Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
• • 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
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/10—Separation; Purification; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to solid forms comprising stereomerically pure (-)-
• O-desmethylvenlafaxine including salts thereof, compositions comprising the solid forms, methods of making the solid forms and methods of their use for the treatment of various diseases and/or disorders.
• Each pharmaceutical compound has an optimal therapeutic blood concentration and a lethal concentration.
• the bioavailability of the compound determines the dosage strength in the drug formulation necessary to obtain the ideal blood level. If the drug can crystallize as two or more crystal forms differing in bioavailability, the optimal dose will depend on the crystal form present in the formulation. Some drugs show a narrow margin between therapeutic and lethal concentrations.
• Chloramphenicol-3-palmitate (CAPP) for example, is a broad-spectrum antibiotic known to crystallize in at least three polymorphic crystal forms and one amorphous form. The most stable form, A, is marketed.
• New solid forms of a pharmaceutical agent can further the development of formulations for the treatment of illnesses.
• solid forms of salts of a compound are known in the pharmaceutical art to affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, fractability, and compressibility of the compound as well as the safety and efficacy of drug products based on the compound (see, e.g., Byrn, S. R., Pfeiffer, R. R., and Stowell, J.G. (1999) Solid-State Chemistry of Drugs, 2nd ed., SSCI, Inc.: West Lafayette, IN).
• a solid form comprising a salt or free base of a compound with optimal physical and chemical properties will advance the development of the compound as a pharmaceutical.
• Useful physical and chemical properties include: reproducible preparation, non-hygroscopicity, aqueous solubility, stability to visible and ultraviolet light, low rate of degradation under accelerated stability conditions of temperature and humidity, low rate of isomerization of between isomeric forms, and safety for long-term administration to humans. Crystallinity is often desirable, although in some instances enhanced dissociation profiles may be attained via preparation of an amorphous form.
• O-desmethylvenlafaxine chemically named 1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]cyclohexanol, is a metabolite of the compound venlafaxine, a hydrochloride salt of which is currently commercially available under the trade name Effexor ® .
• Effexor ® which is a racemic mixture of the (+) and (-) enantiomers of venlafaxine, is indicated for the treatment of depression.
• Racemic O-desmethylvenlafaxine has been exemplified as a fumarate salt in U.S. Patent No. 4,535,186, and a succinate and formate salts were disclosed in U.S.
• Patent Nos. 6,673,838 and 7,001 ,920 respectively.
• Stereomerically pure (-)-O-desmethylvenlafaxine and its pharmaceutically acceptable salts have been disclosed in U.S. Patent Nos. 6,342,533 B1 , 6,441 ,048 B1 and 6,911 ,479 B2.
• the present invention provides novel solid forms, including amorphous forms and crystal forms, comprising (-)-O-desmethylvenlafaxine and salts thereof, having particular utility for the treatment, prevention or management of conditions and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome,
• affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder,
• the solid forms are crystal forms, including polymorphs, of salts of the invention.
• the invention also encompasses both hydrous and anhydrous crystal forms comprising (-)-O-desmethylvenlafaxine and salts thereof.
• the storage stability, compressibility, bulk density or dissolution properties of the solid forms are believed to be beneficial for manufacturing, formulation and bioavailability of (-)-O-desmethylvenlafaxine and salts thereof.
• the invention provides pharmaceutical compositions comprising the solid forms and methods of their use for the treatment, prevention and/or management of conditions and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and neuropathic pain, cerebral function disorders, senile dementia, memory loss, amnesia/amnestic syndrome; disturbances of consciousness, coma, speech disorders, Lennox syndrome, autism, hyperkinetic syndrome, schizophrenia, migraine, obesity and
• the compounds and compositions of the invention are used to treat, prevent and/or manage the above-described conditions and disorders while reducing or avoiding adverse effects including, but not limited to, sustained hypertension,
• LAI-2932341vl headache asthenia, sweating, nausea, constipation, somnolence, dry mouth, dizziness, insomnia, nervousness, anxiety, blurred or blurry vision, and abnormal ejaculation/orgasm or impotence in males.
• the present invention provides crystalline salts of (-)-O- desmethylvenlafaxine. In other embodiments, the present invention provides crystalline hydrochloride salts of (-)-O-desmethylvenlafaxine. In certain embodiments, crystalline hydrochloride salts of (-)-O-desmethylvenlafaxine possess unexpected excellent properties, described in detail below. In certain embodiments, the present invention provides polymorphs of the hydrochloric acid salts of (-)-O-desmethylvenlafaxine. In certain embodiments, the present invention provides solvates of the hydrochloride salts of (-)-O-desmethylvenlafaxine.
• the present invention provides polymorphs of solvates of the hydrochloride salts of (-)-O-desmethylvenlafaxine. In certain embodiments, the present invention provides hydrates of the hydrochloride salts of (-)-O-desmethylvenlafaxine. In certain embodiments, the present invention provides polymorphs of hydrates of the hydrochloride salts of (-)-O- desmethylvenlafaxine. In certain embodiments, the present invention provides amorphous salts of (-)-O-desmethylvenlafaxine. In certain embodiments, the present invention provides amorphous hydrochloride salts of (-)-O-desmethylvenlafaxine.
• the present invention provides pharmaceutical compositions comprising a crystal form, a crystalline salt form, a polymorph of a salt form, a solvate of a salt form, a hydrate of a salt form or an amorphous salt form of the invention and/or a
• the present invention further provides methods for the treatment, prevention and/or management of one or more of the following conditions or disorders: affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and neuropathic pain, cerebral function disorders, senile dementia, memory loss, amnesia/amnestic syndrome; disturbances of consciousness, coma, speech disorders, Lennox syndrome
• affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity,
• the present invention also provides methods for the treatment, prevention and/or management of conditions and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and neuropathic pain, cerebral function disorders, senile dementia, memory loss, amnesia/amnestic syndrome; disturbances of consciousness, coma, speech disorders, Lennox syndrome, autism, hyperkinetic syndrome, schizophrenia, migraine, obesity and weight gain, incontinence, chronic fatigue syndrome, sleep
• LAI-2932341vl treatment, prevention or management a /or and prophylactically effective amount of a solid form of the invention is a /or and prophylactically effective amount of a solid form of the invention.
• the present invention provides methods of making, isolating and/or characterizing the solid forms of the invention.
• the novel solid forms of the invention are useful as active pharmaceutical ingredients for the preparation of formulations for use in animals or humans.
• the present invention encompasses the use of these solid forms as a final drug product.
• the solid forms, including crystal forms, amorphous forms and final drug products of the invention are useful, for example, for the treatment, prevention or management of conditions and disorders listed above.
• FIG. 1 provides a thermal gravimetric analysis thermogram of a sample comprising Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 2 provides a differential scanning calorimetry thermogram of a sample comprising Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 3 provides an X-ray powder diffraction pattern of a sample comprising Form
• FIG. 4 provides an infrared spectrum of a sample comprising Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 5 provides a Raman spectrum of a sample comprising Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 6 provides a moisture sorption isotherm of a sample comprising Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 7 provides the asymmetric unit of the crystal structure of Form A obtained by single-crystal X-ray diffraction on a sample comprising Form A of the hydrochloride salt of (-)-O- desmethylvenlafaxine;
• FIG. 8 provides an X-ray powder diffraction pattern simulated from single crystal
• FIG. 9 provides a thermal gravimetric analysis thermogram of a sample comprising Form B of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 10 provides a differential scanning calorimetry thermogram of a sample comprising Form B of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 11 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 12 provides an infrared spectrum of a sample comprising Form B of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 13 provides a Raman spectrum of a sample comprising Form B of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 14 provides a moisture sorption isotherm of a sample comprising Form B of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 15 provides a thermal gravimetric analysis thermogram of a sample comprising Form C of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 16 provides a differential scanning calorimetry thermogram of a sample comprising Form C of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 17 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 18 provides an infrared spectrum of a sample comprising Form C of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 19 provides a Raman spectrum of a sample comprising Form C of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 20 provides a moisture sorption isotherm of a sample comprising Form C of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 21 provides a thermal gravimetric analysis thermogram of a sample comprising Form D of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 22 provides a differential scanning carlorimetry thermogram of a sample comprising Form D of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 23 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 24 provides a thermal gravimetric analysis thermogram of a sample comprising Form E of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 25 provides a differential scanning calorimetry thermogram of a sample comprising Form E of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 26 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 27 provides an infrared spectrum of a sample comprising Form E of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 28 provides a Raman spectrum of a sample comprising Form E of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 29 provides a moisture sorption isotherm of a sample comprising Form E of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 30 provides a thermal gravimetric analysis thermogram of a sample comprising Form F of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 31 provides a differential scanning calorimetry thermogram of a sample comprising Form F of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 32 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 33 provides an X-ray powder diffraction pattern simulated from single crystal
• FIG. 34 provides an infrared spectrum of a sample comprising Form F of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 35 provides a Raman spectrum of a sample comprising Form F of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 36 provides moisture sorption isotherm of a sample comprising Form F of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 37 provides the asymmetric unit of the crystal structure of Form F obtained by single-crystal X-ray diffraction on a sample comprising Form F of the hydrochloride salt of (-)-
• FIG. 38 provides a thermal gravimetric analysis thermogram of a sample comprising Form G of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 39 provides a differential scanning calorimetry thermogram of a sample comprising Form G of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 40 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 41 provides a moisture sorption isotherm of a sample comprising Form G of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 42 provides a thermal gravimetric analysis thermogram of a sample comprising Form H of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 43 provides a differential scanning calorimetry thermogram of a sample comprising Form H of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 44 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 45 provides a thermal gravimetric analysis thermogram of a sample comprising Form I of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 46 provides a differential scanning calorimetry thermogram of a sample comprising Form I of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 47 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 48 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 49 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 50 provides an X-ray powder diffraction pattern simulated from single crystal
• FIG. 51 provides a thermal gravimetric analysis thermogram of a sample comprising Form L of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 52 provides a differential scanning calorimetry thermogram of a sample comprising Form L of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 53 provides an X-ray powder diffraction pattern of a sample comprising
• FIG. 54 provides an X-ray powder diffraction pattern of a sample comprising a desolvated solvate belonging to isostructural family 1 of the hydrochloride salt of (-)-O- desmethylvenlafaxine;
• FIG. 55 provides a thermal gravimetric analysis thermogram of a sample comprising an amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 56 provides a modulated differential scanning calorimetry thermogram of a sample comprising an amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 57 provides an X-ray powder diffraction pattern of a sample comprising an amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine;
• FIG. 58 provides a moisture sorption isotherm of a sample comprising an amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine.
• the term (-)-O-desmethylvenlafaxine means the compound that is chemically named (-)-1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl] cyclohexanol.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable, relatively non-toxic acids, including inorganic acids and organic acids.
• Suitable acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carbonic, citric, dihydrogenphosphoric, ethenesulfonic, fumaric, galactunoric, gluconic, glucuronic, glutamic, hydrobromic, hydrochloric, hydriodic, isobutyric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, monohydrogencarbonic, monohydrogenphosphoric, monohydrogensulfuric, mucic, nitric, pamoic, pantothenic, phosphoric, phthalic, propionic, suberic, succinic, sulfuric, tartaric, toluenesulfonic, including p-toluenesulfonic /n-toluenesulfonic and o-toluenesulfonic acids, and the like (see, e.g., Berge et
• salts of other relatively non-toxic compounds that possess acidic character including amino acids, such as arginine and the like, and other compounds, such as aspirin, ibuprofen, saccharin, and the like.
• Particularly preferred are hydrochloric, hydrobromic, methanesulfonic, and sulfuric acids, and most particularly preferred is the hydrochloride salt.
• Acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. As solids, salts can exist in crystalline and/or amorphous modifications.
• hydrochloride salts include “hydrochloride salts,” “hydrochloric acid salts,” and “HCI salts” of (-)-O-desmethylvenlafaxine of the invention.
• a hydrochloride salt, hydrochloric acid salt or HCI salt is an acid addition salt formed using hydrochloric acid.
• solid forms and related terms used herein, unless otherwise specified, refers to crystal forms and amorphous forms comprising (-)-O-desmethylvenlafaxine, and specifically includes crystal forms and amorphous forms comprising salts of (-)-O- desmethylvenlafaxine.
• LAI-2932341vl The term "crystalline" and related terms used herein, when used to describe a substance, component or product, means that the substance, component or product is crystalline as determined by X-ray diffraction. See, e.g., Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23 rd ed., 1843-1844 (1995).
• crystal forms and related terms herein refers to the various crystalline modifications of a given substance, including, but not limited to, polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. Crystal forms of a substance can be obtained by a number of methods, as known in the art.
• Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
• additives such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
• polymorphs refer to two or more crystal forms that are composed of the same molecule, molecules or ions. Different polymorphs may have different physical properties such as, forexample, melting temperatures, heats of fusion, solubilities, dissolution rates and/or vibrational spectra as a result of the arrangement or conformation of the molecules or ions in the crystal lattice (see, e.g., Byrn, S. R., Pfeiffer, R.R., and Stowell, J.G. (1999) Solid-State Chemistry of Drugs, 2nd ed., SSCI, Inc.: West Lafayette, IN).
• differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
• chemical reactivity e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
• mechanical changes e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph
• both e.g., tablets of one polymorph are more susceptible to breakdown at high humidity.
• polymorphic transitions may result in lack of potency or, at the other extreme, toxicity.
• the physical properties of the crystal may be important in processing, for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (i.e., particle shape and size distribution might be different between polymorphs).
• solvate and "solvated,” as used herein, refer to a crystal form of a substance which contains solvent.
• hydrate and “hydrated” refer to a solvate wherein the solvent is water.
• Polymorphs of solvates refers to the existence of more than one crystal form for a particular solvate composition.
• polymorphs of hydrates refers to the existence of more than one crystal form for a particular hydrate composition.
• desolvated solvate refers to a crystal form of a substance which can be prepared by removing the solvent from a solvate.
• isostructural family refers to a series of two or more crystal forms of a substance which have a common structural similarity, including approximately similar interplanar spacing in the crystal lattice. (A more detailed account of crystal lattices can be found in Chapters 2 and 3 of Stout and Jensen, X-Ray Structure Determination: A Practical Guide, MacMillan Co., New York (1968)). Due to their common structural similarity, members of an isostructural family of crystal forms typically have similar, but not necessarily identical, X-ray powder diffraction patterns. An isostructural family may be based upon a substance that is a neutral molecule, a salt or a molecular complex.
• the series may be composed of solvates, including hydrates, and desolvated solvate crystal forms of the substance.
• Solvated members of an isostructural family of crystal forms typically contain one or more solvents, including water, in the crystal lattice.
• the solvent or solvents in the crystal lattice may be the solvent or solvents of crystallization used in preparing the crystal form.
• Typical solvents of crystallization include water and all classes of organic and other types of laboratory solvents, including, but not limited to: alcohols, such as methanol, ethanol, n-propanol, isopropanol, ⁇ -butanol, sec-butanol, f-butanol, hydroxyphenyl, glycerol, and the like; carbonyl-containing solvents, such as acetone, methyl ethyl ketone, formic acid, acetic acid, ethyl acetate, butyl acetate, ⁇ /, ⁇ /-dimethylformamide, and the like; hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene, xylenes, and the like; halogenated solvents, such as dichlormethane, chloroform, carbon tetrachloride, and the like; and laboratory solvents containing other heteroatoms and/or
• amorphous means that the material, substance, component or product under consideration is not crystalline as determined by X-ray diffraction.
• Amorphous forms of a substance can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, cryo-grinding and freeze drying.
• Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X- ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state NMR, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies.
• TGA thermal gravimetric analysis
• DSC differential scanning calorimetry
• XRPD X- ray powder diffractometry
• IR infrared
• Raman spectroscopy e.g., Raman spectroscopy
• solid-state NMR e.g., optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis
• a numeric value or range of values which is provided to describe a particular solid form e.g., a specific temperature or temperature range, such as, for example, that describing a melting, dehydration, desolvation or glass transition; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form.
• the term “stereomerically pure” means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
• a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
• a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
• a stereomerically pure compound comprises greater than about 80 percent by weight of one
• LAI-2932341vl stereoisomer of the compound and less than about 20 percent by weight of other stereoisomers of the compound greater than about 90 percent by weight of one stereoisomer of the compound and less than about 10 percent by weight of the other stereoisomers of the compound, greater than about 95 percent by weight of one stereoisomer of the compound and less than about 5 percent by weight of the other stereoisomers of the compound, greater than about 97 percent by weight of one stereoisomer of the compound and less than about 3 percent by weight of the other stereoisomers or greater than about 99 percent by weight of one stereoisomer of the compound and less than about 1 percent by weight of the other stereoisomers of the compound.
• the term “enantiomerically pure” means a stereomerically pure composition of a compound having one chiral center.
• the term “substantially free of its (+) stereoisomer” means that the compound is made up of a significantly greater proportion of its (-) stereoisomer than of its optical antipode (i.e., its (+) stereoisomer).
• the term “substantially free of its (+) stereoisomer” means that the compound is made up of at least about 90% by weight of its (-) stereoisomer and about 10% by weight or less of its (+) stereoisomer.
• the term “substantially free of its (+) stereoisomer” means that the compound is made up of at least about 95% by weight of its (-) stereoisomer and about 5% by weight or less of its (+) stereoisomer. In certain embodiments, the term “substantially free of its (+) stereoisomer” means that the compound is made up of at least about 99% by weight of its (-) stereoisomer and about 1% or less of its (+) stereoisomer. In certain embodiments, the term “substantially free of its (+) stereoisomer” means that the compound is made up of approximately 100% by weight of its (-) stereoisomer. The above percentages are based on the total amount of the combined stereoisomers of the compound.
• substantially optically pure (-)-O-desmethylvenlafaxine refers to (-)-O- desmethylvenlafaxine that is substantially free of its (+) stereoisomer.
• substantially optically pure (-)-O-desmethylvenlafaxine refers to (-)-O-desmethylvenlafaxine that is substantially free of its (+) stereoisomer.
• a crystalline or amorphous form that is "pure,” i.e., substantially free of other crystalline or amorphous forms, contains less than about 10 percent by weight of one or more other crystalline or amorphous form, less than about 5 percent by weight of one or more other crystalline or amorphous form, less than about 3 percent by weight of one or more
• LAI-2932341vl other crystalline or amorphous form or less than about 1 percent by weight of one or more other crystalline or amorphous form.
• substantially free of a compound means that the composition contains less than about 20 percent by weight, less than about 10 percent by weight, less than about 5 percent by weight, less than about 3 percent by weight, or less than about 1 percent by weight of the compound.
• treatment refers to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agent, after the onset of symptoms of the particular disease. [0094] As used herein, and unless otherwise specified, the terms “prevent,” “preventing” and “prevention” refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof.
• the terms refer to the treatment with or administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of disease or disorders provided herein.
• the terms encompass the inhibition or reduction of a symptom of the particular disease.
• Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments.
• patients who have a history of recurring symptoms are also potential candidates for the prevention.
• prevention may be interchangeably used with the term “prophylactic treatment.”
• the terms “manage,” “managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a cure of the disease or disorder.
• the term “managing” encompasses treating a patient who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.
• the term "affective disorder” includes depression, attention deficit disorder, attention deficit disorder with hyperactivity, bipolar and manic conditions, and the like.
• the terms "attention deficit disorder” (ADD) and “attention deficit disorder with hyperactivity” (ADDH), or attention deficit/hyperactivity disorder (AD/HD), are used herein in accordance with ADD and ADHD.
• LAI-2932341vl the accepted meanings as found in the Diagnostic and Statistical Manual of Mental Disorders, 4 th ed., American Psychiatric Association (1997) (DSM-IVTM).
• a method of treating depression means relief from the symptoms of depression which include, but are not limited to, changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes may also be relieved, including insomnia, anorexia, weight loss, decreased energy and libido, and abnormal hormonal circadian rhythms.
• a method of treating, preventing or managing obesity or weight gain means reduction of weight, or prevention of or relief from being overweight, gaining weight, or obesity; all of which are usually due to extensive consumption of food.
• a method of treating, preventing or managing disorders ameliorated by inhibition of neuronal monoamine reuptake means prevention of or relief from symptoms of disease states associated with abnormal neuronal monoamine levels; such symptoms are reduced by way of neuronal monoamine reuptake inhibition.
• Monoamines, the reuptake of which are inhibited by the compounds or compositions of the present invention include, but are not limited to, noradrenaline (or norepinephrine), serotonin and dopamine.
• Disorders treated by neuronal monoamine reuptake inhibition include, but are not limited to,
• Parkinson's disease and epilepsy are Parkinson's disease and epilepsy.
• the term "method of treating, preventing or managing Parkinson's disease” means prevention of or relief from the symptoms of Parkinson's disease which include, but are not limited to, slowly increasing disability in purposeful movement, tremors, bradykinesia, rigidity, and a disturbance of posture in humans.
• a method for treating, preventing or managing cerebral function disorders means prevention of or relief from the disease states associated with cerebral function disorders involving intellectual deficits which include but are not limited to, senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome, disturbances of consciousness, coma, lowering of attention, speech disorders, Parkinson's disease, Lennox syndrome, autism, hyperkinetic syndrome and schizophrenia.
• cerebral function disorders disorders caused by cerebrovascular diseases including, but not limited to, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like and where symptoms include disturbances of consciousness, senile dementia, coma, lowering of attention, speech disorders, and the like.
• LAI-2932341vl with their accepted meanings in the art. See, e.g., DSM-I VTM.
• the terms "method of treating, preventing or managing,” “method of treating,” “method of preventing” and “method of managing” when used in connection with these disorders mean the amelioration, prevention or relief from the symptoms and/or effects associated with these disorders. Without being limited by any theory, the treatment, prevention or management of certain of these disorders may be related to the activity of the active ingredient(s) as inhibitors of serotonin uptake.
• a method of treating, preventing or managing incontinence means prevention of or relief from the symptoms of incontinence including involuntary voiding of feces or urine, and dribbling or leakage or feces or urine which may be due to one or more causes including but not limited to pathology altering sphincter control, loss of cognitive function, overdistention of the bladder, hyper-reflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder or neurologic abnormalities.
• a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
• a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or disorder.
• the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.
• a prophylactically effective amount of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence.
• a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
• the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
• composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• pharmaceutically acceptable it is meant the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• LAI-2932341vl refers to the amount of the subject solid form that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician or that is sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the disease being treated.
• subject is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In specific embodiments, the subject is a human. [00109] In certain embodiments, the invention provides compounds which comprise (-)-
• Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
• An example, without limitation, of a prodrug would be a compound which is administered as a carbamate (the "prodrug"), but then is metabolically hydrolyzed to the phenol, the active entity. Additional examples include petidyl derivatives of a compound.
• the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms.
• the compound may be labeled with radioactive and/or nonradioactive isotopes, such as for example deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), carbon-13 ( 13 C) or carbon-14 ( 14 C).
• Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compound of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
• the present invention is directed to solid forms comprising stereomerically pure (-)-O-desmethylvenlafaxine and salts thereof, including solvated and hydrated forms thereof, and amorphous forms, and compositions comprising the solid forms alone or in combination with other active ingredients, methods of their use in the treatment, prevention and/or management of conditions and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and
• the storage stability, compressibility, density or dissolution properties of the solid forms are beneficial for manufacturing, formulation and bio-availability of the present invention.
• the condition or disorder is an affective disorder.
• the condition or disorder is depression.
• the condition or disorder is an anxiety disorder.
• the condition or disorder is a cerebral function disorder.
• the condition or disorder is fibromyalgia.
• the condition or disorder is pain.
• the condition or disorder is neuropathic pain.
• solid forms of the invention are those that are characterized by physical properties, e.g., stability, solubility and dissolution rate, appropriate for clinical and therapeutic dosage forms.
• Certain solid forms of the invention are characterized by physical properties, e.g., crystal morphology, compressibility and hardness, suitable for manufacture of a solid dosage form. Such properties can be determined using techniques such
• LAI-293234W1 as X-ray diffraction, microscopy, IR spectroscopy and thermal analysis, as described herein and known in the art.
• the present invention provides particular pharmaceutically acceptable salts of (-)-O-desmethylvenlafaxine, having utility for the treatment, prevention or management of conditions and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and neuropathic pain, cerebral function disorders, senile dementia, memory loss, amnesia/amnes
• the present invention provides hydrochloride salts of stereomerically pure (-)-O-desmethylvenlafaxine.
• (-)-O-desmethylvenlafaxine has the general formula (I):
• a preferred hydrochloric acid salt of (-)-O-desmethylvenlafaxine is the monohydrochloric acid salt, provided by formula (II):
• Each salt of the invention can be made from a preparation of stereomerically pure
• (-)-O-desmethylvenlafaxine or from an addition salt of (-)-O-desmethylvenlafaxine.
• (-)-O- desmethylvenlafaxine can be synthesized or obtained according to any method apparent to those of skill in the art.
• (-)-O-desmethylvenlafaxine is prepared according to the methods described in detail in the examples below, in U.S. Patent Nos. 6,342,533 B1 , 6,441 ,048 B1 and 6,911 ,479 B2, all of which are hereby incorporated by reference in their entireties.
• (-)-O-desmethylvenlafaxine prepared by any method can be contacted with an appropriate acid, either neat or in a suitable solvent, to yield the salts of the invention.
• (-)-O-desmethylvenlafaxine can be contacted with hydrochloric acid to yield the hydrochloride salts of the invention.
• an (-)-O-desmethylvenlafaxine addition salt prepared by any method known in the art can be contacted with an appropriate acid, either neat or in a suitable solvent, to yield the salts of the invention.
• an appropriate acid either neat or in a suitable solvent
• (-)-O-desmethylvenlafaxine cyclohexylphenylglycolic acid salt can be contacted with hydrochloric acid to yield the hydrochloride salts of the invention.
• hydrochloride salt of (-)-O- desmethylvenlafaxine display superior stability, solubility and hygroscopicity properties in comparison to other forms comprising (-)-O-desmethylvenlafaxine.
• the present invention also provides crystal forms comprising stereomerically pure (-)-O-desmethylvenlafaxine and salts thereof, having particular utility for the treatment, prevention or management of conditions and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and neuropathic pain, cerebral function disorders, senile dementia, memory loss, amnesia/amnestic syndrome; disturbances of consciousness, coma, speech disorders, Lennox
• the solid forms of the invention are crystal forms comprising the hydrochloride salt of (-)-O-desmethylvenlafaxine described above.
• crystal forms of the invention can be made from a preparation of (-)-O-desmethylvenlafaxine. For instance, a salt of (-)-O-desmethylvenlafaxine can be dissolved and then crystallized to yield crystal forms of the invention.
• a hydrochloride salt of (-)-O-desmethylvenlafaxine can be crystallized from particular solvent mixtures, such as those described below, to yield the crystal forms of the invention.
• the present invention provides Form A, a crystal form of a hydrochloride salt of (-)-O-desmethylvenlafaxine ((-)-1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]cyclohexanol hydrochloride salt).
• Form A is a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine.
• a sample of the Form A crystal form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has a water content ranging between about 4% and about 8% of the total mass of the sample. In certain embodiments, Form A has a water content of about 6 % of the
• LAI-2932341vl total mass of the sample which is equal to about one molar equivalent of water per mole of (-)- O-desmethylvenlafaxine.
• Form A when examined by Karl Fisher titration according to the methods described herein, Form A has a water content of about 5.7% by mass.
• Form A has a thermal gravimetric analysis thermogram similar to that of FIG. 1.
• Form A when examined by thermal gravimetric analysis according to the methods described herein, Form A has a weight loss corresponding to about 5.6% of the total mass of the sample occurring between about 25 and about 110 0 C.
• Form A has a differential scanning calorimetry thermogram similar to that of FIG. 2.
• Form A when examined by differential scanning calorimetry according to the methods described herein, has an endotherm with an onset temperature at about 93 0 C.
• the Form A crystal form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 3 using Cu Ka radiation.
• the Form A crystal form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 8, which was simulated for Cu Ka radiation using single-crystal X-ray diffraction structural data obtained on Form A.
• particular Form A crystal forms of the invention have major X- ray powder diffraction pattern peaks at about 12.7, 14.5, 19.1 , 21.4, 23.0, 25.5, 27.3 °2 ⁇ using Cu Ka radiation.
• the Form A crystal form of the invention has major X- ray powder diffraction pattern peaks at one, two, three, four, five, six or seven of the X-ray powder diffraction pattern positions of about 12.7, 14.5, 19.1 , 21.4, 23.0, 25.5, 27.3 °2 ⁇ using Cu Ka radiation.
• the Form A crystal form of the invention has both a water content of about 5.7 % of the total mass of the sample and major X-ray powder diffraction pattern peaks at one, two, three, four, five, six or seven of the X-ray powder diffraction pattern positions of about 12.7, 14.5, 19.1 , 21.4, 23.0, 25.5, 27.3 °2 ⁇ using Cu Ka radiation.
• Form A has an infrared spectrum similar to that of FIG. 4.
• Form A has a Raman spectrum similar to that of FIG. 5.
• Form A crystallizes in space group P2 1 2 1 2 1 .
• the Form A crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has excellent hygroscopicity properties.
• Form A gains ⁇ 1% in mass upon
• the Form A crystal form provided herein has a moisture sorption isotherm similar to that of FIG. 6. [00125] In addition, without being limited by a particular theory, it has been found that the
• Form A crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine also has excellent stability properties.
• Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form A apparent to those of skill in the art based upon the teachings herein.
• Form A can be prepared by crystallization of the hydrochloride salt of (-)-O-desmethylvenlafaxine from a solvent system containing one or more solvents, such as, but not limited to, water, acetone, acetonitrile, ethanol, isopropanol, methanol, methyl ethyl ketone, methyl t-butyl ether, heptane, hexanes toluene and mixtures thereof.
• Form A may be obtained by crystal form conversion from another crystal or amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine, for instance, via a solvent-mediated and/or water-mediated form conversion process.
• the present invention provides Form B, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains the solvent tetrahydrofuran (THF) in the crystal lattice.
• THF solvent tetrahydrofuran
• the THF is present in the approximate ratio of 0.25 molar equivalents of THF per mole of the hydrochloride salt of (-)-O- desmethylvenlafaxine. In terms of mass, this equates to a THF content of approximately 6% of the total mass of a sample of Form B.
• the THF content of Form B ranges from about 4% to about 8% of the total mass of the sample of Form B.
