(SA)-(-)-3-(3-BROMO-4-((2,4-DIFLUOROBENZYL)OXY)-6-METHYL-2

-OXOPYRIDIN-1 (2H)-YL)-N,4-DIMETHYLBENZAMIDE

BACKGROUND OF THE INVENTION

This invention relates to a novel crystalline form of (S _a )-(-)-3-{3-Bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1 (2/-/)-yl}-/\/,4-dimethylbenzamide and methods of preparation.

Synthetic routes for (S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2- oxopyridin-1 (2/-/)-yl}-/V,4-dimethylbenzamide, hereinafter the compound of Formula I, are described in WO 2003/068230 and WO 2008/072079, both incorporated herein by reference in their entirety for all purposes, and has the following structural formula,

I

The compound of Formula I is a selective oral inhibitor of the a-isoform of p38 MAP kinase. It is believed that p38a kinase can cause or contribute to the effects of, for example, inflammation generally; arthritis; neuroinflammation; pain; fever; pulmonary disorders; cardiovascular diseases; cardiomyopathy; stroke; ischemia; reperfusion injury; renal reperfusion injury; brain edema; neurotrauma and brain trauma; neurodegenerative disorders; central nervous system disorders; liver disease and nephritis; gastrointestinal conditions; ulcerative diseases; ophthalmic diseases; opthalmological conditions; glaucoma; acute injury to the eye tissue and ocular traumas; diabetes; diabetic nephropathy; skin-related conditions; viral and bacterial infections; myalgias due to infection; influenza; endotoxic shock; toxic shock syndrome; autoimmune disease; bone resorption diseases; multiple sclerosis; disorders of the female reproductive system; pathological (but non-malignant) conditions, such as hemaginomas, angiofibroma of the nasopharynx, and avascular necrosis of bone; benign and malignant tumors/neoplasia including cancer; leukemia; lymphoma; systemic lupus erthrematosis (SLE); angiogenesis including neoplasia; and metastasis. The compound of Formula I is, therefore, useful as a therapeutic agent for treating many pathological conditions, including the treatment or prevention of inflammatory and respiratory diseases such as chronic obstructive pulmonary disease ("COPD").

The compound of Formula I presents two anhydrous polymorphic forms, of (S _a )-(-)-3-{3-

Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1 (2/-/)-yl}-/\/,4-dimethylbenzamide. Forms A and H are anhydrous crystalline forms, with the present invention being directed to the polymorphic Form H.

Solid forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the solid form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected solid form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain solid forms may also exhibit enhanced stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain solid forms may display other advantageous physical properties such as lack of hygroscopic tendencies, filterability, improved solubility, and enhanced rates of dissolution due to different lattice energies.

The compound of Formula I has been classed as a low solubility compound and as a result particle size control is deemed important for commercialization of the compound. Likewise, there was a need for improved photostability of the compound of Formula I.

SUMMARY OF THE INVENTION

Although multiple solid forms of Compound I have been identified, each solid form can be uniquely identified by several different analytical parameters, alone or in combination, such as, but not limited to: powder X-ray diffraction pattern peaks or combinations of one or more peaks; solid state NMR ¹⁹ F chemical shifts or combinations of one or more chemical shifts; Raman shift peaks or combinations of one or more Raman shift peaks; or combinations thereof. One of ordinary skill in the art would appreciate that Form H of the compound of Formula I could uniquely be identified by several different peaks or patterns in varying combinations. The following are exemplary combinations of characteristic peak values that can be used to identify Form H and in no way should be viewed as limiting other peak value combinations disclosed herein:

i. an X-ray powder or capillary powder diffraction pattern containing the following 2Θ values measured using Cu K _a1 radiation (λ = 1.5406 A): 18.2 and 18.7 ° 2Θ ± 0.2 ° 2Θ; ii. a Raman spectrum containing the following wavenumber (cm ^"1 ) values: 831 cm ^"1 and 814 cm ^"1 ± 1 cm ^"1 ;

iii. a Raman spectrum containing the following wavenumber (cm ^"1 ) values: 831 cm ^"1 , 814 cm ^"1 and 672 cm ^"1 ± 1 cm ^"1 ;

iv. a Raman spectrum containing the following wavenumber (cm ^"1 ) values: 831 cm ^"1 , 814 cm ^"1 , 672 cm ^"1 and 252 cm ^"1 ± 1 cm ^"1 ;

v. a Raman spectrum containing the following wavenumber (cm ^"1 ) values: 1232 cm ^"1 , 831 cm ^"1 , 814 cm ^"1 , 672 cm ^"1 and 252 cm ^"1 ± 1 cm ^"1 ;

vi. a Raman spectrum containing the following wavenumber (cm ^"1 ) values 731 cm ^"1 and 501 cm ^"1 ± 1 cm ^"1 ;

vii. a Raman spectrum containing the following wavenumber (cm ^"1 ) values 977 cm ^"1 , 731 cm ^"1 and 501 cm ^"1 ± 1 cm ^"1 ;

viii. a Raman spectrum containing the following wavenumber (cm ^"1 ) values 977 cm ^"1 , 731 cm ^"1 , 1474 cm ^"1 and 501 cm ^"1 ± 1 cm ^"1 ;

ix. a Raman spectrum containing the following wavenumber (cm ^"1 ) values: 977 cm ^"1 , 731 cm ^"1 , 1474 cm ^"1 , 918 cm ^"1 and 501 cm ^"1 ± 1 cm ^"1 ; and

x. a ¹⁹ F solid state NMR spectrum containing the following resonance (ppm) values: - 112.3 and -109.7 ppm ± 0.2 ppm.

