Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/225—Polycarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/04—Artificial tears; Irrigation solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
  • C07C69/12—Acetic acid esters
  • C07C69/18—Acetic acid esters of trihydroxylic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
  • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
  • C07C69/30—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with trihydroxylic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
  • C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
  • C07C69/58—Esters of straight chain acids with eighteen carbon atoms in the acid moiety
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
  • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
• • 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 disclosure generally relates to co-crystals of N-[2,4-bis(l , 1 - dimethylethyl)-5-hydroxyphenyl]- l ,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1), pharmaceutical compositions thereof, and methods therewith.
• Cystic fibrosis is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.
• CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues.
• CFTR cystic fibrosis transmembrane conductance regulator
• Small molecule drugs known as potentiators that increase the probability of CFTR channel opening represent one potential therapeutic strategy to treat
• CF CF.
• Potentiators of this type are disclosed in WO 2006/002421 , which is herein incorporated by reference in its entirety.
• Another potential therapeutic strategy involves small molecule drugs known as CF correctors that increase the number and function of CFTR channels. Correctors of this type are disclosed in WO
• CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelial cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins.
• epithelial cells normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
• CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
• CFTR cystic fibrosis
• a defect in this gene causes mutations in CFTR resulting in cystic fibrosis ("CF"), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
• the most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as AF508-CFTR.
• This mutation occurs in approximately 70% of cystic fibrosis cases and is associated with a severe disease.
• the deletion of residue 508 in AF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating.
• CFTR transports a variety of molecules in addition to anions
• this role represents one element in an important mechanism of transporting ions and water across the epithelium.
• the other elements include the epithelial Na + channel (ENaC), Na + /2C17K + co-transporter, Na + -K + - ATPase pump and the basolateral membrane K + channels that are responsible for the uptake of chloride into the cell.
• N-[2,4-bis( 1 , 1 -dimethylethyl)-5-hydroxyphenyl]- 1 ,4-dihydro-4- oxoquinoline-3-carboxamide (Compound 1) is a potent and selective CFTR potentiator of wild-type and mutant (including, but not limited to, e.g., AF508 CFTR, Rl 17H CFTR, G551D CFTR, G178R CFTR, S549N CFTR, S549R CFTR, G551S CFTR, G970R CFTR, G1244E CFTR, S I 25 IN CFTR, S 1255P CFTR, and G1349D CFTR) forms of human CFTR.
• wild-type and mutant including, but not limited to, e.g., AF508 CFTR, Rl 17H CFTR, G551D CFTR, G178R CFTR, S549N CFTR, S5
• N-[2,4-bis(l , l-dimethylethyl)-5-hydroxyphenyl]-l ,4- dihydro-4-oxoquinoline-3-carboxamide is useful for treatment of patients age 6 years and older with cystic fibrosis and one of the following mutations in the CFTR gene: G551D CFTR, G1244E CFTR, G1349D CFTR, G178R CFTR, G551 S CFTR, S 1251N CFTR, S 1255P CFTR, S549N CFTR, S549R CFTR, or Rl 17H CFTR
• Compound 1 that can be manufactured easily, including co-crystals comprising N-[2,4-bis(l, l-dimethylethyl)- 5-hydroxyphenyl]- l,4-dihydro-4-oxoquinoline-3-carboxamide, and pharmaceutical compositions thereof, may be useful for developing products and/or methods for treating patients suffering from CF thereof.
• the disclosure provides a co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following formula:
• R ⁇ , R 2 , and R 3 are independently C 1 -29 aliphatic.
• the co-crystal is isolated.
• the stoichiometry of Compound 1 to the co-former ranges from 2 to 1 to 6 to 1.
• the stoichiometry of Compound 1 to the co-former in the co-crystal is 6 to 1 .
• the stoichiometry of Compound 1 to the co-former in the co-crystal is about 6 to about 1.
• the stoichiometry of Compound 1 to the co-former in the co-crystal is 3 to 1.
• the stoichiometry of Compound 1 to the co-former in the co-crystal is about 3 to about 1.
• Compound 1 may form hexameric supermolecules (hexamers) in the co-crystal, wherein each of the hexamers contains six molecules of Compound 1 bound by hydrogen bonds as shown in Figure 1.
• the co-crystals are capable of yielding a concentration of Compound 1 of greater than 0.4 mg/mL when dissolved in simulated intestinal fluid in fed state (FeSSIF).
• the co-crystals are capable of yielding a
• Compound 1 concentration of Compound 1 of greater than 0.4 mg/mL when dissolved in simulated intestinal fluid in fed state (FeSSIF) and the concentration is maintained for at least 10 hours.
• the co-crystals are characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9. [0025] In yet some embodiments, the co-crystals are characterized as having a C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, and 1 19.4.
• the co-crystals are characterized as having a
• compositions comprising a therapeutic effective amount of Compound 1 and a pharmaceutically acceptable carrier or excipient, wherein at least 30% of Compound 1 is present in the form of co-crystals disclosed herein.
• the pharmaceutical composition further comprises an additional therapeutic agent.
• the additional therapeutic agent is selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti -infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1 , or a nutritional agent, or combinations thereof.
• the additional therapeutic agent is a CFTR modulator other than Compound 1.
• the CFTR modulator is (3-(6-(l- (2,2-difluorobenzo[d][l ,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin- 2-yl)benzoic acid or (R)-l-(2,2-difluorobenzo[d][l ,3]dioxol-5-yl)-N-(l-(2,3- dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)- l H-indol-5- yl)cyclopropanecarboxamide.
• the present disclosure provides for a method treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, COPD, or dry-eye disease, the method comprising the step of administering to the patient an effective amount of any of the co-crystals presented herein.
• the disease is cystic fibrosis.
• the method further comprises co-administering one or more additional therapeutic agents to the subject.
• the additional therapeutic agent is (3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid or (R)-l-(2,2- difluorobenzo[d] [ 1 ,3]dioxol-5-yl)-N-( 1 -(2,3-dihydroxypropyl)-6-fluoro-2-( 1 - hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide.
• the additional therapeutic agent is administered concurrently with, prior to, or subsequent to the co-crystal.
• Another aspect of the present disclosure provides for a method of preparing a co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• Rj, R 2 , and R 3 are independently C1.29 aliphatic
• One aspect of the present disclosure provides for a method of preparing a co- crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• R ⁇ , R , and R 3 are independently Ci -2 9 aliphatic.
• Another aspect of the present disclosure provides for a method of preparing co-crystals comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• the co-former is chosen from the following structural formula:
• Ri, R 2 , and R 3 are independently Ci -2 9 aliphatic
• Ri , R 2 , and R 3 are independently Ci -2 g aliphatic
• One aspect of the present disclosure provides for a method of preparing co- crystals comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• the co-former is chosen from the following structural formula:
• Ri, R 2 , and R 3 are independently Ci-29 aliphatic;
• Another aspect of the present disclosure provides for a method of preparing a co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• the co-former is chosen from the following structural formula:
• Rj, R 2 , and R 3 are independently C 1 -2 9 aliphatic,
• the mixture comprising Compound 1 and the co- former is heated for 12 hours. In other embodiments, the mixture comprising Compound 1 and the co-former is heated for at least 12 hours. In some embodiments, the mixture comprising Compound 1 and the co-former is heated for 24 hours. In other embodiments, the mixture comprising Compound 1 and the co-former is heated for at least 24 hours.
• co-crystals disclosed herein may exhibit several advantages.
• Compound 1 : triglyceride co-crystals may show a better maintenance of the supersaturation than both the neat amorphous and solid amorphous dispersed form of Compound 1 (Compound 1 SDD) over longer time periods.
• Compound 1 SDD neat amorphous and solid amorphous dispersed form of Compound 1
• in-vivo the Compound 1 triglyceride co-crystals may be metabolized in the small intestine by lipid esterase (lipases), which would effectively remove the triglycerides and further boost the Compound 1 concentration according to Le-Chatelier's principle.
• co-crystals disclosed herein such as Compound 1 -.triglyceride co-crystals, may have the following advantages over the solid amorphous dispersed form (Compound 1 SDD) of Compound 1 : (1 ) the co-crystals may be formulated, stored, and used under conditions where they are
• thermodynamically stable (2) a controlled crystallization may be developed that can reduces potential impurity levels (impurities include, but are not limited to, solvent); (3) a manufacturing process may be developed that is more efficient and cost effective (for example, less solvent can be used in manufacturing and a lower cost process than spray drying can be developed); and (4) a stabilizing polymer may not be required for formulating co-crystals.
• impurities include, but are not limited to, solvent
• a manufacturing process may be developed that is more efficient and cost effective (for example, less solvent can be used in manufacturing and a lower cost process than spray drying can be developed); and (4) a stabilizing polymer may not be required for formulating co-crystals.
• Figure 1 shows structural features of the Compound 1.triglyceride co-crystal in some embodiments.
• Figure 1 shows a hexamer (six molecules of Compound 1) which are present in a Compound 1 :triglyceride co-crystal.
• Figure 1 shows a hexamer made of two trimers (A and B) each formed by three molecules of Compound 1 (trimer A: Al , A2, and A3; and trimer B: B l , B2, and B3).
• Figure 2 shows examples of hydrogen bonding in a Compound 1 :triglyceride co-crystal in some embodiments.
• Figure 2 (left) shows a trimer A of compound 1 and the hydrogen bonds that may be present between the molecules of Compound 1 (Al , A2, and A3) within a trimer [R3,3(18) >b>b>b].
• Figure 2 (right) depicts hydrogen bonds that may be present within a molecule of compound 1 [S l ,l(6)a], and hydrogen bonds that may be present in between two molecules of compound 1 from two trimers (A and B) [R2,2(20) >c>c]. Trimers A and B form a hexamer.
• Figure 3 is an examplary X-Ray Powder Diffraction (XRPD) pattern of Compound 1 :glyceryltrioctanoate.
• Figure 4 is an examplary 13 C solid state nuclear magnetic resonance spectroscopy ( 13 C ssNMR) spectrum of Compound 1 :glyceryltrioctanoate.
• Figure 5 is an examplary thermal gravimetric analysis (TGA) trace
• Figure 6 is an examplary Differential Scanning Calorimetry (DSC) thermogram of Compound l :glyceryltrioctanoate.
