 respectively , in a minimum volume of distilled water followed by filtration then 
 completed to 100  ml with distilled water . ramipril - phosphomolibdate and ramipril - tetraphenylborate 
 ion - pair sensing materials were individually prepared by mixing 30  ml aliquot 
 of 10  mol  l ramipril solution with a 30  ml aliquot 
 of 10  mol  l aqueous phosphomolibdate and tetraphenylborate solutions , respectively in l00  ml beaker . the obtained precipitates were filtered using a g4 sintered 
 glass crucible , washed thoroughly with distilled water , and dried at room 
 temperature . two 
 pvc master membranes based on the suggested sensing materials containing 0.01  g ion - pair complex , 0.350  g dioctylphthalate 
 ( dop ) , and 0.190  g of poly ( vinyl chloride ) were individually prepared . each membrane contents 
 were thoroughly mixed , dissolved in 6  ml aliquot of thf , and transferred to a 
 glass petri dish ( 3  cm diameter ) . the petri dish was covered with a filter paper 
 and left to stand overnight to allow slow evaporation of the solvent at room 
 temperature . the membranes were sectioned with a cork borer ( 10  mm diameter ) and attached 
 to a length of polyethylene tubing ( 3  cm length , 8  mm i.d ) by using thf .   a home 
 -made electrode body was used , which consists of a glass tube , to one end of 
 which the poly ethylene tubing was attached and filled with an equimolar 
 mixture of 10  mol  l of potassium chloride and 
 ramipril as the internal reference solution . an ag / agc1 internal reference wire 
 electrode ( 1.0  mm diameter ) was immersed in the internal solution . this assembly 
 was used in the potentiometric characterization of the electrodes and the 
 subsequent determination of the drug . 
 in 
 order to calibrate the suggested electrodes , aliquots ( 10  ml ) of aqueous 
 ramipril solutions ( 1.0  101.0  10  mol l ) 
 were transferred into 50  ml beakers , and the pvc membrane electrode , in 
 conjunction with a double junction ag / agcl reference electrode , was immersed in 
 the solution . alternatively , the drug pvc membrane electrode in conjunction 
 with a double junction ag / agc1 reference electrode was immersed in a 50  ml 
 beaker containing a l0  ml aliquot of water . the solutions were gently stirred during the measurements and the potential 
 recorded after stabilization to 0.2  mv and the e.m.f plotted on semilogarithmic 
 paper as a function of the drug concentration . the calibration graphs were used 
 for subsequent determination of unknown concentration of the drug . the 
 potentiometric selectivity coefficient indicates the extent to which a foreign 
 ion b interferes with the response of the electrode to its primary drug ion a. 
 the potentiometric selectivity coefficients k 
 a , b 

 for the suggested electrodes were measured by 
 separate solutions method ssm . in this method , the potential responses of 
 the electrode in 10  mol  l solution of the 
 interferents were measured and recorded . the potential response of the 
 electrode for the drug was separately , obtained in a similar manner at the same 
 concentration level . the selectivity coefficient values were calculated using 
 the simplified form of eisemnan nicolsky equation:(1)ka , bpot = e1e2s+(11z2)log  a1 , where e 
 1 and e 
 2 are the potential readings of the electrode in separate 
 solutions of the same concentration of the drug and interferants , respectively , 
 s is the slope of the drug calibration graph ( mv / concentration decade ) , a 
 1 is the activity of the drug , and z 
 2 is the charge number of the 
 interfering ion . the 
 effect of ph of the test solution on the potential reading of the suggested 
 drug electrodes was studied by immersing a ross combination glass electrode 
 ( orion model 81 - 02 ) , pvc membrane electrode , and a double junction ag / agc1 
 reference electrode in 50  ml beakers containing 30  ml aliquots of 10 and 10  mol  l drug solutions . the ph of each solution 
 was gradually increased and decreased by adding small aliquots of dilute sodium 
 hydroxide and hydrochloric acid , respectively . the mv - ph profile at each drug concentration was plotted for 
 the two electrode systems . in 
 order to investigate the reliability of the proposed electrodes , they have been 
 applied in the determination of the drug using direct potentiometry and 
 potentiometric titration . in the direct potentiometry study , a pvc membrane - based 
 ramipril electrode in conjunction with a double junction reference electrode 
 was immersed in a l0  ml of the appropriate drug solutions of unknown 
 concentration . the potential readings were recorded after stabilization to 0.2  mv and compared with the calibration graph . the solutions were stirred during 
 measurements , and the electrodes were thoroughly washed with distilled water 
 between measurements . in the 
 potentiometric titration of ramipril , aliquots ( 26  ml ) of 10 mol 
 l of ramipril solution were transferred to 50  ml beakers and 
 diluted to 10  ml with distilled water . the solution was stirred and titrated 
 with a standard 10  mol  l sodium tetraphenylborate 
 solution using the suggested ramipril membrane electrode in conjunction with a 
 double junction ag / agc1 reference electrode . the electrode potential ( e ) was 
 recorded as a function of the titrant volume ( v ) added , ( e versus v ) curves were 
 plotted . the end point was calculated from the maximum slope e/v versus 
 v. 
