Search

CN-121985943-A - Solid forms of Fenciclin D-tartrate

CN121985943ACN 121985943 ACN121985943 ACN 121985943ACN-121985943-A

Abstract

Solid forms of (3aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate are disclosed, comprising crystallizing (3aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate (form A of Fenciclin D-tartrate), crystallizing (3aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate dihydrate (form B of Fenciclin D-tartrate) crystalline (3aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate form a (fenciclin D-tartrate form a + pattern C), and amorphous (3aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate salt having peaks of pattern C. Also disclosed are pharmaceutical compositions comprising the form a of the fenpicline D-tartrate, the form B of the fenpicline D-tartrate, the form a of the fenpicline D-tartrate having peaks of the pattern C, and amorphous fenpicline D-tartrate, and methods of treating various conditions by administering these solid forms.

Inventors

  • M. Machigini
  • M. A. Christie
  • V. V. Panecatu
  • C. S. Siddick

Assignees

  • 安诺维斯生物股份有限公司

Dates

Publication Date
20260505
Application Date
20240621
Priority Date
20230621

Claims (20)

  1. 1. A solid form of crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl-carbamate tartrate dihydrate (fenciclin D-tartrate form B).
  2. 2. A solid form of crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate dihydrate (fenciclin D-tartrate form B), characterized by an X-ray powder diffraction pattern having characteristic peaks at 5.16、8.56、10.3、11.24、13.14、13.48、14.66、15.24、15.44、15.76、16.18、16.54、17.48、17.94、18.08、19.72、20.62、20.76、21.22、21.5、22.2、22.54、23.46、24.4、24.72、26.4、26.86、27.14、27.48、27.7、28.52、28.74、29.14、29.96、30.68、31.14、32.3、33.26、35.44、37.24 and 37.74 2Θ.
  3. 3. A solid form of crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate dihydrate (fenciclin D-tartrate form B), characterized by an X-ray powder diffraction pattern having the following characteristic peaks, relative intensities and D-spacing values: 。
  4. 4. the solid form of claim 1, wherein the solid form has the following unit cell information: 。
  5. 5. Substantially pure crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl-carbamate tartrate dihydrate, or as shown by the data herein, form B of the fenpicline D-tartrate with little detectable impurities by analysis as reported herein (e.g., Q-NMR and/or headspace gas chromatography and/or HPLC and/or chiral HPLC), or form B of the fenpicline D-tartrate with a purity of greater than 99.5%, or with a purity of greater than 99.6%, or with a purity of greater than 99.7%, or with a purity of greater than 99.8%, advantageously as determined by one or more of the analyses as reported herein (e.g., Q-NMR and/or headspace gas chromatography and/or HPLC and/or chiral HPLC).
  6. 6. The form B of the fenpicline D-tartrate of any one of claims 1 to 4, wherein the form B of the fenpicline D-tartrate is substantially pure or has little detectable impurity by analysis reported herein (e.g., Q-NMR and/or headspace gas chromatography and/or HPLC and/or chiral HPLC) as shown by data herein, or the form B of the fenpicline D-tartrate has a purity of greater than 99.5%, or has a purity of greater than 99.6%, or has a purity of greater than 99.7%, or has a purity of greater than 99.8%, advantageously as determined by one or more analyses reported herein (e.g., Q-NMR and/or headspace gas chromatography and/or HPLC and/or chiral HPLC).
  7. 7. A process for preparing a substantially pure crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate dihydrate (form B of fencicline D-tartrate), or a process for preparing a form B of fencicline D-tartrate according to claim 5 or 6, comprising preparing a crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate (form a of fencicline D-tartrate) and converting the fencicline D-tartrate form a into a crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl carbamate tartrate dihydrate form B of fencicline D-tartrate, wherein the substantially pure crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl-carbamate tartrate dihydrate (fentanyl D-tartrate form B), i.e., the fentanyl D-tartrate form B is substantially pure or nearly free of detectable impurities by analysis reported herein (e.g., Q-NMR and/or headspace phase chromatography and/or HPLC and/or chiral HPLC) as shown by the data herein, or the fenpicline D-tartrate form B has a purity of greater than 99.5%, or has a purity of greater than 99.6%, or has a purity of greater than 99.7%, or has a purity of greater than 99.8%, advantageously as determined by one or more analyses (e.g., Q-NMR and/or headspace gas chromatography and/or HPLC and/or chiral HPLC) reported herein.
  8. 8. A process for preparing a solid form of crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl-carbamate tartrate dihydrate, which comprises preparing crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl-carbamate tartrate (form a of fenpicline D-tartrate), and converting the fenpicline D-tartrate form a into crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl-carbamate tartrate dihydrate (form B of fenpicline D-tartrate).
