MX2008007297A - Crystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1h-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine - Google Patents

Abstract

The instant disclosure provides crystalline forms of 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine, salts and solvates thereof. The present disclosure also generally relates to pharmaceutical compositions comprising the crystalline form(s), as well of methods of using the crystalline form(s) in the treatment of HIV and/or AIDS, and methods for obtaining such crystalline form(s).

Description

CRYSTALLINE SHAPES OF l-BENZOYL-4- [2- [4-METOXY-7- (3-METHYL-1H-1,2, 4-TRIAZOL-1-IL) -1- [(PHOSPHONOXY) METHYL] -1H- PIRROLO [2,3- C] PYRIDIN-3-IL] -1,2-DIOXOETHYL] -PIPERAZINE FIELD OF THE INVENTION. The present invention relates generally to crystalline forms of l-benzoyl-4- [2- [4-methoxy-7- (3-methyl-lH-1,2,4-triazol-1-yl) -1- [( phosphonoxy) methyl] -lH-pyrrolo [2, 3-c] pyridin-3-yl] -1,2-dioxoethyl] -piperazine. The present invention also relates generally to a pharmaceutical composition comprising crystalline forms, as well as methods for using crystalline forms in the treatment of HIV and / or AIDS, and methods for obtaining such crystalline forms.

BACKGROUND OF THE INVENTION HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 42 million people infected worldwide at the end of 2002. The number of HIV cases and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2002, about 5.0 million new infections were reported, and 3.1 million people died of AIDS. Drugs currently available for the treatment of HIV include nine inhibitors of Ref .: 193634 Nucleoside reverse transcriptase (RT) or approved combinations of single pill (zidovudine or AZT (or Retrovir®), didanosine (or Videx®), stavudine (or Zerit®), lamivudine (or 3TC or Epivir®), zalcitabine (or DDC) or Hivid®), abacavir succinate (or Ziagen®), salt of Tenofovir disoproxil fumarate (or Viread®), Combivir® (contains -3TC plus AZT), Trizivir® (contains abacavir, lamivudine, and zidovudine), three inhibitors of non-nucleoside reverse transcriptase: nevirapine (or Viramune®), delavirdine (or Rescriptor®) and efavirenz (or Sustiva®), and eight peptide protease inhibitors mimetic or approved formulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir , Kaletra® (lopinavir and Ritonavir), and Atazanavir (Reyataz®). Each of these drugs can only stop replication transiently if they are used alone. However, when used in combination, these drugs have a profound effect on the viremia and the progress of the disease. In fact, significant reductions in mortality rates among AIDS patients have recently been documented as a consequence of an expanded application of combination therapy. However, despite these impressive results, 30 to 50% of patients fail at the last minute to combination drug therapies. Insufficient drug potency, non-compliance or attachment, penetration of Restricted tissues and drug-specific limitations within certain cell types (for example, most nucleoside analogs can not be phosphorylated in resting cells), can mean incomplete suppression of sensitive viruses. Additionally, the high rate of replication and the rapid conversion of HIV-1 in combination with the frequent incorporation of mutations leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present (Larder and Kemp; Gulic; Kuritzkes; Morris-Jones et al; Schinazi et al; Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)). Therefore, novel anti-HIV agents exhibiting different resistance patterns, and favorable pharmacokinetics as well as safety profiles are needed to provide more treatment options. The Application of E.U.A. Serial No. 11 / 066,745, filed on February 25, 2005 (claims the benefit of the US Provisional Application Serial Numbers 60 / 635,231 filed on December 10, 2004 and 60 / 553,320 filed on March 15, 2004, and incorporated herein by reference in its entirety) describes a class of compounds (or pharmaceutically acceptable salts thereof) of the formula: where: X is C or N with the proviso that when X is N, R1 does not exist; is C or N with the proviso that when W is N, R2 does not exist; V is C; R1 is hydrogen, methoxy or halogen; R2 is hydrogen; R3 is methoxy or heteroaryl, each of which can be independently optionally substituted with a substituent selected from G; wherein heteroaryl is triazolyl, pyrazolyl or oxadiazolyl; E is hydrogen or a pharmaceutically acceptable mono or bis salt thereof; And it is selected from the group consisting of R10, R11, R12, R13, R14, R15, R16, R17 are each independently H or methyl, with the proviso that no more of two of R10-R17 are methyl; R18 is selected from the group consisting of C (0) -phenyl, C (0) -pyridinyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, azabenzofuryl and azaindolyl; each of which can be independently optionally substituted with from one to two members selected from the group consisting of methyl, -amino, -NHMe, -NMe2, methoxy, hydroxymethyl and halogen; D is selected from the group consisting of cyano, S (0) 2R24, halogen, C (0) NR21R22, phenyl and heteroaryl; wherein the phenyl or heteroaryl is independently optionally substituted with one to three identical or different halogens or from one to three identical or different substituents selected from G; wherein the heteroaryl is selected from the group consisting of pyridinyl and oxadiazolyl; A is selected from the group consisting of phenyl, pyridinyl, furyl, thienyl, isoxazole and oxazole wherein the phenyl, pyridinyl, furyl, thienyl, isoxazole or oxazole are independently optionally substituted with one to three same or different halogens or from one to three identical or different substituents selected from G; G is selected from the group consisting of alkyl (C? -6), alkenyl (C? _5), phenyl, hydroxy, methoxy, halogen, -NR23C (0) - alkyl (C? _6), -NR24R25, -S (O) 2NR2 R25, COOR26 and -C0NR24R25; wherein the alkyl (C? -6) is optionally substituted with hydroxy, dimethylamino or one to three identical or different halogens; R26 is selected from the group consisting of hydrogen and alkyl (C? _6); R20, R21, R22, R23, R24, R25 are independently selected from the group consisting of hydrogen, alkyl (C? -6) and - (CH2) nNR27R28; n is 0-6; and R27 and R28 are each independently H or methyl. The application of E.U.A. Serial No. 11 / 066,745 also specifically describes the compound There is a need for the different forms of the compound l-benzoyl-4- [2- [-methoxy- - (3-methyl-lH-1, 2,4-triazol-1-yl) -1- [(phosphonoxy) methyl] ] -lH-pyrrolo [2, 3-c] pyridin-3-yl] -1,2-dioxoethyl] -piperazine (IUPAC name: diacid phosphate of (3- ((-benzoylpiperazin-1-yl) (oxo) acetyl) -4- methoxy-7- (3-methyl-lH-l, 2,4-triazol-l-yl) -lH-pyrrolo [2,3-c] pyridin-1-yl) methyl), salts and solvates thereof, and that the different forms can have different physical and / or chemical properties. There is also a need to produce a stable form of l-benzoyl-4- [2- [4-methoxy-7- (3-methyl-lH-1, 2,4-triazol-1-yl) -l- [( phosphonoxy) methyl] -1H-pyrrolo [2, 3-c] pyridin-3-yl] -1,2-dioxoethyl] -piperazine, salts and solvates thereof for long term storage etc. There is also a need for reliable and reproducible methods for manufacturing, purification, and formulation to enable their possible commercialization.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides crystalline forms of l-benzoyl-4- [2- [4-methoxy-7- (3-methyl-1H-1,2, -triazol-1-yl) -1- [ (phosphonooxy) methyl] -IH-pyrrolo [2, 3-c] pyridin-3-yl] -1,2-dioxoethyl] -piperazine, salts and solvates thereof. The embodiments of these crystalline forms include those characterized herein as Forms -01-H2-1, -02-SA-1, -03-E.5-1, -03-SA-2, and -03-DSA- 2 etc. The names used in the present to characterize a specific form, for example "-01-H2-1" etc., should not be considered as limiting with respect to any other substances that have similar or identical physical and chemical characteristics, but on the contrary it should be understood that these designations are mere identifiers which should be interpreted in accordance with the characterization information also presented herein. 1-Benzoyl-4- [2- [4-methoxy-7- (3-methyl-1H-1,2,4-triazol-1-yl) -1- [(phosphonooxy) methyl] -lH-pyrrolo [ 2, 3-c] pyridin-3-yl] -1,2-dioxoethyl] -piperazine is identified as the compound (I) herein and I): (I) In a first embodiment, the present disclosure relates to a crystalline form of Compound (I) comprising Form 01-H2-1 of compound (I). In a second embodiment, the present disclosure relates to a crystalline form of compound (I) comprising Form 02-SA-1 of compound (I). In a third embodiment, the present disclosure relates to a crystalline form of compound (I) comprising Form 03-E.5-1 of compound (I). In a fourth embodiment, the present disclosure relates to a crystalline form of compound (I) comprising Form 03-S A-2 of compound (I). In a fifth embodiment, the present description is refers to a crystalline form of the compound (I) comprising Form 03-DSA-2 of the compound (I). These and other aspects of the description will be more apparent from the following detailed description.

