CZ20001404A3 - Novel polymorphous forms of cipamfylin - Google Patents

Abstract

Crystal polymorphic forms of cipamphiline, forms I, II and IV, methods for their preparation and use in the treatment of diseases PDE4 and TFN mediated. Cipamfylin is 1,3- dicyclopropylmethyl-8-aminoxanthine of formula (I).

Description

New polymorphic forms of cipamphylline

Technical field

The present invention relates to novel crystal polymorphic forms of cipamphylline and processes for their preparation.

BACKGROUND OF THE INVENTION

The ability to occur in various crystal structures is known as polymorphism and is known to occur in many organic compounds. These various crystal forms are known as "polymorphic modifications" or "polymorphs" and are realized in their crystalline state. While polymorphic modifications have the same chemical composition,. they are distinguished by the position, geometric arrangement and other descriptive characteristics of the crystalline solid state. As such, these modifications may have different physical properties in the solid state, such as shape, color, hardness, deformability, stability, solubility, etc. The polymorphism of organic drug molecules and its consequences are known to the person skilled in the art.

Cipamphylline, 1,3-dicyclopropylmethyl-8-aminoxanthine has the chemical formula C13H17N5O2, MW 275, 31 and the following structural formula:

Its synthesis is described in Example 9 of Maschler et al., UK Patent Application No. 8906792.0, filed March 23, 1989, and the corresponding European Patent EP 389 282 and the corresponding US Patent 5,734,051, which are hereby incorporated by reference in their entirety.

Cipamphylline is a PDE ₄ inhibitor and is useful in the treatment of. treatment and prophylaxis of disease states mediated by it.

Cipamphylline has also been shown to have TNF inhibitory activity (Esser et al., PCT / US91 / 08734, also published as EP 558 659) and is therefore suitable for the treatment and prophylaxis of TNF-mediated disease states. Suitable assays, dosage forms and dosage ranges, etc. for polymorphs. the compounds of the invention for use in the therapeutic treatment of diseases can be found in the patent applications (Maschler et al., or Esser et al.), which are hereby incorporated by reference in their entirety.

SUMMARY OF THE INVENTION

The present invention relates to a novel crystal polymorphic modification of 1,3-dicyclopropylmethyl-8-aminoxanthine, hereinafter referred to as Form I, which form is useful in the treatment of diseases mediated by PDE ₄ and TNF.

The present invention also relates to a novel crystal polymorphic modification of 1,3-dicyclopropylmethyl-8-aminoxanthine, hereinafter referred to as Form II, which form is useful in the treatment of diseases mediated by PDE ₄ and TNF.

The present invention also relates to a novel crystal polymorphic modification of 1,3-dicyclopropylmethyl-8-aminoxanthine, hereinafter referred to as Form IV, which form is useful in the treatment of diseases mediated by PDE ₄ and TNF.

Description of the drawings

Figure 1 is a characteristic powder X-ray (X-ray diffractogram) of Form I (vertical axis: intensity (CPS); horizontal axis: diffraction angle, at two theta (degrees)).

Figure 2 is a characteristic X-ray powder pattern of Form II (vertical axis: intensity (CPS); horizontal axis: diffraction angle, at two theta (degrees)).

Figure 3 is a table showing the tabulated torsion angle data of Forms II and IV.

Figure 4 is a Raman spectrum of Form I (vertical axis: intensity; lower horizontal axis: wavelength (cm ^-1 ))

Figure 5 is a Raman spectrum of Form II [vertical axis: intensity; lower horizontal axis: wave number (cm ^-1 ))

Figure 6 is a Raman spectrum of Form IV (vertical axis: intensity; lower horizontal axis: wavelength (cm ^-1 ))

Figure 7 is a comparison of the Raman spectra of all three forms, forms I, II and IV and the stretched region of carbonyl 1750 - 1600 cm ^-1 (vertical axis: intensity; lower horizontal axis: wavelength (cm ^-1 ))

Figure 8 is a comparison of the Raman spectra of all three forms, forms I, II and IV and the region 1000-800 cm ^-1 (vertical axis: intensity; lower horizontal axis :, wavelength (cm ^-1 ))

Figure 9 is a comparison of the Raman spectra of all three forms, forms I, II and IV and the region 400-200 cm ^-1 (vertical axis: intensity; lower horizontal axis: wavelet (cm ^-1 ))

Figure 10 shows Form I three-dimensionally with a labeling scheme.

Figure 11 shows a stereoscopic representation of a Form I molecule.

Figure 12 shows a table of binding distances of the Form I molecule in Angstroms.

Figure 13 shows a table of binding angles in degrees for the Form I molecule.

Figure 14 shows a table of torsion angles in degrees for the Form I molecule.

Figure 15 shows a table of positional parameters and their Estimated Standard Deviations estimates for a Form I molecule. The x, y, and z coordinate values indicate the position of the atoms relative to the unit cell origin and B (A2) is an isotropic temperature factor.

Figure 16 is a characteristic infrared absorption spectrum of a single crystal of Form I.

Figure 17 is a characteristic infrared absorption spectrum of a single crystal of Form II.

Figure 18 is a characteristic infrared absorption spectrum of a single crystal of Form IV.

Figure 19 is a comparison of the characteristic infrared absorption spectra of the single crystals of Forms I, II and IV.

Figure 20 is a characteristic infrared absorption spectrum of Form I in potassium bromide (vertical axis: transmittance (%); horizontal axis (wavelength cm ^-1 )).

Figure 21 is a characteristic infrared absorption spectrum of Form II in potassium bromide (vertical axis: transmittance (%); horizontal axis (wavelength cm ^-1 ))

Figure 22 is a characteristic infrared absorption spectrum of a crushed crystal of Form I.

Figure 23 is a characteristic infrared absorption spectrum of a crushed crystal of Form II.

Figure 24 is a characteristic infrared absorption spectrum of a crushed crystal of Form IV.

Figure 25 is a comparison of infrared absorption spectra of single crystal and crushed crystal of Form IV.

Figure 26 shows a three-dimensional molecule of Form IV with a labeling scheme.

Figure 27 is a stereoscopic representation of a Form IV molecule.

Figure 28 is a table of binding distances in Angstroms for the Form IV molecule.

• ·· · · φ · φ · · φ φ

Figure 29 is a table of binding angles in degrees for the Form IV molecule.

Figure 30 is a table of torsion angles in degrees for the Form IV molecule.

Figure 31 shows a table of positional parameters and their standard deviation estimates for the Form IV molecule.

Figure 32 shows a three-dimensional Form II molecule with a labeling scheme.

Figure 33 is a table of binding distances in Angs. For Form II molecule.

Figure 34 is a table of binding angles in degrees for the Form II molecule.

Figure 35 is a table of torsion angles in degrees for the Form II molecule.

