| WO/1987/003584 | SYNTHESIS OF OPTICALLY ACTIVE ARYLOXYPROPANOLAMINES AND ARYLETHANOLAMINES |
| JPS60208949 | NOVEL DIAMINE DERIVATIVE, MANUFACTURE AND MEDICINE |
| JP2001026506 | SULFONAMIDE DERIVATIVE |
MACPHEE MICHAEL (US)
REMENAR JULIUS (US)
ALMARSSON OM (US)
MACPHEE MICHAEL (US)
REMENAR JULIUS (US)
| US3843668A | 1974-10-22 | |||
| US4053617A | 1977-10-11 |
What is claimed is:
1. 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt.
2. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 1, wherein said succinate salt is a monosuccinate salt.
3. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 2, wherein said monosuccinate salt exhibits a powder X-ray diffractogram comprising a peak at about 8.04 degrees 2-theta.
4. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 2, wherein said monosuccinate salt exhibits a powder X-ray diffractogram comprising a peak at about 9.97 degrees 2-theta.
5. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 2, wherein said monosuccinate salt exhibits a powder X-ray diffractogram comprising peaks at about 8.04 and about 9.97 degrees 2-theta.
6. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 2, wherein said monosuccinate salt exhibits a powder X-ray diffractogram comprising peaks at about 8.04, about 9.97, and about 12.73 degrees 2-theta.
7. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 2, wherein said monosuccinate salt exhibits a powder X-ray diffractogram comprising peaks at about 8.04, about 9.97, about 12.73, and about 24.27 degrees 2- theta.
8. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 2, wherein said monosuccinate salt exhibits a DSC thermogram comprising an endothermic transition at about 190 degrees C.
9. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 1, wherein said succinate salt is a hemisuccinate salt.
10. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 9, wherein said hemisuccinate salt is Form A.
11. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 10, wherein said hemisuccinate salt Form A exhibits a powder X-ray diffractogram comprising a peak at about 10.00 degrees 2-theta.
12. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 10, wherein said hemisuccinate salt Form A exhibits a powder X-ray diffractogram comprising a peak at about 10.75 degrees 2-theta.
13. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 10, wherein said hemisuccinate salt Form A exhibits a powder X-ray diffractogram comprising peaks at about 10.00 and about 10.75 degrees 2-theta.
14. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 10, wherein said hemisuccinate salt Form A exhibits a powder X-ray diffractogram comprising peaks at about 10.75, about 13.85, and about 14.99 degrees 2- theta.
15. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 10, wherein said hemisuccinate salt Form A exhibits a powder X-ray diffractogram comprising peaks at about 17.65, about 18.20, about 22.59, and about 24.24 degrees 2-theta.
16. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole succinate salt of claim 10, wherein said hemisuccinate salt Form A exhibits a powder X-ray diffractogram comprising peaks at about 13.85, about 20.46, about 21.52, and about 26.02 degrees 2-theta.
17. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 9, wherein said hemisuccinate salt is Form B.
18. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 17, wherein said hemisuccinate salt Form B exhibits a powder X-ray difrractogram comprising a peak at about 9.99 degrees 2-theta.
19. The 5-chloro-4-(2-irnidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 17, wherein said hemisuccinate salt Form B exhibits a powder X-ray diffractogram comprising a peak at about 1 1.00 degrees 2-theta.
20. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 17, wherein said hemisuccinate salt Form B exhibits a powder X-ray difrractogram comprising peaks at about 9.99 and about 12.41 degrees 2-theta.
21. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 17, wherein said hemisuccinate salt Form B exhibits a powder X-ray diffractogram comprising peaks at about 20.27, about 21.03, and about 24.67 degrees 2- theta.
22. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole succinate salt of claim 17, wherein said hemisuccinate salt Form B exhibits a powder X-ray diffractogram comprising peaks at about 9.99, about 1 1.00, about 20.27, and about 21.03 degrees 2-theta.
23. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 9, wherein said hemisuccinate salt is Form C.
24. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 23, wherein said hemisuccinate salt Form C exhibits a powder X-ray diffractogram comprising a peak at about 10.40 degrees.
25. The 5-chloro-4-(2-imidazolm-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 23, wherein said hemisuccinate salt Form C exhibits a powder X-ray diffractogram comprising a peak at about 11.09 degrees.
26. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 23, wherein said hemisuccinate salt Form C exhibits a powder X-ray diffractogram comprising peaks at about 10.40 and about 11.09 degrees.
27. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 23, wherein said hemisuccinate salt Form C exhibits a powder X-ray diffractogram comprising peaks at about 10.40, about 11.09, and about 22.02 degrees.
28. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 23, wherein said hemisuccinate salt Form C exhibits a powder X-ray diffractogram comprising peaks at about 10.40, about 11.09, about 22.02, and about 24.03 degrees.
29. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole succinate salt of claim 23, wherein said hemisuccinate salt Form C exhibits a DSC thermogram comprising an endothermic transition at about 195 degrees C.
30. A method of making a succinate salt of tizanidine, comprising:
(a) providing tizanidine or a hydrochloride salt thereof;
(b) contacting said tizanidine or a hydrochloride salt thereof with succinic acid; and
(c) crystallizing said succinate salt of tizanidine.
31. A method of treating a mammal suffering from spasticity, multiple sclerosis, or cerebral palsy, comprising administering to said mammal an effective amount of the 5- chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole succinate salt of claim 1.
32. A pharmaceutical composition comprising the 5-chloro-4-(2-imidazolin-2- ylamino)-2,l,3-benzothiadiazole succinate salt of claim 1, wherein said pharmaceutical composition is a controlled release pharmaceutical composition.