In one aspect, this invention relates to a novel crystalline Form H of (S _a )-(-)-3-{3-Bromo- 4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1 (2/-/)-yl}-/V,4-dimethylbenzamide, and compositions thereof, that are useful for the treatment or prevention of inflammatory and respiratory diseases such as COPD, as well as the inhibition of p38 MAP kinase in a mammal, including a human. The novel crystalline form exhibits an x-ray diffraction pattern with characteristic peaks expressed in degrees 2-theta (2Θ) at 8.2 and 18.7 ° 2Θ ± 0.1 ° 2Θ, as depicted in FIG 1. A discussion of the theory of X-ray power diffraction patterns can be found in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, MacMillan Co., New York, N.Y. (1968), which is incorporated by reference in its entirety.

In a further aspect, the present invention contemplates that any one of the solid forms of Compound I as described herein can exist in the presence of the any other of the solid forms or mixtures thereof. Accordingly, in one embodiment, the present invention provides the crystalline form H of Compound I as described herein, wherein said crystalline form is present in a solid form that includes less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other physical forms of Compound I. For example, in one embodiment is a solid form of Compound I comprising crystalline form H of Compound I that has any one of the powder X-ray diffraction patterns, Raman spectra, IR spectra and/or solid state NMR spectra described above, wherein said solid form includes less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1 % by weight of any other physical forms of Compound I.

In certain embodiments, the present invention relates to any of the above-referenced forms of Compound I, wherein said form is substantially pure (i.e., a substantially pure crystalline form.

Another aspect is directed to a pharmaceutical composition of the compound of Formula I for the inhibition of p38a kinase inhibitors that are believed to be useful in the treatment and/or prevention of, for example, inflammation, arthritis; neuroinflammation; pain; fever; pulmonary disorders; cardiovascular diseases; cardiomyopathy; stroke; ischemia; reperfusion injury; renal reperfusion injury; brain edema; neurotrauma and brain trauma; neurodegenerative disorders; central nervous system disorders; liver disease and nephritis; gastrointestinal conditions; ulcerative diseases; ophthalmic diseases; opthalmological conditions; glaucoma; acute injury to the eye tissue and ocular traumas; diabetes; diabetic nephropathy; skin-related conditions; viral and bacterial infections; myalgias due to infection; influenza; endotoxic shock; toxic shock syndrome; autoimmune disease; bone resorption diseases; multiple sclerosis; disorders of the female reproductive system; pathological (but non-malignant) conditions, such as hemaginomas, angiofibroma of the nasopharynx, and avascular necrosis of bone; benign and malignant tumors/neoplasia including cancer; leukemia; lymphoma; systemic lupus erthrematosis (SLE); angiogenesis including neoplasia; and metastasis.

In one embodiment of this invention, a pharmaceutical composition comprises:

(1) a crystalline form of (S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2- oxopyridin-1 (2/-/)-yl}-/V,4-dimethylbenzamide, as described herein, having a particle size of less than or equal to 20 μηι; and

(2) at least one pharmaceutically acceptable excipient.

In another embodiment, the particle size range is 9 m to 11 μηι. In another embodiment, the particle size is less than or equal to 5 μηι.

In another embodiment, the pharmaceutically acceptable excipient is sodium lauryl sulfate.

Definitions:

As used herein, the terms "the present invention," "compound of the invention," "compound of Formula I," "the claimed compound", crystalline and non-crystalline forms, thereof are defined to include all forms of the compound of the invention. Therefore, for example, and not by way of limitation, use of the term "the present invention" will mean compound of Formula I, (S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2-oxopyridin- 1 (2/-/)-yl}-/V,4-dimethylbenzamide, drug product and Form H polymorph. The term "crystalline" refers to any solid substance exhibiting three-dimensional order, which in contrast to an amorphous solid substance, gives a distinctive XRPD pattern with sharply defined peaks.

As used herein, the term "essentially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2Θ) will show some variability, typically as much as 0.1 to 0.2 degrees, as well as on the apparatus being used to measure the diffraction. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measures only. Similarly, as used herein, "essentially the same" with reference to solid state NMR spectra and Raman and IR spectra is intended to also encompass the variabilities associated with these analytical techniques, which are known to those of skill in the art. For example, ¹³ C chemical shifts measured in solid state NMR will typically have a variability of up to 0.2 ppm for well defined peaks, and even larger for broad lines, while Raman and infrared shifts will typically have a variability of about 2 cm ^"1 .

