Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
• • 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
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• VP vasopressin
• OT oxytocin
• V ia, Vi b and V 2 are members of the super-family of seven transmembrane receptors known as G-protein coupled receptors.
• Vasopressin acts on the blood vessels, where it is a potent vasoconstrictor, and on the kidneys, where it promotes water reuptake leading to an antidiuretic effect.
• the cellular receptors that mediate these two actions have been characterised and shown to be different.
• the antidiuretic action is mediated by the type-2 vasopressin receptor, commonly called the V 2 receptor.
• Agents that can interact with the V 2 receptor and activate it in the same way as vasopressin are called V 2 receptor agonists (or simply V 2 agonists).
• Such agents will have an antidiuretic action. If these agents interact selectively with the V 2 receptor and not the other vasopressin receptor subtypes, then they will not have the hypertensive effect of vasopressin. This would be an important safety consideration and would make such agents attractive for the treatment of human disease conditions characterised by polyuria (which is herein taken to mean excessive urine production).
• polyuria which is herein taken to mean excessive urine production.
• vasopressin V 2 receptor agonists that may be used in medicine. Both peptidic and non-peptidic V 2 agonists are known.
• a peptidic V 2 agonist is desmopressin (also known as [l-desamino, D-Arg 8 ], vasopressin, MinirinTM, DDAVPTM), which is a peptide analogue of vasopressin.
• desmopressin also known as [l-desamino, D-Arg 8 ], vasopressin, MinirinTM, DDAVPTM
• Examples of non- peptidic vasopressin V 2 agonists are described in, for example, international patent applications WO 97/22591 , WO 99/06403, WO 99/06409, WO 00/46224, WO 00/46225, WO 00/46227, WO 00/46228, WO 02/00626 and by Yea et al. in the Journal of Medicinal Chemistry (2008), 51(24), 8124-8134.
• desmopressin is used to increase the concentration in the blood of the coagulation proteins known as Factor VIII and von Willebrand factor. In the clinical context, this makes desmopressin useful in the treatment of haemophilia A and von Willebrand's disease. Similar applications would be open to other V 2 agonists.
• the active compound In the manufacture of pharmaceutical formulations, it is important that the active compound be in a form in which it can be conveniently handled and processed in order to obtain a commercially viable manufacturing process. Accordingly, the chemical stability and the physical stability of the active compound are important factors.
• the active compound, and formulations containing it, must be capable of being effectively stored over appreciable periods of time, without exhibiting any significant change in the physico-chemical characteristics (e.g. chemical composition, density, hygroscopicity and solubility) of the active compound.
• the active compound is to be incorporated into a dosage form for oral administration, such as a tablet, it is desirable that the active compound be readily micronised to yield a powder with good flow properties to aid manufacture.
• vasopressin agonist described in PCT/GB2001/000023 is l-(2- methyl-4-(2,3,4,5-tetrahydro-l -benzazepin-l-ylcarbonyl)benzylcarbamoyl)-L-proline- N,N-dimethylamide [CAS 347887-36-9].
• the crystalline form l-(2-methyl-4-(2,3,4,5-tetrahydro-l -benzazepin- 1- ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide (known hereinafter as "the crystalline form"), which has advantageous physico-chemical properties, for example, with regard to chemical stability, hygroscopicity, processability, morphology and technical feasibility.
• the crystalline form is, advantageously, much less hygroscopic than the amorphous form.
• Figure 9 shows the GVA water sorption/desorption isotherm of the crystalline form and
• Figure 10 shows the kinetic water sorption/desorption. These data show that there was no significant water uptake observed between 40 % RH and 90 % RH (approximately 0.3 % w/w) by the crystalline form. Neither is there any change in solid form over the entire water sorbtion range.
• Analogous data in Figures 7 and 8 show that the amorphous form is highly hygroscopic absorbing water into the bulk of the sample upon storage above 30 % RH (total of ca 14 % at equilibration at 90 % RH). Further demonstration of the crystalline form's lack of hygroscopicity is shown by the stability data described below.