• Form B has a thermal gravimetric analysis thermogram similar to that of FIG. 9. In certain embodiments, when examined by thermal gravimetric analysis according to the methods described herein, Form B has a weight loss corresponding to about 5.7% of the total mass of the sample occurring between about 25 and about 180 0 C. In certain embodiments, the Form B crystal form has a differential scanning calorimetry thermogram similar to that of FIG. 10. In certain embodiments, when examined by differential scanning calorimetry according to the methods described herein, Form B has an endotherm with an onset temperature of about 176 0 C and another endotherm with an onset temperature of about 199 0 C. In certain embodiments, Form B has an additional endotherm with a peak temperature at about 160 0 C. In certain embodiments, the Form B crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 11 using Cu Ka radiation. In
• Form B crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 13.1 , 14.7, 18.8, 21.1 , 24.2, 26.3, 29.4 °2 ⁇ using Cu Ka radiation.
• the Form B crystal form of the invention has major X-ray powder diffraction pattern peaks at one, two, three, four, five, six or seven of the X-ray powder diffraction pattern positions of about 13.1 , 14.7, 18.8, 21.1 , 24.2, 26.3, 29.4 °2 ⁇ using Cu Ka radiation.
• the Form B crystal form of the invention has both a THF content of about 6% of the total mass of the sample and major X-ray powder diffraction pattern peaks at one, two, three, four, five, six or seven of the X-ray powder diffraction pattern positions of about 13.1 , 14.7, 18.8, 21.1 , 24.2, 26.3, 29.4 °2 ⁇ using Cu Ka radiation.
• the Form B has an infrared spectrum similar to that of FIG. 12.
• the Form B crystal form of the invention has a Raman spectrum similar to that of FIG. 13.
• Form B has a dynamic vapor sorption isotherm similar to that of FIG. 14.
• Form B when examined by dynamic vapor sorption according to the methods described herein, exhibits a gain in mass of about 25% when increased from 5% to 95% relative humidity, followed by a loss in mass of about 26% when decreased from 95% to 5% relative humidity.
• Form B of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form B apparent to those of skill in the art based upon the teachings herein.
• Form B can be prepared by crystallization from solutions of the hydrochloride salt of (-)-O-desmethylvenlafaxine in THF.
• the present invention provides Form C, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains one or more of the solvents ethyl acetate, ethyl ether and water in the crystal lattice.
• ethyl acetate is present in the approximate ratio of 0.2 molar equivalents of ethyl acetate per mole of the hydrochloride salt of (-)-O-desmethylvenlafaxine. In terms of mass, this equates to an ethyl acetate content of approximately 6% of the total mass of a sample of Form C.
• ethyl ether is present in the approximate ratio of 0.2 molar equivalents of ethyl ether per mole of the hydrochloride salt of (-)-O-desmethylvenlafaxine. In terms of mass, this equates to an ethyl ether content of approximately 5% of the total mass of a sample of Form C. In a particular embodiment, the combined content of ethyl acetate, ethyl ether and water ranges from about 3% to about 8% of the total mass of the sample of Form C. In certain embodiments, Form C has a thermal gravimetric analysis thermogram similar to that of FIG. 15. In certain embodiments, when examined by thermal gravimetric analysis according to the methods described herein, Form C has a weight loss corresponding to about 5.1% of the total
• the Form C crystal form has a differential scanning calorimetry thermogram similar to that of FIG. 16.
• Form C when examined by differential scanning calorimetry according to the methods described herein, Form C has an endotherm with an onset temperature of about 84 0 C, another endotherm with a peak temperature at about 136 0 C, and another endotherm with an onset temperature at about 167 0 C.
• the Form C crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 17 using Cu Ka radiation.
• Particular Form C crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 5.8, 11.7, 14.7, 18.8, 21.0, 21.2 °2 ⁇ using ⁇ radiation.
• the Form C crystal form of the invention has major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 5.8, 11.7, 14.7, 18.8, 21.0, 21.2 °2 ⁇ using Cu Ka radiation.
• the Form C crystal form of the invention has a combined content of ethyl acetate, ethyl ether and water amounting to between about 3% and about 8% of the total mass of the sample and major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 5.8, 11.7, 14.7, 18.8, 21.0, 21.2 °2 ⁇ using Cu Ka radiation.
• the Form C crystal form has an infrared spectrum similar to that of FIG. 18.
• the Form C crystal form of the invention has a Raman spectrum similar to that of FIG. 19.
• Form C has a dynamic vapor sorption isotherm similar to that of FIG. 20. In certain embodiments, when examined by dynamic vapor sorption according to the methods described herein, Form C exhibits a gain in mass of about 27% when increased from 5% to 95% relative humidity, followed by a loss in mass of about 27% when decreased from 95% to 5% relative humidity.
• Form C of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form C apparent to those of skill in the art based upon the teachings herein.
• Form C can be prepared by crystallization from solutions of the hydrochloride salt of (-)-O-desmethylvenlafaxine in ethyl acetate, ethyl ether, water, a mixture of two or more of these solvents, or the like.
• the present invention provides Form D, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains isopropyl alcohol (IPA) and/or water in the crystal lattice.
• IPA isopropyl alcohol
• a sample of the Form D crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has a combined IPA and water content ranging between about 2% and about 8% of the total mass of the sample.
• the Form D crystal form has a thermal gravimetric analysis thermogram
• Form D when examined by thermal gravimetric analysis according to the methods described herein, Form D has a weight loss corresponding to about 5.6% of the total mass of the sample occurring in the range of about 25 to about 150 0 C.
• the Form D crystal form has a differential scanning calorimetry thermogram similar to that of FIG. 22.
• Form D when examined by differential scanning calorimetry according to the methods described herein, Form D has an endotherm with an onset temperature at about 85 0 C.
• the Form D crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG.
• Form D crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 2.4, 5.7, 6.0, 15.9, 19.1 , 19.8, 20.3 °2 ⁇ using Cu Ka radiation.
• the Form D crystal form of the invention has major X-ray powder diffraction peaks at one, two, three, four, five, six or seven of the X-ray powder diffraction pattern positions of about 2.4, 5.7, 6.0, 15.9, 19.1 , 19.8, 20.3 °2 ⁇ using Cu Ka radiation.
• the Form D crystal form of the invention has both a combined IPA and water content ranging between about 2% and about 8% of the total mass of the sample and major X-ray powder diffraction peaks at one, two, three, four, five, six or seven of the X-ray powder diffraction pattern positions of about 2.4, 5.7, 6.0, 15.9, 19.1 , 19.8, 20.3 °2 ⁇ using Cu Ka radiation.
• Form D of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form D apparent to those of skill in the art based upon the teachings herein.
• Form D can be prepared by crystallization from solutions of the hydrochloride salt of (-)-O-desmethylvenlafaxine in IPA.
• the present invention provides Form E, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains methyl t-butyl ether (MTBE) and/or water in the crystal lattice.
• a sample of the Form E crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has a combined MTBE and water content ranging between about 4% and about 10% of the total mass of the sample.
• the Form E crystal form has a MTBE content of about 6% of the total mass of the sample, which is equal to about 0.2 molar equivalent of MTBE per mole of (-)-O- desmethylvenlafaxine.
• Form E has a thermal gravimetric analysis thermogram similar to that of FIG. 24. In certain embodiments, when examined by thermal gravimetric analysis according to the methods described herein, Form E has a weight loss corresponding to about 5.9% of the total mass of the sample occurring in the range of about 25 to about 180 °C. In certain embodiments, Form E has a differential scanning calorimetry
• Form E when examined by differential scanning calorimetry according to the methods described herein, Form E has an endotherm with an onset temperature at about 93 0 C 1 followed by an endotherm with an onset temperature at about 167 0 C.
• the Form E crystal form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 26 using Cu Ka radiation.
• Particular Form E crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 5.8, 11.9, 13.0, 14.4, 18.5, 20.9 °2 ⁇ using Cu Ka radiation.
• the Form E crystal form of the invention has major X-ray powder diffraction peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 5.8, 11.9, 13.0, 14.4, 18.5, 20.9 °2 ⁇ using Cu Ka radiation.
• the Form E crystal form of the invention has both a solvent content ranging between about 4% and about 10% of the total mass of the sample and major X-ray powder diffraction peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 5.8, 11.9, 13.0, 14.4, 18.5, 20.9 °2 ⁇ using Cu Ka radiation.
• the Form E crystal form of the invention has an infrared spectrum similar to that of FIG. 27. In certain embodiments, the Form E crystal form of the invention has a Raman spectrum similar to that of FIG. 28. In certain embodiments of the invention, Form E has a dynamic vapor sorption isotherm similar to that of FIG. 29. In certain embodiments, when examined by dynamic vapor sorption according to the methods described herein, Form E exhibits a net gain in mass of about 4.7% when increased from 5% to 95% relative humidity, followed by a loss in mass of about 5.8% when decreased from 95% to 5% relative humidity.
• Form E of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form E apparent to those of skill in the art based upon the teachings herein.
• Form E can be prepared by the dissolution of a solid form comprising the hydrochloride salt of (-)-O-desmethylvenlafaxine in a solvent or solvent mixture containing, for example, methanol and water, followed by subsequent crystallization brought about by the addition of an anti-solvent, such as methyl t-butyl ether.
• the present invention provides Form F, a hydrate crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine.
• a sample of the Form F crystal form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has a water content ranging between about 4% and about 8% of the total mass of the sample.
• the Form F crystal form has a water content of about 6% of the total mass of the sample, which is equal to about one molar equivalent of water per mole of (-)-O-desmethylvenlafaxine.
• Form F has a
• Form F when examined by thermal gravimetric analysis according to the methods described herein, Form F has a weight loss corresponding to about 5.8% of the total mass of the sample occurring in the range of about 25 to about 125 0 C. In certain embodiments of the invention, Form F has a differential scanning calorimetry thermogram similar to that of FIG. 31. In certain embodiments, when examined by differential scanning calorimetry according to the methods described herein, Form F has an endotherm with an onset temperature at about 89 0 C.
• the Form F crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 32.
• the Form F crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 33, which was simulated for Cu Ka radiation using single-crystal X- ray diffraction structural data obtained on Form F.
• Particular Form F crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 14.4, 16.0, 17.4, 19.0, 25.5, 26.8 °2 ⁇ using Cu Ka radiation.
• the Form F crystal form of the invention has major X-ray powder diffraction peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 14.4, 16.0, 17.4, 19.0, 25.5, 26.8 °2 ⁇ using Cu Ka radiation.
• the Form F crystal form of the invention has both a water content of about 6% of the total mass of the sample and major X-ray powder diffraction peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 14.4, 16.0, 17.4, 19.0, 25.5, 26.8 °2 ⁇ using Cu Ka radiation.
• the Form F crystal form of the invention has an infrared spectrum similar to that of FIG. 34. In certain embodiments, the Form F crystal form of the invention has a Raman spectrum similar to that of FIG. 35. In certain embodiments of the invention, Form F has a dynamic vapor sorption isotherm similar to that of FIG. 36. In certain embodiments, when examined by dynamic vapor sorption according to the methods described herein, Form F exhibits a gain in mass of about 32% when increased from 5% to 95% relative humidity, followed by a loss in mass of about 33% when decreased from 95% to 5% relative humidity. In certain embodiments, when analyzed at approximately 173 K according to a method capable of determining unit cell parameters, e.g.
• Form F crystallizes in space group Pl ⁇ .
• Form F of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form F apparent to those of skill in the art based upon the teachings herein.
• Form F can be prepared by the dissolution of a solid form
• LAI-2932341vl comprising the hydrochloride salt of (-)-O-desmethylvenlafaxine in a solvent mixture containing, for example, methanol and water, followed by subsequent crystallization brought about by the addition of an anti-solvent, such as methyl t-butyl ether.
• the present invention provides Form G, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine.
• a sample of the Form G crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has a water content ranging between 0% and 6% of the total mass of the sample.
• the Form G crystal form has a water content of about 3% of the total mass of the sample, which is equal to about a half molar equivalent of water per mole of (-)-O- desmethylvenlafaxine.
• Form G has a thermal gravimetric analysis thermogram similar to that of FIG. 38.
• Form G when examined by thermal gravimetric analysis according to the methods described herein, Form G has a weight loss corresponding to about 3.0% of the total mass of the sample occurring in the range of about 25 to about 125 °C. In certain embodiments, Form G has a differential scanning calorimetry thermogram similar to that of FIG. 39. In certain embodiments, when examined by differential scanning calorimetry according to the methods described herein, Form G has an endotherm with an onset temperature of about 91 °C. In certain embodiments, the Form G crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 40 using Cu Ka radiation.
• Particular Form G crystal forms of the invention have characteristic X-ray powder diffraction pattern peaks at about 12.6, 15.1 , 16.7, 18.8, 21.0, 25.3 °2 ⁇ using Cu Ka radiation.
• the Form G crystal form of the invention has major X-ray powder diffraction peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.6, 15.1 , 16.7, 18.8, 21.0, 25.3 °2 ⁇ using Cu Ka radiation.
• the Form G crystal form of the invention has both a water content of about 0 to 6% of the total mass of the sample and major X-ray powder diffraction peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.6, 15.1 , 16.7, 18.8, 21.0, 25.3 °2 ⁇ using Cu Ka radiation.
• Form G has a dynamic vapor sorption isotherm similar to that of FIG. 41.
• Form G when examined by dynamic vapor sorption according to the methods described herein, Form G exhibits a gain in mass of about 3% when increased from 5% to 90% relative humidity.
• Form G when examined by dynamic vapor sorption according to the methods described herein, exhibits a gain in mass of about 23% when increased from 5% to 95% relative humidity, and a loss in mass of about 22% when decreased from 95% to 5% relative humidity.
• Form G of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form G apparent to those of skill in the art based upon the teachings herein.
• Form G is prepared by drying the Form A crystal form of this invention, described above and in the examples below, over a suitable drying agent, such as, for example, P 2 O 5 .
• the present invention provides Form H, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains the solvent acetone in the crystal lattice.
• the acetone is present in the approximate ratio of 0.2 molar equivalents of acetone per mole of the hydrochloride salt of (-)-O- desmethylvenlafaxine. In terms of mass, this equates to an acetone content of approximately 4% of the total mass of a sample of Form H.
• the acetone content of Form H ranges from about 2% to about 6% of the total mass of the sample of Form H.
• Form H has a thermal gravimetric analysis thermogram similar to that of FIG. 42. In certain embodiments, when examined by thermal gravimetric analysis according to the methods described herein, Form H has a weight loss corresponding to about 3.7% of the total mass of the sample occurring between about 25 and about 180 0 C. In certain embodiments, the Form H crystal form has a differential scanning calorimetry thermogram similar to that of FIG. 43. In certain embodiments, when examined by differential scanning calorimetry according to the methods described herein, Form H has an endotherm with a peak temperature at about 180 0 C. In certain embodiments, Form H has an additional endotherm with a peak temperature at about 154 0 C.
• the Form H crystal form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 44 using Cu Ka radiation.
• Particular Form H crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 12.1 , 14.6, 18.7, 21.1 , 26.3 °2 ⁇ using Cu Ka radiation.
• the Form H crystal form of the invention has major X-ray powder diffraction pattern peaks at one, two, three, four or five of the X-ray powder diffraction pattern positions of about 12.1 , 14.6, 18.7, 21.1 , 26.3 °2 ⁇ using Cu Ka radiation.
• the Form H crystal form of the invention has both an acetone content of about 4% of the total mass of the sample and major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.1 , 14.6, 18.7, 21.1 , 26.3 °2 ⁇ using Cu Ka radiation.
• Form H of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form H apparent to those of skill in the art based upon the teachings
• Form H can be obtained by stirring a slurry of the Form A crystal form of (-)-O-desmethylvenlafaxine in acetone at elevated temperature, followed by filtration.
• the present invention provides Form I 1 a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains the solvent isopropanol in the crystal lattice.
