Mcoppb hydrochloride hydrate solid forms and their use in treating pain and other disorders

Abstract

The invention provides hydrochloride hydrate solid forms of the compound MCOPPB (i.e., (R)-1-(1-(1-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole), pharmaceutical compositions thereof, methods for preparing the same, and their use in agonizing the NOP receptor (i.e., the nociceptin / orphanin FQ receptor) and treating a disease or condition mediated by a NOP receptor, such as pain.

Description

MCOPPB HYDROCHLORIDE HYDRATE SOLID FORMS AND THEIR USE IN TREATING PAIN AND OTHER DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to International (PCT) Patent Application serial number PCT / CN2024 / 132919, filed November 19, 2024; the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The invention provides hydrochloride hydrate solid forms of the compound MCOPPB (i.e., (7?)-l-(l-(l-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-177-benzo[f / ]iniidazole), pharmaceutical compositions thereof, methods for preparing the same, and their use in agonizing the NOP receptor (i.e., the nociceptin / orphanin FQ receptor) and treating a disease or condition mediated by a NOP receptor, such as pain.BACKGROUND

[0003] Pain can function as a protective mechanism that allows healthy human beings and animals to avoid tissue damage and / or prevent further damage to injured tissue. However, there are many instances in which pain persists beyond its usefulness. Such unnecessary suffering from pain can impair a subject's physical mobility, mental performance, and even contribute to depression. Substantial resources have been devoted over the years to researching the causes of various types of pain and to the development of medicine to attenuate pain experienced by a patient. Exemplary classes of common pain-relief medications include opioids, non-steroidal anti-inflammatory agents, corticosteroids, and centrally acting agents such as anti-depressants and anti-epileptics.

[0004] The compound MCOPPB (i.e., (7?)-l-(l-(l-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-l / / -benzo[r / ]imidazole) was reported as an agonist of the NOP receptor (i.e., the nociceptin / orphanin FQ receptor; see, for example, Hayashi, S. et al. in J. Med. Chem. 2009, Vol. 52, No. 3, p. 610-625), and its use in treating pain has been described in, for example, U. S. Patent Nos. 11,045,459 and U. S. 11,872,219. Physical forms of MCOPPB that are superior for133863801 399251-CNX-035WO (208837)use in manufacturing and / or administration to patients are desirable and beneficial for commercialization of a MCOPPB medicine.

[0005] The present invention provides physical forms of MCOPPB that are superior for use in manufacturing and / or administration to patients other related advantages.SUMMARY

[0006] The invention provides hydrochloride hydrate solid forms of the compound MCOPPB (i.e., (7?)-l-(l-(l-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-17 / -benzo[<f|imidazole), pharmaceutical compositions thereof, methods for preparing the same, and their use in agonizing the NOP receptor (i.e., the nociceptin / orphanin FQ receptor) and treating a disease or condition mediated by a NOP receptor, such as pain. In particular, one aspect of the invention provides a compound in crystalline form represented by Formula I:(I)wherein x is 2.7 to 3.3, and y is 2.7 to 3.3. Crystalline forms of compound of Formula I can provide properties rendering the compound superior for use in manufacturing. For example, crystalline Form B of the compound of Formula I having particularly good properties has been identified. One benefit of crystalline salt Form B is that it has good crystallinity and a relatively high melting point, making it superior to certain other salts of MCOPPB, such as a phosphate, sulfate, fumarate, and certain other salts. Additionally, crystalline salt Form B of Formula I demonstrates low hygroscopicity, in contrast to other salts, such as the L-tartrate salt. Still further, crystalline salt Form B of Formula I demonstrates higher aqueous solubility than other MCOPPB compounds, such as the free base. Additionally, crystalline salt Form B of Formula I is more stable than crystalline MCOPPB trihydrochloride hydrate Form A described herein. Further description of additional features of the compounds are described in the detailed233863801 399251-CNX-035WO (208837)description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0007] Another aspect of the invention provides crystalline l-[l-(l-niethylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-lH-benzimidazole trihydrochloride hydrate. In certain embodiments, the crystalline l-[l-(l-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-IH-benzimidazole trihydrochloride hydrate is crystalline Form B.

[0008] Another aspect of the invention provides a method of making a crystalline compound of Formula I having crystal Form B, comprising the steps of:(a) admixing water, a Ci-4 aliphatic alcohol, and a compound comprising (7?)-l-(l-(l- mcthylcyclooctyl)pipcridin-4-yl)-2-(pipcridin-3-yl)- 1 / / -bcnzofr / ] imidazole) trihydrochloride, to form a first mixture;(b) reducing the temperature of said first mixture to provide a second mixture; and(c) isolating said crystalline compound of Formula I having crystal Form B from the second mixture.

[0009] Another aspect of the invention provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier. In certain embodiments, the invention provides a liquid aqueous pharmaceutical composition formed by dissolving a compound described herein in a liquid aqeous pharmaceutically acceptable carrier.

[0010] Another aspect of the invention provides a method of preparing a pharmaceutical composition, comprising admixing a compound described herein and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutically acceptable carrier comprises water.

[0011] Another aspect of the invention provides a method for treating a disease or condition mediated by the nociceptin / orphanin FQ receptor (NOP receptor). The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein (such as a compound in crystalline form represented by Formula I) or a pharmaceutical composition described herein, to treat the disease or condition. In certain embodiments, the disease or condition is pain.333863801 399251-CNX-035WO (208837)

[0012] Another aspect of the invention provides a method of agonizing a nociceptin / orphanin FQ receptor (NOP receptor). The method comprises contacting a NOP receptor with an effective amount of a compound described herein (such as a compound in crystalline form represented by Formula I) or a pharmaceutical composition described herein, to agonize the NOP receptor.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 depicts an X-ray powder diffractogram of MCOPPB Trihydrochloride Trihydrate Crystal Form B, as further described in Example 2.

[0014] FIG. 2 depicts a differential scanning calorimetry curve of MCOPPB Trihydrochloride Trihydrate Crystal Form B, as further described in Example 2.

[0015] FIG. 3 depicts a thermogravimetric analysis curve of MCOPPB Trihydrochloride Trihydrate Crystal Form B, as further described in Example 2.

[0016] FIG. 4 depicts an X-ray powder diffractogram of MCOPPB Trihydrochloride Hydrate Crystal Form A, as further described in Example 5.

[0017] FIG. 5 depicts a differential scanning calorimetry curve of MCOPPB Trihydrochloride Hydrate Crystal Form A, as further described in Example 5.

[0018] FIG. 6 depicts a thermogravimetric analysis curve of MCOPPB Trihydrochloride Hydrate Crystal Form A, as further described in Example 5.

[0019] FIG. 7 depicts an X-ray powder diffractogram of Amorphous MCOPPB Trihydrochloride Hydrate, as further described in Example 4.

[0020] FIG. 8 depicts a thermogravimetric analysis curve of Amorphous MCOPPB Trihydrochloride Hydrate, as further described in Example 4.

[0021] FIG. 9 depicts an X-ray powder diffractogram of MCOPPB Trihydrochloride Trihydrate Crystal Form B having a moderate degree of crystallinity, which was used as starting material in Example 2.

[0022] FIG. 10 depicts an X-ray powder diffractogram of crystalline MCOPPB L-tartrate hemihydrate, as further described in Example 10.433863801 399251-CNX-035WO (208837)DETAILED DESCRIPTION

[0023] The invention provides hydrochloride hydrate solid forms of the compound MCOPPB (i.e., (7?)-l-(l-(l-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-177-benzo[6 / ]imidazole), pharmaceutical compositions thereof, methods for preparing the same, and their use in agonizing the NOP receptor (i.e., the nocicep tin / orphanin FQ receptor) and treating a disease or condition mediated by a NOP receptor, such as pain.

[0024] MCOPPB is a potent and selective non-peptide agonist for the human nociccptin / orphanin FQ receptor (hNOPR). MCOPPB displays both high binding affinity for hNOPR (Ki = 85 pM; Hayashi, S. et al. in J. Med. Chem. 2009, Vol. 52, No. 3, p. 610-625 ) and high functional potency regarding agonism of hNOPR. In functional assays performed in Chinese Hamster Ovary cells engineered to over-express hNOPR, MCOPPB is a highly potent full agonist of Ci¬ protein signaling pathways as measured by both cAMP accumulation (ECso = 25 pM; see Chang et al. in Mol. Pharmacol. 2015, Vol. 88, p. 502-511) and Ca2+mobilization (EC50 63 pM; see Ferrari et al. in Pharma. Res. Per. 2017, Vol. 5, p. e00333). As compared with its potency in activating hNOPR, the functional potency of MCOPPB at the classical opioid receptors is much lower. It typically shows 1,500-fold and 4,000-fold lower potency for the human mu and kappa opioid receptors, respectively, and activates the human delta receptor only a small amount (see Ferrari et al. in Pharma. Res. Per. 2017, Vol. 5, p. e00333). In animal studies, systemically- administered MCOPPB produces potent anxiolytic effects, with no inhibition of memory or motor function, and only slight sedative side effects which do not appear until much higher doses than the effective anxiolytic dose range (see Hirao et al. in J. Pharmacol. Set. 2008, Vol. 106, p.361-368).

[0025] The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D. M. Weir & C. C.Blackwell, eds.); “Current protocols in molecular biology” (F. M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J. E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.533863801 399251-CNX-035WO (208837)

[0026] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.Definitions

[0027] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0028] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0029] Unless specified otherwise, the term “about” refers to within ±10% of the stated value. The invention encompasses embodiments where the value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0030] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.

[0031] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0032] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0033] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers633863801 399251-CNX-035WO (208837)and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack PubL Co., Easton, PA

[1975] ,

[0034] As used herein, the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0035] MCOPPB refers to the compound (7?)-l-(l-(l-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-177-benzo[6(|imidazole, which has the following chemical structure:

[0036] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there arc compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0037] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.I. Hydrochloride Hydrate Solid Forms of MCOPPB

[0038] The invention provides hydrochloride hydrate solid forms of the compound MCOPPB (i.e., (R)-l-(l-(l-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-17f-benzo[r / ]imidazole). The compounds are described in more detail below. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds733863801 399251-CNX-035WO (208837)are described in the following sections. Exemplary procedures for making the compounds are described in the Examples.A. Crystalline Forms of Compoud of Formula I

[0039] One aspect of the invention provides a compound in crystalline form represented by Formula I:(I)wherein x is 2.7 to 3.3, and y is 2.7 to 3.3.

[0040] The crystalline compound may be more particularly defined according to the definition of variable x and y. For example, in certain embodiments, x is 2.8 to 3.2. In certain embodiments, 2.84 to 3.16. In certain embodiments, x is 2.85 to 3.15. In certain embodiments, x is 2.9 to 3.1. In certain embodiments, x is 3.0.

