(12) United States Patent (10) Patent No.: US 9,139,517 B2 Raillard Et Al

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(12) United States Patent (10) Patent No.: US 9,139,517 B2 Raillard et al. (45) Date of Patent: Sep. 22, 2015

(54) ANHYDROUSAND HEMIHYDRATE WO WO 2008/086492 A1 T 2008 CRYSTALLINE FORMS OF AN WO 2009,096.985 8, 2009 (R)-BACLOFEN PRODRUG, METHODS OF WO WO 2009,096.985 A1 8/2009 SYNTHESIS AND METHODS OF USE OTHER PUBLICATIONS (71) Applicant: XenoPort, Inc., Santa Clara, CA (US) Caira, “Crystalline Polymorphism of Organic Compounds.” Topics (72) Inventors: Stephen P. Raillard, Mountain View, in Current Chemistry, vol. 198, 1998, pp. 163-208. CA (US): Suresh K. Manthati, Lal et al., “Arbaclofen Placarbil, A Novel R-Baclofen Prodrug: Sunnyvale, CA (US); Sudhir Joshi, Visp Improved Absorption, Distribution, Metabolism, and Elimination (CH) Properties Compared with R-Baclofen.” The Journal of Pharmacol ogy and Experimental Therapeutics, The American Society for Phar (73) Assignee: XenoPort, Inc., Santa Clara, CA (US) macology and Experimental Therapeutics, vol. 330, No. 3, Sep. 1, (*) Notice: Subject to any disclaimer, the term of this 2009, pp. 911-921. patent is extended or adjusted under 35 Addolorato et al., “Baclofen efficacy in reducing alcohol craving and U.S.C. 154(b) by 0 days. intake: a preliminary double-blind randomized controlled study.” Alcohol & Alcoholism (2002)37(5):504-508. (21) Appl. No.: 14/076,406 Ahmadi-Abhari et al., “Baclofen versus clonidine in the treatment of (22) Filed: Nov. 11, 2013 opiates withdrawal, side-effects aspect: a double-blind randomized controlled trial.”J Clin Pharm Ther: (2001) 26:67-71. (65) Prior Publication Data Aley et al., “Vincristine hyperalgesia in the rat: a model of painful US 2014/OO665O1 A1 Mar. 6, 2014 vincristine neuropathy in humans.” Neurosci. (1996), 73(1): 259 265. Related U.S. Application Data Anghinah et al., “Effect of baclofen on pain in diabetic neuropathy.” Muscle & Nerve (1994) 17(8):958-9. (63) Continuation of application No. 13/572.367, filed on Argoff, “Pharmacologic management of chronic pain.” JAOA Supp. 3 Aug. 10, 2012, now Pat. No. 8,580,850. (2002), 102(9): S21-S26. (60) Provisional application No. 61/508,286, filed on Aug. ASSadi et al., “Baclofen for maintenance treatment of opioid depen 11, 2011. dence: a randomized double-blind placebo-controlled clinical trial.” BMC Psychiatry (2003), 3(16) (10 pages). (51) Int. C. Authier et al., “Assessment of allodynia and hyperalgesia after C07C 27L/22 (2006.01) cisplatin administration to rats.” Neurosci. Lett. (2000), 291: 73-76. U.S. C. Backonja et al., “Gabapentin dosing for neuropathic pain: evidence (52) from randomaized, placebo-controlled clinical trials.” Clin. Ther. CPC ...... C07C271/22 (2013.01); C07B 2.200/07 (2003), 25: 81-104. (2013.01); C07B 2.200/13 (2013.01) Balerio et al., “Baclofen analgesia: involvement of the GABAergic (58) Field of Classification Search system.” Pharm. Res. (2002) 46(3):281-286. USPC ...... 514/487; 560/30 Baron, “Mechanisms of disease: neuropathic pain—a clinical per See application file for complete search history. spective.” Nat. Clin. Pract. Neurol. (2006), 2(2): 95-106. Becker et al., “Intrathecal baclofen alleviates autonomic dysfunction (56) References Cited in severe brain injury.”J Clin. Neurosci. (2000) 7(4):316-319. Beggs et al., “Neuropathic pain: Symptoms, models and mecha U.S. PATENT DOCUMENTS nisms,” Drug Dev. Res. (2006), 67: 289-301. 4,126,684 A 11, 1978 Robson et al. Bennett et al., “A peripheral mononeuropathy in rat that produces 5,006,560 A 4, 1991 Kreutner et al. disorders of pain sensation like those seen in man.” Pain (1988), 33: 5,719, 185 A 2f1998 Bountra et al. 87-107. 6,117,908 A 9, 2000 Andrews et al. Blackshaw et al., “Inhibition of transient LES relaxations and reflux 7,109,239 B2 9/2006 Gallop et al. in ferrets by GABA receptor agonists.” Am. J. Physiol. (1999), 277: 7,227,028 B2 6/2007 Gallop et al. G867-G874. 2002/0151529 A1 10/2002 Cundy et al. 2003. O133951 A1 7/2003 Coe et al. (Continued) 2003/0171303 A1 9/2003 Gallop et al. 2003/0176398 A1 9/2003 Gallop et al. 2004.0006132 A1 1/2004 Gallop et al. Primary Examiner — San-Ming Hui 2004, OO1494.0 A1 1/2004 Raillard et al. Assistant Examiner — Kathrien Cruz 2004/O138305 A1 7/2004 Dooley et al. 2004/O180959 A1 9/2004 Dooley et al. (74) Attorney, Agent, or Firm — Polsinelli PC 2007/0O32500 A1 2/2007 Sun et al. 2007/0O82939 A1 4/2007 Lippa et al. (57) ABSTRACT Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy FOREIGN PATENT DOCUMENTS loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic EP 1178O34 2, 2002 acid anhydrate and crystalline (3R)-4-(1S)-2-methyl-1-(2- WO 91.0874O 6, 1991 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo WO O1,08675 2, 2001 rophenyl)butanoic acid hemihydrate, pharmaceutical compo WO O1,26638 4/2001 WO O1,900.52 11, 2001 sitions comprising Such compounds, methods of making and WO 02/0964.04 12/2002 methods of using the same are disclosed. WO 2005/019 163 3, 2005 WO 2008/086492 T 2008 16 Claims, 4 Drawing Sheets US 9,139,517 B2 Page 2

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(56) References Cited Zuniga et al., “Intrathecal baclofen: a useful agent in the treatment of well-established complex regional pain syndrome.” Reg Anesth Pain OTHER PUBLICATIONS Med (2002) 27:90-93. ZhangetaL. “Control of transient lower oesophageal sphincter relax ations and reflux by the GABA agonist baclofen in patients with PCT International Search Report and Written Opinion dated Nov. 19. gastro-oesophageal reflux disease.” Gut (2002) 50:19-24. 2012, PCT Appl. No. PCT/US2012/050379, 12 pages. U.S. Patent Sep. 22, 2015 Sheet 1 of 4 US 9,139,517 B2

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yopopo proports s RE: SSX EX xs &: EY: -8 arra s & Ks & Es k US 9,139,517 B2 1. 2 ANHYDROUSAND HEMIHYDRATE tent of the active component of a drug in Solid dosage forms. CRYSTALLINE FORMS OF AN In general, regulatory agencies require batch-by-batch moni (R)-BACLOFEN PRODRUG, METHODS OF toring for polymorphic drugs if anything other than the pure, SYNTHESIS AND METHODS OF USE thermodynamically preferred polymorph is marketed. Accordingly, medical and commercial reasons favor synthe This application is a continuation of U.S. patent applica sizing and marketing the most thermodynamically stable tion Ser. No. 13/572,367, filed Aug 10, 2012 (now U.S. Pat. polymorph of a crystalline drug Substance in Solid drugs, No. 8,580,850), which claims the benefit under 35 U.S.C. which is substantially free of other, less favored polymorphs. S119(e), of U.S. Provisional Patent Application No. 61/508, (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 286 filed Aug. 11, 2011, the contents of which are incorpo 10 poxycarbonylamino-3-(4-chlorophenyl)butanoic acid, (1), rated herein by reference in their entirety.

FIELD (1) Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 15 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu Y1 O tanoic acid anhydrate and crystalline (3R)-4-(1S)-2-me l OH thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- (4-chlorophenyl)butanoic acid hemihydrate, pharmaceutical 1No r compositions comprising Such compounds, methods of mak O ing Such compounds and methods of using Such compounds are disclosed.

BACKGROUND 25 In general, crystalline forms of drugs are utilized in dosage forms rather than amorphous forms of drugs, in part, because is a prodrug of the GABA agonist, (R)-baclofen. (3R)-4- of their Superior stability. For example, in many situations, an {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo amorphous drug converts to a crystalline drug form upon nylamino-3-(4-chlorophenyl)butanoic acid, (1) exhibits storage. Because amorphous and crystalline forms of a drug 30 high bioavailability as R-baclofen when dosed either orally or typically have different physical/chemical properties, poten directly into the colon of a mammal (see, for example, Gallop cies and/or bioavailabilities, such interconversion is undesir et al., U.S. Pat. Nos. 7,109,239 and 7,227,028). able for safety reasons in pharmaceutical administration. Polymorphs are crystals of the same molecule which have SUMMARY different physical properties because the crystal lattice con 35 tains a different arrangement of molecules. For example, Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro certain polymorphs can include different hydration states that panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu incorporate water into the crystalline structure without tanoic acid anhydrate and crystalline (3R)-4-(1S)-2-me chemical alteration of the molecule itself. In that regard, thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- certain compounds can exist in anhydrous and hydrated 40 (4-chlorophenyl)butanoic acid hemihydrate are disclosed. forms, where the hydrated forms can include, for example, In a first aspect, crystalline (3R)-4-(1S)-2-methyl-1-(2- hydrates, dihydrates, trihydrates, and the like, or partial methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo hydrates such as hemihydrates. The different physical prop rophenyl)butanoic acid hemihydrate, which exhibits charac erties exhibited by polymorphs can affect important pharma teristic scattering angles (20) at least at 4.04+0.2°, ceutical parameters such as storage, stability, compressibility, 45 6.47+0.2°, 15.68° 0.2°, 18.91+0.2° and 22.420.2° in an density (important in formulation and product manufactur X-ray powder diffractogram measured using Cu-K radia ing) and dissolution rates (important in determining bioavail tion, is provided. ability). Stability differences may result from changes in In a second aspect, pharmaceutical compositions are pro chemical reactivity (e.g., differential hydrolysis or oxidation, vided comprising crystalline (3R)-4-(1S)-2-methyl-1-(2- Such that a dosage form discolors more rapidly when the 50 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo dosage form contains one polymorph rather than another rophenyl)butanoic acid hemihydrate, which exhibits polymorph), mechanical changes (e.g., tablets crumble on characteristic scattering angles (20) at least at 4.04+0.2°, storage as a kinetically favored crystalline form converts to a 6.47+0.2°, 15.68° 0.2°, 18.91+0.2° and 22.420.2° in an thermodynamically more stable crystalline form) or both X-ray powder diffractogram measured using Cu-K radia (e.g., tablets of one polymorph are more Susceptible to break 55 tion and a pharmaceutically acceptable vehicle. down at high humidity). Solubility differences between poly In a third aspect, methods of preparing crystalline (3R)-4- morphs may, in extreme situations, result in transitions to {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo crystalline forms that lack potency and/or are toxic. In addi nylamino-3-(4-chlorophenyl)butanoic acid hemihydrate, tion, the physical properties of a particular crystalline form which exhibits characteristic scattering angles (20) at least at may be important in pharmaceutical processing. For 60 4.04+0.2°, 6.47+0.2°, 15.68° 0.2°, 18.91+0.2° and example, one particular crystalline form may form Solvates 22.42+0.2 in an X-ray powder diffractogram measured more readily or may be more difficult to filter and wash free of using Cu-K radiation are provided, by steps comprising impurities than other forms (e.g., particle shape and size providing a solution comprising 1-((2,5-dioxopyrrolidin-1- distribution might be different between one crystalline form yl-oxycarbonyloxy)-2-methylpropyl-2-methylpropanoate relative to other forms). 65 prepared as a racemic mixture, (R)-baclofen, water and a Regulatory agencies such as the United States Food and Solvent; and adjusting the temperature of the solution or Sus Drug Administration closely regulate the polymorphic con pension to provide crystalline (3R)-4-(1S)-2-methyl-1-(2- US 9,139,517 B2 3 4 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo In a tenth aspect, kits are provided comprising a pharma rophenyl)butanoic acid hemihydrate. ceutical composition comprising crystalline (3R)-4-(1S)- In a fourth aspect, methods of treating a disease or disorder 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony inapatient are provided comprising administering to a patient lamino-3-(4-chlorophenyl)butanoic acid anhydrate and in need of such treatment a therapeutically effective amount instructions for administering the pharmaceutical composi of a pharmaceutical composition comprising crystalline tion to a patient in need thereof for treating a disease or (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro disorder chosen from selected from spasticity, gastroesoph poxycarbonylamino-3-(4-chlorophenyl)butanoic acid ageal reflux disease, emesis, cough, Substance addiction and hemihydrate, wherein the disease or disorder is selected from abuse, neuropathic pain and musculoskeletal pain. spasticity, gastroesophageal reflux disease, emesis, cough, 10 Substance addiction and abuse, neuropathic pain and muscu BRIEF DESCRIPTION OF THE DRAWINGS loskeletal pain. FIG. 1 shows an X-ray powder diffractogram of crystalline In a fifth aspect, kits are provided comprising a pharma (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro ceutical composition comprising crystalline (3R)-4-(1S)- 15 poxycarbonylamino-3-(4-chlorophenyl)butanoic acid 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony hemihydrate. lamino-3-(4-chlorophenyl)butanoic acid hemihydrate and FIG. 2 shows a Raman spectrum of crystalline (3R)-4- instructions for administering the pharmaceutical composi {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo tion to a patient in need thereof for treating a disease or nylamino-3-(4-chlorophenyl)butanoic acid hemihydrate in disorder chosen from selected from spasticity, gastroesoph the region from 50 to 2000 cm. ageal reflux disease, emesis, cough, Substance addiction and FIG.3 shows an X-ray powder diffractogram of crystalline abuse, neuropathic pain and musculoskeletal pain. (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro In a sixth aspect, crystalline (3R)-4-(1S)-2-methyl-1-(2- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo anhydrate. rophenyl)butanoic acid anhydrate, which exhibits character 25 FIG. 4 shows a Raman spectrum of crystalline (3R)-4- istic scattering angles (20) at least at 4.33°+0.2°, 4.76°+0.2°, {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo 11.06°+0.2° and 11.61°0.2° in an X-ray powder diffracto nylamino-3-(4-chlorophenyl)butanoic acid anhydrate in the gram measured using Cu—K radiation, is provided. region from 50 to 2000 cm. In a seventh aspect, pharmaceutical compositions are pro vided comprising crystalline (3R)-4-(1S)-2-methyl-1-(2- 30 DETAILED DESCRIPTION methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo rophenyl)butanoic acid anhydrate, which exhibits Definitions characteristic scattering angles (20) at least at 4.33°+0.2°, 4.76°+0.2°, 11.06°+0.2° and 11.61°+0.2° in an X-ray powder “Bioavailability” refers to the amount of a drug that diffractogram measured using Cu-K radiation and a phar 35 reaches the systemic circulation of apatient following admin maceutically acceptable vehicle. istration of the drug or prodrug thereof to the patient and may In a eighth aspect, methods of preparing crystalline (3R)- be determined by evaluating, for example, the plasma or 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar blood concentration-versus-time profile for a drug. Param bonylamino-3-(4-chlorophenyl)butanoic acid anhydrate, eters useful in characterizing a plasma or blood concentra which exhibits characteristic scattering angles (20) at least at 40 tion-versus-time curve include the area under the curve 4.33° 0.2°, 4.76°0.2°, 11.06°+0.2° and 11.61°0.2° in an (AUC), the time to maximum concentration (T,), and the X-ray powder diffractogram measured using Cu-K radia maximum drug concentration (C), where C is the maxi tion are provided, by steps comprising providing a solution mum concentration of a drug in the plasma or blood of a comprising 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)- patient following administration of a dose of the drug or 2-methylpropyl-2-methylpropanoate prepared as a racemic 45 prodrug thereof to the patient, and T is the time to the mixture, (R)-baclofen, water and a solvent; adjusting the maximum concentration (C) of a drug in the plasma or temperature of the Solution or Suspension to provide crystal blood of a patient following administration of a dose of the line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro drug or prodrug thereof to the patient. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid "Crystalline” means having a regularly repeating arrange hemihydrate and (3R)-4-(1R)-2-methyl-1-(2-methylpro 50 ment of molecules. panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu “Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro tanoic acid; and converting crystalline (3R)-4-(1S)-2-me panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- tanoic acid anhydrate” refers to a compound in which crys (4-chlorophenyl)butanoic acid hemihydrate into crystalline talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 55 propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid poxycarbonylamino-3-(4-chlorophenyl)butanoic acid is not associated with water molecules. Other chemical names anhydrate by drying and/or by recrystallization. for crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro In a ninth aspect, methods of treating a disease or disorder panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu inapatient are provided comprising administering to a patient tanoic acid anhydrate include, without limitation, anhydrous in need of such treatment a therapeutically effective amount 60 crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy of a pharmaceutical composition comprising crystalline loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro acid. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid “Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro anhydrate, wherein the disease or disorder is selected from panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu spasticity, gastroesophageal reflux disease, emesis, cough, 65 tanoic acid hemihydrate” refers to a compound in which Substance addiction and abuse, neuropathic pain and muscu crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy loskeletal pain. loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic US 9,139,517 B2 5 6 acid is associated with water molecules, including fractional to a drug. For example, the (R)-baclofen prodrug (3R)-4- water molecules. For example, crystalline (3R)-4-(1S)-2- {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo methyl-1-(2-methylpropanoyloxy)propoxycarbony nylamino-3-(4-chlorophenyl)butanoic acid (1) is metabo lamino-3-(4-chlorophenyl)butanoic acid hemihydrate may lized within a patient’s body to form the parent drug (R)- contain less than one molar fraction of water, including frac baclofen. tional moles of water, per mole of crystalline (3R)-4-(1S)- “Promoiety' refers to a group bonded to a drug, typically to 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony a functional group of the drug, via one or more bonds that are lamino-3-(4-chlorophenyl)butanoic acid. In some cleavable under specified conditions of use. The bond(s) embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me between the drug and promoiety may be cleaved by enzy thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 10 matic or non-enzymatic means. Under the conditions of use, rophenyl)butanoic acid hemihydrate contains one-half of one for example following administration to a patient, the bond(s) molar fraction of waterper mole of crystalline (3R)-4-(1S)- between the drug and promoiety may be cleaved to release the 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony parent drug. The cleavage of the promoiety may proceed lamino-3-(4-chlorophenyl)butanoic acid. The molecules of spontaneously, Such as via a hydrolysis reaction, or may be water may be incorporated into the crystal lattice or loosely 15 catalyzed or induced by another agent, such as by an enzyme, bound to the crystal lattice. In certain embodiments, the frac by light, by acid, or by a change of or exposure to a physical tional equivalent of one-half molecule of water per molecule or environmental parameter, such as a change oftemperature, of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy pH, etc. The agent may be endogenous to the conditions of loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic use. Such as an enzyme present in the systemic circulation to acid is incorporated into the crystalline lattice and any addi which the prodrug is administered or the acidic conditions of tional water content is bound to the exterior of the crystalline the stomach, or the agent may be supplied exogenously. For lattice. example, the promoiety of (3R)-4-(1S)-2-methyl-1-(2-me “Disease' refers to a disease, disorder, condition, Symp thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo tom, or indication. This term is used interchangeably with the rophenyl)butanoic acid is: phrase “disease or disorder.” 25 “Dosage form” refers to a form of a formulation that con tains an amount of active agent or prodrug of an active agent, for example the (R)-baclofen prodrug (3R)-4-(1S)-2-me thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- (4-chlorophenyl)butanoic acid (1), which can be adminis 30 tered to a patient to achieve a therapeutic effect. An oral dosage form is intended to be administered to a patient via the mouth and Swallowed. Examples of oral dosage forms include capsules, tablets, and liquid Suspensions. A dose of a “Sustained release” refers to release of a therapeutic or drug may include one or more dosage forms administered 35 preventive amount of a drug or an active metabolite thereof simultaneously or over a period of time. over a period of time that is longer than that of an immediate “Patient' includes mammals, such as for example, humans. release formulation of the drug. For oral formulations, the “Pharmaceutical composition” refers to a composition term “Sustained release' typically means release of the drug comprising at least one compound provided by the present within the gastrointestinal tract lumen over a time period disclosure and at least one pharmaceutically acceptable 40 ranging, for example, from about 2 to about 30 hours, and in vehicle with which the compound is administered to a patient. certain embodiments, over a time period ranging from about “Pharmaceutically acceptable' refers to approved or 4 to about 24 hours. Sustained release formulations achieve approvable by a regulatory agency of a federal or a state therapeutically effective concentrations of the drug in the government, listed in the U.S. Pharmacopeia, or listed in systemic circulation over a prolonged period of time relative other generally recognized pharmacopeia for use in mam 45 to that achieved by oral administration of an immediate mals, including humans. release formulation of the drug. “Pharmaceutically acceptable vehicle' refers to a pharma “Therapeutically effective amount” refers to the amount of ceutically acceptable diluent, a pharmaceutically acceptable a compound that, when administered to a Subject for treating adjuvant, a pharmaceutically acceptable excipient, a pharma a disease or disorder, or at least one of the clinical symptoms ceutically acceptable carrier, or a combination of any of the 50 of a disease or disorder, is sufficient to affect such treatment of foregoing, with which crystalline (3R)-4-(1S)-2-methyl-1- the disease, disorder, or symptom. A “therapeutically effec (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- tive amount can vary depending, for example, on the com chlorophenyl)butanoic acid anhydrate and/or crystalline pound, the disease, disorder, and/or symptoms of the disease (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro or disorder, severity of the disease, disorder, and/or symptoms poxycarbonylamino-3-(4-chlorophenyl)butanoic acid 55 of the disease or disorder, the age, weight, and/or health of the hemihydrate can be administered to a patient, which does not patient to be treated, and the judgment of the prescribing destroy the pharmacological activity thereof, and which is physician. A therapeutically effective amount in any given nontoxic when administered in doses Sufficient to provide a instance can be readily ascertained by those skilled in the art therapeutically effective amount of one or both of the com and/or is capable of determination by routine experimenta pounds. 60 tion. “Prodrug” refers to a derivative of an active compound “Treating or “treatment of any disease or disorder refers (such as a drug) that undergoes a transformation under the to arresting or ameliorating a disease, disorder, or at least one conditions of use. Such as within the body, to release the active of the clinical symptoms of a disease or disorder, reducing the compound or drug. Prodrugs are frequently, but not necessar risk of acquiring a disease, disorder, or at least one of the ily, pharmacologically inactive until converted into the active 65 clinical symptoms of a disease or disorder, reducing the compound or drug. Prodrugs can be obtained by bonding a development of a disease, disorder or at least one of the promoiety (defined herein), typically via a functional group, clinical symptoms of the disease or disorder, or reducing the US 9,139,517 B2 7 8 risk of developing a disease or disorder or at least one of the Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro clinical symptoms of a disease or disorder. "Treating or panoyloxy)propoxycarbonylamino-3-(4-chlo “treatment also refers to inhibiting the disease or disorder, rophenyl)butanoic acid hemihydrate either physically, (e.g., stabilization of a discernible symp tom), physiologically, (e.g., stabilization of a physical param In certain embodiments, crystalline (3R)-4-(1S)-2-me eter), or both, and to inhibiting at least one physical parameter thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- which may or may not be discernible to the patient. In certain (4-chlorophenyl)butanoic acid exists as a hemihydrate. Crys embodiments, “treating or “treatment” refers to delaying the talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) onset of the disease or disorder or at least one or more symp propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid toms thereof in a patient which may be exposed to or predis 10 hemihydrate is a solid exhibiting a highly ordered crystalline posed to a disease or disorder even though that patient does lattice as evidenced by an extensive pattern of both low-angle not yet experience or display symptoms of the disease or and high-angle reflections within the X-ray powder diffrac disorder. tion (XRPD) diffractogram. Reference is now made in detail to certain embodiments of Reference to crystalline (3R)-4-(1S)-2-methyl-1-(2-me compounds, dosage forms, compositions, methods of synthe 15 thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo sis and methods of use. The disclosed embodiments are not rophenyl)butanoic acid hemihydrate includes all possible intended to be limiting of the claims. To the contrary, the tautomeric forms of the conventional chemical structure for claims are intended to cover all alternatives, modifications, this compound and all isotopically labeled derivatives of this and equivalents. compound (e.g., H, H, C, C, N, ''O, O, etc.). In certain embodiments, crystalline (3R)-4-(1S)-2-me Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- panoyloxy)propoxycarbonylamino-3-(4-chlo (4-chlorophenyl)butanoic acid hemihydrate exhibits charac rophenyl)butanoic acid teristic scattering angles (20) at least at 4.04+0.2°, (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 25 6.47+0.2°, 15.68° 0.2°, 18.91+0.2° and 22.420.2° in an poxycarbonylamino-3-(4-chlorophenyl)butanoic acid (1) X-ray powder diffractogram measured using Cu-K radia has the following structure: tion. In certain embodiments, crystalline (3R)-4-(1S)-2-me thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 30 (1) (4-chlorophenyl)butanoic acid hemihydrate exhibits charac teristic scattering angles (20) at least at 4.04+0.2°, 6.47+0.2°, 9.46°-0.2°, 10.10°-0.2°, 10.87° 0.2°, o1 No 12.88° 0.2°, 15.68°+0.2°, 18.91+0.2°, 19.96° 0.2°, 1. 