WO2016209809A1 - Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(compound1) for use in sipi receptor-associated disorders - Google Patents

Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(compound1) for use in sipi receptor-associated disorders Download PDF

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Publication number
WO2016209809A1
WO2016209809A1 PCT/US2016/038506 US2016038506W WO2016209809A1 WO 2016209809 A1 WO2016209809 A1 WO 2016209809A1 US 2016038506 W US2016038506 W US 2016038506W WO 2016209809 A1 WO2016209809 A1 WO 2016209809A1
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WIPO (PCT)
Prior art keywords
indol
benzyloxy
cyclopentyl
trifluoromethyl
acetic acid
Prior art date
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PCT/US2016/038506
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English (en)
French (fr)
Inventor
Anthony C. Blackburn
Ryan O. Castro
Mark A. Hadd
You-An Ma
Antonio Garrido Montalban
Jaimie Karyn Rueter
Lee Alani Selvey
Sagar Raj Shakya
Marlon Carlos
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Arena Pharmaceuticals Inc
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Arena Pharmaceuticals Inc
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Priority to PL16734529.7T priority Critical patent/PL3310760T3/pl
Priority to NZ738862A priority patent/NZ738862B2/en
Priority to AU2016284162A priority patent/AU2016284162A1/en
Priority to JP2017566114A priority patent/JP6838744B2/ja
Priority to CN201680048241.0A priority patent/CN108349891B/zh
Priority to EP16734529.7A priority patent/EP3310760B8/en
Priority to MX2017016530A priority patent/MX383854B/es
Priority to KR1020187001785A priority patent/KR102603199B1/ko
Priority to EP21178613.2A priority patent/EP3939965A1/en
Priority to IL285890A priority patent/IL285890B/en
Priority to CA3002551A priority patent/CA3002551A1/en
Priority to SI201631637T priority patent/SI3310760T1/sl
Priority to KR1020237039088A priority patent/KR102883123B1/ko
Priority to DK16734529.7T priority patent/DK3310760T3/da
Priority to BR112017027656-9A priority patent/BR112017027656B1/pt
Priority to ES16734529T priority patent/ES2929526T3/es
Priority to EA201890096A priority patent/EA201890096A1/ru
Priority to US15/738,175 priority patent/US10301262B2/en
Application filed by Arena Pharmaceuticals Inc filed Critical Arena Pharmaceuticals Inc
Publication of WO2016209809A1 publication Critical patent/WO2016209809A1/en
Priority to IL256084A priority patent/IL256084B/en
Anticipated expiration legal-status Critical
Priority to US16/379,265 priority patent/US10676435B2/en
Priority to US16/862,681 priority patent/US11091435B2/en
Priority to AU2020204164A priority patent/AU2020204164B2/en
Priority to US17/375,063 priority patent/US11884626B2/en
Priority to AU2021249972A priority patent/AU2021249972B2/en
Priority to AU2023200978A priority patent/AU2023200978B2/en
Priority to US18/542,913 priority patent/US12378198B2/en
Priority to US19/272,174 priority patent/US20250346560A1/en
Ceased legal-status Critical Current

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to, inter alia, a novel crystalline free-plate habit or morphology, processes for preparing the crystalline free-plate habit, and uses of the crystalline free -plate habit of the L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo- penta[b]indol-3-yl)acetic acid (Compound 1) in the treatment of SlPi receptor-associated disorders, for example, diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions characterized by an underlying defect in the vascular integrity or that are associated with pathological angiogenesis (e.g., as may occur in inflammation, tumor development, and atherosclerosis).
  • the sphingosine- 1 -phosphate (S IP) receptors 1-5 constitute a family of G protein-coupled receptors with a seven-transmembrane domain. These receptors, referred to as SlPi to S 1P 5 (formerly termed endothelial differentiation gene (EDG) receptor- 1, -5, -3, -6, and -8, respectively; Chun et. ah, Pharmacological Reviews, 54:265-269, 2002), are activated via binding by sphingosine-l-phosphate, which is produced by the sphingosine kinase-catalyzed phosphorylation of sphingosine.
  • EDG endothelial differentiation gene
  • S lPi, SIP 4 , and SIP 5 receptors activate Gi but not Gq, whereas SIP 2 and S1P 3 receptors activate both Gi and Gq.
  • Compound 1 showed calculated lymphocyte lowering IC 50 values in four different species: 0.101 ⁇ (mouse), 0.051 ⁇ (rat), 0.058 ⁇ (dog), and 0.098 ⁇ (monkey).
  • the calculated lymphocyte lowering IC 50 values reflect total plasma concentration wherein Compound 1 is highly protein bound (97.8% human, 98.0% rat).
  • Compound 1 was shown to be efficacious in the murine experimental autoimmune encephalomyelitis (EAE) model that mimics multiple sclerosis. Prophylactically, Compound 1 prevented the onset and severity of disease relative to vehicle up to day 25, at which time dosing was discontinued. All treatment arms went on to develop severe disease. Therapeutic administration of Compound 1 was also examined. Treatment began at day 18, by which time all animals had developed severe disease.
  • EAE murine experimental autoimmune encephalomyelitis
  • Compound 1 was administered from day 18 to day 37 and showed to reverse the disease relative to vehicle and was similar to the efficacy observed with fingolimod (i.e., GILENYA® was approved in September 2010 for the treatment of patients with relapsing forms of multiple sclerosis). Similarly, Compound 1 was efficacious in a collagen induced arthritis (CIA) model. Prophylactic oral administration in female Lewis rats resulted in a significant reduction in ankle diameters on day 17 following a daily oral dose and was similar to that observed in rats treated with fingolimod or methotrexate. Improvement in histological parameters in the knees and ankles of CIA rats was also observed, suggesting that inhibiting lymphocyte entry into arthritic joints with Compound 1 treatment suppresses CIA in rodents. Additional details can be found in the following, PCT application, serial number PCT/US2009/004265, filed 22 July 2009
  • the L-arginine salt of Compound 1 was selected for clinical evaluation.
  • a randomized, double-blind, placebo-controlled Phase lb clinical trial was conducted to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of multiple-ascending doses of the L-arginine salt of Compound 1 in five different dosing cohorts.
  • a total of 50 healthy volunteers received the L- arginine salt of Compound 1 and 10 healthy volunteers received placebo for 21 days.
  • the administration of the L-arginine salt of Compound 1 demonstrated a dose-dependent effect on lymphocyte count lowering in blood, with a mean decrease from baseline of up to 69%. Lymphocyte counts, on average, recovered to baseline within one week of the conclusion of dosing.
  • the present invention relates to, inter alia, a novel crystalline free-plate habit or morphology, processes for preparing the crystalline free-plate habit, and uses of the crystalline free -plate habit of the L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) in the treatment of SIPi receptor- associated disorders, such as, those described herein.
  • free -plate habit Discovery of the novel crystalline plate habit, referred to as "free -plate habit" herein, led to certain advantageous properties, such as, improved in-process filtrations, formulation stability and/or stability to degradation, higher degree of crystallinity, and lower degree of hygroscopicity, see Example 8 for details.
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • R 3 is C C6 alkyl; in the presence of a hydrolyzing mixture comprising a lipase and a hydrolyzing-step solvent to form (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4- tetrahydrocyclopenta[b] indol-3 -y 1) acetic acid ;
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, said method comprising the steps of: a) hydrolyzing a compound of Formula (Ila):
  • R 3 is C C6 alkyl; in the presence of a hydrolyzing mixture comprising a lipase and a hydrolyzing-step solvent to form (R)-2-(7-(4-cyclopent l-3-(trifluoromethyl)benzyloxy)- l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
  • Step e) cycling Step e) optionally one or more times, wherein said first cooling temperature at each cycle may be the same or different and said second heating temperature at each cycle may be the same or different;
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • Step b) cooling the second mixture to a first cooling temperature followed by adding a first additional amount of the water-miscible anti-solvent to the second mixture while maintaining the first cooling temperature and thereafter heating to a second heating temperature to form a suspension; c) cycling Step b) optionally once or twice; and
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, said method comprising the steps of:
  • Step d) cycling Step d) optionally one or more times, wherein the first cooling temperature at each cycle may be the same or different and the second heating temperature at each cycle may be the same or different;
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid further comprising the step of formulating the crystalline free -plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- 1,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid to form a pharmaceutical composition.
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid further comprising the step of admixing the crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid with a pharmaceutical excipient to form a pharmaceutical composition.
  • One aspect of the present invention relates to pharmaceutical compositions prepared according to any of the methods described herein.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid prepared according to any of the methods described herein.
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid prepared according to any of the methods described herein.
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid prepared according to any of the methods described herein and a pharmaceutical excipient.
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) in an amount equivalent to a therapeutically effective amount of Compound 1 of the crystalline free-plate habit, wherein the pharmaceutical composition further comprises a diluent, a disintegrant, and a lubricant.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid having a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.0°C to 208.5°C when scanned at 10°C per minute.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid having a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.3% weight or less at 90% RH.
  • DMS dynamic moisture sorption
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid as described herein.
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid as described herein and a pharmaceutical excipient.
  • One aspect of the present invention relates to methods for treating an S IPi receptor-associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of an S IPi receptor-associated disorder.
  • One aspect of the present invention relates to uses of a composition
  • a composition comprising a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein and an excipient in the manufacture of a medicament for administration in the treatment of an SI Pi receptor-associated disorder.
  • One aspect of the present invention relates to uses of a composition
  • a composition comprising a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein and an excipient for preparation a medicament for administration in the treatment of an S I Pi receptor-associated disorder.
  • One aspect of the present invention relates to uses of a composition
  • a composition comprising a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein and an excipient for compounding a medicament for administration in the treatment of an SIPi receptor-associated disorder.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of the human or animal body by therapy.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of an SIPi receptor-associated disorder.
  • the S IPi receptor-associated disorder is selected from: primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, and ulcerative colitis.
  • Figure 1 shows a micrograph of spherulites/radial clusters using scanning electron microscopy
  • FIG. 2 shows a micrograph of spherulites/radial clusters using polarized light microscopy (PLM), see Example 1 for additional details.
  • PLM polarized light microscopy
  • Figure 3A shows a micrograph of the crystal morphology as described in Example 2 (Lot J2) using scanning electron microscopy (SEM).
  • Figure 3B shows a micrograph of the crystal morphology as described in Example 2 (Lot J2).
  • Figure 4A shows a micrograph of the crystal morphology as described in Example 2 (Lot Jl) using scanning electron microscopy (SEM).
  • Figure 4B shows a micrograph of the crystal morphology as described in Example 2 (Lot Jl).
  • Figure 5A shows a micrograph of the crystal plate morphology as described in Example 3 using polarized light microscopy (PLM).
  • Figure 5B shows the same micrograph as in Figure 5A of the crystal plate morphology as described in Example 3 using polarized light microscopy (PLM) but also includes an added outline of a substantially intact complete free -plate having an elongated hexagonal shape.
  • PLM polarized light microscopy
  • Figure 6 shows a differential scanning calorimetry (DSC) thermogram for Lot Al (plates) as described in Example 3.
  • Figure 7 shows a differential scanning calorimetry (DSC) thermogram for Lot A2 (plates) as described in Example 3.
  • Figure 8 shows a differential scanning calorimetry (DSC) thermogram for Lot A3 (plates) as described in Example 3.
  • Figure 9 shows a differential scanning calorimetry (DSC) thermogram for Lot A4 (plates) as described in Example 3.
  • FIG 10 shows a differential scanning calorimetry (DSC) thermogram for Lot A5 (plates) as described in Example 3.
  • Figure 11 shows a micrograph of the crystal plate morphology as described in Example 4.1
  • Figure 12A shows a micrograph of the crystal plate morphology as described in Example 4.1, Method 1 using polarized light microscopy (PLM).
  • Figure 12B shows a differential scanning calorimetry (DSC) thermogram for a sample from Example 4.1, Method 1 (plates).
  • Figure 13 shows a PXRD pattern overlay for Lot A5 and the sample from Example 4.2, Method 2 showing that the sample has the same crystal phase as the Lot A5 (plates).
  • Figure 14 shows a micrograph for a sample from Example 4.2, Method 2 using polarized light microscopy (PLM). It was observed that the sample consisted predominately as plates.
  • PLM polarized light microscopy
  • Figure 15 shows a flowchart for the preparation of core tablets of the L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1).
  • Figure 16 shows an adsorption phase and a desorption phase from a dynamic moisture-sorption (DMS) analysis for a representative lot having plate morphology (i.e., Lot A2).
  • DMS dynamic moisture-sorption
  • Figure 17 shows an adsorption/desorption cycle for a representative lot having plate morphology (i.e., Lot A2).
  • Figure 18 shows a PXRD pattern overlay for five lots (i.e., Al to A5, plates) of the L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3- yl)acetic acid (Compound 1). See Example 3 for additional details.
  • Figure 19 shows a PXRD Pattern overlay for the L-arginine salt of Compound 1 showing the peak intensity differences between Lot A2 (plates) and Lot H2 (spherulites) indicating a higher degree of crystallinity for the plates compared to the spherulites. Also shown is the lower sample-related background scatter (i.e., a lower amorphous halo contribution) for the Lot A2 (plates).
  • Figure 20 shows a micrograph for a crystalline sample from Example 7, Method 1 Step B (WO2011/094008) using polarized light microscopy (PLM). The sample was observed to have uniform radial cluster (spherulite) shaped particles with a few fine particles.
  • FIG. 21 shows a purification flow chart, see Example 8 for additional details.
  • Figure 22 shows a differential scanning calorimetry (DSC) thermogram for Lot A6 (plates) as described in Example 3.
  • Figure 23 shows a differential scanning calorimetry (DSC) thermogram for Lot A7 (plates) as described in Example 3.
  • Figure 24 shows a differential scanning calorimetry (DSC) thermogram for Lot A8 (plates) as described in Example 3.
  • FIG. 25 shows a differential scanning calorimetry (DSC) thermogram for Lot A9 (plates) as described in Example 3.
  • DSC differential scanning calorimetry
  • L-arginine salt of Compound 1 refers to the L-arginine salt of (R)-2-(1-( - cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid:
  • a crystalline free -plate habit of the L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)-benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)-benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) referred to herein as being characterized by graphical data "as depicted in" a Figure will thus be understood to include any morphologies characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
  • composition refers to a compound or salt thereof, such as, L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)-benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, in combination with at least one additional component.
  • treating refers to the step(s) to transform the bulk active pharmaceutical agent (i.e., API) into the drug substance or drug product for use in an individual for the treatment of a disease, wherein “treatment” and “individual” has the same definitions as described herein.
  • API bulk active pharmaceutical agent
  • free-plate habit refers to the general shape of an independent substantially flat crystal with a length and width of the crystal being similar and substantially greater than the thickness and wherein the plate is not part of a radial cluster such as a spherulite. It is appreciated that due to the thin characteristic of the crystals, the phrase “free-plate habit” encompasses complete plates, substantially complete plates, fragments/broken pieces of plates, and mixtures thereof that are free or substantially free of radial clusters or spherulites.
  • spherulite and "radial cluster” refers to a crystal habit consisting of thin plates or flakes that are clustered in a radial manner around a nucleation site that exhibit a cross when viewed using crossed-polarized light, see Figure 1 and Figure 2 for micrographs of representative
  • the length of the thin plates making up the radial cluster is less than ⁇ .
  • the term "length" in the context of a crystalline habit refers to the longest dimension from edge to edge of a particle oriented parallel to the ocular scale.
  • width in the context of a crystalline habit refers to the longest dimension of the particle measured at right angles to the length.
  • mice refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates and most preferably humans.
  • inert atmosphere refers to an atmosphere substantially free of oxygen.
  • examples of an inert atmosphere include, for example, argon and nitrogen.
  • composition refers to a composition comprising at least one active ingredient; such as Compound 1 and the L-arginine salt thereof, whereby the composition is amenable to investigation for a specified pharmacological outcome in a mammal (for example, without limitation, a human) or the treatment of a disease or disorder as described herein.
  • active ingredient such as Compound 1 and the L-arginine salt thereof
  • Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
  • treatment includes one or more of the following: (1) prevention of a disease, for example, prevention of a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibition of a disease for example, inhibition of a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology);
  • amelioration of a disease for example, amelioration of a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • Whether an individual is in need of treatment is a judgment made by a caregiver (e.g. nurse practitioner, physician, physician assistant, nurse, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by Compound 1 or a pharmaceutically acceptable salt, solvate, and hydrate thereof, such as, the L-arginine salt of Compound 1.
  • Compound 1 and/or pharmaceutically acceptable salts, solvates and hydrates thereof such as, the L- arginine salt of Compound 1, can be used in a protective or preventive manner; or Compound 1 and pharmaceutically acceptable salts, solvates and hydrates thereof, such as, the L-arginine salt of
  • Compound 1 can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.