[0041] In certain embodiments, y is 2.8 to 3.2. In certain embodiments, y is 2.9 to 3.1. In certain embodiments, y is 3.0.

[0042] In certain embodiments, x is 3.0, and y is 3.0.

[0043] Crystalline forms of compound of Formula I can provide properties rendering the compound superior for use in manufacturing. For example, crystalline Form B of the compound of Formula I having particularly good properties has been identified. One benefit of crystalline salt Form B is that it has good crystallinity and a relatively high melting point, making it superior to certain other salts of MCOPPB, such as a phosphate, sulfate, fumarate, and certain other salts. Additionally, crystalline salt Fomi B of Formula I demonstrates low hygroscopicity, in contrast to other salts, such as the L-tartrate salt. Still further, crystalline salt Form B of Formula I demonstrates higher aqueous solubility than other MCOPPB compounds, such as the free base.833863801 399251-CNX-035WO (208837)Additionally, crystalline salt Form B of Formula I is more stable than crystalline MCOPPB trihydrochloride hydrate Form A described herein.1. Crystalline Form B of Compound of Formula I

[0044] One aspect of the invention provides a crystalline compound of Formula I having crystal Form B. Crystal Form B may be characterized according to X-ray powder diffraction and / or differential scanning calorimetry.

[0045] In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (29): 7.5 ± 0.2, 12.8 ± 0.2, 17.5 ± 0.2, 20.8 ± 0.2, 22.7 ± 0.2, 23.7 ± 0.2, and 28.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 11.4 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 19.4 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 22.0 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 22.1 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 25.7 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 27.1 ± 0.2.

[0046] In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising a peak at at least two of the following diffraction angles (20): 7.5 ± 0.2, 12.8 ± 0.2, 17.5 ± 0.2, 20.8 ± 0.2, 22.7 ± 0.2, 23.7 ± 0.2, and 28.6 ± 0.2. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising a peak at at least three of the following diffraction angles (20): 7.5 ± 0.2, 12.8 ± 0.2, 17.5 ± 0.2, 20.8 ± 0.2, 22.7 ± 0.2, 23.7 ± 0.2, and 28.6 ± 0.2. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising a peak at at least five of the following diffraction angles (20): 7.5 ± 0.2, 12.8 ± 0.2, 17.5 ± 0.2, 20.8 ± 0.2, 22.7 ± 0.2, 23.7 ± 0.2, and 28.6 ± 0.2. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising a peak at at least six of the following diffraction angles (20): 7.5 ± 0.2, 12.8 ± 0.2, 17.5 ± 0.2, 20.8 ± 0.2, 22.7 ± 0.2, 23.7 ± 0.2, and 28.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further933863801 399251-CNX-035WO (208837)comprises a peak at the following diffraction angle (20): 11.4 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 19.4 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 22.0 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 22.1 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 25.7 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 27.1 ± 0.2.

[0047] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 30%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 20%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 10%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 5%.

[0048] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):Angle

[0020] d-spacing | A] Relative Intensity [%]7.5 11.7 5710.6 8.3 1611.4 7.8 3612.8 6.9 5414.4 6.2 2715.0 5.9 1917.5 5.1 5717.7 5.0 3719.4 4.6 4320.8 4.3 10022.0 4.0 4622.1 4.0 4922.5 3.9 2122.7 3.9 581033863801 399251-CNX-035WO (208837)Angle

[0029] d-spacing [A] Relative Intensity [%]23.7 3.7 4823.9 3.7 2224.1 3.7 1525.7 3.5 4826.7 3.3 1727.1 3.3 3528.6 3.1 5030.1 3.0 2730.9 2.9 1631.0 2.9 1631.4 2.8 3033.1 2.7 2134.9 2.6 16

[0049] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):Angle [2θ] d-spacing [Å] Relative Intensity [%]7.5 11.7 578.6 10.3 610.6 8.3 1611.4 7.8 3612.8 6.9 5414.4 6.2 2715.0 5.9 1917.1 5.2 1017.5 5.1 5717.7 5.0 3718.4 4.8 719.0 4.7 1319.4 4.6 4319.7 4.5 519.9 4.5 620.8 4.3 1001133863801 399251-CNX-035WO (208837)Angle

[0029] d-spacing [A] Relative Intensity [%]21.1 4.2 622.0 4.0 4622.1 4.0 4922.5 3.9 2122.7 3.9 5823.7 3.7 4823.9 3.7 2224.1 3.7 1524.8 3.6 1125.7 3.5 4826.5 3.4 526.7 3.3 1727.1 3.3 3527.3 3.3 827.7 3.2 1328.4 3.1 528.6 3.1 5028.9 3.1 1329.2 3.1 829.5 3.0 1230.1 3.0 2730.9 2.9 1631.0 2.9 1631.4 2.8 3031.9 2.8 1132.3 2.8 1133.1 2.7 2133.6 2.7 733.8 2.6 633.9 2.6 634.9 2.6 1635.8 2.5 736.1 2.5 636.2 2.5 937.4 2.4 937.7 2.4 638.5 2.3 71233863801 399251-CNX-035WO (208837)Angle [2θ] d-spacing [Å] Relative Intensity [%]39.0 2.3 539.7 2.3 6

[0050] In certain embodiments, the X-ray powder diffraction pattern is substantially as shown in FIG. 1.

[0051] An X-ray powder diffraction pattern may be obtained using CuKa radiation. The temperature at which the X-ray powder diffraction pattern is obtained may be, for example, 25±2 degrees Celsius.

[0052] In certain embodiments, the compound has a dehydration onset as determined by differential scanning calorimetry in the range of from about 85 degrees Celsius to about 105 degrees Celsius. In certain embodiments, the compound has a dehydration onset as determined by differential scanning calorimetry at about 95 degrees Celsius. In certain embodiments, the compound has a dehydration peak as determined by differential scanning calorimetry in the range of from about 105 degrees Celsius to about 125 degrees Celsius. In certain embodiments, the compound has a dehydration peak as determined by differential scanning calorimetry at about 116 degrees Celsius.

[0053] In certain embodiments, the compound has a dehydration onset as determined by differential scanning calorimetry in the range of from about 130 degrees Celsius to about 150 degrees Celsius. In certain embodiments, the compound has a dehydration onset as determined by differential scanning calorimetry at about 141 degrees Celsius. In certain embodiments, the compound has a dehydration peak as determined by differential scanning calorimetry in the range of from about 135 degrees Celsius to about 155 degrees Celsius. In certain embodiments, the compound has a dehydration peak as determined by differential scanning calorimetry at about 146 degrees Celsius.

[0054] In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 220 degrees Celsius to about 240 degrees Celsius. In certain embodiments, the compound has a melting point onset as determined by differential scanning calorimetry at about 228 degrees Celsius. In certain embodiments, the compound has a melting point peak as determined by differential scanning calorimetry in the1333863801 399251-CNX-035WO (208837)range of from about 230 degrees Celsius to about 250 degrees Celsius. In certain embodiments, the compound has a melting point peak as determined by differential scanning calorimetry at about 240 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 2.

[0055] In certain embodiments, the compound has a weight loss in the range of from about 0% to about 2.0% in the temperature range of from about 35 degrees Celsius to about 75 degrees Celsius, by thermogravimetric analysis. In certain embodiments, the compound has a weight loss of about 0.6% in the temperature range of from about 35 degrees Celsius to about 75 degrees Celsius, by thermogravimetric analysis.

[0056] In certain embodiments, the compound has a weight loss in the range of from about 7.5% to about 10.5% in the temperature range of from about 75 degrees Celsius to about 150 degrees Celsius, by thermogravimetric analysis. In certain embodiments, the compound has a weight loss of about 9.1% in the temperature range of from about 75 degrees Celsius to about 150 degrees Celsius, by thermogravimetric analysis.

[0057] In certain embodiments, the compound is further characterized by: weight of the compound increases no more than 5% when placed in an atmosphere that is transitioned from 5% to 95% relative humidity in a dynamic vapor sorption procedure. In certain embodiments, the compound is further characterized by: weight of the compound increases no more than 2% when placed in an atmosphere that is transitioned from 5% to 95% relative humidity in a dynamic vapor sorption procedure. In certain embodiments, the compound is further characterized by: weight of the compound increases no more than 1% when placed in an atmosphere that is transitioned from 5% to 95% relative humidity in a dynamic vapor sorption procedure.B. Crystalline Forms of l-[l-(l-Methylcvclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-lH-benzimidazole Trihydrochloride Hydrate

[0058] One aspect of the invention provides a compound in crystalline 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-lH-benzimidazole trihydrochloride hydrate. In certain embodiments, the l-[l-(l-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-lH-benzimidazole trihydrochloride hydrate is a monohydrate. In certain embodiments, the 1 -[ 1 -( 1 -methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]- 1 H- 1433863801 399251-CNX-035WO (208837)benzimidazole trihydrochloride hydrate is a trihydrate. In certain embodiments, the crystalline 1-[l-(l-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-lH-benzimidazole trihydrochloride hydrate is Form A.1. Crystalline Form A of l-ri-(l-methylcyclooctyl)-4-piperidinyl1-2-r(3R)-3- piperidinyll-lH-benzimidazole trihydrochloride hydrate

[0059] One aspect of the invention provides crystalline l-[l-(l-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-lH-benzimidazole trihydrochloride hydrate having crystal Form A. Crystal Form A may be chacterized according to X-ray powder diffraction and / or differential scanning calorimetry.

[0060] In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (29): 8.0 ± 0.2, 8.9 ± 0.2, 15.3 ± 0.2, 20.2 ± 0.2, 22.0 ± 0.2, 25.8 ± 0.2, and 27.4 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 17.9 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 20.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 21.2 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 23.1 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): and 29.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 17.9 ± 0.2, 20.6 ± 0.2, 21.2 ± 0.2, 23.1 ± 0.2, and 29.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at each of the following diffraction angles (20): 17.9 ± 0.2, 20.6 ± 0.2, 21.2 ± 0.2, 23.1 ± 0.2, and 29.6 ± 0.2.

[0061] In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising a peak at at least two of the following diffraction angles (20): 8.0 ± 0.2, 8.9 ± 0.2, 15.3 ± 0.2, 20.2 ± 0.2, 22.0 ± 0.2, 25.8 ± 0.2, and 27.4 ± 0.2. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising a peak at at least three of the following diffraction angles (20): 8.0 ± 0.2, 8.9 ± 0.2, 15.3 ± 0.2, 20.2 ± 0.2, 22.0 ± 0.2, 25.8 ±1533863801 399251-CNX-035WO (208837)0.2, and 27.4 ± 0.2. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern comprising a peak at at least five of the following diffraction angles (20): 8.0 ± 0.2, 8.9 ± 0.2, 15.3 ± 0.2, 20.2 ± 0.2, 22.0 ± 0.2, 25.8 ± 0.2, and 27.4 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 17.9 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 20.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 21.2 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 23.1 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): and 29.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 17.9 ± 0.2, 20.6 ± 0.2, 21.2 ± 0.2, 23.1 ± 0.2, and 29.6 ± 0.2. In certain embodiments, the X-ray powder diffraction pattern further comprises a peak at each of the following diffraction angles (20): 17.9 ± 0.2, 20.6 ± 0.2, 21.2 ± 0.2, 23.1 ± 0.2, and 29.6 ± 0.2.