BRIEF DESCRIPTION OF THE FIGURES The invention is illustrated by reference to the accompanying figures described below. FIG. 1. Illustrate simulated and experienced powder X-ray diffraction patterns (CuKa? = 1.5418 A to T = 293 K) of the 01-H2-1 form of the compound (I). FIG. 2. Illustrate differential scanning calorimetry patterns and thermogravimetric analysis pattern of the 01-H2-1 form of the compound (I). FIG. 3. Illustrate the labeling of atoms (except H atoms) in the form 01-H2-1 of compound (I). FIG. 4. Illustrate simulated powder X-ray diffraction patterns (CuKa? = 1.5418 A to T = 173 K) of the 02-SA-1 form of the compound (I). FIG. 5. Illustrate the labeling of the atoms (except H atoms) in the 02-SA-1 form of the compound (I). FIG. 6. Illustrate simulated and experienced powder X-ray diffraction patterns (CuKa? = 1.5418 A to T = 293 K) of the form 03-E.5-1 of the compound (I). Fig. 7. Illustrates the scanning calorimetry pattern differential and thermogravimetric analysis pattern of the form 03-E.5-1 of the compound (I). FIG. 8. Illustrate the labeling of the atoms (except H atoms) in the form 03-E.5-1 of the compound (I). FIG. 9. Illustrate simulated and experienced powder X-ray diffraction patterns (CuKa? = 1.5418 A to T = 293 K) of the 03-SA-2 form of the compound (I). FIG. 10. Illustrate the differential scanning calorimetry pattern and thermogravimetric analysis pattern of the 03-SA-2 form of the compound (I). FIG. 11. Illustrate the labeling of the atoms (except H atoms) in the 03-SA-2 form of the compound (I). FIG. 12. Illustrate simulated and experienced powder X-ray diffraction patterns (CuKa? = 1.5418 A to T = 293 K) of the 03-DSA-2 form of the compound (I). FIG. 13. Illustrates the differential scanning calorimetry pattern and thermogravimetric analysis pattern of the 03-DSA-2 form of the compound (I).