  • water-miscible anti-solvent refers to a water soluble solvent in which the product, such as the L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)- benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, has limited solubility.
  • C2-C4 alkanol refers to a straight or branched carbon radical containing 2 to 4 carbons bonded to an -OH group. Some embodiments are 2 to 3 carbons and some embodiments are 3 to 4 carbons. Examples of a C 2 -C 4 alkanol include, but are not limited to, ethanol, 1 -propanol, 2- propanol, 1 -butanol, 2-butanol, and the like.
  • Ci-Ce alkyl refers to a straight or branched carbon radical containing 1 to 6 carbons. Some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons and some embodiments are 1 or 2 carbons.
  • alkyl examples include, but are not limited to, methyl, ethyl, re-propyl, isopropyl, re-butyl, sec-butyl, isobutyl, ferf-butyl, pentyl, isopentyl, ferf-pentyl, reeo-pentyl, 1-methylbutyl [i.e., CH(CH 3 )CH 2 CH 2 CH 3 ], 2-methylbutyl [i.e., CH 2 CH(CH 3 )CH 2 CH 3 ], re-hexyl and the like.
  • one aspect of the present invention relates to methods for preparing a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • R 3 is C C6 alkyl; in the presence of a hydrolyzing mixture comprising a lipase and a hydrolyzing-step solvent to form (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4- tetrahydrocyclopenta[b] indol-3 -y 1) acetic acid ;
  • the method for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid is conducted under an inert atmosphere.
  • the method is conducted under an inert atmosphere comprising nitrogen or argon.
  • the method is conducted under an inert atmosphere comprising nitrogen.
  • the hydrolyzing in Step a) is conducted under an inert atmosphere. In some embodiments, the hydrolyzing in Step a) is conducted under an inert atmosphere comprising nitrogen or argon. In some embodiments, the hydrolyzing in Step a) is conducted under an inert atmosphere comprising nitrogen.
  • R 3 is methyl or ethyl. In some embodiments, R 3 is ethyl.
  • the lipase is Candida antarctica lipase B. In some embodiments, the lipase is immobilized Candida antarctica lipase B.
  • the hydrolyzing-step solvent comprises dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), or acetonitrile. In some embodiments, the hydrolyzing-step solvent comprises acetonitrile.
  • the compound of Formula (Ila) is:
  • the lipase is immobilized Candida antarctica lipase B; and the hydrolyzing-step solvent comprises acetonitrile.
  • the hydrolyzing in Step a) is conducted in the presence of a phosphate buffer. In some embodiments, the hydrolyzing in Step a) is conducted in the presence of a phosphate buffer at a pH of about 6.0 to about 9.0. In some embodiments, the hydrolyzing in Step a) is conducted in the presence of a phosphate buffer at a pH of about 7.0 to about 8.5. In some embodiments, the hydrolyzing in Step a) is conducted in the presence of a phosphate buffer at a pH of about 7.3 to about 8.3. In some embodiments, the hydrolyzing in Step a) is conducted in the presence of a phosphate buffer at a pH of about 7.6 to about 8.0.
  • the hydrolyzing in Step a) is conducted in the presence of a phosphate buffer at a pH of about 7.8.
  • the phosphate buffer is a sodium phosphate buffer.
  • the phosphate buffer is a potassium phosphate buffer.
  • the hydrolyzing in Step a) is conducted at a temperature of about 0°C to about 75°C. In some embodiments, the hydrolyzing in Step a) is conducted at a temperature of about
  • the hydrolyzing in Step a) is conducted at a temperature of about 30°C to about 55°C. In some embodiments, the hydrolyzing in Step a) is conducted at a temperature of about 35 °C to about 45 °C.
  • the hydrolyzing in Step a) further comprises the step of isolating the (i?)-2-(7-(4-cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.
  • the (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)- benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 95% or greater.
  • the (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)- benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 98% or greater.
  • the (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)- benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 99% or greater.
  • Step b) Adding L-Arginine to a Salt-Forming Mixture.
  • the adding in Step b) is conducted under an inert atmosphere. In some embodiments, the adding in Step b) is conducted under an inert atmosphere comprising argon or nitrogen. In some embodiments, the adding in Step b) is conducted under an inert atmosphere comprising nitrogen. In some embodiments, the water-miscible anti-solvent in Step b) comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, and C2-C4 alkanol.
  • the water-miscible anti-solvent in Step b) comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, ethanol, 1-propanol, 2-propanol, and 1 -butanol. In some embodiments, the water-miscible anti-solvent in Step b) comprises 2-propanol.
  • the molar ratio between (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.95 to about 1.0: 1.2. In some embodiments, the molar ratio between (i?)-2-(7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0: 1.0 to about 1.0: 1.2.
  • the molar ratio between (i?)-2-(7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0: 1.0.
  • the salt-forming mixture prior to the adding L-arginine is at a temperature of about 15°C to about 83°C. In some embodiments, the salt-forming mixture prior to the adding L-arginine is at a temperature of about 18°C to about 80°C. In some embodiments, the salt- forming mixture prior to the adding L-arginine is at a temperature of about 20°C to about 40°C.
  • One aspect of the present invention allows for the L-arginine to be added to the salt-forming mixture as a solid.
  • the adding L-arginine in Step b) is conducted by adding L-arginine as a solid to the salt-forming mixture.
  • the adding L-arginine in Step b) is conducted by adding L-arginine as a solid to the salt-forming mixture substantially all at once.
  • the phrase "substantially all at once” or “all at once” refers to the addition of all of the L-arginine to the salt-forming mixture at one time with the only limitation that is placed on the addition is by any limitation associated with the equipment used.
  • the adding L-arginine in Step b) is conducted by adding L-arginine as a solid to the salt-forming mixture over a period of 30 minutes. In some embodiments, the adding L- arginine in Step b) is conducted by adding L-arginine as a solid to the salt-forming mixture over a period of 1 hour. In some embodiments, the adding L-arginine in Step b) is conducted by adding L- arginine as a solid to the salt-forming mixture over a period of 2 hours.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-
  • the salt- forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- 1,2,3, 4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:5.29:0.99 to about 1.00:7.15 : 1.35.
  • the salt-forming mixture comprises (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2- propanol, and water in a weight ratio of about 1.00:5.60: 1.05 to about 1.00:6.84: 1.29.
  • the salt-forming mixture comprises (R)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cycloperita[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:5.72:1.08 to about 1.00:6.72:1.26.
  • the salt- forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- 1,2,3, 4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:5.85: 1.10 to about 1.00:6.59:1.24.
  • the salt-forming mixture comprises (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2- propanol, and water in a weight ratio of about 1.00:5.97:1.12 to about 1.00:6.47:1.22.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:6.10:1.15 to about 1.00:6.34:1.19.
  • the salt- forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- 1,2,3, 4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:6.22: 1.17.
  • the salt-forming mixture during the adding L-arginine is at a temperature of about 15°C to about 83°C. In some embodiments, the salt-forming mixture during the adding L-arginine is at a temperature of about 18°C to about 80°C. In some embodiments, the salt- forming mixture during the adding L-arginine is at a temperature of about 20°C to about 40°C.
  • One aspect of the present invention allows for the L-arginine to be added to the salt-forming mixture as an aqueous solution.
  • the adding L-arginine in Step b) is conducted by adding L-arginine as an aqueous solution to the salt-forming mixture.
  • the adding L-arginine in Step b) is conducted by adding L-arginine to the salt-forming mixture wherein L-arginine is a solution of about 2.1M to about 2.3M aqueous solution at a temperature of about 50°C to about 75°C. In some embodiments, the adding L-arginine in Step b) is conducted by adding L-arginine to the salt-forming mixture wherein L-arginine is a solution of about 2.26 M to about 2.28 M aqueous solution at a temperature of about 55°C to about 65°C.
  • the weight ratio of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3- yl)acetic acid, 2-propanol, and H 2 0 is about 1.00:4.98:0.94 to about 1.00:7.46: 1.40.
  • the weight ratio of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2- propanol, and H 2 0 is about 1.00:5.29:0.99 to about 1.00:7.15:1.35.
  • the weight ratio of (i?)-2-(7-(4-cyclopentyl-3-(trifluoro- methyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and H 2 0 is about 1.00:5.60:1.05 to about 1.00:6.84:1.29.
  • the weight ratio of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and H 2 0 is about 1.00:5.72:1.08 to about 1.00:6.72:1.26.
  • the weight ratio of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- 1,2,3, 4-tetrahydro-cyclo- penta[b]indol-3-yl)acetic acid, 2-propanol, and H 2 0 is about 1.00:5.85: 1.10 to about 1.00:6.59: 1.24.
  • the weight ratio of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and H 2 0 is about 1.00:5.97: 1.12 to about 1.00:6.47 : 1.22.
  • the weight ratio of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and H 2 0 is about 1.00:6.10: 1.15 to about 1.00:6.34: 1.19.
  • the weight ratio of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyl- oxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and H 2 0 is about
  • Step b) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step b) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step b) is conducted at a stir rate of about 150 rpm.
  • Step c) Heating the First Mixture to a First Heating Temperature.
  • the first heating temperature is about 20°C to about 83°C. In some embodiments, the first heating temperature is about 20°C to about 55°C. In some embodiments, the first heating temperature is about 25°C to about 45°C. In some embodiments, the first heating temperature is about 50°C to about 83°C. In some embodiments, the first heating temperature is about 60°C to about 80°C. In some embodiments, the first heating temperature is about 70°C to about 80°C.
  • the first mixture is substantially a homogeneous solution.
  • Step c) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step c) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step c) is conducted at a stir rate of about 150 rpm.
  • Step d) Adding a First Additional Amount of the Water-Miscible Anti-Solvent to the First Mixture to Form a Suspension.
  • the water-miscible anti-solvent in Step b) comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, and C 2 -C4 alkanol.
  • the water-miscible anti-solvent in Step b) comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, ethanol, 1-propanol, 2-propanol, and 1 -butanol.
  • the water-miscible anti-solvent in Step b) comprises 2-propanol.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.46 to about 1.00:8.20.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.81 to about 1.00:7.86.
  • the weight ratio of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:6.15 to about 1.00:7.51.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:6.28 to about 1.00:7.38.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:6.42 to about 1.00:7.24.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:6.56 to about 1.00:7.10.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:6.69 to about 1.00:6.97.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:6.83.
  • adding the first additional amount of 2-propanol to the first mixture is conducted at a rate to complete the addition in about 5.00 hours to about 10.00 hours. In some embodiments, adding the first additional amount of 2-propanol to the first mixture is conducted at a rate to complete the addition in about 6.75 hours to about 8.25 hours. In some embodiments, adding the first additional amount of 2-propanol to the first mixture is conducted at a rate to complete the addition in about 6.90 hours to about 8.10 hours. In some embodiments, adding the first additional amount of 2- propanol to the first mixture is conducted at a rate to complete the addition in about 7.05 hour to about 7.95 hour.
  • adding the first additional amount of 2-propanol to the first mixture is conducted at a rate to complete the addition in about 7.20 hours to about 7.80 hours. In some embodiments, adding the first additional amount of 2-propanol to the first mixture is conducted at a rate to complete the addition in about 7.35 hours to about 7.65 hours. In some embodiments, adding the first additional amount of 2-propanol to the first mixture is conducted at a rate to complete the addition in about 7.50 hours.
  • the first heating temperature is maintained during adding the first additional amount of 2-propanol to the first mixture.
  • the method further comprises forming a second mixture while maintaining the first heating temperature, wherein the second mixture is formed prior to forming the suspension.
  • the method further comprises cooling the second mixture to a first cooling temperature followed by heating to a second heating temperature to form the suspension.
  • cooling the second mixture to the first cooling temperature is conducted at a rate of about 8.80°C/hour to about 14.40°C/hour. In some embodiments, cooling the second mixture to the first cooling temperature is conducted at a rate of about 9.35°C/hour to about
  • cooling the second mixture to the first cooling temperature is conducted at a rate of about 9.90°C hour to about 13.20°C hour. In some embodiments, cooling the second mixture to the first cooling temperature is conducted at a rate of about 10.45°C/hour to about 12.60°C/hour. In some embodiments, cooling the second mixture to the first cooling temperature is conducted at a rate of about 10°C/hour to about 12°C/hour.
  • the first cooling temperature is about 15°C to about 40°C. In some embodiments, the first cooling temperature is about 20°C to about 30°C. In some embodiments, the first cooling temperature is about 22°C to about 24°C.
  • the first cooling temperature is maintained for at least 1 hour prior to heating to the second heating temperature.
  • the second heating temperature is about 65°C to about 83°C. In some embodiments, the second heating temperature is about 70°C to about 80°C. In some embodiments, the second heating temperature is about 70°C to about 75°C.
  • the second heating temperature is maintained for at least 30 minutes.
  • Step d) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step d) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step d) is conducted at a stir rate of about 150 rpm.
  • Step e) Cooling the Suspension to Form the Crystalline Free-Plate Habit of L-Arginine Salt of ( ?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo- penta[b]indol-3-yl)acetic Acid.
  • cooling the suspension in Step e) is conducted at a rate of about 8.8°C/hour to about 14.4°C hour. In some embodiments, cooling the suspension in Step e) is conducted at a rate of about 9.4°C hour to about 13.8°C/hour. In some embodiments, cooling the suspension in Step e) is conducted at a rate of about 9.9°C/hour to about 13.2°C hour. In some embodiments, cooling the suspension in Step e) is conducted at a rate of about 10.5°C/hour to about 12.6°C hour. In some embodiments, cooling the suspension in Step e) is conducted at a rate of about 10°C hour to about 12°C/hour.
  • the temperature of the suspension is about 15°C to about 40°C. In some embodiments, after cooling in Step e) the temperature of the suspension is about 20°C to about 30°C. In some embodiments, after cooling in Step e) the temperature of the suspension is about 22°C to about 24°C.
  • Step e) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step e) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step e) is conducted at a stir rate of about 150 rpm.
  • the method further comprises the step of isolating the crystalline free- plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b] indol-3 -y 1) acetic acid .
  • the step of isolating comprises filtering the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid from the suspension.
  • the step of isolating comprises filtering the crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid from the suspension and drying the crystalline free-plate habit of L-arginine salt at a reduced pressure.
  • (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 205.0°C to 208.5°C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L- arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 205.5°C to 208.5 °C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L-arginine salt of (i3 ⁇ 4-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 206.5°C to 208.5 °C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 207.0°C to 208.1°C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L- arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10.
  • the crystalline free-plate habit of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10 and Figures 22 to 25.
  • the crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.3% weight or less at 90% RH.
  • DMS dynamic moisture sorption
  • (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.2% weight or less at 90% RH.
  • DMS dynamic moisture sorption
  • the DMS features reported herein can also vary by plus or minus about 0.15% weight change (i.e., + 0.15% weight change).
  • the crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a total impurity profile by achiral HPLC of less than or equal to 0.3% by area.
  • the crystalline free-plate habit of L-arginine salt of (i3 ⁇ 4-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a total impurity profile by achiral HPLC of less than or equal to 0.2% by area.
  • the method further comprises the step of formulating the crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid to form a pharmaceutical composition.
  • the method further comprises the step of admixing the crystalline free- plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid with a pharmaceutical excipient to form a pharmaceutical composition.
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • R 3 is C C6 alkyl; in the presence of a hydrolyzing mixture comprising a lipase and a hydrolyzing-step solvent to form (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
  • one aspect of the present invention relates to methods for preparing a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • Another aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • One aspect of the present invention relates to methods for preparing a crystalline free- habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • Step e) cycling Step e) optionally one or more times, wherein the first cooling temperature at each cycle may be the same or different and the second heating temperature at each cycle may be the same or different;
  • the method for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid is conducted under an inert atmosphere.
  • the method is conducted under an inert atmosphere comprising nitrogen or argon.
  • the method is conducted under an inert atmosphere comprising nitrogen.
  • the hydrolyzing in Step a) is conducted under an inert atmosphere. In some embodiments, the hydrolyzing in Step a) is conducted under an inert atmosphere comprising nitrogen or argon. In some embodiments, the hydrolyzing in Step a) is conducted under an inert atmosphere comprising nitrogen.
  • R 3 is methyl or ethyl. In some embodiments, R 3 is ethyl.
  • the lipase is Candida Antarctica lipase B. In some embodiments, the lipase is immobilized Candida Antarctica lipase B.
  • the hydrolyzing-step solvent comprises dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), or acetonitrile. In some embodiments, the hydrolyzing-step solvent comprises acetonitrile.
  • the compound of Formula (Ila) is:
  • the lipase is immobilized Candida Antarctica lipase B; and the hydrolyzing-step solvent comprises acetonitrile.
