HK1178519B - Metaxalone cocrystals - Google Patents

Abstract

The invention relates to improvements of the physiochemical and/or the pharmaceutical properties of metaxalone. Disclosed herein are several new cocrystals of metaxalone, including: a 1:1 metaxalore adipic acid cocrystal, a 1:0.5 metaxalore fumaric acid cocrystal, a 1:1 metaxalone salicyclic acid cocrystal, a 1:0.5 metaxalone succinic acid cocrystal, and a 1:0.5 metaxalone maleic acid cocrystal. The therapeutic uses of these metaxalone cocrystals are described as well as therapeutic compositions containing them.

Description

Metaxalone cocrystals

Reference to related applications

This application claims priority from U.S. provisional application 61/289,766 filed on 23/12/2009 and U.S. provisional application 61/381,244 filed on 9/2009. The disclosures of both provisional applications are incorporated herein by reference.

Technical Field

The present invention relates to a novel crystalline compound comprising metaxalone (metaxalone), more particularly, the present invention relates to metaxalone cocrystals (metaxalone crystals), therapeutic uses of the metaxalone cocrystals and pharmaceutical compositions comprising the same.

Background

Metaxalone, 5- [ (3, 5-dimethylphenoxy) methyl ] -2-oxazolidinone, shown below, is a muscle relaxant (musclerelaxant) used to relax muscles and relieve pain caused by strain, sprain, and other musculoskeletal disorders, particularly muscle spasms and back pain.

Metaxalone is a white to almost white, tasteless crystalline powder largely soluble in chloroform, in methanol and 96% ethanol, but practically insoluble in water. Metaxalone melts without decomposition at 121.5-123 ℃. Metaxalone is further described at monograph number 5838 of Merck Index (Merck Index) (11 th edition (eleven Addition), Merck & co., 1989) and is also identified by CAS accession number: 1665-48-1 identifies it. The preparation of metaxalone is described in Lunsford et al, j.am.chem.soc.82,1166(1960) and U.S. patent 3,062,827.

Metaxalone and pharmaceutically acceptable salts thereofCommercially available as 800mg tablets. As an interneuronal blocker, metaxalone acts on the Central Nervous System (CNS) to produce a muscle relaxing effect and is used as an adjuvant (adjunct) for rest, physiotherapy and other means for alleviating discomfort associated with painful skeletal muscle diseases. Metaxalone is used in the treatment of acute painful muscle spasms. The mechanism of action of metaxalone in humans has not been determined, but may be due to general central nervous system depression. Metaxalone has no direct effect on the contractile mechanisms of striated muscles, motor end plates or nerve fibers. When metaxalone is taken with food, its bioavailability is significantly improved. Specifically, in one study, the presence of food at the time of dosing increased c (max) by 177.5%, and auc (last) by 123.5% and auc (inf) by 115.4% compared to fasted conditions. Base ofIn thatThe information in the product data sheet, the patient receiving the metaxalone treatment, is informed that, due to the effect of the food, taking metaxalone with food results in an improved oral bioavailability of metaxalone compared to taking metaxalone without food. See alsoProduct data sheet, 2008, month 4; us patent 6,407,128; and 6,683,102; andhttp://en.wikipedia.org/wiki/Metaxalone12 and 6 days in 2009. This food effect can be dosed to a particular patient. In view of the food effect on the bioavailability of metaxalone, the currently developed metaxalone formulations do not fulfill the aim of a fully bioavailable form of metaxalone.

Like metaxalone, active pharmaceutical ingredients (API's), which are generally less soluble in water and less bioavailable, pose significant problems to the pharmaceutical industry. Studies have shown that some drug candidates fail in the clinical phase due to poor human bioavailability and formulation-related problems. Traditional approaches to solving these problems without the need for complete redesign of the molecule include salt selection, fabrication of amorphous materials, particle size reduction, prodrugs and different formulation approaches. Some attempts to use this technique with metaxalone are described, for example, in WO 2004/019937A1, WO2005/016310A1, WO 2007/079189A2 and WO 2009/19662A 2.

Although therapeutic efficacy is a major concern for APIs, salts and solid state forms (i.e., crystalline or amorphous forms) of drug candidates can be critical to their pharmacological properties and their development as viable APIs. More recently, crystalline forms of API's have been used to alter the physiochemical properties of particular APIs. Each crystalline form of a drug candidate may have different solid state (physical and chemical) properties. Differences in physical properties exhibited by new solid forms of APIs (e.g., co-crystals or polymorphs of the original therapeutic compound) affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacture), as well as solubility and dissolution rate (important factors in determining bioavailability). Since these actual physical properties are influenced by the solid state properties of the crystalline form of the API, they can significantly influence the choice of compound as API, the final pharmaceutical dosage form, the optimization of the manufacturing process and the absorption in the body. Moreover, finding the most suitable solid state form for further drug development may reduce the time and cost of such development.

Obtaining a crystalline form of an API is extremely useful in drug development. Which allows better characterization of the chemical and physical properties of the candidate drug. The desired properties of a particular API may also be achieved by forming a co-crystal and co-former (former) of the API. Crystalline forms generally have better chemical and physical properties than the free base in the amorphous state. As with the co-crystals of the invention, such crystalline forms may have more favorable pharmaceutical and pharmacological properties or be easier to handle than known forms of the API itself. For example, the co-crystal can have different solubility and solubility properties than the API itself and can be used to deliver the API therapeutically. A novel pharmaceutical formulation comprising a co-crystal of a given API may have superior properties to its existing pharmaceutical formulation. They may also have better storage stability.