• the crystalline form is more stable than the amorphous form.
• both substances are stored for 6 months at 40°C and 75% relative humidity the crystalline form remains as a white powder with no change in water content (3.8% according to Karl Fischer analysis). Also there is no significant degradation as measured by the sum of impurities which increases only from 0.9% to 1.0% (HPLC). However, the amorphous form became glassy in appearance and yellow in colour. It also showed increased moisture content, 5.7% from 1.3%, according to Karl Fischer analysis and faster degradation with increased amounts of impurities, 3.7% from 1.5% (HPLC).
• the amorphous form has been found to entrap organic solvent, making it difficult to dry. This is a problem because if a compound contains too high a level of residual solvent, it may be rendered unsuitable for pharmaceutical use. In contrast, the crystalline form does not entrap organic solvent, meaning that it can be dried easily, using standard procedures.
• the crystalline form has been isolated as a single crystal and subjected to X-ray crystal structure determination. The result is shown in Figure 1 1.
• the X-ray data show that the crystal lattice contains one molecule of water per molecule of active substance, i.e. the crystalline form of the present invention may exist as a hydrate, particularly a monohydrate.
• a crystalline polymorph of 1 -(2-methyl-4-(2,3 ,4,5-tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L- proline-N,N-dirnethylamide In the present application this polymorph may be referred to as 'the crystalline form'.
• the present invention encompasses solvates (e.g. hydrates) of the crystalline form of 1- (2-methyl-4-(2 ,3 ,4,5-tetrahydro- 1 -benzazepin- 1 -y lcarbony l)benzylcarbamoyl)-L- proline-N,N-dimethylamide.
• solvates e.g. hydrates of the crystalline form of 1- (2-methyl-4-(2 ,3 ,4,5-tetrahydro- 1 -benzazepin- 1 -y lcarbony l)benzylcarbamoyl)-L- proline-N,N-dimethylamide.
• the compound of the invention has crystalline properties and is preferably at least 50%, 60%, 70%, 80% or 90% crystalline. In another embodiment, the compound of the invention is >95% crystalline. Crystallinity can be estimated by conventional X-ray diffractometry techniques or differential scanning calorimetry techniques.
• 'Form ⁇ One crystalline polymorph of the compound of the present invention has been isolated and characterised to date, which is herein referred to as 'Form ⁇ .
• X-ray powder diffraction peaks (expressed in degrees 2 ⁇ ) are measured using copper X-rays with a wavelength of 1.5406 A (alphal) and 1.5444 A (alpha2).
• the present invention provides a crystalline form (Form 1) of 1 -(2-methyl-4-(2, 3,4,5- tetrahydro-1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide, which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Koc radiation, expressed in degrees 2 ⁇ ) at approximately:
• the present invention also provides a crystalline form (Form 1) of 1 -(2-methyl-4- (2,3,4,5-tetrahydro-l-benzazepin-l-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N- dimethylamide, having an X-ray powder diffraction pattern comprising specific peaks (expressed in degrees 20) at approximately 5.5, 10.6, 10.9, 14.2, 15.1, 15.6, 18.8, 21.9, 24.0, 26.0, 26.4 and 26.8.
• the present invention also provides a crystalline form (Form 1) of 1 -(2-methyl-4- (2,3,4,5-tetrahydro-l-benzazepin-l-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N- dimethylamide, having an X-ray powder diffraction pattern which exhibits at least the following characteristic d-space values (A) of approximately:
• Figure 1 shows an X-ray powder diffraction pattern of Form 1 of 1 -(2-methyl-4-(2, 3,4,5- tetrahydro-1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide.
• the present invention also provides a provides a crystalline form (Form 1 ) of l-(2- methyl-4-(2,3,4,5-tetrahydro-l-benzazepin-l-ylcarbonyl)benzylcarbamoyl)-L-proline- N,N-dimethylamide having an X-ray powder diffraction pattern substantially the same as that shown in Figure 1.
