WO2017120532A1 - Polymorphes d'un sel de phosphate de quinuclidin-4-ylméthyl 4-méthyl-1h-indole-3-carboxylate et leurs utilisations - Google Patents

Polymorphes d'un sel de phosphate de quinuclidin-4-ylméthyl 4-méthyl-1h-indole-3-carboxylate et leurs utilisations Download PDF

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WO2017120532A1
WO2017120532A1 PCT/US2017/012619 US2017012619W WO2017120532A1 WO 2017120532 A1 WO2017120532 A1 WO 2017120532A1 US 2017012619 W US2017012619 W US 2017012619W WO 2017120532 A1 WO2017120532 A1 WO 2017120532A1
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polymorph
indole
quinuclidin
ylmethyl
methyl
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PCT/US2017/012619
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English (en)
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John Sau-Hoi NG
Raymond Ng
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Alpharmagen, Llc
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Publication of WO2017120532A1 publication Critical patent/WO2017120532A1/fr

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    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • polymorphs of a phosphate salt of quinuclidin-4-ylmethyl 4- methyl-lH-indole-3-carboxylate compositions thereof, methods of preparation thereof, and methods of modulating a7-nicotinic acetylcholine receptors and treating neurological disorders using such polymorphs.
  • Nicotinic compounds are reported as being particularly useful for treating a wide variety of central nervous system (CNS) disorders, and a wide variety of compounds that target nicotinic acetylcholine receptors (NAChRs) have been reported to have therapeutic properties.
  • CNS central nervous system
  • NAChRs nicotinic acetylcholine receptors
  • NAChRs characteristic of the CNS have been shown to occur in several subtypes, the most common of which are the ⁇ 4 ⁇ 2 and a7 subtypes. See, for example, Schmitt, Current Med. Chem. 7, 749 (2000).
  • Ligands that interact with the a7 NAChR subtype have been proposed to be useful in the treatment of schizophrenia.
  • Nicotine improves sensory gating deficits in animals and schizophrenics.
  • Blockade of the al NAChR subtype induces a gating deficit similar to that seen in schizophrenia. See, for example, Leonard et al., Schizophrenia Bulletin 22, 431 (1996). Biochemical, molecular, and genetic studies of sensory processing in individuals with the P50 auditory-evoked potential gating deficit suggest that the oc7 NAChR subtype may function in an inhibitory neuronal pathway. See, for example, Freedman et al., Biological Psychiatry 38, 22 (1995).
  • a7 NAChRs have been proposed to be mediators of angiogenesis, as described by Heeschen et al., J. Clin. Invest. 100, 527 (2002), US 6,417,207, US 7,045,534, WO 01/08683 and WO 01/08684. In these studies, inhibition of the a7 subtype was shown to decrease inflammatory angiogenesis. Also, a7 NAChRs have been proposed as targets for controlling neurogenesis and tumor growth (Utsugisawa et al., Molecular Brain Research 106, 88 (2002) and U.S. Patent Application 2002/0016371).
  • the polymorph is Form A of a phosphate salt of the compound of Formula (I), wherein a powder X-ray diffraction pattern for Form A comprises peaks at angles 2-theta of 4.8 ⁇ 0.2, 15.7 ⁇ 0.2, 19.3 ⁇ 0.2, and 20.0 ⁇ 0.2 degrees.
  • the polymorph is Form A of a phosphate salt of the compound of Formula (I), wherein Form A has a powder X-ray diffraction pattern substantially as shown in FIG. 1A or IB.
  • the polymorph is Form A of a phosphate salt of the compound of Formula (I), wherein Form A has a DSC onset endotherm of 259 ⁇ 9 °C.
  • the polymorph is prepared by a process comprising: (A) combining a compound of Formula ( ⁇ ) with phosphoric acid and a solvent to produce a composition comprising the polymorph; or (B) combining a phosphate salt of Formula (I) with a solvent to produce a composition comprising the polymorph, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetone, acetonitrile, and mixtures thereof.
  • the process further comprises removing substantially all of the solvent present in the composition to produce the polymorph.
  • the polymorph is Form A of a phosphate salt of the compound of Formula (I), and the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetone, and mixtures thereof.
  • the phosphate salt is a monophosphate salt.
  • compositions containing a polymorph as described herein, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier In some embodiments, at least 90% by weight of the phosphate salt of the compound of Formula (I) present in the
  • the pharmaceutical composition is present in Form A. In some embodiments, the pharmaceutical composition is formulated for once-daily administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition further contains an additional pharmaceutical agent.
  • a7-nicotinic acetylcholine receptor a7 NAChR
  • the condition is selected from the group consisting of schizophrenia, cognitive symptoms of schizophrenia, attention deficit symptoms of schizophrenia, cognitive deficits associated with schizophrenia, Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, pre-senile dementia, mild cognitive impairment, senile dementia, Parkinson's disease, psychosis, cognitive deficits associated with psychosis, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), a mood disorder, depression anxiety, post-traumatic stress disorder, cognitive deficits associated with a mood disorder, an affective disorder, pain, symptoms associated with pain, inflammation, traumatic brain injury, and Huntington's disease.
  • the condition is selected from the group consisting of schizophrenia, cognitive symptoms of schizophrenia, attention deficit symptoms of schizophrenia, cognitive deficits associated with schizophrenia, Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, and Parkinson's disease.
  • the polymorph or pharmaceutical composition is administered once per day. In some embodiments, the polymorph or pharmaceutical composition is administered orally. In some embodiments, the method further comprises administering to the individual in need thereof an additional pharmaceutical agent, treatment modality, or combination thereof. In some embodiments, the additional pharmaceutical agent, treatment modality, or combination thereof is selected from the group consisting of an acetylcholinesterase inhibitor, an antipsychotic agent, and an NMD A antagonist.
  • compositions comprising an effective amount of any of the polymorphs or pharmaceutical compositions described herein for use in treating or preventing a condition mediated by the a7-nicotinic acetylcholine receptor (a7 NAChR).
  • the composition is used in the manufacture of a medicament for treating or preventing a condition mediated by the a7-nicotinic acetylcholine receptor (cc7 NAChR).
  • the composition is used for treating or preventing a condition mediated by the ct7-nicotinic acetylcholine receptor (a7 NAChR).
  • kits comprising an effective amount of any of the polymorphs or pharmaceutical compositions described herein and instructions for use.
  • a process for preparing any of the polymorphs described herein comprising: (A) combining a compound of Formula (I) with phosphoric acid and a solvent to produce a composition comprising the polymorph; or (B) combining a phosphate salt of Formula (I) with a solvent to produce a composition comprising the polymorph, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetone, acetonitrile, and mixtures thereof.
  • the process further includes removing substantially all of the solvent present in the composition to produce the polymorph.
  • FIGS. 1A and IB show XRPD patterns and FIG. IC shows differential scanning calorimetry and thermographic analysis of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl- 1 H-indole-3 -carboxylate.
  • FIG. 2A shows an XRPD pattern and FIG. 2B shows thermographic analysis of polymorphic Form B of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate.
  • FIG 3A shows an XRPD pattern and FIG. 3B shows differential scanning calorimetry of polymorphic Form C of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate.
  • FIG. 4A shows an XRPD pattern and FIG. 4B shows differential scanning calorimetry of polymorphic Form D of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate.
  • FIG. 5A shows an XRPD pattern and FIG. 5B shows differential scanning calorimetry of polymorphic Form E of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate.
  • FIG 6A shows an XRPD pattern and FIG. 6B shows differential scanning calorimetry of polymorphic Form F of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate.
  • FIG. 7A shows an XRPD pattern and FIG. 7B shows differential scanning calorimetry of polymorphic Form G of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate.
  • FIG. 8A shows an XRPD pattern and FIG. 8B shows differential scanning calorimetry of polymorphic Form H of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate.
  • FIG. 9A shows the HPLC chromatograph of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate treated with 0.3% and 3% H2O2
  • FIG. 9B shows the HPLC chromatograph of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate treated with 30% H2O2.
  • FIG. 10A, FIG. 10B, and FIG. IOC show the XRPD patterns of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate under 30 °C/65% relative humidity, 40 °C/75% relative humidity, and 60 °C conditions, respectively.
  • FIG. 10D shows the XRPD pattern of polymorphic Form A of a phosphate salt of quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate subjected to visible light (intensity of 4,500 lux).
  • FIG 11A, FIG. 11B, and FIG 11C show the HPLC chromatographs of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate when placed in conditions of 30 °C/65% relative humidity, 40 °C/75% relative humidity, and 60 °C, respectively, over one to two weeks.
  • FIG. 11D shows the HPLC pattern of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate subjected to visible light (intensity of 4,500 lux).
  • polymorphs of a phosphate salt of quinuclidin-4-ylmethyl 4- methyl-lH-indole-3-carboxylate also referred to herein as the compound of Formula (I)
  • processes for the preparation of the polymorphs pharmaceutical compositions containing the polymorphs, and methods for treating cognitive decline using the polymorphs described herein.
  • These polymorphs may be useful in the treatment and prevention of conditions mediated by the a7-nicotinic acetylcholine receptor (a7 NAChR).
  • polymorph refers to a particular solid crystalline form of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate or a particular solid crystalline form of a salt, hydrate, or solvate, of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate, as described herein.
  • terapéuticaally effective amount indicates an amount that results in a desired pharmacological and/or physiological effect for the condition.
  • the effect may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for the condition and/or adverse effect attributable to the condition.
  • a partial or complete cure of schizophrenia may be indicated by a clinical improvement of schizophrenia, such as improvement in cognitive impairment.
  • the term "pharmaceutically acceptable carrier,” and cognates thereof, refers to adjuvants, binders, diluents, etc. known to the skilled artisan that are suitable for administration to an individual (e.g., a mammal or non-mammal). Combinations of two or more carriers are also contemplated.