[0062] In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 15%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 10%. In certain embodiments, the relative intensity of the peak at said diffraction angles (20) is at least 5%.

[0063] In certain embodiments, the compound is characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):Angle [2θ] d-spacing [Å] Relative Intensity [%]8.0 11.0 348.9 9.9 1009.2 9.6 1114.6 6.1 615.3 5.8 4016.0 5.5 1317.9 5.0 171633863801 399251-CNX-035WO (208837)Angle [2θ] d-spacing [Å] Relative Intensity [%]20.1 4.4 3120.6 4.3 1521.2 4.2 1622.0 4.0 2523.1 3.8 1523.7 3.7 724.9 3.6 1325.8 3.5 3326.5 3.4 1026.5 3.4 1326.9 3.3 1327.4 3.3 2128.9 3.1 829.6 3.0 1730.9 2.9 833.9 2.6 5

[0064] In certain embodiments, the compound has an X-ray powder diffraction pattern substantially as shown in FIG. 4.

[0065] An X-ray powder diffraction pattern may be obtained using CuKa radiation. The temperature at which the X-ray powder diffraction pattern is obtained may be, for example, 25±2 degrees Celsius.

[0066] In certain embodiments, the compound has a dehydration onset as determined by differential scanning calorimetry in the range of from about 0 degrees Celsius to about 10 degrees Celsius. In certain embodiments, the compound has a dehydration onset as determined by differential scanning calorimetry at about 4 degrees Celsius. In certain embodiments, the compound has a dehydration peak as determined by differential scanning calorimetry in the range of from about 40 degrees Celsius to about 55 degrees Celsius. In certain embodiments, the compound has a dehydration peak as determined by differential scanning calorimetry at about 48 degrees Celsius. In certain embodiments, the compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 5.1733863801 399251-CNX-035WO (208837)

[0067] In certain embodiments, the compound has a weight loss in the range of from about 4% to about 12% in the temperature range of from about 35 degrees Celsius to about 140 degrees Celsius, by thermogravimetric analysis. In certain embodiments, the compound has a weight loss of about 8.6% in the temperature range of from about 35 degrees Celsius to about 140 degrees Celsius, by thermogravimetric analysis. In certain embodiments, the compound has a thermogravimetric analysis curve substantially the same as shown in FIG. 6.

[0068] In certain embodiments, the compound is a monohydrate

[0069] The description above describes multiple embodiments. The patent application specifically contemplates all combinations of the embodiments.C. Exemplary Further Characterization of Crystalline Forms of Compounds Described Herein

[0070] Crystalline forms of compounds described herein may be further characterized according to purity, hygroscopicity, and stability to storage.

[0071] For example, in certain embodiments, the compound has a purity greater than 90% by weight. In certain embodiments, the compound has a purity greater than 93% by weight. In certain embodiments, the compound has a purity greater than 95% by weight. In certain embodiments, the compound has a purity greater than 97% by weight. In certain embodiments, the compound has a purity greater than 98% by weight. In certain embodiments, the compound has a purity greater than 99% by weight. In certain embodiments, the compound has a purity greater than 99.5% by weight. In certain embodiments, the compound has a purity greater than 99.8% by weight. In certain embodiments, the compound has a purity greater than 99.9% by weight.

[0072] In certain embodiments, the compound is further characterized by hygroscopicity. For example, in certain embodiments, the compound absorbs less than 1 % (w / w) water upon storage for 1 day at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, the compound absorbs less than 1% (w / w) water upon storage for 1 week at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, the compound absorbs less than 1% (w / w) water upon storage for 1 day at a temperature of 25 °C and a relative humidity of 92.5%.1833863801 399251-CNX-035WO (208837)In certain embodiments, the compound absorbs less than 1% (w / w) water upon storage for 1 week at a temperature of 25 °C and a relative humidity of 92.5%.

[0073] In certain embodiments, the compound is further characterized by hygroscopicity. For example, in certain embodiments, the compound absorbs less than 2% (w / w) water upon storage for 1 day at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, the compound absorbs less than 2% (w / w) water upon storage for 1 week at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, the compound absorbs less than 2% (w / w) water upon storage for 1 day at a temperature of 25 °C and a relative humidity of 92.5%. In certain embodiments, the compound absorbs less than 2% (w / w) water upon storage for 1 week at a temperature of 25 °C and a relative humidity of 92.5%.

[0074] In certain embodiments, the compound is further characterized by stability to storage. For example, in certain embodiments, less than 0.5% (w / w) of the compound degrades upon storage for 1 week at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, less than 0.5% (w / w) of the compound degrades upon storage for 1 month at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, less than 0.5% (w / w) of the compound degrades upon storage for 1 week at a temperature of 25 °C and a relative humidity of 92.5%. In certain embodiments, less than 0.5% (w / w) of the compound degrades upon storage for 1 month at a temperature of 25 °C and a relative humidity of 92.5%. In certain embodiments, less than 0.5% (w / w) of the compound degrades upon storage for 1 week at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, less than 0.5% (w / w) of the compound degrades upon storage for 1 month at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, less than 1% (w / w) of the compound degrades upon storage for 2 months at a temperature of 40 °C and a relative humidity of 75%. In certain embodiments, less than 1% (w / w) of the compound degrades upon storage for 2 months at a temperature of 25 °C and a relative humidity of 92.5%.1933863801 399251-CNX-035WO (208837)D. Amorphous Form of Compound of Formula II

[0075] Another aspect of the invention provides a compound in amorphous form represented by Formula II:(II)wherein x is 2.7 to 3.3, and y is 4.5 to 6.0.

[0076] The amorphous compound of Formula II may be more particularly defined according to the definition of variable x and y. In certain embodiments, x is 2.85 to 3.15. In certain embodiments, x is 3.0. In certain embodiments, y is 4.8 to 5.7. In certain embodiments, y is 5.0. In certain embodiments, y is 5.3.

[0077] In certain embodiments, the compound has a weight loss in the range of from about 10% to about 20% in the temperature range of from about 35 degrees Celsius to about 150 degrees Celsius, by thermogravimetric analysis. In certain embodiments, the compound has a weight loss of about 16% in the temperature range of from about 35 degrees Celsius to about 150 degrees Celsius, by thermogravimetric analysis. In certain embodiments, the compound has a thermogravimetric analysis curve substantially the same as shown in FIG. 8.

[0078] The description above describes multiple embodiments relating to an amorphous form of Formula II. The patent application specifically contemplates all combinations of the embodiments.2033863801 399251-CNX-035WO (208837)II. Methods of Making Hydrochloride Hydrate Solid Forms of MCOPPB

[0079] Another aspect of the invention provides a method of making a crystalline compound of Formula I having crystal Form B, comprising the steps of:(a) admixing water, a Ci-4 aliphatic alcohol, and a compound comprising (R)-1-(1-(1-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole) trihydrochloride, to form a first mixture;(b) reducing the temperature of said first mixture to provide a second mixture; and(c) isolating said crystalline compound of Formula I having crystal Form B from the second mixture.

[0080] The method may be further characterized according to various features. For example in certain embodiments, step (a) comprises admixing water, a Ci-4 aliphatic alcohol, and a compound comprising (R)- 1 -( 1 -( 1 -methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3 -yl)- 1H-benzo[d]imidazole) trihydrochloride hydrate, to form a first mixture. In certain embodiments, the Ci-4 aliphatic alcohol is isopropanol. In certain embodiments, the Ci-4 aliphatic alcohol is ethanol or propanol. In certain embodiments, the first mixture has a temperature in the range of from about 55 °C to about 65 °C. In certain embodiments, the second mixture has a temperature in the range of from about -5 °C to about 5 °C.III. Therapeutic Applications of Hydrochloride Hydrate Solid Forms of MCOPPB and Pharmaceutical Compositions Containing Same

[0081] Compounds described herein, such as hydrochloride hydrate solid forms of MCOPPB, such as crystalline compounds of Formula I or amorphous compounds of Formula II, as set forth in Section I, provide therapeutic benefits to subjects suffering from pain and other diseases or conditions. Accordingly, one aspect of the invention provides a method for treating a disease or condition mediated by the nociceptin / orphanin FQ receptor (NOP receptor). The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein (such as a compound in crystalline form represented by Formula I or a compound in amorphous form represented by Formula II) or a pharmaceutical composition comprising a compound described herein, to treat the disease or condition. In certain2133863801 399251-CNX-035WO (208837)embodiments, the particular compound is a compound defined by one of the embodiments described above.Treatment of Pain

[0082] In certain embodiments, the disease or condition mediated by the NOP receptor is pain. Exemplary additional features of the method of treating pain are described below, which include type of pain to be treated, amount of reduction in pain intensity provided by the method, and duration of reduction in pain intensity provided by the method. The invention embraces all permutations and combinations of these features.T pe of Pain

[0083] The method may be further characterized according to the type of pain experienced by the subject. Accordingly, in certain embodiments, the pain is chronic pain. In certain other embodiments, the pain is acute pain.

[0084] In certain other embodiments, the pain is trauma pain. In certain embodiments, the pain is due to surgery.

[0085] In certain embodiments, the pain is neuropathic pain. In certain other embodiments, the pain is inflammatory pain.

[0086] In certain embodiments, the pain is arthritis pain. In certain embodiments, the pain is arthritis pain selected from osteoarthritis pain and rheumatoid arthritis pain.

[0087] In certain other embodiments, the pain is complex regional pain syndrome. In certain embodiments, the complex regional pain syndrome is reflex sympathetic dystrophy pain.

[0088] In certain other embodiments, the pain is pain due to cancer. In certain embodiments, the pain is due to a cancer selected from the group consisting of a solid tumor, leukemia, and lymphoma. In certain embodiments, the pain is due to a cancer selected from the group consisting of a bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomach cancer, testicular cancer, and uterine cancer.

[0089] In certain other embodiments, the pain is due to sickle cell disease.2233863801 399251-CNX-035WO (208837)

[0090] In certain other embodiments, the pain is located in the patient’s hand, wrist, arm, shoulder, back, leg, knee, ankle, foot, or toe. In certain embodiments, the pain is low back pain. In certain embodiments, the pain is chronic low back pain.

