WO2008027419A2

WO2008027419A2 - Tizanidine sulfate salt forms and methods of making and using the same

Info

Publication number: WO2008027419A2
Application number: PCT/US2007/018973
Authority: WO
Inventors: Orn Almarsson; Michael Macphee; Julius Remenar; Mark Tawa
Original assignee: Transform Pharmaceuticals, Inc.
Priority date: 2006-08-31
Filing date: 2007-08-29
Publication date: 2008-03-06
Also published as: WO2008027419A3

Abstract

Disclosed herein is a novel sulfate salt of tizanidine. The invention includes hydrates, solvates, polymorphs, co-crystals, and amorphous forms of tizanidine sulfate salt. Also described herein are novel pharmaceutical compositions comprising tizanidine sulfate salt, methods of making, and related methods of treatment. The present invention provides several dosage forms of tizanidine sulfate salt, such as, controlled release dosage forms.

Description

TIZANIDINE SULFATE SALT FORMS AND METHODS OF MAKING AND

USING THE SAME

FIELD OF THE INVENTION

[001] The present invention relates to a novel sulfate salt of tizanidine. The invention also provides methods of using tizanidine sulfate salt in an oral dosage pharmaceutical composition and related methods of treatment with tizanidine sulfate salt.

BACKGROUND OF THE INVENTION

[002] Tizanidine is pharmacologically characterized as a central-acting α₂ adrenoceptor agonist which has various pharmacological activities. The imidazoline chemical structure of tizanidine is related to other α₂-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, 1 ,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 sulfate salt of tizanidine may be advantageous in the preparation of a controlled release pharmaceutical composition comprising tizanidine.

BRIEF SUMMARY OF THE INVENTION

[005] The present invention relates to a novel sulfate salt of tizanidine. The invention also provides novel pharmaceutical compositions comprising tizanidine sulfate salt, methods of making tizanidine sulfate salt, and related methods of treatment. For example, tizanidine monosulfate, tizanidine hemisulfate Form A, and tizanidine hemisulfate Form B 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] In one embodiment, the sulfate salt of tizanidine can serve as an <x_%- adrenergic agonist. The sulfate salt of tizanidine can be used to provide controlled release pharmaceutical compositions for affecting the adrenergic system, in particular, the α,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 diffractogram of tizanidine monosulfate [0010] Figure 2- DSC thermogram of tizanidine monosulfate [0011] Figure 3- TGA thermogram of tizanidine monosulfate [0012] Figure 4- PXRD diffractogram of tizanidine hemisulfate Form A [0013] Figure 5- DSC thermogram of tizanidine hemisulfate Form A [0014] Figure 6-TGA thermogram of tizanidine hemisulfate Form A [0015] Figure 7- PXRD diffiractogram of tizanidine hemisulfate Form B [0016] Figure 8- DSC thermogram of tizanidine hemisulfate Form B [0017] Figure 9-TGA thermogram of tizanidine hemisulfate Form B

DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention relates to a novel sulfate salt of tizanidine. The sulfate salt can take several forms including, but not limited to, hydrates and solvates as well as various stoichiometric ratios of tizanidine to sulfate counterion. The invention also includes other forms of tizanidine sulfate 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.

[0019] The salt of the present invention is a tizanidine sulfate salt, wherein tizanidine free base has the following structure (I):

[0020] In a first embodiment, the present invention comprises tizanidine sulfate salt.

[0021] In a further embodiment, the sulfate salt of tizanidine can be incorporated into a controlled-release pharmaceutical composition.

[0022] In another embodiment, the sulfate 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 sulfate salt of tizanidine can be incorporated into an OROS® drug delivery system. Such controlled-release pharmaceutical compositions comprising the sulfate 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 sulfate salt controlled-release pharmaceutical composition could enable greater therapeutic control over tizanidine blood levels in vivo.