35 20.23° 0.2°, 22.42°+0.2°, 28.07+0.2° and 28.53° 0.2° in an O X-ray powder diffractogram measured using Cu-K radia tion. In certain embodiments, crystalline (3R)-4-(1S)-2-me thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 40 (4-chlorophenyl)butanoic acid hemihydrate exhibits charac C teristic scattering angles (20) at least at 4.04+0.2°, 6.47+0.2°, 7.97+0.2°, 9.46°-0.2°, 10.10°-0.2°, The synthesis of (3R)-4-(1S)-2-methyl-1-(2-methylpro 10.87°0.2°, 12.889-0.2°, 15.68°+0.2°, 16.72°0.2°, panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu 18.16°0.2°, 18.919-0.2°, 19.33° 0.2°, 19.96° 0.2°, tanoic acid has been previously described in Gallop et al., 45 20.23° 0.2°, 20.62°0.2°, 21.76°0.2°, 22.42°+0.2°, U.S. Pat. Nos. 7,109,239 and 7,227,028, and in Gallop et al., 23.550.2°, 24.02°0.2°, 25.13+0.2°, 25.619-0.2°, PCT Publication No. WO 2005/019163 (see, e.g., PCT Pub 26.09° 0.2°, 28.07+0.2°, 28.53° 0.2°, 29.87°0.2°, lication No. WO 2005/019163, Example 82). A crystalline 30.45°-0.2°, 30.74°0.2°, 31.52-0.2°, 32.60°-0.2°, form of (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) 35.94°+0.2° and 36.63+0.2° in an X-ray powder diffracto propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid 50 gram measured using Cu—K radiation. has also been previously described (see, e.g., PCT Publication In certain embodiments, crystalline (3R)-4-(1S)-2-me Nos. WO 2008/086492 and WO 2009/096985). It is believed thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- that the crystalline form disclosed in these publications is the (4-chlorophenyl)butanoic acid hemihydrate exhibits the char anhydrate polymorph of (3R)-4-(1S)-2-methyl-1-(2-meth acteristic scattering angles (20) in an X-ray powder ylpropanoyloxy)propoxycarbonylamino-3-(4-chlorophe 55 diffractogram measured using Cu-K radiation shown in nyl)butanoic acid. The X-ray powder diffractogram data of the FIG 1. anhydrate presented in this disclosure has not been previously In certain embodiments, crystalline (3R)-4-(1S)-2-me described. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- The inventors of the present disclosure have now discov (4-chlorophenyl)butanoic acid hemihydrate exhibits a strong ered that a hemihydrate form of crystalline (3R)-4-(1S)-2- 60 characteristic Raman spectrum band at 110 cm. methyl-1-(2-methylpropanoyloxy)propoxycarbony In certain embodiments, crystalline (3R)-4-(1S)-2-me lamino-3-(4-chlorophenyl)butanoic acid exists. The thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- hemihydrate polymorph is also disclosed herein. Thus, crys (4-chlorophenyl)butanoic acid hemihydrate exhibits charac talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) teristic Raman spectrum bands at least at 110 cm and 84 propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid 65 cm. can be prepared in more than one polymorphic crystalline In certain embodiments, crystalline (3R)-4-(1S)-2-me form. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- US 9,139,517 B2 9 10 (4-chlorophenyl)butanoic acid hemihydrate exhibits charac thermal decomposition at a temperature ranging from about teristic Raman spectrum bands at least at 779 cm, 110 cm 80° C. to about 130° C., and undergoes a second thermal and 84 cm. decompositionata temperature ranging from about 170° C. to In certain embodiments, crystalline (3R)-4-(1S)-2-me about 190° C., using a thermogravimetric analyzer (TG) thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- coupled with a Fourier-transform infrared (FTIR) spectrom (4-chlorophenyl)butanoic acid hemihydrate exhibits charac eterata scan rate of about 10 K/min. In certain embodiments, teristic Raman spectrum bands at least at 1744 cm, 1600 crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy cm, 1453 cm, 1290 cm, 1238 cm, 1201 cm, 954 loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic cm, 872 cm, 779 cm, 635 cm, 362 cm, 315 cm, acid hemihydrate loses about 2.1% of its total weight during 110 cm and 84 cm. 10 the first thermal decomposition. In some embodiments, the In certain embodiments, crystalline (3R)-4-(1S)-2-me 2.1% weight loss is attributable to water loss. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- In certain embodiments, crystalline (3R)-4-(1S)-2-me (4-chlorophenyl)butanoic acid hemihydrate exhibits the char thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- acteristic Raman spectrum in the region from 50cm to 2000 (4-chlorophenyl)butanoic acid hemihydrate undergoes a cm shown in FIG. 2. 15 melt/phase transitionata temperature ranging from about 90° Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro C. to about 110°C. using differential scanning calorimetry at panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu a heating rate of 20K/min. In certain embodiments the ther tanoic acid hemihydrate can be characterized by the presence mal decomposition occurs at about 100° C. and in certain of two phase changes upon thermal decomposition. For embodiments at about 99.8°C. In certain embodiments, crys example, in certain embodiments two points of thermal talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) decomposition can be observed via TG-FTIR analysis. Addi propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid tionally, in certain embodiments two melting point peaks can hemihydrate undergoes a melt/phase transition at a tempera be observed using DSC analysis. The first phase transition ture ranging from about 105° C. to about 125° C. using can be attributed to the loss of water, which is characteristic of differential scanning calorimetry at a heating rate of 20 the hemihydrate polymorph. In certain embodiments, both 25 K/min. In certain embodiments the thermal decomposition phase changes can be attributable to the hemihydrate from of occurs at about 115° C. and in certain embodiments at about crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy 114.89 C. loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic In certain embodiments, crystalline (3R)-4-(1S)-2-me acid. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- In certain embodiments, crystalline (3R)-4-(1S)-2-me 30 (4-chlorophenyl)butanoic acid hemihydrate undergoes a first thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- melt/phase transitionata temperature ranging from about 90° (4-chlorophenyl)butanoic acid hemihydrate is generated at C. to about 110°C., and also undergoes a second melt/phase room temperature in an acetonitrile/water mixture having a transition at a temperature ranging from about 105° C. to critical water activity (a) of greater than or equal to about about 125° C. using differential scanning calorimetry at a 0.75+0.05. In certain embodiments, crystalline (3R)-4- 35 heating rate of 20 K/min. In certain embodiments the first {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo thermal decomposition occurs at about 100° C. and the sec nylamino-3-(4-chlorophenyl)butanoic acid hemihydrate is ond thermal decomposition occurs at about 115°C. In certain generated at room temperature in an acetonitrile/water mix embodiments the first thermal decomposition occurs at about ture having a water activity (a) of about 0.8. In certain 99.8° C. and the second thermal decomposition occurs at embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me 40 about 114.8° C. thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo In certain embodiments, crystalline (3R)-4-(1S)-2-me rophenyl)butanoic acid hemihydrate is generated at room thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- temperature in an acetonitrile/water mixture having a a of (4-chlorophenyl)butanoic acid hemihydrate is hygroscopic. about 0.9. In certain embodiments, crystalline (3R)-4-(1S)- In certain embodiments, crystalline (3R)-4-(1S)-2-methyl 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony 45 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- lamino-3-(4-chlorophenyl)butanoic acid hemihydrate is chlorophenyl)butanoic acid hemihydrate is slightly hygro generated at room temperature in an acetonitrile/water mix scopic above about 60% relative humidity. In certain ture having a a selected from about 0.8 and about 0.9. embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me In certain embodiments, crystalline (3R)-4-(1S)-2-me thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 50 rophenyl)butanoic acid hemihydrate comprises from about 2 (4-chlorophenyl)butanoic acid hemihydrate undergoes ther wt %-about 3 wt % water. In certain embodiments, crystalline mal decomposition and loses about 2.1% of its total weight at (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro a temperature ranging from about 80° C. to about 130° C. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid using athermogravimetric analyzer (TG) coupled with a Fou hemihydrate contains about 2.15 wt % water at 50% relative rier-transform infrared (FTIR) spectrometer at a scan rate of 55 humidity as measured by dynamic vapor sorption. In certain about 10 K/min. In some embodiments, the 2.1% weight loss embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me is attributable to water loss. thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo In certain embodiments, crystalline (3R)-4-(1S)-2-me rophenyl)butanoic acid hemihydrate contains about 3 wt % thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- water at 95% relative humidity as measured by dynamic (4-chlorophenyl)butanoic acid hemihydrate undergoes ther 60 vapor sorption. mal decomposition at a temperature ranging from about 170° C. to about 190°C. using a thermogravimetric analyzer (TG) Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro coupled with a Fourier-transform infrared (FTIR) spectrom panoyloxy)propoxycarbonylamino-3-(4-chlo eter at a scan rate of about 10 K/min. rophenyl)butanoic acid anhydrate In certain embodiments, crystalline (3R)-4-(1S)-2-me 65 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- In certain embodiments, crystalline (3R)-4-(1S)-2-me (4-chlorophenyl)butanoic acid hemihydrate undergoes a first thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- US 9,139,517 B2 11 12 (4-chlorophenyl)butanoic acid exists as an anhydrate. Crys 954 cm, 868 cm, 798 cm, 637 cm, 401 cm, 348 talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) cm, 317 cm, 244 cm, 119 cm and 85 cm. propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid In certain embodiments, crystalline (3R)-4-(1S)-2-me anhydrate is a Solid exhibiting a highly ordered crystalline thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- lattice as evidenced by an extensive pattern of both low-angle (4-chlorophenyl)butanoic acid anhydrate exhibits the charac and high-angle reflections within the X-ray powder diffrac tion (XRPD) diffractogram teristic Raman spectrum in the region from 50 cm to 2000 Reference to crystalline (3R)-4-(1S)-2-methyl-1-(2-me cm shown in FIG. 4. thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo In certain embodiments, crystalline (3R)-4-(1S)-2-me rophenyl)butanoic acid anhydrate includes all possible tauto 10 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- meric forms of the conventional chemical structure for this (4-chlorophenyl)butanoic acid anhydrate is generated at compound and all isotopically labeled derivatives of this room temperature in an acetonitrile/water mixture having a compound (e.g., H, H, C, C, N, 7O, O, etc.). critical water activity (a) of less than or equal to about In certain embodiments, crystalline (3R)-4-(1S)-2-me 0.75+0.05. In certain embodiments, crystalline (3R)-4- thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 15 {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo (4-chlorophenyl)butanoic acid anhydrate exhibits character nylamino-3-(4-chlorophenyl)butanoic acid anhydrate is istic scattering angles (20) at least at 4.33°+0.2°, 4.76°+0.2°, generated at room temperature in an acetonitrile/water mix 11.06°+0.2° and 11.61°0.2° in an X-ray powder diffracto ture having a water activity (a) of about 0.7. In certain gram measured using Cu—K radiation. embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me In certain embodiments, crystalline (3R)-4-(1S)-2-me thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- rophenyl)butanoic acid anhydrate is generated at room tem (4-chlorophenyl)butanoic acid anhydrate exhibits character perature in an acetonitrile/water mixture having a a of about istic scattering angles (20) at least at 4.33°+0.2°, 4.76°+0.2°, 0.6. In certain embodiments, crystalline (3R)-4-(1S)-2-me 5.83° 0.2°, 9.07+0.2°, 9.46°0.2°, 10.54°0.2°, thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 11.06-0.2°, 11.61-0.2°, 12.940.2°, 17.46°-0.2°, 25 (4-chlorophenyl)butanoic acid anhydrate is generated at 17.84° 0.2°, 18.01-0.2°, 19.36°-0.2°, 20.01°0.2° and room temperature in an acetonitrile/water mixture having a 21.26°+0.2° in an X-ray powder diffractogram measured a of about 0.5. In certain embodiments, crystalline (3R)-4- using Cu—K radiation. {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo In certain embodiments, crystalline (3R)-4-(1S)-2-me nylamino-3-(4-chlorophenyl)butanoic acid anhydrate is thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 30 generated at room temperature in an acetonitrile/water mix (4-chlorophenyl)butanoic acid anhydrate exhibits character ture having a a of about 0.4. In certain embodiments, crys istic scattering angles (20) at least at 4.33°+0.2°, 4.76°+0.2°, talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) 5.83° 0.2°, 6.93°+0.2°, 9.07+0.2°, 9.46°-0.2°, propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid 10.54°0.2°, 11.06-0.2°, 11.61-0.2°, 12.940.2°, anhydrate is generated at room temperature in an acetonitrile/ 15.25-0.2°, 16.550.2°, 17.46°-0.2°, 17.84°0.2°, 35 water mixture having a a of about 0.3. In certain embodi 18.01-0.2°, 18.41+0.2°, 18.69°0.2°, 18.93 +0.2°, ments, crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 19.36°-0.2°, 20.01-0.2°, 20.46°-0.2°, 21.26°-0.2°, panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) 21.75° 0.2°, 22.190.2°, 22.56°-0.2°, 23.35°+0.2°, butanoic acid anhydrate is generated at room temperature in 23.850.2°, 24.84°0.2°, 25.969-0.2°, 26.78°+0.2°, an acetonitrile/water mixture having a a selected from about 27.29°0.2°, 28.69°0.2°, 29.39°0.2°, 31.22+0.2°, 40 0.7, about 0.6, about 0.5, about 0.4 and about 0.3. 32.35°-0.2°, 33.47+0.2°, 34.62+0.2° and 36.08° 0.2° in an In certain embodiments, crystalline (3R)-4-(1S)-2-me X-ray powder diffractogram measured using Cu-K radia thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- tion. (4-chlorophenyl)butanoic acid anhydrate undergoes thermal In certain embodiments, crystalline (3R)-4-(1S)-2-me decompositionata temperature ranging from about 170° C. to thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 45 about 190° C. using a thermogravimetric analyzer (TG) (4-chlorophenyl)butanoic acid anhydrate exhibits the charac coupled with a Fourier-transform infrared (FTIR) spectrom teristic scattering angles (20) in an X-ray powder eter at a scan rate of about 10 K/min. diffractogram measured using Cu-K radiation shown in In certain embodiments, crystalline (3R)-4-(1S)-2-me FIG. 3. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- In certain embodiments, crystalline (3R)-4-(1S)-2-me 50 (4-chlorophenyl)butanoic acid anhydrate undergoes a melt/ thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- phase transition at a temperature ranging from about 120° C. (4-chlorophenyl)butanoic acid anhydrate exhibits a strong to about 140°C. using differential scanning calorimetry at a characteristic Raman spectrum band at 119 cm. heating rate of 20 K/min. In certain embodiments, the melt/ In certain embodiments, crystalline (3R)-4-(1S)-2-me phase transition occurs at about 131° C. and in certain thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 55 embodiments at about 131.3°C. (4-chlorophenyl)butanoic acid anhydrate exhibits character In certain embodiments, crystalline (3R)-4-(1S)-2-me istic Raman spectrum bands at least at 119 cm and 85 cm. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- In certain embodiments, crystalline (3R)-4-(1S)-2-me (4-chlorophenyl)butanoic acid anhydrate is not hygroscopic. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- In certain embodiments, crystalline (3R)-4-(1S)-2-methyl (4-chlorophenyl)butanoic acid anhydrate exhibits character 60 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- istic Raman spectrum bands at least at 1599 cm, 1447 cm, chlorophenyl)butanoic acid anhydrate contains less than 798 cm, 119 cm and 85 cm. about 0.05 wt % water at 50% relative humidity as measured In certain embodiments, crystalline (3R)-4-(1S)-2-me by dynamic vapor sorption. In certain embodiments, crystal thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro (4-chlorophenyl)butanoic acid anhydrate exhibits character 65 poxycarbonylamino-3-(4-chlorophenyl)butanoic acid istic Raman spectrum bands at least at 1747 cm, 1599 cm, anhydrate contains less than about 0.1 wt % water at 95% 1447 cm, 1412 cm, 1335 cm, 1203 cm, 1092 cm, relative humidity as measured by dynamic vapor sorption. US 9,139,517 B2 13 14 Methods of Synthesis -continued O O In certain embodiments, crystalline (3R)-4-(1S)-2-me thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 1N1a C O2 H (4-chlorophenyl)butanoic acid anhydrate can be synthesized s -l H by: (i) forming a solution of diastereomers comprising (3R)- 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar bonylamino-3-(4-chlorophenyl)butanoic acid and (3R)-4- {(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo nylamino-3-(4-chlorophenyl)butanoic acid; (ii) selectively 10 crystallizing the (3R)-4-(1S)-2-methyl-1-(2-methylpro panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu C tanoic acid diastereomer as a hemihydrate; and (iii) separat (4) ing the crystalline (3R)-4-(1S)-2-methyl-1-(2- methylpropanoyloxy)propoxycarbonylamino-3-(4- chlorophenyl)butanoic acid hemihydrate diastereomer from 15 In certain embodiments, crystalline (3R)-4-(1S)-2-me the solution. In certain embodiments, the solution is water thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- containing or aqueous. (4-chlorophenyl)butanoic acid hemihydrate (1b) can be pre In certain embodiments, crystalline (3R)-4-(1S)-2-me pared by steps comprising providing a solution or Suspension thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- comprising 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)- (4-chlorophenyl)butanoic acid hemihydrate can be converted 2-methylpropyl)-2-methylpropanoate (3) prepared as a race into crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro mic mixture of (R)-1-((2,5-dioxopyrrolidin-1-yl-oxycarbo panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu nyloxy)-2-methylpropyl)-2-methylpropanoate and (S)-1-((2. tanoic acid anhydrate by a method selected from drying and 5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)- recrystallization. 2-methylpropanoate, (R)-baclofen (2), water and a solvent; Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 25 and adjusting the temperature of the Solution or Suspension to panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu provide (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) tanoic acid hemihydrate (1b) can be synthesized following propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid the methods described in Scheme 1 and Scheme 2 below. hemihydrate (1b) and (3R)-4-(1R)-2-methyl-1-(2-methyl Additionally, the individual diastereomers of crystalline propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) (3R)-4-(+)-2-methyl-1-(2-methylpropanoyloxy)propoxy 30 butanoic acid (4). carbonylamino-3-(4-chlorophenyl)butanoic acid can be In certain embodiments, the solvent is selected from separated efficiently via the methods described in Scheme 1. methyl tert-butyl ether, acetonitrile, toluene, chlorobenzene, Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy methylcyclohexane, heptane, methanol, ethanol, diethyl loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic ether, tetrahydrofuran, tert-amyl methyl ether and combina acid anhydrate (1a) can be synthesized following the methods tions of the foregoing. In certain embodiments, the solvent is described in Scheme 3 and Scheme 4 below. 35 methyl tert-butyl ether. In certain embodiments, the solvent is not dimethylsulfoxide, dimethylformamide, or n-methylpyr Scheme 1 rolidine. In certain embodiments, the Solution is aqueous. In O the exemplary embodiment depicted in Scheme 1, the solvent is methyl tert-butyl ether. 40 In certain embodiments, the Solution comprises solvent in an amount ranging from about 20 V/v '%-about 50 V/v %. In ul certain embodiments, the Solution comprises solvent in an s O o1 -- amount of about 35 V/v %. In the exemplary embodiment O depicted in Scheme 1, the solution comprises methyl tert (3) 45 butyl ether in an amount of about 35 V/v%. In certain embodi ments, the solution comprises water in an amount ranging HN1N1 Ncott from about 50 V/v '% to about 80 V/v '%. In certain embodi MTBE, H2O ments, the solution comprises water in an amount of about 65 -e- V/v%. In certain embodiments, the solution comprises about 35% 35 V/v % methyl tert-butyl ether and about 65% v/v water. In certain embodiments, the combination and dissolution of 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methyl propyl)-2-methylpropanoate (3) prepared as a racemic mix ture of (R)-1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2- methylpropyl)-2-methylpropanoate and (S)-1-((2.5- 55 dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2- methylpropanoate, and (R)-baclofen (2) in Solution can be carried out at elevated temperature, up to and including the boiling point of the solvent used. Accordingly, in certain embodiments, racemic 1-((2,5-dioxopyrrolidin-1-yl-oxycar 60 bonyloxy)-2-methylpropyl-2-methylpropanoate (3) and (R)- baclofen (2) can be dissolved in a solution with heating and optionally, with shaking and stirring. The heated Solution may be maintained at elevated temperature to ensure complete C dissolution of racemic 1-((2,5-dioxopyrrolidin-1-yl-oxycar 65 bonyloxy)-2-methylpropyl-2-methylpropanoate (3) and (R)- (1b) baclofen (2). The heated solution may also be filtered at elevated temperature to remove any undissolved components. US 9,139,517 B2 15 16 Then racemic 1-((2,5-dioxopyrrolidin-1-yl-oxycarbony (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- loxy)-2-methylpropyl-2-methylpropanoate (3) and (R)-ba chlorophenyl)butanoic acid (4) is achieved by adding a first clofen (2) react in the solution to yield (3R)-4-(1S)-2-me Solution comprising an acid and water to the resultant crys thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- tallization solution from Scheme 1; and thereafter adding a (4-chlorophenyl)butanoic acid (1) and (3R)-4-(1R)-2- base. methyl-1-(2-methylpropanoyloxy)propoxy Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro carbonylamino-3-(4-chlorophenyl)butanoic acid (4). panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro tanoic acid anhydrate (1a) can be synthesized following the poxycarbonylamino-3-(4-chlorophenyl)butanoic acid methods described in Scheme 3 and Scheme 4 below. hemihydrate can then be crystallized out of solution leaving 10 (3R)-4-(1R)-2-methyl-1-(2-methylpropanoyloxy)pro poxycarbonylamino-3-(4-chlorophenyl)butanoic acid (4) Scheme 3 in solution. Crystallization of (3R)-4-(1S)-2-methyl-1-(2- methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo O rophenyl)butanoic acid hemihydrate can occur by any num 15 Drying at 70° C. ber of conventional means and/or by the methods disclosed -e- hereinbelow. --~~ In certain embodiments, (R)-baclofen can be recycled from diastereomer (3R)-4-(1R)-2-methyl-1-(2-methylpro panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu tanoic acid (4) by hydrolysis of the (3R)-4-(1R)-2-methyl 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- chlorophenyl)butanoic acid (4) remaining in Solution C (1b) according to Scheme 2. 25 O

Scheme 2 --~~H O O 1) HCl, 30 HO 2" by NaOH

C 35 (1a)