33. The pharmaceutical composition of claim 32, wherein said pharmaceutical composition is an osmotically active pharmaceutical composition. |
TIZANIDINE SUCCINATE SALT FORMS AND METHODS OF MAKING AND
USING THE SAME
FIELD OF THE INVENTION
[001] The present invention relates to a novel succinate salt of tizanidine. The invention also provides methods of using tizanidine succinate salt in an oral dosage pharmaceutical composition and related methods of treatment with tizanidine succinate salt.
BACKGROUND OF THE INVENTION
[002] Tizanidine is pharmacologically characterized as a central-acting α 2 adrenoceptor agonist which has various pharmacological activities. The imidazoline chemical structure of tizanidine is related to other α 2 -adrenergic agonists.
[003] Tizanidine can be classified generically as an amino-imidazoline adrenergic agent. In chemical nomenclature the molecule is described as 5-chloro-4-(2- imidazolin-2-ylamino)-2,l,3-benzothiadiazole and is also identified with Chemical Abstracts Registry number 51322-75-9. Synthesis of the compound is disclosed in U.S. Pat. Nos. 3,843,668 and 4,053,617. Tizanidine hydrochloride (i.e., ZANAFLEX®) is currently approved by the US Food and Drug Administration for the treatment of spasticity.
[004] Presently, an immediate release pharmaceutical composition of tizanidine hydrochloride is dosed orally up to three times a day. This frequent oral dosing may lead to large fluctuations in the release profile of tizanidine hydrochloride, and subsequently, large fluctuations in the blood serum concentration of tizanidine. Side 'effects of immediate release tizanidine hydrochloride, such as somnolence, may be related to either the fluctuations in tizanidine concentration or excessively high tizanidine concentration, or both. A modified release pharmaceutical composition of tizanidine hydrochloride is approved in some European countries, but this modified release tizanidine hydrochloride does not regularly provide once daily dosing and it has not shown any significant reduction in tizanidine hydrochloride side effects. A controlled release pharmaceutical composition of tizanidine should enable better command over the release profile and consequently, the blood serum concentration of tizanidine. Applicants have discovered several novel forms of tizanidine including
polymorphs of the free base, solvates, and several salt forms (e.g., adipate, besylate, esylate, fumarate, glutarate, glycolate, malate, maleate, mandelate, myristate, nicotinate, oleate, oxalate, palmitate, phosphate, stearate, succinate, sulfate, tartrate, and p- tosylate). The succinate salt of tizanidine may be advantageous in the preparation of a controlled release pharmaceutical composition of tizanidine.
BRIEF SUMMARY OF THE INVENTION
[005] The present invention relates to a novel succinate salt of tizanidine with improved properties, such as, but not limited to, improved processing parameters or granulation properties. The invention also provides novel pharmaceutical compositions comprising tizanidine succinate salt, methods of making tizanidine succinate salt, and related methods of treatment. For example, tizanidine monosuccinate, tizanidine hemisuccinate Form A, tizanidine hemisuccinate Form B, and tizanidine hemisuccinate Form C provide alternatives in a controlled release pharmaceutical composition to the currently marketed form, tizanidine hydrochloride.
[006] Tizanidine free base has the following structure (I):
[007] hi one embodiment, the succinate salt of tizanidine can serve as an ct 2 - adrenergic agonist. The succinate salt of tizanidine can be used to provide controlled release pharmaceutical compositions for affecting the adrenergic system, in particular, the ci 2 -adrenergic system.
[008] For a better understanding of the present invention, together with other and further objects thereof, reference is made to the accompanying drawings and detailed description and its scope will be pointed out in the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[009] Figure 1- PXRD difrractogram of tizanidine monosuccinate [0010] Figure 2- DSC thermogram of tizanidine monosuccinate [0011 ] Figure 3- TGA thermogram of tizanidine monosuccinate
[0012] Figure 4- PXRD diffractogram of tizanidine hemisuccinate Form A
[0013] Figure 5- DSC thermogram of tizanidine hemisuccinate Form A
[0014] Figure 6-TGA thermogram of tizanidine hemisuccinate Form A
[0015] Figure 7- PXRD diffractogram of tizanidine hemisuccinate Form B
[0016] Figure 8- DSC thermogram of tizanidine hemisuccinate Form B
[0017] Figure 9-TG A thermogram of tizanidine hemisuccinate Form B
[0018] Figure 10- PXRD diffractogram of tizanidine hemisuccinate Form C
[0019] Figure 11- DSC thermogram of tizanidine hemisuccinate Form C
[0020] Figure 12-TGA thermogram of tizanidine hemisuccinate Form C
DETAILED DESCRIPTION OF THE INVENTION
[0021] The present invention relates to a novel succinate salt of tizanidine. The properties of the succinate salt of tizanidine are improved relative to one or more other known forms of tizanidine, such as tizanidine free base or tizanidine hydrochloride (the currently available form of tizanidine). Such improvements include, but are not limited to, improved processing parameters or granulation properties. The succinate salt can take several forms including, but not limited to, hydrates and solvates as well as various stoichiometric ratios of ionized tizanidine to succinate counterion. The invention also includes other forms of tizanidine succinate salt including, but not limited to, polymorphs, co-crystals, and amorphous forms. The invention also provides novel pharmaceutical compositions comprising these forms, methods of making these forms, and related methods of treatment.
[0022] The salt of the present invention is a tizanidine succinate salt. Tizanidine free base has the following structure (I):
[0023] In a first embodiment, the present invention comprises tizanidine succinate salt.
[0024] In a further embodiment, the succinate salt of tizanidine can be incorporated into a controlled release pharmaceutical composition.