  • the pharmaceutically acceptable carrier(s) and any additional components, as described herein, should be compatible for use in the intended route of administration (e.g., oral, parenteral) for a particular dosage form, as would be recognized by the skilled artisan.
  • the term "pharmaceutical agent” or “additional pharmaceutical agent,” and cognates of these terms, are intended to refer to active agents other than the claimed polymorphs, for example, drugs, which are administered to elicit a therapeutic effect.
  • the pharmaceutical agent(s) may be directed to a therapeutic effect related to the condition that the claimed polymorphs are intended to treat or prevent (e.g., conditions mediated by a7 NAChR, including, but not limited to those conditions described herein (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, ADHD, etc.))., or the pharmaceutical agent may be intended to treat or prevent a symptom of the underlying condition (e.g., promote cognition enhancement, attention, working memory, episodic secondary memory, memory recall, sensory gating, reaction time, immediate and delayed word recall, visual tracking, and word recognition) or to further reduce the appearance or severity of side effects of administering a claimed polymorph.
  • a symptom of the underlying condition e.g., promote cognition enhancement, attention, working memory, episodic secondary memory, memory recall, sensory gating, reaction time, immediate and delayed word recall, visual tracking, and word recognition
  • an individual "in need thereof may be an individual who has been diagnosed with or previously treated for the condition to be treated.
  • the individual in need thereof may also be an individual who is at risk for a condition (e.g., a family history of the condition, life-style factors indicative of risk for the condition, etc.).
  • the individual is a mammal, including, but not limited to, bovine, horse, feline, rabbit, canine, rodent, or primate.
  • the mammal is a primate.
  • the primate is a human.
  • the individual is human, including adults, children, and premature infants.
  • the individual is a non-mammal.
  • the primate is a non-human primate such as chimpanzees and other apes and monkey species.
  • the mammal is a farm animal such as cattle, horses, sheep, goats, and swine; pets such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like.
  • farm animal such as cattle, horses, sheep, goats, and swine
  • pets such as rabbits, dogs, and cats
  • laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like.
  • rodents such as rats, mice, and guinea pigs
  • non-mammals include, but are not limited to, birds, and the like.
  • the term "individual" does not denote a particular age or sex.
  • the individual has been identified as having one or more of the conditions described herein. Identification of the conditions as described herein by a skilled physician is routine in the art and may also be suspected by the individual or others, for example, due to loss of memory in the case of Alzheimer's, exhibiting the symptoms of schizophrenia, etc.
  • the individual has been identified as susceptible to one or more of the conditions as described herein.
  • the susceptibility of an individual may be based on any one or more of a number of risk factors and/or diagnostic approaches appreciated by the skilled artisan, including, but not limited to, genetic profiling, family history, medical history (e.g., appearance of related conditions), lifestyle or habits.
  • treatment or prevention of a condition mediated by the a7 NAChR indicates administering one or more of the polymorphs or compositions discussed herein, with or without additional pharmaceutical agents, in order to reduce, eliminate, and/or prevent either the condition or one or more symptoms of the condition, or to retard the progression of the disease or of one or more symptoms of the condition, or to reduce the severity of the disease or of one or more symptoms of the condition.
  • a salt selection study was conducted on quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate to identify forms of the compound with desirable properties. Suitable properties include one or more of the following: high degree of crystallinity, sharp melting point, thermodynamic stability, and the ability to purge impurities.
  • Quinuclidin-4-ylmethyl 4-methyl- lH-indole-3-carboxylate is a weak base, and therefore a number of acids were screened for formation of salts with desirable properties.
  • Acids screened included hydrochloric acid, fumaric acid, maleic acid, adipic acid, tartaric acid, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, sulfuric acid, and phosphoric acid.
  • no polymorphic salt forms were observed.
  • one or more polymorphic salt forms were observed, but the polymorphic salt forms identified had disadvantages including desolvation prior to melting, polymorphic form transformation, broad endothermal peaks in the differential scanning calorimetry (DSC) thermogram, absence of a pure melting point in the DSC thermogram, or evidence of liquid crystallinity.
  • DSC differential scanning calorimetry
  • the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate exhibited eight different polymorphic forms (Forms A-H).
  • Polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate was selected for development because it has good crystallinity, water solubility and thermal stability.
  • polymorphic Form A of the phosphate salt also demonstrated superior chemical stability.
  • the phosphate Form A of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate is highly crystalline with a sharp melting point, exhibits no solvation/desolvation in crystallization, indicating chemical and solid state stability, has superior solubility in water compared to the free base and many of the salts studied, and is less hygroscopic compared to other salts studied.
  • Polymorphic Form A of the phosphate salt exhibited a pure melting point and demonstrated greater thermal stability than other salt forms, including the fumarate, citrate, maleate, adipate, tartrate, tosylate, besylate, mesylate, sulfate and hydrochloride salt forms.
  • Polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate was determined to the most thermodynamically stable form in the polymorph screening study.
  • polymorphs of a phosphate salt of quinuclidin-4-ylmethyl 4- methyl-lH-indole-3-carboxylate may have properties such as bioavailability and stability under certain conditions that are suitable for medical or pharmaceutical uses.
  • a polymorph of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate may provide the advantages of bioavailability and stability and may be suitable for use as an active agent in a pharmaceutical composition. Variations in the crystal structure of a pharmaceutical drug substance may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, etc.) and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.) of a pharmaceutical drug product. Such variations may affect the methods of preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage forms including tablets and capsules.
  • polymorphs may provide desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and/or process control.
  • polymorphs of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate provide advantages of improving the manufacturing process of an active agent or the stability or storability of a drug product form of the active agent, or having suitable bioavailability and/or stability as an active agent.
  • the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate is a monophosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate.
  • one or more of the polymorphic forms provided may be a hydrate.
  • thermodynamically stable polymorph A slurry test can be performed, for example, by slurrying the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate in various solvents over many hours or days followed by isolation of the product by filtration and determination of polymorphic form by XRPD.
  • Form A is readily formed from slurrying the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate in the following solvent systems: methanol, ethanol, acetone, or aqueous solutions such as > 55% methanol, > 75% ethanol, and >85% ethanol.
  • polymorphic Form A of a phosphate salt of quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate is a monophosphate salt of quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate.
  • Polymorphic Form A may exhibit an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1A or IB.
  • Polymorphic Form A may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 1C.
  • Polymorphic Form A may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 1C.
  • a powder X-ray diffraction pattern for polymorphic Form A may exhibit peaks at angles 2-theta of 4.8 ⁇ 0.2, 15.7 ⁇ 0.2, 19.3 ⁇ 0.2, and 20.0 ⁇ 0.2 degrees.
  • Polymorphic Form A may exhibit a DSC onset endotherm of 259 ⁇ 9 °C ⁇ e.g., 259 ⁇ 5 °C or 259 ⁇ 2 °C).
  • polymorphic Form A has an XRPD pattern displaying at least two, at least three, at least four, at least five, or at least six of the peaks at angles 2-theta with the greatest intensity in the XRPD pattern substantially as shown in FIG. 1A or IB or as provided in Table 1 A or IB. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum. Relative peak intensities and peak assignments can vary within experimental error, such as across samples, for instance as shown in Tables 1 A and 1 B. In some embodiments, peak assignments listed herein, including for polymorphic Form A, can vary by about ⁇ 0.6 degrees, ⁇ 0.4 degrees, ⁇ 0.2 degrees, or ⁇ 0.1 degrees 2-theta.
  • polymorphic Form A has an XRPD pattern comprising peaks at angles 2-theta of 4.8 ⁇ 0.2, 15.7 ⁇ 0.2, 19.3 ⁇ 0.2, and 20.0 ⁇ 0.2 degrees. In certain embodiments, polymorphic Form A has an XRPD pattern comprising peaks at angles 2-th eta of 4.8 ⁇ 0.4, 15.7 ⁇ 0.4, 19.3 ⁇ 0.4, and 20.0 ⁇ 0.4 degrees. In certain embodiments, polymorphic Form A has an XRPD pattern comprising peaks at angles 2-theta of 4.8 ⁇ 0.6, 15.7 ⁇ 0.6, 19.3 ⁇ 0.6, and 20.0 ⁇ 0.6 degrees.
  • polymorphic Form A has an XRPD pattern comprising peaks at angles 2-theta of 4.8 ⁇ 0.2, 15.7 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 20.5 ⁇ 0.2, 23.1 ⁇ 0.2, and 26.0 ⁇ 0.2 degrees.
  • polymorphic Form A has an XRPD pattern comprising peaks at angles 2-theta of 4.8 ⁇ 0.2, 9.6 ⁇ 0.2, 15.7 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 20.5 ⁇ 0.2, 21.0 ⁇ 0.2, 22.3 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 24.4 ⁇ 0.2, 24.7 ⁇ 0.2, 26.0 ⁇ 0.2, and 29.4 ⁇ 0.2 degrees.
  • polymorphic Form A has an XRPD pattern comprising peaks at angles 2-theta of 4.8 ⁇ 0.2, 8.7 ⁇ 0.2, 9.6 ⁇ 0.2, 11.4 ⁇ 0.2, 12.2 ⁇ 0.2, 13.3 ⁇ 0.2, 14.3 ⁇ 0.2, 15.7 ⁇ 0.2, 16.4 ⁇ 0.2, 17.1 ⁇ 0.2, 17.7 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 20.0 ⁇ 0.2, 20.5 ⁇ 0.2, 21.0 ⁇ 0.2, 22.3 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 24.4 ⁇ 0.2, 24.7 ⁇ 0.2, 25.6 ⁇ 0.2, 26.0 ⁇ 0.2, 26.5 ⁇ 0.2, 27.1 ⁇ 0.2, 29.1 ⁇ 0.2, 29.4 ⁇ 0.2, 30.6 ⁇ 0.2, 31.8 ⁇ 0.2, and 34.3 ⁇ 0.2 degrees.