[0023] hi another embodiment, the present invention comprises tizanidine monosulfate. In another embodiment, the present invention comprises tizanidine monosulfate characterized by a PXRD diffractogram peak at about 12.91 degrees 2- theta. hi another embodiment, the present invention comprises tizanidine monosulfate characterized by a PXRD diffractogram peak at about 14.95 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by a PXRD diffractogram peak at about 21.90 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91 and about 14.95 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 18.34 and about 19.20 degrees 2-theta. hi another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91 and about 21.90 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91, about 14.95, and about 21.90 degrees 2- theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 18.34, about 19.20, about 21.90, and about 24.47 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91, about 14.95, about 18.34, about 19.20, and about 21.90 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91 , about 14.95, about 18.34, and about 19.20 degrees 2-theta. hi another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91, about 14.95, about 21.34, and about 22.53 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91, about 14.95, about 18.34, about 21.90, and about 24.47 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91 , about 14.95, about 18.34, about 19.2O₅ about 21.90, and about 24.47 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by PXRD diffractogram peaks at about 12.91, about 14.95, about 21.34, about 22.53, about 24.47, and about 26.13 degrees 2-theta. In another embodiment, the present invention comprises tizanidine monosulfate characterized by a PXRD diffractogram substantially similar to Figure 1. In another embodiment, the present invention comprises tizanidine monosulfate characterized by a DSC thermogram substantially similar to Figure 2. In another embodiment, the present invention comprises tizanidine monosulfate characterized by a TGA thermogram substantially similar to Figure 3. In another embodiment, tizanidine monosulfate is incorporated into a controlled release pharmaceutical composition.

[0024] In another embodiment, the present invention comprises tizanidine hemisulfate Form A. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by a PXRD diffractogram peak at about 10.80 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by a PXRD diffractogram peak at about 12.37 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 10.19 and about 10.80 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 10.80 and about 12.37 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 10.80, about 12.37, and about 17.69 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 12.37, about 18.67, and about 20.42 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 15.15, about 16.14, about 17.69, and about 23.98 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 10.19, about 10.80, about 12.37, about 13.58, and about 15.15 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 12.37, about 17.69, about 20.42, about 22.41, and about 23.98 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 10.80, about 16.14, about 18.67, about 20.42, and about 21.48 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 12.37, about 17.69, about 20.42, about 22.41, about 23.98, and about 24.89 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by PXRD diffractogram peaks at about 10.80, about 16.14, about 18.67, about 20.42, about 21.48, and about 22.41 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by a PXRD diffractogram substantially similar to Figure 4. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by a DSC thermogram, wherein said DSC thermogram comprises an endothermic transition at about 190 degrees C. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by a DSC thermogram substantially similar to Figure 5. In another embodiment, the present invention comprises tizanidine hemisulfate Form A characterized by a TGA thermogram substantially similar to Figure 6. In another embodiment, tizanidine hemisulfate Form A is incorporated into a controlled release pharmaceutical composition.

[0025] In another embodiment, the present invention comprises tizanidine hemisulfate Form B. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by a PXRD diffractogram peak at about 8.26 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by a PXRD diffractogram peak at about 9.85 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by a PXRD diffractogram peak at about 14.21 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 8.26 and about 9.85 degrees 2-theta. hi another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 21.62 and about 23.58 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 8.26 and about 16.58 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 8.26, about 9.85, and about 16.58 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 14.21, about 16.58, about 20.50, and about 21.29 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 8.26, about 9.85, about 16.58, about 20.50, and about 21.29 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 9.85, about 14.21, about 16.58, and about 19.54 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 8.26, about 9.85, about 21.62, and about 23.58 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 8.26, about 9.85, about 21.29, about 22.97, and about 26.55 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 8.26, about 9.85, about 14.21, about 16.58, about 19.54, and about 20.50 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by PXRD diffractogram peaks at about 8.26, about 9.85, about 17.76, about 21.62, about 23.58, and about 26.55 degrees 2-theta. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by a PXRD diffractogram substantially similar to Figure 7. hi another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by a DSC thermogram substantially similar to Figure 8. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by a TGA thermogram, wherein said TGA thermogram comprises a weight loss of about 3.0 percent between about 90 degrees C and about 180 degrees C. In another embodiment, the present invention comprises tizanidine hemisulfate Form B characterized by a TGA thermogram substantially similar to Figure 9. In another embodiment, tizanidine hemisulfate Form B is incorporated into a controlled release pharmaceutical composition.