C In Scheme 3, crystalline (3R)-4-(1S)-2-methyl-1-(2-me (4) thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 40 rophenyl)butanoic acid hemihydrate (1b) is dried to produce H N O2 crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy ~~ loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid anhydrate (1a). Crystalline (3R)-4-(1S)-2-methyl-1- 45 (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- chlorophenyl)butanoic acid hemihydrate (1b) may be pro C duced, for example, according to the methods described above. (2) Drying can occur via any conventional means including, 50 for example, air drying, drying under vacuum, drying at an elevated temperature, or any combination of the foregoing. In OH | + CO2 certain embodiments, the drying can be carried out at elevated s D temperature, up to but excluding the melting or thermal (5) (6) decomposition temperature of crystalline (3R)-4-(1S)-2- 55 methyl-1-(2-methylpropanoyloxy)propoxycarbony lamino-3-(4-chlorophenyl)butanoic acid anhydrate (1a). In In Scheme 2, the hydrolysis of (3R)-4-(1R)-2-methyl-1- Some embodiments, the drying can be carried out at a tem (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- perature range of about 30° C. to below about 90° C., and in chlorophenyl)butanoic acid (4) yields (R)-baclofen (2), certain embodiments at a temperature range of about 40°C. to isobutyric acid (5), isobutyraldehyde (6), and carbon dioxide. 60 80°C. In the exemplary embodiment depicted in Scheme 3, The recycled (R)-baclofen (2) can then be reused in further the drying occurs at a temperature of about 70° C. syntheses of crystalline (3R)-4-(1S)-2-methyl-1-(2-meth The drying of crystalline (3R)-4-(1S)-2-methyl-1-(2- ylpropanoyloxy)propoxycarbonylamino-3-(4-chlorophe methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo nyl)butanoic acid hemihydrate (1b) via the method of Scheme rophenyl)butanoic acid hemihydrate (1b) yields crystalline 1. 65 (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro Hydrolysis can occur in one or two steps. In certain poxycarbonylamino-3-(4-chlorophenyl)butanoic acid embodiments, the hydrolysis of (3R)-4-(1R)-2-methyl-1- anhydrate (1a) as a white crystalline solid. US 9,139,517 B2 17 18 (4-chlorophenyl)butanoic acid hemihydrate (1b) can be Scheme 4 maintained at ambient or room temperature to crystallize (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro poxycarbonylamino-3-(4-chlorophenyl)butanoic acid Y1 anhydrate (1a). Ambient or room temperature refers to a ul Hexane90% 1)No N 1N1 Scott -e- temperature to which humans are accustomed or have become acclimatized. In certain embodiments, room tem perature includes temperatures in the range of about 20° C.-27°C. and/or temperatures in the range of about 68°F-80° 10 F. In certain embodiments, room temperature is 20° C., in certain embodiments 25°C., in certain embodiments 68° F., C and in certain embodiments 77° F. Other methods known to (1b) those of skill in the crystallization arts, (e.g., Solvent evapo 15 ration, drowning, chemical reaction, seeding with a small O quantity of the desired crystal form, etc.) may also be employed to crystallize (3R)-4-(1S)-2-methyl-1-(2-meth ylpropanoyloxy)propoxycarbonylamino-3-(4-chlorophe --~~H nyl)butanoic acid anhydrate (1a). In certain embodiments, the recrystallization of (3R)-4- {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo nylamino-3-(4-chlorophenyl)butanoic acid anhydrate (1a) from a solution comprising crystalline (3R)-4-(1S)-2-me C thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 25 (4-chlorophenyl)butanoic acid hemihydrate (1b) and a sol (1a) vent can be carried out at elevated temperature, up to and including the boiling point of the solvent used. Accordingly, In certain embodiments, crystalline (3R)-4-(1S)-2-me in certain embodiments, crystalline (3R)-4-(1S)-2-methyl thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- (4-chlorophenyl)butanoic acid hemihydrate (1b) can be 30 chlorophenyl)butanoic acid hemihydrate (1b) can be dis recrystallized to crystallize (3R)-4-(1S)-2-methyl-1-(2- solved in a solvent by heating and optionally, with shaking methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo and stirring. The heated Solution may be maintained at rophenyl)butanoic acid anhydrate (1a). elevated temperature to ensure complete dissolution of crys In certain embodiments, crystalline (3R)-4-(1S)-2-me talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 35 propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid (4-chlorophenyl)butanoic acid anhydrate (1a) can be pre hemihydrate (1b). The heated solution may also be filtered at pared by steps comprising providing a solution or Suspension elevated temperature to remove any undissolved components. comprising crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl Then (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) 40 propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid butanoic acid hemihydrate (1b) and a solvent; and adjusting anhydrate (1a) crystallizes out of the solution. the temperature of the Solution or Suspension to provide crys The recrystallization of crystalline (3R)-4-(1S)-2-me talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid (4-chlorophenyl)butanoic acid hemihydrate (1b) yields crys anhydrate (1a). 45 talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) In certain embodiments, the solvent is selected from propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid acetone, hexane, methyl tert-butyl ether, acetonitrile, toluene, anhydrate (1a) as a white crystalline solid. chlorobenzene, methylcyclohexane, heptane, methanol, etha nol, diethyl ether, tetrahydrofuran, tert-amyl methyl ether and Crystallization of (3R)-4-(1S)-2-methyl-1-(2-me combinations of the foregoing. In certain embodiments, the 50 thylpropanoyloxy)propoxycarbonylamino-3-(4- Solvent is a combination of acetone and hexane. In the exem chlorophenyl)butanoic acid hemihydrate plary embodiment depicted in Scheme 1, the solvent is a combination of acetone and hexane. In certain embodiments, the Solution comprising 1-((2.5- In certain embodiments, the Solution comprises solvent in dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2- an amount ranging from about 70 V/v%-about 100 V/v%. In 55 methylpropanoate (3) prepared as a racemic mixture of (R)- certain embodiments, the Solution comprises solvent in an 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2- amount of about 90 V/v %. In the exemplary embodiment methylpropyl)-2-methylpropanoate and (S)-1-((2.5- depicted in Scheme 1, the Solution comprises a combination dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2- of acetone and hexane in an amount of about 90 V/v '%. In methylpropanoate, and (R)-baclofen (2) can be slowly cooled certain embodiments, the solution comprises water in an 60 to crystallize (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy amount ranging from about 0 V/v % to about 30 V/v %. In loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic certain embodiments, the solution comprises water in an acid hemihydrate (1b). Compound (1b) may be separated amount of about 15 V/v '%. In certain embodiments, the solu from (3R)-4-(1R)-2-methyl-1-(2-methylpropanoyloxy) tion comprises about 90 V/v % of a combination of acetone propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid and hexane and about 10% V/v water. 65 (4) and residual solvent by filtration and/or drying under In certain embodiments, crystalline (3R)-4-(1S)-2-me reduced pressure. In certain embodiments, the solution can be thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- cooled to a temperature ranging from about 0°C. to about 25° US 9,139,517 B2 19 20 C. to crystallize (3R)-4-(1S)-2-methyl-1-(2-methylpro 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu bonylamino-3-(4-chlorophenyl)butanoic acid (1) and (3R)- tanoic acid hemihydrate (1b). 4-(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy In certain embodiments, the Solution comprising racemic carbonylamino-3-(4-chlorophenyl)butanoic acid (4); and 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methyl decreasing the temperature of the second solution to provide crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy propyl-2-methylpropanoate (3) and (R)-baclofen (2) can be loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic maintained at ambient or room temperature to crystallize acid hemihydrate (1b) and (3R)-4-(1R)-2-methyl-1-(2-me (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo poxycarbonylamino-3-(4-chlorophenyl)butanoic acid rophenyl)butanoic acid (4). hemihydrate (1b), which may be separated from (3R)-4- 10 (3R)-4-(1R)-2-methyl-1-(2-methylpropanoyloxy)pro {(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo poxycarbonylamino-3-(4-chlorophenyl)butanoic acid (4) nylamino-3-(4-chlorophenyl)butanoic acid (4) and residual is a diastereomer of (3R)-4-(1S)-2-methyl-1-(2-methylpro Solvent by filtration and/or drying under reduced pressure. panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu Ambient or room temperature refers to a temperature to tanoic acid. In certain embodiments, the Solvent or combina which humans are accustomed or have become acclimatized. 15 tion of solvents is selected so that (3R)-4-(1R)-2-methyl In certain embodiments, room temperature includes tempera 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- tures in the range of about 20°C.-27°C. and/or temperatures chlorophenyl)butanoic acid (4) remains in solution during in the range of about 68° F-80° F. In certain embodiments, crystallization of (3R)-4-(1S)-2-methyl-1-(2-methylpro room temperature is 20°C., in certain embodiments 25°C., in panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu certain embodiments 68°F., and in certain embodiments 77° tanoic acid hemihydrate (1b). In this way, crystalline (3R)-4- F. Other methods known to those of skill in the crystallization {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy arts, (e.g., solvent evaporation, drowning, chemical reaction, carbonylamino-3-(4-chlorophenyl)butanoic acid seeding with a small quantity of the desired crystal form, etc.) hemihydrate (1b) can be readily separated from the diastere may also be employed to crystallize 3R)-4-(1S)-2-methyl omer (3R)-4-(1R)-2-methyl-1-(2-methylpropanoyloxy) 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- 25 propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid chlorophenyl)butanoic acid hemihydrate (1b). (4) in a single crystallization step. Other methods known to Crystallization of (3R)-4-(1S)-2-methyl-1-(2-methyl those of skill in the crystallization arts, (e.g., high perfor propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) mance liquid chromatography, reverse-phase high perfor mance liquid chromatography, extraction, distillation extrac butanoic acid hemihydrate (1b) from the solution affords tion, chromatography, the use of immobilized sorbents, etc.) crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy 30 may also be employed to separate crystalline (3R)-4-(1S)- loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony acid hemihydrate (1b) as a white crystalline solid. lamino-3-(4-chlorophenyl)butanoic acid hemihydrate (1b) In certain embodiments, crystalline (3R)-4-(1S)-2-me from the diastereomer (3R)-4-(1R)-2-methyl-1-(2-methyl thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) (4-chlorophenyl)butanoic acid hemihydrate (1b) can be pre 35 butanoic acid (4). pared by steps comprising providing a solution comprising As used herein, the terms solution and Suspension are used 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methyl interchangeably and are meant to include embodiments in propyl-2-methylpropanoate (3) prepared as a racemic mix which a compound is in a solvent or solvent mixture regard ture, (R)-baclofen (2), water and methyl tert-butyl ether; and less of solubility. A solvent combination can be such that a adjusting the temperature of the solution to provide crystal 40 compound in solution exhibits temperature-dependent solu line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro bility. In general, solvent combinations in which a compound poxycarbonylamino-3-(4-chlorophenyl)butanoic acid is soluble within a first temperature range, and poorly soluble hemihydrate (1b) and (3R)-4-(1R)-2-methyl-1-(2-methyl within a second temperature range, can be used in the crys propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) tallization methods disclosed herein. Mixtures of a “good butanoic acid (4). 45 solvent and an “anti-solvent can also be used with tempera In certain embodiments, crystalline (3R)-4-(1S)-2-me ture dependent solubilization, i.e., dissolving at elevated tem thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- perature and crystallizing at room temperature. Examples of suitable “good solvents, i.e., solvents in which (3R)-4- (4-chlorophenyl)butanoic acid hemihydrate (1b) can be pre {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo pared by steps comprising providing a solution comprising nylamino-3-(4-chlorophenyl)butanoic acid is soluble, 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methyl 50 include methanol, ethanol, isopropanol, acetone, methyl propyl-2-methylpropanoate (3) prepared as a racemic mix isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, ture, (R)-baclofen (2), about 65% V/v water and about 35% 1,4-dioxane, 1.2-ethandiol. 1,2-propanediol, 2-methoxyetha V/v methyl tert-butyl ether; and adjusting the temperature of nol, 2-ethoxyethanol, and a mixture of any of the foregoing. the solution to provide crystalline (3R)-4-(1S)-2-methyl-1- Examples of suitable “anti-solvents', i.e., solvents in which (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- 55 (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro chlorophenyl)butanoic acid hemihydrate (1b) and (3R)-4- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid {(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo exhibits poor solubility, include water, diethyl ether, diiso nylamino-3-(4-chlorophenyl)butanoic acid (4). propyl ether, methyl t-butyl ether, toluene, chlorobenzene, In certain embodiments, crystalline (3R)-4-(1S)-2-me alkanes Such as pentane, hexane, heptane, octane, nonane, thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 60 decane, undecane, dodecane, cis- or trans-decalin, cyclohex (4-chlorophenyl)butanoic acid hemihydrate (1b) can be pre ane, methylcyclohexane, and a mixture of any of the forego pared by steps comprising providing a first Solution 1ng. comprising 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)- 2-methylpropyl-2-methylpropanoate (3) prepared as a race Therapeutic Uses mic mixture, (R)-baclofen (2), about 65% V/v water and about 65 35% V/v methyl tert-butyl ether; increasing the temperature of The high (R)-baclofen oral bioavailability following the first solution to create a second solution comprising (3R)- administration of compound (1) favors the efficacious use of US 9,139,517 B2 21 22 compound (1) in oral dosage forms, including Sustained lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or release oral dosage forms, and the use of Such oral dosage crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy forms for treating diseases Such as spasticity and gastro loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic esophageal reflux disease (van Herwaarden et al., Aliment. acid hemihydrate, both of which are the (R)-baclofen pro Pharmacol. Ther: 2002, 16(9), 1655-62: Ciccaglione and 5 drugs, to a patient can be expected to be useful in treating Marzio, Gut 2003, 52(4), 464-70; Andrews et al., U.S. Pat. diseases and disorders associated with the GABA receptor No. 6,117,908; and Fara et al., International Publication No. and/or any of the diseases and disorders (R)-baclofen is WO 02/096404); in promoting alcohol abstinence in alcohol known to treat. ics (Gessa et al., International Publication No. WO The suitability of the (R)-baclofen prodrugs crystalline 01/26638); in promoting Smoking cessation (Gessa et al., 10 (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro International Publication No. WO 01/08675); in reducing poxycarbonylamino-3-(4-chlorophenyl)butanoic acid addiction liability of narcotic agents (Robson et al., U.S. Pat. anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- No. 4,126,684); in the treatment of emesis (Bountra et al., methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo U.S. Pat. No. 5,719.185); as an anti-tussive for the treatment rophenyl)butanoic acid hemihydrate in treating the above of cough (Kreutner et al., U.S. Pat. No. 5,006,560); as well as 15 listed diseases may be determined by methods described in for treating movement disorders such as dystonia and hic the art (see, e.g., Bowery, Trends Pharmacol. Sci. 1989, 10, cups; peripheral nerve disorders such as muscle stimulation 401–407; Misgeld et al., Prog. Neurobiol. 1995, 46,423-462: disorders; spinal cord disorders such as spastic paraparesis; van Herwaarden et al., Aliment. Pharmacol. Ther: 2002, cranial nerve disorders such as glossopharyngeal neuralgia 16(9), 1655-62: Ciccaglione and Marzio, Gut 2003, 52(4), and trigeminal neuralgia; multiple Sclerosis; and cerebral 20 464-470; Andrews et al., U.S. Pat. No. 6,117,908: Fara et al., palsy. International Publication No. WO 02/096404: Gessa et al., The pharmacological activity of (R)-baclofen, (R)-4- International Publication No. WO 01/26638; Gessa et al., amino-3-(4-chlorophenyl)butanoic acid, is believed to be International Publication No. WO 01/08675); Robson et al., effected through selective activation of GABA receptors, U.S. Pat. No. 4,126,684; Bountra et al., U.S. Pat. No. 5,719, resulting in neuronal hyperpolarization. GABA receptors 25 185; and Kreutneret al., U.S. Pat. No. 5,006,560; Katz, Am. J. are located in laminae I-IV of the spinal cord, where primary Phys. Med. Rehabil. 1988, 67(3), 108-16; Krach, J. Child sensory fibers end. GABA receptors are G-protein coupled Neurol. 2001, 16(1), 31-6; Bryans et al., International Publi receptors that activate conductance by K-selective ion chan cation No. WO 01/90052; Bryans et al., EP 1178034; Cundy nels and can reduce currents mediated by Ca" channels in et al., U.S. Application Publication No. 2002/0151529; Gal certain neurons. Baclofen has a pre-synaptic inhibitory effect 30 lop et al., U.S. Application Publication No. 2003/0176398: on the release of excitatory neurotransmitters and also acts Gallop et al., U.S. Application Publication No. 2003/ postsynaptically to decrease motor neuron firing (see Bow 0171303; Gallop et al., U.S. Application Publication No. ery, Trends Pharmacol. Sci. 1989, 10, 401–407; and Misgeld 2004/0006132; and Raillard et al., U.S. Application Publica et al., Prog. Neurobiol. 1995, 46, 423-462). tion No. 2004/0014940). A principal pharmacological effect of baclofen in mam- 35 A suitable dose of crystalline (3R)-4-(1S)-2-methyl-1- mals is reduction of muscle tone and consequently the drug is (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- frequently used in the treatment of spasticity. Spasticity is chlorophenyl)butanoic acid anhydrate and/or a suitable dose associated with damage to the corticospinal tract and is a of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy common complication of neurological disease. Diseases and loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic conditions in which spasticity may be a prominent symptom 40 acid hemihydrate to be administered to a patient in need of include cerebral palsy, multiple Sclerosis, stroke, head and (R)-baclofen therapy may be estimated based on the mass spinal cord injuries, traumatic brain injury, anoxia, and neu equivalent of (R)-baclofen and the enhanced oral bioavail rodegenerative diseases. Patients with spasticity complain of ability of (R)-baclofen provided by crystalline (3R)-4-(1S)- stiffness, involuntary spasm, and pain. These painful spasms 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony may be spontaneous or triggered by a minor sensory stimulus, 45 lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or Such as touching the patient. crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy Baclofen is also useful in controlling gastro-esophageal loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic reflux disease (van Herwaarden et al., Aliment. Pharmacol. acid hemihydrate. Ther: 2002, 16(9), 1655-62: Ciccaglione and Marzio, Gut In various aspects, crystalline (3R)-4-(1S)-2-methyl-1- 2003, 52(4), 464-70; Andrews et al., U.S. Pat. No. 6,117,908: 50 (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- and Fara et al., International Publication No. WO02/096404); chlorophenyl)butanoic acid anhydrate and/or crystalline in promoting alcohol abstinence in alcoholics (Gessa et al., (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro International Publication No. WO 01/26638); in promoting poxycarbonylamino-3-(4-chlorophenyl)butanoic acid Smoking cessation (Gessa et al., International Publication No. hemihydrate, or pharmaceutical compositions comprising WO 01/08675); in reducing addiction liability of narcotic 55 either of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro agents (Robson et al., U.S. Pat. No. 4,126,684); in the treat panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu ment of emesis (Bountra et al., U.S. Pat. No. 5,719, 185); as an tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2-me anti-tussive for the treatment of cough (Kreutner et al., U.S. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- Pat. No. 5,006,560); in treating neuropathic pain (see e.g., (4-chlorophenyl)butanoic acid hemihydrate, may be Fromm et al., Neurology 1981, 31(6), 683-7; and Ringel and 60 administered to a patient. Such as a human, Suffering from Roy, Ann Neurol 1987, 21 (5), 514-5); and in treating muscu treating a disease or disorder chosen from spasticity, gastroe loskeletal pain (see e.g., Hering-Hanit, Cephalalgia 1999, sophageal reflux disease, emesis, cough, Substance addiction 19(6), 589-591; Hering-Hanit and Gadoth, Headache 2000, and abuse, neuropathic pain and musculoskeletal pain. 40(1), 48-51; Freitag, CNS Drugs 2003, 17(6), 373-81; Slon Further, in certain embodiments, crystalline (3R)-4- imski et al., Reg Anesth Pain Med 2004, 29(3), 269-76). 65 {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo Accordingly, administering crystalline (3R)-4-(1S)-2- nylamino-3-(4-chlorophenyl)butanoic acid anhydrate and/ methyl-1-(2-methylpropanoyloxy)propoxycarbony or crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy US 9,139,517 B2 23 24 loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy acid hemihydrate, or pharmaceutical compositions compris loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic ing crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro acid hemihydrate can be absorbed throughout the gastrointes panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu tinal tract, including the colon, both compounds can be tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- advantageously formulated in Sustained release oral formu methyl-1-(2-methylpropanoyloxy)propoxy lations that provide for sustained release of one or both of the carbonylamino-3-(4-chlorophenyl)butanoic acid compounds over a period of hours into the gastrointestinal hemihydrate, can be administered to a patient, such as a tract. The ability of both crystalline (3R)-4-(1S)-2-methyl human, as a preventative measure against various diseases or 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- disorders. Crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl 10 chlorophenyl)butanoic acid anhydrate and crystalline (3R)- propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy butanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- carbonylamino-3-(4-chlorophenyl)butanoic acid methyl-1-(2-methylpropanoyloxy)propoxy hemihydrate to be used in Sustained release oral dosage forms carbonylamino-3-(4-chlorophenyl)butanoic acid can facilitate therapeutic regimens having a reduced dosing hemihydrate, or pharmaceutical compositions comprising 15 frequency necessary to maintain a therapeutically effective crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy baclofen concentration in the blood. loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic In certain embodiments, crystalline (3R)-4-(1S)-2-me acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- (4-chlorophenyl)butanoic acid anhydrate, crystalline (3R)-4- chlorophenyl)butanoic acid hemihydrate, may be adminis {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy tered as a preventative measure to a patient having a carbonylamino-3-(4-chlorophenyl)butanoic acid predisposition for spasticity, gastroesophageal reflux disease, hemihydrate, combinations thereof, and/or pharmaceutical emesis, cough, Substance addiction and abuse, neuropathic compositions thereof, can be administered to a patient for pain and musculoskeletal pain. Accordingly, crystalline (3R)- treating a disease or disorder selected from spasticity, gas 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar 25 troesophageal reflux disease, emesis, cough, Substance addic bonylamino-3-(4-chlorophenyl)butanoic acid anhydrate tion and abuse, neuropathic pain and musculoskeletal pain. and/or crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro Spasticity panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu In certain embodiments, crystalline (3R)-4-(1S)-2-me tanoic acid hemihydrate, or pharmaceutical compositions thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- comprising crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl 30 (4-chlorophenyl)butanoic acid anhydrate can be adminis propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) tered to a patient to treat spasticity. In certain embodiments, butanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy methyl-1-(2-methylpropanoyloxy)propoxy loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic carbonylamino-3-(4-chlorophenyl)butanoic acid acid hemihydrate can be administered to a patient to treat hemihydrate, may be used for the prevention of one disease or 35 spasticity. disorder and concurrently for the treatment of another (e.g., Spasticity is estimated to affect about 500,000 people in the prevention of spasticity while treating a narcotic addiction; United States and more than 12 million people worldwide. prevention of neuropathic pain while treating gastroesoph Spasticity is an involuntary, Velocity-dependent, increased ageal reflux disease). resistance to stretch. Spasticity is characterized by muscle Both crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 40 hypertonia in which there is increased resistance to externally panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu imposed movement with increasing speed of stretch (Lance et tanoic acid anhydrate and crystalline (3R)-4-(1S)-2-me al., Trans Am. Neurol. Assoc. 