Another potentially important solid state property of an API is its rate of dissolution in aqueous fluids. The rate of dissolution of the active ingredient in the gastric juices of a patient can be of therapeutic importance as it affects the rate at which an orally administered active ingredient can reach the bloodstream of a patient.

A co-crystal of an API is a specific chemical composition of the API and co-former and typically has specific crystalline and spectral properties when compared to the crystalline and spectral properties of the API and co-former alone. Among these, the crystalline and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography. Cocrystals often also exhibit special thermal behavior. Thermal behavior is measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC).

Disclosure of Invention

The present invention relates to novel metaxalone cocrystals having improved physicochemical and/or pharmaceutical properties relative to metaxalone itself. The invention also relates to therapeutic compositions comprising co-crystals of metaxalone and methods of treating muscle pain using co-crystals of metaxalone.

Drawings

Fig. 1 shows the XRPD pattern of a 1:1 metaxalone adipic acid co-crystal.

Figure 2 shows the DSC curve for a 1:1 metaxalone adipic acid co-crystal.

Figure 3 shows a TGA diagram of a 1:1 metaxalone adipic acid co-crystal.

FIG. 4 shows co-crystals of 1:1 metaxalone adipic acid¹H NMR spectrum.

Fig. 5 shows the XRPD pattern of the 1:0.5 metaxalone fumaric acid co-crystal.

Figure 6 shows the ORTEP diagram for the 1:0.5 metaxalone fumaric acid co-crystal.

Figure 7 shows the stacking diagram of the 1:0.5 metaxalone fumaric acid co-crystal.

Figure 8 shows the calculated XRPD pattern for the 1:0.5 metaxalone fumaric acid co-crystal.

Figure 9 shows the DSC curve for a 1:0.5 metaxalone fumaric acid co-crystal.

Figure 10 shows the TGA profile of a 1:0.5 metaxalone fumaric acid co-crystal.

FIG. 11 shows 1:0.5 metaxalone fumaric acid co-crystals¹H NMR spectrum.

Figure 12 shows the XRPD pattern of the 1:1 metaxalone salicylic acid co-crystal.

Figure 13 shows the ORTEP diagram for the 1:1 metaxalone salicylic acid co-crystal.

Figure 14 shows the stacking diagram of 1:1 metaxalone salicylic acid co-crystals.

Figure 15 shows the calculated XRPD pattern of the 1:1 metaxalone salicylic acid co-crystal.

Figure 16 shows the DSC curve for 1:1 metaxalone salicylic acid co-crystal.

Figure 17 shows the TGA profile of a 1:1 metaxalone salicylic acid co-crystal.

FIG. 18 shows 1:1 metaxalone salicylic acid co-crystals¹H NMR spectrum.

Fig. 19 shows the XRPD pattern of the 1:0.5 metaxalone succinic acid co-crystal.

Figure 20 shows the ORTEP profile for the 1:0.5 metaxalone succinic acid co-crystal.

Fig. 21 shows the stacking diagram of the 1:0.5 metaxalone succinic acid co-crystal.

Figure 22 shows the calculated XRPD pattern for the 1:0.5 metaxalone succinic acid co-crystal.

Figure 23 shows the DSC curve for the 1:0.5 metaxalone succinic acid co-crystal.

Figure 24 shows the TGA profile of a 1:0.5 metaxalone succinic acid co-crystal.

FIG. 25 shows 1:0.5 metaxalone succinic acid co-crystal¹H NMR spectrum.

Fig. 26 shows an XRPD pattern of a 1:0.5 metaxalone maleic acid co-crystal.

Figure 27 shows the ORTEP profile for the 1:0.5 metaxalone maleic acid co-crystal.

Figure 28 shows the calculated XRPD pattern for the 1:0.5 metaxalone maleic acid co-crystal.

Figure 29 shows the DSC curve for the 1:0.5 metaxalone maleic acid co-crystal.

Figure 30 shows the TGA profile of a 1:0.5 metaxalone maleic acid co-crystal.

FIG. 31 shows 1:0.5 metaxalone maleic acid co-crystal¹H NMR spectrum.

Figure 32 shows the mean plasma concentration-time curve (time profile) from the pharmacokinetic study of example 6.

Detailed Description

The present invention relates to the enhancement of the physiochemical and/or pharmaceutical properties of metaxalone. Disclosed herein are several novel co-crystals of metaxalone, including: 1:1 metaxalone adipic acid co-crystal, 1:0.5 metaxalone fumaric acid co-crystal, 1:1 metaxalone salicylic acid co-crystal, 1:0.5 metaxalone succinic acid co-crystal and 1:0.5 metaxalone maleic acid co-crystal. Each co-crystal represents a new material composition. Therapeutic uses of these metaxalone co-crystals are described, as well as therapeutic compositions comprising them. The following describes the co-crystals and methods used to characterize them.

Therapeutic use of metaxalone co-crystals

The invention also relates to the therapeutic use of at least one metaxalone cocrystal according to the invention for the treatment of musculoskeletal disorders, for example for relaxing muscles and alleviating pain caused by strain, sprains and other musculoskeletal disorders, in particular for the treatment of muscle spasms and back pain. Accordingly, the present invention relates to a method for the treatment of musculoskeletal disorders comprising the step of administering to a patient in need thereof a therapeutically effective amount of at least one metaxalone cocrystal of the invention or a pharmaceutical composition comprising at least one metaxalone cocrystal.