[0026] According to the present invention, tizanidine sulfate salt can have various stoichiometric ratios of ionized tizanidine (cation) to sulfate 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.

[0027] In another embodiment, the present invention comprises tizanidine sulfate salt, and methods of making and using the same. In another embodiment, the present invention comprises a solvate of tizanidine sulfate salt, and methods of making and using the same. In another embodiment, the present invention comprises a hydrate of tizanidine sulfate salt, and methods of making and using the same. In another embodiment, the present invention comprises one or more polymorphs of tizanidine sulfate salt or one or more polymorphs of a hydrate or a solvate of tizanidine sulfate salt, and methods of making and using the same. In another embodiment, the present invention comprises a co-crystal of tizanidine sulfate salt, and methods of making and using the same. In another embodiment, the present invention comprises an amorphous form of tizanidine sulfate salt, and methods of making and using the same.

[0028] In another embodiment, the present invention provides a method of making a sulfate salt of tizanidine, comprising:

(a) providing tizanidine;

(b) contacting said tizanidine with sulfuric acid; and

(c) crystallizing said sulfate salt of tizanidine from an appropriate solvent. [0029] In a specific embodiment, said tizanidine in the above method of making a sulfate salt of tizanidine is in the form of the free base. In another specific embodiment, said sulfate salt of tizanidine is selected from the group consisting of: tizanidine monosulfate, tizanidine hemisulfate Form A, and tizanidine hemisulfate Form B. hi another embodiment, said tizanidine and said sulfuric acid are dried prior to crystallization. In another embodiment, said appropriate solvent is added to said tizanidine at the same time as said sulfuric acid. In another embodiment, said appropriate solvent is added to said tizanidine subsequent to said sulfuric acid. In another embodiment, said appropriate solvent is selected from the group consisting of: acetone, ethanol, nitromethane, methanol, acetonitrile, water, dichloromethane, and tetrahydrofuran (THF). hi another embodiment, said appropriate solvent comprises a mixture of any two or more solvents, including, but not limited to, acetone, ethanol, nitromethane, methanol, acetonitrile, water, dichloromethane, and tetrahydrofuran (THF).

[0030] Tizanidine free base 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.

[0031] In one embodiment of the present invention, an amount of tizanidine sulfate salt effective to modulate a mammal's physiology and/or to treat a mammal is administered to said mammal. In one aspect, the tizanidine sulfate salt is administered in an amount sufficient to effect modulation and/or treatment via the ct₂-adrenergic system.

[0032] in another embodiment, a method of treating a mammal suffering from spasticity is provided, comprising administering to said mammal an effective amount of a tizanidine sulfate salt. In another embodiment, a method of treating a mammal suffering from multiple sclerosis is provided, comprising administering to said mammal an effective amount of a tizanidine sulfate salt. In another embodiment, a method of treating a mammal suffering from cerebral palsy is provided, comprising administering to said mammal an effective amount of a tizanidine sulfate salt. In another embodiment, said mammal is a human.

[0033] In another embodiment, the present invention includes the preparation of a medicament comprising a sulfate salt of tizanidine. Such a medicament can be used for treating spasticity, multiple sclerosis, or cerebral palsy, in a mammal in need of such treatment. In another embodiment, said mammal is a human.

[0034] Pharmaceutical dosage forms of tizanidine sulfate 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.

[0035] Tizanidine sulfate salt can be administered by controlled- or delayed- release means. Controlled-release pharmaceutical compositions 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 pharmaceutical composition 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, Chemg-ju, Controlled Release Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000).

[0036] 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 sulfate 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 sulfate salt for use in such a composition is tizanidine monosulfate, tizanidine hemisulfate Form A₅ or tizanidine hemisulfate Form B. Typical daily dosages of the invention comprise tizanidine sulfate 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., sulfate) or any water or solvent molecules.