1970, 95, 272-274; and Sanger thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- et al., Pediatrics 2003, 111, e89-e97). Spasticity can be (4-chlorophenyl)butanoic acid hemihydrate may be more caused by lack of oxygen to the brain before, during, or after efficacious than the parent drug molecule (i.e. baclofen) in 45 birth (cerebral palsy); physical trauma (brain or spinal cord treating spasticity, gastroesophageal reflux disease, emesis, injury); blockage of or bleeding from a blood vessel in the cough, Substance addiction and abuse, neuropathic pain and brain (stroke); certain metabolic diseases; adrenolekodystro musculoskeletal pain because, when administered orally, the phy; phenylketonuria; neurodegenerative diseases such as compound provides for sustained therapeutically effective Parkinson's disease and amyotrophic lateral Sclerosis; and blood concentrations of (+)-4-amino-3-(4-chlorophenyl)bu 50 neurological disorders such as multiple Sclerosis. Spasticity tanoic acid. It is believed that metabolites of both crystalline is associated with damage to the corticospinal tract and is a (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro common complication of neurological disease. Diseases and poxycarbonylamino-3-(4-chlorophenyl)butanoic acid conditions in which spasticity may be a prominent symptom anhydrate and crystalline (3R)-4-(1S)-2-methyl-1-(2-me include cerebral palsy, multiple Sclerosis, stroke, head and thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 55 spinal cord injuries, traumatic brain injury, anoxia, and neu rophenyl)butanoic acid hemihydrate are absorbed from the rodegenerative diseases. Patients with spasticity complain of gastrointestinal lumen into the blood by a different mecha stiffness, involuntary spasm, and pain. These painful spasms nism than that by which baclofen and other known GABA may be spontaneous or triggered by a minor sensory stimulus, analogs are absorbed. For example, pregabalin is believed to Such as touching the patient. be actively transported across the gut wall by a carrier trans 60 Symptoms of spasticity can include hypertonia (increased porter localized in the human Small intestine. In contrast, the muscle tone), clonus (a series of rapid muscle contractions), compounds disclosed herein, and/or metabolites thereof are exaggerated deep tendon reflexes, muscle spasms, Scissoring believed to be absorbed across the gut wall along a greater (involuntary crossing of the legs), deformities with fixed portion of the gastrointestinal tract, including the colon. joints, stiffness, and/or fatigue caused by trying to force the Because metabolites of both crystalline (3R)-4-(1S)-2- 65 limbs to move normally. Other complications include urinary methyl-1-(2-methylpropanoyloxy)propoxycarbony tract infections, chronic constipation, fever or other systemic lamino-3-(4-chlorophenyl)butanoic acid anhydrate and illnesses, and/or pressure Sores. The degree of spasticity can US 9,139,517 B2 25 26 vary from mild muscle stiffness to severe, painful, and uncon and spasticity in rat models of cerebral palsy (Zhang et al., trollable muscle spasms. Spasticity may coexist with other Chinese J Clin Rehabilitation 2006, 10(38), 150-151). The conditions but is distinguished from rigidity (involuntary maximal electroshock seizure (MES) threshold test in rodents bidirectional non-velocity-dependent resistance to move is sensitive for detecting potential anticonvulsant properties ment), clonus (self-sustaining oscillating movements second (Loscher and Schmidt, Epilepsy Res 1988, 203), 145-181). In ary to hypertonicity), dystonia (involuntary Sustained con this model, anticonvulsant agents elevate the threshold to tractions resulting in twisting abnormal postures), athetoid electrically-induced seizures while proconvulsants lower the movement (involuntary irregular confluent writhing move seizure threshold. ments), chorea (involuntary, abrupt, rapid, irregular, and The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- unsustained movements), ballisms (involuntary flinging 10 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo movements of the limbs or body), and tremor (involuntary rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- rhythmic repetitive oscillations, not self-sustaining). Spastic {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy ity can lead to orthopedic deformity Such as hip dislocation, carbonylamino-3-(4-chlorophenyl)butanoic acid contractures, or scoliosis; impairment of daily living activi hemihydrate for treating spasticity may also be assessed in ties such as dressing, bathing, and toileting; impairment of 15 humans using double blind placebo-controlled clinical trials mobility such as inability to walk, roll, or sit; skin breakdown (see e.g., Priebe et al., Spinal Cord 1997, 35(3), 171-5: secondary to positioning difficulties and shearing pressure; Gruenthal et al., Spinal Cord 1997, 35(10), 686-9; Tuszynski pain or abnormal sensory feedback; poor weight gain second et al., Spinal Cord 2007, 45,222-231 and Steeves et al., Spinal ary to high caloric expenditure; sleep disturbance; and/or Cord 2007, 45, 206-221 for examples of the conduct and depression that is secondary to lack of functional indepen assessment of clinical trials for spasticity caused by spinal dence. cord injury). Clinical trial outcome measures for spasticity Treatment of spasticity includes physical and occupational include the Ashworth Scale, the modified Ashworth Scale, therapy Such as functional based therapies, rehabilitation, muscle stretch reflexes, presence of clonus and reflex facilitation Such as neurodevelopmental therapy, propriocep response to noxious stimuli. Spasticity can be assessed using tive neuromuscular facilitation, and sensory integration; bio 25 methods and procedures known in the art such as a combina feedback: electrical stimulation; and orthoses. Oral medica tion of clinical examination, rating scales Such as the Ash tions useful in treating spasticity include baclofen, worth Scale, the modified Ashworth scale the spasm fre benzodiazepines such as diazepam, dantrolene Sodium; imi quency scale and the reflex score, biomechanical studies Such dazolines Such as clonidine and tizanidine; and gabapentin. as the pendulum test, electrophysiologic studies including Intrathecal medications useful in treating spasticity include 30 electromyography, and functional measurements such as the baclofen. Chemodenervation with local anesthetics such as Fugl-Meyer Assessment of Sensorimotor Impairment scale. lidocaine and Xylocalne; type A botulinum toxin and type B Other measures can be used to assess spasticity associated botulinum toxin; phenol and alcohol injection can also be with a specific disorder such as the Multiple Sclerosis Spas useful in treating spasticity. Surgical treatments useful in ticity Scale (Hobartet al., Brain 2006, 129(1), 224-234). treating spasticity include neuroSurgery such as selective dor 35 Gastroesophageal Reflux Disease sal rhizotomy; and orthopedic operations such as contracture In certain embodiments, crystalline (3R)-4-(1S)-2-me release, tendon or muscle lengthening, tendon transfer, thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- osteotomy, and arthrodesis. (4-chlorophenyl)butanoic acid anhydrate can be adminis The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- tered to a patient to treat gastroesophageal reflux disease. In methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 40 certain embodiments, crystalline (3R)-4-(1S)-2-methyl-1- rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy chlorophenyl)butanoic acid hemihydrate can be administered carbonylamino-3-(4-chlorophenyl)butanoic acid to a patient to treat gastroesophageal reflux disease. hemihydrate for the treatment of spasticity can be assessed Gastroesophageal reflux disease (GERD) is defined as using animal models of spasticity and in clinically relevant 45 chronic symptoms or mucosal damage produced by abnormal studies of spasticity of different etiologies. Animal models of reflux in the esophagus. Symptoms of GERD include heart spasticity are known (see e.g., Eaton, J Rehab Res Dev 2003, burn, esophagitis, Stictures, dysphagia, chronic chest pain, 40(4), 41-54; Kakinohana et al., Neuroscience 2006, 141, cough, hoarsness, Voice changes, chronic ear ache, burning 1569-1583; Ligresti et al., British J Pharm 2006, 147, 83-91; chest pains, nausea, and sinusitis. Zhang et al., Chinese J Clin Rehab, 2006, 10(38), 150-151: 50 Tonic contraction of the lower esophageal sphincter is the Hefferanet al., Neuroscience Letters 2006, 403, 195-200; and principal factor preventing the reflux of gastric contents into Li et al., J Neurophysiol 2004, 92,2694-2703). For example, the esophagus. Transient lower esophageal sphincter relax animal models of spasticity include: (a) the mutant spastic ation (TLESR) is the major mechanism underlying reflux in mouse (Chai et al., Proc. Soc. Exptl. Biol. Med. 1962, 109, normal subjects and patients with GERD. GABA agonists 491); (b) the acute/chronic spinally transected rat and the 55 such as R-baclofen have been shown to reduce TLESRs in acute decerebrate rat (see e.g., Wright and Rang, Clin Orthop humans (Lidums et al., Gastroenterology 2000, 118(1), 7-13; Relat Res 1990, 253, 12-19: Shimizu et al., J Pharmacol Sci Vela et al., Aliment Pharmacol Ther 2003, 17(2), 243-51: 2004, 96, 444-449; and Li et al., J Neurophysiol 2004, 92, Ciccaglione and Marzio, Gut 2003, 52(4), 464-70; and Zhang 2694-2703); (c) primary observation Irwin Test in the rat et al., Gut 2002, 50(1), 19-24). Reduction of the frequency of (Irwin, Psychopharmacologia 1968, 13, 222-57); and d) 60 TLESRs by baclofen is believed to be due to inhibition of Rotarod Test in the rat and mouse (Dunham et al., J. Am. Vagal afferents, information transfer between the nucleus Pharm. Assoc. 1957, 46, 208-09). Other animal models tractus Solitarious and dorsal motor nucleus of the vagus, and include spasticity induced in rats following transient spinal vagal efferent outflow (Hornby et al., Gastroenterol Clin N cord ischemia (Kakinohana et al., Neuroscience 2006, 141, Am 2002, 31(4 Suppl), S11-S20). 1569-1583; and Hefferan et al., Neuroscience Letters 2006, 65 More specifically, (3R)-4-(1S)-2-methyl-1-(2-methyl 403, 195-200), spasticity in mouse models of multiple scle propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) rosis (Ligresti et al., British J Pharmacol 2006, 147, 83-91); butanoic acid (1) has been shown to reduce reflux episodes in US 9,139,517 B2 27 28 clinical trials (Castell et al., Am J. Gastroenterology 2006, general, adequately controlled, double blind placebo con 101 (suppl 2)(52), S59 and poster presentation at American trolled trails may be used to evaluate efficacy in humans. College of Gastroenterology 2006 Annual Meeting, Oct. Cough 20-25, 2006, Las Vegas, Nev.; and Castell et al., Gastroenter In certain embodiments, crystalline (3R)-4-(1S)-2-me ology 2007, suppl.A., 486 and poster presentation at Digestive 5 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- Disease Week Meeting, May 19-24, 2007, Washington D.C.). (4-chlorophenyl)butanoic acid anhydrate can be adminis The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- tered to a patient to treat cough. In certain embodiments, methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid hemihydrate can be administered to a patient to treat {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy 10 cough. carbonylamino-3-(4-chlorophenyl)butanoic acid Cough reflex, elicited by activation of cough receptors hemihydrate for treating GERD may be assessed using ani located in the respiratory tract, clears inhaled irritants and mal models such as those described by Blackshaw et al., Am. foreign Substances from the respiratory tract and, in conjunc J. Physiol. 1999, 277, G867-G874; Lehmann et al., Gastro tion with the mucociliary system, can expel excessive airway enterology 1999, 117, 1147-1154; and Stakeberg and Leh secretion produced under abnormal conditions from the res mann, Neurogastroenterol. Mot. 1999, 11, 125-132; and in piratory tract. Cough can be caused by mild acuate upper clinical trials. respiratory tract infections, allergies, asthma, chronic Emesis obstructive pulmonary disease, lung cancer, gastroesoph In certain embodiments, crystalline (3R)-4-(1S)-2-me- 20 ageal reflux disease, post-nasal drip, and heart or ear disor thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- ders. However, chronic non-productive cough having no (4-chlorophenyl)butanoic acid anhydrate can be adminis identifiable cause accounts for a significant percent of tered to a patient to treat emesis. In certain embodiments, patients presenting with cough. Chronic cough is associated crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy with exacerbation of asthmatic symptoms, rib fractures, loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic 25 breathlessness, ruptured abdominal muscles, pneumothorax, acid hemihydrate can be administered to a patient to treat Syncope, second and third degree heart block, and loss of emesis. consciousness. Persistent and uncontrollable cough can lead Nausea, vomiting, and retching are basic human protective to morbidity and severely impairs the quality of life of these reflexes against the absorption of toxins as well as responses patients. to certain stimuli. Nausea is a Subjectively unpleasant wave- 30 Cough includes acute and chronic cough of any type, eti like sensation in the back of the throat or epigastrium associ ology, or pathogenesis, and in particular cough associated ated with pallor or flushing, tachycardia, and an awareness of with laryngeal sensory neuropathy. the urge to vomit. Sweating, excess salivation, and a sensation The anti-tussive effects of baclofen are well-known (see of being cold or hot may also occur. Vomiting is characterized e.g., Dicpinigaitis and Dobkin, Chest 1997, 111(4), 996-9: by contraction of the abdominal muscles, descent of the dia- 35 Dicpinigaitis and Rauf Respiration 1998, 65(1), 86-8; Dic phragm, and opening of the gastric cardia, resulting in force pinigaitis et al., J. Clin Pharmacol 1998, 38(4), 364-7; and ful expulsion of stomach contents from the mouth. Retching Kreutner et al., U.S. Pat. No. 5,006,560 and International involves spasmodic contractions of the diaphragm and the Publication No. WO 91/08740). muscles of the thorax and abdominal wall without expulsion The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- of gastric contents. Emesis is used herein to refer to nausea, 40 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo Vomiting, and/or retching. rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- Baclofen has been shown to Suppress the retching and {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy Vomiting induced by morphine, thereby indicating the carbonylamino-3-(4-chlorophenyl)butanoic acid involvement of the GABA receptor in the emetic control hemihydrate for treating cough can be assessed using appro pathway (Suzuki et al., Neuropharmacology 2005, 49(8), 45 priate animal models and using clinical trials. Animal models 1121-31). Baclofen has also been shown to antagonize emesis of cough are reviewed by Lewis et al., Pulmonary Pharma induced by nicotine and motion in animal models (Chanet al., cology & Therapeutics 2007, 20, 325-333. EurJ Pharmacology 2007, 559(2-3), 196-201). Substance Addiction or Abuse The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- In certain embodiments, crystalline (3R)-4-(1S)-2-me methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo- 50 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- (4-chlorophenyl)butanoic acid anhydrate can be adminis {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy tered to a patient to treat Substance addiction or abuse. In carbonylamino-3-(4-chlorophenyl)butanoic acid certain embodiments, crystalline (3R)-4-(1S)-2-methyl-1- hemihydrate for treating emesis can be assessed using appro (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- priate animal models and using clinical trials. For example, 55 chlorophenyl)butanoic acid hemihydrate can be administered efficacy in treating emesis induced by chemotherapeutic to a patient to treat Substance addiction or abuse. agents can be determined based on effects indicative of eme In clinical trials, (R)-baclofen has been shown to be effec sis such as pica, gastric stasis, and reduced food intake in rats, tive in treating cocaine addiction (Brebner et al., Alcohol & mice, or ferrets (see, e.g., Liu et al., Physiology & Behavior; Alcoholism 2002, 37(5), 478-84; and Haney et al., Neuropsy 2005, 85,271-277; Endo et al., Biogenic Amines, 2004, 18(3- 60 chopharmacology 2006, 31, 1814-21); methamphetamine 6), 419-434; and Malik et al., Eur: J. Pharmacol, 2007, 555, dependence (Heinzerling et al., Drug Alcohol Depend 2006, 164-173). In clinical trials, assessment instruments such as 85(3), 177-84); opioid dependence (Assadi et al., BMC Psy the Duke Descriptive Scale, Visual Analog Scales, Morrow chiatry 2003, 3(16); and Ahmadi-Abhariet al., J. Clin Pharm Assessment of Nausea and Emesis, Rhodes Index of Nausea Therapeutics 2001, 26(1), 67-71); alcohol craving and intake and Vomiting Form-2, and Functional Living Index Emesis 65 (Addolorato et al., Alcohol & Alcoholism 2002, 37(5), 504-8; can be used to measure efficacy (see, e.g., Rhodes et al., CA and Flannery et al., Alcohol Clin Exp Res 2004, 28(10), 1517 Cancer J Clin, 2001, 51, 232-248 and references therein). In 23); nicotine use (Markou et al., Ann N.Y. Acad Sci 2004, US 9,139,517 B2 29 30 1025, 491-503); and drug addiction generally (Cousins et al., disc compression, carpal tunnel syndrome; disease-related Drug Alcohol Dependence 2002, 65(3), 209-20). neuropathies, e.g., diabetes and HIV-AIDS; radiculopathy; The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- complex regional pain syndrome; and/or tumor growth lead methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo ing to nerve compression or infiltration. Central neuropathic rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- pain can be the result of stroke, multiple Sclerosis, post {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy ischemic myelopathy; post-herpetic neuralgia; and/or post carbonylamino-3-(4-chlorophenyl)butanoic acid traumatic spinal cord injury. hemihydrate for treating Substance addiction and abuse can An essential part of neuropathic pain is a partial or com be assessed using animal models and in clinical trials. Animal plete loss of afferent sensory function and the paradoxical models of Substance abuse disorders are known (see e.g., 10 presence of certain hyperphenomena in the painful area. The Fattore et al., Alcohol & Alcoholism 2002, 37(5), 495-498 nerve tissue lesion may be found in the brain, spinal cord, or (nicotine); Spano et al., Neuropharmacology 2007, 52, 1555 the peripheral nervous system. Symptoms vary depending on 1562 (opiate addiction); and Maccioni et al., Alcohol 2005, the condition and can manifest as hyperalgesia (the lowering 36, 161-168 (alcohol abuse)). of pain threshold and an increased response to noxious Neuropathic Pain 15 stimuli), allodynia (the evocation of pain by non-noxious In certain embodiments, crystalline (3R)-4-(1S)-2-me stimuli such as cold, warmth, or touch), hyperpathia (an thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- explosive pain response that is Suddenly evoked from cuta (4-chlorophenyl)butanoic acid anhydrate can be adminis neous areas with increased sensory detection threshold when tered to a patient to treat neuropathic pain. In certain the stimulus intensity exceeds sensory threshold), paroxysms embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me (a type of evoked pain characterized by shooting, electric, thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo shock-like or stabbing pain that occur spontaneously, or fol rophenyl)butanoic acid hemihydrate can be administered to a lowing stimulation by an innocuous tactile stimulus or by a patient to treat neuropathic pain. blunt pressure), paraesthesia (abnormal but non-painful sen It is estimated that neuropathic pain affects over 6 million sations, which can be spontaneous or evoked, often described patients in the U.S. and Europe and over 26 million patients 25 as pins and needles), dysesthesia (abnormal unpleasant but worldwide. Neuropathic pain involves an abnormal process not necessarily painful sensation, which can be spontaneous ing of sensory input usually occurring after direct injury or or provoked by external stimuli), referred pain and abnormal damage to nerve tissue. Neuropathic pain is a collection of pain radiation (abnormal spread of pain), and wind-up like disorders characterized by different etiologies including pain and after sensations (the persistence of pain long after infection, inflammation, disease Such as diabetes and mul 30 termination of a painful stimulus). tiple Sclerosis, trauma or compression to major peripheral Patients with neuropathic pain typically describe burning, nerves, and chemical or irradiation-induced nerve damage lancinating, stabbing, cramping, aching, and sometimes Vice (Jensen et al., Eur J Pharmacol 2001, 429, 1-11). Neuro like pain. The pain can be paroxysmal or constant. Pathologi pathic pain typically persists long after tissue injury has cal changes to the peripheral nerve(s), spinal cord, and brain resolved. Prodrugs of GABA agonists provided by the 35 have been implicated in the induction and maintenance of present disclosure can be used to treat neuropathic pain. In chronic pain. Patients suffering from neuropathic pain typi certain embodiments, crystalline (3R)-4-(1S)-2-methyl-1- cally endure chronic, debilitating episodes that are refractory (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- to current pharmacotherapies and profoundly affect their chlorophenyl)butanoic acid anhydrate and/or crystalline quality of life. Currently available treatments for neuropathic (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 40 pain, including tricyclic antidepressants and gabapentin, typi poxycarbonylamino-3-(4-chlorophenyl)butanoic acid cally show limited efficacy in the majority of patients (Sin hemihydrate can be used to treat neuropathic pain including, drup and Jensen, Pain 1999, 83,389-400). for example, post-herpetic neuralgia, peripheral neuropathy, There are several types of neuropathic pain. A classifica trigeminal neuralgia, painful diabetic neuropathy, HIV-re tion that relates to the type of damage or related pathophysi lated neuropathic pain, cancer-related pain, and/or fibromy 45 ology causing a painful neuropathy includes neuropathies algia. associated with mechanical nerve injury Such as carpal tunnel The International Association for the Study of Neuropathic syndrome, vertebral disk herniation, entrapment neuropa Pain defines neuropathic pain states as disorders that are thies, ulnar neuropathy, and neurogenetic thoracic outlet Syn characterized by lesions or dysfunction of the neural drome; metabolic disease associated neuropathies such as system(s) which, under normal conditions, transmit noxious 50 diabetic polyneuropathy; neuropathies associated with neu information to the central nervous system. The mechanisms rotropic viral disease such as herpes Zoster and human immu underlying neuropathic pain conditions are highly heteroge nodeficiency virus disease; neuropathies associated with neu neous, howeverall types of neuropathic pain are presumed to rotoxicity Such as chemotherapy of cancer or tuberculosis, involve nerve injury and certain common aberrations in radiation therapy, drug-induced neuropathy, and alcoholic Somatosensory processing in the central and/or peripheral 55 neuropathy; neuropathies associated with inflammatory and/ nervous system (Baron, Nat Clin Pract Neurol 2006, 2. or immunologic mechanisms such as multiple Sclerosis, anti 95-106; and Beggs and Salter, Drug Dev Res 2006, 67,289 Sulfatide antibody neuropathies, neuropathy associated with 301). Potential causes of neuropathic pain include physical monoclonal gammopathy, Sjogren's disease, lupus, vascu damage, infection, and chemical exposure. Neuropathic pain litic neuropathy, polyclonal inflammatory neuropathies, can be generally classified as a focal/multifocal lesion of the 60 Guillain-Barre Syndrome, chronic inflammatory demyelinat peripheral nervous system, e.g., post-herpetic neuralgia, a ing neuropathy, multifocal motor neuropathy, paraneoplastic generalized lesion of the peripheral nervous system, painful autonomic neuropathy, ganglinoic acetylcholine receptor diabetic neuropathy, HIV-related neuropathic pain, a lesion of antibody autonomic neuropathy, Lambert-Eaton myasthenic the central nervous system, or a more complex neuropathic syndrome and myasthenia gravis; neuropathies associated disorder. Peripheral neuropathic pain can arise as a conse 65 with nervous system focal ischemia Such as thalamic syn quence of trauma and Surgery related nerve injury, e.g., bra drome (anesthesia dolorosa); neuropathies associated with chial plexus injury; entrapment neuropathies such as lumbar multiple neurotransmitter system dysfunction Such as com US 9,139,517 B2 31 32 plex regional pain syndrome; neuropathies associated with have also been shown to be effective in trigeminal, gloospha chronic/neuropathic pain Such as osteoarthritis, low back ryngeal, Vagoglossopharyngeal, and ophthalmic-posther pain, fibromyalgia, cancer bone pain, chronic Stump pain, petic neuralgias (Fromm et al., Neurology 1981,31(6), 683-7; phantom limb pain, and paraneoplastic neuropathies; toxic and Ringel and Roy, Ann Neurol 1987, 21 (5), 514-5); and in neuropathies (e.g., exposure to chemicals such as exposure to patients with diabetic neuropathy (Anghinah et al., Muscle acrylamide, 3-chlorophene, carbamates, carbon disulfide, Nerve 1994, 17(8),958-59). Doses ofbaclofen from about 50 ethylene oxide, n-hexane, methyl n-butylketone, methyl bro mg/day to about 60 mg/day have been shown to be effective in mide, organophosphates, polychlorinated biphenyls, pyrimi treating trigeminal neuralgia (Fromm et al., Ann Neurol 1984, nil, trichlorethylene, or dichloroacetylene), focal traumatic 15(3), 240-4). neuropathies, phantom and stump pain, monoradiculopathy, 10 The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- and trigeminal neuralgia; and central neuropathies including methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo ischemic cerebrovascular injury (stroke), multiple Sclerosis, rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- spinal cord injury, Parkinson's disease, amyotrophic lateral {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy Sclerosis, Syringomyelia, neoplasms, arachnoiditis, and post carbonylamino-3-(4-chlorophenyl)butanoic acid operative pain; mixed neuropathies such as diabetic neuropa 15 hemihydrate for treating one or more types of neuropathic thies (including symmetric polyneuropathies such as sensory pain can be assessed in animal models of neuropathic pain or sensorimotor polyneuropathy, selective Small-fiber poly and in clinical trials (see e.g., Beggs and Salter, Drug Dev Res neuropathy, and autonomic neuropathy, focal and multifocal 2006, 67. 829-301). Useful animal models of neuropathic neuropathies such as cranial neuropathy, limb mononeuropa pain include peripheral nerve injury by ligation or transection thy, trunk mononeuropathy, mononeuropathy multiplex, and including dorsal rhizotomy (Lombard et al., Pain 1979, 6(2), asymmetric lower limb motor neuropathy) and sympatheti 163-174); spinal nerve ligation (Kim and Chung, Pain 1992, cally maintained pain. Other neuropathies include focal neu 50, 355-363; and Hwang and Yaksh, Pain 1997, 70(1), ropathy, glosopharyngeal neuralgia; ischemic pain; trigemi 15-22); sciatic nerve transaction (Wall et al., Pain 1979, 7, nal neuralgia; atypical facial pain associated with Fabry's 103-111); sciatic nerve cuff (Mosconi and Kruger, Pain 1996, disease, Celiac disease, hereditary sensory neuropathy, or 25 64,37-57); partial nerve ligation (Seltzeret al., Pain 1990, 43, B12-deficiency; mono-neuropathies; polyneuropathies; 205-218); chronic constriction (Bennett and Xie, Pain 1988, hereditary peripheral neuropathies such as Carcot-Marie 33, 87-107); rat spinal cord ischemia model (Hao et al., Pain Tooth disease, Refsum’s disease, Strumpell-Lorrain disease, 1991, 45, 175-185; and von Heijne et al., EurJ Pain 2001, 5, and retinitis pigmentosa; acute polyradiculoneuropathy; and 1-10); and spared nerve injury (Decosterd and Woolf, Pain chronic polyradiculoneuropathy. Paraneoplastic neuropa 30 2000, 87, 149-158). Other animal models of neuropathies thies include paraneoplastic Subacute sensory neuropathy, involving immune system activation and metabolic and paraneoplastic motor neuron disease, paraneoplastic neu chemically induced neuropathies include sciatic cyro romyotonia, paraneoplastic demyelinating neuropathies, neurolysis (DeLeo et al., Pain 1994, 56, 9-16); Zymosan paraneoplastic vasculitic neuropathy, and paraneoplastic induced neuritis (Chacur et al., Pain 2001, 94, 231-244); HIV autonomic insufficiency. Prodrugs of GABA agonists, such 35 gp120-induced pain model (Herzberg and Sagen, J Neuroim as crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy munol 2001, 116, 29-39); photochemical ischemia (Kuperset loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic al., Pain 1998, 76(1-2), 45-59); anti-ganglioside antibody acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- (Slart et al., Pain 1997, 69, 119-125); streptozotocin-neur (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- opathy (Fox et al., Pain 1999, 81,307-316); DDI-induced chlorophenyl)butanoic acid hemihydrate, can be used to treat 40 myelinopathy (Joseph et al., Pain 2004, 107, 147-158); for any of the foregoing types of neuropathic pain. In certain malin phase 2 model of hyperalgesic pain (Dirig and Yaksy, J embodiments, the neuropathic pain is chosen from post-her Pharmacology Exper Ther 1995, 275,219-227); vincristine petic neuralgia, peripheral neuropathy, trigeminal neuralgia, induced pain model (Aley et al., Neuroscience 1996, 73. painful diabetic neuropathy, HIV-related neuropathic pain, 259-265); paclitaxel-induced pain model (Cavaletti et al., Exp cancer-related pain, and fibromyalgia. In certain embodi 45 Neurol 1995, 133, 64-72); and cisplatin-induced pain model ments, the neuropathic pain is chosen from post-herpetic (Authier et al., Neurosci Lett 2000, 25, 2576-2585). neuralgia and trigeminal neuralgia. The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- The GABA agonist (R)-baclofen has long been known to methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo have antinociceptive activity in models of acute pain and rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- recent studies have shown that baclofen inhibits allodynia and 50 {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy hyperalgesia in the chronic constriction injury and spinal carbonylamino-3-(4-chlorophenyl)butanoic acid nerve ligation models of persistent neuropathic pain at doses hemihydrate for treating various types of neuropathic pain lower than those required to produce sedation and impairment can also be assessed in clinical trials using, for example, of motor activity (see e.g., Hwang and Yaksh, Pain 1997, randomized double-blind placebo controlled methods. End 70(1), 15-22; Smith et al., Neruopharmacology 1994, 33(9), 55 points used in clinical trials for neuropathic pain can be deter 1103-8: Patel et al., Pain 2001, 90(3), 217-26: Balerio and mined using validated neuropathic pain criteria Such as the Rubio, Pharmacol Res 2002, 46(3), 281-6; and Reis and Brief Pain Inventory, Categorical Scale, Gracety Pain Scale, Duarte, BrJ Pharmacol 2006, 149(6), 733-9). Likert Scale, Neuropathic Pain Scale, Numerical Pain Scale, In clinical studies, intrathecal baclofen administration has Short Form McGill Pain Questionnaire, Verbal Pain Scale, been shown to be effective in treating neuropathic pain asso 60 Visual Analog Scale (VAS), VAS Pain Intensity Scale, and/or ciated with spinal-cord injury and multiple Sclerosis (Herman VAS Pain Relief Scale. et al., Clin J Pain 1992, 8(4), 338-45), painful extremity Musculoskeletal Pain paresthesias (Gatscher et al., Acta Neurochir Suppl 2002, 79, In certain embodiments, crystalline (3R)-4-(1S)-2-me 75-76), sympathetically maintained pain (Van Hilten et al., N thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- EnglJ Med 2000, 343(9), 625-30; Becker et al., J Clin Neu 65 (4-chlorophenyl)butanoic acid anhydrate can be adminis rosci 2000, 7(4), 31.6-9; and Zuniga et al., Reg Anesth Pain tered to a patient to treat musculoskeletal pain. In certain Med 2002, 27(1), 90-3). GABA agonists such as baclofen embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me US 9,139,517 B2 33 34 thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo serious medical problem. Pain accompanied by fever or loss rophenyl)butanoic acid hemihydrate can be administered to a of bowel or bladder control, pain when coughing, and pro patient to treat musculoskeletal pain. gressive weakness in the legs may indicate a pinched nerve or Musculoskeletal conditions causing tenderness, musculos other serious condition. People with diabetes may have severe ketal pain and muscle spasms include fibromyalgia, tension back pain or pain radiating down the leg related to neuropa headaches, myofascial pain syndrome, facet joint pain, inter thy. Low back pain can be caused by bulging disc(s) (e.g., nal disk disruption, Somatic dysfunction, spinal fractures, protruding, herniated, or ruptured disc), Sciatica, spinal Vertebral osteomyelitis, polymyalgia rheumatica, atlanto degeneration, spinal Stenosis, osteoporosis, osteoarthritis, axial instability, atlanto-occipital joint pain, osteoporotic ver compression fractures, skeletal irregularities, fibromyalgia, tebral compression fracture, Scheuermann's disease, spondy 10 spondylolysis and/or spondylolisthesis. Less common spinal loysis, spondylolisthesis, kissing spines, sacroiliac joint pain, conditions that can cause low back pain include ankylosing sacral stress fracture, coccygodynia, failed back syndrome, spondylitis, bacterial infections, osteomyelitis, spinal and mechanical low back or neck pain (see, e.g., Meleger and tumors, Paget’s disease, and Scheuermann's disease. Clinical Krivickas, Neurol Clin 2007, 25, 419-438. In these condi results suggest that GABA agonists such as baclofen can be tions, muscle spasm is related to local factors involving the 15 effective in treating low back pain (Dapas et al., Spine 1985, affected muscle groups without the increased tone or reflex 10(4), 345-9; and Raphael et al., BMC Musculoskeletal Dis characteristic of spasticity. Muscle, tendon, ligament, inter orders 2002, 3(17). For example, doses of baclofen from Vertebral disc, articular cartilage, and bone can be involved in about 20 mg/day to about 80/mg day have been shown to be musculoskeletal pain. Disorders that can produce neck and effective in treating acute low back pain (Dapas et al., Spine back pain include muscle strain, ligament sprain, myofascial 1985, 10(4), 345-9). pain, fibromyalgia, facet joint pain, internal disc disruption, In certain embodiments, methods of treating low back pain Somatic dysfunction, spinal fracture, verterbral osteomyeli provided by the present disclosure comprises treating disor tis, and polymyalgia rheumatica, atlantoaxial instability and ders, conditions, and/or symptoms associated with low back atlanto-occipital joint pain. (see e.g., Meleger and Krivickas, pain such as muscle spasms. Symptoms of low back pain can Neurological Clinics 2007, 25(2), 419-438). 