  • the hydrolyzing is conducted in the presence of a phosphate buffer. In some embodiments, the hydrolyzing is conducted in the presence of a phosphate buffer at a pH of about 6.0 to about 9.0. In some embodiments, the hydrolyzing is conducted in the presence of a phosphate buffer at a pH of about 6.9 to about 8.1. In some embodiments, the hydrolyzing is conducted in the presence of a phosphate buffer at a pH of about 7.0 to about 8.5. In some embodiments, the hydrolyzing is conducted in the presence of a phosphate buffer at a pH of about 7.3 to about 8.3. In some embodiments, the hydrolyzing is conducted in the presence of a phosphate buffer at a pH of about 7.6 to about 8.0.
  • the hydrolyzing is conducted in the presence of a phosphate buffer at a pH of about 7.8.
  • the phosphate buffer is a sodium phosphate buffer.
  • the phosphate buffer is a potassium phosphate buffer.
  • the hydrolyzing is conducted at a temperature of about 0°C to about 75°C. In some embodiments, the hydrolyzing is conducted at a temperature of about 20°C to about 65°C. In some embodiments, the hydrolyzing is conducted at a temperature of about 30°C to about 55°C. In some embodiments, the hydrolyzing is conducted at a temperature of about 35°C to about 45°C.
  • the hydrolyzing further comprises the step of isolating the (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.
  • the (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 95% or greater.
  • the (i?)-2-(7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 98% or greater.
  • the (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 99% or greater.
  • the (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is not isolated.
  • the (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is present in an amount of at least 40% as determined by HPLC.
  • the (i?)- 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is present in an amount of at least 45% as determined by HPLC.
  • forming a first mixture in Step b) is conducted under an inert atmosphere. In some embodiments, forming a first mixture in Step b) is conducted under an inert atmosphere comprising argon or nitrogen. In some embodiments, forming a first mixture in Step b) is conducted under an inert atmosphere comprising nitrogen.
  • a first mixture comprising L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, a water-miscible anti-solvent, and H 2 0, may be performed in any manner routine to the skilled artisan.
  • forming the first mixture may comprise forming the L-arginine salt by reacting L-arginine with (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and mixing the L-arginine salt, the water-miscible anti- solvent, and H 2 0.
  • forming the first mixture may comprise forming a mixture of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the water-miscible anti-solvent and H 2 0; and reacting the L-arginine with (R)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid to form the first mixture.
  • forming the first mixture may comprise forming a mixture of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and the water-miscible anti-solvent; and reacting the L-arginine as an aqueous slurry or solution with (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid to form the first mixture.
  • forming the first mixture may comprise forming a mixture of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the water-miscible anti-solvent and the L-arginine; and adding H 2 0 to form the first mixture.
  • forming the first mixture in Step b) comprises the step of adding L-arginine and H 2 0, either together or separately in any order, to a salt-forming mixture comprising (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid and the water-miscible anti-solvent to form the first mixture.
  • the adding L-arginine and H 2 0 is conducted under an inert atmosphere. In some embodiments, the adding L-arginine and H 2 0 is conducted under an inert atmosphere comprising argon or nitrogen. In some embodiments, the adding L-arginine and H 2 0 is conducted under an inert atmosphere comprising nitrogen.
  • the water-miscible anti-solvent comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, and C 2 -C 4 alkanol. In some embodiments, the water-miscible anti-solvent comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, ethanol, 1-propanol, 2-propanol, and 1 -butanol. In some embodiments, the water-miscible anti-solvent comprises 2-propanol.
  • the salt-forming mixture prior to adding the L-arginine and H 2 0, the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- 1,2,3, 4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:3.0 to about 1.0: 11.0.
  • the salt-forming mixture prior to adding the L-arginine and H 2 0, the salt-forming mixture comprises (i?)-
  • the salt-forming mixture prior to adding the L-arginine and H 2 0, the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:5.0 to about 1.0:9.0.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:6.0 to about 1.0:8.0.
  • the molar ratio between (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.9 to about 1.0: 1.2. In some embodiments, the molar ratio between (i?)-2-(7-(4-cyclopentyl-
  • the molar ratio between (i?)-2-(7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.93 to about 1.0: 1.01.
  • the molar ratio between (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L- arginine is about 1.0:0.93 to about 1.0:0.97. In some embodiments, the molar ratio between (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L- arginine is about 1.0: 1.0.
  • the molar ratio between (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.95.
  • the weight ratio of L-arginine and H 2 0 is about 1.0:0.4 to about 1.0:2.3. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0: 1.6 to about 1.0:2.1. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0:0.8 to about 1.0: 1.9. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0: 1.0 to about 1.0: 1.7. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0: 1.1 to about 1.0: 1.6. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0: 1.2 to about 1.0: 1.5.
  • the salt-forming mixture prior to the adding L-arginine is at a temperature of about 15°C to about 83°C. In some embodiments, the salt-forming mixture prior to the adding L-arginine is at a temperature of about 18°C to about 80°C. In some embodiments, the salt- forming mixture prior to the adding L-arginine is at a temperature of about 20°C to about 40°C. In some embodiments, the salt-forming mixture prior to the adding L-arginine is at a temperature of about 18°C to about 30°C.
  • the adding L-arginine is conducted by adding L-arginine as an aqueous slurry to the salt-forming mixture.
  • the adding L-arginine is conducted by adding L-arginine as a solid to the salt-forming mixture.
  • the adding L-arginine to the salt-forming mixture is conducted by adding L-arginine as a solid to the salt-forming mixture substantially all at once.
  • substantially all at once or “all at once” refers to the addition of all of the L-arginine to the salt- forming mixture at one time with the only limitation that is placed on the addition is by any limitation associated with the equipment used.
  • the adding L-arginine to the salt-forming mixture is conducted by adding L-arginine as a solid to the salt-forming mixture over a period of about 30 minutes. In some embodiments, the adding L-arginine to the salt-forming mixture is conducted by adding L-arginine as a solid to the salt-forming mixture over a period of about 1 hour. In some embodiments, the adding L- arginine to the salt-forming mixture is conducted by adding L-arginine as a solid to the salt-forming mixture over a period of about 2 hours.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-
  • the salt- forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:3.0:0.05 to about 1.0: 11.0: 1.0.
  • the salt- forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:4.0:0.1 to about 1.0: 10.0:0.9.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:5.0:0.15 to about 1.0:9.0:0.8.
  • the salt- forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:6.0:0.25 to about 1.0:8.0:0.7.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:4.98:0.94 to about 1.00:7.46:1.40, about 1.00:5.29:0.99 to about 1.00:7.15:1.35, about 1.00:5.60:1.05 to about 1.00:6.84:1.29, about 1.00:5.72:1.08 to about
  • the salt-forming mixture during the adding L-arginine is at a temperature of about 15°C to about 83°C. In some embodiments, the salt-forming mixture during the adding L-arginine is at a temperature of about 18°C to about 80°C. In some embodiments, the salt- forming mixture during the adding L-arginine is at a temperature of about 20°C to about 40°C. In some embodiments, the salt-forming mixture during the adding L-arginine is at a temperature of about 18°C to about 30°C.
  • the adding L-arginine is conducted by adding L-arginine as an aqueous solution to the salt-forming mixture.
  • the adding L-arginine is conducted by adding L-arginine to the salt- forming mixture wherein L-arginine is a solution of about 2.1M to about 2.3M aqueous solution at a temperature of about 50°C to about 75°C.
  • forming the first mixture in Step b) is conducted at a stir rate of about
  • forming the first mixture in Step b) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, forming the first mixture in Step b) is conducted at a stir rate of about 150 rpm.
  • Step c) Heating the First Mixture to a First Heating Temperature to form a Second Mixture.
  • the first heating temperature is about 20°C to about 85°C. In some embodiments, the first heating temperature is about 20°C to about 83°C. In some embodiments, the first heating temperature is about 20°C to about 55°C. In some embodiments, the first heating temperature is about 25°C to about 45°C. In some embodiments, the first heating temperature is about 50°C to about 83°C. In some embodiments, the first heating temperature is about 60°C to about 80°C. In some embodiments, the first heating temperature is about 70°C to about 80°C. In some embodiments, the first heating temperature is about 79°C to about 85°C.
  • an optional amount of H 2 0 is added to the second mixture.
  • the weight amount of water added is about 0.4 to about 2.3 times the weight of L-arginine originally added in forming the first mixture.
  • the weight amount of water added when the optional amount of H 2 0 is added to the second mixture, is about 1.0:1.6 to about 1.0:2.1 times the weight of L-arginine originally added in forming the first mixture. In some embodiments, when water is added to the second mixture, the weight amount of water added is about 1.0:0.8 to about 1.0: 1.9 times the weight of L-arginine originally added in forming the first mixture. In some embodiments, when water is added to the second mixture, the weight amount of water added is about 1.0:1.0 to about 1.0:1.7 times the weight of L- arginine originally added in forming the first mixture.
  • the weight amount of water added when water is added to the second mixture, is about 1.0: 1.1 to about 1.0: 1.6 times the weight of L-arginine originally added in forming the first mixture. In some embodiments, when water is added to the second mixture, the weight amount of water added is about 1.0: 1.2 to about 1.0: 1.5 times the weight of L-arginine originally added in forming the first mixture.
  • the second mixture is substantially a homogeneous solution.
  • Step c) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step c) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step c) is conducted at a stir rate of about 150 rpm.
  • Step d) Adding a First Additional Amount of the Water-Miscible Anti-Solvent to the Second Mixture while maintaining the First Heating Temperature to Form a Suspension.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.46 to about 1.00:8.20.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:4.70 to about 1.00:7.50.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.20 to about 1.00:7.00.
  • the weight ratio of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.70 to about 1.00:6.50.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.90 to about 1.00:6.30.
  • the weight ratio of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.95 to about 1.00:6.25.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:6.00 to about 1.00:6.20.
  • the first additional amount of the water-miscible anti-solvent is added during a first time point and a second time point. In some embodiments, about 5% to about 15% of the first additional amount of the water- miscible anti-solvent is added at the first time point.
  • about 7% to about 13% of the first additional amount of the water- miscible anti-solvent is added at the first time point.
  • the first additional amount of the water- miscible anti-solvent is added at the first time point. In some embodiments, about 9% to about 11 % of the first additional amount of the water-miscible anti-solvent is added at the first time point.
  • the first additional amount of the water-miscible anti-solvent is added at the first time point to form a cloudy mixture.
  • the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour or greater. In some embodiments, the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 6.00 hours. In some embodiments, the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 5.00 hours. In some embodiments, the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 4.00 hours.
  • the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 3.00 hours. In some embodiments, the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 2.00 hours.
  • the first heating temperature is maintained during the addition of the first additional amount of 2-propanol to the second mixture.
  • Step d) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step d) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step d) is conducted at a stir rate of about 150 rpm.
  • Step e) Cooling the Suspension to a First Cooling Temperature and Thereafter Heating to a Second Heating Temperature.
  • cooling the suspension to the first cooling temperature in Step e) is conducted at a rate of about 8.80°C hour to about 14.40°C/hour. In some embodiments, cooling the suspension to the first cooling temperature in Step e) is conducted at a rate of about 9.35°C/hour to about 13.80°C/hour. In some embodiments, cooling the suspension to the first cooling temperature in Step e) is conducted at a rate of about 9.90°C/hour to about 13.20°C/hour. In some embodiments, cooling the suspension to the first cooling temperature in Step e) is conducted at a rate of about 10.45°C/hour to about 12.60°C hour.
  • cooling the suspension to the first cooling temperature in Step e) is conducted at a rate of about 10°C/hour to about 12°C/hour. In some embodiments, cooling the suspension to the first cooling temperature in Step e) is conducted at a rate of about 9°C hour to about 1 l°C hour. In some embodiments, cooling the suspension to the first cooling temperature in Step e) is conducted at a rate of about 9.5°C/hour to about 10.5°C/hour.
  • the first cooling temperature in Step e) is about 15°C to about 40°C. In some embodiments, the first cooling temperature in Step e) is about 20°C to about 30°C. In some embodiments, the first cooling temperature in Step e) is about 22°C to about 24°C. In some embodiments, the first cooling temperature in Step e) is about 18°C to about 22°C.
  • the first cooling temperature is maintained for at least 1 hour prior to heating to the second heating temperature.
  • the second heating temperature in Step e) is about 65°C to about 83°C. In some embodiments, the second heating temperature in Step e) is about 70°C to about 80°C. In some embodiments, the second heating temperature in Step e) is about 70°C to about 75°C. In some embodiments, the second heating temperature in Step e) is about 69°C to about 73°C.
  • the second heating temperature is maintained for at least 30 minutes.
  • Step e) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step e) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step e) is conducted at a stir rate of about 150 rpm.
  • the cycling in Step f) comprises the cycling Step e) two times.
  • cycling Step e) two times comprises cooling the suspension to a first cycling cooling temperature, heating the suspension to a first cycling heating temperature, cooling the suspension to a second cycling cooling temperature, and heating the suspension to a second cycling heating temperature.
  • the first cycling cooling temperature is about 16°C to about 26°C
  • the first heating cycling temperature is about 55°C to about 65°C
  • the second cycling cooling temperature is about 26°C to about 36°C
  • the second cycling heating temperature is about 45°C to about 55°C.
  • the first cycling cooling temperature is about 19°C to about 23°C
  • the first heating cycling temperature is about 58°C to about 62°C
  • the second cycling cooling temperature is about 29°C to about 33°C
  • the second cycling heating temperature is about 48°C to about 52°C.
  • cooling to each cooling temperature is conducted at a substantially different cooling rate. In some embodiments, cooling to each cooling temperature is conducted at a different cooling rate. In some embodiments, the cycling in Step f) comprises the cycling Step e) two times. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about
  • cooling to the first cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.0°C/hour to about 13.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step f) comprises the cycling Step e) two times.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 7.5°C/hour to about 12.5°C hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 8.5°C hour to about 11.5°C/hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 9.5°C hour to about 10.5°C/hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C/hour.
  • the cycling in Step f) comprises the cycling Step e) three times.
  • cycling Step e) three times comprises: cooling the suspension to a first cycling cooling temperature, heating the suspension to a first cycling heating temperature, cooling the suspension to a second cycling cooling temperature, heating the suspension to a second cycling heating temperature, cooling the suspension to a third cycling cooling temperature, and heating the suspension to a third cycling heating temperature.
  • the first cycling cooling temperature is about 16°C to about 26°C
  • the first heating cycling temperature is about 66°C to about 76°C
  • the second cycling cooling temperature is about 16°C to about 26°C
  • the second cycling heating temperature is about 55°C to about 65°C
  • the third cycling cooling temperature is about 26°C to about 36°C
  • the third cycling heating temperature is about 45°C to about 55°C.
  • the first cycling cooling temperature is about 19°C to about 23°C
  • the first heating cycling temperature is about 69°C to about 73°C
  • the second cycling cooling temperature is about 19°C to about 23°C
  • the second cycling heating temperature is about 58°C to about 62°C
  • the third cycling cooling temperature is about 29°C to about 33°C
  • the third cycling heating temperature is about 48°C to about 52°C.
  • cooling to each cooling temperature is conducted at a substantially different cooling rate. In some embodiments, cooling to each cooling temperature is conducted at a different cooling rate.
  • cooling to the first cycling cooling temperature and the second cycling cooling temperature are each conducted at substantially the same cooling rate.
  • the cycling in Step f) comprises the cycling Step e) three times. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about
  • cooling to the first cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.0°C/hour to about 13.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step f) comprises the cycling Step e) three times.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C/hour to about 15.0°C/hour.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C/hour.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 12.0°C/hour to about 13.0°C/hour.
  • cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step f) comprises the cycling Step e) three times. In some embodiments, cooling to the third cycling cooling temperature is conducted at a rate of about
  • cooling to the third cycling cooling temperature is conducted at a rate of about 8.5°C hour to about 11.5°C/hour. In some embodiments, cooling to the third cycling cooling temperature is conducted at a rate of about 9.5°C/hour to about 10.5°C/hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C/hour.
  • the cycling in Step f) comprises the cycling Step e) four times.
  • cycling Step e) four times comprises: cooling the suspension to a first cycling cooling temperature, heating the suspension to a first cycling heating temperature, cooling the suspension to a second cycling cooling temperature, heating the suspension to a second cycling heating temperature, cooling the suspension to a third cycling cooling temperature, heating the suspension to a third cycling heating temperature, cooling the suspension to a fourth cycling cooling temperature, and heating the suspension to a fourth cycling heating temperature.