[0037] In another embodiment of the invention, a pharmaceutical composition comprising tizanidine sulfate 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 sulfate 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 sulfate salt comprises up to about 36.0 mg tizanidine. In other embodiments, the present invention is directed to compositions comprising tizanidine sulfate 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 or another condition known in the art to be treatable or preventable by the administration of tizanidine. In one embodiment, a controlled release pharmaceutical composition comprising tizanidine sulfate requires a less complex mixture of excipients than other controlled release pharmaceutical compositions with other forms of tizanidine.

[0038] While tizanidine sulfate may have particular advantages for controlled release pharmaceutical compositions, the tizanidine sulfate 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.

[0039] The tizanidine sulfate salt forms of the present invention can be characterized, e.g., by the TGA, DSC, single crystal x-ray 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.

[0040] 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 Monosulfate (5-chloro-4-f2-imidazolin-2-ylamino')-2,l ,3-benzothiadiazole monosulfate^*)

[0041] In a first preparation, tizanidine monosulfate 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. One molar equivalent of sulfuric 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 tetrahydrofuran (THF) 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.

[0042] In a second preparation, tizanidine monosulfate was prepared by the following method: to solid tizanidine (9.957 g; 39.24 mol) was added a solution of sulfuric acid (5.438 g; 55.45 mol) in acetonitrile (175 mL). The yellow solid rapidly converted to a white crystalline solid. The mixture was heated to 60⁰C and stirred for 90 minutes. The mixture was cooled to room temperature and the solid was subsequently filtered and washed with additional acetonitrile (50 mL). The solid was collected via filtration and air-dried.

[0043] Tizanidine monosulfate comprises a 1 to 1 ratio of ionized tizanidine to sulfate counterion.

[0044] Crystals representative of those obtained by completing the methods above were characterized using PXRD, DSC, TGA, and single crystal x-ray analysis. The tizanidine monosulfate can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 1 including, but not limited to, 12.91, 14.95, 18.34, 19.20, 21.34, 21.90, 22.53, 23.07, 24.47, 26.13, 27.56, and 27.81 degrees 2-theta. DSC showed no endothermic transitions up to about 200 degrees C (See Figure 2). TGA showed about a 0.1 percent weight loss between about room temperature and about 150 degrees C (See Figure 3).

[0045] Crystal data: C₉H₁₀ClN₅O₄S₂, M = 351.79, monoclinic P2(l)/n; a = 11.9648(5) angstroms, b = 8.2467(4) angstroms, c = 14.0258(6) angstroms, alpha = 90 degrees, beta = 99.493(2) degrees, gamma = 90 degrees, T = 100(2) K, Z = 4, D_c = 1.712 Mg/m³, V = 1364.98(11) cubic angstroms, λ = 0.71073 angstroms.

[0046] Dynamic vapor sorption (DVS) analysis was completed on tizanidine monosulfate from 0-90 percent relative humidity at 25 degrees C. The DVS analysis showed tizanidine monosulfate is non-hygroscopic and no form conversion was observed.

Example 2 Tizanidine Hemisulfate Form A f5-chloro-4-(2-imidazolin-2-ylaminoV2,l,3- benzothiadiazole hemisulfate Form A)

[0047] To solid tizanidine (131.4 mg; 0.5180 mmol) was added a solution of sulfuric acid (27.5 mg; 0.280 mmol) in acetonitrile (3.0 mL). The resulting mixture was heated at 60 ⁰C for 1 hour during which the yellow solid converted to an off-white solid which was subsequently cooled to 0 ⁰C. The solid was collected via filtration and air-dried.

[0048] Tizanidine hemisulfate Form A comprises a 2 to 1 ratio of ionized tizanidine to sulfate counterion.

[0049] Crystals representative of those obtained by completing the method above were characterized using PXRD, DSC, and TGA. The tizanidine hemisulfate Form A can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 4 including, but not limited to, 5.44, 10.19, 10.80, 12.37, 13.58, 15.15, 16.14, 17.69, 18.67, 20.42, 21.48, 22.12, 22.41, 23.98, 24.89, 25.49, 26.76, 27.96, 32.50, 34.80, and 37.89 degrees 2-theta. DSC showed an endothermic transition at about 190 degrees C (See Figure 5). TGA showed about a 0.1 percent weight loss between about room temperature and about 150 degrees C (See Figure 6).