  • polymorphic Form A has a DSC thermogram with an onset endotherm of 259 ⁇ 9 °C, for example, as measured at 10 °C/min ramp.
  • the DSC thermogram may exhibit an endotherm curve at about 262 ⁇ 9 °C.
  • Polymorphic Form A may exhibit a melting point at about 262.10 °C as determined by DSC. This melting point may be followed by decomposition upon further heating.
  • Polymorphic Form A may exhibit a weight loss of about 0.2 to about 0.3% ⁇ e.g., 0.28%) as determined by TGA when heated from ambient temperature to about 120.0 °C and a weight loss of about 0.9 to about 1.0% (e.g., 0.92%) as determined by TGA when heated from about 120.0 °C to about 233.7 °C.
  • Polymorphic Form A has low hygroscopicity and may exhibit weight gains of about 0.4% to about 0.8% (e.g., 0.59%) at about 85% relative humidity and of about 1.4% to about 1.8% (e.g., 1.58%) at about 95% relative humidity, as determined by Dynamic Vapor Absorption (DVS).
  • Polymorphic Form A may be soluble in a variety of solvent conditions. Solubility of polymorphic Form A in 0.1 N HC1 may be about 0.6 to about 1.0, about 0.7 to about 0.9, or about 0.8 mg/mL. Solubility of polymorphic Form A in 0.01 N HC1 may be about 1.2 to about 1.8, about 1.2 to about 1.7, about 1.3 to about 1.6, or about 1.4 to about 1.5 mg/mL. Solubility of polymorphic Form A in phosphate buffered saline (PBS) at pH 2 may be about 1.2 to about 1.8, about 1.2 to about 1.7, about 1.3 to about 1.6, or about 1.4 to about 1.5 mg/mL.
  • PBS phosphate buffered saline
  • Solubility of polymorphic Form A in PBS at pH 4 may be about 1.2 to about 1.8, about 1.2 to about 1.7, about 1.3 to about 1.6, or about 1.4 to about 1.5 mg/mL.
  • Solubility of polymorphic Form A in PBS at pH 6 may be about 1.2 to about 1.8, about 1.2 to about 1.7, about 1.3 to about 1.6, or about 1.4 to about 1.5 mg/mL.
  • Solubility of polymorphic Form A in PBS at pH 8 may be about 0.2 to about 0.8, about 0.2 to about 0.7, about 0.3 to about 0.6, or about 0.4 to about 0.5 mg/mL.
  • Solubility of polymorphic Form A in simulated gastric fluid (SGF) may be about 0.8 to about 1.2, about 0.9 to about 1.1 , or about 1.0 mg/mL.
  • Solubility of polymorphic Form A in fasted state simulated intestinal media (FaSSIF) may be about 0.9 to about 1.5, about 1.0 to about 1.4, about 1.1 to about 1.3, or about 1.2 mg/mL.
  • Solubility of polymorphic Form A in fed state simulated intestinal media (FeSSIF) may be about 1.1 to about 1.6, about 1.2 to about 1.5, or about 1.3 to about 1.4 mg/mL.
  • polymorphic Form A has solubility in one or more solvents in mg/mL ( ⁇ 0.05) substantially as provided in Table 2.
  • polymorphic Form A at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply: (a) polymorphic Form (A) has an XRPD pattern comprising peaks at angles 2-theta of 4.8 ⁇ 0.2, 15.7 ⁇ 0.2, 19.3 ⁇ 0.2, and 20.0 ⁇ 0.2 degrees; (b) polymorphic Form A has an XRPD pattern substantially as shown in FIG. IA or IB; (c) polymorphic Form A has a DSC thermogram substantially as shown in FIG. IC; (d) polymorphic Form A has a TGA graph substantially as shown in FIG.
  • polymorphic Form A has a melting point as determined by DSC at about 262.10 °C;
  • polymorphic Form (A) has a weight loss of about 0.2818% as determined by TGA when heated from ambient temperature to about 120.0 °C and a weight loss of about 0.9220% as determined by TGA when heated from about 120.0 °C to about 233.7 °C;
  • polymorphic Form (A) has weight gains of about 0.59% at about 85% relative humidity and of about 1.58% at about 95% relative humidity as determined by DVS.
  • thermodynamically stable polymorph A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate has been observed to be a thermodynamically stable polymorph.
  • the determination of the thermodynamically stable polymorph can be performed, for example, by subjecting various polymorphic forms of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate described herein to a slurry test.
  • a slurry test can be performed, for example, by slurrying the various polymorphic forms in various solvents over many hours or days until thermodynamic equilibrium is achieved.
  • the final equilibrated product is isolated by filtration and is characterized by XRPD, HPLC, DSC and/or TGA.
  • Polymorphic Form A of the phosphate salt is readily formed from slurrying the phosphate salt of quinuclidin-4-ylmethyl 4- methyl-lH-indole-3-carboxylate in the following solvent systems: methanol, ethanol, acetone, or aqueous solutions such as > 55% methanol, > 75% ethanol, and > 85% isopropanol.
  • polymorphic Form A is the most stable polymorphic form of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate.
  • polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate is more thermodynamically stable than any of polymorphic Forms B-H.
  • polymorphic Form A of the phosphate salt of quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate is physiochemically stable under conditions of elevated temperature and humidity over long periods of time.
  • polymorphic Form A is physiochemically stable at temperatures of up to at least 60 °C, or up to at least 50 °C.
  • polymorphic Form A is physiochemically stable at relative humidities (RH) of up to 75%, up to 65%, or up to 55%.
  • polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate is stable under elevated temperature and humidity conditions for at least 6 months, at least 3 months, at least 1 month, or at least 2 weeks.
  • polymorphic Form A of the phosphate salt of quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate is physiochemically stable when exposed to light over long periods of time. In some embodiments, polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate is stable when exposed to light (e.g., visible light, such as of intensity 4,500 lux) for at least 2 weeks.
  • light e.g., visible light, such as of intensity 4,500 lux
  • polymorphic Forms B-H have properties as described herein. Each of Forms B-H is a monophosphate salt of quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate.
  • polymorphic Forms B-H may be a hydrate.
  • Polymorphic Form B may exhibit an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 2A.
  • Polymorphic Form B may exhibit a thermographic analysis (TGA) graph substantially as shown in FIG. 2B. Angles 2-theta and relative peak intensities that may be observed for Form B using XRPD are shown in Table 3.
  • Polymorphic Form C may exhibit an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 3A.
  • Polymorphic Form C may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 3B.
  • Polymorphic Form C may exhibit a DSC onset exotherm of 207 ⁇ 9 °C.
  • Polymorphic Form C may exhibit a DSC onset endotherm of 259 ⁇ 9 °C.
  • Angles 2-theta and relative peak intensities that may be observed for Form C using XRPD are shown in Table 4.
  • Polymorphic Form D may exhibit an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 4A.
  • Polymorphic Form D may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 4B.
  • Polymorphic Form D may exhibit a DSC onset exotherm of 159 ⁇ 9 °C.
  • Polymorphic Form D may exhibit a DSC onset endotherm of 60 ⁇ 9 °C.
  • Polymorphic Form D may exhibit a DSC onset endotherm of 255 ⁇ 9 °C.
  • Angles 2-theta and relative peak intensities that may be observed for Form D using XRPD are shown in Table 5.
  • Polymorphic Form E may exhibit an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 5A.
  • Polymorphic Form E may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. SB.
  • DSC differential scanning calorimetry
  • Polymorphic Form E may exhibit a DSC onset exotherm of 199 ⁇ 9 °C.
  • Polymorphic Form E may exhibit a DSC onset endotherm of 95 ⁇ 9 °C.
  • Polymorphic Form E may exhibit a DSC onset endotherm of 259 ⁇ 9 °C.
  • Angles 2-theta and relative peak intensities that may be observed for Form E using XRPD are shown in Table 6.
  • Polymorphic Form F may exhibit an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 6A.
  • Polymorphic Form F may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 6B.
  • Polymorphic Form F may exhibit a DSC onset exotherm of 143 ⁇ 9 °C.
  • Polymorphic Form F may exhibit a DSC onset endotherm of 247 ⁇ 9 °C.
  • Angles 2-theta and relative peak intensities that may be observed for Form F using XRPD are shown in Table 7.
  • Polymorphic Form G may exhibit an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 7A.
  • Polymorphic Form G may exhibit a difFerential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 7B.
  • Polymorphic Form G may exhibit a DSC onset exotherm of 194 ⁇ 9 °C.
  • Polymorphic Form G may exhibit a DSC onset endotherm of 75 ⁇ 9 °C.
  • Polymorphic Form G may exhibit a DSC onset endotherm of 249 ⁇ 9 °C.
  • Angles 2-theta and relative peak intensities that may be observed for Form G using XRPD are shown in Table 8.
  • Polymorphic Form H may exhibit an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 8A.
  • Polymorphic Form H may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 8B.
  • Polymorphic Form H may exhibit a DSC onset exotherm of 95 ⁇ 9 °C.
  • Polymorphic Form H may exhibit a DSC onset endotherm of 248 ⁇ 9 °C.
  • Angles 2-theta and relative peak intensities that may be observed for Form H using XRPD are shown in Table 9.
  • compositions containing a polymorph described herein contain at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the polymorphic Forms A-H of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate as described herein.
  • the composition contains polymorphic Form A described herein.