The term "treatment" or "treating" refers to any treatment of a disease or disorder in a mammal, including: preventing or preventing a disease or disorder, i.e., such that no clinical symptoms are produced; inhibiting the disease or disorder, i.e., arresting or inhibiting the development of clinical symptoms; and/or relieving a disease or condition (including relieving pain associated with the disease or condition), i.e., allowing clinical symptoms to recover. Those skilled in the art will appreciate that in human medicine, it is not always possible to distinguish between "prevention" and "suppression" because one or more of the ultimate evoked events may be unknown, latent, or determined by the patient long after the occurrence of the one or more events. Thus, as used herein, the term "preventing" as an element of "treating" is intended to include both "preventing" and "inhibiting" a disease or disorder. The term "protection" is intended to include "prevention".

Pharmaceutical compositions comprising metaxalone co-crystals

The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one metaxalone cocrystal according to the invention and a pharmaceutically acceptable carrier (also called pharmaceutically acceptable excipient). As mentioned above, these pharmaceutical compositions are therapeutically useful for the treatment of musculoskeletal diseases.

The pharmaceutical composition of the invention may be in any pharmaceutical form comprising at least one metaxalone co-crystal according to the invention. The pharmaceutical composition may be, for example, a tablet, a capsule, a liquid suspension, an injection, a topical preparation or a transdermal preparation. The pharmaceutical compositions typically comprise, for example, from about 1% to about 99% by weight of at least one metaxalone cocrystal of the invention and, for example, from 99% to 1% by weight of at least one suitable pharmaceutical excipient. In one embodiment, the composition may be about 5% to about 75% by weight of at least one metaxalone cocrystal of the invention, with the remainder being at least one suitable pharmaceutical excipient or at least one other adjuvant, as discussed below.

A "therapeutically effective amount of at least one metaxalone co-crystal" according to the invention is an amount which correlates with a therapeutically effective dose of metaxalone itself, typically about 50 to about 800mg metaxalone, preferably about 200 to 800 mg. The actual amount required for treatment of any particular patient may depend upon a variety of factors including, for example, the disease state being treated and its severity; the specific pharmaceutical composition used; the age, weight, general health, sex, and diet of the patient; the mode of administration; the time of administration; the route of administration; and the excretion rate of metaxalone; the duration of the treatment; any drug used in combination or concomitantly with the particular composition used; and other such factors well known in the medical arts. These factors are discussed in Goodman and Gilman, "The Pharmacological Basis of Therapeutics", tenth edition, edited by A.Gilman, J.Hardman and L.Limbird, McGraw-Hill Press, 155-.

Depending on the type of pharmaceutical composition, the pharmaceutically acceptable carrier may be selected from any one or a combination of carriers known in the art. The choice of pharmaceutical carrier depends on the pharmaceutical form used and the desired method of administration. For the pharmaceutical composition of the invention, which is a pharmaceutical composition having at least one metaxalone co-crystal of the invention, a carrier should be chosen which maintains the crystalline form. In other words, the carrier should not substantially alter the metaxalone co-crystal. In addition, the carrier should also not be incompatible with the metaxalone cocrystal used, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other ingredient of the pharmaceutical composition.

The Pharmaceutical compositions of the present invention may be prepared by methods known in the art of Pharmaceutical formulation, see, for example, Remington's Pharmaceutical Sciences, 18 th edition (Mack Publishing Company, Easton, Pa., 1990), which is incorporated herein by reference. In solid dosage forms, at least one metaxalone co-crystal may be mixed with at least one pharmaceutically acceptable excipient such as, for example, sodium citrate or dicalcium phosphate, or as follows: (a) fillers or extenders such as, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, such as, for example, glycerol; (d) disintegrating agents such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid (alginic acid), croscarmellose sodium, complex silicates and sodium carbonate; (e) solution retarders, such as, for example, paraffin; (f) absorption enhancers such as, for example, quaternary ammonium compounds, (g) humectants such as, for example, agaricin, and glycerol monostearate, magnesium stearate, and the like; (h) adsorbents such as, for example, kaolin and bentonite; and (i) a lubricant such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Pharmaceutically acceptable adjuvants known in the art of pharmaceutical formulation may also be used in the pharmaceutical compositions of the present invention. These include, but are not limited to, preservatives, wetting agents, suspending agents, sweetening, flavoring, perfuming, emulsifying and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. The pharmaceutical composition of the present invention may further contain, if necessary, minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants and the like, such as, for example, citric acid, sorbitan laurate, triethanolamine oleate, butylated hydroxytoluene and the like.

Solid dosage forms as described above may be prepared using a solution coating and a shell such as an enteric coating and other solution coatings well known in the art. They may comprise sedatives and may also be compositions which release one or more active compounds in a delayed manner in a specific part of the intestinal tract. Non-limiting examples of embedding compositions (embedding compositions) that can be used are polymeric substances and waxes. Where appropriate, the active compounds may also be in microencapsulated form with one or more of the above-mentioned excipients.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum oxide hydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administration are, for example, suppositories which can be prepared by mixing at least one metaxalone cocrystal according to the invention with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but can be liquid at body temperature and therefore melt in a suitable body cavity and release the active ingredient therein.

Solid dosage forms are preferred for the pharmaceutical compositions of the present invention because the metaxalone co-crystal is maintained at the time of manufacture. Solid dosage forms for oral administration may be used, including capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert, pharmaceutically acceptable excipient (also referred to as a pharmaceutically acceptable carrier). The metaxalone co-crystals according to the invention can also be used as precursors in the formulation of liquid pharmaceutical compositions. Administration of the metaxalone co-crystal in pure form or in a suitable pharmaceutical composition may be carried out by any acceptable mode of administration or agent for providing similar utility. Thus, administration may be such as, for example, in unit dosage forms suitable for the simple administration of precise dosages, in solid, semi-solid, lyophilized powder or liquid dosage forms such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions or sprays and the like, e.g., oral, buccal, nasal, parenteral (intravenous, intramuscular or subcutaneous), topical, transdermal, vaginal, vesical, systemic or rectal administration. One route of administration may be oral administration using a convenient daily dosage regimen that may be adjusted depending on the severity of the musculoskeletal disease to be treated.