The term "polymorph" refers to different crystalline forms of the same Compound and includes, but is not limited to, other solid state molecular forms including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.

The term "powder X-ray diffraction pattern" or "PXRD pattern" refers to the experimentally observed diffractogram or parameters derived therefrom. Powder X-Ray diffraction patterns are characterized by peak position (abscissa) and peak intensities (ordinate).

The term "2 theta value" or "2Θ" refers to the peak position in degrees based on the experimental setup of the X-ray diffraction experiment and is a common abscissa unit in diffraction patterns. The experimental setup requires that if a reflection is diffracted when the incoming beam forms an angle theta (Θ) with a certain lattice plane, the reflected beam is recorded at an angle 2 theta (2Θ). It should be understood that reference herein to specific 2Θ values for a specific solid form is intended to mean the 2Θ values (in degrees) as measured using the X-ray diffraction experimental conditions as described herein. For example, as described herein, CuKc^ (wavelength 1.54056 A) was used as the source of radiation.

As mentioned previously, the compound of Formula I presents two anhydrous polymorphic forms, of (S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2-oxopyridin- 1 (2/-/)-yl}-/V,4-dimethylbenzamide. Forms A and H are anhydrous crystalline forms, with the present invention being directed to the polymorphic Form H. The compound of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ('glass transition').

BRI EF DESCRI PTION OF THE DRAWI NGS

Figure 1 is a characteristic carbon CP MAS spectrum of Form H.

Figure 2 is a characteristic Fluorine MAS spectrum of Form H.

Figure 3 is a characteristic Fluorine MAS spectrum of Form H drug product.

Figure 4 is a characteristic PXRD pattern for Form H.

Figure 5 is a characteristic FT-I R spectrum for Form H.

Figure 6 is a characteristic FT-I R spectrum for Form H (fingerprint region).

Figure 7 is a characteristic FT-Raman spectrum for Form H.

Figure 8 is a characteristic FT-Raman spectrum for Form H (fingerprint region).

Figure 9 is a characteristic Micrograph of micronized Form A.

Figure 10 is a depiction of the comparison of compound of Formula I Form A and Form H micronized on a MC One© at 8 bar mill pressure.

Figure 1 1 is a depiction of Particle size distribution of compound of Formula I Form A and Form H micronized at the same Specific Energy Consumption (SEC).

DETAI LED DESCRI PTION OF THE I NVENTION

For drug development, it is important to provide a compound form (commonly known as a drug substance) that not only is reliably prepared and purified on a large scale, but is also stable and does not degrade on storage. Furthermore, the drug substance must be suitable for formulation in a dosage form chosen according to the intended route of administration. It has been found that the compound of Formula I can exist in a crystalline form, a two-dimensionally ordered liquid crystalline form or an amorphous form. These forms may be used in a formulated product for the treatment of the diseases identified herein.

Form A of (S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2-oxopyridin-1 (2/-/)- yl}-/V,4-dimethylbenzamide is the first crystalline polymorph form developed and was used in Phase I and I I clinical trials. Form A was formed systematically with or without seed from pure starting material. Synthetic routes for 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2- oxopyridin-1 (2H)-yl)-N,4-dimethylbenzamide, hereinafter the compound of Formula I, including Form A, are described in WO 2003/068230 and WO 2008/072079. (S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methy^

dimethylbenzamide is heated to dissolve in methanol at 30 ml_/g, and cooled before seeds of Form A are added at 55 °C. The resulting slurry is distilled to low volume before cooling and solids are isolated by filtration and dried at 50 °C.

Another crystalline polymorph form of (S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-1 (2/-/)-yl}-/V,4-dimethylbenzamide, "Form H", was later discovered that is more suitable for bulk preparation and handling than previous crystalline or amorphous forms. Likewise, Form H is more thermodynamically stable at room temperature. While Forms A and H have similar conformation and solubility, the isolation of Form H was significantly more difficult than the isolation of Form A.

In particular, it was determined that the preparation of Form H with varying seed loadings, supersaturations and seed temperature, gave rise to an undesired mixture of polymorphs Form A and Form H. It was unexpectedly discovered that Form H could be crystallized spontaneously from pure starting material even in the presence of Form A seed by anti-solvent crystallization at low temperature in methanol/water. This latter process does not require Form H seed and gives rise to fine particles.

Preparation of Form H

The crystalline Form H of the compound of Formula I, (-)-3-(4-(2,4-difluorobenzyloxy)-3- bromo-6-methyl-2-oxopyridin-1 (2H)-yl)-N,4-dimethylbenzamide, is prepared as described below:

Form H can be produced by the following process: 200mg of the compound of formula I was dissolved in 5ml_/g NMP and heated to dissolve the solids. The resulting solution was cooled to 5 deg C over a period of approximately 30 minutes. 15ml_/g DIW (deionized water) was added slowly over a period of approximately 8h to precipitate Form H. Form H is isolated from the resultant slurry by filtration and dried under reduced pressure at 70 deg C.