Figure 36 presents a table of positional parameters and their standard deviation estimates for the Form II molecule.

Detailed description of the invention

It has now been found that cipamphylline can exist as any of several new crystal forms, polymorphic forms, which differ in their stability, physical properties, spectra and preparation methods. Three of these new polymorphic forms are referred to in this application as Form I, Form II, and Form IV.

Of the three new polymorphs mentioned above, Form I shows the highest stability. Form I is

characterized by at least five years of crystal stability.

The present invention also provides pharmaceutical compositions comprising an effective amount of polymorph Form I having the characteristics set forth herein and a pharmaceutically acceptable carrier or diluent.

The present invention also provides pharmaceutical compositions comprising an effective amount of polymorph Form II having the characteristics set forth herein and a pharmaceutically acceptable carrier or diluent.

This invention also provides pharmaceutical compositions comprising an effective amount of a polymorphic form IV having the characteristics set forth herein and a pharmaceutically acceptable carrier or diluent.

The invention further relates to the use of Form I for the treatment of PDE ₄ and TNF mediated diseases in a mammal in need thereof, the method comprising administering to said mammal an effective amount of a polymorphic form.

Even with the properties disclosed herein.

The invention further relates to the use of Form II for the treatment of diseases mediated by PDE ₄ and TNF in a mammal in need thereof, the method comprising administering to said mammal an effective amount of a polymorphic form.

II with the properties disclosed herein.

The invention further relates to the use of Form IV for the treatment of diseases mediated by PDE ₄ and TNF in a mammal in need thereof, the method comprising administering to said mammal an effective amount of a polymorphic form IV having the properties described herein.

The present invention is based on the finding that certain batches of cipamphylline exhibit differences in their infrared spectra (IR mull spectra). All batches were prepared ·· ···· · · ··· ·

in the same manner with ethanol as the final solvent for recrystallization, since it appeared that the rate of crystallization could affect the crystal form. Accordingly, recrystallized samples were prepared by suddenly smoothing a portion of the hot liquid while leaving the rest to stand. (crystallize spontaneously. In any case, the batch size was 1 g or less. The samples were dried over silica gel under vacuum (at room temperature vacuum. In this crystallization process three polymorphic forms were positively identified which are described herein as forms I, II and IV.

The invention therefore also relates to a process for the preparation of polymorphic) (Form I having any of the above properties comprising crystallizing cipamphylline in an alcoholic solvent - ((ethanol (s / f), propanol (s / f), butanol (s / f), isopropanol (s)). (f) or an organic solvent -) (ethyl acetate (s / f), toluene * or in water as the solvent. Under certain conditions they may also be used) (tetrahydrofuran (s / f) and acetone (s)).

In the fast cooling process, ie ice water! (bath for use in smaller samples, the time to lower the reaction temperature from boiling to ambient temperature is approximately) (1 minute with ethanol as solvent.

In a preferred embodiment of the invention, 1-propanol is used to prepare (polymorphic forms of Form I).

The invention therefore also relates to a process for the preparation of polymorphic) (Form II having any of the above properties comprising crystallizing cipamphylline in an alcoholic solvent - ((methanol (s / f), or organic solvent tetrahydrofuran (s) or acetone (f). Under certain conditions) (chloroform * or pyridine * may also be used.

·· ···· · · · ·

The invention therefore also relates to a process for the preparation of polymorphic form IV having any of the aforementioned property comprising crystallizing cipamphylline in an organic solvent-mixture [ethanol: isopropanol in a ratio of 50:50.

* Due to the particularly low solubility of cipamphylline! in solvents marked with an asterisk (*), such as toluene or water for Form I, the recrystallization method has been modified, i.e. the hot solution is filtered to remove insoluble matter and the filtrate is allowed to stand and the substance is left to stand! [crystallize.

[As used herein, the term (s) refers to slow, mild recrystallization. It should be noted that the term "slow"! (“Slow”) and “fast” are relative terms. In this particular case, slow cooling may include removal of the oil bath and air cooling.

In relation to the amount itself (approximately gram! [Amount for some experiments, unlike commercial batch sizes), cooling can be quite fast, like! [e.g., between 15 and 30 minutes. However, under controlled conditions, slow cooling is generally defined as! approximately one (1) hour from boiling to ambient temperature. The very slow cooling will be from about four (4) hours [from boiling to ambient temperature. Under these conditions, Form II can also be obtained from ethanol as described below!

[in this document. However, similarly with small batch sizes in some experiments used for Form I,! the ethanol process (slow cooling) was not necessarily a reliable choice of solvent / temperature for Form I. It is! [It should also be noted that in connection with the use of acetone in rapid cooling (ie the use of an ice bath), the form [I. Certain analyzes also show that the use of acetone at »9 ····

- 10; -:

the use of rapid cooling is not necessarily a reliable choice! (solvents / temperatures for Form II.

The designation (f) is used herein to designate! Recrystallization by rapid, sudden cooling, such as placing the flask in an ice water bath, or similar methods for! (processing of larger quantities).

These three new crystal polymorphs!

(Cipamphylline, also referred to as BRL 61063, all melts at about 305 ° C to about 313 ° C.) (Crystal polymorph Form I exhibits a characteristic X-ray powder diffraction pattern (with characteristic peaks expressing distance d (A) at decreasing intensity at 12,302, 7,702 , 8,532, 4,289, and ((2,854, as shown in Figure 1. Theory regarding powder X-ray diffractograms can be found) (in Stout & Jensen, X-Ray Structure Determination; A Practical Guide, Mac Millian Co., New York, (Crystal polymorph Form II exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks expressing distance d (A) at decreasing intensity at 12,001, 6,702, 3, 687, 3,773 and i (7,345, as shown in Figure 2).

The present invention also relates to crystal polymorphic (forms I, II and IV of cipamphylline which are further characterized by crystal parameters obtained by (X-ray crystallographic analysis of single crystals as shown in Tables 1, 2 and 3 below). 3-D data was obtained at ambient temperature.

φφ φφφφ

ΦΦ φ φ φ φ φ φ φ φ φ φ φ φ φ

Table li.

and

Crystal parameters of the mold

Crystal shape (mm):

(Crystal dimensions:

Crystal color:

(Space group Temperature) (Cell constants

Volume ((Molecules / elementary cell P (off), density ί ^μ

F (000) (Table II

Crystal parameters of the mold (Crystal shape (mm):

Crystal color:

Crystal Dimensions: Spatial Group (Flat Needle Cell Constants)

1,0 χ 0,12 χ 0,08 mm colorless!

PI three-slope # 2 295 K (a = 10,829 (2) A (b = 12,636 (2) A (c = 5,105 (3)) and alpha (a) = 99,48 (4) í (beta (β) = 91, 53 (4) gamma (γ) = 83.84 (3) (685.0 (8) Å ³ ((Z) 4)

1.355 g / cm ³ !