DETAILED DESCRIPTION OF THE INVENTION The present disclosure provides, at least in part, crystalline forms of Compound (I), salts and solvates thereof. The present disclosure also generally relates to pharmaceutical compositions comprising crystalline forms, as well as methods for using crystalline forms in the treatment of HIV and / or AIDS, and methods to obtain such crystalline forms. Compound (I) is l-benzoyl-4- [2- [4-methoxy-7- (3-methyl-lH-1, 2,4-triazol-1-yl) -l - [(phosphonoxy) methyl] -lH-pyrrolo [2,3-c] pyridin-3-yl] -l, 2-dioxoethyl] -piperazine. The compound (I) in the present and is described by the formula (I): (i) Definitions As used herein, "polymorph" refers to crystalline forms that have the same chemical composition but different spatial reconfigurations of the molecules, atoms and / or ions that make up the crystal. As used herein, "solvate" refers to a crystalline form of a molecule, atom and / or ions further comprising molecules of a solvent or solvents incorporated in the crystal matrix structure. The solvent molecules in the solvate can be presented in a regular reconfiguration and / or an unordered reconfiguration. The solvate may contain either a stoichiometric amount or not stoichiometry of the solvent molecules. For example, a solvate with a non-stoichiometric amount of the solvent molecules can result from partial loss of the solvate solvent. Solvates can occur as dimers or oligomers comprising more than one molecule or compound (I) within the crystal matrix structure. As used herein, "amorphous" refers to a solid form of a molecule, atom and / or ions that are not crystalline. An amorphous solid does not show a definitive X-ray diffraction pattern. As used herein "substantially pure", when used in reference to a crystalline form, means a compound having a purity greater than 90% by weight, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, and also including equal to about 100% by weight of the compound (I), based on the weight of the compound. The remaining material comprises other forms of the compound, and / or reaction impurities, and / or process impurities resulting from its preparation. For example, a crystalline form of compound (I) can be considered substantially pure in that it has a purity greater than 90% by weight, as measured by means which are at this time known and generally accepted in the art, where the remainder is less than 10% by weight of the material comprising other forms of the compound (I) and / or reaction impurities and / or process impurities.

The term "pharmaceutically acceptable", as used herein, refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings. humans and animals without excessive toxicity, irritation, allergic response, or other complications of the problem of equal measurement with a reasonable benefit / risk ratio. In certain preferred embodiments, the compound (I) or each of its salts or solvates are in substantially pure form. The term "substantially agree", as used herein, means that one skilled in the art will consider to be the same, when taking into account variables such as instrument limitation, and variation of instruments, etc. The term "substantially pure crystal", as used herein, refers to samples of crystalline forms provided with substantially pure phase homogeneity, indicating the presence of a dominant amount of a single polymorph and optionally amounts less than one or more of other polymorphs. The presence of more than one polymorph in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy. For example, the presence of extra spikes compared to a PXRD pattern experimentally measured with a simulated PXRD pattern may indicate more than one polymorph in the sample. The simulated PXRDPXRD can be calculated from single-crystal X-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963). The term "thickened mixture", as used herein, means a saturated solution of the compound, which may also contain an additional amount of the compound to provide a heterogeneous mixture of the compound and a solvent at a given temperature. "Therapeutically effective amount" is intended to include an amount of the crystalline forms of Compound (I) that is effective when administered alone or in combination to treat HIV and AIDS. The crystalline forms of Compound (I) and pharmaceutical compositions thereof may be useful in the treatment of HIV or AIDS. If the compound (I) is used in combination with another medicine, the combination of the compounds described herein may result in a synergistic combination. The synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.

As used herein, "treating" or "treatment" covers the treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease state that occurs in a mammal, in particular, when such a mammal is predisposed to the disease state but has not been diagnosed as having it; (b) inhibit the disease state, that is, stop its development; and / or (c) alleviating the disease state, that is, causing the regression of the disease state.

Synthesis of compound (I): Compound (I) can be prepared using methods well known to those skilled in the art of organic synthesis, as well as methods taught in the U.S. Non-Provisional Patent Application. commonly owned Serial No. 11 / 066,745 (filed February 25, 2005) which is incorporated herein by reference in its entirety.

General Preparation of Crystalline Materials: Methods for the preparation of crystalline forms are known in the art. The crystalline forms can be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth of a solid state transformation, fusion of another phase, crystallization of a supercritical fluid, and jet spray. Techniques for crystallization or recrystallization of crystalline forms of a solvent mixture include, for example, evaporation of the solvent, reduction of the temperature of the solvent mixture, seeding the crystal in a supersaturated solvent mixture of the molecule and / or salt, Dry the solvent mixture by freezing, and add antisolvent (counter-solvents) to the solvent mixture. High performance crystallization techniques can be used to prepare crystalline forms including polymorphs. Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R.

Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999). For crystallization techniques employing solvent, the choice of solvent or solvents typically depends on one or more factors, such as compound solubility, crystallization technique, and vapor pressure of the solvent. The solvent combinations can be used, for example, the compound can be solubilized in a first solvent to provide a solution, followed by the addition of an anti-solvent to decrease the solubility of the compound in the solution and to provide crystal formation. An antisolvent is a solvent in which the compound has lower solubility. Suitable solvents for preparing crystals include polar and non-polar solvents. Examples of solvents for crystallization include, for example, toluene, n-pentane, n-hexane, n-heptane, n-octane, n-decane, n-dodecane, diethyl ether, methyl tertiary butyl ether, triethylamine, diisopropyl, dibutyl ether, 1,4-dioxane, tetrahydrofuran, chloroform, 1,1-dichloroethane, ethyl acetate, 1,2-dichloroethane, 1,2-dibromoethane, dichloromethane, butyl ethanoate, 1-butanol, 2-methyl -2-propanol, 1-propanol, 1-octanol, ethanol, methyl ethyl ketone, acetone, cyclohexanone, 2-hexanone, cyclopentanone, 2-heptanone, 4-methyl-2-pentanone, acetonitrile, butanonitrile, ethylene glycol, methanol, diethylamine, glycerol, water, methyl acetate, isopropyl acetate, butyl acetate, t-butyl acetate, hexachloroacetone, 2-butanol, t-butyl alcohol, diethylene glycol, 1-, 2-, or 3-pentanol, 2-methyl-1-propanol, and 2-butanol.