  • the first cycling cooling temperature is about 16°C to about 26°C
  • the first heating cycling temperature is about 66°C to about 76°C
  • the second cycling cooling temperature is about 16°C to about 26°C
  • the second cycling heating temperature is about 66°C to about 76°C
  • the third cycling cooling temperature is about 16°C to about 26°C
  • the third cycling heating temperature is about 55°C to about 65°C
  • the fourth cycling cooling temperature is about 26°C to about 36°C
  • the fourth cycling heating temperature is about 45°C to about 55°C.
  • the first cycling cooling temperature is about 19°C to about 23°C
  • the first heating cycling temperature is about 69°C to about 73°C
  • the second cycling cooling temperature is about 19°C to about 23°C
  • the second cycling heating temperature is about 69°C to about 73°C
  • the third cycling cooling temperature is about 19°C to about 23°C
  • the third cycling heating temperature is about 58°C to about 62°C
  • the fourth cycling cooling temperature is about 29°C to about 33°C
  • the fourth cycling heating temperature is about 48°C to about 52°C.
  • cooling to each cooling temperature is conducted at a substantially different cooling rate. In some embodiments, cooling to each cooling temperature is conducted at a different cooling rate.
  • cooling to the first cycling cooling temperature, the second cycling cooling temperature, and the third cycling cooling temperature are each conducted at substantially the same cooling rate.
  • the cycling in Step f) comprises the cycling Step e) four times. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about
  • cooling to the first cycling cooling temperature is conducted at a rate of about 11.0°C hour to about 14.0°C hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.0°C hour to about 13.0°C hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step f) comprises the cycling Step e) four times. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about
  • cooling to the second cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 12.0°C hour to about 13.0°C hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step f) comprises the cycling Step e) four times. In some embodiments, cooling to the third cycling cooling temperature is conducted at a rate of about
  • cooling to the third cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C hour. In some embodiments, cooling to the third cycling cooling temperature is conducted at a rate of about 12.0°C hour to about 13.0°C hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step f) comprises the cycling Step e) four times.
  • cooling to the fourth cycling cooling temperature is conducted at a rate of about 7.5°C/hour to about 12.5°C hour. In some embodiments, cooling to the fourth cycling cooling temperature is conducted at a rate of about 8.5°C hour to about 11.5°C/hour. In some embodiments, cooling to the fourth cycling cooling temperature is conducted at a rate of about 9.5°C/hour to about 10.5°C hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C hour.
  • Step f) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step f) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step f) is conducted at a stir rate of about 150 rpm.
  • Step g) - Cooling the Suspension to a Final Cooling Temperature to Form the Crystalline Free-Plate Habit of L-Arginine Salt of (/?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic Acid.
  • cooling the suspension in Step g) is conducted at a rate of about 7.5°C/hour to about 12.5°C hour. In some embodiments, cooling the suspension in Step g) is conducted at a rate of about 8.5°C hour to about 11.5°C/hour. In some embodiments, cooling the suspension in Step g) is conducted at a rate of about 9.5°C/hour to about 10.5°C/hour. In some embodiments, cooling the suspension in Step g) is conducted at a rate of about 10.0°C/hour.
  • cooling the suspension in Step g) is conducted at a rate of about 8.8°C/hour to about 14.4°C hour. In some embodiments, cooling the suspension in Step g) is conducted at a rate of about 9.4°C hour to about 13.8°C/hour. In some embodiments, cooling the suspension in Step g) is conducted at a rate of about 9.9°C/hour to about 13.2°C hour. In some embodiments, cooling the suspension in Step g) is conducted at a rate of about 10.5°C/hour to about 12.6°C hour. In some embodiments, cooling the suspension in Step g) is conducted at a rate of about 10°C/hour to about 12°C/hour.
  • the temperature of the suspension is about 15°C to about 40°C. In some embodiments, after cooling in Step g) the temperature of the suspension is about 20°C to about 30°C. In some embodiments, after cooling in Step g) the temperature of the suspension is about 22 °C to about 24 °C. In some embodiments, after cooling in Step g) the temperature of said suspension is about 18°C to about 22°C.
  • Step g) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step g) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step g) is conducted at a stir rate of about 150 rpm.
  • the method further comprises the step of isolating the crystalline free- plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b] indol-3 -y 1) acetic acid .
  • the step of isolating comprises filtering the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid from the suspension.
  • the step of isolating comprises filtering the crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid from the suspension and drying the crystalline free-plate habit of L-arginine salt at a reduced pressure.
  • the crystalline free -plate habit of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has any one or more of the characteristics as described herein.
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 205.0°C to 208.5 °C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 205.5°C to 208.5°C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L- arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 206.5°C to 208.5 °C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L-arginine salt of (i3 ⁇ 4-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 207.0°C to 208.1 °C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10.
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.3% weight or less at 90% RH.
  • DMS dynamic moisture sorption
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.2% weight or less at 90% RH.
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a total impurity profile by achiral HPLC of less than or equal to 0.5% by area.
  • the crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a total impurity profile by achiral HPLC of less than or equal to 0.3% by area.
  • the crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a total impurity profile by achiral HPLC of less than or equal to 0.2% by area.
  • the method further comprises the step of formulating the crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid to form a pharmaceutical composition.
  • the method further comprises the step of admixing the crystalline free- plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid with a pharmaceutical excipient to form a pharmaceutical composition.
  • the method further comprises the step of admixing the crystalline free- plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid with a pharmaceutical excipient to form a pharmaceutical composition suitable for oral, rectal, nasal, topical, buccal, sub-lingual, or vaginal, or in a form suitable for administration by inhalation, insufflation, or by a transdermal patch.
  • the pharmaceutical composition is suitable for oral administration.
  • one aspect of the present invention relates to methods for preparing a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • Step b) cooling the second mixture to a first cooling temperature followed by adding a first additional amount of the water-miscible anti-solvent to the second mixture while maintaining the first cooling temperature and thereafter heating to a second heating temperature to form a suspension; c) cycling Step b) optionally once or twice; and
  • the water-miscible anti-solvent comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, and C2-C4 alkanol. In some embodiments, the water-miscible anti-solvent comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, ethanol, 1-propanol, 2-propanol, and 1-butanol. In some embodiments, the water-miscible anti-solvent comprises 2-propanol.
  • the L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)- benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid in Step a) is a spherulite, a radial cluster, a fine particle, an agglomerate, a flake, or a mixture thereof.
  • the L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)- benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid in Step a) is a crystalline spherulite habit or a mixture comprising a crystalline spherulite habit.
  • the method for preparing a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid is conducted under an inert atmosphere.
  • the method is conducted under an inert atmosphere comprising nitrogen or argon.
  • the method is conducted under an inert atmosphere comprising nitrogen.
  • the first mixture comprises L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:3.35:0.75 to about 1.00:5.03: 1.13.
  • the first mixture comprises L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:3.56:0.80 to about 1.00:4.82: 1.08.
  • the first mixture comprises L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:3.77 :0.85 to about 1.00:4.61 : 1.03.
  • the first mixture comprises L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:3.85:0.86 to about 1.00:4.52: 1.02.
  • the first mixture comprises L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about
  • the first mixture comprises L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:4.02:0.90 to about 1.00:4.36:0.98.
  • the first mixture comprises L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:4.11 :0.92 to about 1.00:4.27:0.96.
  • the first mixture comprises L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.00:4.19:0.94.
  • the first mixture is at a temperature of about 10°C to about 30°C prior to heating to the first heating temperature. In some embodiments, the first mixture is at a temperature of about 15°C to about 25°C prior to heating to the first heating temperature. In some embodiments, the first heating temperature is about 60°C to about 83°C. In some embodiments, the first heating temperature is about 70°C to about 83°C. In some embodiments, the first heating temperature is about 75°C to about 80°C.
  • the second mixture after heating to the first heating temperature the second mixture is substantially a homogeneous solution.
  • Step a) is conducted at a stir rate of about 50 rpm to about 250 rpm. In some embodiments, Step a) is conducted at a stir rate of about 75 rpm to about 150 rpm.
  • Step b) Cooling the Second Mixture to a First Cooling Temperature.
  • the first cooling temperature is about 50°C to about 70°C. In some embodiments, the first cooling temperature is about 60°C to about 70°C. In some embodiments, the first cooling temperature is about 63 °C to about 67 °C.
  • the first cooling temperature is maintained for at least 30 minutes.
  • adding the first additional amount of 2-propanol to the second mixture is conducted at a rate of about 107.20 g/minute to about 160.80 g/minute. In some embodiments, adding the first additional amount of 2-propanol to the second mixture is conducted at a rate of about 113.90 g/minute to about 154.10 g/minute. In some embodiments, adding the first additional amount of 2- propanol to the second mixture is conducted at a rate of about 120.60 g/minute to about 147.40 g/minute. In some embodiments, adding the first additional amount of 2-propanol to the second mixture is conducted at a rate of about 127.30 g/minute to about 140.70 g/minute. In some embodiments, adding the first additional amount of 2-propanol to the second mixture is conducted at a rate of about 134 g/minute.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:0.98 to about 1.00:1.47.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:1.04 to about 1.00: 1.41.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:1.10 to about 1.00:1.35.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:1.13 to about 1.00: 1.32.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:1.15 to about 1.00:1.30.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:1.18 to about 1.00: 1.27.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:1.20 to about 1.00:1.25.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:1.23.
  • the first cooling temperature is maintained for at least 1 hour prior to heating to the second heating temperature.
  • the second heating temperature is about 65°C to about 83°C. In some embodiments, the second heating temperature is about 70°C to about 80°C. In some embodiments, the second heating temperature is about 70°C to about 75°C.
  • the second heating temperature is at a temperature to retain the suspension.
  • the second heating temperature is maintained for at least 30 minutes while retaining the suspension.
  • Step b) is conducted at a stir rate of about 50 rpm to about 150 rpm. In some embodiments, Step b) is conducted at a stir rate of about 70 rpm to about 110 rpm.
  • cycling Step b) is conducted once.
  • cycling Step b) is conducted once, wherein the cycling conditions are substantially the same conditions as used for Step b).
  • cycling Step b) is conducted once, wherein the cycling conditions are different from the conditions used for Step b); it is understood that the selected cycling conditions are still within the embodiments as described herein for Step b).
  • cycling Step b) is conducted twice.
  • cycling Step b) is conducted twice, wherein the cycling conditions for the first cycle and the second cycle are substantially the same conditions as used for Step b).
  • cycling Step b) is conducted twice, wherein at least one of the conditions for the first cycle, the second cycle, or Step b) is different; it is understood that whether or not the first cycle and/or the second cycle is different from each other or one or both of the cycles are different from Step b) that each of selected conditions for the first cycle and the second cycle are still within the embodiments as described herein for Step b).
  • Step d) Cooling the Suspension to a Second Cooling Temperature to Form the Crystalline Free-Plate Habit of L-Arginine Salt of ( ?)-2-(7-(4-Cyclopentyl-3-(trifluoro- methyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic Acid.
  • the second cooling temperature is about 50°C to about 70°C. In some embodiments, the second cooling temperature is about 60°C to about 70°C. In some embodiments, the second cooling temperature is about 63°C to about 67°C.
  • Step d) is conducted at a stir rate of about 25 rpm to about 105 rpm. In some embodiments, Step d) is conducted at a stir rate of about 45 rpm to about 85 rpm.
  • the method further comprises the step of cooling the suspension to a third cooling temperature.
  • the method further comprises the step of cooling the suspension to a third cooling temperature of about 10°C to about 30°C. In some embodiments, after cooling to the second cooling temperature, the method further comprises the step of cooling the suspension to a third cooling temperature of about 15°C to about 25°C.
  • the cooling rate from the second cooling temperature to the third cooling temperature is about 5°C per hour to about 15°C per hour. In some embodiments, the cooling rate from the second cooling temperature to the third cooling temperature is about 8°C per hour to about 12°C per hour. In some embodiments, the cooling rate from the second cooling temperature to the third cooling temperature is about 10°C per hour.
  • the method further comprises the step of isolating the crystalline free- plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b] indol-3 -y 1) acetic acid .
  • the step of isolating comprises filtering the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid from the suspension.
  • the step of isolating comprises filtering the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid from the suspension and drying the crystalline free-plate habit of L-arginine salt at a reduced pressure.
  • the crystalline free -plate habit of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 205.0°C to 208.5°C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L- arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 205.5°C to 208.5 °C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 206.5°C to 208.5 °C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an onset temperature of 207.0°C to 208.1°C as determined by differential scanning calorimetry at a scan rate of 10°C/minute.
  • the crystalline free-plate habit of L- arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10.
  • the crystalline free-plate habit of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10 and Figures 22 to 25.
  • the crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.3% weight or less at 90% RH.
  • DMS dynamic moisture sorption
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.2% weight or less at 90% RH.
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a total impurity profile by achiral HPLC of less than or equal to 0.5% by area.
  • the crystalline free -plate habit of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a total impurity profile by achiral HPLC of less than or equal to 0.3% by area.
  • the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has a total impurity profile by achiral HPLC of less than or equal to 0.2% by area.
  • the method further comprises the step of formulating the crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid to form a pharmaceutical composition.
  • the method further comprises the step of admixing the crystalline free- plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid with a pharmaceutical excipient to form a pharmaceutical composition.
  • One aspect of the present invention relates to methods for preparing a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopent l-3-(trifluoromethyl)benzyloxy)- 1,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, the method comprising the steps of:
  • a) forming a first mixture comprising L-arginine salt of (R)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, a water-miscible anti-solvent, and H 2 0; b) heating the first mixture to a first heating temperature to form a second mixture; c) adding a first additional amount of the water-miscible anti-solvent to the second mixture while maintaining the first heating temperature to form a suspension;
  • Step d) cycling Step d) optionally one or more times, wherein the first cooling temperature at each cycle may be the same or different and the second heating temperature at each cycle may be the same or different;
  • forming a first mixture in Step a) is conducted under an inert atmosphere. In some embodiments, forming a first mixture in Step a) is conducted under an inert atmosphere comprising argon or nitrogen. In some embodiments, forming a first mixture in Step a) is conducted under an inert atmosphere comprising nitrogen.
  • a first mixture comprising L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, a water-miscible anti-solvent, and H 2 0, may be performed in any manner routine to the skilled artisan, such as, the examples described supra.
  • forming the first mixture in Step a) comprises the step of adding L- arginine and H 2 0, either together or separately in any order, to a salt-forming mixture comprising (i?)- 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and the water-miscible anti-solvent to form the first mixture.
  • the adding L-arginine and H 2 0 is conducted under an inert atmosphere.
  • the adding L-arginine and H 2 0 is conducted under an inert atmosphere comprising argon or nitrogen. In some embodiments, the adding L-arginine and H 2 0 is conducted under an inert atmosphere comprising nitrogen.
  • the water-miscible anti-solvent comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, and C 2 -C4 alkanol. In some embodiments, the water-miscible anti-solvent comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, ethanol, 1-propanol, 2-propanol, and 1 -butanol. In some embodiments, the water-miscible anti-solvent comprises 2-propanol.
  • the salt-forming mixture prior to adding the L-arginine and H 2 0, the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- 1,2,3, 4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:3.0 to about 1.0: 11.0.
  • the salt-forming mixture prior to adding the L-arginine and H 2 0, the salt-forming mixture comprises (i?)- 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:4.0 to about 1.0: 10.0.
  • the salt-forming mixture prior to adding the L-arginine and H 2 0, the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:5.0 to about 1.0:9.0.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:6.0 to about 1.0:8.0.
  • the molar ratio between (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.8 to about 1.0: 1.2.
  • the molar ratio between (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.9 to about 1.0: 1.2. In some embodiments, the molar ratio between (i?)-2-(7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0: 1.0 to about 1.0: 1.2.
  • the molar ratio between (i?)-2-(7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.93 to about 1.0: 1.01. In some embodiments, the molar ratio between (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L- arginine is about 1.0:0.93 to about 1.0:0.97.
  • the molar ratio between (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L- arginine is about 1.0: 1.0. In some embodiments, the molar ratio between (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:0.95.
  • the weight ratio of L-arginine and H 2 0 is about 1.0:0.4 to about 1.0:2.3. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0: 1.6 to about 1.0:2.1. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0:0.8 to about 1.0: 1.9. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0: 1.0 to about 1.0: 1.7. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0: 1.1 to about 1.0: 1.6. In some embodiments, the weight ratio of L-arginine and H 2 0 is about 1.0: 1.2 to about 1.0: 1.5.
  • the salt-forming mixture prior to the adding L-arginine is at a temperature of about 15°C to about 83°C. In some embodiments, the salt-forming mixture prior to the adding L-arginine is at a temperature of about 18°C to about 80°C. In some embodiments, the salt- forming mixture prior to the adding L-arginine is at a temperature of about 20°C to about 40°C. In some embodiments, the salt-forming mixture prior to the adding L-arginine is at a temperature of about 18°C to about 30°C.