• the isopropanol is present in Form I in the approximate ratio of 0.2 molar equivalents of isopropanol per mole of the hydrochloride salt of (- )-O-desmethylvenlafaxine.
• Form I has a thermal gravimetric analysis thermogram similar to that of FIG. 45. In certain embodiments, when examined by thermal gravimetric analysis according to the methods described herein, Form I has a weight loss corresponding to about 4.2% of the total mass of the sample occurring between about 25 and about 180 0 C. In certain embodiments, the Form I crystal form has a differential scanning calorimetry thermogram similar to that of FIG. 46.
• Form I when examined by differential scanning calorimetry according to the methods described herein, Form I has endotherm with a peak temperature at about 178 0 C. In certain embodiments, Form I has an additional endotherm with a peak temperature at about 158 0 C. In certain embodiments, the Form I crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 47 using Cu Ka radiation. Particular Form I crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 13.0, 14.6, 18.7, 21.0, 23.5, 26.2 °2 ⁇ using Cu Ka radiation.
• the Form I crystal form of the invention has major X- ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 13.0, 14.6, 18.7, 21.0, 23.5, 26.2 "29 using Cu Ka radiation.
• the Form I crystal form of the invention has both an isopropanol content of about 4% of the total mass of the sample and major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 13.0, 14.6, 18.7, 21.0, 23.5, 26.2 °2 ⁇ using Cu Ka radiation.
• Form I of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form I apparent to those of skill in the art based upon the teachings herein.
• Form I can be obtained by precipitation from a solution of the hydrochloride salt of (-)-O-desmethylvenlafaxine in isopropanol followed by filtration.
• Form I can be obtained by fast evaporation of an isopropanol solution of the hydrochloride salt of (-)-O-desmethylvenlafaxine.
• the present invention provides Form J, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains the solvent acetonitrile in the crystal lattice.
• the acetonitrile is present in Form J in the approximate ratio of 0.2 molar equivalents of acetonitrile per mole of the hydrochloride salt of (-)- O-desmethylvenlafaxine. In terms of mass, this equates to an acetonitrile content of approximately 3% of the total mass of a sample of Form J.
• the acetonitrile content of Form J ranges from about 1% to about 5% of the total mass of the sample of Form J.
• the Form J crystal form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 48 using Cu Ka radiation.
• Particular Form J crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 12.2, 14.7, 16.9, 18.8, 21.0, 23.7 °2 ⁇ using Cu Ka radiation.
• the Form J crystal form of the invention has major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.2, 14.7, 16.9, 18.8, 21.0, 23.7 °2 ⁇ using Cu Ka radiation.
• the Form J crystal form of the invention has both an acetonitrile content of about 3% of the total mass of the sample and major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.2, 14.7, 16.9, 18.8, 21.0, 23.7 °2 ⁇ using Cu Ka radiation.
• Form J of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form J apparent to those of skill in the art based upon the teachings herein.
• Form J can be obtained by precipitation from a solution of the hydrochloride salt of (-)-O-desmethylvenlafaxine in acetonitrile followed by filtration.
• Form J can be obtained by slurrying Form A of the hydrochloride salt of (-)-O- desmethylvenlafaxine in acetonitrile followed by filtration.
• the present invention provides Form K, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains the solvent ethanol in the crystal lattice.
• the ethanol content of Form K is less than about 13% of the total mass of the sample of Form K, which is less than about one molar equivalent of ethanol per mole of the hydrochloride salt of (-)-O-desmethylvenlafaxine.
• the Form K crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 49.
• the Form K crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 50, which was simulated for Cu Ka radiation according to the methods described herein using single-crystal X-ray diffraction structural data obtained for
• Form K crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 12.1 , 13.1 , 14.6, 18.7, 21.0, 21.2 °2 ⁇ using Cu Ka radiation.
• the Form K crystal form of the invention has major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.1 , 13.1 , 14.6, 18.7, 21.0, 21.2 °2 ⁇ using Cu Ka radiation.
• the Form K crystal form of the invention has both an ethanol content of less than about 13% of the total mass of the sample and major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.1 , 13.1 , 14.6, 18.7, 21.0, 21.2 °2 ⁇ using Cu Ka radiation.
• major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.1 , 13.1 , 14.6, 18.7, 21.0, 21.2 °2 ⁇ using Cu Ka radiation.
• a method capable of determining unit cell parameters e.g.
• Form K crystallizes in space group C2.
• Form K of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form K apparent to those of skill in the art based upon the teachings herein.
• Form K can be obtained by crystallization from a solution of the hydrochloride salt of (-)-O-desmethylvenlafaxine in an ethanol/acetone solvent system.
• the present invention provides Form L, a crystal form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine that contains the solvent 2-methyl- tetrahydrofuran in the crystal lattice.
• the 2-methyl-tetrahydrofuran is present in Form L in the approximate ratio of between 0.1 and 0.3 molar equivalents of 2-methyl- tetrahydrofuran per mole of the hydrochloride salt of (-)-O-desmethylvenlafaxine. In terms of mass, this equates to a 2-methyl-tetrahydrofuran content of between approximately 3% to 8% of the total mass of a sample of Form L. In a certain embodiment, the 2-methyl-tetrahydrofuran content of Form L ranges from about 1 % to about 10% of the total mass of the sample of Form L. In certain embodiments, Form L has a thermal gravimetric analysis thermogram similar to that of FIG. 51.
• Form L when examined by thermal gravimetric analysis according to the methods described herein, Form L has a weight loss corresponding to about 2% of the total mass of the sample occurring between about 25 and about 125 °C and a weight loss corresponding to about 7% of the total mass of the sample occurring between about 25 and about 180 °C.
• the Form L crystal form has a differential scanning calorimetry thermogram similar to that of FIG. 52.
• Form L when examined by differential scanning calorimetry according to the methods described herein, Form L has an endotherm with an onset temperature at about 166 °C. In certain embodiments, the Form L
• LAI-2932341vl crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 53 using Cu Ka radiation.
• Particular Form L crystal forms of the invention have major X-ray powder diffraction pattern peaks at about 12.0, 13.0, 14.5, 18.8, 21.0, 23.4 °2 ⁇ using Cu Ka radiation.
• the Form L crystal form of the invention has major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.0, 13.0, 14.5, 18.8, 21.0, 23.4 °2 ⁇ using Cu Ka radiation.
• the Form L crystal form of the invention has both an 2-methyl-tetrahydrofuran content of between about 1% and about 10% of the total mass of the sample and major X-ray powder diffraction pattern peaks at one, two, three, four, five or six of the X-ray powder diffraction pattern positions of about 12.0, 13.0, 14.5, 18.8, 21.0, 23.4 °2 ⁇ using Cu Ka radiation.
• Form L of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method of making Form L apparent to those of skill in the art based upon the teachings herein.
• Form L can be obtained by slurrying Form A of the hydrochloride salt of (-)-O-desmethylvenlafaxine in 2-methyl-tetrahydrofuran followed by filtration.
• the present invention provides crystal forms comprising the monohydrochloride salt of (-)-O-desmethylvenlafaxine that are members of an isostructural family of crystal forms.
• Members of a particular isostructural family of crystal forms share a certain structural similarity to the other members of that family with regard to features such as, for example, interplanar spacing in the crystal lattice.
• Structural similarity among members of a particular isostructural family results in some common characteristics of these crystal forms, for example, members of an isostructural family of crystal forms comprising the hydrochloric acid salt of (-)-O-desmethylvenlafaxine have similar X-ray powder diffraction patterns.
• Each member of a given isostructural family of crystal forms contains one or more types of organic solvents and/or water in the crystal lattice, or alternatively may be a desolvated solvate.
• Preferred solvents for inclusion in the crystal lattice of a member of a given isostructural family of crystal forms comprising the hydrochloric acid salt of (-)-O-desmethylvenlafaxine include common organic laboratory solvents and water.
• the invention provides desolvated solvate members of an isostructural family of crystal forms comprising the hydrochloric acid salt of (-)-O-desmethylvenlafaxine.
• a desolvated solvate is formed by the removal from the crystal lattice of one or more types of solvents and/or water; as a result, desolvated solvate crystal forms do not possess substantial quantities of solvent or water in the crystal lattice.
• LAI-2932341vl may involve drying, heating and/or vacuum methods, as well as other methods apparent to those skilled in the art.
• the invention provides crystal forms comprising the hydrochloride salt of (-)-O-desmethylvenlafaxine belonging to isostructural family 1.
• members of isostructural family 1 are selected from the group consisting of Form B, Form C, Form H, Form I, Form J, Form K and Form L.
• a member of isostructural family 1 of crystal forms has characteristic X-ray powder diffraction pattern peaks at about 5.8, 13.0, 14.6, 18.7, 21.1 , 26.3°2 ⁇ using Cu Ka radiation.
• a member of isostructural family 1 of crystal forms comprising the hydrochloric acid salt of (-)-O-desmethylvenlafaxine has one, two, three, four, five or six characteristic X-ray powder diffraction pattern peaks at the positions of about 5.8, 13.0, 14.6, 18.7, 21.1 and 26.3 °2 ⁇ using Cu Ka radiation.
• Solvents for inclusion in the crystal lattice of a member of the isostructural family 1 of crystal forms comprising the hydrochloric acid salt of (-)-O-desmethylvenlafaxine include, but are not limited to, tetrahydrofuran, ethyl acetate, ethyl ether, acetone, isopropanol, acetonitrile, ethanol, water, and combinations thereof. Certain embodiments of the invention provide a member of the isostructural family 1 of crystal forms comprising the hydrochloric acid salt of (-)-O- desmethylvenlafaxine that is a desolvated solvate crystal form.
• a desolvated solvate belonging to isostructural family 1 may be prepared by the removal of any of the above-mentioned solvents from the crystal lattice of any solvated and/or hydrated crystal form member of isostructural family 1.
• the solvents ethyl acetate, diethyl ether and/or water are removed from the crystal lattice of Form C (a crystal form of the HCI salt of (-)-O-desmethylvenlafaxine, described herein) by way of heating in order to yield a desolvated solvate member of isostructural family 1.
• a desolvated solvate that is a member of isostructural family 1 has a XRPD pattern similar to that of FIG. 54 using Cu Ka radiation.
• the invention provides crystal forms comprising the monohydrochloride salt of (-)-O-desmethylvenlafaxine belonging to isostructural family 2.
• members of isostructural family 2 are selected from the group consisting of Form E and Form L.
• a crystal form that is a member of isostructural family 2 has characteristic X-ray powder diffraction pattern peaks at about 11.9, 13.0, 14.4, 18.5, and 20.9 °2 ⁇ using Cu Ka radiation.
• a crystal form of the hydrochloride salt of (-)-O-desmethylvenlafaxine that is a member of isostructural family 2 has one, two, three, four or five characteristic X-ray powder
• Solvents for inclusion in the crystal lattice of a member of the isostructural family 2 of crystal forms comprising the hydrochloric acid salt of (-)-O-desmethylvenlafaxine include, but are not limited to, methyl t-butyl ether, 2-methyl-tetrahydrofuran, water and combinations thereof.
• Certain embodiments of the invention include desolvated solvate crystal forms that are members of isostructural family 2.
• desolvated solvate crystal forms that are members of isostructural family 2 are formed by the desolvation and/or dehydration of a crystal form that is a member of isostructural family 2.
• the present invention provides amorphous forms comprising (-)-O-desmethylvenlafaxine and salts thereof, having particular utility for the treatment, prevention or management of conditions and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and neuropathic pain, cerebral function disorders, senile dementia, memory loss, amnesia/amnestic syndrome; disturbances of consciousness, coma, speech disorders,
• affective disorders such as depression
• Amorphous forms of the invention can be made following a preparation of (-)-O-desmethylvenlafaxine, as described herein. Particular embodiments include the amorphous form comprising either the free base or a salt of (-)-O- desmethylvenlafaxine. In certain embodiments, the amorphous forms of the invention are amorphous forms comprising pharmaceutically acceptable salts of (-)-O-desmethylvenlafaxine.
• the present invention provides an amorphous form of the monohydrochloride salt of (-)-O-desmethylvenlafaxine ((-)-1-[2-(dimethylamino)-1-(4- hydroxyphenyl)ethyl]cyclohexanol monohydrochloride salt).
• the amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has a thermal gravimetric analysis thermogram similar to that of FIG 55.
• the amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has a modulated differential scanning calorimetry thermogram similar to that of FIG 56.
• the amorphous form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has a glass transition temperature of approximately 24 0 C.
• the amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine has an X-ray powder diffraction pattern similar to that of FIG. 57 using Cu Ka radiation.
• the amorphous form of the invention has an X-ray powder diffraction pattern do not contain sharp diffraction peaks in the range of about 2.5 to 40.0 °2 ⁇ , measured using Cu Ka radiation.
• the amorphous form of the hydrochloride salt of (-)-O- desmethylvenlafaxine has a dynamic vapor sorption isotherm similar to that of FIG. 58.
• the amorphous form of the hydrochloride salt of the current invention when examined by dynamic vapor sorption according to the methods described herein, exhibits a gain in mass of about 36% when increased from 5% to 95% relative humidity, followed by a loss in mass of about 32% when decreased from 95% to 5% relative humidity.
• the amorphous form of the hydrochloride salt of (-)-O-desmethylvenlafaxine can be made by any method apparent to those of skill in the art to make the amorphous form based upon the teachings herein.
• a crystal form of a hydrochloride salt of (-)-O-desmethylvenlafaxine is dissolved in a solvent or solvent mixture, including solvents such as acetonitrile, isopropanol, ethyl acetate, ethanol, methanol, or the like, which is then evaporated to yield the amorphous forms of the invention.
• a solid form comprising a HCI salt of (-)-O-desmethylvenlafaxine is dissolved in a suitable solvent or solvents, e.g., water, then subjected to a freeze drying procedure to yield the amorphous forms of the invention.
• a suitable solvent or solvents e.g., water
• a hydrate, solvate, or anhydrous crystal form of the HCI salt of (-)-O-desmethylvenlafaxine such as, for example, Form A, is heated to a temperature above its dehydration, desolvation, or melting temperature to yield the amorphous forms of the invention.
• Certain embodiments of the invention provide mixtures, including physical mixtures and/or solid solutions, of solid forms comprising (-)-O-desmethylvenlafaxine or salts thereof. Certain embodiments provide mixtures of solid forms comprising the hydrochloride salt of (-)-O-desmethylvenlafaxine. Certain embodiments provide mixtures comprising an amorphous form of (-)-O-desmethylvenlafaxine HCI salt with one or more crystalline forms of (-)- O-desmethylvenlafaxine HCI salt. Certain embodiments provide mixtures comprising two or more, three or more, four or more, five or more, or six or more solid forms of the HCI salt of (-)-
• LAI-2932341vl O-desmethylvenlafaxine comprising about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% of an amorphous form of a HCI salt of (-)-O- desmethylvenlafaxine.
• Certain embodiments provide mixtures comprising two or more, three or more, four or more, five or more, or six or more crystal forms of a HCI salt of (-)-O- desmethylvenlafaxine, e.g., a mixture comprising Form A and Form F (-)-O- desmethylvenlafaxine HCI salt.
• Certain embodiments provide mixtures comprising two or more, three or more, four or more, five or more, or six or more crystal forms of the HCI salt of (-)-O- desmethylvenlafaxine comprising about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% of one form, e.g. Form A, of a HCI salt of (-)-O- desmethylvenlafaxine.