[0025] In another embodiment, the succinate salt of tizanidine can be incorporated into an osmotically active pharmaceutical composition suitable for oral administration. Osmotically active pharmaceutical compositions, osmotic pumps, osmotic drug delivery, and other osmotic technology suitable for oral administration can include, but are not limited to, OROS® Push-Pull and OROS® Tri-layer pharmaceutical compositions. In another embodiment, the succinate salt of tizanidine can be incorporated into an OROS® drug delivery system. Such controlled release pharmaceutical compositions comprising the succinate salt of tizanidine, such as an osmotically active pharmaceutical composition suitable for oral administration, may lead to a longer lasting therapeutic effect than that of tizanidine hydrochloride salt in the currently marketed form. In addition, such a pharmaceutical composition may also result in either decreased somnolence or a substantial lack of somnolence relative to the currently marketed form. The tizanidine succinate salt controlled release pharmaceutical composition could enable greater therapeutic control over tizanidine blood levels in vivo.
[0026] In another embodiment, the present invention comprises tizanidine monosuccinate. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD diffractogram comprising a peak at about 8.04 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD diffractogram comprising a peak at about 9.97 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD diffractogram comprising a peak at about 12.73 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD diffractogram comprising peaks at about 8.04 and about 9.97 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD diffractogram comprising peaks at about 8.04 and about 12.73 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD diffractogram comprising peaks at about 9.97 and about 12.73 degrees 2-theta. In another embodiment, the present invention
comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD difϊractogram comprising peaks at about 8.04, about 9.97 and about 12.73 degrees 2- theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD difϊractogram comprising peaks at about 8.04, about 9.97, about 12.73, and about 21.64 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD difrractogram comprising peaks at about 8.04, about 9.97, about 12.73, about 21.64, and about 24.27 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD difϊractogram comprising peaks at about 8.04, about 9.97, about 12.73, and about 24.27 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD difϊractogram comprising peaks at about 8.04, about 9.97, about 21.64, and about 26.33 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD diffractogram comprising peaks at about 8.04, about 9.97, about 12.73, about 21.64, and about 25.82 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD difϊractogram comprising peaks at about 8.04, about 9.97, about 12.73, about 21.64, about 21.91, and about 24.27 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD diffractogram comprising peaks at about 8.04, about 9.97, about 12.73, about 21.91, about 25.82, and about 26.33 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a PXRD difϊractogram substantially similar to Figure 1. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a DSC thermogram comprising an endothermic transition at about 190 degrees C. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a DSC thermogram substantially similar to Figure 2. In another embodiment, the present invention comprises tizanidine monosuccinate, wherein the monosuccinate exhibits a TGA thermogram substantially similar to Figure 3. In another embodiment, tizanidine monosuccinate is incorporated into a controlled release pharmaceutical composition.
[0027] In another embodiment, the present invention comprises tizanidine hemisuccinate Form A. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD diffractogram comprising a peak at about 10.00 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difϊractogram comprising a peak at about 10.75 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difrractogram comprising a peak at about 14.99 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difrractogram comprising peaks at about 10.00 and about 10.75 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difϊractogram comprising peaks at about 10.75 and about 14.99 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difrractogram comprising peaks at about 17.65 and about 18.20 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difrractogram comprising peaks at about 10.00, about 10.75 and about 14.99 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difϊractogram comprising peaks at about 13.85, about 17.65, about 24.24, and about 26.02 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difrractogram comprising peaks at about 20.46, about 21.52, about 22.59, about 23.25, and about 24.24 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD difϊractogram comprising peaks at about 10.75, about 14.99, about 17.65, and about 18.20 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.00, about 10.75, about 24.24, and about 26.02 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD
diffractogram comprising peaks at about 10.00, about 13.85, about 20.46, about 21.52, and about 22.59 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemi succinate Form A, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.00, about 10.75, about 13.85, about 14.99, about 17.65, and about 18.20 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.75, about 14.99, about 22.59, about 24.24, about 26.02, and about 27.36 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a PXRD diffractogram substantially similar to Figure 4. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a DSC thermogram substantially similar to Figure 5. In another embodiment, the present invention comprises tizanidine hemisuccinate Form A, wherein the hemisuccinate exhibits a TGA thermogram substantially similar to Figure 6. In another embodiment, tizanidine hemisuccinate Form A is incorporated into a controlled release pharmaceutical composition.
[0028] In another embodiment, the present invention comprises tizanidine hemisuccinate Form B. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising a peak at about 9.99 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising a peak at about 11.00 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising a peak at about 12.41 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 9.99 and about 1 1.00 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 11.00 and about 12.41 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about
20.27 and about 21.03 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 9.99, about 11.00, and about 12.41 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 16.86, about 20.27, about 22.48, and about 24.67 degrees 2- theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 9.07, about 9.99, about 11.00, about 12.41, and about 24.67 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 9.07, about 9.99, about 12.41, and about 16.86 degrees 2- theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD difrractogram comprising peaks at about 16.86, about 20.27, about 21.03, and about 24.67 degrees 2- theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD difrractogram comprising peaks at about 9.99, about 11.00, about 23.68, about 24.67, and about 26.17 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD difrractogram comprising peaks at about 9.07, about 9.99, about 1 1.00, about 12.41, about 16.86, and about 21.03 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD difrractogram comprising peaks at about 9.99, about 16.86, about 17.95, about 20.27, about 21.03, and about 24.67 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a PXRD difrractogram substantially similar to Figure 7. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a DSC thermogram comprising an endothermic transition at about 145 degrees C. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a DSC thermogram substantially similar to Figure 8. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate
exhibits a TGA thermogram comprising about an 8 percent weight loss between about room temperature and about 150 degrees C. In another embodiment, the present invention comprises tizanidine hemisuccinate Form B, wherein the hemisuccinate exhibits a TGA thermogram substantially similar to Figure 9. In another embodiment, tizanidine hemisuccinate Form B is incorporated into a controlled release pharmaceutical composition.
