GB2469915A - 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.13,7]dec- 1-ylmethyl)-benzamide hydrochloride salt - Google Patents

Abstract

A physical form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.13,7]dec-l-ylmethyl)-benzamide hydrochloride salt is characterised by its X-ray powder diffraction peaks (expressed in degrees 2θ when using X-rays of wavelength 1.5406Å). The physical form is defined with reference to the following sets of peaks: (i) 6.9, 9.3, 10.4 and 13.8; (ii) 6.9, 10.4, 13.8 and 24.3; (iii) 6.9, 9.3, 10.4, 13.8 and 24.3; or (iv) 6.9, 9.3, 10.4, 13.8, 16.3 and 24.3. The significant peaks that differentiate this physical form from prior art may be those at 9.25, 13.82 and 24.30. This material may be an anhydrate. It may be a P2X7antagonist and be useful in therapy (e.g. rheumatoid arthritis, Crohn's disease). The physical form may be prepared using crash precipitation techniques (e.g. via dissolution in hot methanol or dioxane followed by precipitation with water or t-butyl methyl ether (TBME)).

Description

New Physical Form The present invention relates to a new physical form of a P2X7 antagonist, pharmaceutical compositions containing the physical form and its use in therapy.

The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes io (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the processing and release of cytokines such as interleukin-1 f3 (TL-113) and IL-18 and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis and L-selectin shedding (lymphocytes). For this reason P2X7 antagonists have been prepared as compounds for use is in the treatment of inflammatory and immune diseases, such as rheumatoid arthritis.

In the manufacture of pharmaceutical formulations, it is important that the active compound is in a form in which it can be conveniently handled and processed in order to obtain a commercially-viable manufacturing process. In this connection, 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.

International patent application WO 01/044170 describes a novel class of P2X7 antagonist.

One such P2X7 antagonist described in WO 01/044170 is 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt. The physical form of 2-chloro-5 -[3-[(3 -hydroxypropyl)amino]propyl]-N-(tricyclo[3.3. 1. 13'7]dec-1-ylmethyl)-benzamide hydrochloride salt prepared according to the methods described in WO 01/044 170 is a crystalline solid having properties suitable for the manufacture of pharmaceutical formulations.

II has now been found possible to prepare an alternative physical form of 2-chloro-5-[3- [(3 -hydroxypropyl)amino]propyl] -N-(tricyclo [3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt to that obtained by the methods described in WO 01/044170.

Thus, in accordance with the present invention, there is provided a physical form of 2- chloro-5 -[3-[(3 -hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 20 when using X-rays of wavelength 1.5406A) 6.9, 9.3, 10.4 and 13.8.

n a further embodiment, there is provided a physical form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt which exhibits at least the following characteristic X-ray powder is diffraction peaks (expressed in degrees 20 when using ?=i.5406) 6.9, 10.4, 13.8 and 24.3.

In a further embodiment, there is provided a physical form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 20 when using X==i.5406) 6.9, 9.3, 10.4, 13.8 and 24.3.

In a further embodiment, there is provided a physical form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1] dec-i -ylmethyl)-benzamide hydrochloride salt which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 20 when using Xr=i.5406) 6.9, 9.3, 10.4, 13.8, 16.3 and 24.3.

In the present specification the physical form of the present invention may be referred to as Form B'. The physical form obtained using the methods described in WO 0 1/044170 may be referred to as Form A'.

The present invention also provides a physical form (Form B) of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt having an X-ray powder diffraction pattern comprising specific peaks (expressed in degrees 20 when using X-rays of wavelength 1.5406A): 6.9, 9.3, 10.4, 13.8, 16.3, 17.2, 17.3 and 24.3.

In the present specification unless otherwise stated the margin of error for X-ray powder diffraction peaks (expressed in degrees 20) is consistent with the United States Pharmacopeia general chapter on X-ray diffraction (USP941) -see the United States io Pharmacopeia Convention. X-Ray Diffraction, General Test <941>. United States Pharmacopeia, 25th ed. Rockville, MD: United States Pharmacopeial Convention; 2002:2088-2089). Tn an embodiment of the invention, the margin of error for X-ray powder diffraction peaks (expressed in degrees 20) is (�0.1°).

is Figure 1 shows an X-ray powder diffraction pattern of a physical form (Form B) of 2- chloro-5 -[3-[(3 -hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt. The present invention also provides a physical form having an X-ray powder diffraction pattern substantially the same as that shown in Figure 1. As will be understood by those skilled in the art, the relative intensities of peaks shown in XRPD figures may vary according to the orientation of the sample under test and on the type and sefting of the instrument used.

