Showing posts with label WO2015128440. Show all posts
Showing posts with label WO2015128440. Show all posts

Monday 7 September 2015

EUTICALS SPA WO2015128440 New patent CRYSTALLINE FORM OF TIOTROPIUM BROMIDE WITH LACTOSE


WO2015128440
CRYSTALLINE FORM OF TIOTROPIUM BROMIDE WITH LACTOSE
EUTICALS SPA [IT/IT]; Viale Bianca Maria, 25 I-20121 Milano (IT)
A tiotropium bromide and cocrystal of lactose monohydrate is Disclosed HEREIN. In the tiotropium bromide cocrystal the components and lactose are preferably present in stoichiometric ratio An almost. Said cocrystal: has a single endothermic event at about 191-3 ° C Determined by DSC. A process for the preparation of the cocrystal est Disclosed. Preferably, the particle size cocrystal: has a distribution of D90 <10μ. The cocrystal est Disclosed for use as medicine, in Particular for the treatment of a respiratory complaint, Such As chronic obstructive pulmonary disease (COPD), bronchitis, emphysema and asthma.A pharmaceutical composition comprenant the active ingredient as cocrystal est Disclosed, in Particular for administration by inhalation. In the lathing box, Said: has a mean particle cocrystal size of 0.5 to 10 .mu.m, preferably 1 to 6 .mu.m, more preferably 1.5 to 5 microns.
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Tiotropium bromide (compound identified by CAS registry number 136310-93-5) was described for the first time in 1991 by Boheringer Inghelheim (EP 0418716) and presents the following structural formula:

Tiotropium bromide is an anticholinergic bronchodilator with a long-lasting effect, 24 hours, which may be used to treat respiratory complaints, particularly COPD (chronic obstructive pulmonary disease), bronchitis, emphisema and asthma.
Tiotropium bromide is preferably administered by inhalation: suitable inhalable powders packed into appropriate capsules may be used (Spiriva®; US7694676 and US8022082) or alternatively, it may be administered by the use of inhalable aerosols (EP2201934).
The correct manufacture of the above mentioned compositions, suitable for the administration of a pharmaceutically active substance by inhalation, is based on the definition of physical parameters, like a particular crystalline form (see for example US6608055 and US677423) and a defined particle size distribution (US7070800), which are connected with the nature of the active substance itself.
From literature data, Tiotropium Bromide is described to exist in different polymorphic forms as well as in an amorphous form. In more details, Tiotropium Bromide is described to exist in a crystalline monohydrate form (US6777423), in several anhydrous (US6608055, WO2006/1 17300, EP1682542) and solvate (US7879871 , W02010/101538, WO201 1/015882) polymorphic forms. Some of these polymorphic forms are unstable and may change. For example, the monohydrate form described in US6777423 may be easily transformed after a mild heating at 40°C for few hours into the corresponding anhydrous form described in US6608055.
Since the quality of a pharmaceutical formulation requires that an active substance should always have the same crystalline modification, the stability and properties of the crystalline active substance are subject to stringent regulatory requirements.
There is the need of a crystalline form of tiotropium bromide which is stable to humidity and to mechanical treatments, like the micronization or other milling techniques, and which meets the high demands mentioned above for any pharmaceutically active substance.
It has now surprisingly been found that a crystal modification of tiotropium bromide meeting the above requirements can be obtained in the form of a cocrystal with lactose. Unexpectedly, this cocrystal is stable towards the influence of moisture and humidity and to physical treatments like the micronization.
In the novel cocrystal the components tiotropium bromide and lactose are present in an almost stoichiometric ratio, as determined for example by NMR spectroscopy. Therefore, the present invention relates to a tiotropium bromide-lactose cocrystal in which the components tiotropium bromide and lactose are present, with the limit of resolution of the employed analytical technique (ie H-NMR), in a ratio of about 1 : 1.
This novel cocrystal is characterized by a single endothermic event at about 191-3°C determined by DSC and by an X-Ray spectrum with characteristic 2theta values at 13.08; 14.16; 14.68; 17.90; 18.58; 19.06; 19.44; 21.02; 22.58; 23.24; 25.26; 26.20; 27.24; 28.08; 28.42; 29.96; 30.18; 31.80; 34.50; 34.82; 35.58; 38.70; 39.26; 41.52 and 50.06.
The present invention also relates to the cocrystal herein disclosed for use as a medicament, in particular for the treatment of respiratory complaints, particularly for the treatment of COPD and/or asthma.