[0091] In certain other embodiments, the pain is a neuropathic pain selected from the group consisting of low back pain, hip pain, leg pain, non-herpetic neuralgia, post-herpetic neuralgia, diabetic neuropathy pain, lumbosacral radiculopathy pain, nerve injury-induced pain, acquired immune deficiency syndrome (AIDS) related neuropathic pain, head trauma pain, phantom limb pain, multiple sclerosis pain, root avulsion pain, painful traumatic mononeuropathy, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury pain, post-surgical pain, carpal tunnel syndrome pain, trigeminal neuralgia pain, post mastectomy syndrome pain, post-thoracotomy syndrome pain, stump pain, repetitive motion pain, neuropathic pain associated hyperalgesia and allodynia, drug-induced pain, toxin-caused nerve injury pain, chemotherapy-caused nerve injury pain, and combinations thereof.Amount of Reduction in Pain Intensity

[0092] The method may be further characterized according to the amount of reduction in pain intensity relative to pain observed without administering the compound. Accordingly, in certain embodiments, the method is characterized by achieving at least a 20% reduction in pain intensity relative to pain observed without administering the compound. In certain embodiments, the method is characterized by achieving at least a 40% reduction in pain intensity relative to pain observed without administering the compound. In certain embodiments, the method is characterized by achieving at least a 60% reduction in pain intensity relative to pain observed without administering the compound. In certain embodiments, the method is characterized by achieving at least an 80% reduction in pain intensity relative to pain observed without administering the compound. In certain embodiments, the method is characterized by achieving at least a 90% reduction in pain intensity relative to pain observed without administering the compound.Duration of Reduction in Pain Intensity

[0093] The method may be further characterized according to the duration of reduction in pain intensity. Accordingly, in certain embodiments, the reduction in pain intensity lasts for at least 1 week. In certain embodiments, the reduction in pain intensity lasts for at least 2 weeks.2333863801 399251-CNX-035WO (208837)In certain embodiments, the reduction in pain intensity lasts for at least 4 weeks. In certain embodiments, the reduction in pain intensity lasts for at least 2 months. In certain embodiments, the reduction in pain intensity lasts for at least 3 months. In certain embodiments, the reduction in pain intensity lasts for at least 6 months.

[0094] In certain embodiments, the reduction in pain intensity lasts for at a duration of 2 months to six months. In certain embodiments, the reduction in pain intensity lasts for a duration of 3 months to 9 months. In certain embodiments, the reduction in pain intensity lasts for a duration of 6 months to 9 months. In certain embodiments, the reduction in pain intensity lasts for a duration of 6 months to 12 months.Treatment of Other Diseases or Conditions Mediated by the NOP Receptor

[0095] In certain embodiments, the disease or condition mediated by the NOP receptor is anxiety. In certain other embodiments, the disease or condition mediated by the NOP receptor involves accumulation of senescent cells. In certain embodiments, the disease or condition mediated by the NOP receptor is cancer, a cardiovascular disease, a neurological disease, or an immune -related disease.Exemplary Further Features of the Therapeutic Methods

[0096] Exemplary additional features of the therapeutic methods are described below, which include the dose of MCOPPB, the duration of administration of the compound, aspects of the pharmaceutical composition, aspects of the administration device, and other features. The invention embraces all pemiutations and combinations of these features.Dose of MCOPPB

[0097] The method may be further characterized according to the dose of MCOPPB administered to the subject. Accordingly, in certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 0.01 pg to 50 pg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 0.01 pg to 0.1 pg, about 0.1 pg to 10 pg, about 10 pg to 20 pg, about 20 pg to 30 pg, about 30 pg to 40 pg, or about 40 pg to 50 pg.

[0098] In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 0.1 pg to 10 pg. In certain embodiments, the administering delivers a daily dose2433863801 399251-CNX-035WO (208837)of MCOPPB in the range of about 0.1 gg to 0.5 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 0.5 gg to 1 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 1 gg to 2 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 2 gg to 3 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 3 gg to 4 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 4 gg to 5 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 5 gg to 6 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 6 gg to 7 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 7 gg to 8 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 8 gg to 9 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 9 gg to 10 gg.

[0099] In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 10 gg to 50 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 10 gg to 12 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 12 gg to 14 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 14 gg to 16 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 16 gg to 18 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 18 gg to 20 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 20 gg to 25 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 25 gg to 30 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 30 gg to 35 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 35 gg to 40 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 40 gg to 45 gg. In certain embodiments, the administering delivers a daily dose of MCOPPB in the range of about 45 gg to 50 gg.

[0100] In general, a suitable dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. When the2533863801 399251-CNX-035WO (208837)compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.Pharmaceutical Composition

[0101] The method may be further characterized according to whether the compound is administered in a pharmaceutical composition, and features of said pharmaceutical composition, for example, components of the composition or the tonicity of the composition. Accordingly, in certain embodiments, the compound is administered in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

[0102] In certain embodiments, the pharmaceutical composition comprises a compound described herein, such as a compound in crystalline form represented by Formula I or a compound in amorphous form represented by Formula II, and water. In certain embodiments, the pharmaceutical composition comprises a compound described herein, such as a compound in crystalline form represented by Formula I or a compound in amorphous form represented by Formula II, water, and an alkali metal salt. In certain other embodiments, the pharmaceutical composition is approximately isotonic.

[0103] A pharmaceutical composition comprising (i) a compound described herein, such as a compound in crystalline form represented by Formula I or a compound in amorphous form represented by Formula II, and (ii) a pharmaceutically acceptable carrier may be prepared by combining (a) a compound described herein, such as a compound in crystalline fomi represented by Formula I or a compound in amorphous form represented by Formula II, with (b) a pharmaceutically acceptable carrier.

[0104] Additional features of the pharmaceutical composition are described in Section IV, below.Administration Method and Device

[0105] The method may be further characterized according to the method of administering the compound or pharmaceutical composition, and any device that is used for the administration. Accordingly, in certain embodiments, the compound is administered intrathecally. In certain embodiments, the pharmaceutical composition is administered intrathecally. In certain2633863801 399251-CNX-035WO (208837)embodiments, the compound is administered orally. In certain embodiments, the pharmaceutical composition is administered orally.

[0106] In certain embodiments, the pharmaceutical composition is administered intrathecally via a pump device. In certain embodiments, the pharmaceutical composition is administered intrathecally via a pump device implanted in the patient. In certain embodiments, when the therapeutic agent is administered intrathecally via a pump device implanted in the patient, the pump device is an osmotic pump. In certain embodiments, the therapeutic agent is administered intrathecally via a spinal catheter that is fluidically connected to a pump device located outside the patient’s body.

[0107] The pump device is desirably programmable. Optionally, the pump may respond to patient request, e.g., where the amount and / or rate of pharmaceutical composition administered by the pump device may be influenced by the patient, where, for example, the patient can have the pump device deliver more pharmaceutical composition (e.g., to control breakthrough pain) or less pharmaceutical composition (where pain is less and, therefore, less pharmaceutical composition is needed).Duration of Administration of the Pharmaceutical Composition

[0108] The method may be further characterized according to the duration of administration of the pharmaceutical composition to the subject. Accordingly, in certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for at least 4 hours per day. In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for at least 8 hours per day. In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for at least 12 hours per day. In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for at least 16 hours per day. In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for at least 20 hours per day.

[0109] In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration during at least 90% of the patient’s waking hours. In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for a period of at least 1 week. In certain embodiments, the pharmaceutical 2733863801 399251-CNX-035WO (208837)composition is administered continuously by intrathecal administration for a period of at least 2 weeks. In certain embodiments, the phamiaceutical composition is administered continuously by intrathecal administration for a period of at least 4 weeks.

[0110] In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for a period ranging from about 1 month to 3 months. In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for a period ranging from about 1 month to 6 months. In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for a period ranging from about 3 months to 6 months. In certain embodiments, the pharmaceutical composition is administered continuously by intrathecal administration for a period ranging from about 6 months to 9 months. In certain embodiments, the phamiaceutical composition is administered continuously by intrathecal administration for a period ranging from about 6 months to 12 months.Patients for Treatment

[0111] The methods may be further characterized according to the subject to be treated. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain other embodiments, the subject is a pediatric human. In certain other embodiments, the subject is a veterinary animal.Use of Compounds and Methods of Agonizing the NOP Receptor

[0112] Another aspect of the invention provides for the use of a compound described herein, such as crystalline compounds of Formula I or amorphous compounds of Formula II, in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease or condition described herein, such as pain.

[0113] Another aspect of the invention provides for the use of a compound described herein, such as crystalline compounds of Formula I or amorphous compounds of Formula II, for treating a disease or condition, such as a disease or condition described herein (for example, pain).

[0114] Further, compounds described herein, such as crystalline compounds of Formula I or amorphous compounds of Formula II, agonize the nociceptin / orphanin FQ receptor (NOP receptor). Accordingly, another aspect of the invention provides a method of agonizing the2833863801 399251-CNX-035WO (208837)nociceptin / orphanin FQ receptor (NOP receptor). The method comprises contacting a NOP receptor with an effective amount of a compound described herein, such as a compound in crystalline form represented by Formula I or a compound in amorphous form represented by Formula II, to agonize the NOP receptor. In certain embodiments, the particular compound is a compound defined by one of the embodiments described above.IV. Pharmaceutical Compositions

[0115] The invention provides pharmaceutical compositions comprising a compound described herein, such as a compound in crystalline form represented by Formula I or a compound in amorphous fomi represented by Formula II. In certain embodiments, the pharmaceutical compositions comprise (i) a compound described herein, such as a compound in crystalline form represented by Formula I or a compound in amorphous form represented by Formula II, and (ii) a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is formulated for intrathecal administration. In certain embodiments, the phamiaceutical composition comprise a therapeutically effective amount of a compound described herein, such as a compound in crystalline form represented by Formula I or a compound in amorphous form represented by Formula II, formulated together with one or more pharmaceutically acceptable carriers.

[0116] The phrase “therapeutically effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment.

[0117] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0118] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous,2933863801 399251-CNX-035WO (208837)subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0119] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0120] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon factors such as the host being treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, from about 5 percent to about 70 percent, from about 10 percent to about 30 percent, or from about 1 percent to about 5 percent.

[0121] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.Pharmaceutical Compositions for Parenteral and Intrathecal Administration

[0122] As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for parenteral administration, more specifically intrathecal administration by, for example, intrathecal injection as, for example, a sterile solution. In certain embodiments, the pharmaceutical compositions my be specially formulated for other modes of parenteral administration, for example, by subcutaneous, intramuscular, or intravenous injection as, for example, a sterile solution or suspension, or sustained-release formulation.3033863801 399251-CNX-035WO (208837)

[0123] Pharmaceutical compositions of this invention suitable for parenteral or intrathecal administration may comprise one or more compounds described herein in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain a preservative, sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood or cerebrospinal fluid of the intended recipient or suspending or thickening agents.