The present invention also provides a physical form (Form B) of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1] dec-i -ylmethyl)-benzamide hydrochloride salt having an X-ray powder diffraction pattern which exhibits at least the following characteristic d-space values: (1) 9.6, 6.4 and 3.7, or (2) 9.6, 8.5, 6.4 and 3.7, or (3) 12.8, 9.6, 8.5, 6.4 and 3.7, or (4) 12.8, 9.6, 8.5, 6.4, 5.4 and 3.7.

The present invention also provides a physical form (Form B) of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt having an X-ray powder diffraction pattern which exhibits at least the following d-space values 12.8, 9.6, 8.5, 6.4, 5.4, 5.2, 5.1 and 3.7.

In an embodiment of the invention, salt Form B is an anhydrate (i.e. a crystalline phase that does not contain water).

An embodiment of the invention provides Form B substantially free of other forms of 2- io chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt, be they crystalline or amorphous forms. Substantially free of other forms means that at least 90% by weight, e.g. 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 1000/o of the material is in that physical form.

is The physical form of 2-chloro-5 -[3-[(3 -hydroxypropyl)amino]propyl]-N- (tricyclo [3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt according to the present invention (Form B) may be prepared from the physical form obtained using the methods described in WO 01/044170 (Form A) using crash-precipitation techniques. For example, Form B may by prepared by dissolving Form A in a solvent such as hot methanol (e.g. 50 - 60 °C) and then adding the solution to an antisolvent such as cold water (e.g. 0 to 5 °C) and then recovering the solid material so formed by filtration. An alternative solvent for dissolving Form A is dioxane. As will be understood by those skilled in the art, crystallisation and crash-precipitation techniques generally require some experimentation and optimisation to obtain satisfactory results. Specific details of a preparation of Form B are described herein below in the experimental section.

The physical form of 2-chloro-5 -[3-[(3 -hydroxypropyl)amino]propyl]-N- (tricyclo [3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt (Form B) according to the present invention has activity as a pharmaceutical, in particular as a P2X7 antagonist. Diseases and conditions which may be treated with the salt include: 1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all seventies, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including crvptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay is fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; 2. bone and joints: arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and o associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies; 3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthritides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scieroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis); 4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous demiatoses, and delayed-type hypersensitivity reactions; phyto-and photodermatitis; seborrhoeic is dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions; 5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial; 6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or o eczema); 7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; 8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner' s ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female); 9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; io 10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes; 11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome; 12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes; 13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins; 14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn' s disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.

Accordingly, the present invention further provides a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)aniino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1 -ylniethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined for use in therapy.

In another aspect, the invention provides the use a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined, in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

A further aspect of the invention provides a method of treating a disease state in a mammal suffering from, or at risk of, said disease, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a crystalline form of 2-chloro- 5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined.

n another aspect, the invention provides a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dee-i -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined for the treatment of rheumatoid arthritis.

The present invention also provides the use of a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis.

The present invention also provides the use of a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined, in the treatment of rheumatoid is arthritis.

The present invention further provides a method of treating rheumatoid arthritis in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined.

In another aspect, the invention provides a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1. i 37] dec-i -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined for the treatment of Crohn's disease.

The present invention also provides the use of a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1. i 37] dec-i -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined, in the manufacture of a medicament for use in the treatment of Crohn's disease.

The present invention also provides the use of a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined, in the treatment of Crohn's disease.

S The present invention further provides a method of treating Crohn's disease in a warm-blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined.

n order to use a compound of the invention for the therapeutic treatment of a warm-blooded animal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

is For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the mode of administration, the treatment desired and the disorder indicated but may typically be in the range from 0.001 mg/kg to 30 mg/kg.

The physical form according to the invention (e.g. Form B) may be used on its own but will generally be administered in the form of a pharmaceutical composition in which Form B of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1-ylmethyl)-benzamide hydrochloride salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals -The Science of Dosage Form Design", M. E. Aulton, Churchill Livingstone, 2001.