25 depend on the cause. For example, symptoms of back sprain Studies have shown that GABA agonists can be effective or back Strain include muscle spasms, cramping, stiffness, in treating muscular pain and/or spasms associated with and pain centered in the back and buttocks. Symptoms of peripheral musculoskeletal conditions. Baclofen has been nerve-root pressure include leg pain, also referred to as sci shown to be effective in treating migraine (Hering-Hanit, atica, and nerve-related manifestations such as tingling, Cephalalgia 1999, 19(6), 589-91; and Hering-Hanit and 30 numbness, or weakness in one leg or in the foot, lower leg, or Gadoth, Headache 2000, 40(1), 48-51) and specifically in both legs. Symptoms of arthritis of the spine include pain and tension-type headaches (Freitag, CNS Drugs 2003, 17(6), stiffness that are worse in the back and hip. 373-81); and in low-back pain and radiculopathy (Slonimski Fibromyalgia is a condition characterized by aching and et al., Reg Anesth Pain Med 2004, 29(3), 269-76; Dapas et al., pain in muscles, tendons and joints all over the body, but Spine 1985, 10(4), 345-9; and Raphael et al., BMC Muscu 35 especially along the spine. The body also is tender to touch in loskeletal Disorders 2002, 3(17). specific areas referred to as tender or trigger points. Other The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- symptoms offibromyalgia include sleep disturbance, depres methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo Sion, daytime tiredness, headaches, alternating diarrhea and rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- constipation, numbness and tingling in the hands and feet, {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy 40 feelings of weakness, memory difficulties, and dizziness. carbonylamino-3-(4-chlorophenyl)butanoic acid Although the etiology of fibromyalgia is not known, stress, hemihydrate for treating one or more types of musculoskel disordered sleep patterns, abnormal production of pain-re etal pain can be assessed in animal models of neuropathic lated chemicals in the nervous system, and/or low levels of pain and in clinical trials. For example, Kehl et al. disclose an growth hormone are believed to contribute to the onset of animal model of muscle hyperplasia that employs intramus 45 fibromyalgia. cular injection of carrageenan as useful for assessing the Fibromyalgia usually occurs in people between 20 and 60 mechanisms and management of musculoskeletal pain (Kehl years of age and is estimated to affect 3.4% of women and et al., Pain 2000, 85,333-343). 0.5% of men. The incidence of juvenile primary fibromyalgia Low back pain generally occurs in the lumbar region of the in School age girls is estimated to be about 1.2%. back in the location of lumbar vertebrae L1-L5. Pain in the 50 Current treatment of fibromyalgia is based on symptoms, lower back can be caused by a sprain, strain, or spasm to one with the goals of alleviating pain, restoring sleep, and improv of the muscles, ligaments, facet joints, and/or sacroiliac joints ing general quality of life. Several nonpharmacologic treat in the back; spinal sprain or overcompression; or disc rupture ments include exercise, education, behavioral therapy and or bulge. Low back pain may also reflect nerve or muscle physical therapy. Pharmacologic treatments include tricyclic irritation or bone lesions. Most low back pain follows injury 55 compounds, serotonin reuptake inhibitors, analgesics, or trauma to the back, but pain may also be caused by degen muscle relaxants, and acetylcholine esterase inhibitors. There erative conditions such as arthritis or disc disease, osteoporo is evidence Suggesting that GABA agonists such as baclofen sis, or other bone diseases, viral infections, irritation to joints may be useful in improving fibromyalgia symptoms (Taylor and discs, or congenital abnormalities in the spine. Obesity, Gjevre and Gjevre, Lupus 2005, 14(6), 486-8). Smoking, weight gain during pregnancy, stress, poor physical 60 The efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2- condition, posture inappropriate for the activity being per methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo formed, and poor sleeping position also may contribute to low rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- back pain. Additionally, scar tissue created when the injured {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy back heals itself does not have the strength or flexibility of carbonylamino-3-(4-chlorophenyl)butanoic acid normal tissue. Buildup of Scar tissue from repeated injuries 65 hemihydrate for treating fibromyalgia may be assessed using eventually weakens the back and can lead to more serious animal models offibromyalgia and in clinical results (see e.g., injury. Occasionally, low back pain may indicate a more Dooley et al., U.S. Patent Application Publication Nos. 2004/ US 9,139,517 B2 35 36 0180959 and 2004/0138305; Crofford et al., Arthritis & tanoic acid anhydrate, or a pharmaceutical composition Rheumatism 2005, 52, 4, 1264-1273: Eaton, J Rehabilitation thereof, and/or crystalline (3R)-4-(1S)-2-methyl-1-(2-me Research and Development 2003, 40(4), 41S-54S; Guay, Am thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo J Geriatr Pharmacother 2005, 3,274-287; Freynhagen et al., rophenyl)butanoic acid hemihydrate, or a pharmaceutical Pain 2005, 115,254-263: Backonja et al., Clin Ther: 2003, 25, composition thereof, can be administered orally. Crystalline 81-104; Gidalet al., Am J Manag Care. 2006, 12, S269-S278: (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro and Argoff, JAOA, 2002, Suppl. 3, 102(9), S21-S26). In par poxycarbonylamino-3-(4-chlorophenyl)butanoic acid ticular, animal models of neuropathic pain or clinically rel anhydrate, or a pharmaceutical composition thereof, and/or evant studies of different types of neuropathic pain have been crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy found useful in assessing therapeutic activity for treating 10 loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic fibromyalgia, Such as are disclosed, for example, in Bennett acid hemihydrate, or a pharmaceutical composition thereof, and Xie, Pain 1988, 33, 87-107: Chaplanet al., J. Neurosci. may also be administered by any other convenient route, for Meth. 1994, 53, 55-63; Fox et al., Pain 2003, 105, 355-362; example, by infusion or bolus injection, or by absorption Milligan et al., Brain Res. 2000, 861, 105-116; DeVry et al., through epithelial or mucocutaneous linings (e.g., oral Eur: J. Pharmacol. 2004, 491, 137-148; and Polomano et al., 15 mucosa, rectal and intestinal mucosa, etc.). Administration Pain 2001, 94, 293-304. can be systemic or local. Various delivery systems are known, (e.g., encapsulation in liposomes, microparticles, microcap Modes of Administration Sules, capsules, etc.) that can be used to administer crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro poxycarbonylamino-3-(4-chlorophenyl)butanoic acid panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu anhydrate, or a pharmaceutical composition thereof, and/or tanoic acid anhydrate, or a pharmaceutical composition that can be used to administer crystalline (3R)-4-(1S)-2- thereof, may be advantageously used in human medicine. methyl-1-(2-methylpropanoyloxy)propoxycarbony Additionally, crystalline (3R)-4-(1S)-2-methyl-1-(2-meth lamino-3-(4-chlorophenyl)butanoic acid hemihydrate, or a ylpropanoyloxy)propoxycarbonylamino-3-(4-chlorophe 25 pharmaceutical composition thereof. Methods of administra nyl)butanoic acid hemihydrate, or a pharmaceutical compo tion include, but are not limited to, intradermal, intramuscu sition thereof, may be advantageously used in human lar, intraperitoneal, intravenous, Subcutaneous, intranasal, medicine. As disclosed herein, crystalline (3R)-4-(1S)-2- epidural, oral, Sublingual, intranasal, intracerebral, intravagi methyl-1-(2-methylpropanoyloxy)propoxycarbony nal, transdermal, rectally, by inhalation, or topically, particu lamino-3-(4-chlorophenyl)butanoic acid anhydrate, or a 30 larly to the ears, nose, eyes or skin. pharmaceutical composition thereof, and/or crystalline (3R)- In certain embodiments, crystalline (3R)-4-(1S)-2-me 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- bonylamino-3-(4-chlorophenyl)butanoic acid hemihydrate, (4-chlorophenyl)butanoic acid anhydrate, or a pharmaceuti or a pharmaceutical composition thereof, are useful for the cal composition thereof, and/or crystalline (3R)-4-(1S)-2- treatment of spasticity, gastroesophageal reflux disease, eme 35 methyl-1-(2-methylpropanoyloxy)propoxy sis, cough, Substance addiction and abuse, neuropathic pain carbonylamino-3-(4-chlorophenyl)butanoic acid and musculoskeletal pain. hemihydrate, or a pharmaceutical composition thereof, may When used to treat the above diseases, crystalline (3R)-4- be delivered via Sustained release systems, such as an oral {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo Sustained release system. nylamino-3-(4-chlorophenyl)butanoic acid anhydrate, or a 40 Both crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro pharmaceutical composition thereof, and/or crystalline (3R)- panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar tanoic acid anhydrate, or a pharmaceutical composition bonylamino-3-(4-chlorophenyl)butanoic acid hemihydrate, thereof, and crystalline (3R)-4-(1S)-2-methyl-1-(2-meth or a pharmaceutical composition thereof, may be adminis ylpropanoyloxy)propoxycarbonylamino-3-(4-chlorophe tered or applied singly, or in combination with other agents. 45 nyl)butanoic acid hemihydrate, or a pharmaceutical compo Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy sition thereof, exhibit enhanced bioavailability as (R)- loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic baclofen compared to the bioavailability of (R)-baclofen acid anhydrate, or a pharmaceutical composition thereof, when administered in an equivalent dosage form of R-ba and/or crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro clofen and/or racemate. The enhanced bioavailability of crys panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu 50 talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) tanoic acid hemihydrate, or a pharmaceutical composition propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid thereof, may also be administered or applied singly or in anhydrate, or a pharmaceutical composition thereof, and combination with other pharmaceutically active agents, crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy including other GABA analogs. loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic Methods of treatment include administering to a patient in 55 acid hemihydrate, or a pharmaceutical composition thereof, need of such treatment a therapeutically effective amount of is believed to be due the efficient absorption of crystalline crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic poxycarbonylamino-3-(4-chlorophenyl)butanoic acid acid anhydrate, or a pharmaceutical composition thereof, anhydrate and crystalline (3R)-4-(1S)-2-methyl-1-(2-me and/or administering to a patient in need of such treatment a 60 thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo therapeutically effective amount of crystalline (3R)-4-(1S)- rophenyl)butanoic acid hemihydrate throughout the gas 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony trointestinal tract, including the colon, via passive and/or lamino-3-(4-chlorophenyl)butanoic acid hemihydrate, or a active transport mechanisms. pharmaceutical composition thereof. The patient may be an Both crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro animal. Such as a mammal, for example, a human. 65 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro tanoic acid anhydrate, or a pharmaceutical composition panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu thereof, and crystalline (3R)-4-(1S)-2-methyl-1-(2-meth US 9,139,517 B2 37 38 ylpropanoyloxy)propoxycarbonylamino-3-(4-chlorophe hemihydrate may be cleaved either chemically and/or enzy nyl)butanoic acid hemihydrate, or a pharmaceutical compo matically. One or more enzymes present in the stomach, sition thereof, provide (R)-baclofen upon in vivo intestinal lumen, intestinal tissue, blood, liver, brain or any administration to a patient. Crystalline (3R)-4-(1S)-2-me other tissue of a mammal may cleave the promoiety of crys thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) (4-chlorophenyl)butanoic acid anhydrate and/or crystalline propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo hemihydrate, or a metabolite thereof, may be absorbed into rophenyl)butanoic acid hemihydrate. The promoiety of crys the systemic circulation from the gastrointestinal tract either 10 by passive diffusion, active transport or by both passive and talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) active processes. propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid Following administration to a patient, crystalline (3R)-4- anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo nylamino-3-(4-chlorophenyl)butanoic acid anhydrate, or a 15 rophenyl)butanoic acid hemihydrate may be cleaved prior to pharmaceutical composition thereof, and crystalline (3R)-4- absorption by the gastrointestinal tract (e.g., within the stom {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo ach or intestinal lumen) and/or after absorption by the gas nylamino-3-(4-chlorophenyl)butanoic acid hemihydrate, or trointestinal tract (e.g., in intestinal tissue, blood, liver or a pharmaceutical composition thereof, provide (R)-baclofen other suitable tissue of a mammal). When the promoiety of in the systemic circulation of a patient. Crystalline (3R)-4- crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic nylamino-3-(4-chlorophenyl)butanoic acid anhydrate and/ acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- or crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic chlorophenyl)butanoic acid hemihydrate is cleaved prior to acid hemihydrate may be absorbed from the gastrointestinal 25 absorption by the gastrointestinal tract, baclofen may be tract and enter the systemic circulation where the promoiety absorbed into the systemic circulation conventionally (e.g., is cleaved to release (R)-baclofen. mediated, in part, via the large neutral amino acid transporter When administered to a patient, for example, by a patient located in the small intestine). When the promoiety of crys Swallowing a dosage form comprising the compounds dis talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) closed herein, crystalline (3R)-4-(1S)-2-methyl-1-(2-me 30 propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy rophenyl)butanoic acid hemihydrate is cleaved after absorp carbonylamino-3-(4-chlorophenyl)butanoic acid tion by the gastrointestinal tract, these baclofen prodrugs may hemihydrate provide a sustained therapeutically effective 35 be absorbed into the systemic circulation either by passive concentration of (R)-baclofen in the blood of a patient during diffusion, active transport, or by both passive and active pro a continuous period of time. In certain embodiments, crystal CCSSCS. line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro When the promoiety of crystalline (3R)-4-(1S)-2-me poxycarbonylamino-3-(4-chlorophenyl)butanoic acid thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- 40 (4-chlorophenyl)butanoic acid anhydrate and/or crystalline methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro rophenyl)butanoic acid hemihydrate may provide a concen poxycarbonylamino-3-(4-chlorophenyl)butanoic acid tration of (R)-baclofen in the blood of a patient that is greater hemihydrate is cleaved after absorption by the gastrointesti than a minimum therapeutically effective concentration and nal tract, these baclofen prodrugs may be absorbed into the less thana minimum adverse concentration of (R)-baclofen in 45 systemic circulation from the large intestine. When absorbed the blood of the patient. In certain embodiments, crystalline by the large intestine, crystalline (3R)-4-(1S)-2-methyl-1- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid chlorophenyl)butanoic acid anhydrate, or a pharmaceutical anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- composition thereof, and/or crystalline (3R)-4-(1S)-2-me methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 50 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- rophenyl)butanoic acid hemihydrate provide a therapeuti (4-chlorophenyl)butanoic acid hemihydrate, or a pharmaceu cally effective concentration of (R)-baclofen in the blood of a tical composition thereof, can be advantageously patient for a continuous period of time without exceeding the administered as a Sustained release system. In certain minimum adverse concentration of (R)-baclofen. In certain embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me embodiments, the concentration of (R)-baclofen in the blood 55 thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo of a patient does not exceed a minimum adverse concentra rophenyl)butanoic acid anhydrate, or a pharmaceutical com tion at any time after crystalline (3R)-4-(1S)-2-methyl-1- position thereof, and/or crystalline (3R)-4-(1S)-2-methyl (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- chlorophenyl)butanoic acid anhydrate and/or crystalline chlorophenyl)butanoic acid hemihydrate, or a (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 60 pharmaceutical composition thereof, can be delivered by oral poxycarbonylamino-3-(4-chlorophenyl)butanoic acid Sustained release administration. When administered using a hemihydrate is administered to a patient. sustained release formulation, crystalline (3R)-4-(1S)-2- The promoiety of crystalline (3R)-4-(1S)-2-methyl-1- methyl-1-(2-methylpropanoyloxy)propoxycarbony (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- lamino-3-(4-chlorophenyl)butanoic acid anhydrate, or a chlorophenyl)butanoic acid anhydrate and/or crystalline 65 pharmaceutical composition thereof, and/or crystalline (3R)- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar poxycarbonylamino-3-(4-chlorophenyl)butanoic acid bonylamino-3-(4-chlorophenyl)butanoic acid hemihydrate, US 9,139,517 B2 39 40 ora pharmaceutical composition thereof, can be administered thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo once per day, twice per day, or in some embodiments more rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- than twice per day. {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro carbonylamino-3-(4-chlorophenyl)butanoic acid panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu hemihydrate together with a Suitable amount of a pharmaceu tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2-me tically acceptable vehicle so as to provide a form for proper thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- oral administration to a patient. In certain embodiments, (4-chlorophenyl)butanoic acid hemihydrate can provide a pharmaceutical compositions provided by the present disclo therapeutically effective concentration of (R)-baclofen in the blood of a patient for a continuous period of time while Sure contain a therapeutically effective amount of crystalline reducing or eliminating adverse drug effects associated with 10 (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro high blood concentrations of (R)-baclofen, e.g., at concentra poxycarbonylamino-3-(4-chlorophenyl)butanoic acid tions above the minimum adverse concentration, that are anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- observed following dosing of (R)-baclofen itself. The high methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo bioavailability of (R)-baclofen that is achievable by adminis rophenyl)butanoic acid hemihydrate together with a suitable tering crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 15 amount of a pharmaceutically acceptable vehicle so as to panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu provide a form for proper oral administration to a patient. tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- Suitable pharmaceutical vehicles include excipients such as methyl-1-(2-methylpropanoyloxy)propoxy starch, glucose, lactose, Sucrose, gelatin, malt, rice, flour, carbonylamino-3-(4-chlorophenyl)butanoic acid chalk, silica gel, Sodium Stearate, glycerol monostearate, talc, hemihydrate may facilitate the use of lower mass equivalents Sodium chloride, dried skim milk, glycerol, propylene, gly of (R)-baclofen in a dose to achieve a sustained therapeuti col, water, ethanol, etc. Pharmaceutical compositions pro cally effective concentration of (R)-baclofen in the blood of a vided by the present disclosure may also contain minor patient, as compared to the amount of (R)-baclofen in a dos amounts of wetting or emulsifying agents or pH buffering age form comprising (R)-baclofen itself. agents. In addition, auxiliary, stabilizing, thickening, lubri In certain embodiments, administration of a Sustained 25 cating and coloring agents may be used. release dosage form comprising crystalline (3R)-4-(1S)-2- methyl-1-(2-methylpropanoyloxy)propoxycarbony Pharmaceutical compositions comprising crystalline (3R)- lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy bonylamino-3-(4-chlorophenyl)butanoic acid anhydrate loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic and/or crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro acid hemihydrate can provide a therapeutically effective con 30 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu centration of (R)-4-amino-3-(4-chlorophenyl)butanoic acid tanoic acid hemihydrate may be manufactured by means of in the blood plasma of a patient for a time period of at least mixing, dissolving, granulating, dragee-making, levigating, about 4 hours after administration of the dosage form, in emulsifying, encapsulating, entrapping, lyophilizing, or certain embodiments for a time period of at least about 8 other process known to those skilled in the art of pharmaceu hours, in certain embodiments for a time period of at least 35 tical formulation. Pharmaceutical compositions may be for about 12 hours, in certain embodiments for a time period of at mulated using one or more pharmaceutically acceptable least about 16 hours, in certain embodiments for a time period vehicles that facilitate processing crystalline (3R)-4-(1S)- of at least about 20 hours, and in certain embodiments, for a 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony time period of at least about 24 hours. lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or In certain embodiments, the concentration of (R)-baclofen 40 crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy in the blood of a patient will not exceed a minimum adverse loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic concentration at any time after crystalline (3R)-4-(1S)-2- acid hemihydrate into oral dosage formulations, such as Sus methyl-1-(2-methylpropanoyloxy)propoxycarbony tained release oral dosage formulations. lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or Pharmaceutical compositions provided by the present dis crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy 45 closure can take the form of Solutions, aqueous or oily Sus loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic pensions, emulsion, tablets, pills, pellets, capsules, capsules acid hemihydrate is administered to the patient. For example, containing liquids, granules, powders, Sustained-release for the concentration of (R)-baclofen in the blood of a patient will not reach a concentration that causes adverse events in the mulations, Suppositories, emulsions, syrups, elixirs or any patient. A therapeutically effective concentration of (R)-ba other form suitable for oral administration. Orally adminis clofen in the blood of a patient may range from about 50 50 tered pharmaceutical compositions may contain one or more ng/mL to about 1,000 ng/mL, and in certain embodiments, optional agents, for example, Sweetening agents such as fruc from about 100 ng/mL to about 500 ng/mL. The pharmaco tose, aspartame or saccharin, flavoring agents such as pepper kinetic profile of the blood (R)-baclofen concentration mint, oil of wintergreen or cherry coloring agents and pre achievable upon administration of crystalline (3R)-4-(1S)- serving agents, to provide a pharmaceutically palatable 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony 55 preparation. Moreover, where in tablet or pill form, the phar lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or maceutical compositions may be coated to delay disintegra crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy tion and absorption in the gastrointestinal tract, thereby pro loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic viding a Sustained action over an extended period of time. acid hemihydrate to a patient can be characterized by a lower Selectively permeable membranes Surrounding an osmoti C/C12 ratio, and a lower C/dose, as compared to for 60 cally active driving compound are also suitable for orally mulations comprising (R)-baclofen itself that provide a simi administering the compounds and compositions disclosed herein. In these later platforms, fluid from the environment lar (R)-baclofen blood AUC, Surrounding the capsule is imbibed by the driving compound, Pharmaceutical Compositions which Swells to displace the agent or agent composition 65 through an aperture. These delivery platforms can provide an Pharmaceutical compositions provided by the present dis essentially Zero order delivery profile as opposed to the closure contain crystalline (3R)-4-(1S)-2-methyl-1-(2-me spiked profiles of immediate release formulations. A time US 9,139,517 B2 41 42 delay material Such as glycerol monostearate or glycerol number of dosage forms provided. Instructions provided with Stearate may also be used. Oral pharmaceutical compositions a kit can include directions for administration and may can include pharmaceutically acceptable vehicles such as include a memory aid. Instructions Supplied with a kit may be mannitol, lactose, starch, magnesium Stearate, sodium sac printed and/or Supplied, for example, as an electronic-read charine, cellulose, magnesium carbonate, and the like. able medium, a video cassette, an audiotape, a flash memory For oral liquid preparations such as, for example, Suspen device, or may be published on an internet web site or dis sions, elixirs and solutions, Suitable vehicles include water, tributed to a patient as an electronic mail. A memory aid may saline, alkyleneglycols (e.g., propylene glycol), polyalkylene be a written memory aid, which contains information and/or glycols (e.g., polyethylene glycol) oils, alcohols, slightly instructions for the physician, pharmacist, and/or patient to acidic buffers between pH 4 and pH 6 (e.g., acetate, citrate, 10 facilitate compliance with a dosing regimen. A memory aid ascorbate at between about 5 mM to about 50 mM), etc. may also be mechanical or electronic. When a therapeutic Additionally, flavoring agents, preservatives, coloring agents, regimen includes administration of crystalline (3R)-4-(1S)- bile salts, acylcarnitines and the like may be added. 