  • the composition contains polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate. In some embodiments, the composition is substantially free of at least one, at least two, at least three, at least four, at least five, at least six, or all of polymorphic Forms B-H of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate. In some embodiments, the composition is substantially free of amorphous forms of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate. In some embodiments, the composition is substantially free of non-salt forms of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate (i.e., free base). In some embodiments, free base.
  • the composition is substantially free of non-phosphate salt forms of quinuclidin-4- ylmethyl 4-methyl - 1 H-indole-3 -carboxylate.
  • the term "substantially free of means that the composition comprising the polymorphic form contains less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the indicated substance or substances.
  • compositions comprising polymorphic Form A at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% by weight of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole- 3-carboxylate present in the composition is present in polymorphic Form A.
  • compositions comprising polymorphic Form A at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% by weight of the total composition is polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate.
  • compositions comprising the polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% by weight of the total composition is impurities (including, without limitation, degradation products, synthetic impurities, by-products or left over reagents from chemical reactions, contaminants, water, and solvents).
  • impurities including, without limitation, degradation products, synthetic impurities, by-products or left over reagents from chemical reactions, contaminants, water, and solvents.
  • the polymorphs and compositions described herein can be in formulations (including pharmaceutical compositions) by formulation with additives such as excipients ⁇ e.g., one or more excipients), antioxidants ⁇ e.g., one or more antioxidants), stabilizers ⁇ e.g., one or more stabilizers), preservatives ⁇ e.g., one or more preservatives), pH adjusting and buffering agents ⁇ e.g., one or more pH adjusting and/or buffering agents), tonicity adjusting agents ⁇ e.g., one or more tonicity adjusting agents), thickening agents ⁇ e.g., one or more thickening agents), suspending agents ⁇ e.g., one or more suspending agents), binding agents ⁇ e.g., one or more binding agents), viscosity-increasing agents ⁇ e.g., one or more viscosity-increasing agents), and the like, provided that the additional components are pharmaceutically acceptable for the particular condition to be
  • the formulation may include combinations of two or more of the additional components as described herein (e.g., 2, 3, 4, 5, 6, 7, 8, or more additional components).
  • the additives include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-P-cyclodextrin,
  • polyvinylpyrrolidinone low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more thereof.
  • suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences,” Mack Pub. Co., New Jersey (1991), and “Remington: The Science and Practice of Pharmacy,” Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005), incorporated herein by reference.
  • Excipient compatibility studies may be performed to ensure stability of the polymorphs with selected excipients or carriers. Excipients may be tested individually or in combinations of two or more excipients or carriers.
  • the composition that contains polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate contains one or more of fillers, disintegrants, flow aids, and lubricants.
  • the composition contains one or more of lactose (e.g., lactose monohydrate), cellulose (e.g., microcrystalline cellulose), crospovidone, silicon dioxide (e.g., colloidal silicon dioxide), and magnesium stearate.
  • the composition contains one or more of lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate.
  • the composition contains one or more of microcrystalline cellulose, pregelatinized starch, lactose monohydrate, anhydrous dicalcium phosphate, colloidal silicon dioxide, povidone,
  • the composition is formulated as a capsule.
  • the composition is substantially free of croscarmellose (e.g., croscarmellose sodium).
  • the composition is substantially free of starch glycolate (e.g., sodium starch glycolate).
  • the composition contains lactose, which may act as a filler.
  • the lactose may be lactose monohydrate. Lactose may have advantages such as widespread usage and acceptance as a pharmaceutical excipient, high solubility, acceptable safety profile, low aldehyde levels (e.g., to avoid cross-linking with gelatin), and low hygroscopicity.
  • Various grades of lactose may be used. A spray-dried grade of lactose having a spherical particle shape may provide desirable flow and compression properties and may assist in powder plug formation and uniform weight control.
  • about 10% to about 90%, about 20% to about 80%, about 30% to about 70%, about 30% to about 50%, about 20% to about 40%, about 40% to about 60%, or about 40% to about 50% by weight of the total composition is lactose. In some embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% by weight of the total composition is lactose.
  • the composition contains cellulose, which may act as a filler (e.g., a secondary filler to the lactose).
  • the cellulose may be microcrystalline cellulose.
  • Microcrystalline cellulose may have advantages such as widespread usage and acceptance as a pharmaceutical excipient and acceptable safety profile.
  • the grade of microcrystalline cellulose may be selected to provide a particle size and shape that complements that found in the lactose grade, allowing for enhanced flow properties and powder plug formation.
  • about 10% to about 90%, about 20% to about 80%, about 30% to about 70%, about 30% to about 50%, about 20% to about 40%, about 40% to about 60%, or about 40% to about 50% by weight of the total composition is cellulose.
  • at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% by weight of the total composition is cellulose.
  • the composition contains crospovidone, which may act as a disintegrant.
  • crospovidone may act as a disintegrant.
  • the water absorption properties of crospovidone may allow for rapid disintegration of a powder plug formed during an encapsulation process.
  • about 0.1% to about 10%, about 0.2% to about 5%, about 0.5% to about 4.0%, about 1% to about 3.0%, about 1.5% to about 2.5%, about 1.0% to about 2.0%, or about 2.0% to about 3.0% by weight of the total composition is crospovidone.
  • the composition contains silicon dioxide, which may act as a flow aid.
  • the silicon dioxide may be colloidal silicon dioxide.
  • Silicon dioxide may have advantages such as widespread usage and acceptance as a pharmaceutical excipient. Silicon dioxide may improve the flow properties of powder blends, especially with higher drug loads, thereby ensuring proper weight control during encapsulation.
  • about 0.01% to about 10%, about 0.05% to about 5.0%, about 0.1% to about 2.0%, about 0.2% to about 1.0%, about 0.1% to about 0.2%, or about 0.2% to about 0.3% by weight of the total composition is silicon dioxide.
  • the composition contains magnesium stearate, which may act as a lubricant.
  • Magnesium stearate may have advantages such as widespread usage and acceptance as a pharmaceutical excipient.
  • Magnesium stearate may have glidant and anti-adherent properties that aid in proper powder manipulation and manufacturability ⁇ e.g., for commercial scale preparation of the composition).
  • about 0.01% to about 10%, about 0.05% to about 5.0%, about 0.1% to about 2.0%, about 0.2% to about 1.0%, about 0.1% to about 0.2%, or about 0.2% to about 0.3% by weight of the total composition is magnesium stearate.
  • the composition contains about 0.5 to about 1.5% by weight polymorphic Form A, about 40% to about 60% by weight lactose monohydrate, about 40% to about 60% by weight microcrystalline cellulose, about 1.0% to about 5.0% by weight crospovidone, about 0.1% to about 1.0% by weight colloidal silicon dioxide, and about 0.1% to about 1.0% by weight magnesium stearate.
  • the composition contains about 1.0 to about 5.0% by weight polymorphic Form A, about 40% to about 60% by weight lactose monohydrate, about 40% to about 60% by weight microcrystalline cellulose, about 1.0% to about 5.0% by weight crospovidone, about 0.1% to about 1.0% by weight colloidal silicon dioxide, and about 0.1% to about 1.0% by weight magnesium stearate.
  • the composition contains about 20% to about 40% by weight polymorphic Form A, about 20% to about 40% by weight lactose monohydrate, about 20% to about 40% by weight
  • microcrystalline cellulose about 1.0% to about 5.0% by weight crospovidone, about 0.1% to about 1.0% by weight colloidal silicon dioxide, and about 0.1% to about 1.0% by weight magnesium stearate.
  • formulations may vary according to the condition to be treated, the amount of compound to be administered, the condition of the individual, and other variables that will readily be apparent to one of ordinary skill in the art in view of the teachings provided herein.
  • the pH of the formulations may be from about 3.5 to about 9.5, or from about 4.5 to about 7.5.
  • Quinuclidin-4-ylmethyl 4-methyl-l H-indole-3-carboxylate and salts thereof may be synthesized through the coupling of a 4-methyl-lH-indole-3-carboxylic acid with a quinuclidin- 4-ylmethanol N-borane complex.
  • the borane complex of the quinuclidin-4-ylmethanol can be prepared from the nitrile by successive treatment with 6 N HC1 and borane-dimethylsulfide.
  • the appropriate indole acid can be transformed into its acid chloride by, for example, reaction of the acid with oxalyl or thionyl chloride.
  • the subsequently formed acid chloride can be coupled with the borane complex of quinuclidin-4-ylmethanol to form the borane complex of the target compound.
  • coupling can be accomplished using common coupling reagents such as ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI). Removal of the borane through acid treatment results in the formation of the salt of the target compound.
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • CDI carbonyl diimidazole
  • Raney nickel treatment of the borane complex can be used to generate the free base form of the target compound.
  • protecting groups may be used to protect certain functional groups from reaction conditions, and that such groups are removed under standard conditions when appropriate.
  • the resultant quinuclidin-4-ylmethyl 4-methyl-l H-indole-3-carboxylate or salt thereof may be characterized using methods generally known in the art (e.g., NMR, mass spectrometry, elemental analysis).
  • Polymorphs of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate and salts thereof can be obtained by techniques known in the art, including solvent recrystallization, desolvation, vapor diffusion, rapid evaporation, slow evaporation, rapid cooling, and slow cooling.
  • polymorphs can be made by dissolving a weighed quantity of quinuclidin-4-ylmethyl 4-methyl-l H-indole-3-carboxylate or a salt thereof (e.g., a phosphate salt) in various solvents at elevated temperatures. The solutions can then be filtered and allowed to evaporate in an open container (for fast hot evaporation) or in a container covered with a lid with holes (for hot slow evaporation). Polymorphs can also be prepared from slurries.
