Polymorphic forms of rifaximin, processes for their production and uses thereof
The present invention relates to rifaximin polymorphic forms α, β and γ, the processes for their preparation and the use thereof in the manufacture of medicinal preparations for the oral or topical route.
1 . A compound formula (I)
in polymorphic form α.
2 . The compound of claim 1 , wherein the polymorph in Form α has an x-ray powder diffraction pattern peak position at about 11.8°; 12.9°; °; and 19.7° degrees 2-θ.
3 . The compound of claim 1 , wherein the polymorph in Form α has an x-ray powder diffraction pattern peak position at about 6.6°; 7.4°; 7.9°; 8.8°; 10.5°; 11.1°; 11.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.4°; and 22.1° degrees 2-θ.
4 . The compound of claim 1 , wherein the polymorph has a water content of from between about 0 to about 3.0%.
5 . The compound of claim 1 , wherein the C max is from between about 2.3 ng/ml to about 2.7 ng/ml.
6 . The compound of claim 1 , wherein the t max is from between about 3.5 h to about 9.5 h.
7 . The compound of claim 1 , wherein the AUC 0-24 h is between about 10 and about 20 ng·h/ml.
8 . The compound of claim 1 , wherein the AUC 0-inf is between about 10 and about 25 ng·h/ml.
9 . A compound of formula (I) in polymorphic Form β.
10 . The compound of claim 9 , wherein the polymorph in Form β has an x-ray powder diffraction pattern peak position at about 5.4°; 10.4°; 18.3° and 20.9° degrees 2-θ.
11 . The compound of claim 9 , wherein the polymorph in Form β has an x-ray powder diffraction pattern peak position at about 5.4°; 6.4°; 7.0°; 7.8°; 9.0°; 10.4°; 13.1°, 14.4°; 17.1°; 17.9°; 18.3°; 20.9° degrees 2-θ.
12 . The compound of claim 9 , wherein the polymorph in Form β has a water content of from between about 4.5 to about 100%.
13 . The compound of claim 9 , wherein the C max is between about 0.9 and about 1.3 ng/ml.
14 . The compound of claim 9 , wherein the t max is between about 3.5 and about 4.5 h.
15 . The compound of claim 9 , wherein the AUC 0-24 h is between about 8 to about 12 ng·h/ml.
16 . The compound of claim 9 , wherein the AUC 0-inf is between about 10 to about 25 ng·h/ml.
17 . The compound of claim 9 , wherein the intrinsic dissolution rate is from between about 0.001 to about 0.016 mg/min/cm 2 .
18 . A compound of formula (I) in polymorphic Form γ.
19 . The compound of claim 18 , wherein the polymorph in Form γ has an x-ray powder diffraction pattern peak position at about 5.0°; 7.1°; 8.4° degrees 2-θ.
20 . The compound of claim 18 , wherein the polymorph in Form γ has a water content of from between 0% to about 2%.
21 . The compound of claim 18 , wherein the C max is from between about 660 to about 1100 ng/ml.
22 . The compound of claim 18 , wherein the t max is from between about 1.5 h to about 4.0 h.
23 . The compound of claim 18 , wherein the AUC 0-24 h is from between about 3600 to about 5000 ng·h/ml.
24 . The compound of claim 18 , wherein the AUC 0-inf is from between about 3700 to about 5000 ng·h/ml.
25 . The polymorph of rifaximin according to claim 18 , wherein the intrinsic dissolution rate is from between about 0.1 to about 0.16 mg/min/cm 2 .
26 . A pharmaceutical composition comprising one or more of a Form α, Form β, or Form γ polymorph of rifaximin and a pharmaceutically acceptable carrier.
27 . The pharmaceutical composition of claim 26 , wherein the pharmaceutical composition further comprises excipients.
28 . The pharmaceutical composition of claim 27 , wherein the excipients are one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, colouring agent, flavouring agent or sweetening agent.
29 . The pharmaceutical composition of claim 26 , wherein the composition is formulated for selected coated and uncoated tablets, hard and soft gelatine capsules, sugar-coated pills, lozenges, wafer sheets, pellets and powders in sealed packet.
30 . The pharmaceutical composition of claim 26 , wherein the composition is formulated for topical use.
