Polymorphic forms of Cyclo (-His-Pro)
The present disclosure relates to synthesis and characterization of novel polymorphic forms of Cyclo (-His-Pro) (“CHP”).
1. A cyclo(-His-Pro) hydrate compound characterized by an X-ray powder diffraction (XRPD) diffractogram comprising peaks at 2θ values of 13.7°±0.2°, 17°±0.2°, and 27.3°±0.2°
2. The compound of claim 1 , wherein the XRPD diffractogram further comprises a peak at 2θ value of 10°±0.2°.
3. The compound of claim 1 , wherein the XRPD is substantially similar as shown in FIG. 2( b ) .
4. The compound of claim 1 having a differential scanning calorimetry (DSC) endotherm onset at about 75° C. to about 100° C.
5. The compound of claim 1 having a DSC exotherm onset of about 115° C. to about 120° C.
6. The compound of claim 1 having a differential scanning calorimetry (DSC) thermogram having two endothermic peaks with peak maxima at about 100° C. and about 170° C.
7. The compound of claim 1 , characterized by at least two of the following:
(a) an X-ray powder diffractogram comprising at least two peaks from the following list: 10, 13.7, 17, 18.1, 20.2 and 27.3 degrees (±0.2° in 20);
(b) birefringent with a fragmented, rod-like morphology when analyzed by polarized light microscopy;
(c) initial weight loss of 6.5% (0.9 equivalent of water), followed by sample degradation at around 280° C. when analyzed by thermogravimetric analysis technique;
(d) an endotherm with an onset of 99° C. and a peak at 102° C. in the first heat cycle of DSC;
(e) start of dehydration below 10% relative humidity (RH), loss of about 6 wt % from 10 to 0% RH (0.8 equivalent of water) and hydration from 0 to 40% RH in the 40° C. dynamic vapor sorption analysis; and
(f) start of dehydration below 20% RH, loss of about 7 wt % from 20 to 0% RH (1.0 equivalent of water), and rehydration from 0 to 40% RH in the 60° C. dynamic vapor sorption analysis.
8. The compound of claim 1 having a purity of at least 90%.
9. The compound of claim 1 , wherein the compound is stable at room temperature for about 6 months.
10. The compound of claim 1 , wherein the compound is free of solvent.
11. A composition comprising the cyclo(-His-Pro) hydrate of claim 1 as an active ingredient.
12. The composition of claim 11 , wherein the composition comprises about 1% to about 50% (w/w) of the cyclo(-His-Pro) hydrate based on the total weight of the composition.
13. The composition of claim 12 , wherein the composition comprises about 1 to about 20 percent (wt %) of the cyclo(-His-Pro) hydrate.
14. The composition of claim 12 , wherein the composition further comprises an additional therapeutically active agent, a pharmaceutically acceptable carrier, or a combination thereof.
15. The of claim 11 , wherein the composition is a dosage form suitable to be administered orally, topically, parenterally, intravenously, intradermally, colonically, rectally, intramuscularly or intraperitoneally.
16. The composition of claim 11 , wherein the composition is formulated for parenteral administration by injection or continuous infusion.
17. The composition of claim 11 , wherein the concentration of cyclo(-His-Pro) hydrate is from about 1 mg/liter to about 200 mg/ml.
18. The composition of claim 11 , wherein the composition is formulated in an oral unit dosage form.
19. The composition of claim 18 , wherein the composition comprises a dosage unit from about 1 mg to about 100 mg of the cyclo(-His-Pro) hydrate.
20. A pharmaceutical composition, comprising:
the cyclo(-His-Pro) hydrate of claim 1 ;
one additional therapeutically active agent selected from zinc; and
at least one pharmaceutically acceptable carrier.
21. A method for synthesizing the cyclo(-His-Pro) hydrate of claim 1 , comprising steps of:
(a) adding cyclo(-His-Pro) anhydrate in EtOH/water to form a mixture;
(b) heating the mixture to about 50° C. to dissolve and form a solution;
(c) cooling the solution of step (b) to about 35° C.;
(d) adding a seeding compound to the solution of step (c) and allow the resulting mixture to stand for about 2 to about 3 hours;
(e) cooling to about 5° C.;
(f) adding MtBE for about 8 hours at about 5° C.;
(g) stirring for about 8 to about 10 hours at about 5° C.;
(h) filtering to get a wet product; and
(i) washing the wet product with EtOH/water/MtBE and drying at about 35° C. under vacuum, thus forming the cyclo(-His-Pro) hydrate.
22. The method of claim 21 , wherein the cyclo(-His-Pro) hydrate is characterized by an XRPD diffractogram comprising peaks at 2θ values of 13.7°±0.2°, 17°±0.2°, and 27.3°±0.2°.
23. The method of claim 22 , wherein the XRPD diffractogram further comprises a peak at 2θ value of 10°±0.2°.
24. The method of claim 23 , wherein the cyclo(-His-Pro) hydrate is stable for at least 20 hours in a solvent at 50° C. wherein the solvent is water, EtOH, acetone, HtBE, or a mixture thereof.
25. The method of claim 21 , further comprising a step of crystallizing the cyclo(-His-Pro) hydrate using solvents.
26. The method of claim 21 , wherein DSC thermogram of the cyclo(-His-Pro) hydrate has two endothermic peaks with peak maxima at about 100° C. and about 170° C.
27. The method of claim 21 , wherein the cyclo(-His-Pro) hydrate is characterized by at least two of the following:
(a) an X-ray powder diffractogram comprising at least two peaks at 2θ values from the following list: 10°±2°, 13.7°±0.2°, 17°±0.2°, 18.1°±0.2°, 20.2°±0.2°, and 27.3°±0.2°;
(b) birefringent with a fragmented, rod-like morphology when analyzed by polarized light microscopy;
(c) an initial weight loss of 6.5% (0.9 equivalent of water), followed by sample degradation at around 280° C. when analyzed by thermogravimetric analysis technique;
(d) an endotherm with an onset of 99° C. and a peak at 102° C. in the first heat cycle of differential scanning calorimetry (DSC);
(e) start of dehydration below 10% RH, loss of about 6 wt % from 10 to 0% RH (0.8 equivalent of water) and hydration from 0 to 40% RH in the 40° C. dynamic vapor sorption analysis; and
(f) start of dehydration below 20% RH, loss of about 7 wt % from 20 to 0% RH (1.0 equivalent of water), and rehydration from 0 to 40% RH in the 60° C. dynamic vapor sorption analysis.
28. The method of claim 21 , wherein the cyclo(-His-Pro) hydrate is at least about 90% pure.