  • the adding L-arginine is conducted by adding L-arginine as an aqueous slurry to the salt- forming mixture. In some embodiments, the adding L-arginine is conducted by adding L-arginine as a solid to the salt-forming mixture.
  • the adding L-arginine to the salt-forming mixture is conducted by adding L-arginine as a solid to the salt-forming mixture substantially all at once.
  • substantially all at once or “all at once” refers to the addition of all of the L-arginine to the salt- forming mixture at one time with the only limitation that is placed on the addition is by any limitation associated with the equipment used.
  • the adding L-arginine to the salt-forming mixture is conducted by adding L-arginine as a solid to the salt-forming mixture over a period of about 30 minutes. In some embodiments, the adding L-arginine to the salt-forming mixture is conducted by adding L-arginine as a solid to the salt-forming mixture over a period of about 1 hour. In some embodiments, the adding L- arginine to the salt-forming mixture is conducted by adding L-arginine as a solid to the salt-forming mixture over a period of about 2 hours.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:3.0:0.05 to about 1.0: 11.0: 1.0.
  • the salt- forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:4.0:0.1 to about 1.0: 10.0:0.9.
  • the salt-forming mixture comprises (i?)-2-(7-(4-cyclopentyl- 3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:5.0:0.15 to about 1.0:9.0:0.8.
  • the salt- forming mixture comprises (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydro- cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:6.0:0.25 to about 1.0:8.0:0.7.
  • the salt-forming mixture during the adding L-arginine is at a temperature of about 15°C to about 83°C. In some embodiments, the salt-forming mixture during the adding L-arginine is at a temperature of about 18°C to about 80°C. In some embodiments, the salt- forming mixture during the adding L-arginine is at a temperature of about 20°C to about 40°C. In some embodiments, the salt-forming mixture during the adding L-arginine is at a temperature of about 18°C to about 30°C.
  • the salt-forming mixture during the adding L-arginine is at a temperature of about 15°C to about 83°C. In some embodiments, the salt-forming mixture during the adding L-arginine is at a temperature of about 18°C to about 80°C. In some embodiments, the salt- forming mixture during the adding L-arginine is at a temperature of about 20°C to about 40°C. In some embodiments, the salt-forming mixture during the adding L-arginine is at a temperature of about 18°C to about 30°C.
  • the adding L-arginine is conducted by adding L-arginine as an aqueous solution to the salt-forming mixture. In some embodiments, the adding L-arginine is conducted by adding L-arginine to the salt- forming mixture wherein L-arginine is a solution of about 2.1M to about 2.3M aqueous solution at a temperature of about 50°C to about 75°C.
  • forming the first mixture in Step a) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, forming the first mixture in Step a) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, forming the first mixture in Step a) is conducted at a stir rate of about 150 rpm.
  • Step b) Heating the First Mixture to a First Heating Temperature to form a Second Mixture.
  • the first heating temperature is about 20°C to about 85°C. In some embodiments, the first heating temperature is about 20°C to about 83°C. In some embodiments, the first heating temperature is about 20°C to about 55°C. In some embodiments, the first heating temperature is about 25°C to about 45°C. In some embodiments, the first heating temperature is about 50°C to about 83°C. In some embodiments, the first heating temperature is about 60°C to about 80°C. In some embodiments, the first heating temperature is about 70°C to about 80°C. In some embodiments, the first heating temperature is about 79°C to about 85°C.
  • an optional amount of H 2 0 is added to the second mixture.
  • the weight amount of water added is about 0.4 to about 2.3 times the weight of L-arginine originally added in forming the first mixture.
  • the weight amount of water added when water is added to the second mixture, is about 1.0:1.6 to about 1.0:2.1 times the weight of L-arginine originally added in forming the first mixture. In some embodiments, when water is added to the second mixture, the weight amount of water added is about 1.0:0.8 to about 1.0: 1.9 times the weight of L-arginine originally added in forming the first mixture. In some embodiments, when water is added to the second mixture, the weight amount of water added is about 1.0: 1.0 to about 1.0:1.7 times the weight of L-arginine originally added in forming the first mixture.
  • the weight amount of water added when water is added to the second mixture, is about 1.0:1.1 to about 1.0:1.6 times the weight of L-arginine originally added in forming the first mixture. In some embodiments, when water is added to the second mixture, the weight amount of water added is about 1.0:1.2 to about 1.0:1.5 times the weight of L-arginine originally added in forming the first mixture.
  • the second mixture is substantially a homogeneous solution.
  • Step b) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step b) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step b) is conducted at a stir rate of about 150 rpm.
  • Step c) Adding a First Additional Amount of the Water-Miscible Anti-Solvent to the Second Mixture while maintaining the First Heating Temperature to Form a Suspension.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.46 to about 1.00:8.20.
  • the weight ratio of L-arginine salt of (R)-2-(7-(4-cyclopent l-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:4.70 to about 1.00:7.50.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.20 to about 1.00:7.00.
  • the weight ratio of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.70 to about 1.00:6.50.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.90 to about 1.00:6.30.
  • the weight ratio of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:5.95 to about 1.00:6.25.
  • the weight ratio of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to the first additional amount of 2-propanol is about 1.00:6.00 to about 1.00:6.20.
  • the first additional amount of the water-miscible anti-solvent is added during a first time point and a second time point.
  • about 5% to about 15% of the first additional amount of the water- miscible anti-solvent is added at the first time point. In some embodiments, about 7% to about 13% of the first additional amount of the water-miscible anti-solvent is added at the first time point. In some embodiments, about 8% to about 12% of the first additional amount of the water-miscible anti-solvent is added at the first time point. In some embodiments, about 9% to about 11 % of the first additional amount of the water-miscible anti-solvent is added at the first time point.
  • the first additional amount of the water-miscible anti-solvent is added at the first time point to form a cloudy mixture.
  • a seed crystal of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is optionally added prior to the second time point.
  • the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour or greater.
  • the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 6.00 hours.
  • the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 5.00 hours. In some embodiments, the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 4.00 hours. In some embodiments, the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 3.00 hours. In some embodiments, the first additional amount of the water-miscible anti-solvent is added at the second time point at a rate to complete the addition in about 1.00 hour to about 2.00 hours.
  • the first heating temperature is maintained during the addition of the first additional amount of 2-propanol to the second mixture.
  • Step c) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step c) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step c) is conducted at a stir rate of about 150 rpm.
  • Step d) Cooling the Suspension to a First Cooling Temperature and Thereafter Heating to a Second Heating Temperature.
  • cooling the suspension to the first cooling temperature in Step d) is conducted at a rate of about 8.80°C hour to about 14.40°C/hour. In some embodiments, cooling the suspension to the first cooling temperature in Step d) is conducted at a rate of about 9.35°C/hour to about 13.80°C/hour. In some embodiments, cooling the suspension to the first cooling temperature in Step d) is conducted at a rate of about 9.90°C/hour to about 13.20°C/hour. In some embodiments, cooling the suspension to the first cooling temperature in Step d) is conducted at a rate of about
  • cooling the suspension to the first cooling temperature in Step d) is conducted at a rate of about 10°C hour to about 12°C hour. In some embodiments, cooling the suspension to the first cooling temperature in Step d) is conducted at a rate of about 9°C hour to about 1 l°C hour. In some embodiments, cooling the suspension to the first cooling temperature in Step d) is conducted at a rate of about 9.5°C hour to about 10.5°C/hour.
  • the first cooling temperature in Step d) is about 15°C to about 40°C. In some embodiments, the first cooling temperature in Step d) is about 20°C to about 30°C. In some embodiments, the first cooling temperature in Step d) is about 22°C to about 24°C. In some embodiments, the first cooling temperature in Step d) is about 18°C to about 22°C.
  • the first cooling temperature is maintained for at least 1 hour prior to heating to the second heating temperature.
  • the second heating temperature in Step d) is about 65°C to about 83°C. In some embodiments, the second heating temperature in Step d) is about 70°C to about 80°C. In some embodiments, the second heating temperature in Step d) is about 70°C to about 75°C. In some embodiments, the second heating temperature in Step d) is about 69°C to about 73°C.
  • the second heating temperature is maintained for at least 30 minutes.
  • Step d) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step d) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step d) is conducted at a stir rate of about 150 rpm.
  • Step d when cycling Step d) more than once that the first cooling temperature at each cycle may be the same or different and the second heating temperature at each cycle may be the same or different.
  • the cycling in Step e) comprises the cycling Step d) two times.
  • cycling Step d) two times comprises cooling the suspension to a first cycling cooling temperature, heating the suspension to a first cycling heating temperature, cooling the suspension to a second cycling cooling temperature, and heating the suspension to a second cycling heating temperature.
  • the first cycling cooling temperature is about 16°C to about 26°C
  • the first heating cycling temperature is about 55°C to about 65°C
  • the second cycling cooling temperature is about 26°C to about 36°C
  • the second cycling heating temperature is about 45°C to about 55°C.
  • the first cycling cooling temperature is about 19°C to about 23°C
  • the first heating cycling temperature is about 58°C to about 62°C
  • the second cycling cooling temperature is about 29°C to about 33°C
  • the second cycling heating temperature is about 48°C to about 52°C.
  • cooling to each cooling temperature is conducted at a substantially different cooling rate. In some embodiments, cooling to each cooling temperature is conducted at a different cooling rate.
  • the cycling in Step e) comprises the cycling Step d) two times. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about
  • cooling to the first cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.0°C hour to about 13.0°C hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step e) comprises the cycling Step d) two times.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 7.5°C/hour to about 12.5°C hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 8.5°C hour to about 11.5°C/hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 9.5°C hour to about 10.5°C/hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C/hour.
  • the cycling in Step e) comprises the cycling Step d) three times.
  • cycling Step d) three times comprises: cooling the suspension to a first cycling cooling temperature, heating the suspension to a first cycling heating temperature, cooling the suspension to a second cycling cooling temperature, heating the suspension to a second cycling heating temperature, cooling the suspension to a third cycling cooling temperature, and heating the suspension to a third cycling heating temperature.
  • the first cycling cooling temperature is about 16°C to about 26°C
  • the first heating cycling temperature is about 66°C to about 76°C
  • the second cycling cooling temperature is about 16°C to about 26°C
  • the second cycling heating temperature is about 55°C to about 65°C
  • the third cycling cooling temperature is about 26°C to about 36°C
  • the third cycling heating temperature is about 45°C to about 55°C.
  • the first cycling cooling temperature is about 19°C to about 23°C
  • the first heating cycling temperature is about 69°C to about 73°C
  • the second cycling cooling temperature is about 19°C to about 23°C
  • the second cycling heating temperature is about 58°C to about 62°C
  • the third cycling cooling temperature is about 29°C to about 33°C
  • the third cycling heating temperature is about 48°C to about 52°C.
  • cooling to each cooling temperature is conducted at a substantially different cooling rate. In some embodiments, cooling to each cooling temperature is conducted at a different cooling rate.
  • cooling to the first cycling cooling temperature and the second cycling cooling temperature are each conducted at substantially the same cooling rate.
  • the cycling in Step e) comprises the cycling Step d) three times. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about
  • cooling to the first cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.0°C/hour to about 13.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step e) comprises the cycling Step d) three times.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C/hour to about 15.0°C/hour.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C/hour.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 12.0°C/hour to about 13.0°C/hour.
  • cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step e) comprises the cycling Step d) three times.
  • cooling to the third cycling cooling temperature is conducted at a rate of about
  • cooling to the third cycling cooling temperature is conducted at a rate of about 8.5°C hour to about 11.5°C/hour. In some embodiments, cooling to the third cycling cooling temperature is conducted at a rate of about 9.5°C/hour to about 10.5°C/hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C/hour.
  • the cycling in Step e) comprises the cycling Step d) four times.
  • cycling Step d) four times comprises: cooling the suspension to a first cycling cooling temperature, heating the suspension to a first cycling heating temperature, cooling the suspension to a second cycling cooling temperature, heating the suspension to a second cycling heating temperature, cooling the suspension to a third cycling cooling temperature, heating the suspension to a third cycling heating temperature, cooling the suspension to a fourth cycling cooling temperature, and heating the suspension to a fourth cycling heating temperature.
  • the first cycling cooling temperature is about 16°C to about 26°C
  • the first heating cycling temperature is about 66°C to about 76°C
  • the second cycling cooling temperature is about 16°C to about 26°C
  • the second cycling heating temperature is about 66°C to about 76°C
  • the third cycling cooling temperature is about 16°C to about 26°C
  • the third cycling heating temperature is about 55°C to about 65°C
  • the fourth cycling cooling temperature is about 26°C to about 36°C
  • the fourth cycling heating temperature is about 45°C to about 55°C.
  • the first cycling cooling temperature is about 19°C to about 23°C
  • the first heating cycling temperature is about 69°C to about 73°C
  • the second cycling cooling temperature is about 19°C to about 23°C
  • the second cycling heating temperature is about 69°C to about 73°C
  • the third cycling cooling temperature is about 19°C to about 23°C
  • the third cycling heating temperature is about 58°C to about 62°C
  • the fourth cycling cooling temperature is about 29°C to about 33°C
  • the fourth cycling heating temperature is about 48°C to about 52°C.
  • cooling to each cooling temperature is conducted at a substantially different cooling rate. In some embodiments, cooling to each cooling temperature is conducted at a different cooling rate.
  • cooling to the first cycling cooling temperature, the second cycling cooling temperature, and the third cycling cooling temperature are each conducted at substantially the same cooling rate.
  • the cycling in Step e) comprises the cycling Step d) four times. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about
  • cooling to the first cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.0°C/hour to about 13.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step e) comprises the cycling Step d) four times.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C/hour to about 15.0°C/hour.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C/hour.
  • cooling to the second cycling cooling temperature is conducted at a rate of about 12.0°C/hour to about 13.0°C/hour.
  • cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step e) comprises the cycling Step d) four times. In some embodiments, cooling to the third cycling cooling temperature is conducted at a rate of about
  • cooling to the third cycling cooling temperature is conducted at a rate of about 11.0°C/hour to about 14.0°C/hour. In some embodiments, cooling to the third cycling cooling temperature is conducted at a rate of about 12.0°C/hour to about 13.0°C/hour. In some embodiments, cooling to the first cycling cooling temperature is conducted at a rate of about 12.5°C hour.
  • the cycling in Step e) comprises the cycling Step d) four times.
  • cooling to the fourth cycling cooling temperature is conducted at a rate of about 7.5°C hour to about 12.5°C hour. In some embodiments, cooling to the fourth cycling cooling temperature is conducted at a rate of about 8.5°C hour to about 11.5°C/hour. In some embodiments, cooling to the fourth cycling cooling temperature is conducted at a rate of about 9.5°C/hour to about 10.5°C/hour. In some embodiments, cooling to the second cycling cooling temperature is conducted at a rate of about 10.0°C hour.
  • Step e) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step e) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step e) is conducted at a stir rate of about 150 rpm.
  • Step f) Cooling the Suspension to a Final Cooling Temperature to Form the Crystalline Free-Plate Habit of L-Arginine Salt of ( ?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic Acid.
  • cooling the suspension in Step f) is conducted at a rate of about
  • cooling the suspension in Step f) is conducted at a rate of about 8.5°C hour to about 11.5°C/hour. In some embodiments, cooling the suspension in Step f) is conducted at a rate of about 9.5°C hour to about 10.5°C hour. In some embodiments, cooling the suspension in Step f) is conducted at a rate of about 10.0°C hour.
  • cooling the suspension in Step f) is conducted at a rate of about
  • cooling the suspension in Step f) is conducted at a rate of about 9.4°C hour to about 13.8°C/hour. In some embodiments, cooling the suspension in Step f) is conducted at a rate of about 9.9°C hour to about 13.2°C hour. In some embodiments, cooling the suspension in Step f) is conducted at a rate of about 10.5°C/hour to about 12.6°C hour. In some embodiments, cooling the suspension in Step f) is conducted at a rate of about 10°C/hour to about 12°C/hour.
  • the temperature of the suspension is about 15°C to about 40°C. In some embodiments, after cooling in Step f) the temperature of the suspension is about 20°C to about 30°C. In some embodiments, after cooling in Step f) the temperature of the suspension is about 22°C to about 24°C. In some embodiments, after cooling in Step f) the temperature of said suspension is about 18°C to about 22 °C.
  • Step f) is conducted at a stir rate of about 100 rpm to about 200 rpm. In some embodiments, Step f) is conducted at a stir rate of about 125 rpm to about 175 rpm. In some embodiments, Step f) is conducted at a stir rate of about 150 rpm.
  • the method further comprises the step of isolating the crystalline free- plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b] indol-3 -y 1) acetic acid .