  • Polymorphs can be crystallized from solutions or slurries using several methods. For example, a solution created at an elevated temperature (e.g., 85 °C) can be filtered quickly and then allowed to cool to room temperature. Once at room temperature, any sample that did not crystallize can be moved to a refrigerator and then filtered. Alternatively, the solutions can be crash-cooled by dissolving the solid in a solvent at an increased temperature (e.g., 45-85 °C) followed by cooling in a cryogenic (e.g., -10 to -78 °C) bath.
  • a cryogenic e.g., -10 to -78 °C
  • a method of producing a composition containing one or more polymorphs of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate comprises combining a compound of Formula (I) with phosphoric acid and a suitable solvent or a mixture of suitable solvents to produce a composition containing one or more polymorphs of the phosphate salt of the compound of Formula (I).
  • a method of producing a composition containing one or more polymorphs of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate comprising combining a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate with a suitable solvent or a mixture of suitable solvents.
  • one or more polymorphs precipitate out of solution.
  • the precipitate may be further processed using methods known in the art (e.g., filtration, drying) to obtain the polymorph.
  • the polymorph is obtained from the solution by slurrying or otherwise actively removing solvent. Further processing (e.g., filtration, drying) may be carried out to afford the polymorph.
  • solvents suitable for polymorph formation may include, for example, methanol, ethanol, isopropanol, water, acetone, acetonitrile, and mixtures thereof.
  • Polymorphs of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate or a salt thereof may be characterized using methods generally known in the art (e.g., X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermographic analysis (TGA)).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermographic analysis
  • Quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate may be slurried in solvent such as water or ethanol or a mixture thereof (e.g., 3:1 ethanol/water) for a period of time (e.g., 30 min to 8 hours, 1 hour to 6 hours, 2 hours to 5 hours, or about 4 hours), optionally at elevated temperature (e.g., about 40 to about 120 °C, about 60 to about 100 °C, or about 80 °C).
  • solvent such as water or ethanol or a mixture thereof (e.g., 3:1 ethanol/water)
  • solvent such as water or ethanol or a mixture thereof (e.g., 3:1 ethanol/water)
  • elevated temperature e.g., about 40 to about 120 °C, about 60 to about 100 °C, or about 80 °C.
  • the mixture may be cooled (e.g., to about 0 to about 40 °C, to about 10 to about 30 °C, or to about 10 to about 20 °C) and optionally stirred for a period of time (e.g., 15 min to 4 hours, 30 min to 3 hours, or 1-2 hours) to form a precipitate.
  • the resulting precipitate may be filtered, washed, and dried (e.g., in vacuo and/or at elevated temperature) to afford polymorphic Form A.
  • the amount of free base may be quantified by HPLC, and 1.05 to 1.10 equivalents of phosphoric acid may be added to form polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4- methyl-lH-indole-3-carboxylate at high (e.g., >99%) purity.
  • a method of producing a composition containing polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate comprises combining quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate with phosphoric acid and a solvent to produce a composition containing polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetone, and mixtures thereof.
  • the method further comprises removing substantially all (e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% by weight) of the solvent present in the composition to produce the polymorph.
  • substantially all e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% by weight
  • quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate is dissolved in an alcohol solution, such as isopropanol, and phosphoric acid is added (e.g., in an ethanolic solution).
  • Form A may precipitate from the solution immediately or after a period of time (e.g., 0.25 to 4 hours, 0.5 to 3 hours, or 1-2 hours) and may be collected by filtration and drying (e.g., under vacuum).
  • a period of time e.g. 0.25 to 4 hours, 0.5 to 3 hours, or 1-2 hours
  • One or more of the steps of the method may be carried out at room temperature or at elevated temperature (e.g., 30 to 50 °C).
  • a method of producing a composition containing polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate comprises combining a phosphate salt of quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate with a solvent to produce a composition containing polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetone, and mixtures thereof.
  • the method further comprises removing substantially all (e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% by weight) of the solvent present in the composition to produce the polymorph.
  • substantially all e.g., at least about 50%, at least about 60%, at least about 70%, at least about 80, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% by weight
  • quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate phosphate is dissolved in an alcohol solution, such as isopropanol.
  • Form A may precipitate from the solution immediately or after a period of time (e.g., 0.25 to 4 hours, 0.5 to 3 hours, or 1-2 hours) and may be collected by filtration and drying (e.g., under vacuum).
  • a period of time e.g. 0.25 to 4 hours, 0.5 to 3 hours, or 1-2 hours
  • One or more of the steps of the method may be carried out at room temperature or at elevated temperature (e.g., 30 to 50 °C).
  • the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate is a monophosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate.
  • Form B may be prepared by slurrying Form A in water or aqueous solution, such as ⁇ 50% methanol, ⁇ 65% ethanol, or ⁇ 20% acetone.
  • Form A is suspended in water and shaken at ambient temperature for one or more days (e.g., 4, 5, 6, 7, or 8 days) to produce Form B. Additional processing steps (e.g., filtration, drying) may be carried out to afford Form B.
  • Form C may be prepared by slurrying Form A in 40-95% aqueous acetone solution.
  • Form A is suspended in 95% aqueous acetone solution and shaken at ambient temperature for one or more days (e.g., 4, 5, 6, 7, or 8 days) to produce Form C. Additional processing steps (e.g., filtration, drying) may be carried out to afford Form C.
  • Form D may be prepared by drying Form B, which is a hydrate, to remove the water.
  • Form B may be dried under vacuum, optionally at elevated temperature (e.g., 40-70 °C). The drying may be carried out for at least 1, 2, 4, 8, 12, 18, 24, 36, or 48 hours.
  • Form B is dried at 60 °C under vacuum for 18 hours to afford Form D.
  • Form E may be prepared from Form A by precipitation from a water/acetonitrile antisolvent mixture.
  • Form A is dissolved in water, and acetonitrile is added (e.g., at ambient temperature). The mixture may be stirred. After a period of time (e.g., 15 min, 30 min, 1 hour, 2, hours, 4 hours), the solids may be isolated by filtration and dried (e.g., at ambient temperature).
  • Form F may be obtained from Form A by evaporation from 1 : 1 (v/v)
  • Form A is dissolved in 1 : 1 (v/v) methanol/acetonitrile, and the solvent is allowed to slowly evaporate to afford Form F.
  • Form G may be obtained from Form A by evaporation from 1 : 1 (v/v)
  • Form A is dissolved in 1:1 (v/v) methanol/ethanol, which may be a turbid solution, and the solvent is allowed to slowly evaporate to afford Form G.
  • Form H may be obtained from Form A by evaporation from methanol.
  • Form A is dissolved in methanol, and the solvent is allowed to slowly evaporate to afford Form H.
  • Individuals suffering from certain conditions may be provided with interruption or amelioration of the symptoms of those conditions, by the administration of a formulation containing an active ingredient (e.g., having nicotinic pharmacology) which has a beneficial effect (e.g., upon the functioning of the CNS), but does not provide any significant associated side effects.
  • a formulation containing an active ingredient e.g., having nicotinic pharmacology
  • the polymorphs and compositions provided herein may have advantageous properties such that administration of the polymorph or composition in an amount sufficient to affect the functioning of the CNS would not significantly affect those NAChR subtypes that have the potential to induce undesirable side effects (e.g., appreciable activity at cardiovascular and skeletal muscle receptor sites).
  • polymorphs and compositions may further affect nicotinic receptors but not muscarinic receptors, as the latter are associated with side effects, such as hypersalivation, sweating, tremors, cardiovascular and gastrointestinal disturbances, related to the function of the parasympathetic nervous system.
  • These polymorphs and compositions may further be selective for the a7 NAChR subtype, for the treatment of certain conditions (e.g., schizophrenia, cognitive symptoms of schizophrenia, attention deficit symptoms of schizophrenia, cognitive deficits associated with schizophrenia, Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, and Parkinson's disease).
  • ct7 NAChR may be contacted in any suitable environment or any suitable sample.
  • the a7 NAChR may be contacted in vitro, within a cell, or within an individual (e.g., a mammal, such as a human).
  • in vitro solutions are selected such that the components do not substantially interfere with the a7 NAChR (e.g., aqueous solutions).
  • the in vitro solution includes a biological sample, such as a mammalian sample.
  • a biological sample such as a mammalian sample.
  • mammalian samples include plasma or serum samples and tissue samples, such as a brain biopsy. Any appropriate cell or cellular sample may be selected in which to contact the ot7 NAChR with the polymorph or composition.
  • Exemplary cells include human embryonic kidney (HEK293) cells, HeLa cells, Chinese hamster ovary cells, neuroblastoma line Ml 7 cells, and 293 cells.
  • the polymorphs or compositions provided herein may selectively modulate a7 NAChR.
  • the polymorphs or compositions selectively modulate a7 NAChR activity over other NAChR receptors (e.g., ⁇ 4 ⁇ 2 NAChR).
  • the polymorphs or compositions selectively modulate ⁇ x7 NAChR activity over hERG activity.
  • the polymorphs or compositions selectively modulate ⁇ x7 NAChR activity over 5-HT3 activity.
  • compositions discussed herein may be useful for treatment or prevention of a condition mediated by or characterized by ct7 NAChR.
  • Conditions which can be treated or prevented with the compositions and methods provided herein include, but are not limited to schizophrenia, cognitive symptoms of schizophrenia, attention deficit symptoms of schizophrenia, cognitive deficits associated with schizophrenia, Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, pre-senile dementia, mild cognitive impairment, senile dementia, Parkinson's disease, psychosis, cognitive deficits associated with psychosis, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), a mood disorder, depression, anxiety, post-traumatic stress disorder, cognitive deficits associated with a mood disorder, an affective disorder, pain, symptoms associated with pain, inflammation, traumatic brain injury, and Huntington's disease.
  • ADHD attention deficit hyperactivity disorder
  • the condition to be treated is one or more of schizophrenia, cognitive symptoms of schizophrenia, attention deficit symptoms of schizophrenia, and cognitive deficits associated with schizophrenia.