• Figure 7 is an examplary ⁇ Nuclear Magnetic Resonance( ⁇ NMR) spectrum of Compound l :glyceryltrioctanoate in DMSO-de.
• Figure 8 is an examplary XRPD pattern of Compound l :glyceryltrioleate.
• Figure 9 is an examplary 13 C ssNMR spectrum of Compound
• Figure 10 is an examplary TGA trace Compound 1 :glyceryltrioleate.
• Figure 1 1 is an examplary DSC thermogram of Compound
• Figure 12 is an examplary ⁇ NMR spectrum of Compound
• Figure 13 is an examplary XRPD pattern of Compound
• Figure 14 is an examplary 13 C ssNMR spectrum of Compound
• Figure 15 is an examplary TGA trace Compound l :glyceryltrilinoleate.
• Figure 16 is an examplary DSC thermogram of Compound
• Figure 17 is an examplary ⁇ NMR spectrum of Compound
• Figure 18 is an examplary XPRD diffraction pattern of cocrystals of Compound 1 with glyceryltriacetate.
• Figure 19 is an examplary 13 C ssNMR spectrium of Compound l :triacetin.
• Figure 20 is an examplary DSC thermogram of Compound
• Figure 21 is an examplary XPRD diffraction pattern of cocrystals of Compound 1 with glyceryltributyrate.
• Figure 22 is an examplary XRPD diffraction pattern of cocrystals of Compound 1 with glyceryltristearate.
• Figure 23 is an examplary 13 C ssNMR spectrium of Compound
• Figure 24 is an examplary DSC thermogram of Compound
• Figure 25 is an examplary XRPD diffraction pattern of cocrystals of Compound 1 with glyceryltripalmitate.
• Figure 26 is an examplary 13 C ssNMR spectrium of Compound
• Figure 27 is an examplary DSC thermogram of Compound
• Figure 28 is an examplary XRPD diffraction pattern of cocrystals of Compound 1 with glyceryltridodecanoate.
• Figure 29 is an examplary 13 C ssNMR spectrium of Compound
• Figure 30 is an examplary XRPD diffraction pattern of cocrystals of Compound 1 with glyceryltrimyristate.
• Figure 31 is an examplary C ssNMR spectrium of Compound
• Figure 32 is an examplary DSC thermogram of Compound
• Figure 33 is an examplary XRPD diffraction pattern of cocrystals of Compound 1 with glyceryl trihexanoate.
• Figure 34 is an examplary XRPD diffraction pattern of cocrystals of Compound 1 with glyceryltridecanoate.
• Figure 35 is an examplary 13 C ssNMR spectrium of Compound 1 :
• Figure 36 is a comparison of examplary dissolution profiles in FeSSIF of Compound 1 :glyceryltrioctanoate (filled circles) Compound 1 :glyceryltrioleate (filled squares), and Compound l .glyceryltrilinoleate (filled triangles) with amorphous Compound 1 (filled diamonds), Compound 1 spray dried dispersion (SDD) (filled upside-down triangles).
• Figure 37 is an examplary XRPD diffraction patterns of cocrystals of Compound 1 with different pure triglycerides and cocrytals isolated from mixture of infant formula and Compuond.
• ABS-transporter as used herein means an ABC-transporter protein or a fragment thereof comprising a binding domain, wherein said protein or fragment thereof is present in vivo or in vitro.
• binding domain as used herein means a domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. et al, J. Gen. Physiol. (1998): 777(3), 477-90.
• CFTR cystic fibrosis transmembrane conductance regulator
• mutants can refer to mutations in the CFTR gene or the CFTR protein.
• a “CFTR mutation” refers to a mutation in the CFTR gene, and a “CFTR mutation” refers to a mutation in the CFTR protein.
• Genetic defects or mutations include, but are not limited to, AF508 CFTR, Rl 17H CFTR, G551D CFTR, G178R CFTR, S549N CFTR, S549R CFTR, G551S CFTR, G970R CFTR, G1244E CFTR, S1251N CFTR, S 1255P CFTR, and G1349D CFTR or AF508 CFTR, Rl 17H CFTR, G551D CFTR, G178R CFTR, S549N CFTR, S549R CFTR, G551S CFTR, G970R CFTR, G1244E CFTR, S 1251N CFTR, S 1255P CFTR, and G1349D CFTR (see, e.g.,
• a "AF508 mutation” or “F508del mutation” is a specific mutation within the CFTR protein.
• the mutation is a deletion of the three nucleotides that comprise the codon for amino acid phenylalanine at position 508, resulting in CFTR protein that lacks this phenylalanine residue.
• the mutated CFTR protein is commonly referred to as "F508del.”
• CFTR gating mutation means a CFTR mutation that results in the production of a CFTR protein for which the predominant defect is a low channel open probability compared to normal CFTR (Van Goor, F., Hadida S. and Grootenhuis P., "Pharmacological Rescue of Mutant CFTR function for the Treatment of Cystic Fibrosis", Top. Med. Chem. 3: 91-120 (2008)).
• Gating mutations include, but are not limited to, G551D, G178R, S549N, S549R, G551 S, G970R, G1244E, S I 25 IN, S 1255P, and G1349D.
• a patient who is "homozygous" for a particular mutation e.g. F508del, has the same mutation on each allele.
• a patient who is "heterozygous" for a particular mutation e.g. F508del, has this mutation on one allele and a different mutation on the other allele.
• a modulator refers to a compound that increases the activity of a compound such as a protein.
• a CFTR modulator is a compound that increases the activity of CFTR.
• the increase in activity resulting from a CFTR modulator may be through a corrector mechanism, a potentiator mechanism, or through a dual corrector and potentiator mechanism.
• CFTR corrector refers to a compound that increases the amount of functional CFTR protein to the cell surface, resulting in enhanced ion transport.
• CFTR potentiator refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport.
• crystalline refers to solid materials comprising atoms, molecules, and/or ions arranged in ordered geometric patterns or lattices. Crystalline solids show definite melting points and have rigid long range order.
• co-crystal as used herein means a crystalline entity containing at least two molecules in either stoichiometric or nonstoichiometric ratio.
• the co-crystal may optionally further contain ions.
• the co-crystals typically comprise an active pharmaceutical ingredient (API) and a co-former.
• the co-former typically may be hydrogen-bonded directly to the API or may be hydrogen-bonded to an additional molecule that is bound to the API.
• Other modes of molecular recognition may also be present including, pi-stacking, guest-host complexation and van der Waals interactions.
• co-former or alternatively “co-crystal former,” refers to a molecule such as a triglyceride in a co-crystal other than an API.
• the co- former may or may not undergo any changes after forming co-crystal with an API.
• Compound 1 :triglyceride refers to co-crystals comprising Compound 1 and a triglyceride.
• Compound 1 :glyceryltrioctanoate is used herein to refer to co-crystals comprising Compound 1 and glyceryltrioctanoate.
• Compound 1 :glyceryltrioleate is used herein to refer to co-crystals comprising Compound 1 and glyceryltrioleate.
• Compound 1 :glyceryltrilinoleate is used herein to refer to co- crystals comprising Compound 1 and glyceryltrilinoleate.
• active pharmaceutical ingredient or “API” refers to a biologically active compound.
• pure as used herein means chemically pure or free from impurities detectable by routine chemical analysis, for example by HPLC.
• substantially pure as used herein means at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% purity of the target material within a mixture.
• the term "isolated,” as in an isolated co-crystal, refers to a co-crystal that is separated away from other materials, such as other crystalline materials that may be distinguished from the target co-crystal through routine analysis such as XRPD.
• the co-crystals may be isolated or separated from other materials by filtration or centrifugation.
• an isolated co-crystal may be at least 50% pure.
• the isolated co-crystal may contain impurities such as, as non-limiting examples, residual co-former, solvent, or other materials presented in the medium in which the co-crystal was produced, which may be difficult to be removed from the co-crystal.
• an isolated co-crystal may be substantially pure.
• aliphatic encompasses substituted or
• alkyl refers to a saturated aliphatic hydrocarbon group containing 1-29 carbon atoms.
• An alkyl group can be straight or branched.
• an "alkenyl” group refers to an aliphatic carbon group that contains 2-29 carbon atoms and a double bond. Like an alkyl group, an alkenyl group can be straight or branched.
• an "alkynyl” group refers to an aliphatic carbon group that contains 2-29 carbon atoms and has a triple bond. An alkynyl group can be straight or branched.
• inducing refers to increasing CFTR activity, whether by the corrector, potentiator, or other mechanism.
• modulating means increasing or decreasing, e.g., activity, by a measurable amount.
• reduced CFTR or "reduced CFTR function” as used herein means less than normal CFTR or less than normal CFTR function.
• a "patient,” “subject” or “individual” are used interchangeably and refer to either a human or non-human animal.
• the term includes mammals such as humans.
• ⁇ dose or “effective amount” are used interchangeably herein and refer to that amount that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF or lessening the severity of CF or a symptom of CF).
• amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical
• treatment generally mean the improvement of CF or its symptoms or lessening the severity of CF or its symptoms in a subject.
• Treatment includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and/or liver function, reduced incidences of chest infections, and/or reduced instances of coughing or shortness of breath.
• the term "in combination with” when referring to two or more compounds or agents means that the order of administration includes the compounds or agents being administered prior to, concurrent with, or subsequent to each other to the patient.
• the present disclosure provides co-crystals comprising N-[2,4-bis(l , l- dimethylethyl)-5-hydroxyphenyl]-l ,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1 ) having the structural formula:
• Compound 1 is described in International PCT publication WO2006002421 and has the molecular formula of C24H28N203.
• the present disclosure provides a co-crystal comprising Compound 1 and a co-former, wherein the co-former is chosen from the following structural formula:
• Ri, R 2 , and R 3 are independently Ci-2 aliphatic.
• the co-crystal is isolated.
• Rl , R2, and R3 are independently CI -29 aliphatic.
• the co-former has an average molecular weight ranging from 470 to 1400 Da.