Examples

The following analytical methods were used to characterize the metaxalone cocrystals of the invention:

powder X-ray diffraction: the X-ray powder diffraction patterns of the samples were obtained on a Bruker D8 diffractometer using CuK α radiation (40kV, 40mA), a θ -2 θ goniometer, a V4 receiving slit, a Ge monochromator and a Lynxeye detector. The instrument was performance checked using the certified Corundum standard (NIST 1976). Data was collected over an angular range of 2 ° to 42 ° 2 θ using a step size of 0.05 ° 2 θ and a step time (step time) of 0.5 seconds. Samples run at ambient conditions were prepared as flat plate coupons using the received unmilled powder. Approximately, 35mg of sample was gently packed into a cavity in a silicon wafer cut into a ground, zero background (510). All samples were analyzed using Diffrac Plus evav11.0.0.2 or v13.0.0.2.

Single crystal X-ray diffraction (SCXRD): data were collected on an atlas CCD diffractometer equipped with an Oxford Cryosys Cryotostream cooling device, Cu at zero, Oxford Diffraction SuperNova Dualsource. The structure was resolved using the Bruker SHELXTL program and fine-tuned using the SHELXTL program as part of the Bruker SHELXTL panel. Unless otherwise stated, the hydrogen atoms attached to the carbon are placed geometrically and allow fine tuning with isotropic displacement parameters that move in a curve. The hydrogen atoms attached to the heteroatoms are arranged in a difference fourier synthesis and allow free fine tuning with isotropic displacement parameters.

Thermal analysis-Differential Scanning Calorimetry (DSC): DSC data were collected on a TA instrument Q2000 equipped with a 50-position autosampler. The calibration of the thermal capacity was performed using sapphire and the calibration of the energy and temperature was performed using certified indium. Typically, 0.8-1.2mg of each sample was heated from 25 ℃ to 350 ℃ at 10 ℃/min in a pinhole aluminum pan. A flow of dry nitrogen of 50 ml/min was maintained over the sample. The instrument control software was Advantage and ThermalAdvantage v4.8.3 for the Q series v2.8.0.392. Using UniversalAnalysis v4.3a software performs all data Analysis.

Thermogravimetric analysis (TGA): TGA data were collected on a TA instrument Q500TGA equipped with a 16 position auto-sampler. The instrument was temperature calibrated using certified nickel aluminum manganese alloy. Typically, 5-30mg of each sample was loaded onto a pre-tared platinum crucible and aluminum DSC pan and heated from room temperature to 350 ℃ at 10 ℃/minute. A nitrogen purge at 60 ml/min was maintained on the sample. The instrument control software was Advantage and Thermal Advantage v4.8.3 for the Q series v2.8.0.392.

Solution proton NMR: recording on a Bruker 400MHz spectrophotometer equipped with an autosampler and controlled by a DRX400 console¹H-NMR spectrum. Samples were dissolved in d6-DMSO for analysis. Data were obtained using a standard Bruker load experiment using ICON-NMR v4.0.4 (configuration 1) run at Topspin v1.3 (patch level) 8).

Example 1.1:1 Metaxalone adipic acid cocrystal

1.11:1 preparation of Metaxalone adipic acid cocrystal

Metaxalone (500mg) and adipic acid (330mg) were weighed into glass bottles. Isopropanol (IPA, 1.67ml) was added to the bottle. The resulting slurry was aged for 5 days (8 hours of cycled RT to 50 ℃, heated to 50 ℃ over 4 hours and then cooled to RT over another 4 hours). The product was then vacuum filtered over about 1 hour. An additional 100 μ l of IPA was added to the filter and the product was left to dry overnight at ambient conditions.

XRPD characterization of 1.21:1 metaxalone adipic acid cocrystal

An XRPD experimental plot of the 1:1 metaxalone adipic acid co-crystal is shown in figure 1. Table 1 lists the angles 2 θ ± 0.2 ° 2 θ, d-spacings and intensities of the peaks identified in the XRPD pattern of fig. 1. A full list of peaks or a subset thereof may be sufficient to characterize the co-crystal. A subset of the peaks from fig. 1 that can be used alone or in combination to characterize the 1:1 metaxalone adipic acid co-crystal include 8.5, 15.8, 18.9, 20.2, and 23.6 ° 2 θ ± 0.2 ° 2 θ. The 1:1 metaxalone adipic acid co-crystal can be characterized by a subset of at least three of these peaks.

TABLE 1

1.31 DSC of 1 Metaxalone adipate cocrystal

The Differential Scanning Calorimetry (DSC) curve of figure 2 shows a melting endotherm with an onset temperature of 112.54 ℃ and a maximum peak at 115.15 ℃.

TGA of 1.41:1 Metaxalone adipate Co-crystals

The thermogravimetric analysis (TGA) curve of figure 3 shows no significant weight loss prior to decomposition and 99.61% weight retention at 142.49 ℃.

1.51:1 Co-crystals of metaxalone adipic acid¹H NMR

Method for preparing metaxalone adipic acid cocrystal shown in figure 4¹The H NMR spectrum shows the following peaks:¹HNMR (400MHz, d 6-DMSO): 12.00(2H), 7.56(1H), 6.59(3H), 4.87(1H), 4.08(2H), 3.60(1H), 3.31(1H), 2.21-2.23(10H), 1.51 (4H). In that¹The peak at 1.51ppm in the H NMR spectrum corresponds to the two CH's of adipic acid₂Four protons of the group. Comparison of the integral of this peak with the integral of the peak at 4.87 corresponding to one CH proton on the oxazolidinone ring of metaxalone indicates that the co-crystal has a metaxalone to co-former stoichiometric ratio of 1: 1.