  9. 9. A pharmaceutical formulation comprising the solid form of (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl-carbamate tartrate dihydrate of any one of claims 1 to 6 or having been prepared by the process of claim 8 (fenciclin D-tartrate form B) and a pharmaceutically acceptable carrier.
  10. 10. A method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising crystalline (3 aR) -1,3a, 8-trimethyl-1, 2, 3a,8 a-hexahydropyrrolo (2, 3-B) indol-5-yl phenyl-carbamate tartrate dihydrate (fenciclin D-tartrate form B), the fenciclin D-tartrate form B of any one of claims 1 to 6, or prepared by the method of claim 8, and a pharmaceutically acceptable carrier, or the method comprises administering to the subject an effective amount of the pharmaceutical composition of claim 9; Wherein the neurological condition comprises: Chronic neurodegeneration, which includes Alzheimer's disease, frontotemporal dementia, chronic traumatic encephalopathy, tauopathies, parkinson's disease and alpha-synucleinopathies, prion diseases, transmissible Spongiform Encephalopathy (TSE), down's syndrome, huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis or other dementias, and neurodegenerative disorders, which manifest as misfolding, aggregation and accumulation of proteins in the brain, leading to axonal transport disorders, inflammation and eventual cell death, or Acute neurodegeneration, wherein the acute neurodegeneration comprises traumatic brain injury, stroke, cerebral ischemia-induced acute brain injury, cerebral hypoxia-or hypoxia-induced acute brain injury, micro-infarction, concussion-induced acute brain injury, postoperative cognitive decline caused by anesthesia or surgery-induced inflammation, drowning-induced acute brain injury, whipping-related acute brain injury, bicycle collision-related acute brain injury, automobile accident-related brain injury, shaking infant syndrome, fall-induced acute brain injury, head physical impact-related acute brain injury or acute angle-closure glaucoma, or A neuropsychiatric indication, wherein the neuropsychiatric indication comprises depression, schizophrenia, dementia, alzheimer's disease, anxiety or a substance abuse disorder, or Mental disorders including autism, attention deficit hyperactivity disorder, bipolar disorder, depression and major depression, behavioral problems, post-traumatic stress disorder or schizophrenia.
  11. 11. The method of claim 10, wherein the neurological disorder is chronic neurodegeneration.
  12. 12. The method of claim 11, wherein the chronic neurodegeneration comprises alzheimer's disease, frontotemporal dementia, chronic traumatic brain disease, tauopathies, parkinson's disease and alpha-synucleinopathies, prion diseases, transmissible Spongiform Encephalopathy (TSE), down's syndrome, huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis or other dementias, and neurodegenerative disorders that manifest as misfolding, aggregation and accumulation of proteins in the brain, resulting in axonal transport disorders, inflammation, and eventual cell death.
  13. 13. The method of claim 10, wherein the neurological disorder is acute neurodegeneration.
  14. 14. The method of claim 13, wherein the acute neurodegeneration comprises traumatic brain injury, stroke, cerebral ischemia-induced acute brain injury, cerebral hypoxia-or hypoxia-induced acute brain injury, micro-infarction, concussion-induced acute brain injury, post-operative cognitive decline caused by anesthesia or surgery-induced inflammation, drowning-induced acute brain injury, whipping-related acute brain injury, bicycle collision-related acute brain injury, car accident-related brain injury, shaking infant syndrome, fall-induced acute brain injury, head physical impact-related acute brain injury, or acute angle closure glaucoma.
  15. 15. The method of claim 10, wherein the neurological disorder is a neuropsychiatric indication.
  16. 16. The method of claim 15, wherein the neuropsychiatric indication comprises depression, schizophrenia, dementia, alzheimer's disease, anxiety disorders, or a substance abuse disorder.
  17. 17. The method of claim 10, wherein the neurological disorder is a mental disorder.
  18. 18. The method of claim 17, wherein the mental disorder comprises autism, attention deficit hyperactivity disorder, bipolar disorder, depression, and major depression, behavioral problems, post-traumatic stress disorder, or schizophrenia.
  19. 19. The method of any one of claims 10 to 18, wherein the dosage of the form B of the fenhexamine D-tartrate is from about 0.1 mg/kg to about 100 mg/kg of body weight, or wherein the dosage of the form B of the fenhexamine D-tartrate is from about 1 mg/kg to about 20 mg/kg of body weight.
  20. 20. The method of any one of claims 10 to 19, wherein the pharmaceutical composition is administered to the subject daily, or wherein the pharmaceutical composition is administered to the subject once daily.