  • the condition to be treated is Alzheimer's disease and/or neurodegeneration associated with Alzheimer's disease.
  • the condition to be treated is Parkinson's disease.
  • the formulation described herein may be administered in conjunction with one or more of the pharmaceutical agents as described herein and as known in the art, including one or more additional pharmaceutical agents to further reduce the occurrence and/or severity of symptoms and/or clinical manifestations thereof, as well as pharmaceutical agents that treat or prevent the underlying conditions, or in conjunction with (e.g., prior to, concurrently with, or after) additional treatment modalities.
  • the formulations as described herein may be administered before, concurrently with, or after the administration of one or more of the pharmaceutical agents described herein.
  • the polymorphs and compositions described herein may also be administered in conjunction with (e.g., prior to, concurrently with, or after) agents to alleviate the symptoms associated with either the condition or the treatment regimen.
  • the pharmaceutical agent(s) may be an acetylcholinesterase inhibitor (e.g., donepezil, rivastigmine, or galantamine), an antipsychotic agent (e.g.,
  • aripiprazole ziprasidone, zotepine, risperidone, quetiapine, clozapine, thiothixene, thioridazine, loxapine, haloperidol, fluphenazine, or chlorpromazine
  • an NMDA antagonist e.g.,
  • formulations and methods described herein may be used alone or in conjunction with (e.g., prior to, concurrently with, or after) other modes of treatments (e.g., adjunctive therapy with additional pharmaceutical agents described herein with reference to pharmaceutical formulations of the claimed compounds or known to the skilled artisan) used to treat or prevent the condition being treated/prevented and/or administration of an additional treatment modality, or combinations of the foregone).
  • additional pharmaceutical agents as described herein and known to those of skill in the art and/or currently available treatment modalities, including, for example, psychotherapy in the treatment of psychological disorders (e.g., schizophrenia) and occupational therapy (e.g., to assist in the prevention or slow the rate of loss of memory, etc.).
  • additional treatment modality refers to treatment/prevention of the conditions described herein without the use of a pharmaceutical agent (e.g., psychotherapy, occupational therapy, etc.). Where combinations of pharmaceutical agent(s) and/or additional treatment modality(ies) are used, they may be, independently, administered prior to, concurrently with, or after administration of one or more of the polymorphs (or formulation(s) thereof) as described herein.
  • a pharmaceutical agent e.g., psychotherapy, occupational therapy, etc.
  • the formulations described herein will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular condition being treated or prevented.
  • the formulations may be administered therapeutically to achieve therapeutic benefit.
  • therapeutic benefit refers to eradication or amelioration of the underlying condition being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying condition such that the individual reports an improvement in feeling or condition, notwithstanding that the individual may still be afflicted with the underlying condition.
  • Therapeutic benefit also includes halting or slowing the progression of the condition, regardless of whether improvement is realized.
  • the amount of the formulation administered in order to administer an effective amount will depend upon a variety of factors, including, for example, the particular condition being treated, the frequency of administration, the particular formulation being administered, the severity of the condition being treated, the age, weight and general health of the individual being treated, and the adverse effects experienced by the individual being treated, etc. Determination of an effective dosage is within the capabilities of those skilled in the art, particularly in view of the teachings provided herein.
  • Dosages may also be estimated using in vivo animal models.
  • compositions provided herein may be administered enterally (e.g., orally or rectally), parenterally (e.g., sublingually, or inhalation (e.g., as mists or sprays)), or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g., via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue.
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, and infusion techniques.
  • compositions are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration.
  • the route of administration is orally.
  • formulations are suitable for oral administration.
  • the polymorphs and compositions described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms.
  • the compositions can also be administered in liposome formulations.
  • the route of administration may vary according to the condition to be treated. Additional methods of administration are known in the art.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol.
  • a nontoxic parenterally acceptable diluent or solvent for example, as a solution in propylene glycol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such formulations may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
  • compositions provided herein can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present formulations in liposome form can contain, in addition to a compound provided herein, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p. 33 etseq (1976).
  • the frequency and duration of administration of the formulation will depend on the condition being treated, the condition of the individual, and the like.
  • the formulation may be administered to the individual one or more times, for example, 2, 3, 4, 5, 10, 15, 20, or more times.
  • the formulation may be administered to the individual, for example, once a day, 2 times a day, 3 times a day, or more than 3 times a day.
  • the formulation may also be administered to the individual, for example, less than once a day, for example, every other day, every third day, every week, or less frequently.
  • the formulation may be administered over a period of days, weeks, or months.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that the specific dose level for any particular individual will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (BMT), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progression, and severity of the particular disease undergoing therapy.
  • BMT body mass index
  • the pharmaceutical unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, tissues, organs, or other targeted region of the body. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
  • Examples of dosages which can be used are a therapeutically effective amount within the dosage range of about 0.1 ⁇ g/kg to about 300 mg/kg, or within about 1.0 ⁇ g/kg to about 40 mg/kg body weight, or within about 1.0 ⁇ g/kg to about 20 mg/kg body weight, or within about 1.0 ⁇ g/kg to about 10 mg/kg body weight, or within about 10.0 ⁇ g/kg to about 10 mg/kg body weight, or within about 100 ⁇ g/kg to about 10 mg/kg body weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg to about 100 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about 200 mg/kg body weight, or within about 150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg to about 300 mg/kg body weight, or within about 250 mg/kg to about 300 mg/kg body weight.
  • Other dosages which can be used are about 0.01 mg/kg body weight, about 0.1 mg/kg body weight, about 1 mg/kg body weight, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 75 mg/kg body weight, about 100 mg/kg body weight, about 125 mg/kg body weight, about 150 mg/kg body weight, about 175 mg/kg body weight, about 200 mg/kg body weight, about 225 mg/kg body weight, about 250 mg/kg body weight, about 275 mg/kg body weight, or about 300 mg/kg body weight.
  • Polymorphs and compositions provided herein may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.
  • the formulation may be administered, for example
  • the formulation may be administered at a dosage of, for example, from about 0.1 mg per day to about 500 mg per day, from about 0.1 mg per day to about 150 mg per day, from about 1 mg per day to about 50 mg per day, or from about 5 mg per day to about 25 mg per day.
  • the formulation may be administered at a dosage of, for example, from about 0.5 mg per day to about 2000 mg per day, from about 1 mg per day to about 1500 mg per day, from about 5 mg per day to about 1000 mg per day, from about 10 mg per day to about 500 mg per day, or from about 25 mg per day to about 100 mg per day.
  • the additional active agents may generally be employed in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 53rd Edition (1999), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art.
  • PDR Physicians' Desk Reference
  • compositions provided herein and the other therapeutically active agents can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the formulations provided herein may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the individual. When administered in combination with other therapeutically active agents
  • the pharmaceutical agents can be formulated as separate formulations that are given at the same time or different times, or the pharmaceutical agents can be given as a single formulation.
  • the article of manufacture may comprise a container with a label.
  • Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container may hold a formulation having an active agent which is effective in treating or preventing conditions mediated by a7 NAChR.
  • the active agent in the formulation is one or more of the compounds described herein.
  • the label on the container may indicate that the formulation is used for treating or suppressing conditions mediated by a7 NAChR, and may also indicate directions for either in vivo or in vitro use, such as those described above.
  • kits comprising any one or more of the polymorphs or compositions described herein.
  • the kit comprises the container described above.
  • the kit comprises the container described above and a second container comprising a buffer. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods described herein.
  • kits may be used for any of the methods described herein, including, for example, to treat an individual with one or more conditions mediated by or characterized by a7 NAChR, or to suppress one or more conditions mediated by or characterized by a7 NAChR.
  • kits may include a dosage amount of at least one formulation as disclosed herein. Kits may also comprise a means for the delivery of the formulation thereof.
  • kits may include other pharmaceutical agents for use in conjunction with the formulation described herein.
  • the pharmaceutical agent(s) may be one or more anti-psychotic drugs. These agents may be provided in a separate form, or mixed with the compounds described herein, provided such mixing does not reduce the effectiveness of either the pharmaceutical agent or formulation described herein and is compatible with the route of administration.
  • the kits may include additional agents for adjunctive therapy or other agents known to the skilled artisan as effective in the treatment or prevention of the conditions described herein.
  • kits may optionally include appropriate instructions for preparation and administration of the formulation, side effects of the formulation, and any other relevant information.
  • the instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, optical disc or directions to internet-based instructions.
  • kits for treating an individual who suffers from or is susceptible to the conditions described herein comprising a first container comprising a dosage amount of a composition as disclosed herein, and instructions for use.
  • the container may be any of those known in the art and appropriate for storage and delivery of intravenous formulation.
  • the kit further comprises a second container comprising a
  • Kits may also be provided that contain sufficient dosages of the polymorphs described herein (including formulations thereof) to provide effective treatment for an individual for an extended period, such as 1-3 days, 1-5 days, a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.
  • Kits may also include multiple doses of the formulation and instructions for use and may be packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
  • kits may include the composition as described herein packaged in either a unit dosage form or in a multi-use form.
  • the kits may also include multiple units of the unit dose form.
  • a formulation described herein in a unit dose form In certain embodiments are provided a formulation described herein in a unit dose form. In other embodiments a formulation may be provided in a multi-dose form (e.g., a blister pack, etc.).
  • compositions and methods provided herein are illustrated by the following non- limiting examples.
  • ACN acetonitrile
  • CDI acetonitrile
  • each sample between 4° and 40° 2-theta.
  • the step size is 0.05 °C and the scan speed is 0.5 second per step.
  • DSC Differential scanning calorimetry
  • Example J Salt selection study for quinuclidin-4-ylmethyl 4-methyl- lH-indole-3-carboxylate
  • a salt selection study was conducted on quinuclidin-4-ylmethyl 4-methyl- lH-indole-3- carboxylate.
