Crystalline forms
Preparation and 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 pharmaceutical composition comprising
(a) a crystalline form (A) of zoledronic acid: DL-lysine, wherein the crystalline form (A) has substantially the same PXRD diffractogram as FIG. 1 ; or has substantially the same PXRD diffractogram as FIG. 2 , and
(b) at least one pharmaceutically acceptable excipient (B),
wherein the pharmaceutical composition comprises additional excess of cocrystal formers;
wherein the pharmaceutical composition contains about 1% to about 99% by weight of the crystalline form (A) and 99% to 1% by weight of a pharmaceutically acceptable excipient (B).
2. The pharmaceutical composition of claim 1 , wherein the excess cocrystal formers consist of standard amino acids.
3. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a solid oral composition.
4. The pharmaceutical composition of claim 3 , wherein the solid oral composition is a tablet or capsule.
5. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a unit dose.
6. A method of treating or preventing a disease for which zoledronic acid is indicated, said method comprising the step of administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 1 .
7. The method of claim 6 , wherein said disease is selected from the group consisting of osteoporosis, hypercalcemia, cancer induced bone metastasis, Paget's disease, adjuvant cancer therapy and neoadjuvant cancer therapy.
8. The method of claim 7 , wherein said hypercalcemia is tumor induced hypercalcemia (TIH).
9. The method of claim 7 , wherein said disease is cancer induced bone metastasis.
10. A method of making the crystalline form of claim 1 , comprising the steps of: dissolving a zoledronic acid: DL-lysine water complex in acetic acid; forming zoledronic acid:DL-lysine crystals; and purifying said zoledronic acid:DL-lysine crystals from said acetic acid.
11. The method of claim 10 , wherein said method comprises the step of contacting said zoledronic acid, DL-lysine and acetic acid with an antisolvent.
12. The method of claim 11 , wherein said antisolvent is selected from the group consisting of ethanol, ethylacetate (EtOAc), isopropanol (IPA), isopropylacetate (IPAc), diethoxymethane (DEM), Toluene, BuOAc, N-methylpyrrolidone (NMP) and a heptane.
13. The method of claim 11 , wherein said antisolvent is selected from the group consisting of dimethylsulfoxide (DMSO), dioxane, NMP, dimethylformamide (DMF), dimethylacetamide (DMA), and DEM.
14. The pharmaceutical composition of claim 1 , wherein the crystalline form (A) of zoledronic acid: DL-lysine has substantially the same PXRD diffractogram as FIG. 1 .
15. The pharmaceutical composition of claim 1 , wherein the crystalline form (A) of zoledronic acid: DL-lysine has substantially the same PXRD diffractogram as FIG. 2 .