Description

Solid forms of Fenciclin D-tartrate Related applications and incorporated by reference The present application claims priority from U.S. provisional patent application Ser. No. 63/580,011, filed on 1 month 9 of 2023, and U.S. provisional patent application Ser. No. 63/509,356, filed on 21 month 6 of 2023, the contents of which are incorporated herein by reference in their entirety. Reference is also made to U.S. patent application Ser. No. 10/042,586 (now U.S. patent No. 6,495,700) filed on month 1 and month 9 of 2002, U.S. patent application Ser. No. 10/415,765 (now U.S. patent No. 7,153,882) filed on month 2 and month 4 and day 9 of 2005, U.S. patent application Ser. No. 10/593,179 (now U.S. patent No. 7,625,942), U.S. patent application Ser. No. 12/357,115 (now U.S. patent No. 7,786,162) filed on month 1 and month 21 of 2009, U.S. patent application Ser. No. 12/841,888 (now U.S. patent No. 8,258,172) filed on month 7 and month 22 of 2010, U.S. patent application Ser. No. 13/041,211 (now giving up), U.S. patent application Ser. No. 15/751,337 (now giving up), U.S. patent application Ser. No. 15/937 (now examined) filed on month 3 and month 6 of 2011 and month 4, U.S. patent application Ser. No. 15/937 (now U.S. 10,383,851), U.S. patent application Ser. No. 12/357 (now filed on month 8 and U.S. 1 and 7,2020), U.S. patent application Ser. No. 12/2020,2020 (now filed on month 7 and U.S. No. 7,2020, and U.S. patent application Ser. No. 35 (now on year 9916) filed on year 7 and 7. All documents cited above, as well as all documents cited therein or during prosecution thereof ("application cited documents"), as well as all documents cited or referenced in the application cited documents, as well as all documents cited or referenced herein ("herein cited documents"), as well as any product mentioned herein or any manufacturer's instructions, descriptions, product specifications and product sheets in any document incorporated by reference herein, are hereby incorporated by reference and may be used in the practice of the present invention. More specifically, all references are incorporated by reference to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. Technical Field The present invention relates to solid forms of fentanyl (posiphen), in particular of the salt of fentanyl D-tartrate, pharmaceutical compositions comprising said novel solid forms, and methods of treating and/or preventing various conditions by administering said novel solid forms. Background The solid form (i.e., crystalline or amorphous form) of a pharmaceutical compound may be important with respect to its pharmacological properties and development as a viable active pharmaceutical ingredient ("API"). Pharmaceutical products are typically formulated from crystalline compounds because crystalline materials can provide higher levels of purity and resistance to physical and chemical instability under ambient conditions relative to amorphous forms. In some cases, crystalline forms of a compound may provide advantages over amorphous forms, such as improved solubility, stability, processing improvements, etc., and different crystalline forms (e.g., polymorphs of a compound) may provide more or less advantages over each other. However, the crystalline form of the compound is unpredictable and, in fact, not always possible. The generally accepted principle is that the formation of a new polymorph or crystalline form of a compound (e.g., a new crystalline salt form) is completely unpredictable and that it cannot be known whether it may exist, how it may be prepared, or what its nature may be prior to the preparation of a particular polymorph. Bernstein, J. Polymorphism in Molecular crystals, new York: oxford University Press, 9 (2002). Unlike crystalline solids that have an ordered unit cell array in three dimensions, amorphous forms lack long range order because molecular packing is more random. Thus, amorphous organic compounds tend to have different properties than their crystalline counterparts. For example, amorphous compounds generally have greater solubility than crystalline forms of the same compound. Thus, by way of example only, in pharmaceutical formulations where the crystalline form is poorly soluble, the amorphous form may provide an attractive formulation option. Thus, amorphous APIs can be used to improve physical and chemical properties of a drug, such as dissolution and bioavailability. Solid forms of the compounds, including crystalline and amorphous forms, are of particular interest to the pharmaceutical industry, for example, for those involved in developing suitable dosage forms, if the solid form of the API (e.g., crystalline polymorph form or amorphous form) does not remain unchanged during clinical or stability studies, the exact dosage form used or studied may not be comparable from batch to batch. Furthermore, regulatory authorities require solid form