Crystallization method and bioavailability
Preparation and in vitro and in vivo characterization of novel forms of active pharmaceutical ingredients, suitable for pharmaceutical compositions in drug delivery systems for humans.
1. A composition comprising at least one API and at least one coformer:
wherein said at least one coformer is a molecular complex coformer and/or an additional coformer;
wherein said API and said molecular complex coformer form a molecular complex;
wherein said API is a bisphosphonic acid and said at least one coformer is selected from the group consisting of sodium, ammonium, ammonia, lysine, nicotinamide, adenine, and glycine; and
wherein said molecular complex is a crystalline molecular complex selected from the group consisting of:
a) a crystalline zoledronic acid, sodium zoledronate and water molecular complex characterized by an X-ray powder diffraction pattern having peaks at about 8.1, 13.3, 21.5, 24.6, and 25.6±0.2 degrees two-theta;
b) a crystalline ammonium zoledronic acid salt and water molecular complex characterized by an X-ray powder diffraction pattern having strong peaks at about 11.0, 14.6, 15.4, 19.9, and 29.4±0.2 degrees two-theta;
c) a crystalline zoledronic diammonia water molecular complex characterized by an X-ray powder diffraction pattern having strong peaks at about 12.2, 13.0, 14.1, 17.1, and 19.3±0.2 degrees two-theta;
d) a crystalline zoledronic acid, L-lysine, and water molecular complex characterized by an X-ray powder diffraction pattern comprising peaks at about 9.0, 14.4, 18.1, 26.0, and 29.6±0.2 degrees two-theta;
e) a crystalline zoledronic acid, L-lysine, and water molecular complex characterized by an X-ray powder diffraction pattern comprising peaks at about 9.6, 10.7, 14.3, 21.4, 23.5±0.2 degrees two-theta;
f) a crystalline zoledronic acid DL-lysine and water molecular complex characterized by an X-ray powder diffraction pattern comprising peaks at about 8.3, 11.8, 12.3, 15.8, and 20.8±0.2 degrees two-theta;
g) a crystalline zoledronic acid, DL-lysine, and water molecular complex characterized by an X-ray powder diffraction pattern comprising peaks at about 9.1, 14.7, 18.0, 21.2, and 26.0±0.2 degrees two-theta;
h) a crystalline zoledronic acid, DL-lysine, and water molecular complex characterized by an X-ray powder diffraction pattern comprising peaks at about 9.7, 10.8, 14.4, 18.9, 21.4±0.2 degrees two-theta;
i) a crystalline zoledronic acid, zoledronic, DL-lysine, ethanol, and water complex characterized by an X-ray powder diffraction pattern comprising peaks at about 8.8, 9.7, 17.6, 23.1, and 26.5±0.2 degrees two-theta;
j) a crystalline zoledronic acid, adenine, and water molecular complex characterized by an X-ray powder diffraction pattern comprising peaks at about 13.6, 15.9, 19.7, 27.9, and 29.5±0.2 degrees two-theta;
k) a crystalline zoledronic acid, nicotinamide, and water molecular complex characterized by an X-ray powder diffraction pattern comprising peaks at about 13.1, 15.2, 21.0, 23.9, and 26.5±0.2 degrees two-theta; and
l) a crystalline zoledronic acid and glycine molecular complex characterized by an X-ray powder diffraction pattern comprising peaks at about 10.2, 17.8, 19.9, 22.9, and 28.1±0.2 degrees two-theta.
2. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable excipient.
3. The pharmaceutical composition of claim 2 , wherein said coformer:
a) increases the intestinal permeability of the API;
b) increases the C max of the API;
c) increases the aqueous solubility of the API;
d) increases the stability of the API under ambient conditions; and/or
e) increases the oral bioavailability of the API.
4. The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is an oral dosage form.
5. A unit dose of the pharmaceutical composition of claim 2 , wherein said unit dose comprises at least about 250 mg of the coformer.
6. The unit dose of claim 5 , wherein the coformer is lysine or glycine.
7. A method for enhancing the oral bioavailability or permeability of a bisphosphonic acid, said method comprising the step of combining said bisphosphonic acid with a coformer selected from the group consisting of sodium, ammonium, ammonia, lysine, nicotinamide, adenine, and glycine, to form the pharmaceutical composition of claim 2 .
8. A method of treating a disease state for which a bisphosphonic acid is indicated, said method comprising the step of administering to a patient in need of said bisphosphonic acid a therapeutically effective amount of said pharmaceutical composition of claim 2 .
9. The method of claim 8 , wherein said disease state is associated with osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease, or adjuvant or neoadjuvant cancer therapies.