• Certain embodiments provide a solid solution of crystal forms of a HCI salt of (-)-O-desmethylvenlafaxine, wherein characteristic structural features (e.g. lattice parameters, XRPD peak positions and/or one or more solvents of crystallization) comprising two or more, three or more, four or more, five or more, or six or more crystal forms which are members of a particular isostructural family of crystal forms, e.g. isostructural family 1 , are exhibited upon analysis of the mixture.
• characteristic structural features e.g. lattice parameters, XRPD peak positions and/or one or more solvents of crystallization
• the present invention provides pharmaceutical compositions for the treatment, prevention or management of conditions and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and neuropathic pain, cerebral function disorders, senile dementia, memory loss, amnesia/amnestic syndrome; disturbances of consciousness, coma, speech disorders, Lennox syndrome, autism, hyperkinetic syndrome, schizophrenia, migraine, obesity and weight gain, incontinence, chronic fatigue syndrome,
• compositions comprise one or more crystal forms and/or amorphous forms of the present invention and a pharmaceutically acceptable diluent, excipient or carrier.
• a pharmaceutical composition of the invention comprises a pure crystal or amorphous form of a salt of (-)-O-desmethylvenlafaxine.
• a pharmaceutical composition of the invention can comprise pure Form A monohydrate hydrochloric acid salt of (- )-O-desmethylvenlafaxine.
• compositions for the administration of the crystalline or amorphous forms of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
• the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
• the crystalline or amorphous form is included in an amount sufficient to produce the desired effect upon the process, condition or disease to be treated, prevented, or managed.
• any suitable route of administration can be employed for providing the patient with a therapeutically and/or prophylactically effective dose of the active ingredient of the present invention.
• this invention comprises single unit dosage forms suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient.
• mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
• parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
• transdermal administration e.g., transdermal administration to a patient.
• dosage forms include, but are not limited to: tablets; caplets; capsules, such as hard gelatin or soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
• suspensions e.g.,
• an active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the
• LAI-2932341vl usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, preferably without employing the use of lactose.
• suitable carriers include powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations.
• composition, shape, and type of dosage forms of the invention will typically vary depending on their use.
• a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
• a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease.
• compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets, chewable tablets, caplets, capsules, and liquids (e.g., flavored syrups).
• dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
• Typical oral dosage forms of the invention are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
• tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid
• LAI-293234W1 carriers finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
• Disintegrants or lubricants can be used in pharmaceutical compositions and dosage forms of the invention.
• Production of pharmaceutical compositions or dosage forms in accordance with the present invention may require, in addition to the therapeutic drug ingredients, excipients or additives including, but not limited to, diluents, binders, lubricants, disintegrants, colorants, flavors, sweetening agents and the like or mixtures thereof.
• excipients or additives including, but not limited to, diluents, binders, lubricants, disintegrants, colorants, flavors, sweetening agents and the like or mixtures thereof.
• unit dose forms or dosage formulation of a pharmaceutical composition of the present invention may be formed by combining a desired amount of each of the active ingredients with one or more pharmaceutically compatible or acceptable excipients, as described below, in pharmaceutically compatible amounts to yield a unit dose dosage formulation the desired amount of each active ingredient.
• the dose form or dosage formulation may be formed by methods well known in the art.
• Tablets are often a preferred dosage form because of the advantages afforded both to the patient (e.g., accuracy of dosage, compactness, portability, blandness of taste as well as ease of administration) and to the manufacturer (e.g., simplicity and economy of preparation, stability as well as convenience in packaging, shipping and dispensing). Tablets are solid pharmaceutical dosage forms containing therapeutic drug substances with or without suitable additives.
• Tablets are typically made by molding, by compression or by generally accepted tablet forming methods. Accordingly, compressed tablets are usually prepared by large-scale production methods while molded tablets often involve small-scale operations. For example, there are three general methods of tablet preparation: (1) the wet-granulation method; (2) the dry-granulation method; and (3) direct compression. These methods are well known to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing Co., Easton, Pa. (1980 and 1990). See also U.S. Pharmacopeia XXI, U.S. Pharmacopeial Convention, Inc., Rockville, Md. (1985).
• Various tablet formulations may be made in accordance with the present invention. These include tablet dosage forms such as sugar-coated tablets, film-coated tablets,
• LAl-2932341vl enteric-coated tablets multiple-compressed tablets, prolonged action tablets and the like.
• Sugar- coated tablets SCT are compressed tablets containing a sugar coating. Such coatings may be colored and are beneficial in covering up drug substances possessing objectionable tastes or odors and in protecting materials sensitive to oxidation.
• Film-coated tablets FCT are compressed tablets which are covered with a thin layer or film of a water-soluble material. A number of polymeric substances with film-forming properties may be used. The film coating imparts the same general characteristics as sugar coating with the added advantage of a greatly reduced time period required for the coating operation. Enteric-coated tablets are also suitable for use in the present invention.
• Enteric-coated tablets are compressed tablets coated with substances that resist dissolution in gastric fluid but disintegrate in the intestine. Enteric coating can be used for tablets containing drug substances which are inactivated or destroyed in the stomach, for those which irritate the mucosa or as a means of delayed release of the medication.
• MCT Multiple compressed tablets
• Layered tablets are prepared by compressing additional tablet granulation on a previously compressed granulation. The operation may be repeated to produce multilayered tablets of two, three or more layers. Typically, special tablet presses are required to make layered tablets. See, for example, U.S. Pat. No. 5,213,738, incorporated herein in its entirety by reference thereto.
• Press-coated tablets are another form of multiple compressed tablets. Such tablets, also referred to as dry-coated tablets, are prepared by feeding previously compressed tablets into a tableting machine and compressing another granulation layer around the preformed tablets.
• Press-coated tablets can also be used to separate incompatible drug substances. Further, they can be used to provide an enteric coating to the core tablets. Both types of tablets (i.e., layered tablets and press-coated tablets) may be used, for example, in the design of prolonged-action dosage forms of the present invention.
• compositions or unit dosage forms of the present invention in the form of prolonged-action tablets may comprise compressed tablets formulated to release the drug substance in a manner to provide medication over a period of time.
• tablet types that include delayed-action tablets in which the release of the drug substance is prevented for an interval of time after administration or until certain physiological conditions exist.
• LAI-2932341vl Repeat action tablets may be formed that periodically release a complete dose of the drug substance to the gastrointestinal fluids. Also, extended release tablets that continuously release increments of the contained drug substance to the gastrointestinal fluids may be formed. [00172]
• solid dosage forms e.g., tablets
• the material either in crystalline or amorphous form, possess a number of physical characteristics. These characteristics can include, for example, the ability to flow freely, as a powder to cohere upon compaction, and to be easily released from tooling.
• tablets and similar dosage forms may contain a number of materials referred to as excipients or additives. These additives are classified according to the role they play in the formulation of the dosage form such as a tablet, a caplet, a capsule, a troche or the like.
• additives include, but are not limited to, binders, diluents (fillers), disintegrants, lubricants, and surfactants.
• the diluent, binder, disi ⁇ tegrant, and lubricant are not the same.
• a binder is used to provide a free-flowing powder from the mix of tablet ingredients so that the material will flow when used on a tablet machine.
• the binder also provides a cohesiveness to the tablet. Too little binder will give flow problems and yield tablets that do not maintain their integrity, while too much can adversely affect the release (dissolution rate) of the drugs or active ingredients from the tablet.
• a sufficient amount of binder should be incorporated into the tablet to provide a free-flowing mix of the tablet ingredients without adversely affecting the dissolution rate of the drug ingredients from the tablet.
• compression aids With lower dose tablets, the need for good compressibility can be eliminated to a certain extent by the use of suitable diluting excipients called compression aids.
• the amount of binder used varies upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art.
• Binders suitable for use with dosage formulations made in accordance with the present invention include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone (povidone), methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.
• natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl
• microcrystalline cellulose or mixtures thereof.
• Suitable forms of microcrystalline cellulose can include, for example, the materials sold as AVICEL-PH-101 , AVICEL-PH-103 and AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa., U.S.A.).
• Fillers or diluents are used to give the powder (e.g., in the tablet or capsule) bulk so that an acceptable size tablet, capsule or other desirable dosage form is produced.
• therapeutic ingredients are formed in a convenient dosage form of suitable size by the incorporation of a diluent therewith.
• binding of the drug(s) to the filler may occur and affect bioavailability. Consequently, a sufficient amount of filler should be used to achieve a desired dilution ratio without detrimentally affecting release of the drug ingredients from the dosage form containing the filler.
• a filler that is physically and chemically compatible with the therapeutic ingredient(s) of the dosage form should be used.
• filler used varies upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art.
• examples of fillers include, but are not limited to, lactose, glucose, sucrose, fructose, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, or mixtures thereof.
• Disintegrants are used to cause the dose form (e.g., tablet) to disintegrate when exposed to an aqueous environment. Too much of a disintegrant will produce tablets which may disintegrate in the bottle due to atmospheric moisture. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of drug(s) or active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the drug ingredients should be used to form the dosage forms made according to the present invention. The amount of disintegrant used varies based upon the type of formulation and mode of administration, and is readily discernible to the skilled artisan.
• disintegrants include, but are not limited to, agar- agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, clays, other algins, other celluloses, gums, or mixtures thereof.
• a super disintegrant can be used, such as, but not limited to, croscarmellose sodium or sodium starch glycolate.
• super disintegrant means a disintegrant that results in rapid disintegration of drug or active ingredient
• LAI-2932341vl in the stomach after oral administration Use of a super disintegrant can facilitate the rapid absorption of drug or active ingredient(s) which may result in a more rapid onset of action.
• adhesion of the dosage form ingredients to the punches of manufacturing machines e.g., a tableting machine
• the tablet surfaces may become pitted and therefore unacceptable.
• sticking of drug or excipients in this way requires unnecessarily high ejection forces when removing the tablet from the die. Excessive ejection forces may lead to a high breakage rate and increase the cost of production not to mention excessive wear and tear on the dies.
• the lubricant is used to enhance the flow of the tableting powder mix to the tablet machine and to prevent sticking of the tablet in the die after the tablet is compressed. Too little lubricant will not permit satisfactory tablets to be made and too much may produce a tablet with a water-impervious hydrophobic coating, which can form because lubricants are usually hydrophobic materials such as stearic acid, magnesium stearate, calcium stearate and the like.
• a water-impervious hydrophobic coating can inhibit disintegration of the tablet and dissolution of the drug ingredient(s).
• a sufficient amount of lubricant should be used that readily allows release of the compressed tablet from the die without forming a water- impervious hydrophobic coating that detrimentally interferes with the desired disintegration and/or dissolution of the drug ingredient(s).
• Suitable lubricants for use with the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof.
• vegetable oil e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil
• zinc stearate ethyl oleate, ethyl laurate, agar, or mixtures thereof.
• Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore Md.), a coagulated aerosol of synthetic silica (marketed by Deaussa Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.) or mixtures thereof.
• AEROSIL 200 manufactured by W.R. Grace Co. of Baltimore Md.
• a coagulated aerosol of synthetic silica marketed by Deaussa Co. of Piano, Tex.
• CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.
• Surfactants are used in dosage forms to improve the wetting characteristics and/or to enhance dissolution, and are particularly useful in pharmaceutical compositions or dosage forms containing poorly soluble or insoluble drug(s) or active ingredients.
• surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, such as
• LAI-2932341vl those commercially available as TWEENs (e.g. Tween 20 and Tween 80), polyethylene glycols, polyoxyethylene stearates, polyvinyl alcohol, polyvinylpyrrolidone, poly(oxyethylene)/ poly(oxypropylene) block co-polyers such as poloxamers (e.g., commercially available as PLURONICs), and tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, such as polyxamines (e.g., commercially as TETRONICs (BASF)), dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OT, sodium lauryl sulfate, alkyl aryl polyether sulfonates or alcohols, such as TRITON X- 200 or tyloxapol, p-isononylphenoxypoly (gly
• Olin-IOG or Surfactant 10-G Olin Chemicals
• Other pharmaceutically acceptable surfactants are well known in the art, and are described in detail in the Handbook of Pharmaceutical Excipients, 4 th ed., Pharmaceutical Press, London, UK and American Pharmaceutical Association, Washington, DC (2003).
• additives for use with the pharmaceutical compositions or dosage forms of the present invention include, but are not limited to, anti-caking or antiadherent agents, antimicrobial preservatives, coating agents, colorants, desiccants, flavors and perfumes, plasticizers, viscosity increasing agents, sweeteners, buffering agents, humectants and the like.
• anti-caking agents include, but are not limited to, calcium silicate, magnesium silicate, silicon dioxide, colloidal silicon dioxide, talc, or mixtures thereof.
• antimicrobial preservatives include, but are not limited to, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride, chlorobutanol, cresol, dehydroacetic acid, ethylparaben, methylparaben, hydroxyphenyl, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimersol, thymol, or mixtures thereof.
• colorants for use with the present invention include, but are not limited to, pharmaceutically acceptable dyes and lakes, caramel, red ferric oxide, yellow ferric oxide or mixtures thereof.
• desiccants include, but are not limited to, calcium chloride, calcium sulfate, silica gel or mixtures thereof.
• Flavors that may be used include, but are not limited to, acacia, tragacanth, almond oil, anethole, anise oil, benzaldehyde, caraway, caraway oil, cardamom oil, cardamom seed, compound cardamom tincture, cherry juice, cinnamon, cinnamon oil, clove oil, cocoa, coriander oil, eriodictyon, eriodictyon fluidextract, ethyl acetate, ethyl vanillin, eucalyptus oil, fennel oil, glycyrrhiza, pure glycyrrhiza extract, glycyrrhiza fluidextract, lavender oil, lemon oil, menthol, methyl salicylate, monosodium glutamate, nutmeg oil, orange flower oil, orange flower
• sweetening agents include, but are not limited to, aspartame, dextrates, mannitol, saccharin, saccharin calcium, saccharin sodium, acesulfame potassium, sucralose (splenda(R) brand), sorbitol, sorbitol solution, or mixtures thereof.
• Exemplary plasticizers for use with the present invention include, but are not limited to, castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono-and di- acetylated monoglycerides, polyethylene glycol, propylene glycol, and triacetin or mixtures thereof.
• Suitable viscosity increasing agents include, but are not limited to, acacia, agar, alamic acid, aluminum monostearate, bentonite, bentonite magma, carbomer 934, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose sodium
• carrageenan cellulose, microcrystalline cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (Nos. 2208; 2906; 2910), magnesium aluminum silicate, methylcellulose, pectin, polyvinyl alcohol, povidone, silica gel, colloidal silicon dioxide, sodium alginate, tragacanth and xanthan gum or mixtures thereof.
• Buffering agents that may be used in the present invention include, but are not limited to, magnesium hydroxide, aluminum hydroxide and the like, or mixtures thereof.
• humectants include, but are not limited to, glycerol, other humectants or mixtures thereof.
• the dosage forms of the present invention may further include one or more of the following: (1) dissolution retarding agents, such as paraffin; (2) absorption accelerators, such as quaternary ammonium compounds; (3) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (4) absorbents, such as kaolin and bentonite clay; (5) antioxidants, such as water soluble antioxidants (e.g., ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite and the like), oil soluble antioxidants (e.g., ascorbyl palmitate, hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha- tocopherol and the like); and (6) metal chelating agents, such as citric acid, ethylenediamine tetracetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid,
• Dosage forms of the present invention may optionally be coated.
• Inert coating agents typically comprise an inert film-forming agent dispersed in a suitable solvent, and may further comprise other pharmaceutically acceptable adjuvants, such as colorants and plasticizers.