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu 15 crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2-me loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- acid hemihydrate and at least one other therapeutic agent, a (4-chlorophenyl)butanoic acid hemihydrate may be kit can include the at least one other therapeutic agent in the formulated in rectal or vaginal compositions such as Supposi same or separate container as the crystalline (3R)-4-(1S)- tories or retention enemas, e.g., containing conventional Sup 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony pository bases such as cocoa butter or other glycerides. lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or In certain embodiments, crystalline (3R)-4-(1S)-2-me crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic (4-chlorophenyl)butanoic acid anhydrate and/or crystalline acid hemihydrate. (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 25 In certain embodiments, a kit comprises a pharmaceutical poxycarbonylamino-3-(4-chlorophenyl)butanoic acid composition comprising crystalline (3R)-4-(1S)-2-methyl hemihydrate can be formulated as a single active agent. In 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- certain embodiments, crystalline (3R)-4-(1S)-2-methyl-1- chlorophenyl)butanoic acid anhydrate and instructions for (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- administering the pharmaceutical composition to a patient in chlorophenyl)butanoic acid anhydrate and crystalline (3R)- 30 need thereof for treating a disease chosen from spasticity, 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy gastroesophageal reflux disease, emesis, cough, Substance carbonylamino)-3-(4-chlorophenyl)butanoic acid addiction and abuse, neuropathic pain and musculoskeletal hemihydrate can be formulated as a mixture. In certain pain. In certain embodiments, a kit comprises a pharmaceu embodiments, crystalline (3R)-4-(1S)-2-methyl-1-(2-me tical composition comprising crystalline (3R)-4-(1S)-2- thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 35 methyl-1-(2-methylpropanoyloxy)propoxycarbony rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- lamino-3-(4-chlorophenyl)butanoic acid hemihydrate and {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy instructions for administering the pharmaceutical composi carbonylamino-3-(4-chlorophenyl)butanoic acid tion to a patient in need thereof for treating a disease chosen hemihydrate can be formulates as a mixture with one or more from spasticity, gastroesophageal reflux disease, emesis, other baclofen prodrugs or salts thereof such as, for example, 40 cough, Substance addiction and abuse, neuropathic pain and (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro musculoskeletal pain. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid. In certain embodiments, a kit comprises a pharmaceutical composition comprising crystalline (3R)-4-(1S)-2-methyl Kits 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- 45 chlorophenyl)butanoic acid anhydrate and instructions for Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro administering the pharmaceutical composition to a patient in panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu need thereof for treating spasticity. In certain embodiments, a tanoic acid anhydrate, or a pharmaceutical composition kit comprises a pharmaceutical composition comprising crys thereof, and/or crystalline (3R)-4-(1S)-2-methyl-1-(2-me talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 50 propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid rophenyl)butanoic acid hemihydrate, or a pharmaceutical hemihydrate and instructions for administering the pharma composition thereof, may be included in a kit that may be ceutical composition to a patient in need thereof for treating used to administer either compound, or both, to a patient for spasticity. treating a disease. A kit can include a pharmaceutical com In certain embodiments, a kit comprises a pharmaceutical position comprising crystalline (3R)-4-(1S)-2-methyl-1- 55 composition comprising crystalline (3R)-4-(1S)-2-methyl (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- chlorophenyl)butanoic acid anhydrate and/or crystalline chlorophenyl)butanoic acid anhydrate and instructions for (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro administering the pharmaceutical composition to a patient in poxycarbonylamino-3-(4-chlorophenyl)butanoic acid need thereof for treating gastroesophageal reflux disease. In hemihydrate Suitable for administration to a patient and 60 certain embodiments, a kit comprises a pharmaceutical com instructions for administering the pharmaceutical composi position comprising crystalline (3R)-4-(1S)-2-methyl-1- tion to a patient. A kit can include one or more containers for (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- containing one or more pharmaceutical compositions and chlorophenyl)butanoic acid hemihydrate and instructions for may include divided containers such as a divided bottle or a administering the pharmaceutical composition to a patient in divided foil packet. A container can be any appropriate shape 65 need thereof for treating gastroesophageal reflux disease. or form made of a pharmaceutically acceptable material. A In certain embodiments, a kit comprises a pharmaceutical particular container can depend on the dosage form and the composition comprising crystalline (3R)-4-(1S)-2-methyl US 9,139,517 B2 43 44 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- composition thereof, can generally be used in an amount that chlorophenyl)butanoic acid anhydrate and instructions for is effective to achieve the intended purpose. Such as to treat a administering the pharmaceutical composition to a patient in disease or disorder selected from spasticity, gastroesophageal need thereof for treating Substance addiction or abuse. In reflux disease, emesis, cough, Substance addiction and abuse, certain embodiments, a kit comprises a pharmaceutical com 5 neuropathic pain and/or musculoskeletal pain. Crystalline position comprising crystalline (3R)-4-(1S)-2-methyl-1- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid chlorophenyl)butanoic acid hemihydrate and instructions for anhydrate, or a pharmaceutical composition thereof, can be administering the pharmaceutical composition to a patient in administered in a therapeutically effective amount. Crystal need thereof for treating Substance addiction or abuse. 10 line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro In certain embodiments, a kit comprises a pharmaceutical composition comprising crystalline (3R)-4-(1S)-2-methyl poxycarbonylamino-3-(4-chlorophenyl)butanoic acid 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- hemihydrate, or a pharmaceutical composition thereof, can chlorophenyl)butanoic acid anhydrate and instructions for be administered in a therapeutically effective amount. administering the pharmaceutical composition to a patient in 15 The amount of crystalline (3R)-4-(1S)-2-methyl-1-(2- need thereof for treating cough. In certain embodiments, a kit methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo comprises a pharmaceutical composition comprising crystal rophenyl)butanoic acid anhydrate, or a pharmaceutical com line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro position thereof, and/or the amount of crystalline (3R)-4- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo hemihydrate and instructions for administering the pharma nylamino-3-(4-chlorophenyl)butanoic acid hemihydrate, or ceutical composition to a patient in need thereof for treating a pharmaceutical composition thereof, that will be effective in cough. the treatment of a particular disease or disorder will depend In certain embodiments, a kit comprises a pharmaceutical on the nature of the disorder or condition, and can be deter composition comprising crystalline (3R)-4-(1S)-2-methyl mined by standard clinical techniques known in the art as 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- 25 previously described. In addition, in vitro or in vivo assays chlorophenyl)butanoic acid anhydrate and instructions for may optionally be employed to help identify optimal dosage administering the pharmaceutical composition to a patient in ranges. The amount of crystalline (3R)-4-(1S)-2-methyl-1- need thereoffortreating emesis. In certain embodiments, a kit (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- comprises a pharmaceutical composition comprising crystal chlorophenyl)butanoic acid anhydrate, or a pharmaceutical line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 30 composition thereof, and/or the amount of crystalline (3R)- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar hemihydrate and instructions for administering the pharma bonylamino-3-(4-chlorophenyl)butanoic acid hemihydrate, ceutical composition to a patient in need thereof for treating emesis. or a pharmaceutical composition thereof, administered will In certain embodiments, a kit comprises a pharmaceutical 35 depend on, among other factors, the Subject being treated, the composition comprising crystalline (3R)-4-(1S)-2-methyl weight of the subject, the severity of the affliction, the manner 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- of administration and the judgment of the prescribing physi chlorophenyl)butanoic acid anhydrate and instructions for C1a. administering the pharmaceutical composition to a patient in A dose of crystalline (3R)-4-(1S)-2-methyl-1-(2-meth need thereof for treating neuropathic pain. In certain embodi 40 ylpropanoyloxy)propoxycarbonylamino-3-(4-chlorophe ments, a kit comprises a pharmaceutical composition com nyl)butanoic acid anhydrate and/or a dose of crystalline (3R)- prising crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) carbonylamino-3-(4-chlorophenyl)butanoic acid butanoic acid hemihydrate and instructions for administering hemihydrate can be adjusted to provide an equivalent molar the pharmaceutical composition to a patient in need thereof 45 quantity or mass equivalent dose of (R)-baclofen. A dose can for treating neuropathic pain. comprise multiple dosage forms. Therapeutically effective In certain embodiments, a kit comprises a pharmaceutical doses of (R)-baclofen are generally from about 0.03 mg to composition comprising crystalline (3R)-4-(1S)-2-methyl about 1 mg per kilogram body weight per day. In certain 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- embodiments, a daily dose can comprise a mass equivalent of chlorophenyl)butanoic acid anhydrate and instructions for 50 (R)-baclofen ranging from about 1 mg to about 100 mg, in administering the pharmaceutical composition to a patient in certain embodiments, from about 5 mg to about 80 mg, in need thereof for treating musculoskeletal pain. In certain certain embodiments, from about 5 mg to about 60 mg, and in embodiments, a kit comprises a pharmaceutical composition certain embodiments, from about 10 mg to about 40 mg. In comprising crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl certain embodiments, a dose of crystalline (3R)-4-(1S)-2- propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) 55 methyl-1-(2-methylpropanoyloxy)propoxycarbony butanoic acid hemihydrate and instructions for administering lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or a the pharmaceutical composition to a patient in need thereof dose of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro for treating musculoskeletal pain. panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu tanoic acid hemihydrate is less than a dose that causes mod Dose 60 erate sedation and impairment of motor activity in a patient. The dose of crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu butanoic acid anhydrate and/or the dose of crystalline (3R)- tanoic acid anhydrate, or a pharmaceutical composition 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy thereof, and/or crystalline (3R)-4-(1S)-2-methyl-1-(2-me 65 carbonylamino-3-(4-chlorophenyl)butanoic acid thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo hemihydrate, and appropriate dosing intervals, can be rophenyl)butanoic acid hemihydrate, or a pharmaceutical selected to maintain a Sustained therapeutically effective con US 9,139,517 B2 45 46 centration of (R)-baclofen in the blood of a patient, and in {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy certain embodiments, without exceeding a minimum adverse carbonylamino-3-(4-chlorophenyl)butanoic acid concentration. hemihydrate that causes moderate sedation and impairment A dose may be delivered in a pharmaceutical composition of motor activity in a patient. by a single administration or by multiple applications of one A dosage regimen employing oral administration of a dose or more dosage forms. In certain embodiments, crystalline or multiple doses of crystalline (3R)-4-(1S)-2-methyl-1-(2- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo poxycarbonylamino-3-(4-chlorophenyl)butanoic acid rophenyl)butanoic acid anhydrate, or a pharmaceutical com anhydrate, or a pharmaceutical composition thereof, and/or position thereof, and/or a dose or multiple doses of crystalline crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy 10 (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic poxycarbonylamino-3-(4-chlorophenyl)butanoic acid acid hemihydrate, or a pharmaceutical composition thereof, hemihydrate, or a pharmaceutical composition thereof, may can be delivered by oral sustained release administration. A be developed to maintain a concentration of (R)-baclofen in Sustained release formulation comprising crystalline (3R)-4- the blood of a patient that is greater than a minimum thera {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo 15 peutically effective concentration and less than a minimum nylamino-3-(4-chlorophenyl)butanoic acid anhydrate, or a adverse concentration for a prolonged period of time. In cer pharmaceutical composition thereof, and/or a Sustained tain embodiments, a minimum therapeutically effective con release formulation comprising crystalline (3R)-4-(1S)-2- centration of (R)-baclofen may range from about 1 ng/mL to methyl-1-(2-methylpropanoyloxy)propoxycarbony about 200 ng/mL, and in certain embodiments, can range lamino-3-(4-chlorophenyl)butanoic acid hemihydrate, or a from about 10 ng/mL to about 100 ng/mL. In certain embodi pharmaceutical composition thereof, can be administered ments, a minimum adverse concentration can range from once per day, twice per day and, in certain embodiments, at about 200 ng/mL to about 2,000 ng/mL, and in certain intervals greater than twice per day. Dosing may be repeated embodiments, can range from about 500 ng/mL to about intermittently, may be provided alone or in combination with 1,000 ng/mL. A minimum therapeutic concentration and a other drugs, and may continue as long as required for effec 25 minimum adverse concentration will depend on a number of tive treatment of the disease or disorder. Dosing includes factors such as the disease being treated, the severity of the administering a dosage form to a mammal, such as a human, disease, the intended clinical outcome, the condition of the in a fed or fasted state. patient being treated, and so forth. An appropriate interval of Appropriate dosage ranges for treating a particular disease dosing may depend, for example, on the amount of crystalline may be readily determined by methods known to the skilled 30 (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro artisan. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid In certain embodiments, a dose or multiple doses of crys anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid rophenyl)butanoic acid hemihydrate in the dosage form, the anhydrate, or a pharmaceutical composition thereof, and/or a 35 composition of the dosage form, the release characteristics of dose or multiple doses of crystalline (3R)-4-(1S)-2-methyl crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic chlorophenyl)butanoic acid hemihydrate, or a pharmaceuti acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- cal composition thereof, can provide between about 10 (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- mg/day and about 2,000 mg/day of (R)-baclofen, in certain 40 chlorophenyl)butanoic acid hemihydrate from the dosage embodiments between about 50 mg/day and about 1,000 form, the disease being treated, the condition of the patient, mg/day of (R)-baclofen, and in certain embodiments, the potential adverse effects, and the judgment of the pre between about 100 mg/day and about 600 mg/day of (R)- scribing physician. Dosage regimens may include repeated baclofen. administration of the same dosage form at each interval or In certain embodiments, a dose or multiple doses of crys 45 different dosage forms at different intervals. For example, a talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) twice-daily dosage regimen can include the administration of propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid a first dosage form in the morning, and a second dosage form anhydrate, or a pharmaceutical composition thereof, and/or a in the evening. dose or multiple doses of crystalline (3R)-4-(1S)-2-methyl Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- 50 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu chlorophenyl)butanoic acid hemihydrate, or a pharmaceuti tanoic acid anhydrate, or a pharmaceutical composition cal composition thereof, is administered to a patient at a dose thereof, and/or crystalline (3R)-4-(1S)-2-methyl-1-(2-me of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic rophenyl)butanoic acid hemihydrate, or a pharmaceutical acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- 55 composition thereof, can be assayed in vitro and in Vivo, for (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- the desired therapeutic or prophylactic activity, prior to use in chlorophenyl)butanoic acid hemihydrate ranging from about humans. A therapeutically effective dose of crystalline (3R)- 5 mg to about 140 mg, and in certain embodiments, from 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar about 10 mg to about 120 mg. In certain embodiments, the bonylamino-3-(4-chlorophenyl)butanoic acid anhydrate, or dose of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 60 a pharmaceutical composition thereof, and/or a therapeuti panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu cally effective dose of crystalline (3R)-4-(1S)-2-methyl-1- tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2-me (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- chlorophenyl)butanoic acid hemihydrate, or a (4-chlorophenyl)butanoic acid hemihydrate administered is pharmaceutical composition thereof, can provide therapeutic less than a dose of crystalline (3R)-4-(1S)-2-methyl-1-(2- 65 benefit without causing Substantial toxicity and/or adverse methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo side effects. The toxicity and adverse side effects of crystal rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro US 9,139,517 B2 47 48 poxycarbonylamino-3-(4-chlorophenyl)butanoic acid propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid anhydrate, or a pharmaceutical composition thereof, and/or anhydrate, or the other therapeutic agent can be in a different of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy pharmaceutical composition. In certain embodiments, a phar loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic maceutical composition comprising crystalline (3R)-4- acid hemihydrate, or a pharmaceutical composition thereof, {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo may be determined using standard pharmaceutical proce nylamino-3-(4-chlorophenyl)butanoic acid hemihydrate dures and may be readily ascertained by the skilled artisan. can be administered concurrently with the administration of The dose ratio between toxic and adverse side effects and another therapeutic agent, which can be part of the same therapeutic effect is the therapeutic index. A dose of crystal pharmaceutical composition as crystalline (3R)-4-(1S)-2- line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 10 methyl-1-(2-methylpropanoyloxy)propoxycarbony poxycarbonylamino-3-(4-chlorophenyl)butanoic acid lamino-3-(4-chlorophenyl)butanoic acid hemihydrate, or anhydrate, or a pharmaceutical composition thereof, and/or a the other therapeutic agent can be in a different pharmaceu dose of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro tical composition. In certain embodiments, a pharmaceutical panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu composition comprising crystalline (3R)-4-(1S)-2-methyl tanoic acid hemihydrate, or a pharmaceutical composition 15 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- thereof, can provide a circulating concentration of (R)-ba chlorophenyl)butanoic acid anhydrate, and/or a pharmaceu clofen that is within a therapeutically effective concentration tical composition comprising crystalline (3R)-4-(1S)-2- with little or no toxicity or adverse side effects. methyl-1-(2-methylpropanoyloxy)propoxy carbonylamino-3-(4-chlorophenyl)butanoic acid Combination Therapy hemihydrate, can be administered prior to or Subsequent to administration of another therapeutic agent. Dosage forms comprising crystalline (3R)-4-(1S)-2-me In certain embodiments, crystalline (3R)-4-(1S)-2-me thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- (4-chlorophenyl)butanoic acid anhydrate, or a pharmaceuti (4-chlorophenyl)butanoic acid anhydrate and/or crystalline cal composition thereof, and/or dosage forms comprising 25 (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy poxycarbonylamino-3-(4-chlorophenyl)butanoic acid loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic hemihydrate may be administered in combination with an acid hemihydrate, or a pharmaceutical composition thereof, amorphous form of (3R)-4-(1S)-2-methyl-1-(2-methylpro may further comprise one or more pharmaceutically active panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu compounds in addition to crystalline (3R)-4-(1S)-2-me 30 tanoic acid; other crystalline form(s) of (3R)-4-(1S)-2-me thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- (4-chlorophenyl)butanoic acid anhydrate and/or crystalline (4-chlorophenyl)butanoic acid; baclofen; (R)-baclofen; or a (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro combination of any of the foregoing. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid In certain embodiments, crystalline (3R)-4-(1S)-2-me hemihydrate. Such compounds may be provided to treat the 35 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- same disease or a different disease than the disease being (4-chlorophenyl)butanoic acid anhydrate and/or crystalline treated with crystalline (3R)-4-(1S)-2-methyl-1-(2-meth (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro ylpropanoyloxy)propoxycarbonylamino-3-(4-chlorophe poxycarbonylamino-3-(4-chlorophenyl)butanoic acid nyl)butanoic acid anhydrate and/or crystalline (3R)-4-(1S)- hemihydrate may be used in combination with at least one 2-methyl-1-(2-methylpropanoyloxy)propoxy 40 other therapeutic agent. In certain embodiments, crystalline carbonylamino-3-(4-chlorophenyl)butanoic acid (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro hemihydrate. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid In certain embodiments, crystalline (3R)-4-(1S)-2-me anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo (4-chlorophenyl)butanoic acid anhydrate, or a pharmaceuti 45 rophenyl)butanoic acid hemihydrate may be administered to cal composition thereof, can be used in combination therapy a patient together with another compound for treating move with at least one other therapeutic agent. Crystalline (3R)-4- ment disorders such as spasticity, digestive disorders such as {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo gastro-esophageal reflux disease and emesis, or addictive or nylamino-3-(4-chlorophenyl)butanoic acid anhydrate, or a abuse disorders such as nicotine addiction or abuse, alcohol pharmaceutical composition thereof, and the at least one 50 addiction or abuse, narcotic addiction or abuse, cough, neu other therapeutic agent can act additively or synergistically. ropathic pain, or musculoskeletal pain. In certain embodi In certain embodiments, crystalline (3R)-4-(1S)-2-methyl ments, the at least one other therapeutic agent may be a 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- different (R)-baclofen prodrug. Crystalline (3R)-4-(1S)-2- chlorophenyl)butanoic acid hemihydrate, or a pharmaceuti methyl-1-(2-methylpropanoyloxy)propoxycarbony cal composition thereof, can be used in combination therapy 55 lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or with at least one other therapeutic agent. Crystalline (3R)-4- crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic nylamino-3-(4-chlorophenyl)butanoic acid hemihydrate, or acid hemihydrate and the at least one other therapeutic agent a pharmaceutical composition thereof, and the at least one may act additively or, in certain embodiments, synergisti other therapeutic agent can act additively or synergistically. 