[0029] In another embodiment, the present invention comprises tizanidine hemisuccinate Form C. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising a peak at about 10.40 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising a peak at about 11.09 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.40 and about 1 1.09 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.40, about 11.09, and about 18.87 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.40, about 1 1.09, about 18.87, and about 22.02 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.40, about 1 1.09, about 18.87, about 22.02, and about 24.03 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.40, about 11.09, about 18.87, about 22.02, and about 24.63 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.40, about 11.09, about 18.59, about 22.02, and about 22.86 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about
10.40, about 11.09, about 18.87, about 22.02, about 24.03, and about 24.63 degrees 2-
theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram comprising peaks at about 10.40, about 11.09, about 18.87, about 22.02, about 24.03, and about 27.13 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a PXRD diffractogram substantially similar to Figure 10. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a DSC thermogram comprising an endothermic transition at about 195 degrees C. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a DSC thermogram substantially similar to Figure 1 1. In another embodiment, the present invention comprises tizanidine hemisuccinate Form C, wherein the hemisuccinate exhibits a TGA thermogram substantially similar to Figure 12. In another embodiment, tizanidine hemisuccinate Form C is incorporated into a controlled release pharmaceutical composition.
[0030] According to the present invention, tizanidine succinate salt can have various stoichiometric ratios of ionized tizanidine (cation) to succinate counterion (anion). For example, the ratio of cation:anion can be 1:1 or 2:1. Other stoichiometric ratios are also included in the invention.
[0031 ] In another embodiment, the present invention comprises tizanidine succinate salt, and methods of making and using the same. In another embodiment, the present invention comprises a solvate of tizanidine succinate salt, and methods of making and using the same. In another embodiment, the present invention comprises a hydrate of tizanidine succinate salt, and methods of making and using the same. In another embodiment, the present invention comprises one or more polymorphs of tizanidine succinate salt or one or more polymorphs of a hydrate or a solvate of tizanidine succinate salt. In another embodiment, the present invention comprises a co- crystal of tizanidine succinate salt. In another embodiment, the present invention comprises an amorphous form of tizanidine succinate salt, and methods of making and using the same.
[0032] In another embodiment, a tizanidine succinate salt form can exist in a form such as, but not limited to, an anhydrous form, a hydrate form, or a solvate form.
In another embodiment, a tizanidine monosuccinate salt can exist in one or more forms,
including an anhydrous form, a hydrate form, or a solvate form of said salt. In another embodiment, a tizanidine hemisuccinate salt can exist in one or more forms, including an anhydrous form, a hydrate form, or a solvate form of said salt. Such hydrate and solvate forms can have various stoichiometric ratios of ionized tizanidine to water or solvate molecules such as, but not limited to, 1 :1, 1:1.5, 2:1, or 1:2.
[0033] hi another embodiment, the present invention provides a method of making a succinate salt of tizanidine, comprising:
(a) providing tizanidine or a hydrochloride salt thereof;
(b) contacting said tizanidine or a hydrochloride salt thereof with succinic acid; and
(c) crystallizing said succinate salt of tizanidine.
[0034] In a specific embodiment, said tizanidine is in the form of the free base. In another embodiment, said tizanidine and said succinic acid are dried prior to crystallization. In another embodiment, a solvent is added to said tizanidine or a hydrochloride salt thereof at the same time as said succinic acid, hi another embodiment, a solvent is added to said tizanidine or a hydrochloride salt thereof subsequent to said succinic acid, hi another embodiment, step (b) is completed in the presence of a solvent such that a solution is formed. In another embodiment, step (b) is completed in the presence of a solvent such that a suspension is formed. In certain embodiments, a solvent is selected from the group consisting of: acetone, ethanol, nitromethane, methanol, acetonitrile, dichloromethane, water, and tetrahydrofuran (THF). hi another embodiment, a solvent comprises a mixture of any two or more solvents, including, but not limited to, acetone, ethanol, nitromethane, methanol, acetonitrile, dichloromethane, water, and tetrahydrofuran.
[0035] Tizanidine free base and tizanidine hydrochloride can be prepared by one or more methods available in the art, including, but not limited to, the method in US Patent No. 3,843,668.
[0036] In one embodiment of the present invention, an amount of tizanidine succinate salt effective to modulate a mammal's physiology and/or to treat a mammal, including a human, is administered to said mammal. In one aspect, the tizanidine succinate salt is administered in an amount sufficient to effect modulation and/or treatment via the α 2 -adrenergic system.
[0037] In another embodiment, a method of treating a mammal, including a human, suffering from spasticity is provided, comprising administering to said mammal an effective amount of a tizanidine succinate salt. In another embodiment, a method of treating a mammal, including a human, suffering from multiple sclerosis is provided, comprising administering to said mammal an effective amount of a tizanidine succinate salt. In another embodiment, a method of treating a mammal, including a human, suffering from cerebral palsy is provided, comprising administering to said mammal an effective amount of a tizanidine succinate salt.
[0038] In another embodiment, the present invention includes the preparation of a medicament comprising a succinate salt of tizanidine. Such a medicament can be used for treating spasticity, multiple sclerosis, or cerebral palsy, in a mammal, including a human, in need of such treatment.
[0039] Pharmaceutical dosage forms of tizanidine succinate salt can be administered in several ways including, but not limited to, oral administration. Oral pharmaceutical compositions and dosage forms are exemplary dosage forms. Optionally, the oral dosage form is a solid dosage form, such as a tablet, a caplet, a hard gelatin capsule, a starch capsule, a hydroxypropyl methylcellulose (HPMC) capsule, or a soft elastic gelatin capsule. Liquid dosage forms may also be provided by the present invention, including such non-limiting examples as a suspension, a solution, syrup, or an emulsion.
[0040] Tizanidine succinate salt can be administered by controlled or delayed release means. Controlled release pharmaceutical products generally have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of API substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled release pharmaceutical compositions generally include: 1) extended activity of the API; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total API; 5) reduction in local or systemic side effects; 6) minimization of API accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of API activity; and 10) improvement in speed of control of diseases or conditions. (Kim, Cherng-ju, Controlled Release Dosage
Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000).