Depending on the mode of administration, the pharmaceutical composition may comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

The present invention also provides a pharmaceutical composition comprising a crystalline form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1-ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a crystalline form of 2-chloro-5-[3- [(3 -hydroxypropyl)amino]propyl] -N-(tricycto [3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt (Form B) as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

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, for example, formulations in the inhaler is device known as the Turbuhaler�; or systemically, e.g. by 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.

For oral administration the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol, dibasic calcium phosphate dihydrate; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; a disintegrant, for example, sodium starch glycolate or croscarmalleose sodium; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a solvent.

For the preparation of soft gelatine capsules, the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.

s Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

When administered via oral administration the daily dosage of active ingredient in the pharmaceutical composition may for example be in the the range from 5 to 1000mg, 5 to 800mg, 5 to 600mg, 5 to 500mg, 5 to 400mg, 5 to 300mg, 5 to 200mg, 5 to 100mg, 5 to is 50mg, 20 to 1000mg, 20 to 800mg, 20 to 600mg, 20 to 500mg, 20 to 400mg, 20 to 300mg, to 200mg, 20 to 100mg, 20 to 50mg, 50 to 1000 mg, 50 to 800mg, 50 to 600mg, 50 to 500mg, 50 to 400mg, 50 to 300mg, 50 to 200mg, 50 to 100mg, 100 to 1000 mg, 100 to 800mg, 100 to 600mg, 100 to 500mg, 100 to 400mg, 100 to 300mg, or 100 to 200mg; which daily doses may be administerted as divided doses from 1 to 4 times a day.

The invention will now be illustrated by the following non-limiting Examples. n the Examples the following Figures are presented: Figure 1: X-ray powder diffraction pattern of Form B of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt Figure 2: X-ray powder diffraction pattern of Form A of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt Instrument Details o Powder X-ray diffraction was recorded with a Philips X-Pert MPD (wavelength of X-rays 1.5406 A, Cu source, Voltage 45 kV, filament emission 40 mA). Samples were scanned from 2400 20 using a 0.008° step width and a nominal 1000 second time count using an X'celerator detector (active length 2.1220 20). The Data was collected on zero background holders dusted with 1mg of the compound to minimise preferred orientation. The holder was made from a single crystal of silicon, which had been cut along a non-diffracting plane and then polished on an optically flat finish. The X-rays incident upon this surface were negated by Bragg extinction.

o DSC thermograms were measured using a TA Q1000 Differential Scanning Calorimeter, with aluminium pans and pierced lids. The sample weights varied between 1.8 to 2.1mg. The procedure was carried out under a flow of nitrogen gas (50m1/min) and a temperature range of from 25 to 3 00°C at a constant rate of temperature increase of 10°C per minute. It is well known that the DSC onset and peak temperatures may vary due to the purity of the sample and instrumental parameters, especially the temperature scan rate, and that optimistaion of instrumental parameters may be required to repeat reported results.

Preparation of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyll-N- (tricyclo 13.3.1.1 3'7i dec-i -ylmethyl)-benzamide hydrochloride salt: Physical Form B Preparation 1 2-Chloro-5 -[3 -[(3 -hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1'] dec-i -ylmethyl)-benzamide hydrochloride salt Form A (30g), prepared according to the method described herein below, was dissolved in methanol (270 mL) with stirring at 60 °C. The mixture was filtered directly into pre-cooled (2 °C) water (450 mL) again with stirring; heavy precipitation was noted half-way through the addition. The mixture was left to stir at 2 °C for 2 hours after which the solid was collected via filtration over 3O hours. The filter cake was removed (in the form of a solid, hardened disc of material) and ground into a fine powder, and the material oven-dried (45 °C) for 16 h to yield 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt Form B (24.2 g) as a white solid.

Preparation 2 A sample of 2-chloro-5-[3 -[(3 -liydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 3'7]dec-1-ylmethyl)-benzamide hydrochloride salt (30g) was purified by recystallisation using the following procedure. Form A, prepared according to the method described herein below, water (25mL) and methanol (125 mL) were charged to a reaction vessel. The resulting suspension was heated to reflux. Once a clear solution was obtained methanol (l5mL) was io added and the solution cooled to 55 °C. TBME (methyl t-butyl ether) (36OrnL) was then added over 2 hours and the mixture cooled to room temperature and stirred overnight. The resulting white suspension was filtered and the solid obtained washed twice with TBME (2 x 6OmL). The recrystallisation procedure was then repeated except that after the addition of TBME over 2 hours the white suspension was cooled to 20 °C and filtered. The solid i5 obtained was washed with TBME and dried in a vacuum oven at 45 °C.