 moreover , 
 different forms and dosages of pharmaceutical preparations were assayed to 
 determine ramipril in different formulations . in this study , aliquot of 5  ml of 
 the drug was transferred to 25  ml beaker containing 15  ml of deionised water , and 
 the ph of the solution was adjusted to ph 3 with a drop of dilute hc1 solution . the solution was then transferred to 25  ml volumetric flask , completed to the 
 mark , shaken well , and transferred to a 100  ml beaker for ise measurement . for 
 the assay of tablet formulations , 10 tablets were finely powdered , mixed , and an 
 accurate weight equivalent to 0.1% of the tablet was transferred into 50  ml 
 beakers containing 20  ml of deionized water , the ph of the solution was 
 adjusted to ph 3 with a drop of dilute hc1 solution , and transferred to 25  ml 
 volumetric flask , completed with water to the mark , shaken well . the suggested 
 ramipril - based membrane electrode was immersed in conjunction with a double 
 junction ag / agc1 reference electrode into the solution . the potential was 
 measured after a stable reading was obtained and compared with that on a 
 calibration graph previously constructed for standard solutions . ramipril  phosphomolibdate and ramipril  tetraphenylborate ion - pair complexes have been 
 prepared and examined as new electroactive ionophores in pvc matrix membranes 
 responsive to ramipril cation . in acid media , ramipril cations readily react 
 with phosphomolibdate and tetraphenylborate anions to form stable water insoluble 
 ion association complexes . the ir studies confirm that the formation of 1:1 
 ramipril : anion ion - pair association . the potentiometric response 
 characteristics of the proposed electrodes were evaluated , according to iupac 
 recommendations   using the following electrochemical cell : ag / agcl  |  102  mol  l1  kc1102  mol  l1  ramipril  |  pvcmembrane  |  |  ramipriltest  solution  |  |  10%kc1  |  agc1/ag 
 
 the potentiometric 
 response characteristics of the investigated ramipril pvc membrane - based electrodes 
 were evaluated from the data collected from four assemblies for each membrane 
 electrode . the responses of ramipril 
 electrode systems are linear over the concentration range 1  101  10  mol  l. the slopes 
 of the calibration plots ( figure 1 ) are typically 53  0.5  mv and 54  0.5 per concentration decade for ramipril deviation from the ideal nernstian 
 slope ( 59.2  mv / concentration 
 decade ) stems from the fact that most potentiometric drug sensors respond to 
 the activity of the drug cations rather than the concentration . the response time and stability of the membranes have been 
 investigated . in these studies , the 
 time required for ramipril poly ( vinyl chloride ) membrane electrodes to reach a 
 value of 1  mv from the final equilibrium potential in the same day after 
 successive immersion in different ramipril solutions was measured . the results 
 obtained ( figure 2 ) show that s the electrode attain stable potential values 
 within 20 seconds . in addition , the potentials displayed by the electrode in 
 the linear concentration range of ramipril in the same day do not vary by more 
 than 0.5  mv . the stability of the potential reading for the ramipril - based 
 electrodes is within 2  mv during the lifetime ( 2 months ) of the electrodes . the 
 effect of ph on the potential readings of the proposed electrode was also examined 
 by recording the e.m.f . of ramipril test solutions ( 10 and 10  mol  l ) at various ph values , which were obtained by the addition 
 of very small volumes of hydrochloric acid and/or sodium hydroxide solutions 10  mol / l of each . -ph plots presented in figures 3 and 4 revealed that 
 the potential readings are insensitive to ph changes in the ranges 1.03.8 and 1.04.0 for the 
 ramipril - phosphomolibdate and ramipeil - tetraphenylborate , respectively . the shape of mv - ph profile depends 
 on the stability of the ion - pair in the membrane as a function of ph , the 
 nature of the drug ( protonation or complexation equilibrium ) in the test 
 solution , and the sensitivity of the membrane to either [ h ] or [ oh ] 
 at low or high ph values , respectively . it was observed that ramipril ion - pair 
 complexes deteriorate in alkaline media causing severe potential shift . at relatively 
 higher ph values , the e.m.f decreased this is probably due to deprotonated 
 species in test solution . the 
 selectivity coefficients of the investigated electrodes were evaluated using 
 separate solution method ( ssm ) . in this study , the performance of the ramipril 
 electrodes in the presence of some tested organic and inorganic cations was studied . the selectivity coefficient values ( k 
 a , b 
 ) are calculated and presented in table 
 2 . as can be seen , the electrode offers a reasonable selectivity for the ramipril 
 cation over most of the tested species . 
 in order to investigate the analytical usefulness of the 
 proposed electrodes , they have been successfully applied in the potentiometer 
 determination of ramipril in aqueous samples as well as in some local pharmaceutical 
 formulations . in the former study , solutions of concentration in the liner 
 range of the tested electrode are prepared from pharmaceutical grade of 
 ramipril and determined by direct potentiometry and potentiometric titration 
 using the proposed ramipril electrodes . some local 
 pharmaceutical formulations have been prepared and analyzed by direct 
 potentiometry using the investigated ramipril electrodes . as can be seen , the two electrodes provide a good 
 accuracy ( average recovery > 96% ) and high 
 precision ( rsd < 3% , n they provide 
 analytical , useful sensitivity to the drug with fast response time , reliable , and 
 reproducible response . the proposed electrodes have been successfully applied 
 in the determination of ramipril in some pharmaceutical formulations with good 
 accuracy and high precision .