[0124] Exemplary suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0125] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.Pharmaceutical Compositions for Other Routes of Administration

[0126] The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (3) intravaginally or intrarectally, for example, as a pessary, cream or foam; (4) sublingually; (5) ocularly; (6) transdermally; or (7) nasally.3133863801 399251-CNX-035WO (208837)

[0127] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0128] Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0129] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[0130] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0131] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic3233863801 399251-CNX-035WO (208837)acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0132] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0133] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions3333863801 399251-CNX-035WO (208837)which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0134] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0135] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0136] 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 metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0137] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0138] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0139] Dosage fomis for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a3433863801 399251-CNX-035WO (208837)pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0140] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0141] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0142] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0143] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.Dosage Levels

[0144] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0145] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the3533863801 399251-CNX-035WO (208837)age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0146] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound described herein in a therapeutically effective amount for the treatment of a disease or condition described herein.Additional Pharmaceutical Compositions

[0147] Another aspect of the invention provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

[0148] Another aspect of the invention provides a liquid aqueous pharmaceutical composition formed by dissolving a crystalline compound represented by Formula I in an aqueous liquid pharmaceutically acceptable carrier.(I)wherein x is 2.7 to 3.3, and y is 2.7 to 3.3.

[0149] The crystalline compound may be more particularly defined according to the definition of variable x and y. For example, in certain embodiments, x is 2.8 to 3.2. In certain embodiments, 2.84 to 3.16. In certain embodiments, x is 2.85 to 3.15. In certain embodiments, x is 2.9 to 3.1. In certain embodiments, x is 3.0. In certain embodiments, y is 2.8 to 3.2. In certain3633863801 399251-CNX-035WO (208837)embodiments, y is 2.9 to 3.1. In certain embodiments, y is 3.0. In certain embodiments, x is 3.0, and y is 3.0.

[0150] The crystalline compound of Formula I may be crytalline Form A or crystalline Form B, each of which are described in more detail herein above.

[0151] Another aspect of the invention provides a liquid aqueous pharmaceutical composition formed by dissolving a crystalline compound represented by Formula I in an aqueous liquid pharmaceutically acceptable carrier, wherein Formula I is• (HCI)X• (H2O)y(I)wherein x is 2.7 to 3.3, and y is 2.7 to 3.3, wherein the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 7.5 ± 0.2, 12.8 ± 0.2, 17.5 ± 0.2, 20.8 ± 0.2, 22.7 ± 0.2, 23.7 ± 0.2, and 28.6 ± 0.2.

[0152] Another aspect of the invention provides a liquid aqueous pharmaceutical composition formed by dissolving a crystalline compound represented by Formula I in an aqeous liquid pharmaceutically acceptable carrier, wherein Formula I is• (HCI)X• (H2O)y33863801 399251-CNX-035WO (208837)wherein x is 2.7 to 3.3, and y is 2.7 to 3.3, wherein the compound exhibits X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):Angle [2θ] d-spacing [Å] Relative Intensity [%]7.5 11.7 5710.6 8.3 1611.4 7.8 3612.8 6.9 5414.4 6.2 2715.0 5.9 1917.5 5.1 5717.7 5.0 3719.4 4.6 4320.8 4.3 10022.0 4.0 4622.1 4.0 4922.5 3.9 2122.7 3.9 5823.7 3.7 4823.9 3.7 2224.1 3.7 1525.7 3.5 4826.7 3.3 1727.1 3.3 3528.6 3.1 5030.1 3.0 2730.9 2.9 1631.0 2.9 1631.4 2.8 3033.1 2.7 2134.9 2.6 16

[0153] In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier for intrathecal administration.3833863801 399251-CNX-035WO (208837)Methods for Preparing a Pharmaceutical Composition

[0154] Another aspect of the invention provides a method of preparing a pharmaceutical composition, comprising admixing a compound described herein and a pharmaceutically acceptable carrier.

[0155] Another aspect of the invention provides a method of preparing a liquid aqueous pharmaceutical composition, comprising admixing a crystalline compound represented by Formula I and a aqueous pharmaceutically acceptable carrier, wherein Formula I is(I)wherein x is 2.7 to 3.3, and y is 2.7 to 3.3.

[0156] The crystalline compound may be more particularly defined according to the definition of variable x and y. For example, in certain embodiments, x is 2.8 to 3.2. In certain embodiments, 2.84 to 3.16. In certain embodiments, x is 2.85 to 3.15. In certain embodiments, x is 2.9 to 3.1. In certain embodiments, x is 3.0. In certain embodiments, y is 2.8 to 3.2. In certain embodiments, y is 2.9 to 3.1. In certain embodiments, y is 3.0. In certain embodiments, x is 3.0, and y is 3.0.

[0157] In certain embodiments, the crystalline compound of Formula I is crystalline Form B.

[0158] Another aspect of the invention provides a method of preparing a liquid aqueous pharmaceutical composition, comprising admixing a crystalline compound represented by Formula I and a aqueous pharmaceutically acceptable carrier, wherein Formula I is3933863801 399251-CNX-035WO (208837)wherein x is 2.7 to 3.3, and y is 2.7 to 3.3, wherein the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 7.5 ± 0.2, 12.8 ± 0.2, 17.5 ± 0.2, 20.8 ± 0.2, 22.7 ± 0.2, 23.7 ± 0.2, and 28.6 ± 0.2.

[0159] Another aspect of the invention provides a method of preparing a liquid aqueous pharmaceutical composition, comprising admixing a crystalline compound represented by Formula I and a aqueous pharmaceutically acceptable carrier, wherein Formula I iswherein x is 2.7 to 3.3, and y is 2.7 to 3.3, and the compound exhibits X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):Angle [2θ] d-spacing [Å] Relative Intensity [%]7.5 11.7 5710.6 8.3 1611.4 7.8 3612.8 6.9 5414.4 6.2 2715.0 5.9 194033863801 399251-CNX-035WO (208837)Angle

[0029] d-spacing [A] Relative Intensity [%]17.5 5.1 5717.7 5.0 3719.4 4.6 4320.8 4.3 10022.0 4.0 4622.1 4.0 4922.5 3.9 2122.7 3.9 5823.7 3.7 4823.9 3.7 2224.1 3.7 1525.7 3.5 4826.7 3.3 1727.1 3.3 3528.6 3.1 5030.1 3.0 2730.9 2.9 1631.0 2.9 1631.4 2.8 3033.1 2.7 2134.9 2.6 16

[0160] In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier for intrathecal administration.V. MEDICAL KITS

[0161] Another aspect of this invention is a kit comprising (i) compound described herein, such as a compound in crystalline form represented by Formula I or a compound in amorphous form represented by Formula II, and (ii) instructions for administration and / or treating a disease or condition, according to procedures described herein. In certain embodiments, the instructions are for intrathecal administration. In certain embodiments, the disease or condition is pain.4133863801 399251-CNX-035WO (208837)EXAMPLES

[0162] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Starting materials described herein can be obtained from commercial sources or may be readily prepared from commercially available materials using transformations known to those of skill in the art.EXAMPLE 1 - Preparation of MCOPPB Trihydrochloride Trihydrate Crystal Form B from Amorphous MCOPPB Trihydrochloride Hydrate

[0163] An aliquot of amorphous MCOPPB trihydrochloride hydrate (about 40-60 mg) was placed into a mixture of ethanol and water (86 / 14 v / v) at 5 °C with stirring at 300-400 rpm for 2 days, where the combined total volume of ethanol and water was in the range of 0.1 mL to 0.4 mL. Then, the resulting mixture was subjected to centrifugation fdtration at 14,000 rpm through a 0.45 pm nylon membrane filter to isolate the title compound. The crystalline form of the title compound was determined by X-ray powder powder diffraction (XRPD) analysis.EXAMPLE 2 - Preparation of MCOPPB Trihydrochloride Trihydrate Crystal Form B

[0164] An aliquot of MCOPPB trihydrochloride trihydrate crystal Form B (512.72 mg) having a moderate degree of crystallinity (see Fig. 9) was weighed into an 8-mL glass vial.Methanol (1 mL) was added into the vial at 25 °C with stirring for 5 minutes to obtain a suspension. After stirring the mixture at 25 °C for 4 days, solids from the mixture were collected by centrifugation filtration and then dried at 30 °C under vacuum for about 12 hours to provide the title comopund in 46% yield (239.25 mg).

[0165] The mole ratio of HC1 to MCOPPB in the title compound was determined to be 3.0 to 1 according to HPLC and ion chromatography analysis. The mole ratio of H2O to MCOPPB in the title compound was determined to be 2.8 to 1 according to Karl Fisher analysis. Karl Fischer (KF) titration for water determination was performed using a Mettler Toledo Coulometric KF Titrator C30 or a Metrohm 851 / 885 system, both of which used a coulometric method on a sample mass of about 5-30 mg.4233863801 399251-CNX-035WO (208837)

[0166] X-ray powder diffraction was performed using a Bruker D8 Advance equipped with LYNXEYE detector operated in reflection mode (i.e. Bragg-Brentano geometry). Samples were prepared on monocrystalline silicon, flat surface sample holders. Parameters for XRPD were:Parameter Regular Scan High-Resolution Scan X-ray wavelength Cu Kal, 1.5406 A Cu Kal, 1.5406 AX-ray tube setting 40 kV, 40 mA 40 kV, 40 mA10.0 mm by sample length 10.0 mm by sample length + Primary Beam Slit+ 2.50soller 2.50sollerSecondary Beam Slit 5.2 mm + 2.5 ° soller 5.2 mm + 2.50sollerScan mode Step StepScan range (°20) 3-40 2-40Step size (°20) 0.02 0.02Dwell time (s / step) 0.12 0.3Spin Yes (15 rpm) Yes (15 rpm)

[0167] An X-ray powder diffractogram taken on the title compound is provided in FIG. 1. Tabulated characteristics of the X-ray powder diffractogram in FIG. 1 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-RAY POWDER DIFFRACTOGRAM DATAAngle [2θ] d-spacing [Å] Relative Intensity [%]7.5 11.7 578.6 10.3 610.6 8.3 1611.4 7.8 3612.8 6.9 5414.4 6.2 2715.0 5.9 1917.1 5.2 1017.5 5.1 5717.7 5.0 3718.4 4.8 719.0 4.7 1319.4 4.6 434333863801 399251-CNX-035WO (208837)Angle

[0029] d-spacing [A] Relative Intensity [%]19.7 4.5 519.9 4.5 620.8 4.3 10021.1 4.2 622.0 4.0 4622.1 4.0 4922.5 3.9 2122.7 3.9 5823.7 3.7 4823.9 3.7 2224.1 3.7 1524.8 3.6 1125.7 3.5 4826.5 3.4 526.7 3.3 1727.1 3.3 3527.3 3.3 827.7 3.2 1328.4 3.1 528.6 3.1 5028.9 3.1 1329.2 3.1 829.5 3.0 1230.1 3.0 2730.9 2.9 1631.0 2.9 1631.4 2.8 3031.9 2.8 1132.3 2.8 1133.1 2.7 2133.6 2.7 733.8 2.6 633.9 2.6 634.9 2.6 1635.8 2.5 736.1 2.5 636.2 2.5 94433863801 399251-CNX-035WO (208837)Angle [2θ] d-spacing [Å] Relative Intensity [%]37.4 2.4 937.7 2.4 638.5 2.3 739.0 2.3 539.7 2.3 6

[0168] Differential scanning calorimetry analysis was performed on the title compound using a TA Discovery 2500 (with nitrogen gas flow of 50 mL / min) instrument. The sample (1-2 mg) was weighed directly into a hermetic aluminum pan with a pinhole (0.7 mm diameter) and analyzed according to the following parameters: ramp method, heating rate 10 °C / min, temperature range 30 to 250 °C or before decomposition. A differential scanning calorimetry curve of the title compound obtained according to this procedure is provided in FIG. 2.