• Figure 3 shows an IR spectrum of Form 1 of l-(2-methyl-4-(2,3,4,5-tetrahydro-l- benzazepin-l-ylcarbonyl)benzylcarbamoyl)-L-proline-NN-dimethylamide.
• the present invention also provides a provides a crystalline form (Form 1) of l-(2-methyl-4-(2, 3,4,5- tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-NN-dimethylamide which is characterised by an IR spectrum having characteristic peaks expressed in cm "1 at approximately 3525, 3425, 2932, 2873, 2135, 1958, 1925, 1631 , 1529, 1489, 1439, 1377, 1355, 131 1, 1260, 770, 743.
• the term “approximately” means in this context that the cm “1 values can vary, e.g. by up to ⁇ 1 cm "1 . Additionally, the present invention provides a crystalline form (Form 1) of 1- (2-methyl-4-(2,3,4,5-tetrahydro-l -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L- proline-N N-dimethylamide having an IR spectrum substantially the same as that shown in Figure 3.
• the crystalline form of the present invention can exist in both unsolvated and solvated forms.
• the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and an amount of one or more pharmaceutically acceptable solvents, for example, ethanol.
• the term 'hydrate' is employed when the solvent is water.
• the present invention also encompasses a process for the preparation of the crystalline form of the present invention, said process comprising the crystallisation of said crystalline form from a solution of 1 -(2-Methyl-4-(2,3, 4,5 -tetrahydro-1 -benzazepin- 1- ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide (prepared using the method described in PCT/GB2001/000023) in a solvent comprising water.
• the solvent is water.
• the processes of the present invention may also comprise the addition of crystalline seeds of the crystalline form of the invention.
• the present invention provides a crystalline form of the invention when manufactured by a process according to the invention.
• the crystalline form of the present invention has a number of therapeutic applications, particularly in the treatment of diseases or conditions mediated by vasopressin V 2 .
• the present invention provides a crystalline form of l-(2-methyl-4-(2,3,4,5- tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,/V-dimethylamide, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined, for use in therapy.
• the present invention also provides for the use of a crystalline form of l-(2-methyl-4- (2,3,4, 5-tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,N- dimethylamide, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined, in the manufacture of a medicament for the treatment of a disease or condition mediated by vasopressin V 2 receptors.
• the present invention also provides a crystalline form of l -(2-methyl-4-(2,3,4,5- tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-NN-dimethylamide, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined, for use in the treatment of a disease or condition mediated by vasopressin V 2 receptors.
• the present invention also provides a method of treatment of a disease or condition mediated by vasopressin V 2 receptors, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a crystalline form of 1 -(2-methyl-4-(2,3,4, 5-tetrahydro- 1 -benzazepin- 1 - ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined.
• the disease or condition mediated by vasopressin V 2 receptors is selected from nocturnal enuresis, nocturia, polyuria resulting from central diabetes insipidus, urinary incontinence and bleeding disorders. In an aspect, the disease or condition mediated by vasopressin V 2 receptors is nocturia.
• references herein to “treatment” include references to curative, palliative and prophylactic treatment, unless there are specific indications to the contrary.
• the terms “therapy, “therapeutic” and “therapeutically” should be construed in the same way.
• the crystalline form of the present invention may be administered alone or in combination with one or more other drugs. Generally, it will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
• excipient is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic to the formulations.
• a functional i.e., drug release rate controlling
• a non-functional i.e., processing aid or diluent
• the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
• compositions suitable for the delivery of the crystalline form of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
• the total daily dose of the crystalline form of the invention is typically in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg depending, of course, on the mode of administration.
• the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a crystalline solid form of l -(2-methyl-4-(2,3,4,5-tetrahydro-l-benzazepin-l- ylcarbonyl)benzylcarbamoyl)-L-proline-NN-dimethylamide, or a pharmaceutically acceptable solvate thereof, as hereinbefore defined, and a pharmaceutically acceptable carrier, diluent or excipient.
• the pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations; or systemically, e.g.
