Method and device in a packaging machine for achieving a stable and reproducible geometry of a forced preformed tubular-shaped web.

Field of the invention

The present invention relates to a novel crystalline form of 3,5-dibromo-N-[(2.S)-2-(4- fluorophenyl)-4-(3-morpholin-4-ylazetidm-l-yl)butyl]-iV-meth ylbenzamide. Further, the present invention also relates to the use of the novel crystalline form for the treatment of gastrointestinal disorders, pharmaceutical compositions containing it as well as processes for the preparation of the novel crystalline form.

Background of the invention

The compound 3,5-dibromo-iV-[(2 ₁ S)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylazetidin-l- yl)butyl]-iV-methylbenzamide as its dihydrochloride salt is described in WO2004/110344.

Brief description of the drawings

Figure 1 is an X-ray powder diffractogram of 3,5-dibromo-N-[(2>S)-2-(4-fluorophenyl)-4- (3-morpholin-4-ylazetidin-l-yl)butyl]-iV-methylbenzamide modification B.

Description of the invention

It has surprisingly been found that 3,5-dibromo-N-[(2iS)-2-(4-fluorophenyl)-4-(3- morpholin-4-ylazetidin-l-yl)butyl]-iV-methylbenzamide can exist in crystalline neutral, non-salt form. The novel crystal form for the first time disclosed is hereinafter referred to as 3,5-dibromo-iV-[(25)-2-(4-fluorophenyl)-4-(3-moφholin-4-yla zetidin-l-yl)butyl]-iV- methylbenzamide modification B. The neutral, non-salt form can be characterized by its optical rotation in a 1% methanol solution of -14.0°.

It is thus an object of the present invention to provide a crystalline form of the neutral form of 3,5-dibromo-N-[(2 _J S)-2-(4-fluorophenyl)-4-(3-moφholin-4-ylazetidin-l-yl)butyl ]-N- methylbenzamide with advantageous properties.

It is an aspect of the present invention to provide 3,5-dibromo-iV-[(2 ₁ S)-2-(4-fluorophenyl)- 4-(3-morpholin-4-ylazetidin-l -yl)butyl]-iV-methylbenzamide modification B.

3 ,5-Dibromo-iV-[(26)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylaz etidin- 1 -yl)butyl]-JV- methylbenzamide modification B is characterized in providing an X-ray powder diffraction pattern, exhibiting substantially the following main peaks with d-values (d-value: the spacing between successive parallel hkl planes in a crystal lattice):

The peaks, identified with d-values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of 3,5-dibromo-N-[(25)-2-(4-fluorophenyl)-4-(3- morpholin-4-ylazetidin-l-yl)butyl]-N-methylbenzamide modification B. Only the main peaks, that are the most characteristic, significant, distinct and/or reproducible, have been tabulated (a number of weak peaks have been omitted. Peaks are only listed up to 35 degrees 2θ), but additional peaks can be extracted, using conventional methods, from the

diffractogram. The presence of these main peaks, reproducible and within the error limit, is for most circumstances sufficient to establish the presence of said crystal modification.

3,5-Dibromo-iV-[(2 _l S)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylazetidin-l-yl)butyl ]-iV- methylbenzamide modification B is further characterized by an X-ray powder diffraction pattern essentially as shown in Figure 1.

3,5-Dibromo-iV-[(2 ₎ S)-2-(4-fluorophenyl)-4-(3-moφholin-4-ylazetidin-l-yl)butyl ]-iV- methylbenzamide modification B is a crystalline form exhibiting advantageous properties over the amorphous form, such as increased chemical and physical stability, lower hygroscopicity, higher purity and better yield in manufacturing.

It is possible to crystallize 3,5-Dibromo-N-[(2iS)-2-(4-fluorophenyl)-4-(3-morpholin-4- ylazetidin-l-yl)butyl]-iV-methylbenzamide modification B, i.e. the compound of the present invention in one single solvent or in a mixture of solvents.

Crystallization may be initiated and/or effected with or without seeding with crystals of the appropriate crystalline compound of the invention.