A purified sample of 2-chloro-5-[3 -[(3 -hydroxypropyl)arnino]propyl] -N- (tricyclo [3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt Form A (58.4mg) was contacted with 1.5mL of methanol followed by 3.5mL of water. A clear solution resulted.

More Form A was added to give a cloudy solution. The sample was then capped, parafilmed and shaken on a shaker block at 68 °C for 9 days. The sample was then taken off the shaker block and isolated by vacuum filtration. Analysis of the sample by XRPD indicated that material was of a different physical form to Form A. Further investigation of the new physical form led to Preparation I and confirmed that the material obtained in Preparation 2 was Form B. Analysis of Physical Form B A sample of Physical Form B obtained by Preparation 1 was analysed by XRPD and DSC.

The melting temperature of Form B as determined by DSC was found to be 268°C (onset) o (�2 °C). An XRPD spectrum of Form B is presented in Figure 1. Peak listings from the XRPD are as follows. Significant peaks differentiating Form B from Form A are denoted with an asterix (*) 2-theta d-spacing counts 6.90 12.80 2641 9.25* 9.55 317 10.35 8.54 8820 13.82* 6.40 1704 16.31 5.43 1281 17.22 5.15 627 io 17.28 5.13 717 24.30* 3.66 355 Physical Form A A sample of 2-chloro-5 -[3 -[(3 -hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt was prepared as follows: 2-Chloro-5 -(3 -oxopropyl)-N-(tricyclo [3.3.1.1 3'7ldec-1 -ylmethyl)-benzamide Chloro-5 -iodo-N-(tricyclo [3.3.1. i'] dec-i -ylmethyl)-benzamide' (100. Og), Bu4NC1 (67.91g), diisopropylethylamine(56.7mL), Pd(OAc)2 (0.104g) and toluene (i000mL) were charged to a flask under an inert atmosphere, followed by allyl alcohol (19.8mL). This gave an orange suspension that was heated at 80°C (�3°C), a dark brown biphasic mixture was obtained. The reaction was monitored by HPLC. The mixture was then cooled to 20- 25°C and 1.OM hydrochloric acid (500rnL) was added and the mixture was stirred for a minimum of 30 mm. The resulting suspension was filtered through a GF/F paper and the solid cake was washed with toluene (200mL). The combined toluene solution was washed with water (5 OOmL). The resulting solution (approximately 1 200mL) was used without further purification. A preparation of Chloro-5 -iodo-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide is described in WO 2008/030 160.

2-Chloro-5-[3-[(3-hydroxypropvl)aminolpropyll-N-(tricvclo[3.3.1.1 3'7ldec-1 -ylmethyl) o benzamide free base 3 -Aminopropan-1-ol(89. 00rnL,) was added to the solution of 2-chloro-5 -(3 -oxopropyl)-N- (tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide in toluene prepared herein above (approximately 1 200m1) under an inert atmosphere, and then toluene was distilled out of the reaction mixture (volume of remaining solution was approximately 420mL including excess 3-aminopropan-1-ol) at atmospheric pressure. The solution was then cooled to 50- 60°C and then propan-2-ol (350mL) was added and the mixture was cooled to 20-30°C and filtered through a GE/F filter. Dimethylsuiphoxide (0.385mL) and 5%Pt/C (PMC type 2020C, 20.Og, 20%w/w -based on wet weight of catalyst) were added and the mixture was then purged with nitrogen (x3) and then subjected to hydrogenation at 3BarG and 50° io (�3°C) for approximately 4.5h. The reaction was then quenched by purging with nitrogen and the solution cooled to 20-25°C. The mixture was filtered through a GF/F filter and washed with a propan-2-ol:toluene (1:1 (v:v), 2x200mL) and then toluene (200mL). The resulting solution was washed with water (2x500mL). The crude mixture was used in the next step without further purification.