• HFA heptafluoroalkane
• oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.
• the active ingredient is administered orally.
• Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
• Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
• Formulations suitable for oral administration may also be designed to deliver the crystalline form in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said crystalline form.
• Means to deliver compounds in a rate-sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
• rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.
• rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
• Liquid (including multiple phases and dispersed systems) formulations include emulsions, suspensions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
• the crystalline form of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.
• Figure 1 X-ray powder diffraction pattern of Form 1 of l-(2-methyl-4-(2,3,4,5- tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,N- dimethylamide.
• Figure 2 SEM images of Form 1 of l-(2-Methyl-4-(2,3,4,5-tetrahydro-l -benzazepin-l - ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide.
• Figure 3 IR spectrum of Form 1 of l -(2-methyl-4-(2,3,4,5-tetrahydro-l-benzazepin-l- ylcarbonyl)benzylcarbamoyl)-L-proline-iV,N-dimethylamide.
• Figure 4 IR spectrum of amorphous l-(2-methyl-4-(2,3,4,5-tetrahydro-l-benzazepin-l- ylcarbony benzylcarbamoy -L-proline- N-dimethylamide.
• Figure 5 X-ray powder diffraction pattern of amorphous l-(2-methyl-4-(2,3,4,5- tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzy lcarbamoyl)-L-proline-N, N- dimethylamide.
• Figure 6 SEM images of amorphous l-(2-Methyl-4-(2,3,4,5-tetrahydro-l -benzazepin-l- ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide.
• Figure 7 GVA water sorption/desorption isotherm of amorphous 1 -(2-Methyl-4- (2,3,4,5-tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline- N,N-dimethylamide.
• Figure 8 GVA kinetic water sorption/desorption isotherm of amorphous 1 -(2-Methyl-4- (2,3,4,5-tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline- N,N-dimethylamide.
• Figure 9 GVA water sorption/desorption isotherm of Form 1 of l-(2-Methyl-4-(2, 3,4,5- tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,N- dimethylamide.
• Figure 10 GVA kinetic water sorption/desorption isotherm of Form 1 of 1 -(2-Methyl-4- (2,3,4, 5-tetrahydro-l -benzazepin- l-ylcarbonyl)benzylcarbamoyl)-L-proline-
• Figure 1 1 Single crystal X-ray structure of Form 1 of l -(2-methyl-4-(2,3,4,5-tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide.
• Figure 12 X-ray powder diffraction pattern of a mixture of 95% amorphous l-(2- methyl-4-(2,3,4,5-tetrahydro-l -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L- proline-NN-dimethylamide and 5% Form 1 of l -(2-methyl-4-(2,3,4,5- tetrahydro- 1 -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,N- dimethylamide.
• the sample was then dried by maintaining a 0 % humidity environment until no further weight change was recorded (alternatively, the sorption/desorption cycle is initiated at typical ambient conditions of 40 % relative humidity). Subsequently, the sample was then subjected to a ramping profile up to 90 % relative humidity at 10 % relative humidity increments, maintaining the sample at each step until equilibration had been attained (99.5 % step completion). Upon reaching equilibration, the relative humidity within the apparatus was ramped to the next step and the equilibration procedure repeated. After completion of the sorption cycle, the sample was then dried using the same procedure. The weight change during the sorption/desorption cycles was then monitored, allowing for the hygroscopic nature of the sample to be determined.
• HPLC data were collected using a Zorbax Extend CI 8, 2.1 mm x 150 mm, 5 ⁇ d.p. column. Flow rate was 0.3 mL/min. Injection volume was 10 ⁇ , detector wavelength 220 nm and column temperature 40°C. Eluent A was 10 mM aqueous ammonium acetate, pH 5.0. Eluent B was 20:80 v/v 10 mM aqueous ammonium acetate : acetonitrile. The gradient programme is shown below:
• DSC Differential scanning calorimetry
• Hyper differential scanning calorimetry Approximately 1 to 3mg of the sample was accurately weighed into an aluminium DSC pan and sealed using a non-hermetic lid. Subsequently, the sample was loaded into a Diamond DSC (Perkin-Elmer Instruments, US) equipped with a liquid nitrogen cooling unit and cooled to 0°C. Once a stable baseline had been attained, the samples were heated from 0 to 200°C at 200°C/min and the change in heat-flow response monitored. A helium purge gas was used at a flow rate of 20 ml/min in order to improve the heat transfer process from the sample to the thermocouples and ultimately improve sensitivity. Prior to analysis the instrument was temperature and heat-flow calibrated using an indium reference standard.