7,362 cm ^-1 292 (rectangular blocks colorless!

0.8 x 0.50 x 0.15 mm P2 i / c monoclinic # 14 a = 12.227 (4) A ib = 7.448 (2) A (c = 14.94 6 (8) A alpha (a) = 90 (4) (. (Beta (β) = 97.95 (4) gamma (γ) = 90 (4) (· 4 4 ·

- 15 * • »4 44 4

• 4 44

4 4 4

4 4 4

4 4 4

4 4 4

44

Volume

Molecules / elementary cell P (off), density μ

F (000)

1348.1 (9) A ³ (Z) 4

1.356 g / cm ³

0.8 96 cm ^-1 584

Table III

Crystal parameters of form IV

Crystal shape (mm)

Color of crystal

Crystal dimensions

Spatial group

Temperature

Colorless flat needle cell constants

0, 60 x 0, 10 x 0,05 mm PI triplex # 2 295 K a = 10,210 (3) A b = 13,753 (2) A c = 4,942 (31) A

Ob j em

Molecules / elementary cell (Z) P (off), density μ

F (000)

alpha (?) = 97.94 (2) beta (β) = 97.95 (4) gamma (Y) = 83.33 (2) 677.1 (5) A ³ 2 1,350 g / cm ³ 7,448 cm ^-1

292

The size of an elementary cell is defined by three parameters; the length of the sides of the cell, the relative relative angles of the sides, and the cell volume. The lengths of the sides of an elementary cell are defined by a, b and c. The relative angles of the cell sides are defined as alpha, beta, and gamma. Unit volume is defined as V. Further detailed description of unit cells can be found in Chapter 3 of Stout & Jensen,

9 «999 * ·

· · · 9 9 9 * 99 9

X-Ray Structure Determinatio; A Practiccal Guide, Mac Millian Co., New York, N.Y. (1968).

The crystal state of a compound can be unambiguously described by several crystallographic parameters: the dimensions of an elemental cell, the spatial group, and the position of all atoms in the compound relative to the origin of the elemental cell. These single crystal parameters are experimentally determined by crystal X-ray analysis. It is possible for the compound to form more than one type of crystal. These various crystal forms are called polymorphic forms. It has now been found that there are three polymorphic forms of cipamphylline. This finding was confirmed by three different X-ray analyzes of single crystals. Comparisons of unit cell dimensions and spatial groups of these three crystal states are shown in Tables 1-3 above.

The depiction of the atom positions of the three polymorphic forms derived from single crystal X-ray analysis confirms that the crystals contain cipamphylline and no other crystal or impurity molecules.

Figure 10 shows a three-dimensional molecule with a labeling scheme. Figure 11 provides a stereo image. Generally, the molecular alignment found in Form I is identical to Form IV except for the clear difference for one of the cyclopropyl groups (C12 and C13 atoms), which has been depicted in two positions in the same position for each of these atoms. A high degree of thermal motion for another cyclopropyl group (C16 and C17 atoms) suggests that structural modifications can be expected.

The elemental crystal cells of Form I are the same as those of Form III, with similar cell dimensions, with 8 Å ³ higher volume and a density reduced correspondingly by 0.15 g.cm ^-3 . All of these effects are consistent • · · · • ·

- * 1 4 4 * · · ♦ ····· with the presence of a change in the line occupied by cyclopropyl groups.

The hydrogen bond in this crystal structure is always inherently intermolecular and is similar in terms of the specific interactions observed in Form IV. As with the structure of Form IV, the hydrogen position of the amino group is indicated from the difference of the Fourier electron density maps. The position of H2N2 does not correspond to the participation of this hydrogen in the interaction with hydrogen bonds. However, the distance of 3,399 (3) Å between the N2 and 05 atoms in Form I indicates the possibility of weak interactions analogous to those occurring in the structure of Form II, although the distance observed in this form is greater by 0.4 Angstrom (Å). When the position of H (2) N (2), which should correspond to this interaction with hydrogen bonds, was calculated and attempts were made to refine it, the thermal values became overly large, which means they were found. values do not support this alternative position. The refinement was made with H2N2 in its original position as found by the difference of Fourier syntheses. The metric details of the other two hydrogen bonds are:

Summary of hydrogen bonds of Form I

H-binding atoms Distance atom atom - Angle N (2) ----- -N (1) 3,067 (3 AND H (2) N (2) --- —N (l) 2.16 (3) AND 173 (3) ⁰ N (3) ------ -0 (5) 2,793 (3 AND HN (2) ----- -0 (5) 2.02 (3) AND 165 (4) °

For Form IV, Figure 26 describes a three-dimensional molecule with a labeling scheme. Figure 27 provides a stereoscopic representation of Form IV. The data presented in this section was obtained from Form IV crystals that were allowed to grow from a 50/50 ethanol / isopropanol mixture with slow evaporation. It was further observed that Form II crystals formed from this solvent mixture earlier than Form IV needles, which formed after several days when the solution was evaporated. The overall molecular structure observed with Form IV was very similar to that of Form II. The principal differences lie in the rotational orientation of the cyclopropyl groups, which represent an almost enantiomorphic relationship to their counterparts in the structure of Form II, as summarized in the tabular values of torsion angles in Table 4 and shown in Figure 3.

The hydrogen bond in the crystal structure of Form IV is always intrinsically molecular in nature and is similar with respect to the specific interactions observed with Form II.

The main differences are one of the two hydrogens on N2. There is a clear indication of the position for H1N2 from differences in Fourier electron density maps. This position does not correspond to the participation of this hydrogen in the interaction with hydrogen bonds. However, the distance of 3,273 (3) Å between N2 and 05 atoms in Form IV indicates the possibility of weak interactions analogous to those occurring in the structure of Form II, although the distance observed in this form is greater by 0.2 Angstroms. When the position of H (1) N (2), which should correspond to this hydrogen bond interaction, was calculated and attempts made to refine it, the thermal values became overly large, meaning that the values found do not support this alternative position. The refinement was made with H1N2 in its original position as found by the difference of Fourier syntheses. The metric details of the other two hydrogen bonds are:

»· · · · · · · · · · · ·

Summary of Hydrogen Bonds of Form IVi

H-binding atoms Distance atom atom - Angle N (2) ------ -N (1) 3,042 (2 AND H (1) N (2) - —N (l) 2,10 mm (2) AND 173 (2) ° N (3) —— -0 (5) 2,731 (2 AND HN (2) ----- -0 (5) 1.91 (2) AND 160 (2) ⁰

With respect to Form II, Figure 32 describes three-dimensionally! The hydrogen bonds for the crystal structure of polymorphic form II are all) substantially intermolecular. The corresponding metric details are :( (Summary of Form II hydrogen bonds)

H-binding atoms Distance atom atom Angle N2 ------ 05 H (1) N (2) ----- (5) 3.049 (3) A 2.26 (3) angle 151 (2) ° N2 ------ Previsão para 3 dias H2N2 ----- NI 3.071 (3) A 2.41 (3) A angle 137 (3) ° N3 ------ 05 HN3 ------ 5-päeva prognoos 2.741 (3) A 1.90 (3) A angle 168 (2) °

(This structure information clearly shows that all forms I, II and IV of cipamphylline are crystallographically) (different. The hydrogen bond in all these forms is essentially intermolecular and all three have hydrogen bonds (between HN (2) ---- N (1) and HN (3) ----- O (5).