[0169] Thermogravimetric analysis on the title compound was performed using a TA Discovery 5500 instrument. Nitrogen flow rate was 10 mL / min at the balance and 25 mL / min in the sample chamber. The sample (2-10 mg) was weighed directly into an open aluminum pan and analyzed according to the following parameters: ramp method, heating rate 10.0 °C / min, and temperature range ambient temperature (below 35 °C) to 300 °C (or until weight <80%). A thermogravimetric analysis curve of the title compound is provided in FIG. 3.

[0170] The title compound was analyzed by1H NMR, and determined to have no residual solvent above the limit of detection. Proton nuclear magnetic resonance (' H NMR) spectroscopy was performed on a Bruker Avance-AV 400 MHz spectrometer. Solids were dissolved in deuterated solvent and analyzed according to the following parameters:Parameter ValueTemperature 297.6 KProbe 5 mmPABBO BB / 19F-1H / D Z-GRD Z108618 / 0406 Number of Scans 8Relaxation Delay 1 sSpectrometer Frequency 400 MHz4533863801 399251-CNX-035WO (208837)

[0171] The title compound was determined to be 99.7% pure by high-pressure liquid chromatography (HPLC), which was conducted on a Shimadzu LC-20AD with a DAD detector at 272 nm and XBridge® C18 column (3.5 pm, 4.6 x 150 mm), with the following additional parameters:Parameter ValueColumn Temperature 40 °CFlow Rate 1.2 mL / minMobile Phase A 0.1 % Trifluoroacetic acid in waterMobile Phase B AcetonitrileDiluent Water: Acetonitrile 1:1 (v / v)Injection Volume 5 pLDiluent Water: Acetonitrile 1:1 (v / v)Initial: 95% Mobile Phase AGradient 9 Minutes: 5% Mobile Phase A13 Minutes: 5% Mobile Phase A17 Minutes: 95% Mobile Phase A

[0172] An aliquot of the title compound was evaluated for crystal form stability upon subjection to compression force. In particular, an aliquot of the title compound (20 mg) was compressed for 5 minutes under either 2MPa, 5MPa, or lOMPa using a hydraulic press. Crystal form of the material at the end of the compressive force experiment was evaluate by X-ray powder diffractogram. Results of the experiment are that the title compound had good stability to compressive force - material analyzed at the end of the compression force experiment was still crystalline Fomi B.

[0173] An aliquot of the title compound was evaluated for crystal form stability upon subjection to dry ginding. In particular, an aliquot of the title compound (20 mg) was ground manually with a mortar and a pestle for a duration of 1, 3, or 5 minutes. Crystal form of the material at the end of the dry ginding experiment was evaluate by X-ray powder diffractogram. Results of the experiment are that the title compound had good stability to dry grinding -material analyzed at the end of the dry grinding experiment was still crystalline Form B.

[0174] An aliquot of the title compound was evaluated for crystal form stability upon subjection to wet ginding. In particular, 20 LIL of ethanol or water was added drop wise to an aliquot of the title compound (about 15 mg) until the sample was wetted sufficiently. Wet 4633863801 399251-CNX-035WO (208837)sample was ground gently with in a mortar and a pestle for 10 minutes. Then, the sample was dried under ambient conditions for 10 min, and evaluated by X-ray powder diffractogram to determine crystalline form. Results of the experiment are that the title compound had good stability to wet grinding - material analyzed at the end of the wet grinding experiment was still crystalline Fomi B.

[0175] XRPD analysis was also conducted on a sample of the title compound that had been subjected to additional drying at a temperature of 120 °C under vacuum for 2 hours. XRPD analysis of the material subjected to additional drying at a temperature of 120 °C under vacuum for 2 hours showed no change in crytal form.EXAMPLE 3 - Preparation of Multi-gram Quantity of MCOPPB Trihydrochloride Trihydrate Crystal Form B

[0176] Starting material MCOPPB trihydrochloride hydrate (10.0 g) was charged into a vessel, and then water / isopropanol (1 / 3 v / v, 5 volumes) was added. The mixture was warmed to 55-65 °C and stirred until a clear solution formed. To this mixture was added activated carbon (0.15X), and the resulting mixture was stirred at 55-65 °C for 4 hours. Then, the mixture was filtered with kieselguhr, and the resulting filter cake was washed with water / isopropanol (1 / 3 v / v, 1 volume). The combined filtrates were adjusted to a temperature in the rnage of 45-55 °C, and then isopropanol (1.5 volumes) was added dropwise to the mixture. A seed was added to the mixture, and the resulting mixture was stirred for 2 hours. Next, the mixture was cooled to a temperature in the range of from -5 °C to 5 °C over 6 hours, and then stirred an additional 9.5 hours. Next, isopropanol (16.5 volumes) was added dropwise to the mixture over 8 hours, with the mixture being maintained at a temperature in the range of -5 °C to 5 °C. Then, the mixture was stirred for 20 hours at a temperature in the range of -5 °C to 5 °C, and then the mixture was filtered. The recovered solid was dried to provide the title comopund. The crystalline form of the title compound was determined by X-ray powder powder diffraction (XRPD) analysis.

[0177] According to Karl-Fischer titration analysis, the title compound had a water content of 9.2%. According to high-pressure liquid chromatography (HPLC) and ion chromatography analysis, the title compound had a mole ratio of HC1 to MCOPPB of 2.99 to 1.4733863801 399251-CNX-035WO (208837)EXAMPLE 4 - Preparation of Amorphous MCOPPB Trihydrochloride Hydrate

[0178] An aliquot of MCOPPB trihydrochloride trihydrate crystal Form B (1.3 g) having a moderate degree of crystallinity was weighed into an 40-mL glass vial. Water (30 mL) was added into the vial at 25 °C with ultrasound to obtain a clear solution. Then, the solution was filtered with a 0.45 pm syringe membrane filter. Then, the filtrate was transferred to a 500-mL glass bottle and frozen in a dry ice / ethanol bath for 2 hours. Next, the sample was lyophilized at -90 °C and 0.1 Pa for 20 hours to afford the title compound as a yellow solid in 84% yield (1.1 g).

[0179] In the title compound prepared according to the procedure outlined above, the mole ratio of HC1 to MCOPPB was determined to be 3.0: 1 by HPLC and ion chromatography.Figure 7 depicts an X-ray powder diffractogram of this amorphous form. Figure 8 depicts a thermogravimetric analysis curve of this amorphous form; the thermogravimetric analysis shows a weight loss of 15.9% at 150 °C corresponding to loss of water. The HPLC, ion chromatography, XRPD, and thermogravimetric analysis were obtained according to the methods described in Example 2.EXAMPLE 5 — Preparation of MCOPPB Trihydrochloride Hydrate Crystal Form A

[0180] An aliquot of amorphous MCOPPB trihydrochloride hydrate was slurried in a mixture of ethanol and ethyl acetate at 25 °C. Then, the resulting solid was collected to provide the title compound.

[0181] Figure 4 depicts an X-ray powder diffractogram taken on the title compound.Tabulated characteristics of the X-ray powder diffractogram in FIG. 4 are provided in the following table, which lists diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):X-RAY POWDER DIFFRACTOGRAM DATAAngle [2θ] d-spacing [Å] Relative Intensity [%]8.0 11.0 348.9 9.9 1009.2 9.6 1114.6 6.1 64833863801 399251-CNX-035WO (208837)Angle

[0029] d-spacing [A] Relative Intensity [%]15.3 5.8 4016.0 5.5 1317.9 5.0 1720.1 4.4 3120.6 4.3 1521.2 4.2 1622.0 4.0 2523.1 3.8 1523.7 3.7 724.9 3.6 1325.8 3.5 3326.5 3.4 1026.5 3.4 1326.9 3.3 1327.4 3.3 2128.9 3.1 829.6 3.0 1730.9 2.9 833.9 2.6 5

[0182] Figure 5 depicts a differential scanning calorimetry curve take on the title compound.

[0183] Figure 6 depicts a thermo gravimetric analysis curve take on the title compound; where a 8.6% weight loss is observed at about 140 °C. Proton nuclear magnetic resonance spectroscopy (1H NMR) of a sample of the title compound showed no residual solvent above the limit of detection.

[0184] The HPLC, ion chromatography, X-ray powder diffractogram, differential scanning calorimetry curve, thermogravimetric analysis curve, and 'H NMR were obtained according to the methods described in Example 2. Based in part on results of thermogravimetric analysis, the title compound is understood to be a monohydrate.

[0185] The mole ratio of HC1 to MCOPPB in the title compound was determined to be 2.93: 1 by HPLC and ion chromatography.4933863801 399251-CNX-035WO (208837)

[0186] Upon storage of the title crystalline compound at ambient conditions (20-25 °C, 31-74% RH) for 5 months, the title crystalline compound was found to convert completely to MCOPPB trihydrochloride trihydrate crystal Form B.EXAMPLE 6 - Hygroscopicity Determination by Dynamic Vapor Sorption

[0187] MCOPPB trihydrochloride trihydrate crystal Form B (prepared as described in Example 2) and crystalline MCOPPB L-tartrate hemihydrate (prepared as described in Example 10) were analyzed for hygroscopicity by dynamic vapor sorption. Dynamic vapor sorption was performed using an Advantage. The sample (10-15 mg) was loaded into a sample pan and exposed to a humidified stream of gas. The total gas flow was 200sccm, and the oven temperature was 25 °C. The program used was:• Cycle: 40-95-0-95-40% Relative Humidity (RH)• Stage Step: 10%• Equilibrium: 0.002 dm dt (% / min.)• Minimum equilibration time: 60 min.• Maximum equilibration time: 360 min.