Characterization of Form H.

The solid anhydrous polymorph Form H of the compound of Formula I can be distinguished and characterized by one or more of the following: powder X-ray diffraction pattern (i.e., X-ray diffraction peaks at various diffraction angles (2Θ)), solid state nuclear magnetic resonance (ssNMR) spectra, Raman spectra, Infrared spectra, aqueous solubility, light stability under International Conference on Harmonization (ICH) high intensity light conditions, and physical and chemical storage stability. One of ordinary skill in the art would appreciate that Form H may be distinguished by a combination of characteristic peaks disclosed in the Tables herein and that characteristic peaks in bold or discussed herein are not meant to limit in any way other potential combination of peaks set forth in the aforesaid mentioned Tables. (a) Characterization of Form H by ssNMR

Instrument Method: Approximately 80 mg of sample were tightly packed into a 4 mm Zr0 ₂ rotor. Spectra of Form H were collected at ambient temperature and pressure on a Bruker-Biospin 4 mm CPMAS probe positioned into a wide-bore Bruker-Biospin Avance III 500 MHz ( ¹ H frequency) NMR spectrometer. The packed rotor was oriented at the magic angle and spun at 15.0 kHz. The ¹³ C solid state spectra were collected using a proton decoupled cross- polarization magic angle spinning (CPMAS) experiment. The cross-polarization contact time was set to 2.0 ms. A phase modulated proton decoupling field of approximately 85 kHz was applied during acquisition. The carbon spectrum of Form H was acquired for 900 scans with a 17 second recycle delay. (Figure 1) The carbon spectrum was referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm (Table 1). The fluorine solid state spectra were collected using a proton decoupled magic angle spinning (MAS) experiment. A phase modulated proton decoupling field of approximately 85 kHz was applied during acquisition. The fluorine spectrum of Form H was acquired for 32 scans with a 185 second recycle delay (Figure 2). The fluorine spectrum was referenced using an external standard of trifluoroacetic acid (50% V/V in H ₂ 0), setting its resonance to -76.54 ppm (Table 2). Note that one of ordinary skill in the art would appreciate that the method required to analyze a dosage form for the presence of Form H would need to be adjusted slightly, as compared to that described above. A dosage form, such as a tablet, would need to be first reduced to powder via trituration in a mortar and pestle. Additionally, an increased number of scans may be desired in order to improve detection of Form H once diluted with excipients.

Table 1. Crystalline Form H characterized by the following ¹³ C chemical shifts expressed in parts per million. Characteristic peaks are bolded. All peaks in the peak set must be included to define this form (± 0.2 ppm).

*Referenced to external sample of solid phase adamantane at 29.5 ppm.

Table 2. Crystalline Form H characterized by the following ¹⁹ F chemical shifts expressed in parts per million. Characteristic peaks are bolded. All peaks in the peak set must be included to define this form (± 0.2 ppm).

F Chemical Shifts [ppm]

-112.2

-109.7

"Referenced to external standard of trifluoroacetic acid (50% V/V in H ₂ 0) at 76.54 ppm

(b) Characterization of Form H API Drug Product Instrument Method:

Tablets were gentle ground to a free flowing powder using a mortar and pestle. Approximately 80 mg of powdered tablets were tightly packed into a 4 mm Zr0 ₂ rotor. Spectra was collected at ambient temperature and pressure on a Bruker-Biospin 4 mm CPMAS probe positioned into a wide-bore Bruker-Biospin Avance III 500 MHz ( ¹ H frequency) NMR spectrometer. The packed rotor was oriented at the magic angle and spun at 15.0 kHz. The fluorine solid state spectra were collected using a proton decoupled magic angle spinning (MAS) experiment. A phase modulated proton decoupling field of approximately 85 kHz was applied during acquisition. The fluorine spectrum of Form H drug products was acquired for 400 scans with a 185 second recycle delay (Figure 3). The fluorine spectrum was referenced using an external standard of trifluoroacetic acid (50% V/V in H ₂ 0), setting its resonance to -76.54 ppm (Table 3). Table 3 Form H drug product characterized by the following ¹⁹ F chemical shifts expressed in parts per million.

*Referenced to external standard of trifluoroacetic acid (50% V/V in H ₂ 0) at -76.54 ppm. (c) Characterization of Form H by Powder X-Ray Diffraction (PXRD)

PXRD patterns were determined using a Bruker-AXS Ltd. D4 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slit, and a PSD Vantec-1 detector, calibrated for peak 2-theta positions against a Corundum standard (NIST: SRM 1976 XRD). The sample was prepared for analysis by mounting on a low background silicon wafer specimen mount. The specimen was rotated whilst being irradiated with copper K-alpha _! X-rays (wavelength = 1.5406 Angstroms) with the X-ray tube operated at 40kV/30mA. The analyses were performed with the goniometer running in continuous mode set for a 0.2 second count per 0.018° step over a two theta range of 2° to 55°. Peaks were selected manually using Bruker-AXS Ltd. evaluation software.