• the co-former is chosen from glyceryl trioleate, glyceryltristearate, glyceryltrihexanoate, glyceryltridecanoate, glyceryltrioctanoate, glyceryltrimyristate, glyceryltripalmitate, glyceryltributyrate, glyceryltrilinoleate, glyceryltridodecanoate, glyceryltripalmitoleate, glyceryltrierucate,
• glyceryltripropionate palmitodiolein, triarachidonin, glyceryl trilinolenate, trierucin, glycerol triarachidate, glyceryl tri(cis-13-docosenoate), glyceryl tripetroselinate, glyceryl tribehenate, glyceryl trielaidate, glyceryltriacetate (triacetin),
• the co-former is chosen from:
• the co-former is chosen from: glyceryltrioleate, glyceryltristearate, glyceryltrihexanoate, glyceryltridecanoate, glyceroltnoctanoate, glyceryltrimyristate, glyceryltripalmitate, glyceryltnlinoleate, glyceryltndodecanoate,, glyceryltripalmitoleate, glyceroltrierucate, palmitodiolein, triarachidonin, glyceryl trilinolenate, trierucin, glycerol triarachidate, glyceryl tri(cis-13-docosenoate), glyceryl tripetroselinate, glyceryl tribehenate, and glyceryl trielaidate.
• the co-former is chosen from glyceryltrioctanoate, glyceryltrioleate, glyceryltrilinoleate, glyceryltrihexanoate, glyeryltristearate, glyceryltridecanoate, glycerltripalmitate, glyceryltrimyristate, glyceryltripalmitate, glyceryltristearate, and glyceryltridodecanoate.
• the co-former is chosen from glyceryltriacetate and glyceryltributyrate.
• the co-crystal of Compound 1 comprises only
• glyceryltrihexanoate only glyeryltristearate, only glyceryltridecanoate, only glycerltripalmitate, only glyceryltridodecanoate, only glyceryltriacetate, or only glyceryltributyrate.
• the co-crystal of Compound 1 comprises two triglycerides, such as (i) glyceryltrioctanoate and glyceryltrioleate; (ii) glyceryltrioleate and glyceryltrilinoleate; or (iii)
• the stoichiometry of Compound 1 to the co-former ranges from 2 to 1 to 6 to 1. In one embodiments, in the co-crystal, the stoichiometry of Compound 1 to the co-former ranges from 3 to 1 to 6 to 1. In one embodiments, in the co-crystal, the stoichiometry of Compound 1 to the co-former ranges from 4 to 1 to 6 to 1. In one embodiments, in the co-crystal, the stoichiometry of Compound 1 to the co-former ranges from 5 to 1 to 6 to 1.
• the stoichiometry of Compound 1 to the co-former is about 6 to about 1. In one embodiment, in the co-crystal, the stoichiometry of Compound 1 to the co-former is 6 to 1.
• the co-crystal of Compound 1 comprises a co- former chosen from glyceryltrioleate, glyceryltrilinoleate, glyceryltristearate, and glyceryltripalmitate, and the stoichiometry of Compound 1 to the co-former in the co- crystal is about 6 to about 1.
• the co-crystal comprises Compound 1 and glyceryltrioleate, wherein the stoichiometry of Compound 1 to glyceryltrioleate is about 6 to about 1.
• the co-crystal comprises Compound 1 and glyceryltrilinoleate, wherein the stoichiometry of Compound 1 to glyceryltrilinoleate is about 6 to about 1.
• the co-crystal comprises Compound 1 and glyceryltristearate, wherein the stoichiometry of Compound 1 to glyceryltristearate is about 6 to about 1.
• the co-crystal comprises Compound 1 and glyceryltripalmitate, wherein the stoichiometry of Compound 1 to glyceryltripalmitate is about 6 to about 1.
• the ratio or stoichiometry of Compound 1 to the co-former in Compound 1 :triglyceride is 6 to 1.
• the stoichiometry of Compound 1 to the co-former in the co-crystal is about 3 to about 1. In one embodiment, the stoichiometry of
• Compound 1 to the co-former in the co-crystal is 3 to 1.
• the co-crystal of Compound 1 comprises a co- former chosen from glyceryltrioctanoate, glyceryltridodecanoate, and
• glyceryltridecanoate and the stoichiometry of Compound 1 to the triglyceride in the co-crystal is about 3 to about 1.
• the present disclosure provides for a co-crystal comprising Compound 1 and glyceryltrioctanoate, wherein the stoichiometry of Compound 1 to glyceryltrioctanoate is about 3 to about 1 .
• the present disclosure provides a co-crystal comprising
• Compound 1 and glyceryltridodecanoate wherein the stoichiometry of Compound 1 to glyceryltridodecanoate is about 3 to about 1.
• the present disclosure provides a co-crystal comprising Compound 1 and glyceryltridecanoate, wherein the stoichiometry of Compound 1 to glyceryltridecanote is about 3 to about 1.
• the ratio or stoichiometry of Compound 1 to triglyceride co-former in Compound l :triglyceride is 3 to 1.
• , R 2 , and R 3 are independently C7.29 aliphatic and Compound 1 may be present in the form of a hexamer in the co-crystal.
• Compound 1 may be present in the form of a hexamer in the co-crystal, wherein each of the hexamers contains six molecules of Compound 1 bonded by hydrogen bonding as shown in Figure 1.
• Compound 1 may be present in the form of a hexamer in the co-crystal, wherein each of the hexamers contains six molecules of Compound 1 bonded by hydrogen bonding as shown in Figure 1 , and further wherein Ri, R 2 , and R 3 are independently C 7-2 9 aliphatic.
• molecules of Compound 1 may be bound by the one or more of the following hydrogen bonds to form a hexamer:
• 1 triglyceride co-crystal is stabilized by the presence of the triglyceride co-former.
• the co-crystals are capable of yielding a concentration of Compound 1 of greater than 0.4 mg/mL when dissolved in simulated intestinal fluid in fed state (FeSSIF).
• the co-crystals are capable of yielding a
• Compound 1 concentration of Compound 1 of greater than 0.4 mg/mL when dissolved in simulated intestinal fluid in fed state (FeSSIF) and the concentration is maintained for at least 10 hours.
• the co-crystals are characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
• the co-crystals are characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, and 18.0.
• the co-crystals are characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, 18.0, and 23.8.
• the co-crystals are characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, and 1 19.4.
• the co-crystals are characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, 130.5, and 1 19.4.
• the present disclosure also provides a co-crystal comprising Compound 1 and a co-crystal former selected from the group consisting of glyceryltrioctanoate, glyceryltrioleate, and glyceryltrilinoleate, wherein Compound 1 is represented by the following structural formula:
• the co-crystal described in the paragraph immediately above dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is maintained for at least 10 hours.
• FeSSIF simulated intestinal fluid in fed state
• the co-crystal former is glyceryltrioctanoate.
• glyceryltrioctanoate is 3 to 1.
• the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
• the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.1, 10.9, 16.9, 18.0, and 23.8.
• the co-crystal is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, and 1 19.4.
• the co-crystal is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 186.7 ⁇ 0.5°C.
• the co-crystal former is glyceryltrioleate.
• the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
• the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, 18.1 and 23.8.
• the co-crystal is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, 130.5, and 1 19.4.
• the co-crystal is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 197.5 ⁇ 0.5°C.
• the co-crystal former is glyceryltrilinoleate.
• the stoichiometry of Compound 1 to glyceryltrilinoleate is 6 to 1.
• the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
• the co-crystal is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.2, 10.9, 17.0, 18.1 , and 23.8.
• the co-crystal is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.5, 155.0, 130.6, and 1 19.3.
• the co-crystal is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 182.3 ⁇ 0.5°C.
• deuterium (2H) may be incorporated into Compound 1 to manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect.
• the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.
• Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially.
• pharmacokinetic profiles are susceptible to oxidative metabolism.
• In vitro liver microsomal assays currently available provide valuable information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of Compound 1 with improved stability through resistance to such oxidative metabolism.
• Significant improvements in the pharmacokinetic profiles of Compound 1 are thereby obtained and can be expressed quantitatively in terms of increases in the in vivo half-life (tl/2), concentration at maximum therapeutic effect (Cmax), area under the dose response curve (AUC), and bioavailability; and in terms of reduced clearance, dose and materials costs.
• At least one hydrogen atoms in Compound 1 are replaced by deuterium atoms to provide a deuterated compound.
• one or both of the t-butyl groups in Compound 1 is replaced by d9-t-butyl.
• the t-butyl group adjacent to the OH group in Compound 1 is replaced d9-t-butyl (Compound 2).
• Co-crystals of Compound 2 may be formed using the methods described herein.
• Compound 1 can also be used to achieve a favorable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon- hydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated compound will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange may be found, for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem.
• the co-crystal comprising Compound 1 and glyceryltrioctanoate is hereinafter referred to as "Compound l :glyceryltrioctanoate”.
• Figure 3 is an examplary X-Ray Powder Diffraction (XRPD) pattern of Compound 1 :glyceryltrioctanoate.
• Figure 4 is an examplary 13C solid state nuclear magnetic resonance spectroscopy (13C ssNMR) spectrum of Compound 1 :glyceryltrioctanoate.
• Figure 5 is an examplary thermal gravimetric analysis (TGA) trace Compound 1 :glyceryltrioctanoate.
• Figure 6 is an examplary Differential Scanning Calorimetry (DSC) thermogram of Compound l :glyceryltrioctanoate.
• Figure 7 is an examplary 1H Nuclear Magnetic Resonance (1H NMR) spectrum of Compound 1 iglyceryltrioctanoate in DMSO-d6.
• Compound 1 iglyceryltrioctanoate is characterized as having an X-ray powder diffraction (XRPD) pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.1 , 10.9, 12.0, 12.5, 13.2, 13.7, 15.0, 16.2, 16.9, 18.0, 19.3, 20.2, 21.7, 22.5, 23.8, 25.8, 27.0, 27.6, 28.3, 30.0, 31.0, and 32.6.