  • the step of isolating comprises filtering the crystalline free-plate habit of
  • the step of isolating comprises filtering the crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid from the suspension and drying the crystalline free-plate habit of L-arginine salt at a reduced pressure.
  • the crystalline free-plate habit of L-arginine salt of (R)-2- (7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has any one or more of the characteristics as described herein.
  • Another aspect of the present invention relates to pharmaceutical compositions prepared according to any of the methods as described herein.
  • Another aspect of the present invention relates to a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid prepared according to any of the methods as described herein.
  • composition comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid prepared according to any of the methods as described herein.
  • a pharmaceutical composition comprising a crystalline free-plate habit of L-arginine salt of
  • the pharmaceutical composition is suitable for oral, rectal, nasal, topical, buccal, sub-lingual, or vaginal, or in a form suitable for administration by inhalation, insufflation, or by a transdermal patch. In some embodiments, the pharmaceutical composition is suitable for oral administration.
  • the present invention is directed, inter alia, to a crystalline free-plate habit or morphology and processes useful in the preparation of a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)-benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.
  • the plates were discovered from the novel synthetic methods as described herein and were shown to be thin hexagonal-like plates with two opposite sides of the plate being longer that the other sides (i.e., elongated hexagonal plate). However, due to the thin characteristic of the plates, a complete unbroken plate is rarely seen.
  • Figure 5B shows a copy of Figure 5A that has been modified to add an outline to highlight the substantially intact/complete free-plate with an elongated hexagonal shape. It is understood by those skilled in the art that microscopy is one of the more useful techniques to distinguish two crystalline habits or morphologies. This is particularly useful when 2 or more morphologies are associated with the same or substantially the same crystal phase as is the case with the L-arginine salt of Compound 1. Comparing the PXRD patterns of the habit prepared previously (i.e., WO2011/094008 and Example 2 infra) and the plate habit prepared as described herein (i.e., see
  • microscopy is one of the more useful methods. Accordingly, the skilled person would be capable of reviewing a micrograph for a crystal habit prepared by the processes described herein and readily acknowledge that the crystal habit was a free-plate or pieces resulting from a broken free -plate and not some other habit, such as, what was prepared previously in the art. Similarly, by simple inspection of two micrographs, such as Figure 1 (spherulites) and Figure 5A (free-plates), one can readily confirm they are different habits.
  • specific surface can also be used to characterize the free-plates of the present invention. Accordingly, the specific surface area values disclosed in the present invention have been obtained by means of a specific surface area analysis technique based on the BET (Brunauer, Emmett and Teller) theory, which is a well-accepted theory known in the art for the calculation of surface areas of solids by means of measuring their physical adsorption of gas molecules (see: Brunauer, S.; Emmett, P. H.; and Teller, E.; /. Am. Chem. Soc, 1938, 60, 309).
  • BET Brunauer, Emmett and Teller
  • the specific surface area values measured in the present invention have been calculated from the BET surface area plot obtained by measuring the quantity of nitrogen gas molecules adsorbed by a weighted amount of solid at different relative pressures (P/Po) within the range 0.05-0.3 (P/Po), at 77.3 K.
  • the measurement of the adsorption of gas molecules was carried out by means of a MicromeriticsTM TriStar ⁇ BET surface analyzer having the characteristics as set out below in Example 14. Namely, nitrogen gas was used for the adsorption measurement. The sample for each analysis was degassed at 25°C for 960 minutes under vacuum (i.e., 100 mm/Hg).
  • the determination of the adsorption of nitrogen was measured at 77.3 K at eleven relative pressures (P/Po) sufficiently dispersed within the range of about 0.05 to about 0.30 (i.e. eleven absolute pressures in the range of about 36 mm Hg to about 223 mm Hg relative to the saturated pressure at the time of measurement that ranged from about 738 mmHg to about 743 mmHg).
  • One aspect of the present invention relates to a novel crystalline plate morphology of L- arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo- penta[b]indol-3-yl)acetic acid as described herein.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.
  • the crystalline free -plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, and 20.5° + 0.2°. In some embodiments, the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°.
  • the crystalline free -plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°.
  • the crystalline free -plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 (9, at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, and 28.8° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 (9, at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, 28.8° + 0.2°, and 37.3° + 0.2°.
  • the crystalline free -plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.0°C to 208.5°C at a scan rate of 10°C/minute. In some embodiments, the crystalline free -plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.0°C to 208.1°C at a scan rate of 10°C/minute. In some embodiments, the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5°C to 208.5°C at a scan rate of 10°C/minute.
  • the crystalline free -plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 206.0°C to 208.5 °C at a scan rate of 10°C/minute. In some embodiments, the crystalline free -plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 206.5°C to 208.5°C at a scan rate of 10°C/minute. In some embodiments, the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5°C to 208.1°C at a scan rate of 10°C/minute.
  • the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 206.5 °C to 208.1°C at a scan rate of 10°C/minute. In some embodiments, the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 207.0°C to 208.1°C at a scan rate of 10°C/minute. In some embodiments, the crystalline free-plate habit has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10. In some embodiments, the crystalline free-plate habit has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10 and Figures 22 to 25.
  • the crystalline free -plate habit has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.3% weight or less at 90% RH.
  • the crystalline free-plate habit has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.2% weight or less at 90% RH.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid having a BET specific surface area of about 0.05 m 2 /g, about 0.1 m 2 /g, about 0.15 m 2 /g, about 0.2 m /g, about 0.25 m /g, about 0.3 m /g, about 0.35 m /g, about 0.4 m /g, about 0.45 m /g, about 0.5 m 2 /g, about 0.55 m 2 /g, about 0.6 m 2 /g, about 0.65 m 2 /g, or about 0.7 m 2 /g to about 2.0 m 2 /g, about 2.5 m 2 /g, about 3.0 m 2
  • the crystalline free -plate habit has a BET specific surface area of about 0.1 m 2 /g to about 5.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.1 m 2 /g to about 4.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.3 m 2 /g to about 4.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.5 m 2 /g to about 4.0 m 2 /g.
  • the crystalline free-plate habit has a BET specific surface area of about 0.6 m 2 /g to about 4.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.3 m 2 /g to about 3.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.4 m 2 /g to about 2.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.5 m 2 /g to about 1.8 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.6 m 2 /g to about 1.6 m 2 /g.
  • the crystalline free -plate habit has: 1) a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, 28.8° + 0.2°, and 37.3° + 0.2°;
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has: 1) a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5°C to 208.5 °C at a scan rate of 10°C/minute; and/or
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • the crystalline free-plate habit has:
  • the crystalline free-plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • the crystalline free -plate habit has:
  • the crystalline free -plate habit has:
  • DMS dynamic moisture sorption
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of
  • the crystalline free -plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2(9, at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, and 28.8° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, 28.8° + 0.2°, and 37.3° + 0.2°.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid having a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.0°C to 208.5°C when scanned at 10°C per minute.
  • the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.0°C to 208.1°C at a scan rate of 10°C/minute.
  • the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5°C to 208.5°C at a scan rate of 10°C/minute. In some embodiments, the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5 °C to 208.1°C at a scan rate of 10°C/minute. In some embodiments, the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 206.0°C to 208.5°C at a scan rate of 10°C/minute.
  • the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 206.5°C to 208.5°C at a scan rate of 10°C/minute. In some embodiments, the crystalline free -plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 206.5°C to 208.1 °C at a scan rate of 10°C/minute. In some embodiments, the crystalline free -plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 207.0°C to 208.1°C at a scan rate of 10°C/minute.
  • the crystalline free-plate habit has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10. In some embodiments, the crystalline free-plate habit has a differential scanning calorimetry trace conducted at a scan rate of 10°C/minute comprising an endotherm substantially as depicted in any one of Figures 6 to 10 and Figures 22 to 25. In some embodiments, the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, and 20.5° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2(9, at 8.2° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°. In some embodiments, the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, and 28.8° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, 28.8° + 0.2°, and 37.3° + 0.2°.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of
  • the crystalline free-plate habit has a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein the crystalline free-plate habit gains about 0.2% weight or less at 90% RH.
  • the crystalline free -plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 (9, at 8.2° + 0.2°, 16.4° + 0.2°, and 20.5° + 0.2°. In some embodiments, the crystalline free -plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2(9, at 8.2° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°. In some embodiments, the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, and 28.8° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, 28.8° + 0.2°, and 37.3° + 0.2°.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l ,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid having a BET specific surface area of about 0.1 m 2 /g to about 5.0 m 2 /g.
  • the crystalline free-plate habit has a BET specific surface area of about 0.1 m 2 /g to about 4.0 m 2 /g.
  • the crystalline free-plate habit has a BET specific surface area of about 0.3 m 2 /g to about 4.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.5 m 2 /g to about 4.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.6 m 2 /g to about 4.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.3 m 2 /g to about 3.0 m 2 /g.
  • the crystalline free-plate habit has a BET specific surface area of about 0.4 m 2 /g to about 2.0 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.5 m 2 /g to about 1.8 m 2 /g. In some embodiments, the crystalline free-plate habit has a BET specific surface area of about 0.6 m 2 /g to about 1.6 m 2 /g. In some embodiments, the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 (9, at 8.2° + 0.2°, 16.4° + 0.2°, and 20.5° + 0.2°.
  • the crystalline free -plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2(9, at 8.2° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°. In some embodiments, the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, and 24.6° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, and 28.8° + 0.2°.
  • the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.2° + 0.2°, 16.4° + 0.2°, 20.5° + 0.2°, 24.6° + 0.2°, 28.8° + 0.2°, and 37.3° + 0.2°.
  • lymphopenia also referred to as peripheral lymphocyte lowering (PLL); Hale et al, Bioorg. Med. Chem. Lett., 14:3351-3355, 2004. This is attended by clinically useful
  • lymphocyte sequestration for example in lymph nodes, is thought to be a consequence of concurrent agonist-driven functional antagonism of the SIPi receptor on T-cells (whereby the ability of S IP to mobilize T-cell egress from lymph nodes is reduced) and persistent agonism of the S IPi receptor on lymph node endothelium (such that barrier function opposing transmigration of lymphocytes is increased) (Matloubian et al., Nature, 427:355-360, 2004; Baumruker et al., Expert Opin. Investig. Drugs, 16:283-289, 2007).
  • agonism of the SIPi receptor alone is sufficient to achieve lymphocyte sequestration (Sanna et al., J Biol Chem. , 279: 13839-13848, 2004) and that this occurs without impairment of immune responses to systemic infection (Brinkmann et al.,
  • That agonism of endothelial S IPi receptors has a broader role in promoting vascular integrity is supported by work implicating the S IPi receptor in capillary integrity in mouse skin and lung (Sanna et al., Nat Chem Biol., 2:434-441, 2006).
  • Vascular integrity can be compromised by inflammatory processes, for example as may derive from sepsis, major trauma and surgery so as to lead to acute lung injury or respiratory distress syndrome (Johan Groeneveld, Vascul. Pharmacol., 39:247-256, 2003).
  • SIP receptor agonist having agonist activity on the S I Pi receptor is FTY720, an immunosuppressive agent (Martini et al., Expert Opin. Investig. Drugs, 16:505-518, 2007) that was approved by the FDA as Gilenya® (fingolimod) in September 2010 for the treatment of relapsing multiple sclerosis.
  • FTY720 acts as a prodrug which is phosphorylated in vivo; the phosphorylated derivative is an agonist for S IPi, S1P 3 , SIP 4 , and S1P 5 receptors (but not the S IP 2 receptor) (Chiba, Pharmacology & Therapeutics, 108:308-319, 2005).
  • FTY720 has been shown to rapidly and reversibly induce lymphopenia (also referred to as peripheral lymphocyte lowering (PLL); Hale et al, Bioorg. Med. Chem. Lett, 14:3351 -3355, 2004). This is attended by clinically useful immunosuppression by virtue of sequestering T- and B-cells in secondary lymphoid tissue (lymph nodes and Peyer' s patches) and thus apart from sites of inflammation and organ grafts (Rosen et al, Immunol. Rev., 195: 160-177, 2003; Schwab et al, Nature Immunol, 8: 1295-1301, 2007). FTY720 has been reported to have therapeutic efficacy in at least: a rat model for autoimmune myocarditis and a mouse model for acute viral myocarditis (Kiyabayashi et al, J. Cardiovasc.
  • lymphopenia also referred to as peripheral lymphocyte lowering (PLL); Hale et al,
  • KRP-203 an S IP receptor agonist having agonist activity on the SI Pi receptor, has been reported to have therapeutic efficacy in a rat model for autoimmune myocarditis (Ogawa et al, BBRC, 361 :621-628, 2007).
  • SEW2871 agonism of endothelial SI Pi receptors prevents
  • FTY720 has been reported to have therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE) in rats and mice, a model for human multiple sclerosis
  • FTY720 has been found to have therapeutic efficacy for multiple sclerosis in clinical trials.
  • FTY720 was found to reduce the number of lesions detected by magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis (Kappos et al, N. Engl. J. Med., 355:1124-1140, 2006; Martini et al, Expert Opin. Investig. Drugs, 16:505-518, 2007; Zhang et al, Mini-Reviews in Medicinal Chemistry, 7:845-850, 2007; Brinkmann, Pharmacology & Therapeutics, 115:84-105, 2007).
  • FTY720 is currently in Phase III studies of remitting-relapsing multiple sclerosis (Brinkmann, Pharmacology &
  • FTY720 has also been reported to have anti-viral activity. Specific data has been presented in the lymphocytic choriomeningitis virus (LCMV) mouse model, wherein the mice were infected with either the Armstrong or the clone 13 strain of LCMV (Premenko-Lanier et al, Nature, 454, 894, 2008).
  • LCMV lymphocytic choriomeningitis virus
  • FTY720 has also been reported to impair migration of dendritic cells infected with Francisella tularensis to the mediastinal lymph node, thereby reducing the bacterial colonization of it.
  • Francisella tularensis is associated with tularemia, ulceroglandular infection, respiratory infection and a typhoidal disease (E. Bar-Haim et al, PLoS Pathog 4(11): el000211. doi: 10.1371/journal.ppat.l000211, 2008).
  • oligodendrocyte progenitor cells survival of oligodendrocyte progenitor cells is a required component of the remyelination process. Remyelination of multiple sclerosis lesions is considered to promote recovery from clinical relapses. (Miron et al, Ann. Neurol, 63:61-71, 2008; Coelho et al, J.
  • Agonism of the SI Pi receptor has also been reported to mediate migration of neural stem cells toward injured areas of the central nervous system (CNS), including in a rat model of spinal cord injury (Kimura et al, Stem Cells, 25:115-124, 2007).
  • Agonism of the SI Pi receptor has been implicated in the inhibition of keratinocyte proliferation (Sauer et al, J. Biol. Chem., 279:38471-38479, 2004), consistent with reports that SIP inhibits keratinocyte proliferation (Kim et al, Cell Signal, 16:89-95, 2004).
  • the hyperproliferation of keratinocytes at the entrance to the hair follicle, which can then become blocked, and an associated inflammation are significant pathogenetic factors of acne (Koreck et al, Dermatology, 206:96-105, 2003; Webster, Cutis, 76:4-7, 2005).
  • FTY720 has been reported to have therapeutic efficacy in inhibiting pathologic angiogenesis, such as that as may occur in tumor development. Inhibition of angiogenesis by FTY720 is thought to involve agonism of the SIPi receptor (Oo et al, J. Biol Chem., 282;9082-9089, 2007; Schmid et al, J. Cell Biochem., 101 :259-270, 2007). FTY720 has been reported to have therapeutic efficacy for inhibiting primary and metastatic tumor growth in a mouse model of melanoma (LaMontagne et al, Cancer Res., 66:221-231, 2006). FTY720 has been reported to have therapeutic efficacy in a mouse model for metastatic hepatocellular carcinoma (Lee et al, Clin. Cancer Res., 11 :84588466, 2005).
  • FTY720 has been shown to have therapeutic efficacy in transplant rejection both as a monotherapy and in synergistic combination with a classical immunosuppressant, including cyclosporin A, FK506 and RAD (an mTOR inhibitor). It has been shown that, unlike the classical immunosuppressant, including cyclosporin A, FK506 and RAD (an mTOR inhibitor). It has been shown that, unlike the classical immunosuppressant, including cyclosporin A, FK506 and RAD (an mTOR inhibitor). It has been shown that, unlike the classical immunosuppressant, including cyclosporin A, FK506 and RAD (an mTOR inhibitor). It has been shown that, unlike the classical immunosuppressant, including cyclosporin A, FK506 and RAD (an mTOR inhibitor). It has been shown that, unlike the classical immunosuppressant, including cyclosporin A, FK506 and RAD (an mTOR inhibitor). It has been shown that, unlike the classical
  • Agonism of the SIPi receptor has been reported to have therapeutic efficacy for prolonging allograft survival in mouse and rat skin allograft models (Lima et al, Transplant Proc ., 36:1015-1017, 2004; Yan et al, Bioorg. & Med. Chem. Lett., 16:3679-3683, 2006).