31 . A method of treating, preventing, or alleviating a bowel related disorder comprising administering to a subject in need thereof a cell infected with a virus with an effective amount of one or more of a Form α, Form β, or Form γ polymorph of rifaximin.
32 . The method of claim 31 , wherein the bowel related disorder is one or more of irritable bowel syndrome, travelers' diarrhea, small intestinal bacterial overgrowth, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, or colitis.
33 . A method of assessing the efficacy of a bowel related disorder treatment in a subject, monitoring the progress of a subject being treated for a bowel related disorder, or a method of selecting a subject for treatment of a bowel disorder, comprising:
determining a pre-treatment level of bacterial overgrowth;
administering a therapeutically effective amount of one or more of a Form α, Form β, or Form γ polymorph of rifaximin to the subject; and
determining a post-treatment level of bacterial overgrowth after an initial period of treatment with the one or more of Form α, Form β, or Form γ polymorph of rifaximin.
34 . The method of claim 33 , wherein the modulation of the level of bacterial overgrowth indicates efficacy of the treatment.
25 . The method of claim 33 , wherein a decrease in bacterial overgrowth indicates that the treatment is efficacious.
36 . The method of claim 33 , wherein the modulation of the bacterial overgrowth is an indication that the subject is likely to have a favourable clinical response to the treatment.
37 . A kit for treating a bowel disorder in a subject, comprising:
one or more of a Form α, Form β, or Form γ polymorph of rifaximin and instructions for use.
38 . A packaged composition comprising, a therapeutically effective amount of one or more of a Form α, Form β, or Form γ polymorph of rifaximin and a pharmaceutically acceptable carrier or diluent, wherein the composition is formulated for treating a subject suffering from or susceptible to a bowel disorder, and packaged with instructions to treat a subject suffering from or susceptible to a bowel disorder.
39 . A process for the production of one or more of a Form α, Form β, or Form γ polymorph of rifaximin, comprising:
reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine in a solvent mixture comprising water and ethyl alcohol in volumetric ratios between about 1:1 and about 2:1 for a time between about 2 and about 8 hours;
treating the reaction mixture at room temperature with a solution of ascorbic acid in a mixture of water, ethyl alcohol and concentrated aqueous hydrochloric acid;
adjusting the pH of the solution to about 2.0 with hydrochloric acid concentrated aqueous solution,
filtering and washing the resulting solid with the same water/ethyl alcohol solvent mixture;
purifying the raw rifaximin by dissolution in ethyl alcohol;
precipitating rifaximin by addition of water, with between about 15% to about 70% to the weight amount of ethyl alcohol used for the dissolution at a temperature of from between about 50° C. to about 0° C. under stirring for between about 4 to about 36 hours;
filtering and washing a resulting solid with water; and
drying the rifaximin at a temperature of from between about room temperature to about 105° C.
40 . The method of claim 39 , wherein the drying is for form between about 2 hours and about 72 hours.
41 . The method of claim 39 , wherein the reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine is at a temperature of from between about 40° C. to about 60° C.
42 . The method of claim 39 , wherein the purifying the raw rifaximin by dissolution in ethyl alcohol is at a temperature of from between about 45° C. to about 65° C.
43 . The method of claim 39 , wherein the reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine is from between about 2.0 to about 3.5 molar equivalents.
44 . A method according to claim 39 , wherein after precipitating rifaximin by addition of water, the method further comprises lowering the temperature to between about 28° C. to about 32° C. to start crystallization.
45 . The method according to claim 44 , wherein the resulting suspension is kept at a temperature of from between about 40° C. to about 50° C. under stirring for a time from between about 6 to about 24 hours.
46 . The method according to claim 45 , further comprising, cooling the suspension to about 0° C. for from between about 15 minutes and about one hour;
filtering the resulting solid; and
drying the solid to a water content of from between 0% and about 3.0% water to form Form α.
47 . The method according to claim 39 , wherein after precipitating rifaximin by addition of water, the method further comprises:
cooling the solution to a temperature of from between about 28° C. to about 32° C.;
maintaining the solution at from between about 40° C. and about 50° C. under stirring for between about 6 to about 24 hours;
cooling the solution to about 0° C. for between about 15 minutes to about one hour;
filtering a resulting solid;
drying the solid from between about 4.5 to about 100% water content to form Form β.