99

9

9 9 9

9 · 99

Experimental details!

iForma I:

[Flat needles were obtained by slow evaporation from a mixture of ethyl acetate and butanol. Spatial parameters! [The structural gratings were found from the arrangement of the angles of 25 reflections distributed in the reciprocal spaces on the diffractometer! [Enraf Nonius CAD-4 and are further shown in Table 5. Complete intensity values were also obtained at! [diffractometer using graphite monochromated copper radiation;

[from rotating anode source and using variable speed ω-2θ. Intensity of three monitored reflections! [measured at the beginning, end and every two hours of exposure time varied by a maximum of +/- 0.1%. Three! [orientation controls to assess any crystal displacement during the experiment. The data was corrected for Lorentz and β polarization effects and using the DIFABS algorithm for absorption effects. Redundant observations were averaged [to obtain a final set of data.

The structure was solved by direct methods using! [SHELXS files. The positions of the atoms were originally refined using isotropic temperature factors α1 and subsequently anisotropic displacement parameters. Minimized feature was!

£ w (| (Fo | - | Fc |) ^{2. The} weights, w, were optionally assigned to the data as w = l / o2 (fo) = {σ ² (Ιο) + (0.041) ² ]. [[hydrogen atoms attached to nitrogen were found in the following difference of Fourier maps. Position for hydrogen atoms! [carbon linked to them were calculated on the basis of geometric considerations and kept fixed in the final refinement phase according to! [isotropic temperature factors assigned 1.3 (Beq) The hydrogen atoms on the cyclopropyl groups have been omitted when refined All other positions • · · *; - -;; -;;;;;;;;; ,::

The hydrogen atoms have been specified along with isotropic temperature; (factors. Refinement of the whole lattice by least squares method led to (max Δ / σ = 0.05) the maximum value of conventional) (crystallographic residues R = 0.056, wR = 0.092. The final differences of Fourier maps were without special characters) (with maximum density + / - 0.285 eA ^3. Scattering values (neutral atomic factors) were taken from international tables for X-ray crystallography .;

t (Table 5 Intensity measurement data for form (i) (Diffractometer: Radiation:( (Monochromator Enraf Nonius CAD4 CuKa λ = 1.5406 Å ( Graphite single crystal Scanning technique scanning ω-2θ ( (Frame Rate: variable from 1.50 to 6.7 deg min ^-1 in ω ( Background measurement mobile crystal - mobile counter at each end of the scan (range; shooting time / time background = 2.0 '. Data range :( 2 ° <2 ° (<60 °) (-12 <h <12 * -14 <k <14 -5 <1 <5 Standard Reflections: Three standards measured every three) (hours of exposure time of X-rays! Total reflections: 2320 (2032 unambiguous Rint: 1.2%

• • 44

4 ·· · 4 ·· 4! “JlSj J i 4 *« 4 Z Z Z • 44 4 444 4 · 4 · • 4 · 4 44 * 4 · 4 »

Number of data obtained 1749 I> 3σ (I) i (Number of variables 199 P- ( 0, 04! IR (0.066% Rw 0, 092% ( (Conformity: .3,311 Absorption correction: 0.868 min., 1254 max Avg.

Complete experimental X-ray data for! (The single crystal used to obtain the structure shown in Figure 10 for Form I is shown in Figures 12 and 15. (15) The parameters shown in these tables are measured in units commonly known to one of ordinary skill in the art. Interanional Tables for X-ray Crystalography, Vol.

(pp. 55, 99, 149, Birmingham: Kynoch Press, 1974 and G. M. Sheldrick, SHELXTL. User Manual, Nicolet! (Instrument Co., 1981.

Form II: Rectangular plates were obtained by slow evaporation from methanol / 2-butanone. Spatial structural parameters (gratings were determined from the arrangement of angles of 25 reflections distributed in reciprocal spaces on diffractometer by Nrafus CAD-4 and are shown in the table below. 6. Intensity values were also obtained on a diffractometer using: (graphite monochromated molybdenum radiation) and using a variable velocity ω-2θ.

: The data was used as a correction of 4.8% decrease in intensity of three observed reflections measured at the beginning.

end and every two hours of exposure time. (Three orientation controls were also performed to assess any crystal displacement during the experiment. Data was corrected for) Aorentz and polarization effects and using DIFABS for absorption effects. The equivalents of symmetry and zonal reflection were averaged to obtain a finite set of data.

The structure was solved by direct methods using MULTAN80 program files. Atom positions were originally refined using isotropic temperature factors (a) (subsequently anisotropic displacement parameters.) The minimized function was ESw, (| (Fo | - | Fc |) ^2. Masses, w, were eventually assigned to data as w = 1 / a2 (fo) = [a ² (Ic) + (0.041) ² ] The position for the 1 H hydrogen atoms were found in the following Fourier map difference The position and isotorption temperature factors for the hydrogen and amino groups on the cyclopropyl ring were The positions of all other hydrogen atoms ¹ were calculated based on geometric considerations and kept fixed in the final refinement phase by isotropic) (temperature factors assigned to 1.3 (Beq) to the attached atom. Refinement of the whole grid by least squares led)) (max Δ / σ = 0,005) to the value of conventional crystallographic residues R = 0.044, wR = 0.054. Finite Differences) (Fourier maps were without special features with a maximum density of +/- 0.196 eA ^-3 . Scattering Factor Values) (neutral atoms were taken from international X-ray crystallography tables.)) Complete experimental single-crystal X-ray data used to obtain the structure shown in Figure 32 for Form II are shown in Figures 33 to 36. The parameters set forth in these tables are measured in units commonly known to one of ordinary skill in the art.

• 21 «

Table 6!

(Intensity measurement data for Form II

Difraktometr :! (Radiation:

[Monochromator Scanning Technique (Scanning Speed:

[Background measurement

Data range:

Standard Reflections:

Total number of reflections

Rint: [[Number of obtained data [Number of variables p: '[R

Rw: [[Match:

Extinction coefficient

Enraf Nonius CAD4I [ΜοΚα λ = 0.71073 Á

Graphite single crystal scanning ω-2θ! variable from 2.50 to 6.7 deg min ¹ in ω [moving crystal - moving counter at each end of sensing] [range; Shooting Time / Background Time = 2.0!