• Suitable inert coating agents, and methods for coating are well known in the art, including without limitation aqueous or non-aqueous film coating techniques or
• film-forming or coating agents include, but are not limited to, gelatin, pharmaceutical glaze, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, celluloses, such as methylcellulose, hydroxymethyl cellulose, carboxymethycellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose (e.g., Nos.: 2208, 2906, 2910), hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate (e.g., Nos.: 200731 , 220824), hydroxyethylcellulose, methylhydroxyethylcellulose, ethylcellulose which may optionally be cross- linked, and sodium carboxymethyl cellulose; vinyls, such as polyvinyl pyrrolidione, polyvinyl acetate phthalate,; glycols, such as polyethylene glycols; acrylics, such as dimethylaminoethyl methacrylate-methacrylate
• a coating of a film forming polymer may optionally be applied to a tablet or caplet
• a capsule shaped tablet in accordance with the present invention by using one of several types of equipment such as a conventional coating pan, Accelacota, High-Cola or Worster air suspension column.
• equipment typically has an exhaust-system to remove dust and solvent or water vapors to facilitate quick drying.
• Spray guns or other suitable atomizing equipment may be introduced into the coating pans to provide spray patterns conducive to rapid and uniform coverage of the tablet bed. Normally, heated or cold drying air is introduced over the tablet bed in a continuous or alternate fashion with a spray cycle to expedite drying of the film coating solution.
• the coating solution may be sprayed by using positive pneumatic displacement or peristaltic pump systems in a continuous or intermittent spray-dry cycle.
• the particular type of spray application is selected depending upon the drying efficiency of the coating pan. In most cases, the coating material is sprayed until the tablets are uniformly coated to the desired thickness and the desired appearance of the tablet is achieved.
• Many different types of coatings may be applied such as enteric, slow release coatings or rapidly dissolving type coatings for fast acting tablets.
• rapidly dissolving type coatings are used to permit more rapid release of the active ingredients, resulting in hastened onset.
• the thickness of the coating of the film forming polymer applied to a tablet may vary.
• the thickness simulate the appearance, feel (tactile and mouth feel) and function of a gelatin capsule. Where more rapid or delayed release of the therapeutic agent(s) is desired, one skilled in the art would easily recognize the film type and thickness, if any, to use based on characteristics such
• LAI-2932341vl as desired blood levels of active ingredient, rate of release, solubility of active ingredient, and desired performance of the dosage form.
• a number of suitable film forming agents for use in coating a final dosage form, such as tablets include, for example, methylcellulose, hydroxypropyl methyl cellulose (PHARMACOAT 606 6 cps), polyvinylpyrrolidone (povidone), ethylcellulose (ETHOCEL 10 cps), various derivatives of methacrylic acids and methacrylic acid esters, cellulose acetate phthalate or mixtures thereof.
• the method of preparation and the excipients or additives to be incorporated into dosage form are selected in order to give the tablet formulation the desirable physical characteristics while allowing for ease of manufacture (e.g., the rapid compression of tablets).
• the dose form preferably should have a number of additional attributes, for example, for tablets, such attributes include appearance, hardness, disintegration ability and uniformity, which are influenced both by the method of preparation and by the additives present in the tablet formulation.
• tablets or other dosage forms of the pharmaceutical compositions of the invention should retain their original size, shape, weight and color under normal handling and storage conditions throughout their shelf life.
• excessive powder or solid particles at the bottom of the container, cracks or chips on the face of a tablet, or appearance of crystals on the surface of tablets or on container walls are indicative of physical instability of uncoated tablets.
• the effect of mild, uniform and reproducible shaking and tumbling of tablets should be undertaken to insure that the tablets have sufficient physical stability.
• Tablet hardness can be determined by commercially available hardness testers.
• the in vitro availability of the active ingredients should not change appreciably with time.
• the tablets, and other dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
• a lubricant in pharmaceutical composition and dosage forms of the invention that include an ARB that is poorly soluble or insoluble in water.
• Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular,
• parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient.
• parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
• Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
• Compounds that increase the solubility of one or more of the active ingredients disclosed herein i.e., the compounds of this invention
• Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be
• Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Phanvaceutical Sciences, 16 th and 18 th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4 th ed., Lea & Febiger, Philadelphia (1985).
• Transdermal dosage forms include "reservoir type” or "matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
• Suitable excipients e.g., carriers and diluents
• other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
• additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention.
• penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
• the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
• the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
• Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
• stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.
• Different crystal or amorphous forms of the active ingredients can be used to further adjust the properties of the resulting composition.
• the suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
• the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water.
• Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition.
• This invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or di-saccharides.
• lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
• Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002).
• lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
• Preferred lactose- free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
• This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
• water e.g., 5%
• water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Carstensen, Drug Stability: Principles & Practice, 2 nd ed., Marcel Dekker, New York, NY, pp. 379-80 (1995).
• water and heat accelerate the decomposition of some compounds.
• the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly
• LAI-293234W1 encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
• Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
• Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
• anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. [00212] The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. [00213] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
• Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591 ,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference.
• Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, eudragit L-100, carnauba wax, magnesium stearate, methocel K4M CR, Surelease, Kollidon SR, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
• Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the compounds of this invention.
• LAI-2932341vl invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
• All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
• the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
• Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
• controlled- release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
• Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
• Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
• Certain embodiments of the invention provide delayed-release formulations comprising (-)-O-desmethylvenlafaxine, including salts thereof.
• the delayed-release formulation comprising (-)-O- desmethylvenlafaxine, including salts thereof, has an advantageous, e.g., slowed, dissolution profile of the (-)-O-desmethylvenlafaxine, including salts and derivatives thereof.
• the formulation comprises the ingredients as described in the "Formulation of Premix” and "Final Formulation” as provided in the Examples section, infra.
• active ingredients of the invention are preferably not administered to a patient at the same time or by the same route of administration.
• This invention therefore encompasses kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.
• a typical kit of the invention comprises a single unit dosage form of the compounds of this invention, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, clathrate or stereoisomer thereof, and a single unit dosage form of another agent that may be
• Kits of the invention can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers. [00219] Kits of the invention can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a pa rticu late-free sterile solution that is suitable for parenteral administration.
• Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
• aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
• water-miscible vehicles such as, but not limited to, ethyl alcohol
• compositions and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment, prevention or management of the above mentioned pathological conditions.
• O-desmethylvenlafaxine or salts thereof in the treatment, prevention and/or management of the conditions described herein results in clearer dose-related definitions of efficacy, diminished adverse effects, and accordingly an improved therapeutic index as compared to venlafaxine itself.
• the present invention provides methods of treating, preventing or managing one or more diseases, disorders or conditions by administering a therapeutic and/or prophylactic dose of a solid form comprising (-)-O-desmethylvenlafaxine described herein, e.g. a crystal form comprising a hydrochloride salt of (-)-O- desmethylvenlafaxine, to a subject, e.g. a human, in need of such treatment, prevention and/or management, wherein said diseases, disorders or conditions include, but are not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder,
• LAI-2932341vl attention deficit disorder with hyperactivity anxiety disorders, panic disorder, social anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder, borderline personality disorder, fibromyalgia, agoraphobia, obsessive compulsive disorder, anorexia and bulimia nervosa, obesity, weight gain, Gilles de Ia Tourette Syndrome, Shy-Drager syndrome, Alzheimer's disease, Parkinson's disease, epilepsy, narcolepsy, smoking cessation, drug craving, neurally mediated sexual dysfunction, pain, including chronic and neuropathic pain, cerebral function disorders, senile dementia, memory loss, amnesia/amnestic syndrome, disturbances of consciousness, coma, speech disorders, Lennox syndrome, autism, hyperkinetic syndrome, schizophrenia, migraine, obesity and weight gain, incontinence, chronic fatigue syndrome, sleep apnea, menopausal vasomotor symptoms such as hot flashes, disorders ameliorated by inhibition of neuronal monoamine uptake,
• the magnitude of a prophylactic or therapeutic dose of (-)-O- desmethylvenlafaxine (herein also referred to as an "active ingredient"), in the acute or chronic management of a disease will vary with the severity of the condition to be treated and the route of administration.
• the dose, and in certain embodiments the dose frequency, will also vary according to age, body weight, response, and the past medical history of the individual patient.
• the recommended daily dose range for the conditions described herein lie within the range of from about 10 mg to about 1000 mg per day.
• the recommended daily dose is given as a single once-a-day dose, e.g. in the morning.
• the recommended daily dose is given as divided doses throughout the day taken with food.
• a daily dose range is from about 50 mg to about 500 mg per day. In certain embodiments, a daily dose range is between about 75 mg and about 300 mg per day. In certain embodiments, a daily dose range is from about 50 mg to about 200 mg per day. In certain embodiments, a daily dose range is from about 25 mg to about 250 mg per day.
• the therapy should be initiated at a lower dose, perhaps about 50 mg to about 75 mg, and increased if necessary up to about 250 mg to about 325 mg per day as either a single dose or divided doses, depending on the patient's global response. If a dosage is increased, it is preferably done in intervals of about 75 mg separated by at least 4 days.
• LAI-2932341vl patients with mild to moderate renal impairment.
• the total daily dose be reduced by 5% and that the dose be withheld until the dialysis treatment is completed.
• (-)-O-desmethylvenlafaxine not be administered to patients currently taking such inhibitors.
• the concurrent administration of the compounds of this invention with other drugs, particularly other serotonin uptake inhibitors should be done with care. See, e.g., von Moltke, et al. Biol. Psychiat, 41 :377-380 (1997); and Sinclair, J. et al. Rev. Contemp. Pharmacother., 9:333-344 (1998).
• LAI-293234W1 effects associated with venlafaxine are also encompassed by the above described dosage amounts and dose frequency schedule.
• Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA). Routine chemical analyses were conducted using NMR, MS and HPLC. Significant NMR peaks are tabulated by chemical shift and labeled with multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet) and number of protons. Mass spectrometry data is provided in relation to the mass of the parent ion, M. HPLC data is provided as a purity percentage.
• X-ray powder diffraction (XRPD) data were obtained by one of the two following methods.
• XRPD analyses were performed using an lnel XRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 20 range of 120°.
• Real time data were collected using Cu-Ka radiation starting at approximately 2.5 °2 ⁇ at a resolution of 0.03 °2 ⁇ .
• the tube voltage and amperage were set to 40 kV and 30 mA, respectively.
• the slit was set at 5 mm by 130 or 160 ⁇ m.
• Samples were prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. The samples were analyzed for five or ten minutes. Instrument calibration was performed using a silicon reference standard.
• 6000 X-ray powder diffractometer using Cu-Ka radiation The instrument is equipped with a long fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A ⁇ -2 ⁇ continuous scan at 3 7min (0.4 sec/0.02 o step) from 2.5 to 40 °2 ⁇ was used. A silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6000 v. 4.1. Samples were prepared for analysis by placing them in a silicon sample holder.
• XRPD peak position is about ⁇ 0.1 °2 ⁇ .
• DSC was performed using a TA Instruments 2920 differential scanning calorimeter. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was covered with a lid and then crimped, unless otherwise noted. The sample cell was equilibrated at 25 0 C and heated under a nitrogen purge at a rate of 10 "C/rnin, up to a final temperature of 350 0 C. Indium metal was used as the calibration standard.
• Modulated DSC (MDSC) data were obtained on a TA Instruments 2920 differential scanning calorimeter equipped with a refrigerated cooling system (RCS). The sample was placed into an aluminum DSC pan, and the weight accurately recorded.
• RCS refrigerated cooling system
• the pan was covered with a lid and then crimped.
• MDSC data were obtained using a modulation amplitude of +/- 0.80 0 C and a 60 second period with an underlying heating rate of 2 °C/min from -20 to 120 0C.
• the temperature and the heat capacity were calibrated using indium metal and sapphire as the calibration standards, respectively.
• the reported glass transition temperature was obtained from the half-height/inflection of the step change in the reversible heat flow versus temperature curve.
• TGA analyses were performed using a TA Instruments 2950 thermogravimetric analyzer. Each sample was placed in an aluminum sample pan and inserted into the TGA furnace. Conditions of routine thermal gravimetric analysis involved equilibrating the furnace at 25 0 C 1 followed by heating under nitrogen at a rate of 10 °C/min up to a final temperature of 350 0C. Modifications were made to this procedure in cases involving non-routine analysis, such as not equilibrating prior to heating, heating at different rates and heating to temperatures below 350 0C. Nickel and AlumelTM were used as calibration standards.
• Hot stage microscopy was performed using a Linkam hot stage (model FTIR 600) mounted on a Leica DM LP microscope. Samples were observed using a 20 ⁇ objective and a lambda plate with crossed polarizers. Samples were placed on a coverslip, and another coverslip was then placed over the sample. Each sample was visually observed as the stage was heated. Images were captured using a SPOT InsightTM color digital camera with SPOT Software v. 3.5.8. The hot stage was calibrated using USP melting point standards.
• TG-IR analyses were acquired on a TA Instruments 2050 TGA analyzer interfaced to a Magna 560® FT-IR spectrophotometer (Thermo Nicolet) equipped with an Ever- GIo mid/far IR source, a potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
• the TGA instrument was operated under a flow of helium at 90 and 10 cc/min for the purge and balance, respectively. Each sample was placed in a platinum sample
• LAI-2932341vl pan inserted into the TGA furnace, accurately weighed by the instrument, and the furnace was heated from 20 0 C to 200 or 250 0 C at a rate of 20 °C/min.
• the TGA instrument was started first, immediately followed by the FT-IR instrument. Each IR spectrum represents 32 co-added scans collected at a spectral resolution of 4 cm "1 . A background scan was collected before beginning the experiment. Wavelength calibration was performed using polystyrene.
• the TGA calibration standards were nickel and AlumelTM. Volatiles were identified from a search of the High Resolution Nicolet TGA Vapor Phase spectral library.
• Sorption Analyzer Sorption and desorption data were collected over a range of 5% to 95% relative humidity (RH) at 10% RH intervals under a nitrogen purge. For some samples, a step at 90% RH was added to the sorption cycle. Samples were not dried prior to analysis. Equilibrium criteria used for analysis were less than 0.0100% weight change in 5 minutes, with a maximum equilibration time of 3 hours if the weight criterion was not met. Data were not corrected for the initial moisture content of the samples. NaCI and PVP were used as calibration standards. [00238] The IR spectra were acquired on a Magna-IR 860® FT-IR spectrophotometer
• Thermo Nicolet equipped with an Ever-Glo mid/far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
• An attenuated total reflectance (ATR) accessory (the ThunderdomeTM, ThermoSpectra-Tech), with a germanium (Ge) crystal was used for data acquisition.
• Each spectrum represents 256 co-added scans collected at a spectral resolution of 4 cm "1 .
• a background data set was acquired with air.
• FT-Raman spectra were acquired on a Raman accessory module interfaced to a Magna 860® FT-IR spectrophotometer (Thermo Nicolet). This module used an excitation wavelength of 1064 nm and an indium gallium arsenide (InGaAs) detector. Approximately 0.7 W of Nd:YVO 4 laser power was used to irradiate the sample. The samples were prepared for analysis by placing the material in a glass tube or capillary, which was then positioned in a gold-coated tube or capillary holder in the accessory. A total of 256 sample scans were collected at a spectral resolution of 4 cm "1 , using Happ-Genzel apodization. Wavelength calibration was performed using sulfur and cyclohexane.