Example 1
Preparation of Tiotropium Bromide Cocrystal with lactose in dimethylsulfoxide and acetone
Tiotropium Bromide (4.25g; 8.99 mmoles) and lactose monohydrate (3.58g; 9.9 mmoles) were dispersed at room temperature in dimethylsulfoxide (7.2 ml). The mixture was heated under stirring at the temperature of 50-55°C to obtain a limpid solution. Then acetone (55 ml) was added dropwise in 30' maintaining the reaction mixture under stirring at 50-55°C. The obtained solution was cooled down at 20-25°C and kept at this temperature under stirring for 2 hours. After this period a suspension was obtained. The precipitate was recovered by suction and the wet product slurried in acetone (14.9 ml) under stirring for 90'. The product was recovered by filtration, washed on the filter with acetone (4 times with 8.5 ml each) and dried under vacuum at 40°C for 48 hours to afford 6.76g (8.1 1 mmoles; 90% molar yields) of dry product.
The obtained crystals were analysed by X-Ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and H-NMR (500 MHz) indicating that a new crystalline form, namely a cocrystal of Tiotropiumbromide with lactose is formed.
A representative DRX spectrum of Tiotropium Bromide cocrystal with lactose is shown in Figure 1 (third DRX spectrum from the bottom) overlapped with the DRX spectra of the employed starting materials (from the top respectively the DRX spectra of lactose monohydrate and of Tiotropium Bromide). The list of the characteristic diffraction peaks including normalised intensities of Tiotropium Bromide cocrystal is shown in table 1.
Table 1
2theta Intensity l/lo
11.360 420 21
12.340 453 23
13.080 366 18
13.520 843 42
14.160 1026 51
14.680 1098 54
15.280 659 33
theta Intensity l/lo 5.960 696 35 6.300 524 26 6.960 872 43 7.900 1472 73 8.580 1897 93 9.060 1847 91 9.440 1938 95 0.460 791 39 1.020 826 41 1.720 819 41 2.580 1712 84 3.240 2044 100 3.980 919 45 4.380 853 42 5.260 1499 74 6.200 1156 57 7.240 1240 61 8.080 1554 77 8.420 1935 95 9.960 1043 52 0.180 1024 51 0.500 819 41 0.900 924 46 1.800 1399 69 2.340 960 47 2.980 839 42 3.440 937 46 theta Intensity l/lo 4.500 1032 51 4.820 1424 70 5.580 1196 59 6.380 899 44 6.880 964 48 7.220 917 45 7.740 913 45 7.960 982 49 8.700 1163 57 9.260 1035 51 9.880 833 41 1.520 1396 69 1.940 976 48 3.400 1005 50 3.600 989 49 4.900 1074 53 5.360 893 44 6.920 1001 49 7.480 932 46 8.060 958 47 9.540 1107 55 0.060 1023 51 1.820 995 49 4.440 990 49 5.220 946 47 6.340 960 47 8.100 926 46 The DSC-thermograms of the lactose cocrystal with Tiotropium bromide shows an endothermic event at ca. 191-193°C indicating melting of this material. The obtained DSC-diagram is depicted in Figure 2.
In order to get an idea on the stoichiometry of the obtained cocrystal H-NMR spectra (500 MHz) were recorded. The samples were dissolved in d6-DMSO for analysis. The corresponding spectrum is shown in Figures 3 and 3A. In addition to the characteristic H-NMR signals of tiotropium there is a signal at 4,17 and 4, 18 ppm which is indicative of H1 ' of lactose (integration 1 H; ref Hyunnsook Ko et al. Bull. Korean Chem. Soc. 2005, Vol 26, No12, 2001-6). Integration of this signal compared to the signal at 4,12 ppm of CH 1 and 5 (integration 2H; ref. Zhenguang Lin et al. Spectrochimica Acta Part A 75 (2010), 1 159-1162) of Tiotropium shows that the cocrystal has a stoichiometry which is close to 1 : 1.

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