Example 2.1:0.5 Metaxalone fumaric acid cocrystals

2.11:0.5 preparation of Metaxalone fumaric acid cocrystals

Metaxalone (500mg) and fumaric acid (262mg) were weighed into a glass vial. Isopropanol (IPAc, 1.67ml) was added to the bottle. The resulting slurry was aged for 5 days (8 hours of cycled RT to 50 ℃, heated to 50 ℃ over 4 hours and then cooled to RT over another 4 hours). The product was then vacuum filtered over about 1 hour. An additional 100 μ l of IPAc was added to the filter and the product was left to dry overnight at ambient conditions.

XRPD characterization of 2.21:0.5 Metaxalone fumaric acid cocrystal

The XRPD experimental pattern of the 1:0.5 metaxalone fumaric acid co-crystal is shown in figure 5. Table 2 lists the angles 2 θ ± 0.2 ° 2 θ, d-spacings and intensities of the peaks identified in the XRPD pattern of fig. 5. A full list of peaks or a subset thereof may be sufficient to characterize the co-crystal. A subset of the peaks from figure 1 that can be used alone or in combination to characterize the 1:0.5 metaxalone fumaric acid co-crystal include 5.6, 11.0, 13.1, 18.3, 21.6 and 22.7 ° 2 θ ± 0.2 ° 2 θ. The 1:0.5 metaxalone fumaric acid co-crystal can be characterized by a subset of at least three of these peaks.

TABLE 2

SCXRD characterization of 2.31:0.5 metaxalone fumaric acid cocrystals

Crystals for single crystal structure determination were prepared as follows:

a batch of about 5mg (estimated by eye) of metaxalone fumaric acid co-crystals prepared as described above was placed into a 1.5ml HPLC vial and 500 μ l IPA was added. The sample was placed on a shaker at 50 ℃ and held for about 30 minutes before removal, and 250 μ Ι was flash filtered into a clean 1.5ml HPLC vial. The vial was covered with a membrane, which was then punctured to allow slow evaporation and crystal formation. A suitable single crystal is separated from the crystal formed by this method.

The single crystal data and structure refinement parameters are reported in table 3. Figure 6 shows the ORTEP diagram of the asymmetric units from the crystal structure of the 1:0.5 metaxalone fumaric acid cocrystal showing the atom numbering used. Anisotropic atom displacement ellipses of non-hydrogen atoms are shown at the 50% likelihood level and the hydrogen atoms are shown as spheres of arbitrary radius. The atom of the fumaric acid co-former labeled with suffix a, which is bound to the second metaxalone molecule, is generated by a symmetrical operation. Figure 7 shows the crystal packing of the 1:0.5 metaxalone fumaric acid co-crystal; the diagram is along the a-axis of the unit cell. XRPD calculated plots based on single crystal data and structure of the 1:0.5 metaxalone fumaric acid co-crystal are shown in fig. 8. It is also noted that there are some small temperature changes in some peaks due to the fact that the XRPD experimental patterns were collected at room temperature and the XRPD calculated patterns were derived from the data collected at 120K. There is also a small intensity difference because of the preferred orientation effect present in the experimental plot.

TABLE 3

2.41 DSC of 0.5 Metaxalone fumaric acid cocrystal

The Differential Scanning Calorimetry (DSC) curve of figure 9 shows a single endotherm with an onset temperature of 153.45 ℃ and a maximum peak at 154.34 ℃.

TGA of 2.51:0.5 Metaxalone fumaric acid cocrystal

The thermogravimetric analysis (TGA) curve of figure 10 shows no significant weight loss prior to decomposition and 99.75% weight retention at 165.53 ℃.

2.61:0.5 Metaxalone fumaric acid cocrystals¹H NMR Spectrum

In FIG. 11Of the shown metaxalone fumaric acid cocrystal¹The H NMR spectrum shows the following peaks:¹h NMR (400MHz, d 6-DMSO): 13.12(1H), 7.56(1H), 6.63(1H), 6.59(3H), 4.86(1H), 4.08(2H), 3.60(1H), 3.31(1H), 2.23 (6H). In that¹The peak at 6.63ppm in the H NMR spectrum corresponds to two protons on the double bond of fumaric acid. Comparison of the integral of this peak with the integral of the peak at 4.86 corresponding to one CH proton on the oxazolidinone ring of metaxalone indicates that the co-crystal has a metaxalone to co-former stoichiometric ratio of 1: 0.5.

2.71:0.5 gram Scale preparation of Metaxalone fumaric acid cocrystals

Metaxalone (3.00g) and fumaric acid (787mg) were weighed into a round bottom flask. IPAc (10ml) was added to the flask. The resulting slurry was heated to-60 ℃ over 30 minutes with stirring, and then stirred at room temperature for 3 days. The product was filtered under vacuum and air dried overnight. XRPD analysis confirmed the product to be a 1:0.5 metaxalone fumaric acid co-crystal.

Example 3 Metaxalone 1:1 salicylic acid cocrystals

Preparation of 3.11:1 Metaxalone salicylic acid cocrystals

Metaxalone (100mg) and salicylic acid (62.4mg) were placed in a stainless steel ball mill. Water (2 drops) was added. The two ingredients were milled together at 20Hz for 60 minutes. The product was removed from the ball mill and allowed to dry overnight at room temperature.