[0188] For MCOPPB trihydrochloride trihydrate crystal Form B, the analysis for hygroscopicity by dynamic vapor sorption determined an about 0.8% water absorption at 95% RH. Additionally, the obtained sample was still crystalline Form B (by XRPD analysis) and there was no change in the ratio of MCOPPB to HCL

[0189] For the crystalline MCOPPB L-tartrate hemihydrate, the analysis for hygroscopicity by dynamic vapor sorption determined an about 17.76% water absorption between 40% RH and 80% RH. Additionally, the sample obtained after subjection to the dynamic vapor sorption procedure was found to have a new crystalline form by XRPD analysis.EXAMPLE 7 - Analysis of Aqueous Solubility

[0190] Test compounds in an amount equivalent to 4.0 mg of MCOPPB free base were weighed into 4-mL glass vials, and 2 mL of water was added. The resulting mixtures were stirred at 400 rpm and 37 °C for 2 hours and 24 hours. The mixtures were centrifuged through a filter membrane, and then solubility was determined by HPLC. The test compounds, and their solubilities at both 2 hours and 24 hours were:5033863801 399251-CNX-035WO (208837)MCOPPB trihydrochloride trihydrate crystal Form B, >2.0 mg / mLMCOPPB Free Base, less than the limit of quantification, andCrystalline MCOPPB L-Tartrate Hemihydrate, >2.0 mg / mL.EXAMPLE 8 - Stability Analysis

[0191] Stability studies were conducted on MCOPPB trihydrochloride trihydrate crystal Form B (prepared as described in Example 2) and crystalline MCOPPB L-tartrate hemihydrate (prepared as described herein below). Samples were stored for one week under one of the following conditions:• 25 °C and 92.5% RH in an open container,• 40 °C and 75% RH in an open container, or• 60 °C in a tightly scaled container.

[0192] For MCOPPB trihydrochloride trihydrate crystal Form B, no change in purity was observed for all three samples by HPLC, color, and XRPD. The mole ratio of MCOPPB to HC1 in MCOPPB trihydrochloride trihydrate crystal Form B (which was 1: 3.0 in the material at the beginning of this stability analysis) was determined to be 1: 2.97, 1: 3.0, and 1: 2.87, in the three stability study samples, respectively.

[0193] For crystalline MCOPPB L-tartrate hemihydrate stored at 25 °C and 92.5% RH in an open container, the material analyzed at the end of storage was found to have a purity of 99.4% by HPLC; however, a different crystalline form was observed in the material according to XRPD analysis, and the material had a light yellow color at the end of the storage duration.

[0194] For crystalline MCOPPB L-tartrate hemihydrate stored at 40 °C and 75% RH in an open container, the material analyzed at the end of storage was found to have a purity of 99.6% by HPLC; however, the material had converted to an amorphous form according to XRPD analysis, and the material had a light yellow color at the end of the storage duration.

[0195] For crystalline MCOPPB L-tartrate hemihydrate stored at 60 °C in a tightly sealed container, the material analyzed at the end of storage was found to be unchanged by HPLC, XRPD, and inspection of color.5133863801 399251-CNX-035WO (208837)EXAMPLE 9 - Preparation of Amorphous MCOPPB Free Base

[0196] An aliquot of amorphorous MCOPPB trihydrochloride (51 mg) was weighed into an 4-mL glass vial. Then, water (1 mL) was added into the vial at 25 °C with stirring to obtain a clear solution. Next, sodium hydroxide (13.6 mg, 3.1 equiv.) was dissolved in 1.5 mL water, and the resulting solution was added over ~1 minute to the solution of MCOPPB trihydrochloride. The resulting mixture became a suspension. After stirring the suspension at 25 °C for 1 hour, solids from the suspension were collected by centrifugation filtration at 14,000 rpm through a 0.45 μm filter to afford free-base MCOPPB in amorphous form, as determined by XRPD. No chloride was detected by ion chromatography. XRPD and ion chromatography were conducted according to the methods described in Example 2.EXAMPLE 10 - Preparation of Crystalline MCOPPB L-Tartrate Hemihydrate

[0197] An aliquot of amorphorous MCOPPB free base (~50 mg) and L-tartaric acid (2 equiv.) were added into butan-2-one in a 2-mL glass vial. The resulting mixture was stirred at 50 °C for 2 hours, then at 25 °C for at least 48 hours. Then, the resulting suspension was filtered through filter paper, and the collected solids were dried at 50 °C under vacuum for 2 hours to afford crystalline MCOPPB L-tartrate hemihydrate as a white solid.

[0198] The mole ratio of L-tartaric acid to MCOPPB in the title compound was determined to be 1: 1 by *H NMR, which also showed no residual solvent above the limit of detection. Karl Fischer titration of the title compound determined a water content of 1.25% (w / w), corresponding to 0.39 molar equivalents relative to MCOPPB L-tartrate. The material had a purity of 99.62% by HPLC. Figure 10 depicts an X-ray powder diffractogram of this crystalline salt. The NMR, HPLC, and XRPD were obtained according to the methods described in Example 2.5233863801 399251-CNX-035WO (208837)INCORPORATION BY REFERENCE

[0199] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.EQUIVALENTS

[0200] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.5333863801 399251-CNX-035WO (208837)

Claims

Claims:

1. A compound in crystalline form represented by Formula I:wherein x is 2.7 to 3.3, and y is 2.7 to 3.3.

2. The compound of claim 1, wherein x is 2.8 to 3.2.

3. The compound of claim 1, wherein x is 2.84 to 3.16.

4. The compound of claim 1, wherein x is 2.9 to 3.1.

5. The compound of claim 1, wherein x is 3.0.

6. The compound of any one of claims 1-5, wherein y is 2.8 to 3.2.

7. The compound of any one of claims 1-5, wherein y is 2.9 to 3.1.

8. The compound of any one of claims 1-4, wherein y is 3.0.

9. The compound of claim 1, wherein x is 3.0, and y is 3.0.

10. The compound of any one of claims 1-9, wherein the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 7.5 ± 0.2, 12.8 ± 0.2, 17.5 ± 0.2, 20.8 ± 0.2, 22.7 ± 0.2, 23.7 ± 0.2, and 28.6 ± 0.2.

11. The compound of claim 10, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 11.4 ± 0.2.

12. The compound of claim 10 or 11, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 19.4 ± 0.2.

13. The compound of any one of claims 10-12, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 22.0 ± 0.2.5433863801 399251-CNX-035WO (208837)14. The compound of any one of claims 10-13, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 22.1 ± 0.2.

15. The compound of any one of claims 10-14, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 25.7 ± 0.2.

16. The compound of any one of claims 10-15, wherein the X-ray powder diffraction pattern further comprises a peak at the following diffraction angle (20): 27.1 ± 0.2.

17. The compound of any one of claims 10-16, wherein the relative intensity of the peak at said diffraction angles (20) is at least 30%.

18. The compound of any one of claims 10-16 wherein the relative intensity of the peak at said diffraction angles (20) is at least 20%.

19. The compound of any one of claims 1-9 characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):Angle [2θ] d-spacing [Å] Relative Intensity [%]7.5 11.7 5710.6 8.3 1611.4 7.8 3612.8 6.9 5414.4 6.2 2715.0 5.9 1917.5 5.1 5717.7 5.0 3719.4 4.6 4320.8 4.3 10022.0 4.0 4622.1 4.0 4922.5 3.9 2122.7 3.9 5823.7 3.7 4823.9 3.7 2224.1 3.7 1525.7 3.5 485533863801 399251-CNX-035WO (208837)Angle [29] d-spacing [A] Relative Intensity [%]26.7 3.3 1727.1 3.3 3528.6 3.1 5030.1 3.0 2730.9 2.9 1631.0 2.9 1631.4 2.8 3033.1 2.7 2134.9 2.6 1620. The compound of any one of claims 1-9 characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):Angle [2θ] d-spacing [Å] Relative Intensity [%]7.5 11.7 578.6 10.3 610.6 8.3 1611.4 7.8 3612.8 6.9 5414.4 6.2 2715.0 5.9 1917.1 5.2 1017.5 5.1 5717.7 5.0 3718.4 4.8 719.0 4.7 1319.4 4.6 4319.7 4.5 519.9 4.5 620.8 4.3 10021.1 4.2 622.0 4.0 4622.1 4.0 4922.5 3.9 215633863801 399251-CNX-035WO (208837)Angle [29] d-spacing [A] Relative Intensity [%]22.7 3.9 5823.7 3.7 4823.9 3.7 2224.1 3.7 1524.8 3.6 1125.7 3.5 4826.5 3.4 526.7 3.3 1727.1 3.3 3527.3 3.3 827.7 3.2 1328.4 3.1 528.6 3.1 5028.9 3.1 1329.2 3.1 829.5 3.0 1230.1 3.0 2730.9 2.9 1631.0 2.9 1631.4 2.8 3031.9 2.8 1132.3 2.8 1133.1 2.7 2133.6 2.7 733.8 2.6 633.9 2.6 634.9 2.6 1635.8 2.5 736.1 2.5 636.2 2.5 937.4 2.4 937.7 2.4 638.5 2.3 739.0 2.3 539.7 2.3 65733863801 399251-CNX-035WO (208837)21. The compound of any one of claims 1-9, wherein the compound has an X-ray powder diffraction pattern substantially as shown in FIG. 1.

22. The compound of any one of claims 1-21, wherein the compound has a dehydration onset as determined by differential scanning calorimetry in the range of from about 85 degrees Celsius to about 105 degrees Celsius.

23. The compound of any one of claims 1-21, wherein the compound has a dehydration onset as determined by differential scanning calorimetry at about 95 degrees Celsius.

24. The compound of any one of claims 1-23, wherein the compound has a dehydration onset as determined by differential scanning calorimetry in the range of from about 130 degrees Celsius to about 150 degrees Celsius.

25. The compound of any one of claims 1-23, wherein the compound has a dehydration onset as determined by differential scanning calorimetry at about 141 degrees Celsius.

26. The compound of any one of claims 1-25, wherein the compound has a melting point onset as determined by differential scanning calorimetry in the range of from about 220 degrees Celsius to about 240 degrees Celsius.

27. The compound of any one of claims 1-25, wherein the compound has a melting point onset as determined by differential scanning calorimetry at about 228 degrees Celsius.

28. The compound of any one of claims 1-21, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 2.

29. Crystalline l-[l-(l-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-lH- benzimidazole trihydrochloride hydrate.

30. The compound of claim 29, wherein the compound exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (20): 8.0 ± 0.2, 8.9 ± 0.2, 15.3 ± 0.2, 20.2 ± 0.2, 22.0 ± 0.2, 25.8 ± 0.2, and 27.4 ± 0.2.