As will be appreciated by the skilled person, the relative intensities of the various peaks given below may vary due to a number of factors such as orientation effects of crystals in the X- ray beam, the purity of the material being analysed or the degree of crystallinity of the sample. The peak positions may also shift for variations in sample height but the peak positions will remain substantially as defined.

The skilled person will also appreciate that measurements using a different wavelength will result in different shifts according to the Bragg equation - ηλ = 2d sin Θ. Such further PXRD patterns generated by use of alternative wavelengths are considered to be alternative representations of the PXRD patterns of the crystalline materials of the present invention and as such are within the scope of the present invention.

The PXRD pattern for Form H is shown in Figure 4. The main 2-theta peak positions and relative intensities are listed in Table 4. Table 4. 2-theta peak positions (+ 0.2 degrees) and relative intensities for the diffraction peaks observed for Form H PXRD pattern.

(d) Characterization of Form H in Drug Product by Capillary Powder X-Ray Diffraction (PXRD)

The powder X-ray diffraction pattern was determined using a Bruker-AXS Ltd. D8 Advance powder X-ray diffractometer fitted with a theta-theta goniometer, antiscattering slit and a PSD LynxEye detector. The sample was prepared for analysis by filling a 1.5 mm diameter borosilicate glass capillary. The tablet was lightly ground and added into the capillary in small portions. In between additions, the capillary was lightly tapped in order to avoid voids in the capillary. The specimen was rotated whilst being irradiated with copper K-alpha _! X-rays (wavelength = 1.5406 Angstroms) with the X-ray tube operated at 40kV/40mA. The analyses were performed with the goniometer running in continuous mode set for a 12 second count per 0.011 ° step over a two theta range of 2° to 55°. Note that an increased scanning time may be desired in order to improve detection of Form H once diluted with excipients.

The most characteristic peaks were selected using Bruker-AXS Ltd. Evaluation software with a threshold of 1 and a peak width of 0.3° two theta. The data were collected at 21 °C (Table 5).

Table 5. 2-theta peak positions (+ 0.2 degrees) for the diffraction peaks observed for Form H in drug product PXRD pattern.

(e) Characterization of Form H by FTIR and FT-Raman

FT-IR. The IR spectrum was acquired using a ThermoNicolet Nexus FTIR spectrometer equipped with a 'DurasampllR' single reflection ATR accessory (diamond surface on zinc selenide substrate) and d-TGS KBr detector. The spectrum was collected at 2cm ^"1 resolution and a co-addition of 512 scans (Figures 5 and 6). Happ-Genzel apodization was used. Because the FT-IR spectrum was recorded using single reflection ATR, no sample preparation was required. Using ATR FT-IR will cause the relative intensities of infrared bands to differ from those seen in a transmission FT-IR spectrum using KBr disc or nujol mull sample preparations. Due to the nature of ATR FT-IR, the bands at lower wavenumber are more intense than those at higher wavenumber. Experimental error, unless otherwise noted, was ± 2 cm ^"1

FT-Raman. The Raman spectrum was collected using a Bruker Vertex70 FT-IR spectrometer with Rami I Raman module, equipped with a 1064nm NdYAG laser and LN- Germanium detector. All spectra were recorded using 2cm ^"1 resolution and Blackman-Harris 4- term apodization. The laser power was 300mW and 1024 scans were collected for Form H and 2048 scans for Form A (Figures 7 and 8). The sample was placed in a glass vial and exposed to the laser radiation. The data is presented as intensity as a function of Raman shift. Experimental error, unless otherwise noted, was ± 1 cm ^"1

FTIR and Raman peaks were picked using ThermoNicolet Omnic 6.1 a software. Intensity assignments were relative to the major band in the spectrum so are not based on absolute values measured from the baseline. Absorbance is stated on all Raman spectra - this should be arbitrary intensity and the X-axis as Raman shift (cm ^"1 ). The spectra are maximized to the maximum intensity band.

Absorption band frequencies of Form H are listed below at Table 6. The whole spectrum uniquely identifies Form H.

Table 6 FTIR Peak table for Form H Experimental error is ± 2 cm ^"1 *error could be considerably larger.

FT-Raman Peak table data for Form H. Table 7 shows relative intense, well defined FT-

Raman bands for which the whole spectrum could be used to identify Form H. Experimental error is ± 1 cm ^"1 . Table 7 FT-Raman Peak Data for Form H; Experimental error is ± 1 cm ^"1 .

*error could be considerably larger (f) Characterization of Form H in Drug Product by Raman Mapping

The tablet was prepared by sticking it to a glass microscope slide with superglue and using a Leica MZ6 EM RAPID Trim to cut off the coating and to obtain a optically flat surface (last cutting step was 0.5 μηι with 10 repeats).