• FT-Raman spectra were acquired on an FT-Raman 960 spectrometer (Thermo Nicolet). This module used an excitation wavelength of 1064 nm and an indium gallium arsenide (InGaAs) detector. Approximately 1 W of Nd:YVO 4 laser power was used to irradiate the sample. The samples were prepared for analysis by placing the material in
• LAI-2932341vl a glass tube or capillary, which was then positioned in a gold-coated tube or capillary holder in the accessory.
• a total of 256 sample scans were collected at a spectral resolution of 4 cm '1 , using Happ-Genzel apodization. Wavelength calibration was performed using sulfur and cyclohexane.
• a first method comprises the isolation of (-)-venlafaxine, followed by selective demethylation.
• a second method comprises separating a racemic mixture of ( ⁇ )-O- desmethylvenlafaxine into its optically pure components.
• a third method comprises synthesizing ( ⁇ )-O-benzyl-O-desmethylvenlafaxine, separating the resulting optically pure components, and debenzylating said components.
• LAI-2932341vl 6.2.1.2 1-[2-Amino-1-(4-methoxyphenyl)ethyl]cyclohexanol
• the aqueous layer was cooled in ice/water and was basified by slow addition of 50% NaOH.
• the aqueous layer was extracted with ethyl acetate (3*75 mL). Combined ethyl acetate layer was washed with water (3*25 mL), brine (1 *25 mL) and dried (Na 2 SO 4 ). Ethyl acetate was evaporated in vacuo to give yellow gum that turned slowly in to pale yellow solid (34.0 g, 92.6% yield).
• Venlafaxine hydrochloride was prepared from venlafaxine freebase by the addition of hydrochloric acid in an appropriate solvent or according to US patent # 4535186. [00247] A mixture of 2.50 kg of 1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl) cyclohexanol hydrochloride, 16.8 kg of ethyl acetate and 14.0 kg of 1 N NaOH (aq) was stirred for 15 min. The stirring was stopped and the lower layer removed. The organic layer was washed twice with 3.5 kg of water.
• LAI-2932341vl stirred for 1 hour. It was then refluxed overnight. The reaction was cooled to room temperature and was poured slowly into 30 mL cold 3N HCI maintaining the temperature below 15 0 C. After stirring for 10 minutes, the aqueous layer was extracted with ethyl acetate (3*30 mL). The aqueous layer was adjusted to pH 6.8-6.9 by slow addition of solid NaHCO 3 . It was then saturated by adding NaCI and was extracted with ethyl acetate (6*30 mL). Combined ethyl acetate layer was dried (Na 2 SO 4 ), ethyl acetate was evaporated in vacuo to give colorless solid.
• (-)-O-desmethylvenlafaxine was prepared from (-)-venlafaxine by following the procedure described above.
• (-)-O-desmethylvenlafaxine can also be directly prepared from (-)-venlafaxine- hemi-DTTA salt by following the procedure described below.
• a solution of lithium diphenylphosphide was generated by adding 6.2 kg of n- butyllithium, 1.6M (15%wt) to a mixture of 22.9 kg of tetrahydrofuran and 2.2 kg of diphenylphosphine.
• the THF solution of (-)-venlafaxine was added to the lithium diphenylphosphide.
• the mixture was stirred at 50 0 C and hold until reaction is complete (approximately 24 hr).
• the mixture was cooled to 22 0 C, 11.95 kg of Dl water and 3.94 kg of 6N HCI was added. The mixture was stirred for 15 minutes, the stirring stopped and the upper
• LAI-2932341vl organic phase was removed and discarded.
• the aqueous layer was washed twice with 7.98 kg of methylene chloride.
• the pH of the aqueous was adjusted to 9.5 using concentrated ammonium hydroxide.
• 19.4 kg of 2-methyltetrahydrofuran was added.
• the mixture was heated to 65°C and the aqueous phase was removed.
• the organic was washed at 65 0 C with 8 kg of water and the organic was concentrated to 4.5 L. 14.3 kg of ethyl acetate was added and the mixture stirred at 45-55 0 C for 30 minutes. The mixture was stirred at 0 0 C for 30 min.
• (-)-O-desmethylvenlafaxine was synthesized via the resolution of ( ⁇ )-O- desmethylvenlafaxine.
• LAI-2932341vl 1.0 g of ( ⁇ )-O-desmethylvenlafaxine, 0.89 g (24 mmol) of (R)-1-phenyl-1- cyclohexyl-1-hydroxyacetic acid, 7.9 g of ethanol and 1.05 g of water were charged to a 25 mL flask. The mixture was stirred at 75 0 C for 30 min and cooled to room temperature. The resulting solid was collected by filtration and washed with ethanol.
• (R)-1-Phenyl-1-cyclohexyl-1-hydroxyacetic acid is made according to the procedure outlined in Tetrahedron: Asymmetry 14 (2003) 3593, which is hereby incorporated by reference.
• the following procedure was employed. 150 g of 2-(4- benzyloxy)phenyl-N,N-dimethylacetamide, 945 g (1062 mL) of THF was charged to a 5 L jacketed reactor. 550 mL of isopropylmagnesium chloride (2.0 M in tetrahydrofuran) was added and the mixture was stirred for 1 h. 115 g of cyclohexanone was added to the reactor and mixed for 1 h. 360 g of RedAI (sodium bis(2-methoxyethoxy)aluminum hydride-65% w/w in toluene) was added to the reactor and stirred for 16 h. When the reaction was complete the mixture was
• LAI-2932341vl added to 2005 g of 22% w/w aqueous citric acid.
• 420 g (600 mL) of heptane was charged to the reactor and stirred for 15 min. The stirring was stopped and the top layer was removed. 250 g of 50% NaOH was added to adjust the pH to 9-10, followed by stirring. 1114 g (1500 mL) of MTBE was added to the reactor. The mixture was warmed to 45 ⁇ 5°C to dissolve the solids. The stirring was stopped and the bottom layer was removed. The organic layer was washed twice with 750 g of water at 45 0 C. 750 mL of MTBE was removed by distillation and 750 mL of methanol was added.
• the reactor was charged 169.9 kg of MTBE and the temperature was adjusted to 40-50 0 C. The contents were agitated for 14 minutes and the agitation was stopped to allow the phases to separate for 15 minutes. The aqueous layer was removed and 115 L of USP purified water was added. The temperature was adjusted to 40 0 C to 50 0 C. The contents were agitated for 15 minutes and the agitation was stopped to allow the phases to separate for 13 minutes. The aqueous bottom layer was removed. The reactor was charged with 115 L of USP purified water and the temperature was adjusted to 40 0 C to 50 0 C. The contents were agitated for 15 minutes and the agitation was stopped to allow the phases to separate. The aqueous bottom layer was removed. The solution was distilled under vacuum to a final volume of 188 L. To the reactor
• LAI-2932341vl was charged 115.2 kg of methanol and the solution was distilled under vacuum to a final volume of 131 L.
• To the reactor was charged 46.0 kg of methanol and 57 L of USP purified water. The temperature was adjusted to 0 0 C. The slurry was stirred for 41 minutes at -5 0 C to 5 C C and the mixture was filtered. The cake was washed with 46.2 kg of methanol and 11.6 kg of USP purified water (cooled to -5 0 C to 5 0 C). The wet cake (30.66 kg) was dried at 40-50 0 C to yield 24.47 kg of 1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol.
• the following procedure was employed. To a reactor was charged 60.64 kg of 1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol, 42.01 kg of D-di-p-toluoyltartaric acid, 512.7 kg of acetone, and 61 L of USP purified water. The temperature was adjusted to 50 0 C to 55 0 C, and the contents were agitated at this temperature range for 16 minutes. The mixture was cooled to 36 0 C and stirred at 36 0 C for a period of 35 minutes. The mixture was cooled to -2 0 C to 2 0 C over 105 minutes and agitated for 122 minutes.
• LAI-2932341vl 1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol.
• the mixture was agitated at 48 0 C to 52 0 C for 25 minutes, the agitation was stopped and the phases were allowed to separate for a period of 7 minutes.
• the aqueous bottom phase was removed and 179.8 kg of USP purified water was added.
• the mixture was agitated at 48 C C to 52 0 C for 17 minutes, the agitation was stopped and the phases were allowed to separate for a period of 7 minutes.
• the aqueous bottom layer was removed and the solution was distilled to a final volume of 170 L. 265.7 kg of methanol was added and the solution was distilled to a final volume of 170 L.
• the reaction was cooled to 23 0 C to 27 0 C over 1 hour and 9 minutes.
• the mixture was cooled to 20 0 C and seeded with 20 g of 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl) cyclohexanol hydrochloride monohydrate.
• the mixture was stirred for 2 h at 40 0 C and 6.06 kg of MtBE was added over 8 hours.
• the mixture was stirred for 2h and cooled to 0 0 C.
• the slurry was filtered, washed with 1.67 kg of MTBE:ethanol (5.4:1) and 1.66 kg of MTBE to yield after drying 1.1 kg of 1-(2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl) cyclohexanol hydrochloride monohydrate.
• the resulting product was confirmed to be form A.
• the following procedure was employed.
• the reactor was charged with 31.80 kg of (f?)-1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol.
• the atmosphere of the reactor was evacuated and replaced with nitrogen three times to exclude air.
• the reactor was charged with 56.1 kg of ethanol followed by 17.4 kg of 20 wt% HCI solution.
• the temperature was adjusted to 20-25 0 C.
• the solids completely dissolved after 35 minutes while bubbling nitrogen through the solution to degas.
• the reaction was pressurized once with 45 to 55 psig of hydrogen, vented, and then repressurized to 45 to 55 psig with hydrogen.
• the mixture was agitated at 20 to 30 0 C until the reaction was complete.
• the hydrogen was vented and the reactor was pressurized with nitrogen to 50 to 60 psig three times.
• the reaction mixture was filtered through a 3 ⁇ m filter and the reactor/filter was rinsed with 12.0 kg of ethanol.
• the combined filtrate/washes were added to 157.0 kg of MTBE at 40 0 C to 45 0 C. Seeds of the hydrochloride salt of (-)-O-desmethylvenlafaxine (635g) were added and the mixture was mixed for 2 hours and 4 minutes at 35 0 C to 45 0 C.
• Determination of receptor binding of the compounds of this invention preferably is performed by the methods disclosed by Muth et al., and using the protocols summarized in U.S. Patent Nos. 6,342,533 B1 , 6,441 ,048 B1 and 6,911 ,479 B2.
• tissue homogenates used are preferably whole brain except cerebellum
• cortex corthelial adrenergic receptor binding, monoamine uptake
• striatum dopamine-2 and muscarinic cholinergic receptor binding
• a P2 pellet is prepared from fresh rat brain tissue by sucrose density gradient centrifugation using a vertical rotor.
• buffer 135 mM NaCI, 5 mM KCI, 1.2 mM MgCI 2 , 2.5 mM CaCI 2 , 10 mM glucose, 1 mM ascorbic acid, 20 mM Tris, pH 7.4, gassed with O 2 for 30 min prior to use.
• test drug Various concentrations of test drug are preincubated with 0.1 ⁇ M [ 3 H]dopamine or 0.1 ⁇ M [ 3 H]norepinephrine (130,000 dpm/tube) and 0.1 ⁇ M [ 14 C]serotonin (7,500 dpm/tube) in 0.9 ml buffer for 5 min at 37 0 C.
• One-tenth milliliter of synaptosomal preparation is added to each tube and incubated for a further 4 min at 37 0 C.
• the reaction is then terminated by the addition of 2.5 ml buffer, after which the mixture was filtered under vacuum using cellulose acetate filters (0.45
• Test compounds suspended or solubilized in 0.25% Tween ⁇ O® in water, are then administered i.p. at several dose levels to male mice (8/dose level) who had been treated 18 hr previously with 45.0 mg/kg reserpine s.c.
• a vehicle control group is run simultaneously with drug groups.
• Test compounds, vehicle, and reserpine are administered at a volume of 0.01 ml/g.
• Reserpine is solubilized by the addition of a small amount (approximately 4 drops) of concentrated acetic acid and then brought to the proper volume by the addition of distilled water. Rectal temperatures are recorded by a Yellow Springs Instruments thermistor probe at a depth of 2 cm. Measurements are taken 18 hr after reserpine pretreatment and at hourly intervals for 3 hr following administration of either test compound or vehicle.
• Rectal temperatures for all time periods are subjected to a two-way analysis of variance for repeated measures with subsequent Dunnett's comparison to control values to determine the minimum effective dose (MED) for antagonizing reserpine-induced hypothermia.
• MED minimum effective dose
• Suitable rats are male Sprague-Dawley rats (250-300 g, Charles River) which should be maintained in continuous light throughout all experiments so as to attenuate the diurnal fluctuation in beta-adrenergic receptor density in the pineal gland and to maintain a consistent supersensitive response to noradrenergic agonists (Moyer, J. A. er a/. Soc. Neurosci. Abstract 10:261 (1984)). After 2 days of continuous light exposure, the rats are then injected twice daily with either saline or test compound (10 mg/kg i.p.) for 5 days (total of 9 injections).
• mice should receive saline injections twice daily for 4 days followed by a single injection of test compound (10 mg/kg i.p.) on the 5th day.
• test compound 10 mg/kg i.p.
• animals are administered either 0.1% ascorbic acid (controls), or isoproterenol (2 ⁇ mol/kg i.p. in 0.1% ascorbic acid). Rats are decapitated 2.5 minutes later, the time at which preliminary experiments have shown that the isoproterenol-induced increases in cyclic AMP levels in pineal glands are maximal (Moyer, J. A. er a/. MoI. Pharmacol. 19:187-193
• the rat brain A stereotaxic atlas of the forebrain and lower parts of the brain stem Baltimore: Williams and Wilkins (1963), the electrode tips should be lowered via a hydraulic microdrive from a point 1.00 mm above the locus coeruleus (AP 2.00 mm caudal to the interaural line and 1.03 mm lateral to midline). Drugs are administered i.v. through a lateral tail vein cannula. Only one cell should be studied in each rat in order to avoid residual drug effects.
• compositions of this invention may be administered in a variety of ways, including orally.
• suitable capsule forms of the pharmaceutical compositions of this invention may be found in U.S. Patent Nos. 6,342,533 B1 , 6,441 ,048 B1 and 6,911 ,479 B2.
• the active ingredient (optically pure (-)-O-desmethylvenlafaxine, or pharmaceutically acceptable salt thereof) is sieved and blended with the excipients listed. The mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery and
• LAI-2932341vl methods well known in the art. See Remington's Pharmaceutical Sciences, 16th or 18th Editions, each incorporated herein in its entirety by reference thereto.
• Other doses may be prepared by altering the fill weight and, if necessary, by changing the capsule size to suit. Any of the stable hard gelatin capsule formulations above may be formed.
• the active ingredient is sieved through a suitable sieve and blended with the excipients until a uniform blend is formed.
• the dry blend is screened and blended with the magnesium stearate.
• the resulting powder blend is then compressed into tablets of desired shape and size. Tablets of other strengths may be prepared by altering the ratio of the active ingredient to the excipient(s) or modifying the tablet weight.
• (-)-O-desmethylvenlafaxine was crystallized as Form A of the HCI salt of (-)-O- desmethylvenlafaxine.
• the freebase of (-)-O-desmethylvenlafaxine was prepared according to Example 1.
• Form A of the HCI salt of (-)-O-desmethylvenlafaxine was prepared from Form B of (-)-O-desmethylvenlafaxine HCI salt, described below, according to the following procedure: A 3.09 gram sample of (-)-O-desmethylvenlafaxine hydrochloride salt (form B) was placed in a 70 X 50 mm crystallization dish and stored at 40°C/75%RH for 3 days. The sample was then dried under vacuum at ambient temperature for 2 days.