60 cally. In certain embodiments, a pharmaceutical composition Accordingly, methods provided by the present disclosure comprising crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl can further include, in addition to administering crystalline propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro butanoic acid anhydrate can be administered concurrently poxycarbonylamino-3-(4-chlorophenyl)butanoic acid with the administration of another therapeutic agent, which 65 anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- can be part of the same pharmaceutical composition as crys methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo talline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) rophenyl)butanoic acid hemihydrate, administering one or US 9,139,517 B2 49 50 more therapeutic agents effective for treating the same dis stances to enhance, modulate and/or control release, bioavail ease as, or a different disease than, the disease being treated ability, therapeutic efficacy, therapeutic potency, stability, by crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro and the like of crystalline (3R)-4-(1S)-2-methyl-1-(2-me panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2-me rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy (4-chlorophenyl)butanoic acid hemihydrate. Methods carbonylamino-3-(4-chlorophenyl)butanoic acid provided by the present disclosure include administration of hemihydrate. For example, to enhance the therapeutic effi crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy cacy of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic 10 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- methyl-1-(2-methylpropanoyloxy)propoxy chlorophenyl)butanoic acid hemihydrate and one or more carbonylamino-3-(4-chlorophenyl)butanoic acid other therapeutic agents, provided, however, that the com hemihydrate or the metabolite of such compounds, (R)-ba bined administration does not inhibit the therapeutic efficacy 15 clofen, crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- methyl-1-(2-methylpropanoyloxy)propoxy (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- carbonylamino-3-(4-chlorophenyl)butanoic acid chlorophenyl)butanoic acid hemihydrate and/or does not pro hemihydrate may be co-administered with, or a dosage form duce adverse combination effects. comprising crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl In certain embodiments, crystalline (3R)-4-(1S)-2-me propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- butanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- (4-chlorophenyl)butanoic acid anhydrate and/or crystalline methyl-1-(2-methylpropanoyloxy)propoxy (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 25 carbonylamino-3-(4-chlorophenyl)butanoic acid poxycarbonylamino-3-(4-chlorophenyl)butanoic acid hemihydrate may comprise, one or more active agents that act hemihydrate may be administered concurrently with the to increase the absorption or diffusion of crystalline (3R)-4- administration of another therapeutic agent, which may be {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo part of the same dosage form as, or in a different dosage form nylamino-3-(4-chlorophenyl)butanoic acid anhydrate and/ than that comprising crystalline (3R)-4-(1S)-2-methyl-1- 30 O crystalline (3R)-4-(1S)-2-methyl-1-(2- (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- methylpropanoyloxy)propoxycarbonylamino-3-(4- chlorophenyl)butanoic acid anhydrate and/or crystalline chlorophenyl)butanoic acid hemihydrate or (R)-baclofen (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro from the gastrointestinal tract to the systemic circulation, or poxycarbonylamino-3-(4-chlorophenyl)butanoic acid to inhibit degradation of crystalline (3R)-4-(1S)-2-methyl hemihydrate. Crystalline (3R)-4-(1S)-2-methyl-1-(2-me 35 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- thylpropanoyloxy)propoxycarbonylamino-3-(4-chlo chlorophenyl)butanoic acid anhydrate and/or crystalline rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy poxycarbonylamino-3-(4-chlorophenyl)butanoic acid carbonylamino-3-(4-chlorophenyl)butanoic acid hemihydrate or (R)-baclofen in the blood of a patient. In hemihydrate may be administered prior to, or Subsequent to, 40 certain embodiments, crystalline (3R)-4-(1S)-2-methyl-1- administration of another therapeutic agent. In certain (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- embodiments of combination therapy, the combination chlorophenyl)butanoic acid anhydrate and/or crystalline therapy may comprise alternating between: administering (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy poxycarbonylamino-3-(4-chlorophenyl)butanoic acid loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic 45 hemihydrate may be co-administered with an active agent acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- having pharmacological affects that enhance the therapeutic (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- efficacy of crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl chlorophenyl)butanoic acid hemihydrate; and administering propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) a composition comprising another therapeutic agent, e.g., to butanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- minimize adverse drug effects associated with a particular 50 methyl-1-(2-methylpropanoyloxy)propoxy drug. When crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl carbonylamino-3-(4-chlorophenyl)butanoic acid propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) hemihydrate. butanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- Additionally, crystalline (3R)-4-(1S)-2-methyl-1-(2- methyl-1-(2-methylpropanoyloxy)propoxy methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo carbonylamino-3-(4-chlorophenyl)butanoic acid 55 rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- hemihydrate is administered concurrently with another thera {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy peutic agent that may potentially produce an adverse drug carbonylamino-3-(4-chlorophenyl)butanoic acid effect including, but not limited to, toxicity, the other thera hemihydrate may be used in combination with other drugs peutic agent may advantageously be administered at a dose that are themselves known to cause spasticity, gastroesoph that falls below the threshold at which the adverse drug reac 60 ageal reflux disease, emesis, cough, Substance addiction and tion is elicited. abuse, neuropathic pain and/or musculoskeletal pain as an In certain embodiments, crystalline (3R)-4-(1S)-2-me adverse effect, thereby preventing or reducing the occurrence thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- of such adverse effects. (4-chlorophenyl)butanoic acid anhydrate and/or crystalline In certain embodiments, crystalline (3R)-4-(1S)-2-me (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 65 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid (4-chlorophenyl)butanoic acid anhydrate and/or crystalline hemihydrate may be administered with one or more sub (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro US 9,139,517 B2 51 52 poxycarbonylamino-3-(4-chlorophenyl)butanoic acid inoids such as dronabinol; and benzodiazepines such as hemihydrate may be administered to a patient for treating a lorazepam, midazolam, alprazolam, and olanzapine. movement disorder Such as spasticity in combination with a In certain embodiments, crystalline (3R)-4-(1S)-2-me therapy or another therapeutic agent known or believed to be thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- effective in treating a movement disorder Such as spasticity. (4-chlorophenyl)butanoic acid anhydrate and/or crystalline Examples of drugs for treating movement disorders such as (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro spasticity and which may be administered in conjunction with poxycarbonylamino-3-(4-chlorophenyl)butanoic acid crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy hemihydrate may be administered to a patient for treating loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic alcohol addiction or abuse in combination with a therapy or acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- 10 another therapeutic agent known or believed to be effective in (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- treating alcohol addiction or abuse. Examples of drugs for chlorophenyl)butanoic acid hemihydrate include levodopa; treating alcohol addiction or abuse and which may be admin mild sedatives Such as benzodiazepines including alpra istered in conjunction with crystalline (3R)-4-(1S)-2-me Zolam, chlordiazepoxide, clonazepam, cloraZepate, diaz thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- epam, lorazepam, and oxazepam, muscle relaxants such as 15 (4-chlorophenyl)butanoic acid anhydrate and/or crystalline baclofen; anticholinergic drugs such as trihexyphenidyl and (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro diphenhydramine; antipsychotics such as chlorpromazine, poxycarbonylamino-3-(4-chlorophenyl)butanoic acid fluiphenazine, haloperidol, loxapine, mesoridazine, molin hemihydrate include disulfuram, naltrexone, clonidine, done, perphenazine, pimozide, thioridazine, thiothixene, tri methadone, 1-alpha-acetylmethadol, buprenorphine, and fluoperazine, aripiprazole, clozapine, olanzapine, quetiapine, bupropion. risperidone, and Ziprasidone; and antidepressants such as In certain embodiments, crystalline (3R)-4-(1S)-2-me amitriptyline. thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- In certain embodiments, crystalline (3R)-4-(1S)-2-me (4-chlorophenyl)butanoic acid anhydrate and/or crystalline thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro (4-chlorophenyl)butanoic acid anhydrate and/or crystalline 25 poxycarbonylamino-3-(4-chlorophenyl)butanoic acid (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro hemihydrate may be administered to a patient for treating poxycarbonylamino-3-(4-chlorophenyl)butanoic acid narcotic addiction or abuse in combination with a therapy or hemihydrate may be administered to a patient for treating a another therapeutic agent known or believed to be effective in gastrointestinal disorder Such as gastro-esophageal reflux dis treating narcotic addiction or abuse. Examples of drugs for ease in combination with a therapy or another therapeutic 30 treating narcotic addiction or abuse and which may be admin agent known or believed to be effective in treating a gas istered in conjunction with crystalline (3R)-4-(1S)-2-me trointestinal disorder such as gastro-esophageal reflux dis thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- ease. Examples of drugs for treating gastrointestinal disor (4-chlorophenyl)butanoic acid anhydrate and/or crystalline ders such as gastro-esophageal reflux disease and which may (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro be administered in conjunction with crystalline (3R)-4- 35 poxycarbonylamino-3-(4-chlorophenyl)butanoic acid {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo hemihydrate include buprenorphine, tramadol, methadone, nylamino-3-(4-chlorophenyl)butanoic acid anhydrate and/ and naltrexone. or crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy In certain embodiments, crystalline (3R)-4-(1S)-2-me loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- acid hemihydrate include H-receptor inhibitors such as 40 (4-chlorophenyl)butanoic acid anhydrate and/or crystalline cimetidine, famotidine, nizatidine, and ranitidine; proton (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro pump inhibitors such as omeprazole, lanSoprazole, pantopra poxycarbonylamino-3-(4-chlorophenyl)butanoic acid Zole, rabeprazole, and exomeprazole; and prokinetics such as hemihydrate may be administered to a patient for treating cisparide, bethanechol, and metoclopramide. nicotine addiction or abuse in combination with a therapy or In certain embodiments, crystalline (3R)-4-(1S)-2-me 45 another therapeutic agent known or believed to be effective in thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- treating nicotine addiction or abuse. Examples of drugs for (4-chlorophenyl)butanoic acid anhydrate and/or crystalline treating nicotine addiction or abuse and which may be admin (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro istered in conjunction with crystalline (3R)-4-(1S)-2-me poxycarbonylamino-3-(4-chlorophenyl)butanoic acid thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- hemihydrate may be administered to a patient for treating 50 (4-chlorophenyl)butanoic acid anhydrate and/or crystalline emesis in combination with a therapy or another therapeutic (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro agent known or believed to be effective in treating emesis. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid Examples of drugs for treating emesis (nausea and Vomiting) hemihydrate include bupropion, clonidine, and nicotine. and which may be administered in conjunction with crystal In certain embodiments, crystalline (3R)-4-(1S)-2-me line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 55 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid (4-chlorophenyl)butanoic acid anhydrate and/or crystalline anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo poxycarbonylamino-3-(4-chlorophenyl)butanoic acid rophenyl)butanoic acid hemihydrate include benzamines hemihydrate may be administered to a patient for treating Such as metoclopramide, phenothiazines Such as prochlor 60 cough in combination with a therapy or another therapeutic perazine, perphenazine, chlorpromazine, promethazine, and agent known or believed to be effective in treating cough. thiethylperazine; butyrophenones such as droperidol and Examples of drugs for treating cough and which may be haloperidol; dopamine 2 antagonists such as metoclorpam administered in conjunction with crystalline (3R)-4-(1S)- ide; 5-HT antagonists such as ondansetron, granisetron, 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony dolasetron, palomosetron; NK-1 receptor antagonists Such as 65 lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or aprepitant, corticosteroids such as dexamethaZone; antihista crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy mines such as diphenhydramine and hydroxy Zine; cannab loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic US 9,139,517 B2 53 54 acid hemihydrate include dextromethorphan, guaifenesin, In certain embodiments, a drug useful for treating neuro hydrocodone, benzonatate, diphenhydramine, pseudoephe pathic pain and which may be administered in conjunction drine, acetaminophen, and carbinoxamine. with crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro In certain embodiments, crystalline (3R)-4-(1S)-2-me panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2-me (4-chlorophenyl)butanoic acid anhydrate and/or crystalline thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro (4-chlorophenyl)butanoic acid hemihydrate is chosen from a poxycarbonylamino-3-(4-chlorophenyl)butanoic acid nicotine receptor partial agonist and an analgesic agent as hemihydrate may be administered to a patient for treating disclosed by Coe et al., U.S. Patent Application Publication neuropathic pain in combination with a therapy or another 10 No. 2003/0133951; a 1-aryl-3-azabicyclo[3.1.0) hexane as therapeutic agent known or believed to be effective in treating disclosed by Lippa et al., U.S. Patent Application Publication neuropathic pain. Examples of drugs useful for treating pain No. 2007/00892939; and a nitro (cyano)Vinylpiperazine com and which may be administered in conjunction with crystal pound as disclosed by Sun and Tafesse, U.S. Patent Applica line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro tion Publication No. 2007/0032500. poxycarbonylamino-3-(4-chlorophenyl)butanoic acid 15 Non-pharmacological therapies for treating neuropathic anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- pain and which may be administered in conjunction with methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy rophenyl)butanoic acid hemihydrate include opioid analge loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic sics such as morphine, codeine, fentanyl, meperidine, acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- methadone, propoxyphene, levorphanol, hydromorphone, (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- oxycodone, oxymorphone, tramadol and pentazocine; nono chlorophenyl)butanoic acid hemihydrate include transcuta pioid analgesics Such as aspirin, ibuprofen, ketoprofen, neous electrical nerve stimulation, percutaneous electrical naproxen, and acetaminophen; non-steroidal anti-inflamma nerve stimulation, and acupuncture. tory drugs such as aspirin, choline magnesium trisalicylate, In certain embodiments, crystalline (3R)-4-(1S)-2-me diflunisal, salsalate, celecoxib, rofecoxib, Valdecoxib, 25 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- diclofenac, etodolac, fenoprofen, flubiprofen, ibuprofen, (4-chlorophenyl)butanoic acid anhydrate and/or crystalline indomethacin, ketoprofen, ketorolac, meclofanamate, mefe (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro namic acid, meloxicam, nabumetone, naproxen, oxaprozin, poxycarbonylamino-3-(4-chlorophenyl)butanoic acid piroXicam, Sulindac, and tometin; antiepileptics Such as gaba hemihydrate may be administered to a patient for treating pentin, pregabalin, carbamazepine, phenyloin, lamotrigine, 30 fibromyalgia in combination with a therapy or another thera and topiramate; antidepressants such as duloxetine, amitrip peutic agent known or believed to be effective in treating tyline, Venlafaxine, nortryptyline, imipramine, and fibromyalgia, or in certain embodiments, a disease, disorder, desipramine; local anesthetics such as lidocaine, and mexi or condition associated with fibromyalgia. Drug therapy for letine; NMDA receptor antagonists such as dextropethor fibromyalgia may be tailored to the severity and frequency of phan, memantine, and ketamine; N-type calcium-channel 35 fibromyalgia episodes. For occasional episodes, acute treat blockers such as Ziconotide; Vanilloid receptor-1 modulators ment may be indicated. For fibromyalgia episodes occurring Such as capsaicin; cannabinoid receptor modulators such as two or more times per month, or when attacks greatly impact sativeX: neurokinin receptor antagonists such as lanepitant; the patient’s daily life, chronic therapy on an ongoing basis other analgesics such as neurotropin; and other drugs such as may be appropriate. desipramine, clonazepam, divalproex, oXcarbazepine, dival 40 Treatments for fibromyalgia that reduce the frequency of proex, butorphanol, Valdecoxib, Vicoprofen, pentazocine, episodes and which may be administered in conjunction with propoxyhene, fenoprofen, piroxicam, indometnacin, hydrox crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy yZine, buprenorphine, benzocaine, clonidine, flurbiprofen, loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic meperidine, lacosamide, desvenlafaxine, and bicifadine. acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- In certain embodiments, a drug useful for treating neuro 45 (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- pathic pain and which may be administered in conjunction chlorophenyl)butanoic acid hemihydrate include non-steroi with crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro dal anti-inflammatory agents (NSAIDs), adrenergic beta panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu blockers, calcium channel blockers, tricyclic antidepressants, tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2-me selective serotonin reuptake inhibitors, anticonvulsants, thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- 50 NMDA receptor antagonists, dopamine agonists, selective (4-chlorophenyl)butanoic acid hemihydrate is chosen from 5-HT receptor antagonists, opioids, muscle relaxants, seda propoxyphene, meperidine, hydromorphone, hydrocodone, tive hypnotics, and other therapy. Examples of NSAIDs use morphine, codeine, 2-piperidinol-1-alkanol, eliprodil, ifen ful for treating fibromyalgia and which may be administered prodil, rofecoxib, celecoxib, salicylic acid, diclofenac, in conjunction with crystalline (3R)-4-(1S)-2-methyl-1-(2- piroXicam indomethacin, ibuprofen, naproxen, gabapentin, 55 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo carbemazepine, pregabalin, topiramate, valproic acid, rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- Sumatriptan, elitriptan, rizatriptan, Zolmitriptan, naratriptan, {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy flexeril, carisoprodol, robaxisal, norgesic, dantrium, diaz carbonylamino-3-(4-chlorophenyl)butanoic acid epam, chlordiazepoxide, alprazolam, lorazepam, acetami hemihydrate include aspirin, ibuprofen, fenoprofen, flurbi nophen, nitrous oxide, halothane, lidocaine, etidocaine, ropi 60 profen, ketoprofen, mefenamic acid, and naproxen. vacaine, chloroprocaine, Sarapin, bupivacaine, capsicin, Examples of adrenergic beta-blockers useful for treating desipramine, amitriptyline, doxepin, perphenazine, protrip fibromyalgia and which may be administered in conjunction tyline, tranylcypromine, baclofen, clonidine, mexelitine, with crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro diphenhydramine, hydroxyzine, caffeine, prednisone, panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu methyl-prednisone, decadron, Sertraline, paroxetine, fluoxet 65 tanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2-me ine, tramadol, levodopa, dextromethorphan, Substance P thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- antagonists, and botulinum toxin. (4-chlorophenyl)butanoic acid hemihydrate include US 9,139,517 B2 55 56 acebutolol, atenolol, imilol, metoprolol, nadolol, pindolol. acid hemihydrate are tramadol, oxycodone, and methadone. propranolol, and timolol. Examples of calcium channel An example of a muscle relaxant useful for treating fibromy blockers useful for treating fibromyalgia and which may be algia and which may be administered in conjunction with administered in conjunction with crystalline (3R)-4-(1S)- crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony 5 loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic chlorophenyl)butanoic acid hemihydrate is cyclobenzaprine. acid hemihydrate include amlodipine, diltiazem, dotarizine, Examples of therapies useful for treating fibromyalgia and felodipine, flunarizine, nicardipine, nifedipine, nimodipine, 10 which may be administered in conjunction with crystalline nisoldipine, and Verapamil. Examples of tricyclic antidepres (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro sants useful for treating fibromyalgia and which may be poxycarbonylamino-3-(4-chlorophenyl)butanoic acid administered in conjunction with crystalline (3R)-4-(1S)- anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or 15 rophenyl)butanoic acid hemihydrate include exercise, inter crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy feron, growth hormone, hormone therapy, diet low in animal loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic fat and high in fiber, and complementary therapies such as acid hemihydrate include amitriptyline, desipramine, dox counseling/psychotherapy, relaxation training, progressive epin, imipramine, nortriptyline, cyclobenzaprine, and prot muscle relaxation, guided imagery, diaphragmatic breathing, riptyline. Examples of selective serotonin reuptake inhibitors biofeedback, acupuncture, and physical and massage therapy. useful for treating fibromyalgia and which may be adminis Acute fibromyalgia treatments intended to eliminate or tered in conjunction with crystalline (3R)-4-(1S)-2-methyl reduce the severity of muscular/skeletal pain and any associ 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- ated symptoms, and which may be administered in conjunc chlorophenyl)butanoic acid anhydrate and/or crystalline tion with crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 25 propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) poxycarbonylamino-3-(4-chlorophenyl)butanoic acid butanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- hemihydrate include fluoxetine, methysergide, nefazodone, methyl-1-(2-methylpropanoyloxy)propoxy paroxetine, Sertraline, citalopram, and Venlafaxine. Examples carbonylamino-3-(4-chlorophenyl)butanoic acid of otherantidepressants useful for treatingg fibromyalgia and hemihydrate, include serotonin receptor agonists, such as which may be administered in conjunction with crystalline 30 triptans (5-hydroxytryptophan (5-HTP) agonists), for (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro example, almotriptan, eletriptan, froVatriptan, naratriptan, poxycarbonylamino-3-(4-chlorophenyl)butanoic acid rizatriptan, Sumatriptan, and Zolmitriptan; ergotamine-based anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- compounds such as dihydroergotamine and ergotamine; anti methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo emetics Such as metoclopramide and prochlorperazine; and rophenyl)butanoic acid hemihydrate include bupropion, 35 compounds that provide analgesic effects. nefazodone, norepinephrine, Venlafaxine, dulloxetine, and Other examples of drugs useful in treating fibromyalgia traZodone. Examples of anticonvulsants (antiepileptics) use and which may be administered in conjunction with crystal ful for treating fibromyalgia and which may be administered line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro in conjunction with crystalline (3R)-4-(1S)-2-methyl-1-(2- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 40 anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy rophenyl)butanoic acid hemihydrate include acetaminophen carbonylamino-3-(4-chlorophenyl)butanoic acid aspirin, caffeine, cyproheptadine, methysergide, Valproic hemihydrate include divalproex sodium, felbamate, gabapen acid; NSAIDs such as diclofenac, flurbiprofen, ketaprofen, tin, lamotrigine, levetiracetam, oXcarbazepine, tiagabine, 45 ketorolac, ibuprofen, indomethacin, meclofenamate, and topiramate, valproate, and Zonisamide. Examples of NMDA naproxen Sodium; opioids such as codeine, meperidine, and receptor antagonists useful for treating fibromyalgia and oxycodone; and glucocorticoids such as dexamethasone, which may be administered in conjunction with crystalline prednisone, and methylprednisolone. (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro In certain embodiments, crystalline (3R)-4-(1S)-2-me poxycarbonylamino-3-(4-chlorophenyl)butanoic acid 50 thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1-(2- (4-chlorophenyl)butanoic acid anhydrate and/or crystalline methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro rophenyl)butanoic acid hemihydrate include dextromethor poxycarbonylamino-3-(4-chlorophenyl)butanoic acid phan, magnesium, and ketamine. Examples of dopamine hemihydrate may be administered to a patient for treating agonists useful for treating fibromyalgia and which may be 55 musculoskeletal pain in combination with a therapy or administered in conjunction with crystalline (3R)-4-(1S)- another therapeutic agent known or believed to be effective in 2-methyl-1-(2-methylpropanoyloxy)propoxycarbony treating musculoskeletal pain. Examples of drugs useful for lamino-3-(4-chlorophenyl)butanoic acid anhydrate and/or treating musculoskeletal pain and which may be