[0041] Like the amounts and types of excipients, the amounts and specific type of active ingredient in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to mammals. However, typical daily dosage forms of the invention comprise tizanidine succinate salt, in an amount of from about 1.0 mg to about 15.0 mg, from about 1.0 mg to 10.0 mg, or from about 1.0 mg to about 8.0 mg. In a particular embodiment, the tizanidine succinate salt for use in such a composition is tizanidine monosuccinate, tizanidine hemisuccinate Form A, tizanidine hemisuccinate Form B, or tizanidine hemisuccinate Form C. Typical daily dosages of the invention comprise tizanidine succinate salt, in an amount of from about 1.0 mg to about 50.0 mg, from about 1.0 mg to about 40.0 mg, or from about 1.0 mg to about 25.0 mg. The dosage amounts described herein are expressed in amounts of tizanidine free base and do not include the weight of a counterion (e.g., succinate) or any water or solvent molecules.
[0042] In another embodiment of the invention, a pharmaceutical composition comprising tizanidine succinate salt is administered orally as needed in an amount of from about 0.1 mg to about 20.0 mg, from about 0.5 mg to about 15.0 mg, from about 1.0 mg to about 8.0 mg, or from about 2.0 mg to about 6.0 mg. For example, about 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, or 12.0 mg. In specific embodiments, pharmaceutical compositions comprising tizanidine succinate salt can be administered orally in amounts of about 2.0 mg or about 4.0 mg or about 6.0 mg or about 8.0 mg. The dosage amounts can be administered in single or divided doses. In another embodiment, a daily dose of a pharmaceutical composition comprising tizanidine succinate salt comprises up to about 36.0 mg tizanidine. hi other embodiments, the present invention is directed to compositions comprising tizanidine succinate salt as described herein and one or more diluents, carriers, and/or excipients suitable for the administration to a mammal for the treatment or prevention of one or more of the conditions described herein. In one embodiment, a controlled release pharmaceutical composition of tizanidine succinate requires a less complex mixture of excipients than other pharmaceutical compositions.
[0043] While tizanidine succinate has particular advantages for controlled release pharmaceutical compositions, the tizanidine succinate salt of the present invention may also be used to prepare pharmaceutical dosage forms other than the oral dosage forms described above, such as topical dosage forms, parenteral dosage forms,
transdermal dosage forms, and mucosal dosage forms. For example, such forms include creams, lotions, solutions, suspensions, emulsions, ointments, powders, patches, suppositories, and the like.
[0044] The tizanidine succinate salt forms of the present invention can be characterized, e.g., by the TGA, DSC, single crystal x-ray diffractometer data, or by any one, any two, any three, any four, any five, any six, any seven, any eight, any nine, any ten, or any single integer number of PXRD 2-theta angle peaks, or by any combination of the data acquired from the analytical techniques described herein.
[0045] Although the invention has been described with respect to various embodiments, it should be realized this invention is also capable of a wide variety of further and other embodiments within the spirit and scope of the appended claims.
EXAMPLES
Example 1
Tizanidine Monosuccinate ( 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1,3- benzothiadiazole monosuccinate)
[0046] In a first preparation, tizanidine monosuccinate was prepared by the following method: 1 mg of tizanidine free base (0.00394 mmol) was dispensed into a glass vial from a 10 mg/mL stock solution in methanol. The methanol was evaporated by heating to 60 degrees Celsius under nitrogen flow until dry. Two molar equivalents of succinic acid were dispensed into the same vial from a methanol solution. The methanol was evaporated by heating to 60 degrees Celsius under nitrogen flow until dry. After drying, 100 microliters of ethanol was dispensed. The vial was crimp sealed and heated to 70 degrees Celsius for 2 hours before being cooled to 5 degrees Celsius at 0.5 degrees per minute. The samples were allowed to incubate at 5 degrees Celsius for up to about two days before crystals were harvested and analyzed.
[0047] In a second preparation, tizanidine monosuccinate was prepared by the following method: to solid tizanidine free base (1 19.2 mg; 0.4700 mmol) was added a hot suspension of succinic acid (52.9 mg; 0.448 mmol) in acetonitrile (5.0 mL). The resulting mixture was heated at 60 degrees C for 1 hour during which the yellow solid converted to an off-white solid which was subsequently cooled to 0 degrees C. The solid was collected via filtration and air-dried.
[0048] Tizanidine monosuccinate comprises a 1 to 1 ratio of ionized tizanidine to succinate counterion.
[0049] Crystals representative of those obtained by completing the methods above were characterized using PXRD, DSC, and TGA. The tizanidine monosuccinate exhibits a PXRD diffractogram comprising peaks, for example, at about 8.04, 9.97, 12.73, 15.38, 19.51, 20.02, 21.64, 22.60, 24.27, 25.82, 26.33, 28.61, and about 29.25 degrees 2-theta (See Figure 1 ). DSC showed an endothermic transition at about 190 degrees C (See Figure 2). TGA showed the tizanidine monosuccinate is anhydrous (See Figure 3).
[0050] Dynamic vapor sorption (DVS) analysis was completed on tizanidine monosuccinate from about 0 to about 90 percent relative humidity at 25 degrees C. The DVS analysis showed tizanidine monosuccinate is non-hygroscopic.
Example 2
Tizanidine Hemisuccinate Form A (5-ch1oro-4-(2-imidazolin-2-ylamino)-2.1 ,3- benzothiadiazole hemisuccinate Form A)
[0051] A solid mixture of tizanidine free base (14.603 g; 57.556 mmol) and succinic acid (3.402 mg; 28.81 1 mmol) was suspended in acetonitrile (150 mL). The mixture was stirred at 60 degrees C for 2 hours. A pale yellow crystalline solid was formed. The mixture was cooled to room temperature, then filtered. The solid was dried overnight at 60 degrees C.