In a method for preparing crystals, a compound is suspended and / or stirred in a suitable solvent to provide a thick mixture, which can be heated to promote dissolution. Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a particular polymorph or to control the distribution of particle size of the crystalline product. Accordingly, the calculation of the amount of sowing necessary depends on the size of the available seed and the desired size of an average product particle as described, for example, in "Programming cooling of batch crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science (1971) 26: 369-377. In general, small-sized plantings are necessary to effectively control the growth of crystals in the lot. Small-sized plantings can be generated by sifting, grinding, or micronizing larger crystals, or by micro-crystallization of solutions. Care should be taken when grinding or micronizing crystals that do not result from any change in the crystallinity form of the desired crystal shape (ie change to amorphous or other polymorph). A cooled crystallization mixture can be filtered under vacuum, and the isolated solids can be washed with an appropriate solvent, such as a cold recrystallization solvent, and dried under a nitrogen purge to provide the desired crystalline form. The isolated solids can be analyzed by an appropriate spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, or the like, to ensure the formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount greater than about 70% by weight of isolated yield, preferably greater than 90% by weight of isolated yield, based on the weight of the compound originally employed in the crystallization process. The product can be co-milled or passed through a mesh screen to undo product lumps, if necessary. The crystalline forms can be prepared directly from the reaction medium of the final step of the process to prepare the compound (I). This can be achieved, for example, by employing in the final stage of the process a solvent or mixture of solvents from which the compound (I) can be crystallized. Alternatively, the crystalline forms can be obtained by distillation or solvent addition techniques. Solvents suitable for this purpose include, for example, non-polar solvents and polar solvents, including protic polar solvents such as alcohols, and polar aprotic solvents such as ketones.

Characterization: The crystalline forms of Compound (I), its salts and solvates can be characterized by a number of methods, including but not limited to, powder X-ray diffraction (PXRD), simulated powder X-ray patterns (Yin. S.; Scaringe, RP; DíMarco, J.; Galella, M. and Gougoutas, JZ, American Pharmaceutical Review, 2003, 6.2, 80), differential scanning calorimetry (DSC) experiments, measurements of C-13 solid state NMR, (WL Earl and DL VanderHart, J. Magn. Reson., 1982, 48, 35-54), Raman spectroscopy, infrared spectroscopy, moisture absorption isotherms (VTI variable temperature isotherms), and hot storage techniques. The shapes can be characterized and distinguished using simple crystal X-ray diffraction, which is based on unit cell measurements of a single crystal of a particular form at a fixed analytical temperature. A detailed description of unit cells is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, the unique configuration of atoms in the spatial relationship within the crystalline matrix can be characterized according to the observed fractional atomic coordinates. Other means to characterize the crystal structure is by powder X-ray diffraction analysis in which the diffraction profile is compared for a simulated profile representing the pure powder material, both are run at the same analytical temperature, and measured by the object form characterized as a series of 2T values. Someone of skill in the art will appreciate that a X-ray diffraction pattern can be obtained with a measurement error that depends on the measurement conditions used. In particular, it is generally known that the intensities in an X-ray diffraction pattern can fluctuate depending on the measurement conditions employed. It should be understood that the relative intensities may also vary depending on the experimental conditions and, consequently, the exact order of intensity should not be taken into account. Additionally, a measurement error of the diffraction angle for a conventional X-ray diffraction pattern is typically around 5% or less, and such a degree of measurement error should be taken into account as belonging to the aforementioned diffraction angles. . Accordingly, it will be understood that the crystal forms of the present invention are not limited to the crystal forms that provide the X-ray diffraction patterns completely identical to the X-ray diffraction patterns described in the accompanying Figures described herein. . Any of the crystal forms that provide X-ray diffraction patterns substantially identical to those described in the accompanying Figures fall within the scope of the present invention. The ability to investigate substantial identities of X-ray diffraction patterns is within the field of vision of someone of ordinary skill in art. Similarly, it is understood that any crystal forms that provide differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and / or moisture absorption isotherms substantially identical to those described in the accompanying figures fall within the scope of the present invention. . The ability to investigate substantial identities of these patterns is within the field of vision of someone of ordinary skill in the art.

Utility: The crystalline forms of Compound (I), its salts and solvates, alone or in combination with other compounds, can be used to treat AIDS and / or HIV infection. The crystalline forms of the invention can be formulated with one or more excipients or other materials to provide formulations suitable for the treatment of the indications identified above. The crystalline forms of the present invention can be administered by several routes, and can be dissolved in several solvents prior to administration. In accordance with the present invention there is further provided a method for treating and a pharmaceutical composition to treat viral infections such as HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a crystalline form of the present disclosure. The pharmaceutical composition may be in the form of orally administrable suspensions or tablets; nasal sprays, sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions or suppositories. When administered orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may contain microcrystalline cellulose to impart volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as an enhancer of viscosity, and sweetening / flavoring agents known in the art. As immediate release tablets, these compositions may contain, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, diluents, disintegrants, dilution agents and lubricants known in the art. Injectable solutions or suspensions may be formulated according to the known art, using diluents or parenterally acceptable solvents, suitable non-toxic, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting or suspending agents, such as fixed, soft, sterile oils, including mono or synthetic diglycerides, and fatty acids, including oleic acid. The compound (I) can be present in the novel crystalline forms such as the pure form, solvate and / or hydrate. A wide variety of solvents can be used in the preparation of the solvates of the compound (I). Preferred solvents include, for example, polar solvents, including polar protic solvents and polar aprotic solvents. Preferably, the solvent employed in the preparation includes, for example, DMF or acetone, preferably acetone. The ratio of the compound (I) to solvent in the solvates can vary and depends, for example, on the particular solvent selected and the methods for preparing the solvates. Preferably, the solvates are monosolvates, hemisolvates, non-stoichiometric or we dissolve.