• Infra-red spectra were measured using a system set to a Diffuse Reflectance configuration, with samples prepared with potassium bromide, and scanned from 4000 cm “1 to 400 cm “1 .
• XRPD X-Ray Powder Diffraction
• Time per step 2.5 seconds (X-Pert MPD) or 31 seconds (X-Pert Pro).
• Scanning electron micrographs were produced by coating the desired material with a thin layer of gold (sputter coating) and examined using a FEI-Philips XL30 Scanning S electron microscope. The acceleration voltage of the electrons used for analysis was 10 KV. All images were captured with a computer controlled CCD camera attachment.
• Method C 1 -(2-Methyl-4-(2,3,4,5-tetrahydro-l -benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L- proline-N,N-dimethylamide 200 g; prepared using the method described in PCT/GB2001/000023
• acetone / water 20 / 80
• the mixture was heated to 50°C over 15 minutes to give an emulsion, stirred at 50°C for 10 minutes and cooled to 27°C over 38 minutes to give a clear solution.
• a "cloud point" was noted at approximately 38°C during cooling.
• Form 1 Seeds of the crystalline l -(2-methyl-4-(2,3,4,5-tetrahydro-l -benzazepin- 1 - ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-di
• the suspension was filtered and the solids air dried for approximately 30 minutes.
• the solids were washed with mixtures of acetone / water (5 / 95, 3 x 100 mL) and air dried for approximately 3 hours.
• the solids were dried further at 45°C in vacuo to afford the crystalline solid form as a white powder, yield 166 g (76%).
• the SEM images showed that the crystals of Form 1 have rectangular morphology (see figure 2).
• the SEM images of the amorphous form showed that the samples studied consisted of predominantly large (> 5 ⁇ in diameter) aggregates (see figure 6).
• spectrum comprises peaks at wavelengths of approximately 3524.6, 3425.0, 2932.2, 2872.6, 2134.7, 1958.0, 1924.7, 1630.7, 1528.8, 1489.0, 1438.6, 1377.4, 1354.6, 1310.7, 1259.8, 770.4, 742.7 cm “1 .
• the spectrum is presented in Figure 3.
• Hyper DSC onset approximately 1 14°C.
• Karl Fisher analysis indicates a moisture content of 3.8% which is equivalent to a stoichiometric amount of water and consistent with isolation of a hydrate.
• the amorphous form is hygroscopic as indicated by Gravimetric Vapour Sorption Analysis (GVA).
• GVA Gravimetric Vapour Sorption Analysis
• the water sorption/desorption isotherms are shown in Figures 7 and 8.
• the GVA revealed that the amorphous form was highly hygroscopic, absorbing water into the bulk of the sample upon storage above 30% RH (total of ca. 14% at equilibration at 90% RH).
• the amorphous state remained stable to recrystallisation over the entire water sorption range investigated however a degree of physical form change was observed as the sample passed through its glass transition temperature.
• the crystalline solid form is more stable than the amorphous form.
• the crystalline form remains as a white powder with no change in water content (3.8% according to Karl Fischer analysis).
• the amorphous form showed increased moisture content, 5.7% from 1.3%, according to Karl Fischer analysis.
• the amorphous form also shows faster degradation with increased amounts of impurities, 3.7% from 1.5% (HPLC).
• the amorphous form was initially a white powder but became glassy in appearance and became yellow in colour upon storage.