• XRPD X-ray powder diffraction
• Compound l :glyceryltrioctanoate is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2- theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
• Compound 1 :glyceryltrioctanoate is characterized as having a X-ray powder diffraction pattern with characteristic peaks expressed in 2- theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.1, 10.9, 16.9, 18.0, and
• Compound l :glyceryltrioctanoate is characterized as having an X-ray powder diffraction pattern substantially the same as shown in Figure 3.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound l :glyceryltrioctanoate is characterized as having a 13C solid state nuclear magnetic resonance (13C ssNMR) spectrum with one or more characteristic peaks expressed in ppm ⁇ 0.1 selected from: 178.6, 172.9, 171.6, 169.9, 165.1, 155.0, 143.2, 139.4, 137.3, 134.6, 133.0, 126.0, 1 19.4, 1 17.7, 1 12.1 , 67.3, 64.0, 62.0, 59.6, 54.2, 35.8, 34.8, 31.7, 30.5, 23.5, and 14.6.
• 13C solid state nuclear magnetic resonance (13C ssNMR) spectrum with one or more characteristic peaks expressed in ppm ⁇ 0.1 selected from: 178.6, 172.9, 171.6, 169.9, 165.1, 155.0, 143.2, 139.4, 137.3, 134.6, 133.0, 126.0, 1 19.4, 1 17.7, 1 12.1 , 67.3, 64.0, 62.0, 59.6,
• Compound l :glyceryltrioctanoate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, and 1 19.4.
• Compound 1 :glyceryltrioctanoate is characterized by having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions 178.6, 155.0, 134.6, 126.0, 1 19.4, and 35.8.
• Compound l :glyceryltrioctanoate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 186.7°C.
• Compound 1 :glyceryltrioctanoate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 186.7 ⁇ 0.2 °C.
• Compound 1 :glyceryltrioctanoate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 186.7 ⁇ 0.5 °C.
• the ratio or stoichiometry of Compound 1 to glyceryltrioctanoate in Compound l :glyceryltrioctanoate is 3: 1.
• the ratio or stoichiometry of Compound 1 to glyceryltrioctanoate in Compound 1 glyceryltrioctanoate is about 3 to about 1.
• Figure 9 is an examplary 13C ssNMR spectrum of Compound 1 :glyceryltrioleate.
• Figure 10 is an examplary TGA trace Compound
• Figure 1 1 is an examplary DSC thermogram of Compound 1 :glyceryltrioleate.
• Figure 12 is an examplary 1H NMR spectrum of Compound 1 :glyceryltrioleate in acetone-d6.
• Compound l .glyceryltrioleate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 9.8, 10.4, 10.9, 12.0,
• Compound 1 :glyceryltrioleate is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
• Compound 1 :glyceryItrioleate is characterized as having a X-ray powder diffraction pattern with characteristic peaks expressed in 2- theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 10.9, 16.9, 18.1 and 23.8.
• Compound 1 :glyceryltrioleate is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2- theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 9.8, 10.9, 12.0, 12.7, 13.3,
• Compound l :glyceryltrioleate is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, 9.2, 9.8, 10.4,
• Compound l :glyceryltrioleate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 8.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound 1 :glyceryltrioleate is characterized as having a 13C solid state nuclear magnetic resonance (13C ssNMR) spectrum with one or more characteristic peaks expressed in ppm ⁇ 0.1 selected from: 178.6, 172.9, 171.6, 169.9, 165.0, 155.0, 142.9, 139.3, 137.4, 134.5, 133.0, 130.5, 127.3, 126.0, 1 19.4, 1 17.7, 112.1, 67.2, 63.9, 59.6, 35.8, 34.8, 31.7, 30.5, 28.2, 24.6, 23.6, and 14.7.
• 13C solid state nuclear magnetic resonance (13C ssNMR) spectrum with one or more characteristic peaks expressed in ppm ⁇ 0.1 selected from: 178.6, 172.9, 171.6, 169.9, 165.0, 155.0, 142.9, 139.3, 137.4, 134.5, 133.0, 130.5, 127.3, 126.0, 1 19.4, 1 17.7, 112.1, 67.2, 63.9,
• Compound 1 :glyceryltrioleate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, 130.5, and 1 19.4.
• Compound 1 :glyceryltrioleate is characterized by having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, 134.5, 130.5, 126.0, 119.4, and 35.8.
• Compound 1 :glyceryltrioleate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 172.9, 171.6, 169.9, 165.0, 155.0, 142.9, 139.3, 137.4, 134.5, 133.0, 130.5, 127.3, 126.0, 119.4, 1 17.7, 112.1 , 67.2, 63.9, 59.6, 35.8, 34.8, 31.7, 30.5, 28.2, 24.6, 23.6, and 14.7.
• Compound 1 :glyceryltrioleate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 197.5°C.
• Compound l iglyceryltrioleate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 197.5 ⁇ 0.2 °C.
• Compound 1 :glyceryltrioleate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 197.5 ⁇ 0.5 °C.
• the ratio or stoichiometry of Compound 1 to glyceryltrioleate in Compound 1 : glyceryltrioleate is 6: 1 . In some embodiments, the ratio or stoichiometry of Compound 1 to glyceryltrioleate in Compound 1 :
• glyceryltrioleate is about 6 to about 1.
• the co-crystal comprising Compound 1 and glyceryltrilinoleate is hereinafter referred to as "Compound 1 glyceryltrilinoleate”.
• Figure 14 is an examplary 13C ssNMR spectrum of Compound
• Figure 16 is an examplary DSC thermogram of Compound
• Compound 1 glyceryltrilinoleate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.2, 10.9, 12.0, 12.5, 13.8, 15.1 , 16.3, 17.0, 18.1 , 19.4, 20.2, 21.8, 22.6, 23.8, 25.9, 27.1 , 27.8, 28.4, and 32.7.
• Compound 1 glyceryltrilinoleate is
• Compound 1 glyceryl trilinoleate is characterized as having a X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
• Compound 1 glyceryl trilinoleate is characterized as having a X-ray powder diffraction pattern with characteristic peaks expressed in 2- theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.2, 10.9, 17.0, 18.1 , and 23.8.
• Compound l :glyceryltrilinoleate is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.2, 10.9, 12.0, 12.5, 13.8, 15.1 , 16.3, 17.0, 18.1 , 19.4, 20.2, 21.8, 22.6, 23.8, 25.9, 27.1 , 27.8, 28.4, and 32.7.
• Compound l :glyceryltrilinoleate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 13.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound 1 :glyceryltrilinoleate is characterized as having a 13C solid state nuclear magnetic resonance (13C ssNMR) spectrum with one or more characteristic peaks expressed in ppm ⁇ 0.1 selected from: 178.6, 172.8,
• Compound l :glyceryltrilinoleate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 155.0, 130.6, and 1 19.4.
• Compound l :glyceryltrioleate is characterized by having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions 178.6, 155.0, 134.4, 130.6, 126.0, 1 19.4, and 35.8.
• Compound 1 :glyceryltrilinoleate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.6, 172.8, 171.5, 169.8, 165.1 , 155.0, 142.9, 139.3, 137.4, 134.4, 133.1, 130.6, 126.0, 1 19.4, 1 17.6, 112.0, 86.5, 67.2, 63.9, 59.7, 35.8, 34.8, 31.7, 30.6, 28.2, and 14.8.
• Compound 1 :glyceryltrilinoleate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 182.3°C.
• Compound l :glyceryltrilinoleate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 182.3 ⁇ 0.2 °C.
• Compound 1 :glyceryltrilinoleate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 182.3 ⁇ 0.5 °C.
• the ratio or stoichiometry of Compound 1 to glyceryltrilinoleate in Compound 1 : glyceryltrilinoleate is 6: 1. In some embodiments, the ratio or stoichiometry of Compound 1 to glyceryltrilinoleate in Compound 1 : glyceryltrilinoleate is about 6 to about 1.
• the co-crystal comprising Compound 1 and glyceryltriaceatate (triacetin) is hereinafter referred to as "Compound 1 :glyceryltriaceate” or "Compound l :triacetin”.
• Figure 18 is an examplary XRPD pattern of Compound l :triacetin.
• Figure 19 is a 13C ssNMR spectrum of Compound l :triacetin.
• Figure 20 is a DSC thermogram of Compound l :triacetin.
• Compound 1 :triacetin is characterized as having an X- ray powder diffraction pattern with one or more characteristic peaks expressed in 2- theta ⁇ 0.2 degrees at the following positions: 4.9, 9.5, 9.8, and 14.7.
• Compound l :triacetin is characterized as having an X- ray powder diffraction pattern with one or more characteristic peaks expressed in 2- theta ⁇ 0.2 degrees at the following positions: 4.9, 9.5, 9.8, 14.7, 16.5, 18.2, and 23.1.
• Compound l :triacetin is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 18.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound 1. triacetin is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.2, 155.1 , 154.8, 1 19.7, and 1 19.2.
• Compound l :triacetin is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.2, 155.1 , 154.8, 134.1 , 125.9, 125.6, 1 19.7, 1 19.2, and 35.3.
• Compound l :triacetin is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.2, 165.4, 164.3, 155.1 , 154.8, 154.1 , 149.4, 146.8, 145.6, 140.0, 134.1, 133.2, 132.3, 127.0, 125.9, 125.6, 124.3, 120.6, 1 19.7, 1 19.2, 1 18.3, 1 17.6, 1 1 1.9, 1 1 1.1, 1 10.4, 35.3, 35.0, 31.8, 29.8, 21.9, 20.4, and 18.9.
• Compound l :triacetin is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 123.9°C (peak) that corresponds to the melting of the Compound 1 :glyceryltritriacetin co-crystal. This event is followed by another endotherm at 141.9°C and yet another endotherm at 193.8 °C.
• DSC differential scanning calorimetry
• the co-crystal comprising Compound 1 and glyceryltributyrate is hereinafter referred to as "Compound 1 : glyceryltributyrate”.
• Compound 1 glyceryltributyrate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 6.8, 9.5, and 22.6.
• Compound 1 glyceryltributyrate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 4.8, 4.9, 6.8, 9.5, 9.6, 14.3, 18.0, 19.0, 19.8, 21.4, 22.6, and 23.8.
• Compound 1 glyceryltributyrate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 21.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• the co-crystal comprising Compound 1 and glyceryltristearate is hereinafter referred to as "Compound 1 : glyceryltristearate”.
• Figure 24 is a DSC thermogram of Compound
• Compound 1 glyceryl tristearate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.6, 6.9, and 1 1.0.
• Compound 1 glyceryl tristearate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.6, 6.2, 6.9, 9.3, 11.0, 17.0, and 18.2.