XRPD characterization of 3.21:1 Metaxalone salicylic acid cocrystal

The XRPD experimental pattern of the 1:1 metaxalone salicylic acid co-crystal is shown in figure 12. Table 4 lists the angles 2 θ ± 0.2 ° 2 θ, d-spacings and intensities of the peaks identified in the XRPD pattern of fig. 12. A full list of peaks or a subset thereof may be sufficient to characterize the co-crystal. A subset of the peaks from fig. 12 that can be used alone or in combination to characterize the 1:1 metaxalone salicylic acid co-crystal include 6.8, 16.1, 17.2, 22.6 and 24.6 ° 2 θ ± 0.2 ° 2 θ. The 1:1 metaxalone salicylic acid co-crystal can be characterized by a subset of at least three of these peaks.

TABLE 4

Analysis of the XRPD experimental plot in figure 12 and comparison with the calculated XRPD plot of figure 15 shows that there are very trace amounts of metaxalone free base present in the sample, although this is from DSC curves or calculated from the XRPD plot¹Not evident in the H NMR spectrum (below).

SCXRD characterization of 3.31:1 Metaxalone salicylic acid cocrystal

Crystals for single crystal structure determination were prepared as follows:

1.1 equivalents of salicylic acid was added to 75mg of metaxalone in a 1.5ml HPLC vial. Then, enough solvent (water) was added to cover the solid (550 μ l). The sample was then sonicated using a 100W sonication probe for 20 minutes using a pulse sequence of 10s on and 4s off. An additional portion of cold solvent (water, 100 μ Ι) was added to the bottle prior to filtration. The sample was then vacuum filtered over about 2 hours. After this time, the sample was removed from the vacuum and dried at room temperature for at least 16 hours. Then, the crystals were separated from the bulk dry material and the single crystal structure on the crystals was determined to confirm that it was a 1:1 metaxalone salicylic acid co-crystal.

The single crystal data and structure refinement parameters are reported in table 5. Figure 13 shows the ORTEP diagram of the asymmetric units from the crystal structure of the 1:1 metaxalone salicylic acid cocrystal showing the atom numbers used. Anisotropic atom displacement ellipses of non-hydrogen atoms are shown at the 50% likelihood level and the hydrogen atoms are shown as spheres of arbitrary radius. Figure 14 shows the crystal packing of 1:1 metaxalone salicylic acid co-crystals; the diagram is along the b-axis of the unit cell. XRPD calculated plots based on single crystal data and structure of the 1:1 metaxalone salicylic acid co-crystal are shown in figure 15. Comparison of the simulated powder pattern of the crystal with the experimental powder pattern of the bulk material shows that the material is heterogeneous and consists of co-crystals and traces of metaxalone. It is also noted that there are some small temperature changes in some peaks due to the fact that the XRPD experimental patterns were collected at room temperature and the XRPD calculated patterns were derived from the data collected at 120K. There is also a small intensity difference because of the preferred orientation effect present in the experimental plot.

TABLE 5

DSC of 3.41:1 Metaxalone salicylic acid cocrystal

The Differential Scanning Calorimetry (DSC) curve of figure 16 shows a melting endotherm with an onset temperature of 101.55 ℃ and a maximum peak at 102.89 ℃.

TGA of 3.51:1 Metaxalone salicylic acid cocrystal

In the thermogravimetric analysis (TGA) of fig. 17, it can be seen that there is a 38.5% weight loss after the eutectic melting temperature, followed by significant sublimation.

3.61:1 Metaxalone salicylic acid cocrystals¹H NMR Spectrum

Method for preparing metaxalone fumaric acid cocrystal shown in figure 18¹The H NMR spectrum shows the following peaks:¹h NMR (400MHz, d 6-DMSO): 7.80(1H), 7.60(1H), 7.51(1H), 6.93(2H), 6.59(3H)4.88(1H), 4.08(2H), 3.60(1H), 3.31(1H), 2.23 (6H). The peak at 7.80ppm in the 1H NMR spectrum corresponds to one aromatic proton on salicylic acid. The integral of this peak corresponds to the peak at 4.88 of one CH proton on the oxazolidinone ring of metaxaloneA comparison of the integrals of (a) shows that the co-crystal has a metaxalone to co-former stoichiometric ratio of 1: 1.

Example 4.1:0.5 Metaxalone succinic acid cocrystal

4.11:0.5 preparation of Metaxalone succinic acid cocrystal

Metaxalone (500mg) was weighed into a glass vial. 1.67ml of a hot saturated solution of succinic acid in THF was then added to the flask. The resulting slurry was aged for 5 days (8 hours of cycled RT to 50 ℃, heated to 50 ℃ over 4 hours and then cooled to RT over another 4 hours). The product was then vacuum filtered over about 1 hour. An additional 200 μ l of THF was added to the filter and the product was left to dry overnight at ambient conditions.

XRPD characterization of 4.21:0.5 metaxalone succinic acid co-crystal

The XRPD experimental pattern of the 1:0.5 metaxalone succinic acid co-crystal is shown in figure 19. Table 6 lists the angles 2 θ ± 0.2 ° 2 θ, d-spacings and intensities of the peaks identified in the XRPD pattern of fig. 19. A full list of peaks or a subset thereof may be sufficient to characterize the co-crystal. A subset of the peaks from fig. 19 that can be used alone or in combination to characterize the 1:0.5 metaxalone succinic acid co-crystal include 6.4, 9.7, 10.2, 12.7, 20.6 and 21.7 ° 2 θ ± 0.2 ° 2 θ. The 1:0.5 metaxalone succinic acid co-crystal can be characterized by a subset of at least three of these peaks.