Abbreviations The following abbreviations, most of which are conventional abbreviations well known to those skilled in the art, are used throughout the description of the invention and the examples. Some of the abbreviations used are as follows: h = time (s) ta = room temperature mol = mol (s) mmol = millimol (s) g = gram (s) mg = milligram (s) mL = milliliter (s) TFA = trifluoroacetic acid DCE = 1,2-Dichloroethane CH2C12 = Dichloromethane TPAP = tetrapropylammonium perruthenate THF = Tetrahydrofuran DEPBT = 3- (Diethyphosphoryloxy) -1,2, 3-benzotriazin-4 (3H) -one DMAP = 4-dimethylaminopyridine P-EDC = polymer supported on 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide DMF-N, N-dimethylformamide Base Hunig = N, N- Diisopropylethylamine mCPBA meta-chloroperbenzoic acid azaindole = HH-pyrrolo-pyridine 4-azaindole = lH-pyrrolo [3,2-b] pyridine 5-azaindole = HH-pyrrolo [3, 2-c] pyridine 6-aza? Ndol = lH-p? Rrolo [2,3-c] p? R? D? Na 7-aza? Ndol = lH-P? Rrolo [2, 3-b] p? R? D? Na PMB = 4-Methoxybenzyl DDQ = 2, 3-D? Chloro-5,6-d? C? Ano-l, 4-benzoquinone OTf = Trifluoromethanesulfonoxy NMM = 4-Met? Lmorpholine PIP-COPh = 1-Benzo? Lp? Peraz? Na NaHMDS = sodium hexamethyldisilazide EDAC = 1- (3-D? Met? Lam? Noprop? L) -3-et? lcarbod ?? m? da TMS = Tpmetilsililo DCM = Dichloromethane DCE = Dichloroethane MeOH = Methanol THF = Tetrahydrofuran EtOAc = Acetate LDA = Lithium Dusopropylamide TMP-L? = 2, 2, 6, 6-tetramet? lp? pepd? n? ll itio DME = Dimetoxyethane DIBALH = dusobutylaluminum hydride HOBT = 1-hydroxylbenzotr? a zol CBZ = Benzyloxycarbonyl PCC = pipdinio chlorochromate Me = methyl Ph = f enyl The crystalline materials of Compound (I) described herein may be formulated in pharmaceutical compositions and / or employed in therapeutic and / or prophylactic methods. These methods include, but are not limited to, the administration of the crystalline compound (I), alone or in combination with one or more other pharmaceutically active agents, including agents that may be useful in the treatment of the disorders mentioned herein. The methods preferably comprise administering to a patient a pharmaceutically effective amount of the novel crystals of the present invention, preferably in combination with one or more carriers and / or excipients. The relative proportions of active ingredient and carrier and / or excipient can be determined, for example, by the solubility and chemical nature of the materials, chosen routes of administration and standard pharmaceutical practice. The crystalline forms of Compound (I) can be administered to a patient in such oral dosage forms as tablets, capsules (each of which includes sustained release or sustained release formulations), pills, powders, granules, elixirs, dyes, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously, or intramuscularly, all using dosage forms well known to those skilled in the art. pharmaceutical technique. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected from the bases of the chosen route of administration and standard pharmaceutical practice. The dosage regimen for the crystalline forms of Compound (I), of course, will vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the type of simultaneous treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counteract, or stop the progress of thromboembolic disorder. Obviously, various forms of unit doses can be administered almost at the same time. The dose of the crystalline form of Compound (I) which will be most suitable for prophylaxis or treatment may vary with the form of administration, the particular crystalline form of the compound chosen and the psychological characteristics of the particular patient under treatment. Broadly, small doses can be used initially and, if necessary, increased in small increments until the desired effect under the circumstances is reached.

As a general guideline, in the adult, the appropriate dose may range from about 0.001 to about 1000 mg / Kg body weight, and all combinations and subcombinations of specific intervals and doses in the. Preferred doses may be from about 0.01 to about 100 mg / kg of body weight per day per inhalation, preferably 0.1 to 70, more preferably 0.5 to 20 mg / kg of body weight per day per oral administration, and from about 0.01 to about 50, preferably 0.01 to 10 mg / Kg of body weight per day by intravenous administration. In each particular case, the doses can be determined in accordance with the distinguishing factors to the subject to be treated, such as age, weight, general state of health and other characteristics that can influence the efficacy of the medicinal product. The crystalline forms of Compound (I) can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three, four times daily. For oral administration in solid form such as a tablet or capsule, the crystalline forms of Compound (I) can be combined with a pharmaceutically acceptable, non-toxic inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.