• Compound l :glyceryltristearate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.6, 5.4, 6.2, 6.9, 9.3, 1 1.0, 12.1 , 12.6, 13.4, 13.9, 15.4, 16.4, 17.0, 18.2, 18.5, 19.4, 20.0, 20.4, 21.8, 23.8, 26.0, 27.0, 28.4, 29.1, 29.9, 31.2, and 32.8.
• Compound l :glyceryltristearate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 22.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound 1 glyceryl tristearate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.5, 155.0, and 1 19.5.
• Compound 1 :glyceryltristearate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.5, 155.0, 134.4, 126.1, 1 19.5, and 35.7.
• Compound 1 :glyceryltristearate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.5, 172.9, 171.6, 169.9, 165.0, 155.0, 143.6, 139.4, 137.2, 135.1 , 134.4, 133.0, 127.3, 126.1 , 1 19.5, 117.6, 1 12.0, 67.3, 64.1 , 59.6, 35.7, 34.7, 31.7, 30.6, 23.6, and 14.8.
• Compound l :glyceryltristearate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 55.1 °C that corresponds to the eutectic melt of Compound 1 :glyceryltrilstearate co-crystal and glyceryltristearate. This event is followed by another endotherm at 71.3 °C, corresponding to the melt of neat glyceryltristearate. Overlapping endotherm at 201.3°C and exotherm at 208.1 °C correspond to the cocrystal melt and crystallization of neat Compound 1, respectively. Another endotherm at 284.7°C corresponds to the melt of a neat form of Compound 1.
• DSC differential scanning calorimetry
• Figure 27 is a DSC thermogram of Compound
• Compound 1 iglyceryltripalmitate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 1 1.0.
• Compound 1 iglyceryltripalmitate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.3, 17.0, 18.2, and 23.7.
• Compound 1 glyceryltripalmitate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.9, 9.3, 1 1.0, 13.8, 15.1 , 16.3, 17.0, 1 8.2, 19.4, 19.9, 20.3, 21.8, and 23.7.
• Compound 1 glyceryltripalmitate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 25.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound 1 glyceryltripalmitate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.4, 155.0, 144.0, and 1 19.6.
• Compound 1.-glyceryltripalmitate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.4, 155.0, 134.5, 126.0, 1 19.6, and 35.7.
• Compound 1 glyceryltripalmitate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.4, 173.0, 169.9, 165.0, 155.0, 144.0, 139.5, 137.2, 134.5, 133.0, 127.2, 126.0, 1 19.6, 117.5, 1 12.0, 67.2, 64.0, 59.7, 35.7, 34.6, 31.7, 30.6, 23.7, and 14.8.
• Compound 1 :glyceryltripalmitate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 47.7°C (peak) that corresponds to the eutectic melt of ivacaftonglyceryltripalmitate co-crystal and glyceryltripalmitate. This event is followed by another endotherm at 63.0 °C (peak), corresponding to the melt of neat glyceryltripalmitate. Overlapping endotherm at 174.9°C (peak) and exotherm at 186.7°C (peak) correspond to the cocrystal melt and crystallization of neat ivacaftor, respectively. Another endotherm at 266.2°C (peak) corresponds to the melt of a neat form of ivacaftor.
• DSC differential scanning calorimetry
• the co-crystal comprising Compound 1 and glyceryltridodecanoate is hereinafter referred to as "Compound 1 : glyceryltridodecanoate”.
• Compound l :glyceryltridodecanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 4.4, 6.1, 6.9, 8.6, 9.3, 1 1.0, 12.1 , 12.6, 13.2, 13.8, 15.0, 16.3, 17.0, 18.1 , 19.5, 20.3, 21.9, 23.3, 23.9, 24.8, and 30.2.
• Compound 1 glyceryltridodecanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 1 1 .0.
• Compound 1 glyceryltridodecanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.1 , 6.9, 9.3, 1 1.0, 17.0, 18.1 , and 23.3.
• Compound 1 glyceryltridodecanoate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 28.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound 1 glyceryltridodecanoate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.4, 155.0, and 119.6.
• Compound 1 :glyceryltridodecanoate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.4, 155.0, 134.6, 126.1, 1 19.6, and 35.6.
• Compound 1 glyceryltridodecanoate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.4, 173.1, 171.5, 169.8, 165.0, 155.0, 143.0, 139.4, 137.2, 134.6, 133.0, 127.3, 126.1, 1 19.6, 1 17.6, 1 12.1 , 67.1 , 63.9, 59.7, 35.6, 31.7, 30.6, and 23.6.
• the co-crystal comprising Compound 1 and glyceryltrimyristate is hereinafter referred to as "Compound 1 : glyceryltrimyristate”.
• Figure 32 is a DSC thermogram of Compound
• Compound 1 glyceryltrimyristate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.8, and 10.9.
• Compound 1 glyceryltrimyristate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.8, 9.2, 10.9, 16.9, and 18.0.
• Compound 1 glyceryltrimyristate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.0, 6.8, 7.4, 8.3, 9.2, 9.9, 10.9, 12.0, 12.5, 13.2, 13.7, 14.9, 16.2, 16.9, 17.6, 18.0, 18.5, 19.4, 20.0, 21.2, 22.1 , 23.2, 24.1, 25.1, 26.4, 27.2, 27.7, 28.3, 29.2, 29.7, 31.0, and 32.7.
• Compound l :glyceryltrimyristate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 30.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound l :glyceryltrimyristate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.1 , 155.0, and 1 19.9,
• Compound l :glyceryltrimyristate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.1, 155.0, 134.6, 126.0, 1 19.9, and 35.6.
• Compound l :glyceryltrimyristate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.1 , 171.4, 169.8, 165.0, 155.0, 142.9, 139.5, 137.2, 134.6, 133.1 , 127.3, 126.0, 1 19.9, 1 17.4, 1 12.0, 67.0, 63.7, 61.4, and 35.6.
• Compound 1 :glyceryltrimyristate is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 59.2 °C that corresponds to the melt of glyceryltrimyristate. This event is followed by a broad exotherm at 134.4 °C that is overlapping with an endotherm. This event is followed by an exotherm at 171.3 °C corresponding to the crystallization of neat Compound ] . Another endotherm at 280.1 °C corresponds to the melt of a neat form of Compound 1.
• DSC differential scanning calorimetry
• the co-crystal comprising Compound 1 and glyceryltrihexanoate is hereinafter referred to as "Compound 1 -.glyceryltrihexanoate”.
• Compound 1 glyceryltrihexanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 6.5, 9.2, and 21.4.
• Compound 1 glyceryltrihexanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 4.7, 6.5, 9.2, 14.5, 17.4,
• Compound 1 glyceryltrihexanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 4.7, 6.5, 9.2, 9.9, 1 1.8, 12.5, 14.5, 15.1 , 15.6, 17.4, 18.7, 19.9, 21.4, 23.0, 24.4, 25.2, 26.5, 28.3, 29.1, 30.5, and 35.6.
• Compound 1 glyceryltrihexanoate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 33.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• the co-crystal comprising Compound 1 and glyceryltridecanoate is hereinafter referred to as "Compound l :glyceryltridecanoate”.
• Compound 1 glyceryltridecanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.9, and 10.9.
• Compound 1 glyceryltridecanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.1 , 6.9, 9.2, 10.9, 16.9, 18.1 , and 23.9.
• Compound 1 glyceryltridecanoate is characterized as having an X-ray powder diffraction pattern with one or more characteristic peaks expressed in 2-theta ⁇ 0.2 degrees at the following positions: 3.5, 6.1 , 6.9, 9.2, 10.9,
• Compound 1 glyceryltridecanoate is characterized as having an XRPD powder diffraction pattern substantially the same as shown in Figure 34.
• the X-ray powder diffraction patterns are obtained at room temperature using Cu K alpha radiation.
• Compound l iglyceryltridecanoate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.5, 155.0, and 1 19.5.
• Compound l iglyceryltridecanoate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.5, 155.0, 134.9, 126.1 , and 35.7.
• Compound l :glyceryltridecanoate is characterized as having a 13C ssNMR spectrum with characteristic peaks expressed in ppm ⁇ 0.1 at the following positions: 178.5, 171.6, 169.9, 165.0, 155.0, 143.3, 139.5, 137.2, 134.9, 133.0, 127.3, 126.1 , 1 19.5, 1 17.6, 1 12.1 , 67.2, 64.0, 59.8, 35.7, 34.7, 31.7, 30.5, and 25.8, 23.5.
• the Compound 1 triglyceride co-crystals have similar performance in terms of dissolution rate and maintenance of the high solution concentrations in FeSSIF to each other.
• the Compound 1 triglyceride co-crystals also show a better maintenance of the supersaturation than both the neat amorphous and solid amorphous dispersed form of Compound 1 (Compound 1 SDD) over longer time periods.
• the Compound 1 triglyceride co-crystals should be metabolized in the small intestine by lipid esterase (lipases), which would effectively remove the triglycerides and further boost the Compound 1 concentration according to Le-Chatelier's principle.
• lipases lipid esterase
• the crystalline Compound 1 triglyceride co-crystals may have the following advantages over the solid amorphous dispersed form (Compound 1 SDD) of Compound 1 : (1) the co-crystals can be formulated, stored and used under conditions where they are thermodynamically stable; (2) a controlled crystallization can be developed that can reduces potential impurity levels (impurities include, but are not limited to, solvent); (3) a manufacturing process can be developed that is more efficient and cost effective (for example, less solvent can be used in manufacturing and a lower cost process than spray drying can be developed); and (4) a stabilizing polymer is not required for co-crystals.
• impurities include, but are not limited to, solvent
• a manufacturing process can be developed that is more efficient and cost effective (for example, less solvent can be used in manufacturing and a lower cost process than spray drying can be developed)
• (4) a stabilizing polymer is not required for co-crystals.
• the co-crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL.
• the co-crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is maintained for at least 10 hours.
• the co- crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) at a temperature of 37 °C to yield a concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is maintained for at least 10 hours.
• the co-crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL within 2 hours.
• the co-crystal dissolves in simulated intestinal fluid in fed state (FeSSIF) to yield a concentration of Compound 1 of greater than 0.4 mg/mL and the concentration is maintained for at least 10 hours without need for a stabilizing polymer.