administered crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy in conjunction with crystalline (3R)-4-(1S)-2-methyl-1-(2- loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic 60 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo acid hemihydrate include C-dihydroergocryptine. Examples rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- of opioids useful for preventing fibromyalgia and which may {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy be administered in conjunction with crystalline (3R)-4- carbonylamino-3-(4-chlorophenyl)butanoic acid {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo hemihydrate include cyclobenzaprine, dantrolene, methocar nylamino-3-(4-chlorophenyl)butanoic acid anhydrate and/ 65 bamol, orphenadrine, tizanidrine, metaxalone, carisoprodol. or crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy chlorphenesin, chlorZoxaZone, alprazolam, bromazepam, loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic chlordiazepoxide, cloraZepate, diazepam, flunitriazepam, US 9,139,517 B2 57 58 lorazepam, medazepam, midazolam, oxazepam, prazepam, hemihydrate. It will be apparent to those skilled in the art that triazolam, temazepam, and botulinum toxin. In certain many modifications, both to materials and methods, may be embodiments, any of the drugs useful for treating neuropathic practiced without departing from the scope of the disclosure. pain may be coadministered with a prodrug of a GABA agonist for treating musculoskeletal pain. Example 1 In certain embodiments, crystalline (3R)-4-(1S)-2-me thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- Synthesis of (3R)-4-(1S)-2-methyl-1-(2-methyl (4-chlorophenyl)butanoic acid anhydrate and/or crystalline propanoyloxy)propoxycarbonylamino-3-(4-chlo (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro rophenyl)butanoic acid (1) and (3R)-4-(1R)-2- poxycarbonylamino-3-(4-chlorophenyl)butanoic acid 10 methyl-1-(2-methylpropanoyloxy)propoxy hemihydrate may be administered to a patient for treating low carbonylamino-3-(4-chlorophenyl)butanoic acid; back pain in combination with a therapy or another therapeu and Separation by Crystallization tic agent known or believed to be effective in treating low back pain. Examples of drugs useful for treating low back To 3 moles of 2-methyl-1-(methylthiocarbonyloxy)propyl pain and which may be administered in conjunction with 15 isobutyrate is added N-hydroxysuccinimide and a mixture of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoy dichloromethane and peracetic acid. The mixture is cooled to loxy)propoxycarbonylamino-3-(4-chlorophenyl)butanoic 15° C. during the addition of the mixture of dichloromethane acid anhydrate and/or crystalline (3R)-4-(1S)-2-methyl-1- and peracetic acid. 1-(2,5-dioxopyrrolidin-1-yl-oxycarbo (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- nyloxy)-2-methylpropyl)-2-methylpropanoate (3) is chlorophenyl)butanoic acid hemihydrate include NSAIDs extracted from the final solution via cold water extraction. To Such as aspirin, naproxen, and ibuprofen; anticonvulsants; the extracted compound (3) a 1:1 mixture ofisopropyl alco antidepressants such as amitriptyline and desipramine; and hol:hexane is added and the mixture cooled in a dry-ice bath. opioids such as codeine, oxycodone, hydrocodone, and mor Compound (3) crystallizes in this reaction mixture. The prod phine. In certain embodiments, any of the drugs useful for uct is collected by filtration and dried to afford 470 g (53%) of treating neuropathic pain may be coadministered with a pro 25 crystalline 1-((2,5-dioxopyrrolidin-1-yl-oxycarbonyloxy)-2- drug of a GABA agonist for treating low back pain. Thera methylpropyl)-2-methylpropanoate (3). pies for low back pain and which may be administered in To a 500 mL, round bottomed flask, is added 21.3 g (R)- conjunction with crystalline (3R)-4-(1S)-2-methyl-1-(2- baclofen (2) and 30.1 g compound (3). The two compounds methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo are mixed and a mixture of 100 mL acetonitrile and 100 mL rophenyl)butanoic acid anhydrate and/or crystalline (3R)-4- 30 water is added at room temperature. The reaction is stirred at {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy room temperature for 4 hours. The reaction mixture is diluted carbonylamino)-3-(4-chlorophenyl)butanoic acid with 500 mL methyl tert-butyl ether, washed twice with 200 hemihydrate include the use of cold and hot compresses, bed mL water, and washed once with 100 mL of brine. The methyl rest, exercise, spinal manipulation, acupuncture, biofeed tert-butyl ether layer is dried to afford a mixture of (3R)-4- back, interventional therapy, traction, transcutaneous electri 35 {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo cal nerve stimulation, ultrasound, Vertebroplasty, kyphop nylamino-3-(4-chlorophenyl)butanoic acid (1) and (3R)-4- lasty, discectomy, foraminotomy, intradiscal electrothermal {(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo therapy, nucleoplasty, radiofrequency lesioning, spinal nylamino-3-(4-chlorophenyl)butanoic acid. fusion, and spinal laminectomy. To 40 g of the mixture of (3R)-4-(1S)-2-methyl-1-(2- In certain embodiments, crystalline (3R)-4-(1S)-2-me 40 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- rophenyl)butanoic acid (1) and (3R)-4-(1R)-2-methyl-1- (4-chlorophenyl)butanoic acid anhydrate and/or crystalline (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro chlorophenyl)butanoic acid is added 800 mL of a 1:1 mixture poxycarbonylamino-3-(4-chlorophenyl)butanoic acid of toluene:methylcyclohexane. (3R)-4-(1S)-2-methyl-1- hemihydrate may be administered to a patient for treating low 45 (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- back pain in combination with a therapy or other therapeutic chlorophenyl)butanoic acid (1) crystallizes in this reaction agent for treating muscle spasms, for example muscle spasms mixture to afford 13 g (65%) of crystalline compound (1). associated with low back pain, such as muscle relaxants. This crystallization reaction separates (3R)-4-(1S)-2-me Examples of drugs useful as muscle relaxants for treating thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- muscle spasms and which may be administered in conjunc 50 (4-chlorophenyl)butanoic acid (1) from (3R)-4-(1R)-2-me tion with crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) (4-chlorophenyl)butanoic acid. butanoic acid anhydrate and/or crystalline (3R)-4-(1S)-2- methyl-1-(2-methylpropanoyloxy)propoxy Example 2 carbonylamino-3-(4-chlorophenyl)butanoic acid 55 hemihydrate include baclofen, carisoprodol, chlorZoxaZone, Separation of (3R)-4-(1S)-2-methyl-1-(2-methyl cyclobenzaprine, diazepam, metaxalone, methocarbamol. propanoyloxy)propoxycarbonylamino-3-(4-chlo orphenadrine, and tizanidine. rophenyl)butanoic acid (1) from (3R)-4-(1R)-2- methyl-1-(2-methylpropanoyloxy)propoxy EXAMPLES 60 carbonylamino-3-(4-chlorophenyl)butanoic acid by Crystallization The following examples describe in detail the preparation, properties, and uses of crystalline (3R)-4-(1S)-2-methyl-1- From 3:1 Toluene:Methylcyclohexane (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- A portion of the mixture of (3R)-4-(1S)-2-methyl-1-(2- chlorophenyl)butanoic acid anhydrate and crystalline (3R)- 65 methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy rophenyl)butanoic acid (1) and (3R)-4-(1R)-2-methyl-1- carbonylamino-3-(4-chlorophenyl)butanoic acid (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- US 9,139,517 B2 59 60 chlorophenyl)butanoic acid produced according to Example methyl-1-(2-methylpropanoyloxy)propoxycarbony 1 is separated as follows: to 110 g of the mixture of (3R)-4- lamino-3-(4-chlorophenyl)butanoic acid hemihydrate (1b). {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo The resulting mixture was cooled to 5°C. over a period often nylamino-3-(4-chlorophenyl)butanoic acid (1) and (3R)-4- hours. Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro {(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxy 5 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu carbonylamino-3-(4-chlorophenyl)butanoic acid is added tanoic acid hemihydrate (1b) was isolated via centrifugation, 3.3 L of a 3:1 mixture of toluene:methylcyclohexane. (3R)- washed with a mixture of 34.4 kilograms of MTBE and 82.6 4-(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycar kg of methylcyclohexane, and dried at a temperature between bonylamino-3-(4-chlorophenyl)butanoic acid (1) crystal 45° C. to 75° C. using a vacuum of 25 to 50 mbar. This lizes in this reaction mixture to afford 88 g (80%) of 10 resulted in 51.75 kg of crystalline (3R)-4-(1S)-2-methyl-1- crystalline compound (1). (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- A second crystallization is performed as follows: to 20 g of chlorophenyl)butanoic acid hemihydrate (1b). the mixture of (3R)-4-(1S)-2-methyl-1-(2-methylpro panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu Example 4 tanoic acid (1) and (3R)-4-(1R)-2-methyl-1-(2-methylpro 15 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) Crystallization of (3R)-4-(1S)-2-methyl-1-(2-me butanoic acid produced according to Example 1 is added 400 thylpropanoyloxy)propoxycarbonylamino-3-(4- mL of a 3:1 mixture of toluene:methylcyclohexane. (3R)-4- chlorophenyl)butanoic acid anhydrate (1a) {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo nylamino-3-(4-chlorophenyl)butanoic acid (1) crystallizes To a 2,500 L reactor was added 51.1 kg of crystalline in this reaction mixture to afford 5 g (25%) of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro compound (1). poxycarbonylamino-3-(4-chlorophenyl)butanoic acid From 1.5:1 Methanol:Water hemihydrate (1b) and 104.4 kg of acetone, at 35°C. To this A portion of the mixture of (3R)-4-(1S)-2-methyl-1-(2- mixture was added 247.15 kg of hexane and the mixture was methylpropanoyloxy)propoxycarbonylamino-3-(4-chlo 25 heated to 50° C. and stirred for 10 minutes at this temperature. rophenyl)butanoic acid (1) and (3R)-4-(1R)-2-methyl-1- The temperature was then reduced to 45°C. Thereafter 98 kg (2-methylpropanoyloxy)propoxycarbonylamino-3-(4- of hexane was added, followed by 50 g of (3R)-4-(1S)-2- chlorophenyl)butanoic acid produced according to Example methyl-1-(2-methylpropanoyloxy)propoxycarbony 1 is separated as follows: 40 g of the mixture of (3R)-4- lamino-3-(4-chlorophenyl)butanoic acid anhydrate seed {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo 30 crystals. A further 488.4 kg of hexane was added at 45° C. and nylamino-3-(4-chlorophenyl)butanoic acid (1) and (3R)-4- the mixture was cooled to 0°C. within 2.5 hours. Crystalline {(1R)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro nylamino-3-(4-chlorophenyl)butanoic acid is dissolved in a poxycarbonylamino-3-(4-chlorophenyl)butanoic acid mixture of 150 mL methanol and 100 mL water. The mixture anhydrate was isolated via centrifugation, washed with a is heated to 60° C. and then cooled to room temperature. The 35 mixture of 168.1 kg of hexane in 23 L of acetone, and dried at heating and cooling procedure is performed 5 times in Suc 50° C. using a vacuum of 22-49 mbar for 15 hours. This cession to yield 6 g (30%) of crystalline (3R)-4-(1S)-2- resulted in 45.15 kg of (3R)-4-(1S)-2-methyl-1-(2-methyl methyl-1-(2-methylpropanoyloxy)propoxycarbony propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) lamino-3-(4-chlorophenyl)butanoic acid (1). butanoic acid anhydrate. 40 Example 3 Example 5 Crystallization of (3R)-4-(1S)-2-methyl-1-(2-me Differential Scanning calorimetry of Crystalline thylpropanoyloxy)propoxycarbonylamino-3-(4- (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) chlorophenyl)butanoic acid hemihydrate (1b) 45 propoxycarbonylamino-3-(4-chlorophenyl)bu tanoic acid hemihydrate (1b) A 2,500 L reaction vessel was charged with 313 L of methyl tert-butyl ether (MTBE) and 224 L of water, to which Differential scanning calorimetry was performed using a was added 100 kg of (R)-baclofen and 134 kg of 1-((2.5- Perkin Elmer DSC-7 instrument. DSC on the hemihydrate dioxopyrrolidin-1-yl-oxycarbonyloxy)-2-methylpropyl)-2- 50 was carried out in a gold sample pan sealed in air. Heating methylpropanoate (3) at 20° C. The charging lock and the occurred at a rate of 20K/min over a temperature range of 0° reactor walls were each rinsed with 67 liters of MTBE. The C-150° C. reaction mixture was heated to 45° C. and stirred for 6.25 Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro hours. The reaction mixture was then cooled to 20° C., the panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu aqueous phase was separated and discarded. The organic 55 tanoic acid hemihydrate prepared according to Example 3 phase was washed with 224 kg of 1N hydrochloric acid, exhibited two distinct melt transitions. The first melt transi followed by two washes with 224 kg of water each. The tion occurred from about 70° C. to about 110°C., with a peak product-containing organic phase was filtered through a char maximum at about 100° C. and a AH of about 58.3 J/g. The coal cartridge. The reactor and lines were rinsed with 137 second melt transition occurred from about 110° C. to about liters of MTBE, which was also filtered through the charcoal 60 125°C., with a peak maximum at about 115° C. and a AH of filter and combined with the previous filtrate. The combined about 39.1 J/g. organic phase was washed once more with 224 kg of water. The lower melting peak near 100° C. corresponds to melt To the filtrate was added 277 L of methylcyclohexane, and ing of crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 67 L of MTBE followed by an additional 768 L of methylcy panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu clohexane. The resulting mixture was heated to 50° C. to 65 tanoic acid hemihydrate, while the second melting peak near dissolve all solids. The solution was then cooled to 35° C. 115° C. corresponds to the melting of crystalline (3R)-4- within one hour and seeded with 0.25 kg of (3R)-4-(1S)-2- {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo US 9,139,517 B2 61 62 nylamino-3-(4-chlorophenyl)butanoic acid anhydrate, TABLE 1-continued which exhibits a depressed melting point in this case, because XRPD Scattering Angles. of the presence of water released from the hemihydrate. 020 (deg) Example 6 16.72° 0.2° 18.16° 0.2 18.91° 0.2° Thermogravimetric Analysis of Crystalline (3R)-4- 19.33° 0.2° {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy 19.96 O.2° carbonylamino-3-(4-chlorophenyl)butanoic acid 20.23° 0.2 10 20.62° 0.2 hemihydrate (1b) 21.76° 0.2 22.42° 0.2 Thermogravimetric measurements were carried out with a 23.SS O.2 24.O2 O.2 Netzsch Thermo-Microbalance TG 209 coupled to a Bruker 25.130.2 FTIR Spectrometer Vector 22. The sample was contained in 15 25.61° 0.2 sample pans with a pinhole, under a N2 atmosphere. The 26.09° 0.2 28.07 - 0.2 heating rate was set at 10 K/min. 28.53° 0.2 Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 29.87° 0.2 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu 30.45° 0.2 tanoic acid hemihydrate prepared according to Example 3 30.74° 0.2 31.52° 0.2 exhibited a weight loss of about 2.1% up to 170° C. when 32.60° 0.2 heated at a scan rate of 10 K/min. This weight loss, which 35.94° 0.2 occurred predominantly between 80° C. and 130°C., is attrib 36.639 O.2 utable to water. Under the conditions used for TG-FTIR thermal decom position began slowly at about 170° C. and increased strongly above 190° C. Example 8 Raman Spectroscopy Analysis of Crystalline (3R)-4- Example 7 {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy X-Ray Powder Diffraction Analysis of Crystalline 30 carbonylamino-3-(4-chlorophenyl)butanoic acid (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) hemihydrate (1b) propoxycarbonylamino-3-(4-chlorophenyl)bu tanoic acid hemihydrate (1b) FT-Raman spectra were recorded on a Bruker RFS 100 FT-Raman system with a near infrared Nd:YAG laser operat X-ray powder diffraction analyses were performed using a 35 ing at 1064 nm and a liquid nitrogen-cooled germanium Bruker D8 Advance powder X-ray diffractometer using detector. A total of 64 scans with a resolution of 2 cm were CuKO. radiation. 20 values are accurate within an error of accumulated in the range from 3500 to 50 cm. In general, +0.1-0.2°. The tube voltage and amperage were set to 35 kV 100 mW laser power was used. Dispersive Raman spectra and 45 mA, respectively. The step size was set at 0.017° (20), were taken on a Renishaw RM1000 System using a 20x long the step time was set at 105-5 sec, and the scanning range was 40 working distance objective lens in conjunction with a diode 2-50° (20). The samples were rotated. Differential radiation laser operating at 785 nm. The measurements were carried was detected by a VANTEC1 detector having an opening out over the range 2000 cm to 100 cm. angle of 3° and a total number of active channels of 360+10. The Raman spectrum for crystalline (3R)-4-(1S)-2-me The y-axis (counts or CPS) of the diffractogram depicted in thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- FIG. 1 does not show the total intensity (/sec) but rather the 45 (4-chlorophenyl)butanoic acid hemihydrate prepared accord value intensity/number of active detector channels(/sec). ing to Example 3 is shown in FIG. 2. Sample holders were siliconsingle crystal and sample dimen The most prominent bands were found at 1744 cm, 1600 sions were a depth/diameter: 0.1 mm/~12 mm. cm, 1453 cm, 1290 cm, 1238 cm, 1201 cm, 954 The X-ray powder diffractogram for crystalline (3R)-4- cm, 872 cm, 779 cm, 635 cm, 362 cm, 315 cm', {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo 50 110 cm, and 84 cm. The band at 110 cm was the stron nylamino-3-(4-chlorophenyl)butanoic acid hemihydrate gest Raman spectrum band displayed. prepared according to Example 3 is shown in FIG. 1. The characteristic scattering angles for the same crystalline prepa Example 9 ration shown in FIG. 1 are presented in Table 1. 55 Differential Scanning Calorimetry of Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) TABLE 1. propoxycarbonylamino-3-(4-chlorophenyl)bu XRPD Scattering Angles. tanoic acid anhydrate (1a) 020 (deg) 4.04° 0.2 60 Differential scanning calorimetry was performed using a 6.47° 0.2° Perkin Elmer DSC-7 instrument. DSC on the hemihydrate 7.97° 0.2 was carried out in a gold sample pan sealed under nitrogen. 9.46° 0.2 Heating occurred at a rate of 20K/min over a temperature 10.10° 0.2° 10.87° 0.2° range of 0° C.-150° C. 12.88° 0.2° 65 Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 15.68° 0.2° panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu tanoic acid anhydrate prepared according to the methods of US 9,139,517 B2 63 64 the present disclosure exhibited a single melt transition from TABLE 2-continued about 120° C. to about 145° C., with a peak maximum at XRPD Scattering Angles. about 131° C. and a AH of about 92.6 J/g. 020 (deg) Example 10 15.25° 0.2° 16.5S0.2 Thermogravimetric Analysis of Crystalline (3R)-4- 17.46° 0.2° 17.84° 0.2° {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy 18.01° 0.2 carbonylamino-3-(4-chlorophenyl)butanoic acid 18.41° 0.2 anhydrate (1a) 10 18.69 O.2° 18.939 O.2° 19.36° 0.2° Thermogravimetric measurements were carried out with a 20.01° 0.2 Netzsch Thermo-Microbalance TG 209 coupled to a Bruker 20.46° 0.2 FTIR Spectrometer Vector 22. The sample was contained in 21.26 O2 sample pans with a pinhole, under a N2 atmosphere. The 15 21.75° 0.2 22.190.2 heating rate was set at 10 K/min. 22.56° 0.2 Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 23.350.2 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu 23.850.2 tanoic acid anhydrate prepared according to the methods of 24.84° 0.2 25.969 O.2 the present disclosure showed very little weight loss up to 26.78° 0.2 180°C. when heated at a scan rate of 10 K/min. 27.29° 0.2 Under the conditions used for TG-FTIR, thermal decom 28.69 O.2 position began slowly at about 170° C. and increased strongly 29.39° 0.2 31.22° 0.2 above 190° C. 32.350.2 25 33.47° 0.2 Example 11 34.62° 0.2 36.08° 0.2 X-Ray Powder Diffraction Analysis of Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) propoxycarbonylamino-3-(4-chlorophenyl)bu 30 Example 12 tanoic acid anhydrate (1a) Raman Spectroscopy Analysis of Crystalline (3R)-4- X-ray powder diffraction analyses were performed using a {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy Bruker D8 Advance powder X-ray diffractometer using carbonylamino-3-(4-chlorophenyl)butanoic acid CuKO. radiation. 20 values are accurate within an error of 35 anhydrate (1a) +0.1-0.2°. The tube voltage and amperage were set to 35 kV and 45 mA, respectively. The step size was set at 0.017° (20), FT-Raman spectra were recorded on a Bruker RFS 100 the step time was set at 105-5 sec, and the scanning range was FT-Raman system with a near infrared Nd:YAG laser operat 2-50° (20). The samples were rotated. Differential radiation ing at 1064 nm and a liquid nitrogen-cooled germanium was detected by a VANTEC1 detector having an opening 40 detector. A total of 64 scans with a resolution of 2 cm were angle of 3° and a total number of active channels of 360+10. accumulated in the range from 3500 to 50 cm. In general, The y-axis (counts or CPS) of the diffractogram depicted in 100 mW laser power was used. Dispersive Raman spectra FIG. 3 does not show the total intensity (/sec) but rather the were taken on a Renishaw RM1000 System using a 20x long value intensity/number of active detector channels(/sec). working distance objective lens in conjunction with a diode Sample holders were siliconsingle crystal and sample dimen 45 laser operating at 785 nm. The measurements were carried sions were a depth/diameter: 0.1 mm/~12 mm. out over the range 2000 cm to 100 cm. The X-ray powder diffractogram for crystalline (3R)-4- The Raman spectrum for crystalline (3R)-4-(1S)-2-me {(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxycarbo thyl-1-(2-methylpropanoyloxy)propoxycarbonylamino-3- nylamino-3-(4-chlorophenyl)butanoic acid anhydrate pre (4-chlorophenyl)butanoic acid anhydrate prepared according pared according to the methods of the present disclosure is 50 to the methods of the present disclosure is shown in FIG. 4. shown in FIG. 3. The characteristic scattering angles for the The most prominent bands were found at 1747 cm, 1599 same crystalline preparation shown in FIG.3 are presented in cm, 1447 cm, 1412 cm, 1335 cm, 1203 cm, 1092 Table 2. cm, 954 cm, 868 cm, 798 cm, 637 cm, 401 cm, 348 cm, 317 cm, 244 cm, 119 cm, and 85 cm. The TABLE 2 55 band at 119 cm was the strongest Raman spectrum band displayed. XRPD Scattering Angles. 020 (deg) Finally, it should be noted that there are alternative ways of implementing the embodiments disclosed herein. Accord 4.33° 0.2° 4.76° 0.2° ingly, the present embodiments are to be considered as illus 5.83° 0.2 60 trative and not restrictive. Furthermore, the claims are not to 6.93° 0.2° be limited to the details given herein, and are entitled their full 9.07 O.2 Scope and equivalents thereof. 9.46° 0.2 10.54° 0.2° 1106° 0.2 What is claimed is: 11.61° 0.2 65 1. Crystalline (3R)-4-(1S)-2-methyl-1-(2-methylpro 12.94° 0.2 panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu tanoic acid anhydrate which exhibits characteristic scattering US 9,139,517 B2 65 66 angles (20) at least at 4.33°+0.2°, 4.76°+0.2°, 11.06°+0.2° 8. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl and 11.61+0.2 in an X-ray powder diffractogram measured propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) using Cu-K radiation. butanoic acid anhydrate of claim 1, which has a critical water 2. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl activity of less than or equal to about 0.75+0.05. propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) 9. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl butanoic acid anhydrate of claim 1, comprising characteristic propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) scattering angles (20) at least at 4.33°+0.2°, 4.76°+0.2°, butanoic acid anhydrate of claim 1, which undergoes thermal 5.83° 0.2°, 9.07+0.2°, 9.46°0.2°, 10.54°0.2°, decompositionata temperature ranging from about 170° C. to 11.06-0.2°, 11.61-0.2°, 12.940.2°, 17.46°-0.2°, about 190° C. using a thermogravimetric analyzer coupled 17.84° 0.2°, 18.01-0.2°, 19.36°-0.2°, 20.01°0.2° and 10 21.26°+0.2° in an X-ray powder diffractogram measured with a Fourier-transform infrared spectrometer at a scan rate using Cu-K radiation. of about 10 K/min. 3. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl 10. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) butanoic acid anhydrate of claim 1, which undergoes a melt/ butanoic acid anhydrate of claim 1, comprising characteristic 15 phase transition at a temperature ranging from about 120° C. scattering angles (20) at least at 4.33°+0.2°, 4.76°+0.2°, to about 140°C. using differential scanning calorimetry at a 5.83° 0.2°, 6.93°+0.2°, 9.07+0.2°, 9.46°-0.2°, heating rate of 20K/min. 10.54°0.2°, 11.06-0.2°, 11.61-0.2°, 12.940.2°, 11. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl 15.25-0.2°, 16.550.2°, 17.46°-0.2°, 17.84°0.2°, propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) 18.01-0.2°, 18.41+0.2°, 18.69°0.2°, 18.93 +0.2°, butanoic acid anhydrate of claim 10, wherein the melt/phase 19.36°-0.2°, 20.01-0.2°, 20.46°-0.2°, 21.26°-0.2°, transition occurs at about 131° C. using differential scanning 21.75° 0.2°, 22.190.2°, 22.56°-0.2°, 23.35°+0.2°, calorimetry at a heating rate of 20 K/min. 23.850.2°, 24.84°0.2°, 25.969-0.2°, 26.78°+0.2°, 12. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl 27.29°0.2°, 28.69°0.2°, 29.39°0.2°, 31.22+0.2°, propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) 32.35°-0.2°, 33.47+0.2°, 34.62+0.2° and 36.08° 0.2° in an 25 X-ray powder diffractogram measured using Cu-K radia butanoic acid anhydrate of claim 10, wherein the melt/phase transition occurs at about 131.3°C. using differential scan tion. ning calorimetry at a heating rate of 20 K/min. 4. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl 13. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) butanoic acid anhydrate of claim 1, which exhibits a strong 30 butanoic acid anhydrate of claim 1, which contains less than characteristic Raman spectrum band at 119 cm. about 0.05 wt % water at 50% relative humidity as measured 5. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl by dynamic vapor sorption. propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) 14. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl butanoic acid anhydrate of claim 1, which exhibits character propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) istic Raman spectrum bands at least at 119 cm and 85 cm. 35 6. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl butanoic acid anhydrate of claim 1, which contains less than about 0.1 wt % water at 95% relative humidity as measured by propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) dynamic vapor sorption. butanoic acid anhydrate of claim 1, which exhibits character 15. A pharmaceutical composition comprising the crystal istic Raman spectrum bands at least at 1599 cm, 1447 cm', line (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro 798 cm, 119 cm and 85 cm. 40 7. The crystalline (3R)-4-(1S)-2-methyl-1-(2-methyl poxycarbonylamino-3-(4-chlorophenyl)butanoic acid propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) anhydrate of claim 1 and a pharmaceutically acceptable butanoic acid anhydrate of claim 1, which exhibits character vehicle. istic Raman spectrum bands at least at 1747 cm, 1599 cm', 16. The pharmaceutical composition of claim 15, wherein 1447 cm, 1412 cm, 1335 cm, 1203 cm, 1092 cm, 45 the pharmaceutical composition is a Sustained release oral 954 cm, 868 cm, 798 cm, 637 cm, 401 cm, 348 dosage formulation. cm, 317 cm, 244 cm, 119 cm and 85 cm.