2 ° <2 ° <60 °;

[0 <h <14 <k <8;

-17 <1 <17 three standards measured every three! [X-ray exposure time of 2469!

(2353 unambiguous

3,4% [

1417 I> 3σ

202

0,04!

0,044%

0.054% [[1.403

7869 (1) x 10 ^-7

0, 9769 min., 1.1374 r.ax.

• 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

Form IV :( (Flat needles were obtained by slow evaporation from a 50/50 mixture of ethanol and isopropanol. The spatial parameters) of the structural lattice were determined by arranging angles of 25 reflections distributed in reciprocal spaces on a diffractometer) (Bnraf Nonius CAD-4) Complete intensity values were also obtained on a) (diffractometer using graphite monochromated copper radiation) from a rotating anode source and using a variable rate of ω-2θ. The intensities of the three monitored reflections) measured at the beginning, end, and every two hours of exposure time varied by a maximum of +/- 0.1%. Three) were also performed (orientation checks to assess any crystal displacement during the experiment. Data was corrected for Lorentz a) (polarization effects and absorption effects using the DIFABS algorithm). I The symmetry equivalents and Friedl coupling were averaged to obtain the final set of data. ) (Structure was solved by direct methods using SHELXS files. Atom positions were originally) (refined using isotropic temperature factors followed by anisotropic displacement parameters. Minimized function was Zw (| (Fo | - | Fc | ) ^2. Weights, w, were eventually assigned) • to the data as w = 1 / σ2 (ίο) = [σ ² (Ιο) + (0.041) ^2]. Positions for hydrogen atoms attached to nitrogens were discovered in subsequent difference Fourier The positions of the hydrogen atoms attached to the cyclopropylmethylene carbons were calculated on the basis of ¹ geometric considerations and kept fixed Endless refinement phase according to isotropic temperature factors assigned ¢ 3:

1.3 (Beq) attached atom. All other hydrogen positions were specified along with isotropic temperature factors. The refinement of the whole grid by the method of least squares led!

(max Δ / σ = 0.01) to the value of conventional crystallographic residues R = 0.049, wR = 0.071. Final differences! Fourier maps were devoid of special features with a maximum density of +/- 0.515 eA ~ ³ . Scattering factor values; neutral atoms were taken from international tables for X-ray crystallography.

Table 7

Intensity measurement data for form ΓΥ ^ Diffractometer: Radiation

Monochromator Scanning technique ^; Frame Rate:

Measuring background

Data range:

Standard Reflections:

Total reflections:

Enraf Nonius CAD4

CuKa λ = 1.5406 Å ¹

Graphite single crystal scanning ω-2θ, variable from 2.50 to 6.7 deg min ^-1 in ω movable crystal - movable counter at each end of sensed ¹ range; capture / background time = 2.0 ^

2 ° <2 ° <60 ° ·

-11 <h <11

-15 <to <15 ^ ’-5 <1 <5

Three standards measured every three AODs X-ray exposure time of ¹ 3998

2017 unambiguous

Φ · ··· ♦

- v

99

9 9

9 9

Rint:

'Number of data obtained iPet variables ^p:

R

Rwt

Conformity:

Extinction coefficient: Absorption correction:

2,5% '

1662 I> 3σ (I)

202

0.04) '0.049%

0.071%

2,095

1,411 (1) χ10 ~ ^δί ,

0.911 min., 1.088 max., 0, 997) Avg.

The complete experimental single crystal x-ray data used to obtain the structure shown in Figures 26 and 27 for Form IV are shown in Figures 28-31. The parameters shown in these tables are measured in units commonly known to one of ordinary skill in the art. The results of single crystal X-ray analysis are limited, as the name implies, to one crystal placed:

) in the X-ray beam. Powder X-ray diffraction provides crystallographic data on a large group of crystals.) If the powder is a pure crystalline compound, a simple powder diagram is obtained. To compare the results)) single crystal and powder X-ray analysis can be performed by simple calculation to convert) data obtained from single crystal X-ray analysis to powder x-ray x-ray diagram using computer software SHELXTL Plus (Trademark), Reference Manual by Siemens Analytical X Ray Instrument, Chapter 10, pp. 19-181, 1990. This conversion is possible because single crystal experiments routinely determine the dimensions of an elemental cell, the spatial group, and the positions of the atoms. These parameters provide the basis for calculating '• · ··· · ·· ····

perfect powder diffractograms. A comparison of these calculated powder diffractograms and powder diffractograms experimentally obtained from a large number of crystals will confirm whether the results of the two techniques are the same.

X-ray powder diffractxoxi XRD

X-ray powder diffraction shows the differences between all three polymorphic forms. Analyzes of 4 samples of Form I and 4 samples of Form II showed that corresponding diffractograms were obtained for each set. These values are shown here in Figures 1 and 2.

Infrared spectroscopy (IR)

Infrared absorption spectra positively identified the existence of Forms I, II and IV. These data are shown in Figures 16 to 25 for the compound, single crystal, and crushed crystals of various polymorphic forms.

The compression and comminution test showed the form

Even as stable in compression and comminution, while mold

II has proven stable in compression but not in comminution.

Comparisons of IR spectra of forms I and IV show marked differences. The main zone in the area of methylene deformation at .1430 cm ^-1 (with arm at 1442 cm ^-1 ) for Form I is divided in form IV into a zone at 1424 cm ^-1 (with arm at 1434 cm ^-1 ) and a zone at 1455 (s) arm at 1466 cm ¹ ). The stretched carbonyl bands of Form I appear at 164 8 cm ¹ (with arm at 1656 cm ^-1 ) and 1682 cm ¹ , while for Form IV they appear at 1656 cm ^-1 and 1694 cm ¹ . Weak values for the Form IV spectrum at about 2000 and 2300 cm ^-1 are absent for Form I, but these may represent the influence of the carbonyl region.

♦ · φ »»::::::::::::::

ΦΦΦΦ φφφ φφφφ φφ φφ φφ φ φφ φφ

Spectra were determined using a Spectra-i microscope (Tech Pian II coupled to a PE 1760 FTIR spectrometer (64-256, relative mode, MCT detector, 4 cm ^-1) resolution (dry air purge). Crushed crystals were prepared using a Spectra-Tech micro-Sample Pian (compression chamber) equipped with diamond windows. The stereomicroscope was used to observe the behavior of the crystals during compression. and the spectrum was determined from the substance that adhered to one of the windows.) The IR spectra of the single crystals of Forms I, II and IV also show many differences and are easily distinguishable. (There are significant differences in relative band intensities between IR spectra of single crystals of Form I and II and ((corresponding spectra obtained from potassium bromide disks; these differences will appear) eats throughout the spectrum!