• the stabilizing polymer is HPMCAS.
• the present disclosure is directed to a method of preparing a co-crystal comprising Compound 1 and a co-former, wherein the co-crystal is chosen from the following structural formula:
• Rj, R 2 , and R 3 are independently C 1 -2 9 aliphatic, wherein Compound 1 is represented by the following structural formula:
• Ri, R 2 , and R 3 are independently C 7 . 2 9 aliphatic
• the co-former has an average molecular weight between 470 and 1400 Da.
• the co-former is chosen from glyceryl trioleate, glyceryl tristearate, glycerol tridecanoate, glycerol trihexanoate, glyceryl
• tritridecanoate glycerol trioctanoate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tributyrate, glyceryl trilinoleate, glyceryl tridodecanoate, glyceryl decanoate, glyceryl tripalmitoleate, glycerol trierucate, glyceryl tripropionate, palmitodiolein, triarachidonin, glyceryl trilinolenate, trierucin, glycerol triarachidate, glyceryl tri(cis- 13-docosenoate), glyceryl tripetroselinate, glyceryl tribehenate, glyceryl trielaidate, and triacetin.
• the co-former is chosen from
• Compound 1 is neat amorphous. In another embodiment, the co-former is neat. In one embodiment, Compound 1 and the co- former are stirred for at least 0.5 hours. In another embodiment, Compound 1 and co- former are stirred for 18 hours. In yet another embodiment, Compound 1 and the co- former are stirred for at least 18 hours. In one embodiment, Compound 1 and the co- former are stirred for more than 0.5 hours (including, but not limited to, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours).
• Compound 1 and the co-former are stirred at 40 °C. In another embodiment, Compound 1 and the co-former are stirred at about 40 °C. In yet other embodiments, Compound 1 and the co-former are stirred at 35-45 °C (for example, at 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C or 45 °C). In one embodiment, Compound 1 and the co-former are stirred for at least 18 hours at 40°C. In one embodiment, Compound 1 and the co-former are stirred for at least 0.5 hours at 40°C. In one embodiment, Compound 1 and the co-former are stirred for at least 18 hours at 40°C.
• glyceryltrioctanoate are stirred for at least 0.5 hours; in yet one embodiment, Compound 1 and glyceryltrioctanoate are stirred for 0.5 hours; in yet another embodiment, Compound 1 and glyceryltrioctanoate are stirred for at least 0.5 hours at 40°C; in also yet another embodiment, Compound 1 and glyceryltrioctanoate are stirred for 0.5 hours at 40°C.
• the present disclosure provides a method of preparing a co-crystal comprising Compound 1 and a co-former,
• R ⁇ , R 2 , and R 3 are independently Ci -2 9 aliphatic
• the method optionally, further comprises, the steps of:
• One aspect of the present disclosure provides for a method of preparing a co- crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• Rj , R 2 , and R 3 are independently Q-29 aliphatic;
• Compound 1 and the co-former are heated to about 80°C. In one embodiment, Compound 1 and the co-former are heated to 80°C. In another embodiment, Compound 1 and the co-former are heated to about 80°C for 12 hours. In yet another embodiment, Compound 1 and the co-former are heated to 80°C for 12 hours. In another embodiment, Compound 1 and the co-former are heated to about 80°C for 24 hours. In yet another embodiment, Compound 1 and the co-former are heated to 80°C for 24 hours.
• One aspect of the present disclosure provides for a method of preparing a co- crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• the co-former is chosen from the following structural formula:
• Rj, R 2 , and R 3 are independently C 1 -2 9 aliphatic,
• Compound 1 and the co-former are heated to 80°C for 12 hours. In yet another embodiment, Compound 1 and the co-former are heated to 80°C for 24 hours.
• Ri, R 2 , and R 3 are independently C 1 .2 aliphatic,
• One aspect of the present disclosure provides for a method of preparing a co- crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• Ri, R 2 , and R are independently C 1.29 aliphatic
• Compound 1 and the co-former are heated to about 80°C. In another embodiment, Compound 1 and the co-former are heated to about 80°C and cooled down to about 40°C. In one embodiment, Compound 1 and the co- former are heated to 80°C. In another embodiment, Compound 1 and the co-former are heated to 80°C and cooled down to 40°C. In another embodiment, Compound 1 and the co-former are heated to 80°C for 12 hours. In another embodiment,
• Compound 1 and the co-former are heated to 80°C for 24 hours. In yet another embodiment, Compound 1 and the co-former are heated to 80°C for 12 hours and cooled down to about 40°C. In another embodiment, Compound 1 and the co-former are heated to 80°C for 12 hours. In yet another embodiment, Compound 1 and the co- former are heated to 80°C for 24 hours and cooled down to about 40°C. In any of the above embodiments, the steps of heating and cooling are repeated.
• Another aspect of the present disclosure provides for a method of preparing a co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• R R 2 , and R 3 are independently C 1.29 aliphatic
• Another aspect of the present disclosure provides for a method of preparing a co-crystal comprising Compound 1 and a co-former, wherein Compound 1 is represented by the following structural formula:
• Rj, R 2 , and R 3 are independently C
• co-crystals can be prepared by slurrying Compound 1 and a co-former in a suitable solvent at a slurry composition at which the co-crystal is stable in the ternary phase diagram, for example: by co-grinding Compound 1 and a co-former, by co-grinding Compound 1 and a co-former and adding a small amount of suitable solvent, by co-grinding Compound 1 and a co-former and subsequently annealing, by co-grinding Compound 1 and a co-former and subsequently annealing at elevated temperature, by co-grinding Compound 1 and a co-former and
• Co-crystals may be made with multiple co- formers in a similar manner.
• the co-crystals are collected by centrifugal filtration at a temperature above the melting temperature of the co-former.
• the co-crystals are washed after filtration to remove excess co-former.
• Co-crystals produced by any of the methods above are isolated or purified. Co-crystals are pure as measured by HPLC. In one embodiment, the co-crystal is over 99% (w/w). In another embodiment, the Compound 1 triglyceride co-crystal is over 99.5% (w/w). In one embodiment, the Compound 1 triglyceride co-crystal is 99.5% (w/w). In another embodiment, the Compound 1 triglyceride co-crystal is 99.6% (w/w). In another embodiment, the Compound 1 triglyceride co-crystal is 99.7% (w/w).
• the Compound 1 triglyceride co-crystal is 99.8% (w/w). In another embodiment, the Compound 1 triglyceride co-crystal is 99.9% (w/w)). In one embodiment, the Compound l :glyceryltrioctanoate co-crystal is 99.9% (w/w). In another embodiment, the Compound 1 :glyceryltrioleate co-crystal is 99.9% (w/w). In yet another embodiment, the Compound 1 glyceryltrilinoleate co- crystal is 99.5% (w/w). The detection limit for impurities by HPLC is 0.005%.
• the present disclosure also provides a method of preparing a co-crystal comprising Compound 1 and a co-crystal former selected from the group consisting of glyceryltrioctanoate, glyceryltrioleate, and glyceryltrilinoleate, wherein Compound 1 is represented by the following structural formula:
• the co-crystal former is glyceryltrioctanoate.
• the co-crystal former is glyceryltrioleate.
• the co-crystal former is glyceryltrilinoleate.
• the present disclosure also provides a method of preparing a co-crystal comprising Compound 1 and a co-crystal former selected from the group consisting of glyceryltrioctanoate, glyceryltrioleate, and glyceryltrilinoleate, wherein Compound 1 is represented by the following structural formula:
• compositions comprising co-crystal of any one of the embodiments above and a pharmaceutically acceptable carrier or excipient.
• At least 30% of Compound 1 present in the pharmaceutically acceptable compositions are in the form of Compound 1 triglyceride co-crystals described herein.
• at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 92.5%, 95%, 97.5%, 98%, or 99% of Compound 1 are present in the form of Compound 1 triglyceride co-crystals described herein.
• compositions optionally further comprise one or more additional therapeutic agents.
• the pharmaceutically acceptable compositions of the present disclosure additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions
• any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure.
• materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, poly aery lates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin;
• COPD chronic obstructive pulmonary disease
• COPD dry eye disease
• Sjogren's Syndrome a chronic obstructive pulmonary disease
• COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis.
• Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
• CFTR Dry eye disease
• tear aqueous production and abnormal tear film lipid, protein and mucin profiles There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as cystic fibrosis and Sjogrens's syndrome.
• Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration.
• Sjogrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Augmenters or inducers of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.
• the disclosure provides a method of treating or lessening the severity of a disease in a patient comprising administering to said patient co-crystals of any one of the embodiments described above, and said disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1
• chylomicronemia chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1 , congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranu
• the method includes treating or lessening the severity of cystic fibrosis in a patient comprising administering to said patient a co-crystal of any one of the embodiments described above.
• the co-crystal is a Compound 1 : triglyceride co-crystal as described herein.
• the patient possesses mutant forms of human CFTR.
• the patient possesses one or more of the following mutations AF508, Rl 17H, and G551D of human CFTR.
• the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the AF508 mutation of human CFTR comprising administering to said patient Compound 1 triglyceride co-crystals described herein. In one embodiment, the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR comprising administering to said patient Compound 1 : triglyceride co-crystals described herein.
• the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the AF508 mutation of human CFTR on one allele comprising administering to said patient Compound 1 triglyceride co- crystals described herein. In one embodiment, the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the AF508 mutation of human CFTR on both alleles comprising administering to said patient Compound 1 triglyceride co-crystals described herein. In one embodiment, the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR on allele comprising administering to said patient
• the method includes treating or lessening the severity of cystic fibrosis in a patient possessing the G551D mutation of human CFTR on both alleles comprising administering to said patient Compound 1 triglyceride co-crystals described herein.
• the present disclosure provides a method of treating or lessening the severity of a condition, disease, or disorder implicated by CFTR mutation.
• the present disclosure provides a method of treating a condition, disease, or disorder implicated by a deficiency of the CFTR activity, the method comprising administering a composition comprising co-crystals of any one of the embodiments described above, to a subject, preferably a mammal, in need thereof.
• the co-crystal is a Compound 1 :triglyceride co- crystal as described herein.