The Raman spectrum was collected using a Horiba Jobin-Yvon LabRamHR Raman microscope equipped with a 785nm laser, 12001/mm grating and air cooled CCD detector. A 50x, 0.55NA objective was used, with the pinhole set to 200μηι and the slit to 150μηι. Approximately 90mW of laser power at the sample was used.

The spectrum was collected using the extended scan function (240cm ^"1 to 1700cm ^"1 ) with an exposure time of 240s with 1 accumulation (100 pixels are overlapped when stitching the different spectra together). The wavenumber accuracy was then verified by collecting single spectra without stitching and comparing the wavenumbers with the spectrum that was stitched together. Note that an increased number of scans or higher laser power may be desired in order to improve detection of Form H once diluted with excipients. Raman peaks were picked using ThermoNicolet Omnic 6.1a software.

For the selected grating, the wavenumbers recorded by a dispersive Raman spectrometer are the same as for an FT-Raman spectrometer and the wavenumber accuracy was verified prior and after data collection. By collecting Raman spectra from such a small volume (as defined amongst others by the microscope objective, its numerical aperture, slit width and pinhole setting) the API Raman spectrum was collected with minimal overlap of excipients. Routes of Administration

Polymorphic Form H of (S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2- oxopyridin-1 (2/-/)-yl}-/V,4-dimethylbenzamide provided by the invention (referred to herein as the compound of the invention) may be administered alone but will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound of the invention. 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.

Pharmaceutical compositions suitable for the delivery of the compound of the 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 compound of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules 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 compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 1 1 (6), 981- 986, by Liang and Chen (2001). For tablet dosage forms, depending on dose, the compound of the invention may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.

In addition, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

Binders are also generally used to impart cohesive qualities to a tablet formulation.

Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.

Other possible tablet ingredients include anti-oxidants, colouring agents, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

Tablet blends may be compressed directly or by roller compaction to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

The compound of the invention may also be orally administered in the form of a consumable oral film for human or veterinary use. Such a film is typically a pliable water-soluble or water-swellable thin film dosage form which may be rapidly dissolving or mucoadhesive and typically comprises the compound of the invention, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.

Other possible film ingredients include anti-oxidants, colouring agents, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuum drying.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release.

Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6, 106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO-A-00/35298.

The compound of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Such parenteral administration may be via the intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous route. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi- solid or thixotropic liquid for administration as an implanted depot providing modified release of the compound of the invention. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

The compound of the invention may also be administered topically to the skin or mucosa, i.e. dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J. Pharm. Sci., 88 (10), 955-958, by Finnin and Morgan (October 1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release.

The compound of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 , 1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. Administration in the form of a dry powder from a dry powder inhaler is a particularly preferred form of delivery.

The pressurized container, pump, spray, atomizer or nebuliser contains a solution or suspension of the compound of the invention comprising, for example, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, solubilising or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from ^g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 μΙ to 100μΙ. A typical formulation may comprise the compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavouring agents, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit may be determined by means of a valve which delivers a metered amount. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

The compound of the invention may be administered rectally or vaginally, in the form, for example, of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. The compound of the invention may also be administered by the ocular or aural route.

The compound of the invention may be combined with a soluble macromolecular entity, such as a cyclodextrin or a suitable derivative thereof or a polyethylene glycol-containing polymer, in order to improve its solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in WO- A-91/11 172, WO-A-94/02518 and WO-A-98/55148.

For administration to human patients, the total daily dose of the compound of the invention will typically be in the range 0.002 mg/kg to 100 mg/kg 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. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

Inhibitors of p38 MAP kinase, such as the compound of the invention, may advantageously be administered in combination with one or more other therapeutic agents, particularly in the treatment of respiratory diseases such as chronic obstructive pulmonary disease. Examples of such further therapeutic agents include: (i) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists; (ii) leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4; (iii) histamine receptor antagonists including H1 , H3 and H4 antagonists; (iv) a1- and a2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for nasal decongestant use; (v) muscarinic M3 receptor antagonists or anticholinergic agents; (vi) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors; (vii) theophylline; (viii) sodium cromoglycate; (ix) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs); (x) oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor); (xi) monoclonal antibodies active against endogenous inflammatory entities; (xii) anti-tumor necrosis factor (anti-TNF-a) agents; (xiii) adhesion molecule inhibitors including VLA-4 antagonists; (xiv) kinin-B1 - and B2 -receptor antagonists; (xv) immunosuppressive agents; (xvi) inhibitors of matrix metalloproteases (MMPs); (xvii) tachykinin NK1 , NK2 and NK3 receptor antagonists; (xviii) elastase inhibitors; (xix) adenosine A2a receptor agonists; (xx) inhibitors of urokinase; (xxi) compounds that act on dopamine receptors, e.g. D2 agonists; (xxii) modulators of the N FKP pathway, e.g. IKK inhibitors; (xxiii) modulators of cytokine signaling pathways such as a p38 MAP kinase or JAK kinase inhibitor; (xxiv) agents that can be classed as mucolytics or anti-tussive; (xxv) antibiotics; (xxvi) HDAC inhibitors; (xxvii) PI3 kinase inhibitors; (xxviii) β2 agonists; and (xxix) dual compounds active as β2 agonists and muscarinic M3 receptor antagonists. Additional therapeutic agents for combination therapies with the compound of Formula I include (i) CXCR2 chemokine receptor antagonists; (ii) soluble epoxide hydrolase inhibitors; (iii) phosphoinositide 3 kinase inhibitors; NF-E2 related factor-2 (Nrf2) activators; ASK1 inhibitors; and Bromodomain- containg protein 4 (BRD4) inhibitors.

