Norastemizole polymorphs

Details Norastemizole polymorphs Norastemizole polymorphs

2001-07-17

2003-09-30

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S303000, C514S313000, C546S199000

Reexamination Certificate

active

06627646

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to polymorphic crystalline forms of the antihistaminic drug norastemizole and to processes for the production of the preferred polymorph.
BACKGROUND OF THE INVENTION
Norastemizole, 1-[(4-fluorophenyl)methyl]-N-4-piperidinyl-1H-benzimidazol-2-amine, is an active metabolite of the histamine H
1
-receptor antagonist astemizole (HISMANAL™). It is described in U.S. Pat. No. 6,124,320 for use in the treatment of allergic disorders.
The polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology. Polymorphs are, by definition, crystals of the same molecule having different physical properties as a result of the order of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Differences in stability can result from changes in chemical reactivity (e.g. differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g. tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g. tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing: for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (i.e particle shape and size distribution might be different between one polymorph relative to the other).
Each pharmaceutical compound has an optimal therapeutic blood concentration and a lethal concentration. The bio-availability of the compound determines the dosage strength in the drug formulation necessary to obtain the ideal blood level. If the drug can crystallize as two or more polymorphs differing in bio-availability, the optimal dose will depend on the polymorph present in the formulation. Some drugs show a narrow margin between therapeutic and lethal concentrations. Chloramphenicol-3-palmitate (CAPP), for example, is a broad spectrum antibiotic known to crystallize in at least three polymorphic forms and one amorphous form. The most stable form, A, is marketed. The difference in bio-activity between this polymorph and another form B, is a factor of eight—creating the possibility of fatal overdosages of the compound if unwittingly administered as form B due to alterations during processing and/or storage. Therefore, regulatory agencies, such as the US Food and Drug Administration, have begun to place tight controls on the polymorphic content of the active component in solid dosage forms. In general, for drugs that exist in polymorphic forms, if anything other than the pure thermodynamically preferred polymorph is to be marketed, the regulatory agency will require batch-by-batch monitoring. Thus, it becomes important for both medical and commercial reasons to produce and market the most thermodynamically stable polymorph, substantially free of other kinetically favored polymorphs.
From thermodynamic considerations, only one polymorph will be stable; the one with the lowest free energy at a given temperature and pressure. From the industrial crystallization point of view, however, thermodynamic stability is not sufficient to ensure that the stable polymorph will always be produced. During primary nucleation, in the absence of seed crystals, it is the unstable polymorph or pseudo polymorph in the form of a hydrate or solvate that tends to crystallize first (kinetic form). This is, in essence, Ostwald's Rule of Stages, which posits that an unstable system does not transform directly to the most stable state. Instead, it transforms to a transient state accompanied by the smallest loss of free energy. The eventual transition(s) to the most stable phase is inevitable but the transformation can be extremely fast or extremely slow depending on the process conditions present. Most transformations occur in suspension and are solvent mediated. Some polymorphic transformations can be reversible when the relative solubilities of the polymorphs invert over a range of temperatures (enantiotropic). Other transformations are irreversible (monotropic) over a broad range of temperatures.
Although several syntheses of norastemizole are described in the literature, polymorphism of the solid product is not disclosed. Applicants have now discovered that solid norastemizole exists in two polymorphic forms. As is shown in the results of applicants' experiments below, the product produced by methods previously described in the literature of which applicants are aware is in every case composed of greater than 80% of the kinetically favored polymorph and less than 20% of the desired thermodynamically stable polymorph. Those references which have been examined include:(1) Janssen et al. U.S. Pat. No. 4,695,569, column 24, lines 22-32;(2) Hong et. al. U.S. Pat. No. 5,817,823, column 32, lines 9-18; column 33, lines 16-23; column 36, lines 31-41; and column 43, lines 19-24; and (3) Maynard et al. U.S. Pat. No. 5,922,737, and column 39, lines 20-30.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to norastemizole in the form of a crystalline solid comprising at least 95% of a first polymorph (hereinafter referred to as polymorph A) defined by the X-ray powder diffraction pattern (including both characteristic peaks and intensities) shown below.
TABLE 1
No.
2&thgr;, degrees
d
1
9.0329
6.78217
2
10.24
8.63159
3
10.588
8.34866
4
11.7273
7.54003
5
12.5417
7.05218
6
13.38
6.61217
7
13.6284
6.4922
8
14.5846
6.06864
9
15.8358
5.59185
10
17.26
5.13352
11
18.1
4.89713
12
19.32
4.59055
13
19.62
4.52103
14
20.12
4.40979
15
20.5005
4.3288
16
20.9946
4.22802
17
21.22
4.18362
18
21.8351
4.06714
19
22.0887
4.02101
20
22.9427
3.87323
21
23.56
3.77313
22
24.7
3.6015
23
25.4419
3.49814
24
26.98
3.3021
25
27.5
3.24083
26
27.98
3.18632
27
29
3.07652
28
29.46
3.02952
29
29.8
2.99573
30
30.66
2.91363
31
31.0238
2.88029
32
31.991
2.79538
33
32.8
2.72826
This is the more thermodynamically stable polymorph. The kinetically favored polymorph B exhibits an XRPD pattern as follows:
TABLE 2
No.
2&thgr;, degrees
d
1
9.0453
9.76879
2
10.4129
8.48865
3
11.5309
7.66801
4
13.0056
6.80166
5
13.42
6.59255
6
15.54
5.69762
7
15.9321
5.55827
8
16.26
5.44691
9
17.3399
5.11004
10
18.1381
4.88693
11
19.54
4.53936
12
20.125
4.40871
13
20.56
4.3164
14
21.22
4.18362
15
23.08
3.8505
16
23.78
3.73871
17
24.3
3.65987
18
25.0012
3.55879
19
26.34
3.38087
20
27.1506
3.28174
21
27.92
3.19303
22
28.76
3.10165
23
29.32
3.04367
24
29.76
2.99966
25
30.14
2.9627
26
31.42
2.84487
27
32.16
2.78107
28
32.56
2.74782
In another aspect, the invention relates to a process for producing crystalline norastemizole, predominantly as polymorph A. In a generic sense the process comprises:
(a) dissolving norastemizole in just enough solvent to achieve dissolution at a first elevated temperature;
(b) adding an amount of anti-solvent just sufficient to initiate crystallization at the first temperature (sufficient means that less than 5% of the norastemizole crystallizes);
(c) stirring the first temperature for a period of time to allow crystallization of a small amount (less than 5%) of the norastemizole; the combination of time and low equilibration of the crystallizing norastemizole to temperature is such as to allow equilibration of the crystallizing norastemizole to greater than 95% polymorph A;
(d) adding a second portion of anti-solvent at the same elevated first temperature and over a second period of time such that norastemizole that crystallizes during the second addition of anti-solvent is greater than 95% of the

Affiliated with

Also associated with

Rating

Norastemizole polymorphs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Norastemizole polymorphs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Norastemizole polymorphs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3039340