• the present disclosure provides a method of treating diseases associated with reduced CFTR function due to mutations in the gene encoding CFTR or environmental factors (e.g., smoke).
• diseases include, cystic fibrosis, chronic bronchitis, recurrent bronchitis, acute bronchitis, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), female infertility caused by congenital absence of the uterus and vagina (CAUV), idiopathic chronic pancreatitis (ICP), idiopathic recurrent pancreatitis, idiopathic acute pancreatitis, chronic rhinosinusitis, primary sclerosing cholangitis, allergic bronchopulmonary aspergillosis, diabetes, dry eye, constipation, allergic
• ABPA bronchopulmonary aspergillosis
• bone diseases e.g., osteoporosis
• asthma comprising administering to said patient a co-crystal of any one of the embodiments described above.
• the co-crystal is a Compound 1 :triglyceride co-crystal as described herein.
• the present disclosure provides a method for treating diseases associated with normal CFTR function.
• diseases include, chronic obstructive pulmonary disease (COPD), chronic bronchitis, recurrent bronchitis, acute bronchitis, rhinosinusitis, constipation, pancreatitis including chronic pancreatitis, recurrent pancreatitis, and acute pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, liver disease, hereditary emphysema, gallstones, gastroesophageal reflux disease, gastrointestinal malignancies, inflammatory bowel disease, constipation, diabetes, arthritis, osteoporosis, and osteopenia, comprising administering to said patient co-crystals of any one of the embodiments described above.
• the co-crystals are
• hemochromatosis coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulinemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary
• hypoparathyroidism melanoma
• glycanosis CDG type 1 congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurohypophyseal DI, nephrogenic DI, Charcot-Marie Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (due to prion protein processing defect), Fabry disease, Straussler-
• co-crystals are Compound 1 :triglyceride co-crystals as described herein.
• the present disclosure provides a method of treating cystic fibrosis comprising the step of administering to said mammal a composition comprising the step of administering to said mammal an effective amount of a composition comprising Compound 1 : triglyceride co-crystals described herein.
• Compound 1 :triglyceride co-crystals described herein, or a pharmaceutically acceptable composition thereof may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited above.
• Compound 1 itriglyceride co-crystals described herein, or a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia.
• the presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo
• Compound 1 itriglyceride co-crystals described herein, described herein or a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients who have residual CFTR activity induced or augmented using pharmacological methods or gene therapy. Such methods increase the amount of CFTR present at the cell surface, thereby inducing a hitherto absent CFTR activity in a patient or augmenting the existing level of residual CFTR activity in a patient.
• Compound 1 itriglyceride co-crystals described herein, or a pharmaceutically acceptable composition thereof is useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, e.g., class III mutations (impaired regulation or gating), class IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis
• patient genotypes that exhibit residual CFTR activity include patients homozygous for one of these classes or heterozygous with any other class of mutations, including class I mutations, class II mutations, or a mutation that lacks classification.
• Compound 1 triglyceride co-crystals described herein, or a pharmaceutically acceptable composition thereof, is useful for treating or lessening the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia.
• phenotypes include patients exhibiting pancreatic insufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease.
• the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
• the compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
• dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
• the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
• patient means an animal, preferably a mammal, and most preferably a human.
• compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally,
• the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 0.5 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
• Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• 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, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• the rate of compound release can be controlled.
• biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
• compositions for rectal or vaginal administration are preferably
• suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example,
• the dosage form may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
• the active compounds can also be in microencapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active compound may be admixed with a inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• buffering agents include polymeric substances and waxes.
• Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this disclosure.
• the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
• Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin.
• the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
• the co-crystals of any one of the embodiments described above e.g., Compound 1 : triglyceride co-crystals described herein
• a pharmaceutically acceptable composition thereof can be employed in combination therapies, that is, co-crystals of any of the embodiments described above (e.g., Compound 1 triglyceride co-crystals described herein) or a pharmaceutically acceptable composition thereof, can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
• the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated.”
• the additional therapeutic agent is selected from a mucolytic agent, bronchodilator, an anti-biotic, an anti-infective agent, an antiinflammatory agent, a CFTR modulator other than a compound of the present disclosure, or a nutritional agent.
• the additional therapeutic agent is a compound that stabilizes the presence of CFTR at the cell surface such as activators of Racl signaling, of which hepatocyte growth factor (HGF) is an example.
• HGF hepatocyte growth factor
• the additional therapeutic agent is an antibiotic.
• Examplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, cayston, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.
• TIP tobramycin inhaled powder
• azithromycin azithromycin
• cayston aztreonam
• amikacin including liposomal formulations thereof
• ciprofloxacin including formulations thereof suitable for administration by inhalation
• levoflaxacin including aerosolized formulations thereof
• combinations of two antibiotics e.g., fosfomycin and tobramycin.
• the additional therapeutic agent is a mucolyte.
• Examplary mucolytes useful herein includes Pulmozyme®.
• the additional therapeutic agent is a bronchodialator.
• Examplary bronchodialtors include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.
• the additional therapeutic agent is effective in restoring lung airway surface liquid.
• Such agents improve the movement of salt in and out of cells, allowing mucus in the lung airway to be more hydrated and, therefore, cleared more easily.
• Examplary such agents include hypertonic saline, denufosol tetrasodium ([[(3S,5R)-5-(4-amino-2-oxopyrimidin-l-yl)-3-hydroxyoxolan- 2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-l-yl)-3,
• the additional therapeutic agent is an antiinflammatory agent, i.e., an agent that can reduce the inflammation in the lungs.
• an antiinflammatory agent i.e., an agent that can reduce the inflammation in the lungs.
• agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.
• the additional therapeutic agent is a compound that augments or induces CFTR activity other than a co-crystal of Compound 1.
• the additional therapeutic agent is a nutritional agent.
• Examplary nutritional agents include pancrelipase (pancreating enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®,
• the additional nutritional agent is pancrelipase.
• the additional therapeutic agent is a compound selected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat, felodipine, nimodipine, Philoxin B, geniestein, Apigenin, cAMP/cGMP augmenters or inducers such as rolipram, sildenafil, milrinone, tadalafil, amrinone, isoproterenol, albuterol, and almeterol, deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors, proteosome inhibitors such as epoxomicin, lactacystin, etc.
• inducers such as rolipram, sildenafil, milrinone, tadalafil, amrinone, isoproterenol, albuterol, and almeterol, deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors, proteosome inhibitors
• the additional therapeutic agent reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., seine proteases, channel-activating proteases).
• Examplary such agents include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-941 1 , INO- 4995, Aerolytic, and amiloride.
• Additional therapeutic agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example in PCT Publication No. WO2009/074575, the entire contents of which are incorporated herein in their entirety.
• modulators such as Compound 1 : triglyceride co-crystals described herein, and agents that reduce the activity of ENaC are used for treating Liddle's syndrome, cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma, respiratory tract infections, lung carcinoma, xerostomia and keratoconjunctivitis sire, respiratory tract infections (acute and chronic; viral and bacterial) and lung carcinoma.
• Combinations of CFTR modulators, such as Compound 1 : triglyceride co- crystals described herein, and agents that reduce the activity of ENaC are also useful for treating diseases mediated by blockade of the epithelial sodium channel also include diseases other than respiratory diseases that are associated with abnormal fluid regulation across an epithelium, perhaps involving abnormal physiology of the protective surface liquids on their surface, e.g., xerostomia (dry mouth) or keratoconjunctivitis sire (dry eye).
• blockade of the epithelial sodium channel in the kidney could be used to promote diuresis and thereby induce a hypotensive effect.
• Chronic obstructive pulmonary disease includes chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular, other inhaled drug therapy.
• the combinations of CFTR modulators, such as Compound 1 triglyceride co-crystals described herein, and agents that reduce the activity of ENaC are useful for the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
• the additional therapeutic agent is a CFTR modulator other than Compound 1 rtriglyceride co-crystals described herein, i.e., an agent that has the effect of modulating CFTR activity.
• Examplary such agents include ataluren ("PTC 124®”; 3-[5-(2-fluorophenyl)-l ,2,4-oxadiazol-3-yl]benzoic acid), sinapultide, lancovutide, depelestat (a human recombinant neutrophil elastase inhibitor), cobiprostone (7- ⁇ (2R, 4aR, 5R, 7aR)-2-[(3S)-l , l-difluoro-3-methylpentyl]-
• the additional therapeutic agent is (3-(6-(l-(2,2-difluorobenzo[d][ l ,3]dioxol-5-yl) cyclopropanecarboxamido)-3- methylpyridin-2-yl)benzoic acid, or (R)- l-(2,2-difluorobenzo[d][ l,3]dioxol-5-yl)-N- (l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yI)-lH-indol-5- yl)cyclopropanecarboxamide.
• the additional therapeutic agent is (3-(6-( l-(2,2-difluorobenzo[d][ l ,3]dioxol-5-yl) cyclopropanecarboxamido)-
• the additional therapeutic agent is (R)- 1 -(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl)-N-( 1 -(2,3-dihydroxypropyl)-6- fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide.
• the additional therapeutic agent is a CFTR modulator other than a compound of the present disclosure.
• compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
• the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50 % to 100 % of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
• Co-crystals of any of the embodiments described above may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
• an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
• the present disclosure in another aspect, includes a composition for coating an implantable device comprising a compound of the present disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
• the present disclosure includes an implantable device coated with a composition comprising a compound of the present disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
• Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121.
• the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
• the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
• the disclosure features a kit comprising a tablet of the present disclosure, and a separate therapeutic agent or pharmaceutical composition thereof.
• the additional therapeutic agent is a CFTR corrector.
• the therapeutic agent is (3-(6-(l-(2,2- difluorobenzo[d][ l ,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2- yl)benzoic acid or (R)- l-(2,2-difluorobenzo[d][l ,3]dioxol-5-yl)-N-(l-(2,3- dihydroxypropyl)-6-fluoro-2-( l -hydroxy-2-methylpropan-2-yl)-l H-indol-5- yl)cyclopropanecarboxamide.
• the therapeutic agent is (3-(6- (l -(2,2-difluorobenzo[d][l ,3]dioxol-5-yl) cyclopropanecarboxamido)-3- methylpyridin-2-yl)benzoic acid.
