Crystallization method and bioavailability
Preparation, in-vitro and in vivo characterization of novel forms of (1-hydroxy-2-imidazol-1-yl-1-phosphono-ethyl)phosphonic acid, suitable for pharmaceutical compositions in drug delivery systems for humans.
1. A crystalline molecular complex of zoledronic acid selected from the group consisting of:
a crystalline zoledronic acid, sodium zoledronate, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 1 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 2 ,
a crystalline ammonium zoledronic acid salt and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 3 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 4 ,
a crystalline zoledronic diammonia water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 17 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 18 ,
a crystalline zoledronic acid, L-lysine, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 5 or 25 , or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 6 or 26 ,
a crystalline zoledronic acid, DL-lysine, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 7, 19, 21 , or 23 , or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 8, 20, 22 , or 24 ,
a crystalline zoledronic acid, zoledronic, DL-lysine, ethanol, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 9 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 10 ,
a crystalline zoledronic acid, adenine, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 13 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 14 ,
a crystalline zoledronic acid, nicotinamide, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 11 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 12 , and
a crystalline zoledronic acid and glycine complex characterized by a powder x-ray diffraction pattern as shown in FIG. 15 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 16 .
2. A pharmaceutical composition comprising a composition of claim 1 and a pharmaceutically acceptable excipient.
3. A pharmaceutical composition of claim 1 wherein the pharmaceutical composition is an oral dosage form.
4. A pharmaceutical composition of claim 2 further comprising an excess amount of lysine.
5. A zoledronic acid, DL-lysine and water complex, wherein the complex is a crystalline.
6. A molecular complex of claim 5 wherein the molecular complex is a crystalline molecular complex selected from the group consisting of:
a crystalline zoledronic acid, DL-lysine, and water complex characterized by an X-ray powder diffraction pattern having peaks at about 8.3, 11.8, 12.3, 15.8, and 20.8 ±0.2 degrees two-theta;
a crystalline zoledronic acid, DL-lysine, and water complex characterized by an X-ray powder diffraction pattern having peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0 ±0.2 degrees two-theta;
a crystalline zoledronic acid, DL-lysine, and water complex characterized by an X-ray powder diffraction pattern having peaks at about 9.7, 10.8, 14.4, 18.9, 21.4 ±0.2 degrees two-theta; and
a crystalline zoledronic acid, zoledronic, DL-lysine, ethanol, and water complex characterized by an X-ray powder diffraction pattern having peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5 ±0.2 degrees two-theta.
7. A pharmaceutical composition comprising a composition of claim 5 and a pharmaceutically acceptable excipient.
8. A pharmaceutical composition of claim 7 wherein the pharmaceutical composition is an oral dosage form.
9. A pharmaceutical composition of claim 7 further comprising an excess amount of lysine.
10. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline zoledronic acid, sodium zoledronate, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 1 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 2 .
11. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline ammonium zoledronic acid salt and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 3 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 4 .
12. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline zoledronic diammonia water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 17 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 18 .
13. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline zoledronic acid, L-lysine, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 5 or 25 , or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 6 or 26 .
14. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline zoledronic acid, DL-lysine, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 7, 19, 21 , or 23 , or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 8, 20, 22 , or 24 .
15. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline zoledronic acid, zoledronic, DL-lysine, ethanol, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 9 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 10 .
16. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline zoledronic acid, adenine, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 13 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 14 .
17. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline zoledronic acid, nicotinamide, and water complex characterized by a powder x-ray diffraction pattern as shown in FIG. 11 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 12 .
18. A crystalline molecular complex of zoledronic acid of claim 1 selected from a crystalline zoledronic acid and glycine complex characterized by a powder x-ray diffraction pattern as shown in FIG. 15 or characterized by a Fourier transform infrared spectroscopy pattern as shown in FIG. 16 .
19. A method for enhancing the bioavailability or permeability of zoledronic acid or salt thereof comprising the step of administering to a patient in need thereof a therapeutically effective amount of zoledronic acid in the form of a molecular complex according to claim 1 .
20. A method for the treatment of disease states associated with osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease or adjuvant or neoadjuvant cancer therapies comprising the step of administering to a patient in need thereof a therapeutically effective amount of a molecular complex according to claim 1 .
21. A method for enhancing the bioavailability or permeability of zoledronic acid or salt thereof comprising the step of administering to a patient in need thereof a therapeutically effective amount of zoledronic acid in the form of a molecular complex according to claim 5 .
22. A method for the treatment of disease states associated with osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease or adjuvant or neoadjuvant cancer therapies comprising the step of administering to a patient in need thereof a therapeutically effective amount of a molecular complex according to claim 5 .