In one embodiment the examples of such therapeutic agents include: (a) glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate; (b) muscarinic M3 receptor antagonists or anticholinergic agents including ipratropium salts such as the bromide, tiotropium salts such as the bromide, oxitropium salts such as the bromide, perenzepine and telenzepine; and (c) β2 agonists including salbutamol, terbutaline, bambuterol, fenoterol, salmeterol, formoterol, tulobuterol. . Where it is desirable to administer a combination of active compounds, two or more pharmaceutical compositions, at least one of which contains the compound of the invention, may conveniently be combined in the form of a kit suitable for co-administration.

Such a kit comprises two or more separate pharmaceutical compositions, at least one of which contains the compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

Such a kit is particularly suitable for administering different dosage forms, for example, oral and parenteral dosage forms, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

EXAMPLES

The examples which follow will further illustrate the different characteristics of the distinct forms of the invention, i.e. a crystalline form, a two-dimensionally ordered liquid crystalline form and an amorphous form, but are not intended to limit the scope of the invention as defined herein or as claimed below.

Micronization Experiment

(S _a )-(-)-3-{3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2-oxopyridin-1 (2/-/)-yl}-/\/,4- dimethylbenzamide was classed as low solubility and, as a result, particle size control was important to ensure suitable bioavailability. To date particle size control was achieved though micronization (jet milling) of the active pharmaceutical ingredient (API). The compound of Formula I exists in two anhydrous polymorphic forms, Form A and Form H. Form A was initially identified as the thermodynamically stable form and was used in both Phase I and Phase II clinical trial studies. Improved stability was desired, however, and through additional research and experimentation, the anhydrous polymorphic Form H was unexpectedly discovered and demonstrated improved stability making it a much more desirable commercial form.

Assessment of micronization behaviour of Form A and Form H. Micronization feasibility and assessment studies were carried out through the span of the project. Initial studies were commenced with Form A, given that it was the initial commercial form contemplated. A series of lab scale trials were carried out on a JetPharma MC One© jet mill system to support drug product studies designed to investigate the effect of particle size on dissolution behavior, thus providing a starting point for setting a particle size target. These trials indicated that Form A was difficult to micronize. Micronization through jet milling is typically understood as a high energy process that produces particles < 10 μηι, which are generally desired to increase the dissolution rate of low solubility compounds. Forms A was found to be very challenging to micronisation and it was not possible to produce a particles where 90% (by volume) were < 10 μηι diameter even using the most energetic process conditions. However it was possible to micronise Form H to produce > 90% (by volume) were < 10 μηι diameter, which is a significant advantage for Form H .

Particle size is not the only important aspect of the micronization process, also of concern was the affect of micronization on crystallinity. During Scanning Electron Microscopy (SEM) analysis post-micronization recrystallisation was observed after about 2 weeks in ambient conditions, as shown in Figure 9. Additional micronized batches were generated and submitted for PXRD analysis to assess the crystallinity post micronization. The PXRD data indicated that Form A was prone to significant disorder (reduction of crystallinity) on micronization, (Tables 8 and 9). It was also observed that there was no significant loss in Form H crystallinity by powder X-ray diffraction as a result of size reduction and no apparent recrystallization events were observed upon storage by SEM analysis.

In addition a build-up of powder on the grinding ring was observed for all runs with Form A. This build-up was relatively hard and ranged in thickness from about 1 to 3 mm depending on the operating conditions employed.

Micronization performance was also assessed for Form H. Initial lab scale trials indicated Form H material was more readily micronized with a typical particle size < 5 μηι and a size range of < 1 to 20 μηι. Form A material micronized at the same conditions was shown to have particles up to 200μηι. present (Figure 10). It was also observed that micronization of Form H did not lead to any abnormal build-up of material on the grinding ring.

Additional Form H micronization studies were carried out to enable a comparison of particle size distributions (Figure 11). This clearly demonstrated that Form H material micronized more readily than Form A material. When mixtures of Form H and Form A were micronized, differences in process performance were observed at levels of Form A of 6% and above. These were seen as increased build-up on the grinding ring and an increase in particle size.