• Form A crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by analytical techniques including thermal gravimetric analysis, differential scanning calorimetry, X-ray powder diffraction, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the analytical parameters described supra.
• LAI-2932341vl 276:307 (1997)).
• the space group was determined using the program XPREP (Bruker AXS Inc., Madison, Wisconsin, USA, (2002)). Data integration was performed with DENZO-SMN (Otwinowski and Minor, Methods Enzymol. 276:307 (1997)). An empirical absorption correction was applied, obtained using SCALEPACK (Otwinowski and Minor, Methods Enzymol. 276: 307 (1997)).
• SIR2004 Bitmap et al., J. Appl. Cryst, 36:1103 (2003)
• refinements were performed on an LINUX PC using SHELX97 (Sheldrick, University of G ⁇ ttingen, Germany, (1997)).
• FIG. 7 An ORTEP drawing of the asymmetric unit from the single crystal structure solution of the Form A crystal form of the HCI salt of (-)-O-desmethylvenlafaxine is shown in FIG. 7 (ORTEP-3 for Windows, v. 1.05. Farrugia, J. Appl. Cryst, 30:565 (1997)).
• the asymmetric unit shown in the drawing contains one (-)-O-desmethylvenlafaxine cation, one chloride anion and one water molecule.
• PowderCell 2.3 (Kraus and Nolze, Federal Institute for Materials Research and Testing, Berlin, Germany, (1999)) with the atomic coordinates, space group, and unit cell parameters from the single crystal data of Form A; see FIG. 8.
• the Form A experimental X-ray powder diffraction pattern matched the pattern simulated from the single crystal X-ray diffraction data. Slight shifts in XRPD peak location resulted from small changes in the unit cell parameters due to temperature differences: the calculated X-ray powder diffraction pattern was generated from the
• LAI-2932341vl single crystal data which was collected at 150 K 1 while the experimental powder pattern was collected at ambient temperature. Collecting data at low temperature is typically used in single crystal analysis to improve the quality of the data.
• (-)-O-desmethylvenlafaxine was crystallized as Form B of the HCI salt of (-)-O- desmethylvenlafaxine.
• (-)-O-Desmethylvenlafaxine was prepared according to Example 1. 5.07 g of the HCI salt of (-)-O-desmethylvenlafaxine was dissolved in 400 mL of tetrahydrofuran at 40 0C. The solution was cooled to 25 0 C and 10.6 mL of 2.0 M HCI in diethyl ether was added. The mixture was cooled to 0 0 C and filtered.
• Form B crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the analytical parameters described above.
• (-)-O-Desmethylvenlafaxine was crystallized as Form C of the HCI salt of R-O- desmethylvenlafaxine.
• (-)-O-Desmethylvenlafaxine was prepared according to Example 1. 0.18 g of (-)-O-desmethylvenlafaxine and 0.35 mL of 37 wt% aqueous hydrochloric acid were mixed at 60 0 C for 1 h. The mixture was cooled to 0 0 C, filtered and washed with ethyl acetate. The solid was dried in vacuo at ambient temperature to yield 0.22 g of 1-(2-(dimethylamino)-1- (4-hydroxyphenyl)ethyl) cyclohexanol hydrochloride.
• Form C crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the analytical parameters described above.
• (-)-O-desmethylvenlafaxine was crystallized as Form D of the HCI salt of (-)-O- desmethylvenlafaxine.
• (-)-O-desmethylvenlafaxine was prepared according to Example 1.
• Form A (42.8 mg) of (-)-O-desmethylvenlafaxine HCI salt, obtained as described in Example 4, was weighed into a vial, and 0.5 mL of IPA was added. The sample was sonicated, and became very thick. The solids were isolated by vacuum filtration, and the sample was air dried in a hood. After a day of drying, the sample was stored at ambient conditions for four days, at which point the XRPD analysis was performed.
• Form D crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, differential scanning calorimetry and thermal gravimetric analysis, according to the analytical parameters described above.
• (-)-O-Desmethylvenlafaxine was crystallized as Form E of the HCI salt of (-)-O- desmethylvenlafaxine.
• (-)-O-Desmethylvenlafaxine was prepared according to Example 1. 0.35 mL of 37 wt% aqueous hydrochloric acid was added to 5.0 g of (-)-O-desmethylvenlafaxine in 25 mL of methanol. The resulting solution was stirred at 25 0 C for 20 minutes. The methanol/hydrochloric acid solution was added with stirring to 300 mL of methyl-tert butyl ether at 25 0 C. Following the addition of the methanol/hydrochloric acid solution the mixture was stirred at 25 0 C for 2 hours and then the solid was collected by filtration and washed with 20 mL of
• Form E crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the analytical parameters described above.
• Form A of the HCI salt of (-)-O-desmethylvenlafaxine (19.47 mg) was weighed into a vial, and 3 mL of ethyl acetate was added. Solids remained after sonication.
• the sample was placed on a hot plate set at 75 0 C, and stirred using a magnetic stirrer set at 350 rpm. After approximately 2.5 hours of stirring at 75 0 C, the sample was syringe filtered into a warm, 1-dram vial. (Prior to filtering, the filter, syringe, and vial were warmed on the hot plate with the sample.) The sample was capped, set on the bench top, and allowed to cool to ambient temperature. The sample was vacuum filtered and analyzed as Form F.
• Form F crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis, moisture sorption, infrared spectroscopy and Raman spectroscopy, according to the analytical parameters described above.
• Crystals of Form F of the HCI salt of (-)-O-desmethylvenlafaxine suitable for single crystal X-ray diffraction were prepared by a vapor diffusion technique. Three milliliters of 2- butanone were added to 7.71 mg of Form A, obtained as described above. Not all of the solids dissolved. The sample was filtered into a 1 dram vial. The vial was placed into a 20 mL scintillation vial containing toluene. The larger vial was then capped, and the sample was allowed to equilibrate. Single crystals of Form F were isolated, and the structure was solved.
• FIG. 37 An ORTEP drawing of the asymmetric unit from the single crystal structure solution of the Form F crystal form of the HCI salt of (-)-O-desmethylvenlafaxine is shown in FIG. 37 (ORTEP-3 for Windows, v. 1.05. Farrugia, J. Appl. Cryst, 30:565 (1997)).
• the asymmetric unit shown in the drawing contains one (-)-O-desmethylvenlafaxine cation, one chloride anion and one water of hydration.
• PowderCell 2.3 (Kraus and Nolze, Federal Institute for Materials Research and Testing, Berlin, Germany, (1999)) and the atomic coordinates, space group, and unit cell parameters from the single crystal data of Form F; see FIG. 33.
• the Form F experimental X-ray powder diffraction pattern matched the pattern simulated from the single crystal X-ray diffraction data. Differences in intensities may have resulted from preferred orientation. Preferred orientation is the tendency for crystals, usually plates or needles, to align in a non-random manner. Preferred orientation affects peak intensities in X-ray powder diffraction patterns. Slight shifts in peak location may have resulted from experimental temperature differences: the experimental powder pattern was collected at ambient temperature, while the single crystal data was collected at 173 K. Certain
• LAI-2932341vl Form F samples which were isolated as physical mixtures with Form A exhibited peaks characteristic of Form A in the XRPD pattern, which were not present in the simulated Form F XRPD pattern.
• (-)-O-desmethylvenlafaxine was crystallized as Form G of the HCI salt of (-)-O- desmethylvenlafaxine.
• (-)-O-desmethylvenlafaxine was prepared according to Example 1.
• the Form A crystal form of (-)-O-desmethylvenlafaxine (31.50 mg), prepared according to Example 4, was placed into a 20 mL scintillation vial, which was placed, uncapped, into a P 2 O 5 chamber at ambient temperature. After three days, the chamber containing the sample was placed into a 70 0C oven. Analysis performed ten days after the sample was placed in the oven indicated that the sample was Form G.
• Form G crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis and moisture sorption, according to the analytical parameters described above.
• (-)-O-desmethylvenlafaxine was crystallized as Form H of the HCI salt of (-)-O- desmethylvenlafaxine.
• (-)-O-desmethylvenlafaxine was prepared according to Example 1.
• Form H was prepared by slurring Form A of the HCI salt of (-)-O-desmethylvenlafaxine in acetone on a hot plate set at 55 0 C. The samples were stirred in half dram vials on the hot plate using a magnetic stirrer set at 300 rpm. In each case, 0.5 mL of acetone was used.
• (-)-O-desmethylvenlafaxine was crystallized as Form I of the HCI salt of (-)-O- desmethylvenlafaxine.
• (-)-O-desmethylvenlafaxine was prepared according to Example 1. Form I was precipitated from isopropanol. One sample was prepared by dissolving 46.01 mg of Form A of the HCI salt of (-)-O-desmethylvenlafaxine in 0.5 mL isopropanol using sonication. The sample was prepared in a 1-dram vial. Precipitation was observed after approximately 10-15 minutes. The solids were isolated by vacuum filtration.
• the second sample was prepared using the procedure described for the first sample, except that 25.86 mg of Form A of the HCI salt of (-)-O-desmethylvenlafaxine was dissolved. Precipitation for this second sample was observed after approximately ten minutes. Following synthesis, solids were isolated and characterized as the Form I crystal form of the HCI salt of (-)-O-desmethylvenlafaxine.
• Form I crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, differential scanning calorimetry and thermal gravimetric analysis, according to the analytical parameters described above.
• (-)-O-desmethylvenlafaxine was crystallized as Form J of the HCI salt of M-O- desmethylvenlafaxine.
• (-)-O-desmethylvenlafaxine was prepared according to Example 1.
• Form J of the HCI salt of (-)-O-desmethylvenlafaxine was prepared by slurring Form A in acetonitrile for approximately one day on a hot plate set at 55 0 C.
• Form A of the HCI salt of M-O- desmethylvenlafaxine 43.66 mg
• Form J crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, and NMR spectroscopy, according to the analytical parameters described above. About 0.2 mole of acetonitrile per mole of the HCI salt of (-)-O-desmethylvenlafaxine was present in a Form J sample, as observed using NMR spectroscopy.
• EXAMPLE 14 CRYSTALLIZATION AND CHARACTERIZATION OF FORM K OF THE HYDROCHLORIDE SALT OF (-)-O-DESMETHYLVENLAF AXINE.
• (-)-O-desmethylvenlafaxine was crystallized as Form K of the HCI salt of (-)-O- desmethylvenlafaxine.
• (-)-O-desmethylvenlafaxine was prepared according to Example 1.
• Form K of the HCI salt of (-)-O-desmethylvenlafaxine was prepared from a vapor diffusion experiment using ethanol as the solvent and acetone as the antisolvent.
• the sample was prepared by adding 0.3 mL of ethanol to 22.20 mg of Form A of the HCI salt of (-)-O-desmethylvenlafaxine.
• the sample dissolved and was filtered into a 1-dram vial.
• the vial was placed into a 20 mL scintillation vial containing acetone.
• the larger vial was then capped, and the sample was allowed to equilibrate. Single crystals were isolated from this experiment.
• the crystals thus obtained were characterized as the Form K crystal form of the HCI salt of (-)-O-
• Form K crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, and single-crystal X-ray diffraction, according to the analytical parameters described above.
• LAI-2932341vl refinements were all carried out using the software APEX Il (Bruker AXS, Inc., Madison, Wl, USA (2005)). Frame integration and final cell refinements were done using the software SAINT (v. 6.45A, Bruker AXS, Inc., Madison, Wl, USA (2003)). The space group was determined by the program XPREP (SHELXTL v. 6.12, Bruker AXS, Inc., Madison, Wl, USA). An empirical absorption correction was applied using SADABS (Blessing, Acta Cryst, A51 :33 (1995)). The structure was solved by direct methods using SHELXS-97 (Sheldrick, University of G ⁇ ttingen, Germany, (1997)).
• the complete contents of the asymmetric unit of the crystal structure of Form K includes two (-)-O-desmethylvenlafaxine cations, two chloride anions and one partially occupied, highly disordered ethanol molecule. Since the ethanol molecule is not fully occupied, Form K is termed a partial ethanol solvate.
• PowderCell 2.3 (Kraus and Nolze, Federal Institute for Materials Research and Testing, Berlin, Germany (1999)) and the atomic coordinates, space group, and unit cell parameters from the single crystal data of Form K; see FIG. 50.
• the Form K experimental X-ray powder diffraction pattern matched the pattern simulated from the single crystal X-ray diffraction data. Differences in intensities may have resulted from preferred orientation. Slight shifts in peak location may have resulted from experimental temperature differences: the experimental powder pattern was collected at ambient temperature, while the single crystal data was collected at 173 K.
• (-)-O-desmethylvenlafaxine was crystallized as Form L of the HCI salt of (-)-O- desmethylvenlafaxine.
• (-)-O-desmethylvenlafaxine was prepared according to Example 1.
• Form L was prepared from a prolonged ambient temperature slurry in 2-methyl-tetrahydrofuran. The sample was prepared by adding 20 mL of 2-methyl-tetrahydrofuran to 38.75 mg of Form A of the HCI salt of (-)-O-desmethylvenlafaxine. A 20 mL scintillation vial was used for the experiment, and the 2-methyl-tetrahydrofuran was added slowly.
• Solids were present after the solvent addition, and the sample was capped and placed on a rotating wheel at ambient temperature. After 97 days on the wheel, the sample of Form L was removed, vacuum filtered, and submitted for analysis. The solids thus obtained were characterized as the Form L crystal form of the HCI salt of (-)-O-desmethylvenlafaxine.
• the Form L crystal form of the HCI salt of (-)-O-desmethylvenlafaxine prepared according to the procedure above was characterized by techniques such as X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis and NMR spectroscopy, according to the analytical parameters described above. Between about 0.13 and 0.14 mole of 2-methyl-tetrahydrofuran per mole of the HCI salt of (-)-O-desmethylvenlafaxine was present in a Form L sample, as observed using NMR spectroscopy.
• Form C of the HCI salt of (-)-O-desmethylvenlafaxine was prepared as described above. Form C was heated to 100 0 C in a TGA furnace, according to the procedure described above, and a weight loss of 5.4% was observed. The material was removed from the furnace; analysis confirmed that the material was a desolvated solvate.
• the desolvated solvate was analyzed by X-ray powder diffraction.
• the locations of the peaks in the X-ray powder diffraction pattern of the desolvated solvate were similar to the locations of the XRPD peaks in the Form C starting material. This data, in conjunction with the
• LAI-2932341vl TGA weight loss data indicated that the solvent evacuated the crystal lattice of Form C while maintaining structural features of Form C in the form of a desolvated solvate.
• (-)-O-desmethylvenlafaxine was prepared as an amorphous form of the HCI salt of (-)-O-desmethylvenlafaxine.
• An aqueous solution of the HCI salt of (-)-O- desmethylvenlafaxine was prepared, filtered and frozen. The sample was then placed under vacuum on a freeze dryer and lyophilized until all solvent had been removed.
• the resulting product was characterized by X-ray powder diffraction and modulated differential scanning calorimetry. XRPD data confirmed that the material was amorphous. Based on modulated differential scanning calorimetry data, the glass transition temperature of the amorphous form of the HCI salt of (-)-O-desmethylvenlafaxine was approximately 24 0 C.
• API and Avicel were added to a high shear granulator and blended briefly. Surelease suspension was added drop-wise with the high shear process operating. The wet granulation was removed from the high shear granulator, dried in a fluid bed dryer, blended with Methocel and magnesium stearate, and compressed on a suitable tablet machine.

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