US 7,943,176 B2  14  13  of propiverine-hydrochloride and 49.8% of citric acid, deter› mined according to the method described in Example 6. The  molar ratio of active agent to citric acid was 1 :5.6.  240 mg of the thus obtained pellets each, corresponding to  45 mg propiverine-hydrochloride were filled into hard  gelatine capsules and used for the bioequivalence study of  Example 15.  mined by the methods described in Example 6. This results in  a molar ratio of active agent to citric acid of 1 :4.0.  The release of propiverine from the pellets was determined  by the method described in Example 5 and is indicated in the  Table provided there.  The release of propiverine from the pellets was carried out  under the conditions as described in Example 5. The results  are listed in the Table provided there.  2400 g spherical citric acid cores which were produced in  the same manner as already described in Example 3.2 were  coated in a fluidised bed at an air feed temperature of 40-7 4 °  C. with a suspension consisting of 48 g Eudragitfi S 100, 48 g  Eudragit Ll00, 13 g triethylcitrate, 65 g microfine talcum,  1860 g isopropanol and 200 g water.  2500 g of the thus obtained retarded starter cores were  sprayed under the same technical conditions with a suspen› sion of 828 g propiverine base, 177 g polyvinylpyrrolidone  (Kollidonfi K25), 63 g citric acid, 200 g microfine talcum and  32 g magnesiumstearate in 3100 g 2-propanol and 400 g  water. The total amount obtained was 3740 g active agent  pellets corresponding to 98.4% of the theoretical amount,  referring to the dry substance used.  In the same manner 3250 g of the active agent pellets were  sprayed with a suspension of720 g Eudragitfi RL 12.5 (90 g  dry mass Eudragitfi RS), 368 g Eudragitfi RL 12.5 (46 g  Eudragitfi RL dry mass), 90 g Eudragitfi Sl00, 24 g trieth› ylcitrate and 146 g micro fine talcum in 1930 g 2-propanol and  300 g demineralised water.  3500 g of thus obtained retarded active agent pellets were  sprayed in the fluidised bed under identical conditions with a  suspension consisting of 86 g Eudragitfi S 100, 9 g triethyl› citrate, 52 g microfine talcum, 129.9 g 2-propanol and 80 g  water.  The thus obtained pellets showed a content of 19.4%  propiverine as well as a content of 40.4% citric acid as deter- The release data obtained are shown in Tables 1 and 2 as the  mean values of a six fold determination.  The calculation of the release data is carried out in relation  to one sample of a reference substance which is measured  under the same conditions in the UV NIS-spectrometer. The  amount of propiverine-hydrochloride or propiverine, respec› tively, which is released during the first hour in 0.1 M hydro› chloric acid is added to the further release values.  The quantification of propiverine-hydrochloride or propiv› erine, respectively, in the release medium is carried out by  means of an on-line coupled UV NIS-spectrophotometer. For  the measurement the release medium is pumped at predefined  periods from each release container through polypropylen  filters via a 6-channel tube pump into the flow vessel of the  UVNIS-spectrophotometer. The measurement of the extinc› tion is at 239 nm whereby the extinction at 247 nm is addi› tionally determined as the background. For calculation of the  amount of propiverine-hydrochloride/propiverine the extinc› tion value at the background wavelength is subtracted from  the extinction value at the measurement wavelength.  For this an amount of pellets corresponding to 45 mg  propiverine-hydrochloride each was weighed into 6 baskets.  The release is carried out for one hour in 7 50 ml gastric fluid  medium (0.1 M hydrochloric acid solution) at 37°  C. This  medium is thrown away after measurement of the 1 hour  value and the release is then carried out in 7 50 ml of an 50 mM  potassium dihydrogenphosphate buffer at pH 5 .8 at 3 7°  C. for  further 16 hours.  The determination of the release of propiverine-hydrochlo› ride orpropiverine, respectively, from all of the described oral  dosage forms was made with the help of the basket apparatus  as described in Ph. Eur. 3, 2.93 at 100 rpm for 17 hours.  Example 5  Determination of the Release Data-Comparison of  the Release Data of Examples 1-4, 7-13  Example 4  Pellet Formulation with Propiverine  Tabelle 1: Release ofpropiverine-hydrochloride/propiverine in percent- Exam12les 1-4(n.d.-not determined)  Example 3.1 (Pellet) Example 3.2 (Pellet)  Example 1 (pellet)  Example 2 (Pellet)  Propiverine- Propiverine- Example 4 (Pellet)  Propiverine- Propiverine- hydrochloride- hydrochloride- Propiverine- Time  hydrochloride- hydrochloride- 20% after 3 h, 80%  20% after 3 h 80%  20% after 3 h 70%  [h]  100% after 15 min  50% after 3 h  after 10 h  after 10 h  after 10 h  0.08  103.06  n.d.  n.d.  n.d.  n.d.  0.17  101.41  n.d.  nd.  n.d.  n.d.  0.25  100.05  n.d.  nd.  n.d.  n.d.  0.5  n.d.  0.43  0.00  0.69  0.59  101.08  6.41  0.85  1.00  2.76  1.5  14.75  4.70  1.38  7.57  2  23.92  10.01  5.26  13.01  3  42.07  22.65  20.61  23.64  4  57.78  35.87  33.37  32.80  5  70.11  48.18  44.82  41.13  6  79.16  58.83  55.28  48.49  7  85.44  67.55  64.15  54.84  8  89.62  74.38  71.03  60.66  9  92.29  79.53  76.16  65.48  10  93.94  83.29  79.88  69.73  11  94.93  85.96  82.50  72.95  12  95.51  87.80  84.58  75.78 