[0050] Dynamic vapor sorption (DVS) analysis was completed on tizanidine hemisulfate Form A from 0-90 percent relative humidity at 25 degrees C. The DVS analysis showed tizanidine hemisulfate Form A is stable up to about 70 percent relative humidity, after which a hydrate is formed.

Example 3

Tizanidine Hemisulfate Form B (5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3- benzothiadiazole hemisulfate Form B)

[0051] To solid tizanidine (3.734 g; 14.72 mmol) was added a solution of sulfuric acid (1.108 g; 11.22 mmol) in water (50 mL). Upon stirring, the yellow solid disappeared while a white crystalline material formed. The mixture was allowed to sit at 5 ⁰C overnight. The solid was collected via filtration and dried with flowing N₂.

[0052] Tizanidine hemisulfate Form B comprises a 2 to 1 ratio of ionized tizanidine to sulfate counterion, and was determined to be a hemihydrate. [0053] Crystals representative of those obtained by completing the method above were characterized using PXRD, DSC, TGA, and single crystal x-ray analysis. The tizanidine hemisulfate Form B can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in Figure 7 including, but not limited to, 8.26, 9.85, 13.72, 14.21, 16.58, 17.52, 17.76, 19.54, 20.50, 21.29, 21.62, 22.97, 23.58, 25.42, 26.55, 27.95, and 29.98 degrees 2-theta. DSC showed no endothermic transitions up to about 200 degrees C (See Figure 8). TGA showed about a 3.0 percent weight loss between about room temperature and about 200 degrees C (See Figure 9).

[0054] Crystal data: C_I8H_2OCI₂NI_OO_SS₃, M = 623.52, triclinic P-I; a = 6.9150(3) angstroms, b = 10.6662(4) angstroms, c = 16.3473(6) angstroms, alpha = 92.2360(10) degrees, beta = 96.8810(10) degrees, gamma = 93.6620(10) degrees, T = 100(2) K, Z = 2, D_c = 1.735 Mg/m³, V = I 193.27(8) cubic angstroms, λ = 0.71069 angstroms.

[0055] Dynamic vapor sorption (DVS) analysis was completed on tizanidine hemisulfate Form B from 0-90 percent relative humidity at 25 degrees C. The DVS analysis showed tizanidine hemisulfate Form B is non-hygroscopic and no form conversion was observed.

DIFFERENTIAL SCANNING CALORIMETRY

[0056] 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 78.0j 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.

[0057] 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 T_min (typically 30°C) to T_max (typically 300⁰C) 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

[0058] 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.

[0059] For the TGA experiments, the purge gas used was dry nitrogen, the balance purge was 40 mL/minute N₂, and the sample purge was 60 mL/minute N₂.

[0060] TGA was performed on the sample by placing a sample of the tizanidine sulfate 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

[0061] Powder x-ray diffraction patters were obtained using a D/Max Rapid X- ray Diffractometer (Rigaku/MSC, The Woodlands, TX, U.S.A.).

[0062] The D/Max Rapid X-ray Diffractometer was equipped with a copper source (Cu/K_αl.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 (RESfT 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 5 minutes unless otherwise specified.

[0063] 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. Unless otherwise specified, all diffractograms show raw data (i.e., without background subtraction).

[0064] 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

[0065] 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 4 Aqueous Solubility of Several Forms of Tizanidine

[0066] 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 waterrmethanol 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. (⁰C): 30 SAMPLE TEMP. (⁰C): 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

Claims

What is claimed is:

1. 5-chloro-4-(2-iτnidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole sulfate salt.

2. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole sulfate salt of claim 1, wherein said sulfate salt is a monosulfate.

3. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole sulfate salt of claim 2, wherein said monosulfate salt exhibits a powder X-ray diffractogram comprising a peak at about 12.91 degrees 2-theta.

4. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole sulfate salt of claim 2, wherein said monosulfate salt exhibits a powder X-ray diffractogram comprising a peak at about 14.95 degrees 2-theta.

5. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole sulfate salt of claim 2, wherein said monosulfate salt exhibits a powder X-ray diffractogram comprising peaks at about 12.91 and about 14.95 degrees 2-theta.

6. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole sulfate salt of claim 2, wherein said monosulfate salt exhibits a powder X-ray diffractogram comprising peaks at about 18.34, about 19.20, and about 21.90 degrees 2-theta.

7. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole sulfate salt of claim 2, wherein said monosulfate salt exhibits a powder X-ray diffractogram comprising peaks at about 12.91, about 14.95, about 18.34, and about 19.20 degrees 2- theta.

8. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole sulfate salt of claim 1 , wherein the salt is a hemisulfate.

9. The 5-chloro-4-(2-imidazolin-2-ylarnino)-2,l ,3-benzothiadiazole sulfate salt of claim 8, wherein the salt is hemisulfate Form A.

10. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole sulfate salt of claim 9, wherein said hemisulfate Form A exhibits a powder X-ray diffractogram comprising a peak at about 10.80 degrees 2-theta.

11. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole sulfate salt of claim 9, wherein said hemisulfate Form A exhibits a powder X-ray diffractogram comprising a peak at about 12.37 degrees 2-theta.

12. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3 -benzothiadiazole sulfate salt of claim 9, wherein said hemisulfate Form A exhibits a powder X-ray diffractogram comprising peaks at about 10.80 and about 12.37 degrees 2-theta.

13. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole sulfate salt of claim 9, wherein said hemisulfate Form A exhibits a powder X-ray diffractogram comprising peaks at about 17.69, about 20.42, and about 22.41 degrees 2-theta.

14. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole sulfate salt of claim 9, wherein said hemisulfate Form A exhibits a powder X-ray diffractogram comprising peaks at about 10.80, about 12.37, about 16.14, and about 17.69 degrees 2- theta.

15. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole sulfate salt of claim 9, wherein said hemisulfate Form A is characterized by a DSC thermogram, and said DSC thermogram comprises an endothermic transition at about 190 degrees C.

16. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole sulfate salt of claim 8, wherein the salt is a hemisulfate hydrate.

17. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole sulfate salt of claim 8, wherein the salt is hemisulfate Form B.

18. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole sulfate salt of claim 17, wherein said hemisulfate Form B exhibits a powder X-ray diffractogram comprising a peak at about 8.26 degrees 2-theta.

19. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole sulfate salt of claim 17, wherein said hemisulfate Form B exhibits a powder X-ray diffractogram comprising a peak at about 9.85 degrees 2-theta.

20. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l ,3-benzothiadiazole sulfate salt of claim 17, wherein said hemisulfate Form B exhibits a powder X-ray diffractogram ' comprising peaks at about 8.26 and about 9.85 degrees 2-theta.

21. The 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole sulfate salt of claim 17, wherein said hemisulfate Form B exhibits a powder X-ray diffractogram comprising peaks at about 14.21, about 16.58, and about 21.62 degrees 2-theta.

22. The 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3-benzothiadiazole sulfate salt of claim 17, wherein said hemisulfate Form B exhibits a powder X-ray diffractogram comprising peaks at about 8.26, about 9.85, about 19.54, and about 20.50 degrees 2- theta.

23. A method of making a sulfate salt of 5-chloro-4-(2-imidazolin-2-ylamino)- 2,1,3-benzothiadiazole , comprising:

(a) providing 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazole ;

(b) contacting said 5-chloro-4-(2-imidazolin-2-ylamino)-2,l,3- benzothiadiazole with sulfuric acid; and

(c) crystallizing said sulfate salt of 5-chloro-4-(2-imidazolin-2-ylarnino)- 2,1,3-benzothiadiazole from an appropriate solvent.

24. 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 sulfate salt of claim 1.

25. A pharmaceutical composition comprising the 5-chloro-4-(2-imidazolin-2- ylamino)-2,l,3-benzothiadiazole sulfate salt of claim 1, wherein said pharmaceutical composition is a controlled-release pharmaceutical composition.