It was observed that there was no significant loss in Form H crystallinity as a result of size reduction and no apparent recrystallization events were observed during SEM analysis. Further evidence of the difference in micronization performance between Forms A and H was observed during clinical manufacture of the API using an 8" jet mill. Form A was micronized at a mill pressure of 100 psi and a feed rate of 3 kg/hr to reach a composite particle size of D[v, 0,9] = 31.65 μηι. During the micronization of Form A, the mill blocked every 10 minutes and the residual material had to be removed. This residual material accounted for about 9.2% of the ingoing material. On the other hand, Form H material was micronized at a mill pressure of 100 psi and a feed rate of 2.4 kg/hr to reach a composite particle size of D[v, 0,9] = 3.39 μηι . There was no reported residual material during this micronization campaign. These properties demonstrate that Form H offers a significant improvement in the API milling efficiency during API manufacturing operation.

Photostability Experiments

The photostability characteristics of drug substances and drug products should be assessed to understand if exposure to light compromises product quality. ICH Q1 B states that "samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter". (ICH Topic Q1 B: Photostability Testing of New Active Substances and Medicinal Products (CPMP/ICH/279/95)). Photolabile products may require specific labeling requirements or protective packaging configurations to mitigate light exposure. As discussed above, the compound of Formula I was originally crystallized as the polymorph Form A. Subsequently, polymorph Form H was discovered and identified as the more thermodynamically stable form. Comparison studies of the photostability of Form A and Form H drug substance and tablets manufactured from Form A and Form H were performed as follows:

Photostability of Drug Substance. Pre- and post-micronization samples of Form A and Form H drug substance batches were exposed to 750 Watt hrs/m ² for 36 hours in an Atlas Suntest Photostability Cabinet. This is equivalent to a dose of 97200 KJ/m ² and significantly exceeds the ICH requirements for UV and visible light exposure requirements. As summarized in Table 9, Form A is significantly more photolabile compared to Form H. Although amorphous content had some influence on the photostability of the compound (severely disordered Form H degraded to a greater extent than unmicronized or micronized Form H), it does not fully explain the photostability differences between the two solid Forms A and H.

Table 8: Summary of photostability data for compound of Formula I drug substance (36 hours at 750 watt hrs/m2)

Total degra-

% area parent RRT 0.66, RRT 0.79, % area parent RRT 1 .02,

dants, #1 % area parent % area parent #2 % area parent

Batch details % area

parent

Exposed -

Control Exposed Control Exposed Control Exposed Control Exposed Control Exposed

Control

Micronized NMT NMT NMT NMT

3.9 0.76 0.18 0.1 1 3.5 0.15 8.4 Form A 0.05 0.05 0.05 0.05

Micronized NMT NMT

0.07 0.09 0.15 Form H 0.05 0.05

Table 9: Summary of photostability data for compound of Formula I drug substance (36 hours at 750 watt hrs/m2)

% area parent RRT 0.66, RRT 0.79, RRT 0.88, RRT 0.94, % area parent RRT 0.96, RRT 1 .02,

Batch #1 % area parent % area parent % area parent % area parent #2 % area parent % area parent details

Control Exposed Control Exposed Control Exposed Control Control Control Exposed Control Exposed Control Exposed ontrol Exposed

Unmicro-

NMT NMT NMT NMT

nized Form 7.4 0.40 0.35 0.10 8.0 0.12

0.05 0.05 0.05 0.05

A

Micronized

Form H,

NMT

< 1 % Form 0.09

0.05

A

Unmicro- nized Form NMT NMT

0.24 0.33

H, approx. 0.05 0.05

2% Form A

Severly

disordered,

unmicro-

NMT NMT NMT NMT NMT NMT NMT

nized Form 0.64 0.48 0.13 0.15 0.14 0.14 0.10

0.05 0.05 0.05 0.05 0.05 0.05 0.05

H (approx.

2% Form

A)

Less photodegradation was also observed for micronized Form H compared to micronized Form A under ICH photostability conditions, when packaged in double low density polyethylhene bags within a high density polyethylene drum (refer to Table 10). This demonstrated that the trends observed under the harsher conditions above are also observed under more representative photostability conditions.

Table 10: Summary of photostability data for compound of Formula I drug substance under ICH conditions

In general, one would expect that micronized material would contain more disorder and have a greater surface area than unmicronized material, thus, increasing the likelihood of photodegradation for the micronized material. It is noted, however, that micronized compound of Formula I drug substance unexpectedly appears more photostable than unmicronized drug substance, for both Form A and Form H. Photostability of Drug Product. Form A and Form H tablets were exposed to 750 Watt hrs/m ² for 36 hours in an Atlas Suntest Photostability Cabinet. This is equivalent to a dose of 97200 KJ/m ² and significantly exceeds the ICH requirements for UV and visible light exposure requirements. The Form A and Form H formulations studied in this experiment differ in the blend strength, tablet size and in small changes to the ratios of excipients used. The same excipients are used in both formulations.As can be seen from the data summarized in Table 1 1 , Form A is again significantly more photolabile than Form H. Film coating on the compound of Formula I tablets provided a measure of protection against photodegradation of the drug substance. Table 1 1 : Summary of photostability data for compound of Formula I drug product