48 . The method according to claim 39 , wherein after precipitating rifaximin by addition of water, the method further comprises:
cooling the solution to a temperature of from between about 28° C. to about 32° C.;
cooling the solution to about 0° C., under stirring, for between about 6 to about 24 hours;
filtering a resulting solid; and
drying the sold to a water content of between about 1.0% and about 2.0% to form Form γ.
49 . A method for the production of rifaximin O, comprising:
reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine in a solvent mixture comprising water and ethyl alcohol to form a reaction mixture;
treating the reaction mixture with a solution of a weak acid, water, and alcohol to lower the pH of the solution to form a suspension;
filtering the suspension and washing the resulting solid with a water, alcohol, and solvent mixture to form raw rifaximin;
purifying the raw rifaximin by dissolution in an alcohol at a temperature between about 45° C. and about 65° C.;
precipitating the raw rifaximin by the addition of water;
lowering of the temperature of the suspension to between about 50° C. to about 0° C. under stirring to form a second suspension;
filtering the second suspension; and
washing a resulting solid with water and drying.
50 . The method of claim 49 , wherein the reacting a molar equivalent of rifamycin O with an excess of 2-amino-4-methylpyridine is from between about 2.0 to about 3.5 molar equivalents.
51 . The method of claim 49 , wherein the reacting a solvent mixture comprising water and ethyl alcohol is in volumetric ratios from between about 1:1 to about 2:1.
52 . The method of claim 51 , wherein the alcohol is one or more of ethyl alcohol, menthol, propanol, or 2-butanol.
53 . The method of claim 49 , wherein the reacting a solvent mixture comprising water and ethyl alcohol is for a time from between about 2 to about 8 hours.
54 . The method of claim 49 , wherein the reacting a solvent mixture comprising water and alcohol is at a temperature from between about 40° C. to about 60° C.
55 . The method of claim 49 , wherein the treating the reaction mixture is at about room temperature.
56 . The method of claim 49 , wherein the solution to treat the reaction mixture comprises a weak reducing agent in a mixture of water, alcohol and a strong acid.
57 . The method of claim 56 , wherein the weak acid is one or more of ascorbic acid, sodium dithionate, or sodium thiosulphate.
58 . The method of claim 55 , wherein the strong acid is one or more of hydrochloric acid, sulphuric acid, phosphoric acid.
59 . The method of claim 49 , wherein when treating the reaction mixture the pH is lowered to about 2.0.
60 . The method of claim 49 , wherein the drying is by one or more of under vacuum, under conditions of normal pressure, or in the presence of a drying agent.
61 . The method of claim 49 , wherein the drying is at a temperature between about room temperature to about 105° C.
62 . The method of claim 49 , wherein the drying is for a time from between about 2 to about 72 hours.
63 . The method of claim 49 , wherein the precipitating the rifaximin is by the addition of water in weight amounts of from between about 15% to about 70% of the weight amount of ethyl alcohol used for the reacting.
64 . The method of claim 49 , wherein the under stirring for a time from between about 4 to about 36 hours.
65 . The method of claim 49 , wherein after the precipitation of raw rifaximin the method further comprises:
lowering the temperature to between about 28° C. to about 32° C.;
maintaining the temperature at between about 40° C. to about 50° C. under stirring for between about 6 to about 24 hours;
cooling to about 0° C. for between about 15 minutes to about one hour;
filtering a resulting solid; and
drying the resulting solid to a water content from between about 3.0% to 0%, wherein the method forms Form α of rifaximin.
66 . The method of claim 49 , wherein after the precipitation of raw rifaximin the method further comprises:
lowering the temperature to between about 28° C. to about 32° C.;
maintaining the temperature at between about 40° C. to about 50° C. under stirring for between about 6 to about 24 hours;
cooling to about 0° C. for between about 15 minutes and about one hour;
filtering a resulting solid; and
drying the solid to a water content greater than about 4.5% to form Form β of rifaximin.
67 . The method of claim 49 , wherein after the precipitation of raw rifaximin the method further comprises:
lowering the temperature to between about 28° C. to about 32° C.;
cooling the temperature to about 0° C. under stirring for between about 6 to about 24 hours;
filtering a resulting solid; and
drying the solid to a water content of between about 1.0% to about 2.0%, wherein the method produces Form γ of rifaximin.