(but are noticeably below 1700 cm -1 ⁾ . In particular, there are significant differences in relative intensities of bands close to 1530, 1440, 1260 and 800 cm ^-1 in the Form I spectrum and bands close to (1540, 1420, 1260 and 1060 cm ^{- 1} in the spectrum of Form II.

and

The spectra of crushed crystals are very similar! (corresponding to the spectrum of the KBr disk. This is not surprising since both the crushed crystals and the KBr disks represent) (molecular orientation. In many cases, proper IR transmissions of crystalline samples can only be obtained by crushing.) in the 1660 - 1620, 1260 - 1180, 1000 - 920 and 800 - 750 cm ^{-1 areas} . The crushed crystal forms of Form IV are) (but very similar to those of the crushed crystal of Form I. For these IR spectra, the crystals of Form IV were obtained!

(in the presence of Form II crystals by slow evaporation from the mixture

4444

44

4 44 44 4444 ϊ- 27: -::.: :::

¹ 4444 444 4444

Ethanol: isopropanol in a ratio of 50:50 and by hand separation. The conversion of Form IV to Form I is perhaps not surprising; three-dimensional X-ray diffraction data! [show that the molecular conformations (apart from the orientation of the cyclopropyl groups) and the hydrogen bonds (in the sense of the [specific interactions) are similar for forms I and IV. In Forms I and IV, only one of the amino groups of hydrogen is involved [in the hydrogen bonds (which is in contrast to Form II, in which all hydrogen donors are involved). These findings! well correspond to the conclusions derived from infrared spectra of single crystals of these three forms, where! [stretched regions of the N-H forms I and IV are similar, and different from form II. Forms I and IV are close to each band!

[3455 cm &^lt; -1 ^&gt; which was assigned to the non-involved functional group [NH. In Form II, this band is absent and it is clear that all hydrogen donors are involved in hydrogen bonds.

[IR spectra of single crystals of Form IV were detected by different instruments and are the same, with the exception of) [areas 1280 to 1260 cm ^-1 . This can be explained by orientation effects. The final spectrum of Form IV is shown here as Figure 18.)

RAMAN spectra [Raman spectra for forms I, II and IV are also shown here as Figures 4 to 9. As can be clearly seen,! [There are considerable differences between the spectra of these three forms, which allow them to be easily distinguished.

[It has been shown that Form IV under pressure and under certain circumstances converts to Form I, therefore the usual test! [methods such as using alkali metal halide disks or "Nujol mull may not be the best way to obtain!" [infrared spectrum for these polymorphic forms, since the time required to select crystals of appropriate size and recovery;

• · φφφφ

Φ · φφφφ

φ · · · · · φ φ φ φ φ φ φ φ φ φ dobré of good quality spectrum is long. Raman Spectroscopy) (provides a rapid method of distinguishing between forms I, II and IV without sample preparation.) (Spectra were obtained using a Perkin-Elmer-2000 FT-Raman spectrometer equipped with an Nd: YAG NIR laser) ((1.064 pm). scans were 64 - 256 images, quartz light divider, 4 cm ^-1 resolution and 1W laser. (The spectrum of Form IV (Figure 6) shows a significant amount of Raman lines from a glass ampoule. This is seen as a curve (with a wide maximum near 400 cm ^-1. Glass contributes only marginally to the relative intensity of the spectra of forms I and II) ((figures 4 and 5).

(Raman spectra of Forms I, II and IV show a number of differences and are easily distinguishable. Detailed region) (carbonyl, 1750 to 1600 cm ^-1 (Figure 7) shows the most noticeable difference between these forms (as found) in the case of IR spectra recorded for individual crystals (shown here as Figures 16 to 18). There is significant) (difference between the three forms in the range of 1000 to 800 cm ^-1 (Figure 8). An area of 400 to 200 cm ^-1 (unavailable when obtained) is a spectrum using microscope operating in the infrared region) also shows significant differences (Figure 9), though) (sensitivity in this region is relatively poor due to detector response.)

Heating of the solution (Heating of the solution was determined using acetone and methanol as suitable solvents. Endothermic values) are given in Table 8 below. Different polymorphic forms give different heating of the solution. This is documented by the) data). The value of H _T , the heat required to change, is equal to the energy difference of the crystal lattice of the two forms and is) ·· ··· · ·· ♦ ···

same for both solvents. This is assumed, although individual enthalpy is solvent dependent, but the differences are not. These results suggest that dissolution of Form II is more endothermic in both solvents and therefore represents a more stable form. Heating the solution for Form IV! are tracked.

Table 8i

Form Methanol (kcal / mol) Acetone (kcal / mol) 1 4.81 3, 93 2 6.47 5.59 ΔΗ _Τ 1, 66 1, 66

Thermal analysis!

Differential Scanning Calorimetry (DSC) cannot distinguish these three forms of cipamphylline. In any case, the thermograms show melting only at the same initial and final (peak) maximum temperatures, typically T _e 312, T _p 314 ° C. However, when the heating rate was sufficiently reduced, the melting appeared to be a combined melting, i.e. melting of the two components.

This behavior was common to both Form I and Form II:

Thermomicroscopic observation showed that all three forms were sublimating. The onset of sublimation was different for each) (mold and continued over a wide temperature range (130-290 ° C on an uncalibrated instrument). This is not apparent from DSC: (thermograms. Melting was in the range (310-332 ° C on an uncalibrated instrument) The sublimate was collected in all three forms and was analyzed by IR and iNMR, and it was found that Form I was formed.

···· * · φ φ (- φ - - - - - - - - - φ φ φ φ φ · · · · · · · · · · · · ·

Forms I and II were annealed and IR was used. (found to convert to Form I. The annealing process consisted of heating at 10 ° C / min from ambient temperature to about (250 ° C and maintaining this temperature for 0.5 to 1 hour and then allowing the sample to cool slowly to room temperature). . ¹ 'it appears that the above thermal experiments show that form I is the most stable form. This would explain the' similarity melting points of these three forms.

Synthetic methods of recrystallization

Different batches of cipamphylline were prepared in the same manner and the solvent used in the final recrystallization and cooling rate were varied as shown in Table 9 below. ((Table 9)

Solvent Speed cooling Yield Produced polymorphic! i forma Ethanol slow 75% Form of IT (Ethanol very slow 75% Form II Methanol slow 70% Form II ( : Acetone fast 22% Form I Tetrahydrofuran fast 33% Form I and III * ( Tetrahydrofuran slow 58% Form I

* For THF (rapid), it appears that Form I produced ((contaminated by another form, Form III. Data indicates that Form III may be a polymorphic form but was not) (characterized and always appeared to be produced in mixtures Slow cooling in this solvent gave form (I.

to ··· • to «· · · to to» to · <·· si i- · ..::. ·.: :::

• · · · toto toto toto toto toto toto

Recrystallization of Form II [The following experimental method was used to recrystallize Form II from a methanol / 2-butanone solvent mixture. [method:

[A solid sample of cipamphylline was added to an aliquot of 2-butanone in a glass ampoule and the sample was gently! [heated with stirring on hot plate. Methanol was added dropwise to the stirred hot solution until all the solid had dissolved. Holes were made into the plastic cap of the ampoule and the clear, colorless solution was! [let slowly evaporate in a fume cupboard at ambient temperature.