31. The compound of claim 30, wherein the X-ray powder diffraction pattern further comprises a peak at one or more of the following diffraction angles (20): 17.9 ± 0.2, 20.6 ± 0.2, 21.2 ± 0.2, 23.1 ± 0.2, and 29.6 ± 0.2.5833863801 399251-CNX-035WO (208837)32. The compound of claim 30, wherein the X-ray powder diffraction pattern further comprises a peak at each of the following diffraction angles (20): 17.9 ± 0.2, 20.6 ± 0.2, 21.2 ± 0.2, 23.1 ± 0.2, and 29.6 ± 0.2.

33. The compound of any one of claims 30-32, wherein the relative intensity of the peak at said diffraction angles (20) is at least 15%.

34. The compound of claim 29 characterized by the following X-ray powder diffraction pattern expressed in terms of diffraction angle 20, inter-planar distances d, and relative intensity (expressed as a percentage with respect to the most intense peak):Angle [2θ] d-spacing [Å] Relative Intensity [%]8.0 11.0 348.9 9.9 1009.2 9.6 1114.6 6.1 615.3 5.8 4016.0 5.5 1317.9 5.0 1720.1 4.4 3120.6 4.3 1521.2 4.2 1622.0 4.0 2523.1 3.8 1523.7 3.7 724.9 3.6 1325.8 3.5 3326.5 3.4 1026.5 3.4 1326.9 3.3 1327.4 3.3 2128.9 3.1 829.6 3.0 1730.9 2.9 833.9 2.6 55933863801 399251-CNX-035WO (208837)35. The compound of claim 29, wherein the compound has an X-ray powder diffraction pattern substantially as shown in FIG. 4.

36. The compound of any one of claims 29-35, wherein the compound has a dehydration onset as determined by differential scanning calorimetry in the range of from about 0 degrees Celsius to about 10 degrees Celsius.

37. The compound of any one of claims 29-35, wherein the compound has a dehydration onset as determined by differential scanning calorimetry in the range of from about 0 degrees Celsius to about 10 degrees Celsius.

38. The compound of any one of claims 29-35, wherein the compound has a dehydration onset as determined by differential scanning calorimetry at about 4 degrees Celsius.

39. The compound of any one of claims 29-35, wherein the compound has a differential scanning calorimetry curve substantially the same as shown in FIG. 5.

40. The compound of any one of claims 29-39, wherein the compound is a monohydrate.

41. The compound of any one of claims 1-40, wherein the compound has a purity of greater than 99% by weight.

42. The compound of any one of claims 1-40, wherein the compound has a purity of greater than 99.5% by weight.

43. The compound of any one of claims 1-40, wherein the compound has a purity of greater than 99.8% by weight.

44. The compound of any one of claims 1-43, wherein the compound absorbs less than 1% (w / w) water upon storage for 1 day at a temperature of 40 °C and a relative humidity of 75%.

45. The compound of any one of claims 1-43, wherein the compound absorbs less than 1% (w / w) water upon storage for 1 week at a temperature of 40 °C and a relative humidity of 75%.

46. The compound of any one of claims 1-45, wherein the compound absorbs less than 1% (w / w) water upon storage for 1 day at a temperature of 25 °C and a relative humidity of 92.5%.

47. The compound of any one of claims 1-45, wherein the compound absorbs less than 1% (w / w) water upon storage for 1 week at a temperature of 25 °C and a relative humidity of 92.5%.6033863801 399251-CNX-035WO (208837)48. The compound of any one of claims 1-45, wherein less than 0.5% (w / w) of the compound degrades upon storage for 1 week at a temperature of 40 °C and a relative humidity of 75%.

49. The compound of any one of claims 1-45, wherein less than 0.5% (w / w) of the compound degrades upon storage for 1 month at a temperature of 40 °C and a relative humidity of 75%.

50. The compound of any one of claims 1-45, wherein less than 0.5% (w / w) of the compound degrades upon storage for 1 week at a temperature of 25 °C and a relative humidity of 92.5%.

51. The compound of any one of claims 1-45, wherein less than 0.5% (w / w) of the compound degrades upon storage for 1 month at a temperature of 25 °C and a relative humidity of 92.5%.

52. The compound of any one of claims 1-45, wherein less than 1% (w / w) of the compound degrades upon storage for 2 months at a temperature of 40 °C and a relative humidity of 75%.

53. A method of making a crystalline compound of any one of claims 10-21, comprising the steps of:(a) admixing water, a Ci-4 aliphatic alcohol, and a compound comprising ( )-l-(l-(l- mcthy Icyclooctyl )pipcridin-4-yl )-2-fpipcridin-3-yl )- 1 / / -bcnzo[<7] imidazole) trihydrochloride, to form a first mixture;(b) reducing the temperature of said first mixture to provide a second mixture; and(c) isolating said crystalline compound of any one of claims 10-21 from the second mixture.

54. The method of claim 53, wherein step (a) comprises admixing water, a C aliphatic alcohol, and a compound comprising ( / ?)-! -(1 -( l-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl )- I / / -bcnzo| / ]imidazolc) trihydrochloride hydrate, to form a first mixture.

55. The method of claim 53 or 54, wherein the C aliphatic alcohol is isopropanol.

56. The method of any one of claims 53-55, wherein the first mixture has a temperature in the range of from about 55 °C to about 65 °C.

57. The method of any one of claims 53-56, wherein the second mixture has a temperature in the range of from about -5 °C to about 5 °C.6133863801 399251-CNX-035WO (208837)58. A pharmaceutical composition comprising a compound of any one of claims 1-52 and a pharmaceutically acceptable carrier.

59. A liquid aqueous pharmaceutical composition formed by dissolving a compound of any one of claims 1 -52 in a liquid aqeous pharmaceutically acceptable carrier.

60. A liquid aqueous pharmaceutical composition formed by dissolving a compound of claim 10 and in a liquid aqeous pharmaceutically acceptable carrier.

61. A liquid aqueous pharmaceutical composition formed by dissolving a compound of claim 19 and in a liquid aqeous pharmaceutically acceptable carrier.

62. The pharmaceutical composition of any one of claims 58-61, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier for intrathecal administration.

63. A method of preparing a pharmaceutical composition, comprising admixing a compound of any one of claims 1-52 and a pharmaceutically acceptable carrier.

64. A method of preparing a liquid aqueous pharmaceutical composition, comprising admixing a compound of any one of claims 1-52 and an aqueous pharmaceutically acceptable carrier.

65. A method of preparing a liquid aqueous pharmaceutical composition, comprising admixing a compound of claim 10 and a aqueous pharmaceutically acceptable carrier.

66. A method of preparing a liquid aqueous pharmaceutical composition, comprising admixing a compound of claim 19 and a aqueous pharmaceutically acceptable carrier.

67. The method of any one of claims 63-66, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier for intrathecal administration.

68. A method for treating a disease or condition mediated by the nociceptin / orphanin FQ receptor (NOP receptor), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-52 or a pharmaceutical composition of any one of claims 58-62, to treat the disease or condition.

69. The method of claim 68, wherein the disease or condition mediated by the NOP receptor is pain.

70. The method of claim 69, wherein the pain is acute pain.6233863801 399251-CNX-035WO (208837)71. The method of claim 69, wherein the pain is chronic pain.

72. The method of any one of claims 69-71, wherein the pain is due to surgery.

73. The method of any one of claims 69-71, wherein the pain is trauma pain.

74. The method of any one of claims 69-73, wherein the pain is neuropathic pain.

75. The method of any one of claims 69-73, wherein the pain is inflammatory pain.

76. The method of any one of claims 69-71, wherein the pain is arthritis pain.

77. The method of any one of claims 69-71, wherein the pain is arthritis pain selected from osteoarthritis pain and rheumatoid arthritis pain.

78. The method of any one of claims 69-71, wherein the pain is complex regional pain syndrome.

79. The method of claim 78, wherein the complex regional pain syndrome is reflex sympathetic dystrophy pain.

80. The method of any one of claims 69-71, wherein the pain is due to cancer.

81. The method of any one of claims 69-71, wherein the pain is due to a cancer selected from the group consisting of a solid tumor, leukemia, and lymphoma.

82. The method of any one of claims 69-71, wherein the pain is due to a cancer selected from the group consisting of a bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomach cancer, testicular cancer, and uterine cancer.

83. The method of any one of claims 69-71, wherein the pain is due to sickle cell disease.

84. The method of any one of claims 69-83, wherein the pain is located in the patient’s hand, wrist, arm, shoulder, back, leg, knee, ankle, foot, or toe.

85. The method of any one of claims 69-71, wherein the pain is low back pain.

86. The method of any one of claims 69-71, wherein the pain is chronic low back pain.

87. The method of any one of claims 69-71, wherein the pain is a neuropathic pain selected from the group consisting of low back pain, hip pain, leg pain, non-herpetic neuralgia, post- 6333863801 399251-CNX-035WO (208837)herpetic neuralgia, diabetic neuropathy pain, lumbosacral radiculopathy pain, nerve injury- induced pain, acquired immune deficiency syndrome (AIDS) related neuropathic pain, head trauma pain, phantom limb pain, multiple sclerosis pain, root avulsion pain, painful traumatic mononeuropathy, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury pain, post-surgical pain, carpal tunnel syndrome pain, trigeminal neuralgia pain, post mastectomy syndrome pain, post-thoracotomy syndrome pain, stump pain, repetitive motion pain, neuropathic pain associated hyperalgesia and allodynia, drug- induced pain, toxin-caused nerve injury pain, chemotherapy-caused nerve injury pain, and combinations thereof.

88. The method of any one of claims 69-87, wherein the method is characterized by achieving at least a 40% reduction in pain intensity relative to pain observed without administering said compound.

89. The method of any one of claims 69-87, wherein the method is characterized by achieving at least a 60% reduction in pain intensity relative to pain observed without administering said compound.

90. The method of any one of claims 69-87, wherein the method is characterized by achieving at least an 80% reduction in pain intensity relative to pain observed without administering said compound.

91. The method of any one of claims 68-90, wherein the method comprises administering a compound of any one of claims 1-52.

92. The method of any one of claims 68-91, wherein the compound is administered intrathecally.

93. The method of any one of claims 68-92, wherein the administering delivers a daily dose of MCOPPB in the range of about 0.01 pg to 50 pg.

94. The method of any one of claims 68-93, wherein the subject is a human.

95. The method of any one of claims 68-93, wherein the subject is an adult human.

96. A method of agonizing the nociccp tin / orphanin FQ receptor (NOP receptor), comprising contacting an NOP receptor with an effective amount of a compound of any one of claims 1- 52 or a pharmaceutical composition of any one of claims 58-62 to agonize the NOP receptor.6433863801 399251-CNX-035WO (208837)

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