[0052] Tizanidine hemisuccinate Form A comprises a 2 to 1 ratio of ionized tizanidine to succinate counterion.
[0053] Crystals representative of those obtained by completing the method above were characterized using PXRD, DSC, and TGA. The tizanidine hemisuccinate Form A exhibits a PXRD diffractogram comprising peaks, for example, at about 10.00, 10.75, 13.85, 14.99, 17.65, 18.20, 20.46, 21.52, 22.59, 23.25, 24.24, 26.02, 27.36, 28.61, and about 30.11 degrees 2-theta (See Figure 4). DSC showed no endothermic transitions between about room temperature and about 180 degrees C (See Figure 5). TGA showed the tizanidine hemisuccinate Form A is anhydrous (See Figure 6).
[0054] Dynamic vapor sorption (DVS) analysis was completed on tizanidine hemisuccinate Form A from about 0 to about 90 percent relative humidity at 25 degrees
C. The DVS analysis showed tizanidine hemisuccinate Form A is non-hygroscopic.
Example 3
Tizanidine Hemisuccinate Form B (5-chloro-4-(2-imidazolin-2-ylamino)-2.1,3- benzothiadiazole hemisuccinate Form B)
[0055] To a solution of tizanidine HCl (779.0 mg; 2.746 mmol) in water (9.0 mL) was added a solution of sodium succinate (233.1 mg; 1.438 mmol) in water (1.0 mL). The resulting solution immediately yielded a pale yellow crystalline material. The mixture was cooled to 0 degrees C then the solid was filtered and air-dried.
[0056] Tizanidine hemisuccinate Form B was found to be a sesquihydrate and comprises a 2 to 1 to 3 ratio of ionized tizanidine to succinate counterion to water.
[0057] Crystals representative of those obtained by completing the method above were characterized using PXRD, DSC, TGA, and single crystal x-ray diffraction. The tizanidine hemisuccinate Form B exhibits a PXRD diffractogram comprising peaks, for example, at about 9.07, 9.99, 11.00, 12.41, 16.86, 17.95, 20.27, 21.03, 22.48, 23.68, 24.67, 25.30, 26.17, 27.10, 28.18, and about 29.37 degrees 2-theta (See Figure 7). DSC showed an endothermic transition at about 145 degrees C (See Figure 8). TGA showed the tizanidine hemisuccinate Form B undergoes a weight loss of about 8 percent between about room temperature and about 150 degrees C (See Figure 9).
[0058] Crystal data: C 22 H 2 SCl 2 Ni 0 O 7 S 2 , M = 679.56, oithorhombic P2( 1)2(1)2(1), a = 11.6094(6) angstroms, b = 14.1312(7) angstroms, c = 34.7964(19) angstroms, alpha = 90 degrees, beta = 90 degrees, gamma = 90 degrees, T = 100(2) K, Z = 8, D c = 1.581 Mg/m 3 , V = 5708.5(5) angstroms 3 , λ = 0.71073 angstroms.
[0059] Dynamic vapor sorption (DVS) analysis was completed on tizanidine hemisuccinate Form B from about 0 to about 90 percent relative humidity at 25 degrees C. The DVS analysis showed tizanidine hemisuccinate Form B loses some water between about 30 percent and about 40 percent relative humidity.
Example 4
Tizanidine Hemisuccinate Form C (5-chloro-4-(2-imidazoIin-2-ylamino)-2,l,3- benzothiadiazole hemisuccinate Form C)
[0060] 1 mg of tizanidine free base (0.00394 mmol) was dispensed into a glass vial from a 10 mg/mL stock solution in methanol. The methanol was evaporated by heating to 60 degrees Celsius under nitrogen flow until dry. One molar equivalent of
succinic acid was dispensed into the same vial from a methanol solution. The methanol was evaporated by heating to 60 degrees Celsius under nitrogen flow until dry. After drying, 100 microliters of acetone was dispensed. The vial was crimp sealed and heated to 70 degrees Celsius for 2 hours before being cooled to 5 degrees Celsius at 0.5 degrees per minute. The samples were allowed to incubate at 5 degrees Celsius for up to about two days before crystals were harvested and analyzed.
[0061] Tizanidine hemisuccinate Form C was found to be an acetone solvate and comprises a 2 to 1 to 2 ratio of ionized tizanidine to succinate counterion to acetone.
[0062] Crystals representative of those obtained by completing the method above were characterized using PXRD, DSC, and TGA. The tizanidine hemisuccinate Form C exhibits a PXRD diffractogram comprising peaks, for example, at about 10.40, 11.09, 18.87, 22.02, 22.86, 24.03, 24.63, 25.68, 27.13, 27.80, 28.29, 29.34, and about 30.96 degrees 2-theta (See Figure 10). DSC showed an endothermic transition at about 195 degrees C (See Figure 11). TGA showed the tizanidine hemisuccinate Form C undergoes a weight loss of about 15 percent between about room temperature and about 125 degrees C (See Figure 12).
DIFFERENTIAL SCANNING CALORIMETRY
[0063] DSC analysis of each sample was performed using a QlOOO Differential Scanning Calorimeter (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 (©2001 TA Instruments-Water LLC), with the following components: QDdv.exe version 1.0.0.78 build 78.2; RHBASE.DLL version 1.0.0.78 build 78.2; RHCOMM.DLL version 1.0.0.78 build 78.0; RHDLL.DLL version 1.0.0.78 build 78.1; an TGA.DLL version 1.0.0.78 build 78.1. In addition, the analysis software used was Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.1E; Build 3.1.0.40 (©2001 TA Instruments- Water LLC), or another version as specified in the drawings or otherwise herein.