  • FTY720 has been reported to have therapeutic efficacy for prolonging allograft survival in a rat cardiac allograft model (Suzuki et al, Transpl. Immunol., 4:252-255, 1996).
  • FTY720 has been reported to act synergistically with cyclosporin A to prolong rat skin allograft survival (Yanagawa et al, J.
  • KRP-203 an SIP receptor agonist has been reported to have therapeutic efficacy for prolonging allograft survival in a rat skin allograft model and both as monotherapy and in synergistic combination with cyclosporin A in a rat cardiac allograft model (Shimizu et al, Circulation, 111 :222-229, 2005).
  • KRP-203 also has been reported to have therapeutic efficacy in combination with mycophenolate mofetil (MMF; a prodrug for which the active metabolite is mycophenolic acid, an inhibitor of purine biosynthesis) for prolonging allograft survival both in a rat renal allograft model and in a rat cardiac allograft model (Suzuki et al, J.
  • MMF mycophenolate mofetil
  • FTY720 has been reported to have therapeutic efficacy in a mouse islet graft model (Fu et al, Transplantation, 73: 1425-1430, 2002; Liu et al, Microsurgery, 27 :300-304; 2007) and in a study using human islet cells to evidence no detrimental effects on human islet function (Truong et al., American Journal of Transplantation, 7:2031-2038, 2007).
  • FTY720 has been reported to reduce the nociceptive behavior in the spared nerve injury model for neuropathic pain which does not depend on prostaglandin synthesis (O. Costu et al, Journal of Cellular and Molecular Medicine 12(3), 995-1004, 2008).
  • FTY720 has been reported to impair initiation of murine contact hypersensitivity (CHS). Adoptive transfer of immunized lymph node cells from mice treated with FTY720 during the sensitization phase was virtually incapable of inducing CHS response in recipients (D. Nakashima et al, J. Investigative Dermatology (128(12), 2833-2841, 2008).
  • S lPi receptor agonists are useful for treating or preventing conditions where suppression of the immune system or agonism of the SlPi receptor is in order, such as diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders, and conditions that have an underlying defect in vascular integrity or that relate to angiogenesis such as may be pathologic.
  • an S lPi receptor-associated disorder is selected from, for example, diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions that have an underlying defect in vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development and atherosclerosis).
  • Such conditions where suppression of the immune system or agonism of the S lPi receptor is in order include diseases and disorders mediated by lymphocytes, conditions that have an underlying defect in vascular integrity, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), acute or chronic rejection of cells, an autoimmune disease of the liver including biliary cirrhosis, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cholangitis, tissue or solid organ grafts, arthritis including psoriatic arthritis and rheumatoid arthritis, diabetes including type I diabetes and the disorders associated therewith, myasthenia gravis, demyelinating disease including multiple sclerosis, ischemia-reperfusion injury including renal and cardiac ischemia-reperfusion injury, inflammatory skin disease including psoriasis, atopic dermatitis and acne, hyperproliferative skin disease including acne, inflammatory
  • One aspect of the present invention relates to methods for treating an S IPi receptor-associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to methods for treating an S IPi receptor-associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein, wherein the disorder is selected from the group consisting of a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, primary biliary cirrhosis, cancer, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis
  • One aspect of the present invention relates to methods for treating a disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein, wherein the disorder is selected from the group consisting of primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, and ulcerative colitis.
  • One aspect of the present invention relates to methods for treating a disease or disorder mediated by lymphocytes in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to methods for treating primary biliary cirrhosis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i3 ⁇ 4-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to methods for treating psoriasis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to methods for treating psoriatic arthritis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-
  • One aspect of the present invention relates to methods for treating rheumatoid arthritis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-
  • One aspect of the present invention relates to methods for treating Crohn' s disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-
  • One aspect of the present invention relates to methods for treating multiple sclerosis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-
  • One aspect of the present invention relates to methods for treating inflammatory bowel disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to methods for treating systemic lupus
  • erythematosus in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4- cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to methods for treating ulcerative colitis in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-
  • One aspect of the present invention relates to methods for treating an autoimmune disease or disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to methods for treating an inflammatory disease or disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to methods for treating a microbial or viral infection or disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein, a composition as described herein, or a pharmaceutical composition as described herein.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of an S IPi receptor-associated disorder.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of an S IPi receptor-associated disorder selected from the group consisting of a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, primary biliary cirrhosis, cancer, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn' s disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, type I diabetes, and acne.
  • an S IPi receptor-associated disorder selected from the group consisting of a disease or disorder mediated
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of an S IPi receptor-associated disorder selected from the group consisting of primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn' s disease, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, and ulcerative colitis.
  • an S IPi receptor-associated disorder selected from the group consisting of primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn' s disease,
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of a disease or disorder mediated by lymphocytes.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of primary biliary cirrhosis.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of psoriasis.
  • One aspect of the present invention relates to uses a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of psoriatic arthritis.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of rheumatoid arthritis.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of Crohn' s disease.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of multiple sclerosis.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of inflammatory bowel disease.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of systemic lupus erythematosus.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of ulcerative colitis.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of an autoimmune disease or disorder.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of an inflammatory disease or disorder.
  • One aspect of the present invention relates to uses of a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)acetic acid as described herein in the manufacture of a medicament for the treatment of a microbial or viral infection or disease.
  • One aspect of the present invention relates to uses of a composition
  • a composition comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein and an excipient in the manufacture of a medicament for administration in the treatment of an S IPi receptor-associated disorder.
  • One aspect of the present invention relates to uses of a composition
  • a composition comprising a crystalline free -plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein and an excipient for preparation a medicament for administration in the treatment of an SIPi receptor-associated disorder.
  • One aspect of the present invention relates to uses of a composition
  • a composition comprising a crystalline free -plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein and an excipient for compounding a medicament for administration in the treatment of an SIPi receptor-associated disorder.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of the human or animal body by therapy.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of an SlPi receptor-associated disorder selected from the group consisting of a disease or disorder mediated by lymphocytes, an autoimmune disease or disorder, an inflammatory disease or disorder, primary biliary cirrhosis, cancer, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn' s disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, type I diabetes, and acne.
  • an SlPi receptor-associated disorder selected from the group consisting of a disease or disorder mediated
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of an SlPi receptor-associated disorder selected from the group consisting of primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn' s disease, multiple sclerosis, inflammatory bowel disease, systemic lupus
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of a disease or disorder mediated by lymphocytes.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of primary biliary cirrhosis.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of psoriasis.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of psoriatic arthritis.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of rheumatoid arthritis.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of multiple sclerosis.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of inflammatory bowel disease.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of systemic lupus erythematosus.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of ulcerative colitis.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of an autoimmune disease or disorder.
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of
  • One aspect of the present invention relates to a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromemyl)benzyloxy)-l,2 ,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid as described herein for use in a method for the treatment of a microbial or viral infection or disease.
  • the SlPi receptor-associated disorder is mediated by lymphocytes. In some embodiments, the SlPi receptor-associated disorder is primary biliary cirrhosis. In some embodiments, the SlPi receptor-associated disorder is psoriasis. In some embodiments, the SlPi receptor-associated disorder is psoriatic arthritis. In some embodiments, the SlPi receptor-associated disorder is rheumatoid arthritis. In some embodiments, the SlPi receptor-associated disorder is Crohn's disease. In some embodiments, the SlPi receptor-associated disorder is multiple sclerosis. In some embodiments, the SlPi receptor-associated disorder is inflammatory bowel disease. In some embodiments, the SlPi receptor-associated disorder is systemic lupus erythematosus. In some embodiments, the SlPi receptor-associated disorder is ulcerative colitis.
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid as described herein and a pharmaceutical excipient.
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid prepared according to any of the methods described herein and a pharmaceutical excipient.
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Compound 1) in an amount equivalent to a therapeutically effective amount of Compound 1 of the crystalline free-plate habit, wherein the pharmaceutical composition further comprises a diluent, a disintegrant, and a lubricant.
  • the diluent comprises a first diluent and a second diluent.
  • the first diluent comprises mannitol. In some embodiments, the first diluent comprises mannitol 200 SD, USP.
  • the second diluent comprises microcrystalline cellulose. In some embodiments, the second diluent comprises Avicel®. In some embodiments, the second diluent comprises Avicel® PHI 02, NF.
  • the disintegrant is sodium starch glycolate. In some embodiments, the disintegrant is Explotab®, NF.
  • the lubricant is magnesium stearate, NF.
  • the pharmaceutical composition has a diluent content of about 91% to about 95%.
  • the pharmaceutical composition has a first diluent content of about 51% to about 55%.
  • the pharmaceutical composition has a second diluent content of about 37% to about 43%.
  • the pharmaceutical composition has a disintegrant content of about 3% to about 5%.
  • the pharmaceutical composition has a lubricant content of about 0.2% to about 0.8%.
  • the pharmaceutical composition has:
  • the pharmaceutical composition has:
  • the pharmaceutical composition has:
  • the pharmaceutical composition has:
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclo-penta[b]indol-3-yl)acetic acid as described herein or prepared according to any of the methods described herein.
  • compositions comprising a crystalline free-plate habit of L-arginine salt of (i?)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)- l,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid as described herein or prepared according to any of the methods described herein, and a pharmaceutical excipient.
  • composition and/or pharmaceutical composition is suitable for oral, rectal, nasal, topical, buccal, sub-lingual, or vaginal, or in a form suitable for administration by inhalation, insufflation, or by a transdermal patch. In some embodiments, the composition and/or pharmaceutical composition is suitable for oral administration.
  • Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
  • Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.
  • the oral preparations can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants can be added to the liquid preparations.
  • Parenteral dosage forms can be prepared by dissolving the compound provided herein in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
  • the compounds provided herein such as, the L-arginine salt of Compound 1, can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically-acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al).
  • composition refers to at least one compound of the invention in combination with at least one other component.
  • compositions include, but are not limited to, a reference standard comprising a compound of the present invention (e.g., for use in method development, in- process testing, and the like); bulk API (i.e., Active Pharmaceutical Ingredient) of a compound of the present invention (e.g., for use in formulating a pharmaceutical composition, compounding to form a medicament for use in administrating to a patient, and the like); a combined preparation (i.e., a compound of the present invention in combination with a pharmaceutical/therapeutic agent or agents); a biological sample comprising a compound of the present invention (e.g., for use in or obtained from a patient, an animal, a pharmacokinetic study, ADME study, LADME study, and the like); a reaction mixture comprising a compound of the present invention, such as, a reaction mixture as described in any of the Examples herein; a manufacturing reaction mixture comprising a compound of the present
  • Techniques used in “compounding” are well known to those in the art, such as, the Compounding Pharmacist.
  • “compounding” refers to the practice of preparing a prescription medication for a specific patient. Compounding can involve the preparation, mixing, assembling, packaging, and/or labeling of a drug (1) as the result of a practitioner's Prescription Drug Order or initiative based on the
  • Compounding also includes the preparation of drugs in anticipation of Prescription Drug Orders based on routine, regularly observed patterns.
  • Compounding services provide a vital role in health care as commercially manufactured drugs may not be suited for every person. Due to patient differences, such as, body size, varying drug tolerances, allergies, and/or special requirements (e.g., dosages that are sugar-free, gluten- free, casein-free, soy-free, and/or dye-free), a patient may require a medication that is not commercially available with the exact strength needed or may require a medication that lacks a certain component found in the commercial drug.
  • the pharmacist can adjust the medication to the exact dosage and excipient(s) needed by the patient, for example, a medication or medicament suitable for oral, rectal, nasal, topical, buccal, sub-lingual, vaginal, parenteral, intramuscular, sub-cutaneous, or intravenous administration, or in a form suitable for administration by inhalation, insufflation, or by a transdermal patch.
  • a medication or medicament suitable for oral, rectal, nasal, topical, buccal, sub-lingual, vaginal, parenteral, intramuscular, sub-cutaneous, or intravenous administration, or in a form suitable for administration by inhalation, insufflation, or by a transdermal patch.
  • a compound provided herein can, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • the compounds provided herein such as, the L-arginine salt of Compound 1, together with a conventional adjuvant, carrier, or diluent, can thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof can comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitably effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a solid formulation, such as, a tablet, capsule, suspension for oral administration, and the like.
  • Compound 1 can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the individual, such as a patient, on the compound employed, on whether an acute or chronic disease state is treated, or prophylaxis conducted, or on whether further active compounds are administered in addition to the compounds provided herein, such as, the L-arginine salt of Compound 1.
  • Representative doses include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the healthcare provider it may be necessary to deviate upward or downward from the doses described herein.
  • the dose is 0.5 mg. In some embodiments, the dose is 1.0 mg. In some embodiments, the dose is 2.0 mg. In some embodiments, the dose is 3.0 mg. In some embodiments, the dose is 5.0 mg.
  • the amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the individual and will ultimately be at the discretion of the attendant physician or clinician.
  • a model system typically an animal model
  • these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • Representative factors include the type, age, weight, sex, diet and medical condition of the individual, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, whether an acute or chronic disease state is being treated or prophylaxis conducted or whether further active compounds are administered in addition to the compounds provided herein (e.g. L-arginine salt of Compound 1) such as part of a drug combination.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions provided herein is selected in accordance with a variety of factors as cited above.
  • the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods disclosed herein.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3, or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the compounds provided herein can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the dosage forms may comprise, as the active component, either a compound provided herein or a pharmaceutically acceptable salt, hydrate, or solvate of a compound provided herein.
  • a suitable pharmaceutically acceptable carrier can be a solid, liquid, or a mixture of both.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desired shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary.
  • Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like.
  • the term "preparation” refers to the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water -propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds provided herein such as, the L-arginine salt of Compound 1, may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • the compounds provided herein such as, the L- arginine salt of Compound 1
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • the compounds provided herein, such as, the L-arginine salt of Compound 1, or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.
  • compositions or dispersions of the compounds provided herein in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as,
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
  • the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
  • TLC Thin-layer chromatography
  • PK6F silica gel 60 A 1 mm plates (Whatman) and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done under reduced pressure on a Buchi rotary evaporator. Celite ® 545 was used for filtration of palladium.
  • LCMS spec HPLC- Agilent 1200; pumps: G1312A; DAD:G1315B; Autosampler: G1367B; Mass spectrometer- Agilent G1956A; ionization source: ESI; Drying Gas Flow: 10 L/min; Nebulizer Pressure: 40 psig; Drying Gas Temperature: 350°C; Capillary Voltage: 2500 V) Software: Agilent Chemstation Rev.B.04.03.
  • Example 1 Preparation and Crystallization of L-Arginine Salt of (/?)-2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic Acid as Crystalline Spherulite Morphology.
  • the ethyl acetate phase was washed with water (2 x 58 mL) and then with brine (3 x 58 mL) at least twice and until the pH of the brine wash was 4 to 7 and the level of citric acid in the ethyl acetate phase was verified to be ⁇ 0.1 % by ⁇ NMR spectroscopy.
  • Ethyl acetate was replaced with 2-propanol (3 x 87 mL) by vacuum distillation.
  • the L-arginine salt was isolated by filtration and washed with 2- propanol (3 x 3 mL) and then ethyl acetate (3 x 3 mL) until no wet cake impurity exceeds 1 % area by HPLC.
  • Example 2 Preparation and Crystallization of L-Arginine Salt of (/?)-2-(7-(4-Cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic Acid.
  • the morphology was characterized as a very fine powder, consisting of small, tightly-layered agglomerates, thin flakes, and very fine, irregularly-shaped fragments (see Figure 3A and Figure 3B).
  • HPLC 99.5% area (achiral); DSC: 204.11°C (melting onset); Particle size: 14 ⁇ (mean length), 1.94 ⁇ minimum and 54.79 ⁇ maximum based on PLM.
  • Yields for the dry unmilled L-arginine salt based on ethyl ester ranged from 39.4 mol % to 43.6 mol % and averaged 42.2 mol %.
  • Total product impurities based on achiral HPLC ranged from 0.5% area to 1.2% area and averaged 0.8% area. Levels of the corresponding (S)-acid were less than the quantitation limit (0.7% area).
  • Lot J2 the morphology of Lot Jl was also analyzed by microscopy.
  • the morphology for Lot Jl was characterized as thin lamellar (stacked) flakes, layered into agglomerates that were tightly-layered and the agglomerates not very porous (see Figure 4A and Figure 4B).
  • Example 3 Preparation of a Crystalline Plate Habit or Morphology by Recrystallization of L- Arginine Salt of (/?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic Acid.