TABLE 6

SCXRD characterization of 4.31:0.5 metaxalone succinic acid cocrystal

Crystals for single crystal structure determination were prepared as follows:

250 μ l of a hot saturated solution of succinic acid in THF were pipetted into a 1.5ml HPLC vial. Then, metaxalone was gradually added until a slurry was obtained. The samples were left to mature for 5 days with a heating/cooling (50 ℃/RT) cycle every four hours. To filter the bulk sample, an additional portion of cold solvent (THF, 100 μ l) was added to the vial. The sample was then vacuum filtered over about 2 hours. After this time, the sample was removed from the vacuum and stored at room temperature to dry for at least 16 hours.

The appropriate single crystals were separated from the bulk dry material and determined to be 1:0.5 metaxalone succinic acid co-crystal by SCXRD analysis. The single crystal data and structure refinement parameters are reported in table 7. Figure 20 shows the ORTEP diagram of the asymmetric units from the crystal structure of the metaxalone succinic acid co-crystal showing the atom numbers used. Anisotropic atom displacement ellipses of non-hydrogen atoms are shown at the 50% likelihood level and the hydrogen atoms are shown as spheres of arbitrary radius. The atom of the co-former labeled with suffix a that binds to the second metaxalone molecule is produced by a symmetric operation. Figure 21 shows the crystal packing of the 1:0.5 metaxalone succinic acid co-crystal; the diagram is along the b-axis of the unit cell. XRPD calculations based on single crystal data and structure of the 1:0.5 metaxalone succinic acid co-crystal are shown in fig. 22. It is also noted that there are some small temperature changes in some peaks due to the fact that the XRPD experimental patterns were collected at room temperature and the XRPD calculated patterns were derived from the data collected at 120K. There is also a small intensity difference because of the preferred orientation effect present in the experimental plot.

TABLE 7

DSC of 4.41:0.5 Metaxalone succinic acid cocrystal

The Differential Scanning Calorimetry (DSC) curve of figure 23 shows a single endotherm with an onset temperature of 137.44 ℃ and a maximum peak at 148.54 ℃.

TGA of 0.5 Metaxalone succinic acid cocrystal 4.51

The thermogravimetric analysis (TGA) curve of figure 24 shows no significant weight loss prior to decomposition and 99.6% weight retention at 148.54 ℃.

4.61:0.5 Metaxalone succinic acid co-crystal¹H NMR Spectrum

Method for preparing metaxalone succinic acid co-crystal shown in figure 25¹The H NMR spectrum shows the following peaks:¹h NMR (400MHz, d 6-DMSO): 12.15(1H), 7.56(1H), 6.59(3H), 4.87(1H), 4.10(2H), 3.60(1H), 3.31(1H), 2.42(2H), 2.23 (6H). In that¹The peak at 2.42ppm in the H NMR spectrum corresponds to the two CH's from succinic acid₂Four protons of the group. Comparison of the integral of this peak with the integral of the peak at 4.87 corresponding to one CH proton on the oxazolidinone ring of metaxalone indicates that the co-crystal has a metaxalone to co-former stoichiometric ratio of 1: 0.5.

4.71:0.5 gram Scale preparation of Metaxalone succinic acid cocrystal

Metaxalone (3.00g) was placed in a round bottom flask. 10ml of a saturated solution of succinic acid in THF were added. The resulting slurry was gradually heated with stirring using a water bath until the solid dissolved to give a clear colorless solution. The water bath was then removed and the solution was gradually cooled to room temperature, resulting in the precipitation of a white solid. The slurry was then allowed to stir at room temperature for 4 days, after which the product was vacuum filtered and air dried overnight. XRPD analysis confirmed the product to be a 1:0.5 metaxalone succinic acid co-crystal.

Example 5.1:0.5 Metaxalone maleic acid cocrystal

5.11:0.5 preparation of Metaxalone maleic acid cocrystal

Metaxalone (500mg) was weighed into a glass vial. Then 2ml of a saturated solution of maleic acid in EtOAc was added to the bottle. The resulting slurry was aged for 5 days (8 hours of cycled RT to 50 ℃, heated to 50 ℃ over 4 hours and then cooled to RT over another 4 hours). The product was then vacuum filtered over about 1 hour. An additional 200 μ l of EtOAc was added to the filter and the product was left to dry overnight at ambient conditions.

XRPD characterization of 5.21:0.5 Metaxalone maleic acid cocrystal

An XRPD experimental plot of the 1:0.5 metaxalone maleic acid co-crystal is shown in figure 26. Table 8 lists the angles 2 θ ± 0.2 ° 2 θ, d-spacings and intensities of the peaks identified in the XRPD pattern of fig. 26. A full list of peaks or a subset thereof may be sufficient to characterize the co-crystal. A subset of the peaks from fig. 26 that can be used alone or in combination to characterize the 1:0.5 metaxalone maleic acid co-crystal include 6.4, 9.7, 10.3, 12.8, 17.8 and 21.9 ° 2 θ ± 0.2 ° 2 θ. The 1:0.5 metaxalone maleic acid co-crystal can be characterized by a subset of at least three of these peaks.

TABLE 8

SCXRD characterization of 5.31:0.5 Metaxalone maleic acid cocrystal

Crystals for single crystal structure determination were prepared as follows:

about 500mg of metaxalone was weighed into a glass vial and then 0.5 equivalent of maleic acid was added. Then, 1.67ml of toluene was added to the bottle. Subsequently, the samples were matured for 5 days with a heating/cooling (50 ℃/RT) cycle every four hours. XRPD analysis of the samples showed incomplete co-crystal formation. At this point, the sample was divided in half. To one half is added an additional 0.25 equivalents of acid with 200. mu.l of toluene. The samples were then subjected to the same maturation cycle previously used for an additional 1 day. Reanalysis by XRPD showed that co-crystal formation was complete, but that an excess of maleic acid was also present. To filter the block sample, an additional portion of cold toluene (200 μ l) was added to the bottle. The sample was then vacuum filtered over about 30 minutes. After this time, the samples were removed from the vacuum and stored at room temperature to dry for at least 16 hours.