[0064] For all of the DSC analyses, an aliquot of a sample was weighed into either a standard aluminum pan (Pan part # 900786.091 ; lid part # 900779.901 ) or a hermetic aluminum pan (Pan part # 900793.901; lid part # 900794.901 (TA Instruments, New Castle DE USA)). Non-solvated samples were loaded into standard pans and were sealed either by crimping for dry samples or press fitting for wet samples (such as slurries). Solvated samples (including hydrates) were loaded into hermetic pans and hermetically sealed. The sample pan was loaded into the QlOOO Differential Scanning Calorimeter, which is equipped with an autosampler, and a thermogram was obtained by individually heating the same using the control software at a rate of 10°C/minute from Tmin (typically 30 0 C) to T 1113x (typically 300 0 C) using an empty aluminum pan as a reference. Dry nitrogen (compressed nitrogen, grade 4.8 (BOC Gases, Murray Hill, NJ USA)) was used as a sample purge gas and was set at a flow rate of 50 mL/minute. Thermal transitions were viewed and analyzed using the analysis software provided with the instrument.
THERMOGRAVIMETRIC ANALYSIS
[0065] Thermogravimetric analysis (TGA) of samples was performed using a Q500 Thermogravimetric Analyzer (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments- Water LLC). In addition, the analysis software used was Universal Analysis 2000 for Windows 95/98/2000/NT, version 3.1E; Build 3.1.0.40 (2001 TA Instruments- Water LLC), or another version as specified in the drawings or otherwise herein.
[0066] For the TGA experiments, the purge gas used was dry nitrogen, the balance purge was 40 mL/minute N 2 , and the sample purge was 60 mL/minute N 2 .
[0067] TGA was performed on the sample by placing a sample of the tizanidine succinate salt in a platinum pan. The starting temperature was typically 20 degrees C with a heating rate of 10 degrees C/minute, and the ending temperature was 300 degrees C.
POWDER X-RAY DIFFRACTION [0068] Powder x-ray diffraction patters were obtained using a D/Max Rapid X- ray Diffractometer (Rigaku/MSC, The Woodlands, TX, U.S.A.).
[0069] The D/Max Rapid X-ray Diffractometer was equipped with a copper source (Cu/K α l .5406A), manual x-y stage, and 0.3 mm collimator. A sample was . .. loaded into a 0.3 mm quartz capillary tube (Charles Supper Company, Natick, MA, U.S.A.) by sectioning off the closed end of the tube and tapping the small, open end of the capillary tube into a bed of the powdered sample or into the sediment of a slurried sample. The loaded capillary tube was mounted in a holder that was placed and fitted into the x-y stage. A diffractogram was acquired using control software (RINT Rapid Control Software, Rigaku Rapid/XRD, version 1.0.0 (©1999 Rigaku Co.)) under ambient conditions at a power setting of 46 kV at 40 mA in transmission mode, while oscillating about the omega-axis from 0-5 degrees at 1 degree/second, and spinning about the phi-axis over 360 degrees at 2 degrees/second. The exposure time was 15 minutes unless otherwise specified.
[0070] The diffractogram obtained was integrated of 2-theta from 2-40 degrees and chi (1 segment) from 0-36 degrees at a step size of 0.02 degrees using the cyllnt utility in the RINT Rapid display software (RINT Rapid display software, version 1.18 (Rigaku/MSC)) provided by Rigaku with the instrument. The dark counts value was set to 8 as per the system calibration by Rigaku. No normalization or omega, chi, or phi offsets were used for the integration. The diffractograms included herein show raw data (no background subtraction).
[0071] The relative intensity of peaks in a diffractogram is not necessarily a limitation of the PXRD pattern because peak intensity can vary from sample to sample, e.g., due to crystalline impurities. Further, the angles of each peak can vary by about +/- 0.1 degrees, or by about +/- 0.05. The entire pattern or most of the pattern peaks may also shift by about +/- 0.1 degrees to about +/- 0.2 degrees due to differences in calibration, settings, and other variations from instrument to instrument and from operator to operator. All reported PXRD peaks in the Figures, Examples, and elsewhere herein are reported with an error of about ± 0.1 degrees 2-theta. Unless otherwise noted, all diffractograms are obtained at about room temperature (about 24 degrees C to about 25 degrees C).
SINGLE CRYSTAL X-RAY ANALYSIS [0072] Single crystal x-ray data were collected on a Bruker Kappa-APEX II
CCD diffractometer. Lattice parameters were determined from least squares analysis.
Reflection data was integrated using the program SAINT. The structure was solved by direct methods and refined by full matrix least squares using the program SHELXTL (Sheldrick, G. M. SHELXTL, Release 5.03; Siemans Analytical X-ray Instruments Inc.: Madison, WI).
Example 5
Aqueous Solubility of Several Forms of Tizanidine
[0073] A small amount of a tizanidine form (~10 mg) was added to a 1 mL glass vial. To the vial was added 500 microliters of deionized water at room temperature. The sample was vortexed to mix. If the entire sample dissolved, another 10 mg aliquot of the tizanidine form was added and vortexed to mix. This procedure was repeated until no more sample would dissolve and solid tizanidine form could be observed suspended in solution, indicating saturation. Saturated solutions were filtered using a 0.45 micrometer Teflon syringe filter. Filtered samples were diluted based on approximate solubility to a concentration between 1-1000 micrograms/mL with a 50:50 wateπmethanol solution and analyzed by HPLC. The solubilities of tizanidine forms in water at room temperature were calculated from the HPLC data and are shown in Table A.