Form II.i rectangular crystals appeared over 11 days. In a further experiment, cipamphylline (1 g) was dissolved in EtOH (55 volumes) and the solution was cooled to 20-25 ° C over 1 and 4 hours, respectively. The results are shown in Table 10 below.

Table 10 Recrystallization of cipamphylline from EtOH

Example Range (mmol) Time to cool down to 20 to 21 ° C (h) Yield (%) Polymorph form ^b 1 3.6 1 74, 9 II 2 3, 6 4 75.2 II

Remarks: ^a Time to cool from boiling point (about 78 ° C) [to about 20 to 25 ° C ^b Detected by IR spectroscopy!

[In both cases cooling for a longer period (> 1 h) gave cipamphylline in polymorphic form II!

• · · ·

Recrystallization of Form IV [In another attempt to recrystallize Form IV, a solid sample of cipamphylline was added to an aliquot of isopropanol! in a glass ampoule and the sample was gently heated with stirring on a hot plate. An aliquot of ethanol was added and [(stirring continued until all solid was dissolved. Holes were made into the plastic cap of the ampoule and ([the clear, colorless solution was left, slowly evaporated in a fume hood at ambient temperature. After a short time they appeared; rectangular crystals of Form II and then after a few days of the needles, one of which was used to determine the structure (Form IV.

Recrystallization of Form I;

[In another purification method, cipamphylline (15.5 g) was dissolved in n-propanol (300 mL) at reflux temperature. Cooling to room temperature resulted in the precipitation of the purified product, Form I, which was isolated by filtration and dried at 70 ° C overnight. Weight of the obtained [cipamphylline - 11.96 g; yield 63%. Alternative solvents such as n-propanol / water 3: 1 also led!

[to similar yield and results.

As mentioned above, 1-propanol was preferred; [solvent for the preparation of cipamphylline in polymorph form I. The recrystallization process with 1-propanol was carried out over a wider range, approximately 2 kg, with repeated success.

Cooling time from 97 ° C to ambient temperature was changed from! [about 70 minutes to overnight (approximately 8 to 12 hours). Form I was created repeatedly. [·· ···· ·· ···· ·· ··

This process can be summarized as follows: [Crude BRL-61063 (2.06 kg) was dissolved in 1-propanol (40 L) at about 97 ° C. The reaction mixture was then cooled to about 18 ° C over about 70 minutes. The resulting slurry was filtered, the solid was washed with pre-cooled 1-propanol (3 x 0.6 L) and air dried at about 50 ° C overnight to purify the [cipamphylline product Form I (1, 85 kg, 90%).

A further recrystallization was carried out, similar to the one) [mentioned above in Table 9, again using MeOH, THF and acetone, the results are shown in Table 11 below.] [Table 11 [Recrystallization of cipamphylline from various solvents ³

Try Solvent Conc. ⁿ (g / ml) Cooling time ¹³ to 20 to 25 ° C (min) Yield (%) Polymorph form ^c 1 MeOH 0.018 60 70 II 2 acetone 0.004 40 64 II ^d + I 3 acetone 0.004 «L ^e 22nd AND 4 acetone 0.004 «L ^e 49 AND 5 THF 0, 017 «L ^e 33 I + III 6 THF 0.017 60 58 AND

Comment:

^and General Method: xg BRL-61063 was suspended in 1 ml of a suitable solvent and the mixture was heated to reflux with dissolution. The solution was then cooled over an appropriate time and the product was isolated by filtration.

• 3 · 4 j- · Ι ,: ·. · '. · I ί ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ^b Time to cool from boiling to 20-25 ° C. ^c Detected by IR spectroscopy ^d Mostly Form II, Certain Form I ^e Very rapid cooling with ice bath solution.

These values (Table 11) show that slow crystallization of BRL-61063 from MeOH (Experiment 1) gives the product in polymorphic form II. Polymorph form II was the predominant form obtained by slow cooling of the acetone solution of BRL-61063 (experiment 2). Sudden cooling of identical solutions ((Experiment 3) gave BRL-61063 in Form I. The rapid cooling experiment was repeated to give the product exclusively in) (Form I (Experiment 4) to confirm the original observations).

BRL-61063 was dissolved in THF and quenched (resulting in the isolation of a substance existing in polymorphic forms I and III (experiment 5). Form I was exclusively obtained by slow (cooling (experiment 6)).

(These experiments thus provide further aspects of the present invention, which is a process for producing Form I, comprising (placing crude cipamphylline in an organic solvent, dissolving the crude product by heating to about boiling point a) (then cooling to crystallize the desired form).

For Form I, the preferred solvent is 1-propanol, (acetone or THF, preferably 1-propanol. For Form I, the cooling time is determined as the minimum cooling time) (from the boiling point or from the temperature at which the crude product dissolves in a solvent, i.e. minimal) (time to suddenly cool the solution, which is on an industrial scale of about 15 minutes. Preferably, the minimum real time) (cooling time is about 50 to 70 minutes to any desired time such as overnight (i.e. Preferably, the time! (cooling is about 60 to 70 minutes with a range of about 120 minutes to overnight, if desired. The cooling temperature is (· · ··· · • ·

preferably from about 0 ° C to about 25 ° C, more preferably from about 15 ° C to [about 25 ° C, particularly preferably from about 18 ° C to about 25 ° C.

Ethanol is also a possible solvent, but only if sudden cooling is used. If the form is required! [II, ethanol or methanol is appropriate if long cooling times are used (see Table 9 or 11).

[When THF is used as a solvent to produce Form I, slow cooling is required when acetone is used. [then quick cooling is needed.

It has been found that other combinations may be used! [solvents under suitable conditions, these combinations may include mixtures with water or other organic! [solvents such as DMF, heptanes, MeCN, n-butanol, isopropanol, ethyl acetate, TBME, toluene, decalin etc.!

[All these solvents are within the scope of the modifications or improvements herein set forth specifically! [design] It is believed that one skilled in the art is able to find the optimum solvent for use in recrystallization [on a laboratory or industrial scale using the information provided herein.] [[All publications including, but not limited to, patents and patent applications!

[In this description, reference is hereby made in its entirety, as well as to any specific publication.

[The above description fully describes the invention, including preferred embodiments thereof. Modifications and improvements herein are specifically within the scope of the following claims. It is believed that without further investigation! one skilled in the art using the above description can practice the invention in its entirety. Therefore, the examples herein are intended to be illustrative only and not intended to limit the scope of the invention in any way. The embodiments of the invention for which exclusive protection is sought are (claimed below).