Preferably, in addition to the active ingredient, solid dosage forms may contain a number of additional ingredients referred to herein as "excipients". These excipients include among other diluents, binders, lubricants, flow improvers and disintegrants. Colorants can also be incorporated. "Diluents", as used herein, are agents that impart volume to the formulation to make a practical-sized tablet by compression. Examples of diluents are lactose and cellulose. "Binders", as used herein, are agents used to impart cohesive qualities to the powder material to help ensure that the tablet will remain intact after compression, as well as improve the free-flowing qualities of the powder. Examples of typical binders are lactose, starch and various sugars. "Lubricants", as used herein, have various functions including preventing adhesion of the tablets to the compression equipment and improving the flow of the granulation prior to compression or encapsulation. Lubricants are in most cases hydrophobic materials. The excessive use of lubricants is undesirable, however, this can result in a formulation with reduced disintegration and / or delayed dissolution of the drug substance. "Flow improving agents", as used herein, refers to substances that can improve the flow characteristics of the material of granulation. Examples of flow improver agents include talc and colloidal silicon dioxide. "Disintegrants", as used herein, are substances or a mixture of substances added to a formulation to facilitate dissolution or disintegration of the solid dosage form after administration. Materials that can serve as disintegrants include starches, clays, celluloses, clays, gums and cross-linking polymers. A group of disintegrants that are referred to as "super-disintegrants" are generally used at a low level in the solid dosage form, typically 1% up to 10% by weight relative to the total weight of the dose unit. Croscarmellose, crospovidone and sodium, starch glycolate represent examples of a cross-linked cellulose, a cross-linked polymer and a cross-linked starch, respectively. Sodium starch glycolate is swollen seven to twelve times in less than 30 seconds by effectively disintegrating the granulations that contain it.

The disintegrant preferably used in the present invention is selected from the group comprising modified starches, sodium croscarmalosa, calcium carboxymethylcellulose and crospovidone. A more preferred disintegrant in the present invention is a modified starch such as sodium starch glycolate. Preferred carriers include capsules or compressed tablets containing the dosage forms pharmaceutically solid described herein. The capsule or compressed tablet forms generally comprise a therapeutically effective amount of the crystalline forms of Compound (I) and one or more disintegrants in an amount greater than about 10% by weight relative to the total weight of the contents of the capsule or capsule. the total weight of the tablet. Preferred capsule formulations may contain the crystalline forms of Compound (I) in an amount of from about 5 to about 1000 mg per capsule. Preferred tablet formulations contain the crystalline forms of Compound (I) in an amount from about 5 mg to about 800 mg per tablet. More preferred formulations contain about 50 to about 200 mg per capsule or tablet. Preferably, the pharmaceutical dosage form in capsule or compressed tablet comprises a therapeutically effective amount of a crystalline form of Compound (I); a surfactant; a disintegrant; a binder; a lubricant; and optionally additional pharmaceutically acceptable excipients such as diluents, flow improvers and the like; wherein the disintegrants are selected from modified starches; croscarmalosa sodium, carboxymethylcellulose calcium and crospovidone. For oral administration in liquid form, the forms Crystalline compounds of Compound (I) can be combined with any oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. The liquid composition may contain a sweetening agent that can make the compositions more acceptable. The sweetening agent can be selected from a sugar such as sucrose, mannitol, sorbitol, xylitol, lactose, etc. or a sugar substitute such as cyclamate, saccharin, aspartame, etc. If the sugar substitutes are selected as the sweetening agent the amount employed in the compositions of the invention will be substantially lower than if sugars are employed. With this in mind, the amount of sweetening agent may be in the range of from about 0.1 to about 50% by weight, and all combinations and subcombinations of ranges and specific amounts therein. The preferred amounts are in the range of from about 0.5 to about 30% by weight. The most preferred sweetening agents are sugars and particularly sucrose. The particle size of the sucrose powder used has been found to have an important influence on the physical appearance of the finished composition and its ultimate acceptance for taste. The preferred particle size of the sucrose component when used is in the range from 200 to less than 325 US Standard Sieve mesh, and all combinations and subcombinations of specific particle sizes and intervals in this. Sterile injectable solutions can be prepared by incorporating the crystalline forms of Compound (I) in the required amounts, in the appropriate solvent, with various of the other ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions can be prepared by incorporating the sterilized active ingredient into a sterile vehicle containing the dispersion medium and any other required ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation they can include vacuum drying and the freeze drying technique which can provide a powder of the active ingredient, as well as any additional desired ingredient of the previously sterile filtered solution thereof. As will be apparent to a person of ordinary skill in the art, once armed with the teachings of the present disclosure, when dissolved, Compound (I) loses its crystalline structure, and is therefore considered a solution of the Compound (I ). All forms of the present invention, however, can be used for the preparation of liquid formulations in which Compound (I) can, for example, be dissolved or suspended. In addition, the crystalline forms of Compound (I) can be incorporated into solid formulations. The liquid compositions may also contain other components routinely used in the formulation of pharmaceutical compositions. An example of such components is lecithin. It is used in the compositions of the invention as an emulsifying agent in the range from 0.05 to 1% by weight and all combinations and sub-combinations of the ranges and specific amounts therein. More preferably, the emulsifying agents can be employed in an amount of from about 0.1 to about 0.5% by weight. Other examples of the components that can be used are antimicrobial preservatives, such as benzoic acid or parabens; suspension agents; such as colloidal silicon dioxide; antioxidants; topical oral anesthetics; flavoring and coloring agents. The selection of such optional components and their level of use in the compositions of the invention is within the level of skill in the art and will be better appreciated from the working examples provided hereinafter. The crystalline forms of Compound (I) can also be coupled with soluble polymers as targeted drugs carrier. Such polymers may include the copolymer of pilivinylpyrrolidine pyran, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidaphenol or polyethylene oxide-polylysine substituted with palmimethylsidue residues. The gelatin capsules of the crystalline forms of Compound (I) may contain the crystalline Compound (I) and the liquid or solid compositions described herein. Gelatin capsules also contain powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide continuous release of the drug over a period of hours. The tablets can be sugar coated or film coated to mask any unpleasant taste and to protect the tablet from the atmosphere or an enteric coating for selective disintegration in the gastrointestinal tract. In general, water, a suitable oil, saline solution, aqueous dextrose (glucose) and solutions related to sugar and glycols, such as propylene glycol or pilietylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral solutions are prepared by dissolving the crystalline Efavirenz in the carrier and, if necessary, adding buffer substances. Anti-oxidants such as sodium bisulfite, sodium sulfite or ascorbic acids, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA can also be used. Parenteral solutions may also contain preservatives, such as benzalkonium chloride, methyl propyl paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., the disclosure of which is incorporated herein by reference in its entirety. The preferred crystalline form of Compound (I) can serve as component (a) of this invention and can independently be in any dosage form, such as that described above, and can also be administered in various combinations, as described above. In the following description component (b) is understood to represent one or more agents as described herein suitable for combination therapy. Pharmaceutical kits which may be useful for the treatment of various disorders, and which comprise a therapeutically effective amount of a pharmaceutical composition comprising a novel form of Compound (I) in one or more sterile containers, are also within the scope of the present invention. invention. The kits may also comprise conventional pharmaceutical kit components which will be readily apparent to those skilled in the art, once armed with the present disclosure. Sterilization of the container can be carried out using conventional sterilization methodology well known to those of skill in the art. Form 01 -H2-1 of Compound (I) Form 01-H2-1 of Compound (I) is a di-hydrate with the empirical formula C25H26N708P? -2H20 The single crystal of Form 01-H2-1 is characterized in Table 1. Each of the atoms (except H) in Form 01-H2-1 is labeled according to FIG. 3. Fractional atomic coordinates are listed in Table 2.