HPLC method:
COLUMN: Symmetry Cl 8 DIAMETER (mm): 4.6 LENGTH (mm): 75 PARTICLE SIZE (μm): 3.5 PART NO.: WAT066224 SERIAL NO.: W21431B CO8
FLOW PROGRAM: isocratic MOBILE PHASE A:B: 90:10 FLOW RATE (mL/min): 1.0 MOBILE PHASE A: 10 mM ammonium acetate, pH=4.5 adjusted with acetic acid
MOBILE PHASE B: 70:30 (v/v) acetonitrile/methanol PURGE SOLVENT: 90:10 (v/v) water/acetonitrile WASH SOLVENT: 90:10 (v/v) water/acetonitrile
COLUMN TEMP. ( 0 C): 30
SAMPLE TEMP. ( 0 C): ambient
DILUENT: 50:50 (v/v) methanol/water
SOL. IN DIL. (mg/mL): -0.10 mg/mL
INJECTION VOLUME (μL): 10
DETECTION (nm): 280
RANGE (μg/mL): 40-800
LOD (μg/mL): 1
S/N AT LOD: 3
LOQ (μg/mL): 6
S/N AT LOQ: 10
RETENTION TIME (min): 2.09
RUN TIME (min): 5
Table A- Solubility of Tizanidine Forms in Water at Room Temperature
Example 6
Fluid Bed Granulation of Tizanidine Succinate Salt
[0074] Fluid bed granulations of tizanidine hydrochloride and tizanidine succinate salt were carried out using a Vector MFL.01 microgranulator with inlet temperature set at 45 0 C. For the purpose of these granulations 50 % of the binder (Povidone) was dry blended into the formulation and the rest was sprayed via the nozzle as an aqueous solution. A 10 % Povidone solution was pumped through the granulator at 40 rpm (corresponding to approximately 0.5g/min). Various formulations containing different concentrations of tizanidine salt forms were granulated as given in Table B. It was observed that the formulations containing the hydrochloride salt were static and were difficult to process and collect using the fluid bed granulator resulting in poor recovery. The tested tizanidine succinate salt was not as static and easier to granulate and collect.
[0075] As can be seen in Table B above, the yield (percent recovered) of the granulated tizanidine succinate salt tested was better than that of the hydrochloride salt.
[0076] The tizanidine succinate salt formulation described in Table B was prepared as an OROS®-type ascending release formulation and is described in more detail below:
[0077] Drug Layer 1 : A mixture containing 1.67 g tizanidine hemisuccinate Form B, 15.2 g polyethylene oxide N80 (average molecular weight of 200K), 2.0 g NaCl and 0.5 g Povidone were dry blended for 10 min. This mixture was charged into a fluid bed granulator (capacity 1Og to 20Og) and sprayed with 10% povidone in water solution with an inlet temperature set at 45°C. The solution was pumped in the granulator at 40 rpm corresponding to a spray rate of about 0.5g/min for about 15-20 minutes. About 18.3 g (90%) was recovered from the granulator. Stearic acid was sieved through a 40-mesh screen and butylated hydroxytoluene (BHT) was sieved through a 20-mesh screen. Next 0.05g of stearic acid and 0.003g of BHT were added to the fluid bed granulations and were mixed in ajar on a roller mill. Moisture content of this granulation was determined to be 0.43%.
[0078] Drug layer 2: The second drug layer was granulated in a similar fashion as drug layer 1 using 5.5 g tizanidine hemisuccinate Form B, 13.4 g polyethylene oxide N-80 (average molecular weight of 200K), 0.5 g povidone and 10 mg ferric oxide (red). About 16.5 g (83%) was recovered after the granulation. Next, 0.05g of stearic acid and 0.003g of BHT were added to the fluid bed granulations and were mixed in ajar on a roller mill. Moisture content for this granulation was determined to be 0.83%.
[0079] Push layer: Next, a push layer comprising of 330.16 kg polyethylene oxide (approx molecular weight of 7,000,000), 89.6 kg sodium chloride and 4.48 kg Iron oxide (green) was made by charging them into a GLATT® fluid bed granulator and sprayed with 22.4 kg povidone in water binder solution. Then the granulation was sized using a mill with a 7-mesh screen. The granulation was transferred to a tote tumber, mixed with 0.224 kg BHT and lubricated with 1.12 kg stearic acid.
[0080] Tri-layer Tizanidine cores: Compressing drug layers 1 and 2 with the push layer in a tri-layer fashion resulted in an ascending release profile tizanidine tablet. First, 82 mg of the drug granulation layer 1 is added to the 7/32" diameter deep concave die cavity and pre-compressed. Next, 82 mg of the drug granulation layer 2 is added to the die cavity and compressed followed by the addition of 125 mg of the push layer into the die cavity and compression into a three-layer longitudinal deep concave arrangement.
[0081] Sub-coating: A sub-coat solution was prepared by dissolving 84 g of hydroxypropyl cellulose and 36 g of povidone in 1.38 kg of ethyl alcohol. The tri-layer tizanidine compositions stated above were then sub-coated using the sub-coat solution till a target weight of 15 mg on each core was achieved.
[0082] Membrane coating: Next a semi-permeable membrane coating solution comprising of 173.3 g of cellulose acetate, 1.753 g of polyethylene glycol 3350 was prepared in 3158.8 g of acetone and 166.3 g of water. The sub-coated cores were then coated with a semi -permeable membrane until approximately 20-25 mg of membrane was applied onto each tri-layer system.
[0083] Drilling and drying: Next, two 25 mil (0.64 mm) orifices were hand drilled through the semi-permeable membrane and sub-coat. The drilled cores were dried in an oven for approximately 3 days at 45 0 C and 45% relative humidity.
[0084] The above formulation was manufactured using tizanidine succinate salt (both milled and sieved), and was also repeated with tizanidine hydrochloride while adjusting the formulation slightly for the different molecular weight of the
hydrochloride salt. The results from fluid bed granulations and moisture content (% LOD) are given in Table B. As can be seen in Table B, the tizanidine succinate salt tested has a better recovery than that of the hydrochloride salt.