• the 2 ⁇ values are accurate within an error of ⁇ 0.1-0.2°.
• the relative peak intensities can vary considerably for different samples of the same crystalline form because of different preferred orientations of the crystals.
• the samples were prepared without any special treatment other than the application of slight pressure to get a flat surface. Silicon single crystal sample holders of 1.0 mm depth and 12 mm cavity diameter were used. The tube voltage and current were 40 kV and 40 mA, respectively.
• the X-ray diffractometer is equipped with a LynxEye detector. A variable divergence slight was used with a 3° window. The step size was 0.02° 2 ⁇ with a step time of 37 seconds. The samples were rotated at 0.5 rps during the measurement.
• Figure 12 shows the XRPD pattern of a mixture with 95% amorphous form and 5% crystalline form (Form 1) showing small peaks in the X-ray diffractogram as listed below.
• a sample should be at least 5% crystalline in order to see significant XRPD peaks with a reasonable signal to noise ratio.
• DSC Differential Scanning Calorimetry
• Sample amounts are generally about 4mg and peak integration is carried out from about 80°C to about 130°C.
• Samples containing at least 50% crystalline form exhibit an enthalpy of fusion greater than approximately 30 J/g.
• Samples containing at least 70% crystalline form exhibit an enthalpy of fusion greater than approximately 45 J/g.
• Samples containing at least 90% crystalline form exhibit an enthalpy of fusion greater than approximately 58 J/g and samples containing at least 95% crystalline form exhibit an enthalpy of fusion greater than about 62 J/g.
• Tablet manufacture Active substance is passed through a through a U3 Comil ® (Quadro Engineering) fitted with a 457 micron mesh and weighed into a stainless steel container. Lactose monohydrate is added and the mixture blended and passed through a 600 micron sieve. Microcrystalline cellulose was passed through a 600 micron sieve, added and blended. Magnesium stearate was passed through a 600 micron sieve, added and blended. Tablet cores are compressed on a suitable tablet press. A suspension of the film coating material, containing hypromellose, talc, titanium dioxide, polyethylene glycol and saccharin sodium is prepared in purified water, and sprayed onto the tablet cores in a fluid bed coater. The water is removed during processing.
• the ability of the crystalline form of the invention to agonise the vasopressin V 2 receptor may be determined using the in vivo assay described in PCT/GB2001/000023.
• a suspension (15 mL) of amorphous 1 -(2 -methyl -4-(2,3, 4,5-tetrahydro- 1-benzazepin-l - ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide (prepared using the method described in PCT/GB2001/000023) at a concentration of 387 mg/mL in a mixture of n- propyl acetate and water (81 : 19) was prepared and heated at 80°C for 10 minutes to give an almost clear solution. The mixture was cooled at a rate of 1°C per minute to 10°C and heated again to 40°C.
• Crystalline seeds of l-(2-methyl-4-(2,3,4,5-tetrahydro-l- benzazepin- 1 -ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide (Form 1) (approximately 50 mg) were added and the mixture cooled at a rate of 0.5°C per minute to 38°C. The mixture heated again to 39°C and an additional amount of crystalline seeds of l -(2-methyl-4-(2,3,4,5-tetrahydro-l-benzazepin-l-ylcarbonyl)benzylcarbamoyl)-L- proline-N,N-dimethylamide (Form 1) (approximately 50 mg) were added.
• the mixture was stirred at 39°C for 6 hours then cooled to 35°C at a rate of 0.1°C per minute.
• the mixture was stirred at 35°C for 6 hours then cooled to 30°C at a rate of 0.1 °C per minute.
• the mixture was then stirred for three days at 30°C. It was observed that the reaction vessel contained a suspension and some relatively large crystals on the sides of the vessel.
• the suspension was removed and filtered and the resulting filtrate was used to rinse the larger crystals away from the sides of the vessel which were recovered as a suspension.
• the suspension of the large crystals was stored in a sealed vessel at room temperature for two weeks which resulted in dissolution of the crystals.
• Theta range 1.00°-28.70°

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