Form 02-SA-1 of Compound (I) Form 02-SA-1 of Compound (I) is a di-sodium salt hemiethanolate octahydrate with the empirical formula of C25H24N708P? Na2 • 8H20 • 0.5 • C2H5OH. The simple crystal of Form 02-Sa-l is characterized in Table 3. Each of the atoms (except H) in Form 02-SA-1. it is labeled according to FIG. 5. Fractional atomic coordinates are listed in the Table.

Form 03-E. 5-1 of Compound (I) Form 03-E.5-1 of Compound (I) is a hemiethanolate of the mono-TRIS salt with the empirical formula of C25H26 7O8P1 • C4HuN? 03 - 0.5 C2H5OH. The single crystal of Form 03-E.5-1 is characterized in Table 5. Each of the atoms (except H) in the form 03-E.5-1 is labeled according to FIG.8. The fractional atomic coordinates are listed in Table 6.

Form 03-SA-2 of Compound (I) Form 03-SA-2 of Compound (I) is a hemiacetonate salt hemihydrate mono-TRIS with an empirical form of C25H26N7? 8P? • C4HuN103 • 0.5H20 • 0.5C3H6O. The single crystal of Form 03-SA-2 is characterized in Table 7. Each of the atoms (except H) in Form 03-SA-2 is labeled according to FIG. 11. The fractional atomic coordinates are listed in Table 8.

Form 03-DSA-2 of Compound (I) Form 03-DSA-2 of Compound (I) is a mono-TRIS salt which is a dehydrated and desolvated form of Form 03-SA-2.