  • Several acids were screened, including hydrochloric acid, fumaric acid, maleic acid, adipic acid, tartaric acid, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, sulfuric acid, and phosphoric acid.
  • the acid salts of quinuclidin-4-ylmethyl 4-methyl- lH-indole- 3-carboxylate were characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and/or thermographic analysis (TGA).
  • a hydrochloride salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate was prepared.
  • the DSC thermogram showed two endothermic peaks with onsets at 120.82 °C and 268.05 °C, and an exothermic peak with an onset at 171 °C.
  • a weight loss of 5.349 % when heated from ambient temperature to 159.36 °C was observed, which was due to volatilization of hydrochloric acid.
  • the solubility of the hydrochloride salt in 0.1 N HC1, 0.01 N HC1, pH 2 PBS, pH 4 PBS, pH 6 PBS, pH 8 PBS, water, SGF, FaSSIF and FeSSIF was 0.728, 1.673, 1.647, 1.623, 1.620, 1.471, 1.640, 1.183, 1.178, and 1.604 mg/mL, respectively.
  • the fumarate salt was observed to have at least 3 forms, and DSC thermograms showed that the endothermal peaks were all broad.
  • the XRPD patterns showed that there were 3 polymorphic forms.
  • the DSC thermograms showed that Form I has a relatively sharp melting in EtOH with a desolvation peak before melting.
  • Form ⁇ had no desolvation peak, however the melting peak of Form ⁇ was not very sharp.
  • the XRPD patterns showed at least 2 forms. No pure melting point was observed for both forms from the DSC results.
  • Form I the thermodynamically stable form, was found to be the ethyl sulfate salt.
  • Polymorphic Form A of the phosphate salt exhibited a melting point at 262.10 °C followed by decomposition, a weight loss of 0.2818% when heated from ambient temperature to 120.0 °C, and a weight loss of 0.9220% when heated from 120.0 °C to 233.7 °C.
  • the phosphate salt was slightly hygroscopic with weight gains of 0.587% at 85% relative humidity and 1.584% at 95% relative humidity.
  • the percentages of elements in the phosphate salt such as carbon, hydrogen, nitrogen, oxygen and phosphorus were 54.31%, 6.295%, 6.98%, 26.144% and 6.271% respectively (Theoretical value: 54.54%, 6.36%, 7.07%, 24.22% , 7.81% respectively).
  • the solubility of polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate in 0.1 N HC1, 0.01 N HC1, pH 2 PBS, pH 4 PBS, pH 6 PBS, pH 8 PBS, water, SGF, FaSSIF and FeSSIF was 0.800, 1.457, 1.463, 1.465, 1.441, 0.483, 1.448, 0.964, 1.202 and 1.354 mg/mL, respectively.
  • Polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate was determined by slurry tests to be the thermodynamically stable polymorph.
  • the method includes slurrying the phosphate salt of quinuclidin-4-ylmethyl 4- methyl-lH-indole-3-carboxylate in various solvents over several hours or days followed by isolation of the product by filtration and determination of polymorphic form by XRPD.
  • Polymorphic Form A of the phosphate salt is readily formed from slurrying the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate in the following solvent systems: methanol, ethanol, acetone, or aqueous solutions such as > 55% methanol, > 75% ethanol, and > 85% isopropanol.
  • solvent systems methanol, ethanol, acetone, or aqueous solutions such as > 55% methanol, > 75% ethanol, and > 85% isopropanol.
  • Example 2 Procedure for preparing a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate
  • Form A was converted to Form B (hydrate form) by slurrying Form A in water and shaking at ambient temperature for 6 days.
  • the XRPD and TGA of Form B are shown in Figures 2A and 2B, respectively.
  • Form C was obtained by slurrying Form A in a 95/5 acetone/water solution and shaking at ambient temperature for 6 days.
  • the XRPD and DSC of Form C are shown in Figures 3A and 3B, respectively.
  • the DSC shows an exothermic peak with onset at 206.99 °C and an endothermic peak with onset at 258.66 °C (melting decomposition).
  • Form D was obtained from Form B by drying Form B at 60 °C under vacuum for 18 hours.
  • the XRPD and DSC of Form D are shown in Figures 4 A and 4B, respectively.
  • the DSC shows an exothermic peak with onset at 159.17 °C and endothermic peaks with onset at 59.80 °C and 254.59 °C (melting decomposition).
  • Form E shows an exothermic peak with onset at 159.17 °C and endothermic peaks with onset at 59.80 °C and 254.59 °C (melting decomposition).
  • Form E was obtained from Form A by precipitation from a water/acetonitrile antisolvent mixture.
  • To a clear solution of 150 mg of quinuclidin-4-ylmethyl 4-methyl-lH- indole-3-carboxylate phosphate (Form A) in water (3 mL) was added 30 mL of acetonitrile. The mixture was stirred for one hour at ambient temperature. The solids were isolated by filtration and allowed to dry at ambient temperature for one hour.
  • the XRPD and DSC of Form E are shown in Figures 5A and 5B, respectively.
  • the DSC shows an exothermic peak with onset at 198.74 °C and endothermic peaks with onset at 94.59 °C and 258.70 °C (melting
  • Form F was obtained by evaporation from 1/1 (v/v) methanol/ acetonitrile.
  • the XRPD and DSC of Form F are shown in Figures 6 A and 6B, respectively.
  • the DSC shows an exothermic peak with onset at 142.63 °C and endothermic peak with onset at 247.31 °C (melting decomposition).
  • Form G was obtained by evaporation from 1/1 (v/v) methanol/ ethanol.
  • the XRPD and DSC of Form F are shown in Figures 7 A and 7B, respectively.
  • the DSC shows an exothermic peak with onset at 193.59 °C and endothermic peaks with onset at 75.45 °C and 249.49 °C (melting decomposition).
  • Form H was obtained by evaporation from methanol.
  • a clear solution of 10 mg of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate phosphate (Form A) in 5.5 mL of methanol was allowed to slowly evaporate to afford Form H.
  • the XRPD and DSC of Form H are shown in Figures 8A and 8B, respectively.
  • the DSC shows an exothermic peak with onset at 95.16 °C and endothermic peak with onset at 247.75 °C (melting decomposition).
  • Example 3 Preparation of qtnnuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate phosphate salt Form A -Method 1
  • the reaction mixture was concentrated under vacuum (0.08 Mpa) at 30-35 °C to about 15-20 L and evaporated at 35 ⁇ 5 °C using a rotary evaporator to remove DCM and oxalyl chloride until an obvious distillate was observed.
  • the reaction mixture was charged with DCM (15.0 kg) and evaporated to dryness, and this charge-evaporate procedure was repeated for two cycles. Fifteen kilograms of DCM was charged to the mixture and stirred to obtain a clear solution, and an additional 15 kg of DCM was charged to the mixture in the rotary evaporator. The solution in the rotary evaporator was transferred to a dropping tank under nitrogen.
  • Step 1 Formation of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate - (mixture ofAl, A2 mid free base)
  • the reaction mixture was concentrated under vacuum (0.08 Mpa) at 30-35 °C to about 15-20 L and evaporated at 35 ⁇ 5 °C using a rotary evaporator to remove DCM and oxalyl chloride until an obvious distillate was observed.
  • the reaction mixture was charged with DCM (15.0 kg) and evaporated to dryness, and this charge-evaporate procedure was repeated for two cycles. Fifteen kilograms of DCM was charged to the mixture and stirred to obtain a clear solution, and an additional 15 kg of DCM was charged to the mixture in the rotary evaporator. The solution in the rotary evaporator was transferred to a dropping tank under nitrogen.
  • Step 2 Formation of crude quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate phosphate salt
  • Step 4 Formation of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate phosphate salt, Form A
  • FIG. 9A shows the HPLC chromatograph of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate treated with 0.3% and 3% H2O2
  • FIG. 9B shows the HPLC chromatograph of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate treated with 30% 3 ⁇ 4(1 ⁇ 4.
  • Table 11 shows the physical stability results of the polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate after being exposed to different conditions.
  • FIG. 10A, FIG. 10B, and FIG. IOC show the XRPD patterns of polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate under 30 °C/65% RH, 40 °C/75% RH, and 60 °C, respectively.
  • FIG. 10A, FIG. 10B, and FIG. IOC show the XRPD patterns of polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3- carboxylate under 30 °C/65% RH, 40 °C/75% RH, and 60 °C, respectively.
  • 10D shows the XRPD pattern of polymorphic Form A of a phosphate salt of quinuclidin-4-ylmethyl 4-methyl- lH-indole-3-carboxylate subjected to visible light (intensity 4,500 lux).
  • FIGs. 11A-D show the HPLC chromatographs of polymorphic Form A of the phosphate salt of quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate when placed in conditions of 30 °C/65% RH, 40 °C/75% RH, 60 °C, and visible light (intensity 4,500 lux), respectively, over one to two weeks.
  • Excipient compatibility studies were performed to ensure chemical stability with selected components.
  • the excipient compatibility study was evaluated by mixing quinuclidin-4- ylmethyl 4-methyl-lH-indole-3-carboxylate phosphate salt (Form A) with each individual excipient.
  • the excipients included microcrystalline cellulose, pregelatinized starch, lactose monohydrate, anhydrous dicalcium phosphate, colloidal silicon dioxide, povidone,
  • Lactose monohydrate was selected as a filler based on its compatibility with quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate phosphate salt (Form A), wide usage, safety, high solubility, low aldehyde levels (to avoid crosslinking with gelatin), and low hygroscopicity.