Crystallization of compounds of the present invention can be achieved starting from an amorphous form or from a salt of 3,5-dibromo-λ ^r -[(2.S)-2-(4-fiuorophenyl)-4-(3-morpholin- 4-ylazetidin-l-yl)butyl]-N-methylbenzamide of any form, or mixtures of any forms.

In one embodiment of the present invention, 3,5-dibromo-N-[(26)-2-(4-fluorophenyl)-4-(3- morpholin-4-ylazetidin-l-yl)butyl]-iV-methylbenzamide modification B is obtained upon crystallization from ethyl acetate.

One object of the present the invention is to provide a process for the preparation of 3,5- dibromo-N- [(25)-2-(4-fiuorophenyl)-4-(3 -morpholin-4-ylazetidin- 1 -yl)butyl] -N- methylbenzamide modification B.

3,5-Dibromo-N-[(2 ₁ S)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylazetidin-l-yl)butyl ]-iV- methylbenzamide modification B obtained according to the present invention is substantially free from other crystal and non-crystal forms of 3,5-dibromo-N ^' -[(25)-2-(4- fluorophenyl)-4-(3-morpholin-4-ylazetidin-l-yl)butyl]-iV-met hylbenzamide. The term "substantially free from other crystal and non-crystal forms of 3,5-dibromo-iV-[(25)-2-(4- fluorophenyl)-4-(3-morpholin-4-ylazetidin- 1 -yl)butyl]-iV-methylbenzamide" shall be understood to mean that the desired crystal form of 3,5-dibromo-iV-[(25)-2-(4- fluorophenyl)-4-(3-morpholin-4-ylazetidin-l -yl)butyl]-N-methylbenzamide contains less than 15%, preferably less than 10%, more preferably less than 5% of any other forms of 3,5 -dibromo-N-[(25}-2-(4-fluorophenyl)-4-(3 -morpholin-4-ylazetidin- 1 -yl)butyl] -N- methylbenzamide.

The crystal modification according to the present invention is useful for the prevention or treatment of respiratory, cardiovascular, neuro, pain, oncology and/or gastrointestinal disorders. Examples of such disorders are asthma, allergic rhinitis, pulmonary diseases, cough, cold, inflammation, chronic obstructive pulmonary disease, airway reactivity, urticaria, hypertension, rheumatoid arthritis, edema, angiogenesis, pain, migraine, tension headache, psychoses, depression, anxiety, Alzheimer's disease, schizophrenia, Huntington's disease, bladder hypermotility, urinary incontinence, eating disorder, manic depression, substance dependence, movement disorder, cognitive disorder, obesity, stress disorders, micturition disorders, mania, hypomania and aggression, bipolar disorder, cancer, carcinoma, fibromyalgia, non cardiac chest pain, gastrointestinal hypermotility, gastric asthma, Crohn's disease, gastric emptying disorders, ulcerative colitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), emesis, gastric asthma, gastric motility disorders, functional dyspepsia or gastroesophageal reflux disease (GERD).

It is further provided a pharmaceutical composition comprising the crystal modification according to the present invention, as active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other active pharmaceutical ingredients. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for

example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the crystal modification according to the present invention may be formulated by means known in the art into the form of, for example, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the crystal modification according to the present invention, the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.

The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.

Typically, unit dosage forms will contain about 1 mg to 500 mg of a compound of the crystal modification according to this invention. For example, a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of the crystal modification according to the present invention. In another example, for administration by inhalation, the crystal modification of the present invention may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of the crystal modification of the present invention may be used.

In the practice of the invention, the most suitable route of administration as well as the therapeutic dose will depend on the nature and severity of the disease to be treated. The dose, and dose frequency, may also vary according to the age, body weight and response of the individual patient,

The crystal modification according to the present invention may be further processed before formulation into a suitable pharmaceutical formulation. For example, the crystal modification may be milled or ground into smaller particles.

For the avoidance of doubt, "treatment" includes the therapeutic treatment, as well as the prophylaxis, of a condition.