  • the slurry was stirred at 66°C for 1 hour 57 minutes. Then, the slurry was heated again to 75°C over 1 hour, stirred at 75°C to 78°C for 40 minutes, and gradually cooled to 67°C over approximately 1 hour. The slurry was stirred at about 66°C to 67°C for 34 minutes and the slurry was further cooled to 20°C over 10 hour 48 minutes and continued to stir for additional 6 hour 10 minutes prior to filtration. The resultant slurry was filtered. The filter cake was rinsed with 19.31 kg of 2- propanol. No filtration problems were observed.
  • FIG. 5A shows the plates using polarized light microscopy (PLM).
  • DSC 207.19°C
  • PLM Mean Length: 80 ⁇ , (65 ⁇ std dev), 12 ⁇ minimum and 266 ⁇ maximum.
  • Figure 5B shows a copy of Figure 5A that has been modified to add an outline of a substantially intact/complete free-plate with an elongated hexagonal shape.
  • L-arginine salt 44.95 kg, described in Example 2
  • L-arginine salt lots totaling 33.19 kg.
  • Lot A3 was prepared as described directly above.
  • Lots Al, A2, A4, and A5 were prepared by substantially the same procedure as described for Lot A3.
  • total impurities by achiral HPLC were about 0.1 % area, and achiral assays were 100.0% w/w - 101.2% w/w and averaged 100.3% w/w.
  • Levels of the corresponding (S)-acid were below the quantitation limit at 0.14% area.
  • the DSC onset temperatures for the five batches are shown below in TABLE Al.
  • Example 4 Preparation of a Crystalline Plate Habit or Morphology of L-Arginine Salt of (R)-2- (7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic Acid from ( ?/5)-Ethyl 2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclo- penta[b]indol-3-yl)acetate.
  • Method 1 Three methods, referred to as Method 1, Method 2, and Method 3, are described in this example.
  • the crystalline free -plate habit of the L-arginine salt of (i?)-2-(7-(4- cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid was prepared by enzymatic hydrolysis of the corresponding (i?/5)-ethyl ester to the (i?)-acid followed by a modified L-arginine salt-forming procedure compared to what was previously disclosed in
  • Example 4.1 Method 1, Preparation of a Crystalline Plate Morphology of L-Arginine Salt of ( ?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]-indol-3- yl)acetic Acid.
  • the organics were concentrated to 107 g using a rotary evaporator under vacuum (bath at 55°C, pressure dropping to 20 mmHg).
  • the residue was dissolved in 80 g (101 mL) of 2-propanol and concentrated to 140 g using a rotary evaporator under vacuum (bath at 55°C, pressure dropping to 20 mmHg).
  • the residue was diluted with 2-propanol to a weight of 300 g (160 g of 2-propanol, 202 mL, was added).
  • the solution was passed through a medium porosity filter and then transferred to a one liter jacketed reaction vessel.
  • the reaction vessel was equipped with an overhead stirrer, curved stir paddles, reflux condenser, internal temperature probe, and Mini Huber recirculating heating/cooling control. An additional 100 g of 2-propanol were used in transfer.
  • the product solution which contained a total of 300 g (379.7 mL) 2-propanol was clear, containing no detectable solids or cloudiness.
  • To the stirred solution was added 23.4 g of water followed by solid L-arginine 17.94 g, (103.0 mmol, 0.5 eq. based on (i?/5)-ethyl ester). The reaction mixture was heated to an internal temperature of 40°C. The reaction mixture changed consistence after 5 minutes and then the mixture was heated to an internal temperature of 76°C.
  • the mixture was heated to an internal temperature of 55°C to 60°C, held for 1 hour and then cool slowly (3 hours) to 30°C. After a 30 minute hold, the mixture was heated to 50°C to 55°C, held for 1 hour and then cooled slowly (3 hours) to 20°C and held.
  • the solids were isolated by filtration using a medium porosity filter paper and a slight pressure reduction (60 mmHg reduction from atmospheric).
  • the filter cake was washed (reslurry) with 125 g of 2-propanol and followed with a displacement wash with 75 g of 2-propanol.
  • the semi-dry cake was washed (reslurry) with 100 g of ethyl acetate followed by displacement wash with 100 g of ethyl acetate.
  • the cake was dried in a vacuum oven (40°C, high house vacuum) to give 65.2 g of the L- arginine salt as an off-white solid (plates, see Figure 12A) with an onset temperature of 205.6°C by DSC ( Figure 12B).
  • Example 4.2 Method 2, Preparation of a Crystalline Plate Morphology of L-Arginine Salt of ( ?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]-indol-3- yl)acetic Acid.
  • a 1.0M buffer solution (pH of 7-8) was prepared by mixing a solution of potassium phosphate monobasic (942 mg, 6.92 mmol) in 7.0 g of water with a solution containing potassium phosphate dibasic (12.0 g, 68.90 mmol) in 69.2 g of water.
  • the reaction mixture was cooled to room temperature and the pH of the reaction mixture was adjusted to 4-5 with a slow addition of a solution containing citric acid (9.0 g, 46.84 mmol) dissolved in 47.9 g of water.
  • the solids were filtered off and washed with acetonitrile (150 g).
  • the filtrates were combined and concentrated to 121.4 g using a rotary evaporator under vacuum (bath at 55°C, pressure dropping to 141 mmHg).
  • the residue was dissolved in 200 g of ethyl acetate. With good stirring, 200 g of water were added followed by 39.5 g of saturated sodium chloride brine.
  • the solution was passed through a medium porosity filter and then transferred to a 1-L jacketed reaction vessel.
  • the reaction vessel was equipped with an overhead stirrer, curved stir paddles, reflux condenser, internal temperature probe, and Mini Huber recirculating heating/cooling control.
  • An additional 2-propanol (187.3 g) was used for rinses and transfer. Total amount of 2-propanol was 300.1 g. Material was a solution.
  • the reaction suspension was subjected to two cycles of heating to an internal temperature of 75°C-78°C, hold for 45 min, and cooling to 24°C over 5 hours. After the first cycle a 500 mg sample of the mixture held at 24°C was centrifuged, and the resultant solids were slurried in 0.5 mL of 2- propanol. The resultant solids obtained by centrifuging off 2-propanol was again slurried in 0.5 mL of ethyl acetate, centrifuged, dried at 40°C in a vacuum oven at 100 mm Hg, and checked for morphology. PLM showed predominantly plate morphology with a few aggregates. DSC showed a bimodal melt. The mixture in the jacketed reactor was held at 24°C and at a stir rate of 180 rpm.
  • the solids were isolated by filtration using a medium porosity filter paper and a slight pressure reduction.
  • the initial deliquoring time was 90 minutes.
  • the filter cake was washed with 79 g of 2- propanol (by a reslurry method) and with 79 g of 2-propanol (by a displacement method).
  • Total deliquoring time for 2-propanol washes was 45 min.
  • the semi-dry cake was washed with 90.2 g of ethyl acetate (by a reslurry method) and with 90.2 g of ethyl acetate (by a displacement wash).
  • Total deliquoring time for ethyl acetate washes was 40 min.
  • Example 4.3 Method 3, Preparation of a Crystalline Plate Morphology of L-Arginine Salt of ( ?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]-indol-3- yl)acetic Acid (Lot 06GSp).
  • Isopropanol was added or removed (vacuum distilled) to provide a solution of the (i?)-free carboxylic acid in isopropanol with a concentration in the range of 11-14 wt%, for this batch the concentration was 12.4%.
  • the isopropanol product solution was treated with the calculated amount of water (23 g) and L- arginine (15.9 g) and heated to 83°C + 2°C. At this temperature, water (28.1 g) was added until the solids dissolved. Subsequently, the solution was cooled to 73 °C + 2°C and was treated with isopropanol (26.1 g) to obtain a hazy solution.
  • the heating/cooling cycles were conducted in the following manner.
  • the stirred product mixture was heated to 71°C + 2°C and then cooled over 4 h to 21 °C +2°C.
  • the mixture was then heated to 60°C+ 2°C, stirred at that temperature for 60 + 10 min before being cooled over 3 h to 31°C + 2°C.
  • the stirred mixture was heated to 50°C + 2°C, stirred at that temperature for 45 + 5 min, and then cooled over 3 h to 20°C + 2°C.
  • the heating/cooling cycles can be represented as 71 °C to 21°C to 60°C to 31°C to 50°C; temps + 2°C for comparison with the cycles described for other lots shown in TABLE 2A. Stirring at 20°C + 2°C was continued for at least 2 h before suspension was filtered.
  • the product was vacuum dried at 40°C + 5°C until loss on drying (LOD) was passed ( ⁇ 2%, for a 12h period), providing 54.9 g of the L- arginine salt of (i?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]-indol-3-yl)acetic acid as off-white crystalline plates with 100.0 area % by HPLC, L-arginine content of 27.5%, and chiral purity of 99.67%.
  • Example 5A Formulations - Evaluation of Spherulites and Plates on Formulation Stability.
  • Example 5B Formulations for L-Arginine Salt of (/?)-2-(7-(4-Cyclopentyl-3-(trifluoromethyl)- benzyloxy)-l,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic Acid.
  • Example 6 Hygroscopicity Comparison between Plates and Spherulites by Dynamic Moisture- Sorption (DMS) Analysis.
  • Example 7 Powder X-ray Diffraction Comparison between Plates and Spherulites.
  • Powder X-ray diffraction showed that Lots Al to A5 from Example 3 (see Table A) were crystalline with matching patterns, indicating the same crystal phase (see Figure 18).
  • a PXRD analysis was performed on representative Lot A2 (see, Example 3, TABLE A) of the L-arginine salt of Compound 1 having the plate morphology and representative Lot H2 (prepared in a similar manner as described in Example 8, Method 2 Steps G and H in WO2011/094008; and described in TABLE K, Example 8 herein) of the L-arginine salt of Compound 1 having the spherulite morphology.
  • Lot A2 plate morphology
  • Lot H2 spherulite morphology

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PCT/US2016/038506 2015-06-22 2016-06-21 Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(compound1) for use in sipi receptor-associated disorders Ceased WO2016209809A1 (en)

Priority Applications (27)

Application Number Priority Date Filing Date Title
EA201890096A EA201890096A1 (ru) 2015-06-22 2016-06-21 КРИСТАЛЛИЧЕСКАЯ L-АРГИНИНОВАЯ СОЛЬ (R)-2-(7-(4-ЦИКЛОПЕНТИЛ-3-(ТРИФТОРМЕТИЛ)БЕНЗИЛОКСИ)-1,2,3,4-ТЕТРАГИДРОЦИКЛОПЕНТА[b]ИНДОЛ-3-ИЛ)УКСУСНОЙ КИСЛОТЫ (СОЕДИНЕНИЯ 1) ДЛЯ ПРИМЕНЕНИЯ ПРИ РАССТРОЙСТВАХ, СВЯЗАННЫХ С S1P-РЕЦЕПТОРОМ
BR112017027656-9A BR112017027656B1 (pt) 2015-06-22 2016-06-21 Hábito cristalino de placa livre de sal de l-arginina de ácido (r)-2-(7-(4- ciclopentil-3-(trifluorometil)benzilóxi)- 1,2,3,4-tetra-hidrociclo-penta[b]indol-3- il)acético, composição farmacêutica que o compreende, seus usos e método de preparação do mesmo
AU2016284162A AU2016284162A1 (en) 2015-06-22 2016-06-21 Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(Compound1) for use in SIP1 receptor-associated disorders
JP2017566114A JP6838744B2 (ja) 2015-06-22 2016-06-21 Ｓ１Ｐ１レセプター関連障害における使用のための（Ｒ）−２−（７−（４−シクロペンチル−３−（トリフルオロメチル）ベンジルオキシ）−１，２，３，４−テトラヒドロシクロペンタ［ｂ］インドール−３−イル）酢酸（化合物１）の結晶性Ｌ−アルギニン塩
CN201680048241.0A CN108349891B (zh) 2015-06-22 2016-06-21 用于s1p1受体相关病症的化合物的结晶l-精氨酸盐
EP16734529.7A EP3310760B8 (en) 2015-06-22 2016-06-21 Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid for use in s1p1 receptor-associated disorders
MX2017016530A MX383854B (es) 2015-06-22 2016-06-21 Sal cristalina de l-arginina del acido (r)-2-(7-(4-ciclopentil-3-(trifluorometil) benciloxi)-1,2,3,4-tetrahidrociclopenta[b]indol-3-il) acético (compuesto 1) para ser utilizada en trastornos asociados con el receptor de esfingosina-1-fosfato 1 (s1p1).
KR1020187001785A KR102603199B1 (ko) 2015-06-22 2016-06-21 Ｓ1ｐ1 수용체-관련 장애에서의 사용을 위한 (ｒ)-2-(7-(4-시클로펜틸-3-(트리플루오로메틸)벤질옥시)-1,2,3,4-테트라히드로시클로-펜타[ｂ]인돌-3-일)아세트산 (화합물 1)의 결정성 ｌ-아르기닌 염
EP21178613.2A EP3939965A1 (en) 2015-06-22 2016-06-21 Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid for use in sipi receptor-associated disorders
IL285890A IL285890B (en) 2015-06-22 2016-06-21 Slate-free crystal of the arginine salt of (Ar)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-4,3,2,1-tetrahydro-cyclopent[b]indole-3-yl ) acetic acid
CA3002551A CA3002551A1 (en) 2015-06-22 2016-06-21 Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(com pound 1)for use in s1p1 receptor-associated disorders
SI201631637T SI3310760T1 (sl) 2015-06-22 2016-06-21 Kristalinična L-argininska sol (R)-2-(7-(4-ciklopentil-3-(trifluorometil)benziloksi)-1,2,3,4- tetrahidrociklo-penta(b)indol-3-il)ocetne kisline za uporabo pri motnjah, povezanih z receptorjem S1P1
KR1020237039088A KR102883123B1 (ko) 2015-06-22 2016-06-21 Ｓ1ｐ1 수용체-관련 장애에서의 사용을 위한 (ｒ)-2-(7-(4-시클로펜틸-3-(트리플루오로메틸)벤질옥시)-1,2,3,4-테트라히드로시클로-펜타[ｂ]인돌-3-일)아세트산 (화합물 1)의 결정성 ｌ-아르기닌 염
DK16734529.7T DK3310760T3 (da) 2015-06-22 2016-06-21 Krystallinsk L-argininsalt af (R)-2-(7-(4-cyclopentyl-3-(trifluormethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3- yl)eddikesyre til anvendelse ved S1P1-receptor-associerede lidelser
ES16734529T ES2929526T3 (es) 2015-06-22 2016-06-21 Sal cristalina de L-arginina del ácido (R)-2-(7-(4-ciclopentil-3-(trifluorometil)benciloxi)-1,2,3,4-tetrahidrociclo-penta[b]indol-3-il)acético para su uso en trastornos asociados al receptor S1P1
PL16734529.7T PL3310760T3 (pl) 2015-06-22 2016-06-21 Krystaliczna sól L-argininy kwasu (R)-2-(7-(4-cyklopentylo-3-(trifluorometylo)benzyloksy)- 1,2,3,4-tetrahydrocyklo-penta[b]indol-3-ilo)octowego do zastosowania w zaburzeniach związanych z receptorem S1P1
NZ738862A NZ738862B2 (en) 2016-06-21 Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(compound1) for use in sipi receptor-associated disorders
US15/738,175 US10301262B2 (en) 2015-06-22 2016-06-21 Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compund1) for use in SIPI receptor-associated disorders
IL256084A IL256084B (en) 2015-06-22 2017-12-04 Crystalline arginine salt of (Ar)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-4,3,2,1-tetrahydro-cyclopent[b]indol-3-yl)acetic acid (compound) 1) for use in disorders related to the sphingosine-1-phosphate-A receptor.
US16/379,265 US10676435B2 (en) 2015-06-22 2019-04-09 Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound 1) for use in SIPI receptor-associated disorders
US16/862,681 US11091435B2 (en) 2015-06-22 2020-04-30 Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3, 4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(compound1) for use in S1P1 receptor-associated disorders
AU2020204164A AU2020204164B2 (en) 2015-06-22 2020-06-22 Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US17/375,063 US11884626B2 (en) 2015-06-22 2021-07-14 Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
AU2021249972A AU2021249972B2 (en) 2015-06-22 2021-10-11 Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
AU2023200978A AU2023200978B2 (en) 2015-06-22 2023-02-20 Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US18/542,913 US12378198B2 (en) 2015-06-22 2023-12-18 Crystalline l-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(compound1) for use in SIPI receptor-associated disorders
US19/272,174 US20250346560A1 (en) 2015-06-22 2025-07-17 Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3, 4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(compound1) for use in sipi receptor-associated disorders

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