• the therapeutic agent is (R)- 1 -(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl)-N-( 1 -(2,3-dihydroxypropyl)-6-fluoro-2- (l -hydroxy-2-methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide.
• the tablet and the therapeutic agent are in separate containers.
• the kits of the present disclosure are drawn to kits wherein the compunds or pharmaceutical compositions of the present disclosure and the one or more additional therapeutic agents) are in separate containers.
• the separate containers are bottles.
• the separate containers are vials.
• the separate containers are blister packs.
• the container is a bottle, vial, or blister pack or combination thereof.
• Another aspect of the disclosure relates to modulating CFTR activity in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample co-crystals of any of the embodiments described above (e.g., Compound 1 triglyceride co-crystals described herein) or a pharmaceutically acceptable composition thereof.
• biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
• Modulation of CFTR in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of CFTR in biological and pathological phenomena; and the comparative evaluation of new modulators of CFTR.
• a method of modulating activity of an anion channel in vitro or in vivo comprising the step of contacting said channel with Compound 1 triglyceride co-crystals described herein or a pharmaceutically acceptable composition thereof.
• the anion channel is a chloride channel or a bicarbonate channel. In other embodiments, the anion channel is a chloride channel.
• the present disclosure provides a method of increasing the number of functional CFTR in a membrane of a cell, comprising the step of contacting said cell with co-crystals of any one of the embodiments described above (e.g., Compound 1 triglyceride co-crystals described herein) or a pharmaceutically acceptable composition thereof.
• co-crystals of any one of the embodiments described above (e.g., Compound 1 triglyceride co-crystals described herein) or a pharmaceutically acceptable composition thereof.
• the activity of the CFTR is measured by measuring the transmembrane voltage potential.
• Means for measuring the voltage potential across a membrane in the biological sample may employ any of the known methods in the art, such as optical membrane potential assay or other
• the optical membrane potential assay utilizes voltage-sensitive FRET sensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells.” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997); "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431 -439).
• VIPR Voltage/Ion Probe Reader
• These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor.
• FRET fluorescence resonant energy transfer
• CC2-DMPE fluorescent phospholipid
• Changes in membrane potential (Vm) cause the negatively charged DiSBAC2(3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly.
• the changes in fluorescence emission can be monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
• kits for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo comprising (i) a composition comprising any of the co-crystals of the embodiments described above (e.g., Compound 1 triglyceride co-crystals described herein); and (ii) instructions for a) contacting the composition with the biological sample and b) measuring activity of said CFTR or a fragment thereof.
• the kit further comprises instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and c) comparing the activity of the CFTR in the presence of the additional compound with the density of the CFTR in the presence of co-crystals of any of the embodiments described above (e.g., Compound
• the kit is used to measure the density of CFTR.
• kits for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo comprising:
• composition comprising co-crystals of any of the embodiments described above (e.g., Compound 1 triglyceride co-crystals);
• the kit further comprises instructions for: i. contacting an additional composition with the biological
• the step of comparing the activity of said CFTR, or fragment thereof provides a measure of the density of said CFTR, or fragment thereof
• the reaction mixture was washed with water ( 10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 °C +/- 5 °C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0% w/w.
• the solution was cooled to 20.0 °C +/- 5.0 °C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC.
• Method 1 All pure Compound 1 co-crystals were prepared by slurrying or stirring neat amorphous Compound 1 in neat triglyceride at a 5%-10% weight to volume solids load for at least 18 hours at 40°C or 5°C - 10 °C above the triglyceride melting point in a HEL Polyblock synthesizer. The completion of the conversion was determined by birefringence of the suspended particles with polarized light microscopy. Crude co-crystals were isolated by centrifugal filtration using Millipore 2ml centrifugation devices.
• the mother liquor was collected for preparation of additional Compound 1 co-crystal to increase yield with respect to the triglyceride. This was achieved by slurrying or stirring neat amorphous Compound 1 at a 5%- 10% weight to volume ratio in the mother liquor for at least 18 hours. The mother liquor was used not more than two times for additional conversions. The crude co-crystals of subsequent conversions were combined into 2ml centrifugation devices and heptane was added at a 1.5 to 2 volume to weight ratio. After briefly vortexing of the mixture, the heptane was filtered by centrifugal filtration and the solids collected. Excess heptane was removed by drying in vacuum at 40 to 45°C for at least 18 hours.
• the heptane content was checked periodically by 1H solution state NMR and drying was continued until the heptane was at acceptable levels, e.g., until there was no further decrease in the overlapping triglyceride and heptane CH3 resonance observed.
• Method 2 Approximately 50 mg neat amorphous Compound 1 was added to approximately 1 g triglyceride, heated to 80 °C and kept at this temperature for at least 1 hour. The solution was then cooled to a temperature above the melting point of the triglyceride to crystallize the Compound 1 co-crystal. In order to improve crystal quality and size the system was heated again to 80 °C and cooled down. The temperature cycling was repeated until crystals of suitable size for analysis were obtained. All Compound 1 co-crystals were isolated by centrifugal filtration at temperatures above the melting point of the triglyceride. [00402] Characterization of Compound 1 Co-Crystals
• X-Ray Powder Diffraction (XPRD) Analysis The XRPD patterns were acquired at room temperature in reflection mode using a Pananalytical Empyrean II or a Bruker D8 Advance diffractometer. The powder sample were placed in a
• TPPM15 decoupling sequence was used with the field strength of approximately 100 kHz.
• the relaxation delay was set to 5s in all 13C CPMAS experiments.
• 1H Tl values were measured using a saturation recovery sequence. All spectra were reference externally to the upfield resonance of adamantine at 29.5 ppm. The temperature of the sample was controlled to 275 .
• TGA Thermogravimetric Analysis: Thermal gravimetric analysis (TGA) was conducted on a TA Instruments model Q5000 V3.8 thermogravimetric analyzer. Approximately 5-15 mg of solid sample was placed in a platinum sample pan and heated in a 60 mL/min sample and a 40mL/min balance nitrogen stream at 10°C/min from ambient to 350 °C. All thermograms were analyzed using TA Instruments Universal Analysis 2000 software V4.4A.
• DSC Differential Scanning Calorimetry
• the ratio of integrated intensity for protons in Compound l :glyceryltrioctanoate in the ⁇ NMR spectra indicate a stoichiometry of 3: 1 (Compound 1 triglyceride) in the co-crystal, whereas the integrated intensity of the Compound l :glyceryltrioleate and Compound 1 :glyceryltrilinoleate integrated intensities indicate a 6: 1 (Compound 1 triglyceride) stoichiometry in the respective co-crystals.
• the stoichiometry determined by solution state ⁇ NMR is consistent with the stoichiometry determined by thermogravimetric analysis for the Compound 1 :glyceryltrioctanoate co-crystal.
• Mass Spectrometry Analysis The mass spectrometry analysis was done as outlined for each complex below.
• Single Crystal X-Ray Crystallography The single crystal was prepared by dissolving 56 mg of amorphous Compound 1 in 1000 mg triglyceride in an oven set to 80°C. Upon crystallization, a few crystals were removed for single crystal X-ray analysis. Diffraction data were acquired at ESFR synchrotron source with wavelength 0.70158A at 100K temperature (reference number Phil Pattison 130813). The structure was solved and refined using SHELX program (Sheldrick, G.M., Acta Cryst., (2008) A64, 1 12- 122).
• glyceryltrioctanoate mole ratio based on the weight loss in the material is 1 :3.1.
• DSC for Compound 1 lyceryltrioctanoate:
• thermogram of Compound 1 :glyceryltrioctanoate is shown in Figure 6.
• the thermogram had an endotherm at 186.7°C that corresponds to the melting of the Compound
• Table E and Table F summarize the ⁇ NMR data and assign the Compound 1 and glyceryltrioctanoate hydrogens, respectively.
• the numbering system used for assignment of hydrogens in Compound 1 is as follows:
• glyceryltrioctanoate is as follows:
• thermogram of Compound 1 :glyceryltrioleate is shown in Figure 11.
• the thermogram had an endotherm at 197.5°C that corresponds to the melting of Compound 1 :glyceryltrioleate.
• the error in the endotherm measurement is ⁇ 0.2 °C.
• This endothermic event was followed by an exotherm, corresponding to the crystallization of a neat form of Compound 1.
• Another endotherm corresponding to the melting of this neat form of Compound 1 was observed.
• Another later exothermic recrystallization to a second neat form of Compound 1 was observed.
• a later endotherm corresponds to melting of this second form of Compound 1.
• Table I and Table J summarize the 1H NMR data and assign the Compound 1 and glyceryltrioleate hydrogens, respectively.
• the numbering system used for assignment of hydrogens in Compound 1 was as previously shown above.
• Mass Spectrometry Analysis for Compound l:glyceryltrioleate [00455] The accurate mass of this complex was determined on a Thermo LTQ Orbi Trap XL mass spectrometer. The sample was dissolved to approximately 0.1 mg/ml in MeOH and infused by direct flow injection using a syringe pump at a rate of 50 ⁇ 1/8. 50 scans were collected using the FTMS analyzer at a 30000 resolution setting.
• DSC for Compound l:glyceryltrilinoleate [00470] An examplary DSC thermogram for Compound l :glyceryltrilinoleate is shown in Figure 16.
• the thermogram of Compound l :glyceryltrilinoleate in Figure 16 had an endotherm at 182.3°C that corresponds to the melting of Compound 1 :glyceryltrilinoleate.
• the error in the endotherm measurement is ⁇ 0.2 °C.
• This endothermic event was followed by an exotherm, corresponding to the crystallization of a neat form of Compound 1. Another endotherm corresponding to the melting of this neat form was observed.
• Another later exothermic recrystallization to a second neat form of Compound 1 was observed.
• a later endotherm corresponds to melting of this second form of Compound 1.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Emergency Medicine (AREA)
• Pulmonology (AREA)
• Ophthalmology & Optometry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Quinoline Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (11)

Applications Claiming Priority (2)

Publications (1)

Family

ID=55653742

Family Applications (1)

Country Status (12)

Cited By (25)

Families Citing this family (29)

Citations (5)

Family Cites Families (410)