  • a spray-dried grade was selected based on a spherical particle shape which provides excellent flow and compression properties which assist powder plug formation critical for uniform weight control.
  • Microcrystalline cellulose was selected as a secondary filer based on compatibility with the active agent, wide usage and safety.
  • the grade selected provides particle size and shape, which compliments that found in the lactose grade, allowing for enhanced flow properties and powder plug formation.
  • Crospovidone was primarily selected as a disintegrant based on its compatibility with quinuclidin-4-ylmethyl 4-methyl-lH-indole-3-carboxylate phosphate salt (Form A), as the two other super-disintegrants evaluated during excipient compatibility studies were deemed incompatible.
  • the water absorption properties of crospovidone allow for rapid disintegration of the powder plug formed during the encapsulation process.
  • Colloidal silicon dioxide was selected as a flow aid based on compatibility with the active agent and wide usage. Colloidal silicon dioxide is intended to improve flow properties of powder blends with higher drug loads therefore ensuring proper weight control during encapsulation.
  • Magnesium stearate was selected as a lubricant due to compatibility with the active agent and wide usage. Magnesium stearate' s glidant and anti-adherent properties will be important for proper powder manipulation and manufacturability in future scale up efforts.
  • the quinuclidin-4-ylmethyl 4- methyl-lH-indole-3-carboxylate phosphate salt (Form A)/ microcrystalline cellulose mixture and remaining microcrystalline cellulose were added to a 4 Qt V-Blender and blended.
  • the lactose monohydrate (Foremost Farms, Kerry Biosciences, U.S.A.) was passed through a Comil®, added to the 4 Qt V-Blender and blended.
  • the crospovidone (BASF) and Cab-o-Sil were added to the 4 Qt V-Blender and blended.
  • the magnesium stearate (Brenntag Specialties) was screened, added to the 4 Qt V-Blender, and blended.
  • the capsules (hard gelatin, Capsugel) were filled using Profill 300.
  • Capsules of 1 mg, 5 mg, and 50 mg of quinuclidin-4-ylmethyl 4- methyl-lH-indole-3-carboxylate phosphate salt polymorphic Form A were prepared per equivalent strength of the free base, and Table 12 lists the amount of each component used by weight. Table 12.
  • Embodiment 1 A polymorph of a phosphate salt of a compound of Formula ( ⁇ ):
  • Embodiment 2 The polymorph of embodiment 1, wherein the polymorph is Form A, wherein a powder X-ray diffraction pattern for Form A comprises peaks at angles 2-theta of 4.8 ⁇ 0.2, 15.7 ⁇ 0.2, 19.3 ⁇ 0.2, and 20.0 ⁇ 0.2 degrees.
  • Embodiment 3 The polymorph of embodiment 1, wherein the polymorph is Form A, wherein Form A has a powder X-ray diffraction pattern substantially as shown in FIG. 1A or IB.
  • Embodiment 4 The polymorph of embodiment 1, wherein the polymorph is Form A, wherein Form A has a DSC onset endotherm of 259 ⁇ 9 °C.
  • Embodiment S The polymorph of any one of embodiments 1-4, prepared by a process comprising:
  • the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetone, acetonitrile, and mixtures thereof.
  • Embodiment 6 The polymorph of embodiment 5, wherein the process further comprises removing substantially all of the solvent present in the composition to produce the polymorph.
  • Embodiment 7 The polymorph of embodiment 5 or 6, wherein the polymorph is Form A, and the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetone, and mixtures thereof.
  • Embodiment 8 A polymorph of a phosphate salt of a compound of Formula (I):
  • Embodiment 9 The polymorph of any one of embodiments 1-8, wherein the phosphate salt is a monophosphate salt.
  • Embodiment 10. A pharmaceutical composition comprising a polymorph of any one of embodiments 1-9, and a pharmaceutically acceptable carrier.
  • Embodiment 11 The pharmaceutical composition of embodiment 10, wherein at least 90% by weight of the phosphate salt of the compound of Formula (I) present in the pharmaceutical composition is present in Form A, as defined in any one of embodiments 2-4.
  • Embodiment 12 The pharmaceutical composition of embodiment 10 or 11, wherein the pharmaceutical composition is formulated for once-daily administration.
  • Embodiment 13 The pharmaceutical composition of any one of embodiments 10-12, wherein the pharmaceutical composition is formulated for oral administration.
  • Embodiment 14 The pharmaceutical composition of any one of embodiments 10-13, further comprising an additional pharmaceutical agent.
  • Embodiment 15 A method for treating or preventing a condition mediated by the a7- nicotinic acetylcholine receptor (a7 NAChR), comprising administering to an individual in need thereof an effective amount of a polymorph of any one of embodiments 1-9 or a pharmaceutical composition of any one of embodiments 10-14.
  • a7 NAChR a7- nicotinic acetylcholine receptor
  • Embodiment 16 The method of embodiment 15, wherein the condition is selected from the group consisting of schizophrenia, cognitive symptoms of schizophrenia, attention deficit symptoms of schizophrenia, cognitive deficits associated with schizophrenia, Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, pre-senile dementia, mild cognitive impairment, senile dementia, Parkinson's disease, psychosis, cognitive deficits associated with psychosis, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), a mood disorder, depression anxiety, post-traumatic stress disorder, cognitive deficits associated with a mood disorder, an affective disorder, pain, symptoms associated with pain, inflammation, traumatic brain injury, and Huntington's disease.
  • Embodiment 17 The method of embodiment 15, wherein the condition is selected from the group consisting of schizophrenia, cognitive symptoms of schizophrenia, attention deficit symptoms of schizophrenia, cognitive deficits associated with schizophrenia, Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, and Parkinson's disease.
  • Embodiment 18 The method of any one of embodiments 15-17, wherein the polymorph or pharmaceutical composition is administered once per day.
  • Embodiment 19 The method of any one of embodiments 15-18, wherein the polymorph or pharmaceutical composition is administered orally.
  • Embodiment 20 The method of any one of embodiments 15-19, further comprising administering to the individual in need thereof an additional pharmaceutical agent, treatment modality, or combination thereof.
  • Embodiment 21 The method of embodiment 20, wherein the additional pharmaceutical agent, treatment modality, or combination thereof is selected from the group consisting of an acetylcholinesterase inhibitor, an antipsychotic agent, and an NMD A antagonist.
  • Embodiment 22 A composition comprising an effective amount of a polymorph of any one of embodiments 1-9 or a pharmaceutical composition of any one of embodiments 10-14 for use in treating or preventing a condition mediated by the a7-nicotinic acetylcholine receptor (a7 NAChR).
  • a7 NAChR a7-nicotinic acetylcholine receptor
  • Embodiment 23 Use of a composition comprising an effective amount of a polymorph of any one of embodiments 1-9 or a pharmaceutical composition of any one of embodiments 10-14 in the manufacture of a medicament for treating or preventing a condition mediated by the a7- nicotinic acetylcholine receptor (oc7 NAChR).
  • oc7 NAChR a7- nicotinic acetylcholine receptor
  • Embodiment 24 Use of a composition comprising an effective amount of a polymorph of any one of embodiments 1-9 or a pharmaceutical composition of any one of embodiments 10-14 for treating or preventing a condition mediated by the a7-nicotinic acetylcholine receptor (ct7 NAChR).
  • ct7 NAChR a7-nicotinic acetylcholine receptor
  • Embodiment 25 A kit comprising an effective amount of a polymorph of any one of embodiments 1-9 or a pharmaceutical composition of any one of embodiments 10-14 and instructions for use.
  • Embodiment 26 A process for preparing a polymorph of any one of embodiments 1-9 comprising:
  • the solvent is selected from the group consisting of methanol, ethanol, isopropanol, water, acetone, acetonitrile, and mixtures thereof.
  • Embodiment 27 The process of embodiment 26, further comprising removing substantially all of the solvent present in the composition to produce the polymorph.

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Abstract

L'invention concerne un sel de phosphate de quinuclidin-4-ylméthyl 4-méthyl-1H-indole-3-carboxylate, en particulier la forme A polymorphe, un procédé de préparation dudit sel, en particulier la forme A polymorphe, et une composition pharmaceutique contenant ledit sel.
PCT/US2017/012619 2016-01-08 2017-01-06 Polymorphes d'un sel de phosphate de quinuclidin-4-ylméthyl 4-méthyl-1h-indole-3-carboxylate et leurs utilisations WO2017120532A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009046025A1 (fr) * 2007-10-01 2009-04-09 Comentis, Inc. Dérivés de quinuclidine substitué en position 4, procédés de production et utilisations pharmaceutiques de ceux-ci
WO2016007630A1 (fr) * 2014-07-11 2016-01-14 Alpharmagen, Llc Composés de quinuclidine pour moduler l'activité du récepteur nicotinique alpha7 de l'acétylcholine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009046025A1 (fr) * 2007-10-01 2009-04-09 Comentis, Inc. Dérivés de quinuclidine substitué en position 4, procédés de production et utilisations pharmaceutiques de ceux-ci
WO2016007630A1 (fr) * 2014-07-11 2016-01-14 Alpharmagen, Llc Composés de quinuclidine pour moduler l'activité du récepteur nicotinique alpha7 de l'acétylcholine

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Title
BALBACH, S. ET AL.: "Pharmaceutical evaluation of early development candidates ''the 100 mg-approach", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 275, no. 1-2, 2004, pages 1 - 12, XP055263513 *
CAIRA, M. R. ET AL.: "Crystalline Polymorphism of Organic Compounds", DESIGN OF ORGANIC SOLIDS, vol. 198, 1998, pages 164 - 208 *
SINGHAL, D. ET AL.: "Drug polymorphism and dosage form design: a practical perspective", ADVANCED DRUG DELIVERY REVIEWS, vol. 56, no. 3, 2004, pages 335 - 347, XP055069199 *

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