The presence of additional substances in a sample, like pharmaceutical excipients, to be characterised by X-ray powder diffraction can mask some of the peaks in the above characterized crystal modification. This fact alone can of course not demonstrate that the crystal modification is not present in the sample. Under such circumstances due care must be used and the presence of substantially all main peaks in the X-ray powder diffraction pattern might suffice to characterize the crystal modification. It is thus preferred to analyse the crystal modifications of the present invention without the presence of additional substances.

According to a further aspect of the invention there is provided a method of treatment of a condition where 3,5-dibromo-JV-[(25)-2-(4-fiuorophenyl)-4-(3-morpholin-4-yla zetidin-l - yl)butyl]-iV-methylbenzamide modification B is required or desired, which method includes administering a therapeutically effective amount of the crystal modification according to the present invention to a patient in need of such treatment.

The crystal modification according to the present invention has the advantage that it is in a form that provides for increased chemical and physical stability, lower hygroscopicity, higher purity and better yield in manufacturing, compared to the amorphous form. Further, the modification according to the present invention has the advantage that it may be produced in a form having advantageous chemical and solid state stability. In particular, it

was found that a batch of predominantly crystalline 3,5-dibromo-N ^' -[(2S)-2-(4- fluorophenyl)-4-(3-morpholin-4-ylazetidin-l-yl)butyl]-N-meth ylbenzamide (containing at least 60% of the crystalline form) showed significantly less decomposition than a batch of predominantly amoφhous 3,5-dibromo-iV-[(25)-2-(4-fiuorophenyl)-4-(3-morpholin-4- ylazetidin-l-yl)butyl]-N-methylbenzamide (containing less than 25% of the crystalline form) when stored in a closed container at 25°C/60% relative humidity for 3 months.

The invention is illustrated, but in no way limited, by the following examples.

Examples

General

X-ray powder diffraction analysis (XRPD) was performed on samples prepared according to standard methods, for example those described in Giacovazzo, C. et al (1995),

Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L.

(1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York;

Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P.

& Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York. X-ray analyses were performed using a Siemens D5000 diffractometer.

XRPD distance values may vary in the range ±2 on the last decimal place.

It will be appreciated by the skilled person that XRPD intensities may vary when measured for essentially the same crystalline form for a variety of reasons including, for example, preferred orientation.

Example 1

Preparation of 3, 5-dibromo-N-r(2ιS ^f )-2-(4-fluorophenyl ^' )-4-(3-morpholin-4-ylazetidin-l- yDbutyli-iV-methylbenzamide modification B

Amorphous 3,5-dibromo-iV-[(25)-2-(4-fluorophenyl)-4-(3-morpholin-4-yla zetid.in-l- yl)butyl]-JV-methylbenzamide (1.5g), purified by chromatography was slurried in 5ml acetonitrile. At signs of crystallisation, the material was placed in a freezer for 2 hours. The resulting solid material was then isolated by filtration and washed with acetonitrile. The solid was shown by XRPD to be a mixture of two or more crystal modifications.

3,5-dibromo-N-[(2.S)-2-(4-fluorophenyl)-4-(3-morpholm-4-y lazetidin-l-yl)butyl]-N- methylbenzamide modification B was crystallised by slurring the solid from the previous step in ethyl acetate in room temperature overnight. The solid material was then isolated by evaporation of the solvent under a purge of nitrogen.

The slurried material showed to be pure modification B of 3,5-dibromo-iV-[(25)-2-(4- fluorophenyl)-4-(3-morpholin-4-ylazetidin-l-yl)butyl]-iV-met hylbenzamide. Modification B melts with a melting point onset of 117°C and may be identified by the X-ray powder diffraction (XRPD) pattern in the table below (see also figure 1).

d-value: the spacing between successive parallel hkl planes in a crystal lattice

The peaks, identified with d- values calculated from the Bragg formula and intensities, have been extracted from the diffractogram of 3,5-dibromo-N-[(2 ₁ S}-2-(4-fluorophenyl)-4-(3- morρholin-4-ylazetidm-l-yl)butyl]-iV-methylbenzamide modification B, shown in Figure 1. The relative intensities are less reliable and instead of numerical values the following definitions are used:

The relative intensities are derived from diffractograms measured with variable slits.