2-Chloro-5-(3-oxopropyl)-N-(tricyclo[3.3.1.1 3'7ldec-1 -ylmethyl)-benzamide hydrochloride salt To the solution of 2-Chloro-5 -[3 -[(3 -hydroxypropyl)amino]propyl] -N- (tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide free base prepared above, under an inert atmosphere, 5-6N HC1 in propan-2-ol (69.8 lmL, 0.35Omol) was added dropwise over 1 hour at 5 0°C. Tert-butyl methyl ether (75OmL) was added in one portion and the mixture was stirred at 50°C for 1 hour then cooled to 20-25°C and stirred for a further 1 hour. The solid was then filtered, washed with tert-butyl methyl ether (2x 25 OnTh) and dried in a vacuum oven at 40-45°C until at constant weight. The crude product (15.Og) was charged to a reaction vessel, followed by pre-mixed methanol:water (5:1 (v:v), 64.5mL) and the mixture was heated to reflux (approximately 67°C) under an inert atmosphere to obtain a homogeneous solution. The solution was transferred via an in-line filter to another vessel pre-heated to 60°C under an inert atmosphere. The first reaction vessel was rinsed with methanol (7.5mL), which was added via the in-line filter to the second vessel. The solution o was cooled to 50-55°C and TBME (l8OrnL) was added over 2h. The resulting suspension was then cooled to 20-25°C over 1 h and was then held at this temperature for a further lh.

The mixture was filtered and the filter cake was washed with TBME (2 x 3OmL). The solid was deliquored on the filter and then dried in a vacuum oven at 40-45°C until at constant mass (13.52g).

Analysis of Physical Form A A sample of Physical Form A obtained by the procedure described herein above was analysed by XRPD and DSC. The melting temperature of Form A as determined by DSC io was found to be 269°C (onset) (+2 °C). An XRPD spectrum of Form A is presented in Figure 2. Peak listings from the XRPD are as follows. Signifacant peaks differentiating Form A from Form B are denoted with asterix (*) 2-theta d-spacing counts 6.87 1 2.86 10661 i5 8.75* 10.10 2090 10.01* 8.83 2581 10.31 8.57 53006 13.77* 6.43 12182 14.80 5.98 5872 16.28 5.44 5872 17.21 5.15 11440 19.10 4.64 220 20.10 4.41 725 24.21 3.67 4627

Claims (8)

1. CLAIMS1. A physical form of 2-chloro-5 -[3 -[(3 -hydroxypropyl)amino]propyl] -N-s (tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 20 when using X-rays of wavelength 1.5406A): 6.9, 9.3, 10.4 and 13.8.
2. 2. A physical form of 2-chloro-5 -[3-[(3 -hydroxypropyl)amino]propyl]-N-io (tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 20 when using X-rays of wavelength 1.5406A): 6.9, 10.4, 13.8 and 24.3.
3. 3. A physical form as claimed in claim 1 or claim 2, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 20 when using X-rays of wavelength 1.5406A): 6.9, 9.3, 10.4, 13.8 and 24.3.
4. 4. A physical form as claimed in claim 3, which exhibits at least the following characteristic X-ray powder diffraction peaks (expressed in degrees 20 when using X-rays of wavelength 1.5406A): 6.9, 9.3, 10.4, 13.8, 16.3 and 24.3.
5. 5. A physical form of 2-chloro-5 -[3-[(3 -hydroxypropyl)amino]propyl] -N- (tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt having an X-ray powder diffraction substantially the same as that shown in Figure 1.
6. 6. A pharmaceutical composition comprising a physical form of 2-chloro-5-[3-[(3-hydroxypropyl)amino]propyl]-N-(tricyclo [3.3.1.1 37] dec-i -ylmethyl)-benzamide hydrochloride salt according to any one of claims 1 to 5 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
7. 7. A physical form of 2-chloro-5 -[3 -[(3 -hydroxypropyl)amino]propyl] -N- (tricyclo[3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt according to any one of claims 1 to 5 for use in therapy.
8. 8. Use of a physical form of 2-chloro-5 -[3 -[(3 -hydroxypropyl)amino]propyl] -N- (tricyclo [3.3.1.1 3'7]dec-1 -ylmethyl)-benzamide hydrochloride salt according to any one of claims 1 to 5 in the manufacture of a medicament for use in treating rheumatoid arthritis.