Claims (3)

Patent Claims (1. A crystalline polymorphic form of 1,3-dicyclopropylmethyl-8-aminoxanthine having an X-ray powder diffraction pattern having characteristic peaks expressed by distance d (A) of decreasing intensity at approximately! [12,302, 7, 702, 8,532, 4,289 and 2,854, and as shown in Figure 1! [2. A crystalline polymorphic form of 1,3-dicyclopropylmethyl-8-aminoxanthine which exhibits infrared absorption. (potassium bromide spectrum having characteristic absorption bands expressed in cm ^-1 as shown in the figure! 20 May 3. Crystalline polymorphic aminoxanthine which analysis of an individual which are approximately (crystal shape (mm) crystal dimensions: crystal color: spatial group (cell constant temperature form 1,3-dicyclopropylmethyl-8 shows a crystallographic X-ray crystal with (a) crystal parameters equal to the following values: volume. molecule / elementary cell (Z) of flat needles 1.0 x 0.12 x 0.08 mm colorless Pl triple # 2 295 K a = 10.829 (2) A b = 12.636 (2) A c = 5.105 (3) A (alpha (a) = 99.48 (4) beta (β) = 91.53 (4) [(gamma (γ) = 83.84 (3)) 685.0 (8) A ³ 4 ·· »··· 99 ···· - 48: - ·. p (calc.), density 1.355 g / cm ³ ; ^; , μ (7,362 cm ^-1 ) F (000) 292 positions of all atoms are expressed relative to the origin) (elementary cells as shown in the tables in figures 12 to 15.)) 4. The crystalline polymorphic form of 1,3-dicyclopropylmethyl-8-aminoxanthine, which shows the Raman spectrogram shown in Figure 4. ) 5. A crystalline polymorphic form of 1,3-dicyclopropylmethyl-8-amino-xanthine having an X-ray powder diffraction pattern having characteristic peaks expressed by distances d (A) of decreasing intensity at approximately) 12, 001, 6, 702, 3, 687, 3,773 and 7,345, and as shown in Figure 2. (6) The crystalline polymorphic form of 1,3-dicyclopropylmethyl-8-aminoxanthine having infrared absorption) (potassium bromide spectrum having characteristic absorption bands expressed in cm ^-1 as shown in Figure) 20. (7. Crystal polymorphic form of 1,3-dicyclopropylmethyl-8-aminoxanthine, which shows X-ray crystallography (single crystal analysis with crystal parameters approximately equal to the following values :) (crystal shape (mm): space constant cell group rectangular blocks P2 i / c monoclinic- # 14 ^: a = 12,227 (4) Ά b = 7,448 (2) A (c = 14,946 (8) A φ ΦΦΦ φ «φ φ φ φ φ φ φ φ φ · · · * φ φ φ φ φ φ φ φ φφ volume (molecules / elemenar cell (Z) p (off), density _: ; .μ F (000) (8. Crystal polymorphic beta form (β) = 97,95 (4) 1348.1 (9) Α ³ 4 1, 356 g / cm ³ 0.896 cm ^'1584: 1,3-dicyclopropylmethyl-8-aminoxanthine, which shows the Raman spectrogram shown in Figure 5). ) 9. The crystalline polymorphic form of 1,3-dicyclopropylmethyl-8aminoxanthinu that exhibits an infrared absorption) .spektrum crystal having characteristic absorption bands expressed in cm ^-1, as shown in Figure 18, 24 and 25) (the tenth crystal polymorph of 1,3 -dicyclopropylmethyl-8-aminoxanthine, which shows a crystallographic X-ray) (single crystal analysis with crystal parameters approximately equal to the following :) crystal shape (mm) flat needles spatial group PI triplex # 2; (cell constants a = 10.210 (3) Å b = _S 13.753 (2) Å c = 4.942 (31) A) alpha (a) = 97.94 (1) beta (β) = 97.95 (4)) gamma (γ) = 83.33 (2) volume. 677.1 (5) A ³ · (molecules / elemenary cell (Z) 2 density, g / cm ³ ' 1,350; «· · · A crystal polymorphic form of 1,3-dicyclopropylmethyl-8-aminoxanthine having the Raman spectrogram shown in Figure 6; A pharmaceutical composition comprising an amount of the polymorphic form of any one of claims 1 to 4 and a pharmaceutically acceptable carrier or diluent. 13. A pharmaceutical composition comprising an amount of the polymorphic form of any one; of claims 5 to 8 and a pharmaceutically acceptable carrier or diluent. 14. A pharmaceutical composition characterized in that it comprises an amount of a polymorphic form according to any ^'one of claims 9-11 and a pharmaceutically acceptable carrier or diluent; A method of treating PDE ₄ mediated diseases in a mammal in need thereof, the method comprising administering to said mammal an effective amount of the polymorphic form of any one of claims 1 to 4. A method of treating PDE ₄ mediated diseases in a mammal in need thereof, the method comprising ¹ administering to said mammal an effective amount of a polymorphic form according to any one of claims 5 to 8; A method of treating PDE ₄ mediated diseases in a mammal in need thereof, the method comprising ¹ administering to said mammal an effective amount of a polymorphic form according to any one of claims 9 to 11. '; • · * · - 4jL y A method of treating TNF-mediated diseases in a mammal in need thereof, the method comprising administering to said mammal an effective amount of a polymorphic form [according to any one of claims 1 to 4. A method of treating TNF-mediated diseases in a mammal in need thereof, the method comprising administering to said mammal an effective amount of a polymorphic form according to any one of claims 5 to 8. A method of treating TNF-mediated diseases in a mammal in need thereof, the method comprising administering to said mammal an effective amount of a polymorphic form according to any one of claims 9 to 11. 21. A process for producing a crystalline polymorphic form of 1,3-[[dicyclopropylmethyl-8-aminoxanthine, Form I) comprising: a) dissolving 1,3-dicyclopropylmethyl-8-aminoxanthine in 1-propanol; and ^: b) cooling the solution to crystallize from the solution of the desired polymorphic form 1 / 22. The process of claim 21 wherein the 1-propanol is mixed with water / The method of claim 21, wherein the cooling temperature is from about 0 to about 25 ° C. [24. The method of claim 23, wherein the crystallization time is from about 15 to about 120 minutes. The process of claim 21 wherein the xanthine is dissolved by heating 1-propanol to boiling. - 42 5-: Tj · ♦ • · ® <.. < · · * · · · · · 26. A process for producing a crystalline polymorphic form of 1,3-dicyclopropylmethyl-8-aminoxanthine, Form I, comprising ^: a) dissolving 1,3-dicyclopropylmethyl-8-aminoxanthine in tetrahydrofuran or acetone; and ^: b) cooling the solution to crystallize from the solution of the desired polymorphic form I.-