The appropriate single crystals were separated from the bulk dry material and determined to be 1:0.5 metaxalone maleic acid co-crystal by SCXRD analysis. The single crystal data and structure refinement parameters are reported in table 9. Figure 27 shows the ORTEP diagram of the asymmetric units from the crystal structure of the metaxalone maleic acid cocrystal showing the atom numbers used. Anisotropic atom displacement ellipses of non-hydrogen atoms are shown at the 50% likelihood level and the hydrogen atoms are shown as spheres of arbitrary radius. XRPD calculated plots based on single crystal data and structure of the 1:0.5 metaxalone maleic acid co-crystal are shown in figure 28. It is also noted that there are some small temperature changes in some peaks due to the fact that the XRPD experimental patterns were collected at room temperature and the XRPD calculated patterns were derived from the data collected at 120K. There is also a small intensity difference because of the preferred orientation effect present in the experimental plot.

TABLE 9

5.41 DSC of 0.5 Metaxalone maleic acid cocrystal

The Differential Scanning Calorimetry (DSC) curve of figure 29 shows a single endotherm with an onset temperature of 126.90 ℃ and a maximum peak at 128.13 ℃.

TGA of 0.5 Metaxalone maleic acid cocrystal 5.51: TGA

In the thermogravimetric analysis (TGA) curve of fig. 30, it can be seen that there is a 20.7% weight loss after melting of the eutectic, followed by significant sublimation.

5.61:0.5 Metaxalone maleic acid co-crystal¹H NMR Spectrum

Method for preparing a metaxalone maleic acid co-crystal as shown in figure 31¹The H spectrum shows the following peaks:¹HNMR (400MHz, d 6-DMSO): 7.60(1H), 6.59(3H), 6.27(1H), 4.88(1H), 4.07(2H), 3.60(1H), 3.32(1H), 2.23 (6H). In that¹The peak at 6.27ppm in the H NMR spectrum corresponds to two protons on the double bond of maleic acid. Comparison of the integral of this peak with the integral of the peak at 4.88 corresponding to one CH proton on the oxazolidinone ring of metaxalone indicates that the co-crystal has a metaxalone to co-former stoichiometric ratio of 1: 0.5.

Example 6: pharmacokinetic Studies

6.1 study design

The study was designed to compare the pharmacokinetic profile of 1:0.5 metaxalone fumaric acid (prepared as described in example 2.7) and 1:0.5 metaxalone succinic acid co-crystal (prepared as described in example 4.7) to the kinetic profile of crystalline metaxalone after oral administration in beagle dogs at a 21mg/kg dose level under fasting conditions. A crossover study was performed using 5 male beagle dogs with a 5 day washout period between each treatment. Beagle dogs were fasted overnight, weighed prior to dosing, and the weights were then used to fill capsules with each test compound at an equivalent metaxalone dose of 21 mg/kg. The capsules were orally administered to beagle dogs, which were then allowed to drink about 10mL of water. Food was provided 4 hours after dosing all animals.

6.2 blood sample Collection

Blood samples were collected at 10, 20 and 30 minutes, 1,2, 3, 4, 6, 8, 12 and 24 hours (12 time points) post-dose before and after oral dosing. Approximately 0.8ml of whole blood was removed from the de novo vein and placed in a container containing K₂EDTA as anticoagulant (20. mu.L of 200 mMK)₂EDTA solution/blood). Plasma was separated by centrifugation of whole blood at about 2500g for 10 minutes at 4 ℃. Will be divided intoThe isolated plasma was stored at-70 ℃ until it was analyzed.

6.3 biological analysis

The LC-MS/MS method for appropriate use was used to determine the metaxalone concentration in plasma samples. Use ofThe unpaved analysis tool of the software (version 5.2) was used to calculate pharmacokinetic parameters from each sample. The area under the plasma concentration curve (AUC) was calculated using the linear trapezoidal rule. Peak plasma concentration (C)_max) And the time taken to reach peak plasma concentration (T)_max) Is an observed value.

6.4 pharmacokinetic results

The average pharmacokinetic parameters for each sample are shown in table 10. The mean plasma concentration-time curves for all three samples are shown in figure 32.

Watch 10

Claims (7)

1. A 1:0.5 metaxalone fumaric acid co-crystal characterized by having a powder X-ray diffraction pattern as shown in figure 5.

2. The 1:0.5 metaxalone fumaric acid co-crystal according to claim 1, characterized by a powder X-ray diffraction pattern having peaks selected from 5.6, 11.0, 13.1, 18.3, 21.6 and 22.7 ° 2 Θ ± 0.2 ° 2 Θ.

3. A 1:0.5 metaxalone succinic acid co-crystal characterized by having a powder X-ray diffraction pattern as shown in figure 19.

4. The 1:0.5 metaxalone succinic acid co-crystal according to claim 3, characterized by a powder X-ray diffraction pattern having peaks selected from 6.4, 9.7, 10.2, 12.7, 20.6 and 21.7 ° 2 θ ± 0.2 ° 2 θ.

5. A pharmaceutical composition comprising at least one metaxalone cocrystal according to any one of claims 1-4 and a pharmaceutically acceptable carrier.

6. Use of a metaxalone co-crystal according to any one of claims 1-4 for the preparation of a medicament for the treatment of musculoskeletal diseases.

7. Use of the pharmaceutical composition of claim 5 in the manufacture of a medicament for the treatment of musculoskeletal diseases.