Table 1 . Characterization of the Single Crystal of Form 01-H2-1 Temperature 293 (2) K Wavelength 1.54178 A Crystal system, space group Monoclinic, P2 (l) / c Unit cell dimensions a = 17.2174 (18) A a = 90 ° b = 18.1242 (19) A ß = 105.191 (4) ° c = 9.3705 (9) A Y = 90 ° Volume 2821.9 (5) A3 Z, calculated density 4, 1,458 Mg / m3 Absorption Coefficient 1,474 mm "1 F (000) 1296 Glass size 0.18 x 0.15 x 0.01 mm Interval? for data collection 2.66 to 39.60 ° limiting indexes -13 < = h < 13, -13 < = k = 14, -7 < = 1 < = 7 Reflections collected / unique 4367/1423 [R (int) = 0.1318] Integrity up to? = 39.60 85.5% Adsorption correction SADABS Max. and min. 1,000 and 0.557 Minimum square refinement method in the complete matrix F Data / constraints / parameters 1423/0/379 Ideal for F2 1,066 final R index [I > 2s (I)] Rl = 0.0806, wR2 = 0.1864 R indices (All data) Rl = 0.1146, wR2 = 0.2028 Difference Greater than peak and orifice 0.246 and -0.265 e.A-3 Table 2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (A2 x 103) for Form 01-H2-1. U (eq) is defined as a third part of the orthogonalized Uij tensor trace, x and U (eq) Píl) 8692 (3) 2452 (3) 886 (5) 58 (2) O (l) 7863 (7) 2046 (8) 691 (11) 85 (4) 0 (2) 9208 (6) 2345 (5) 2464 (10) 74 (3) O (3) 9134 (6) 2119 (5) -166 (11) 85 (4) 0 (4) 8450 (6) 3230 (6) 438 (9) 73 (3) 0 (5) 4159 (9) 1141 (5) 590 (10) 57 (3) 0 (6) 5716 (9) 2151 (6) 4721 (15) 81 (5) 0 (7) 4141 (9) 2605 (7) 2202 (13) 82 (5) 0 (8) 2990 (8) -173 (7) 6428 (13) 82 (5) M (l) 6889 (16) 1504 (10) 1580 (30) 55 (6) M (2) 5481 (18) 686 (7) -1765 (18) 62 (6) H (3) 6844 (14) 911 (12) -1530 (30) 50 (4) (4) 7493 (18) 443 (9) -982 (15) 59 (5) M < 5) • 7666 (15) 1106 (13) -2890 (20) 57 (6) N (6) 3989 (13) 1677 (11) 3686 (18) 62 (5) N { 7) 2982 (11) 670 (9) 4620 (20) 61 (5) C (l) 6560 (20) 1757 (8) 2710 (20) 49 (6) C (2) 6280 (20) 1218 (13) 520 (50) 54 (11) C { 3) 6160 (20) 942 (11) -950 (30) 58 (8) C { 4) 4815 (13) 753 (9) -1190 (30) 54 (6) C (5) 4880 (20) 1092 (11) 190 (30) 56 (8) C (6) 5580 (20) 1328 (11) 1000 (40) 64 (13) C (7) 5780 (20) 1689 (10) 2440 (30) 49 (8) C (8) 7729 (15) 1491 (9) 1654 (17) 61 (6) C (9) 6967 (18) 1280 (10) -2670 (30) 57 (6) C (10) 7994 (15) 588 (13) -1820 (40) 63 (7) C (ll) 8805 (12) 276 (9) -1620 (20) 95 (6) C (12) 3391 (11) 1028 (9) -411 (18) 82 (6) C (13) 5320 (20) 1956 (9) 3520 (30) 53 (6) C (14) 4470 (20) 2089 (14) 3030 (20) 63 (7) C (15) 3197 (13) 1884 (8) 3658 (16) 56 (5) C (16) 2626 (10) 1235 (11) 3533 (16) 71 (7) C (17) 3762 (14) 410 (8) 4532 (17) 63 (5) C (18) 4348 (10) 1045 (10) 4757 (15) 57 (5) C (19) 2655 (14) 360 (13) 5690 (30) 55 (6) C (20) 1920 (20) 614 (14) 5970 (20) 80 (10) C (21) 1278 (19) 186 (12) 6130 (20) 95 (9) C { 22) 629 (17) 530 (20) 6570 (30) 154 (13) C (23> 630 (20) 1270 (20) 6770 (30) 153 (12) C (24) 1240 (20) 1703 (14) 6640 (30) 124 (11) C (25) 1878 (12) 1340 (20) 6199 (19) 96 (10) O (IW) 10482 (16) 1379 (15) 2580 (30) 375 (14) 0 (2W) 11290 (90) 1740 (100) 410 (180) 340 (80) Table 3. Simple Crystal Characterization of Form 02-SA-1 Temperature 173 (2) K Wavelength 1.54178 A Crystal system, triclinic space group, Pl Unit cell dimensions a = 6.4392 (12) A a = 99.082 (11) ° b = 13.349 (2) A ß = 95.975 ( 12) ° c = 21.041 (4) AY = 90.207 (12) ° Volume 1775.9 (6) A3 Z, calculated density 2, 1486 Mg / mJ Absorption Coefficient 1,661 mm "1 F (000) 834 Glass size 0.62 x 0.03 x 0.01 mm Interval? for data collection 2.14 to 65.49 ° limiting indexes -7 < = h < 7, -14 < = k = 15, -22 < = 1 < = 24 Reflections collected / unique 9051/5226 [R (int) = 0.0983] Integrity up to? = 39.60 85.1% Adsorption correction SADABS Max. and min. 1,000 and 0.749 Minimum square refinement method in the complete matrix F2 Data / constraints / parameters 5226/0/481 Ideal virtue in F2 1,144 final R index [I > 2s (I)] Rl = 0.1086, wR2 = 0.2554 R indices (All data) Rl = 0.1373, wR2 = 0.2674 Extinction Coefficient 0.0007 (3) Greater Difference of peak and hole 0. 24 6 y -0. 265 e. 3 Table 4. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (A2 x 103) for Form 02-SA-1. U (eq) is defined as one third of the 1 Uij ortog onalized tensioner. X yz U (eq) P (l) -4237 (3) 7620 (2) 623 (1) 16 (1) 0 (1) -4989 (9) 8163 (4) 1326 (3) 25 (1)? ( 2) -5171 (8) 6554 (4) 520 (3) 22 (1) 0 (3) -5197 (8) 8294 (4) 166 (3) 22 (1) 0 (4) -1871 (8) 7657 (4) 690 (3) 25 (1) 0 (5) 2971 (9) 6724 (5) 3257 (3) 37 (2)? (6) -443 (9) 4328 (5) 1972 (3) 34 ( 2)? (7) -623 (10) 5024 (5) 3498 (3) 34 (2)? (8) 8772 (10) 2512 (5) 2958 (3) 40 (2) N (l) -3283 ( 10) 7198 (5) 2088 (3) 22 (2) N (2) 83 (11) 9077 (6) 3216 (4) 33 (2) N < 3) -2903 (11) 9486 (5) 2603 (4! 25 (2) N (4) -4611 (12) 9754 (5) 2928 (4) 31 (2) N (5) -4533 (12) 10601 (5) 2080 (4) 31 (2) N (6) 2561 (12) 4517 (6) 3211 (4) 34 (2) N (7) 5741 (12) 3115 (6) 3293 (4) 32 (2 ) C (l) -2782 (13) 6193 (6) 1988 (4) 25 (2) C (2) -1727 (12) 7723 (6) 2524 (4) 21 (2) C (3) -1474 ( 13) 8732 (6) 2781 (4) 25 (2) C (4) 1524 (14) 8414 (7) 33 «0 (5) 33 (2) C (5) 1479 (14) 7403 (7) 3130 ( 5 29 (2) C (6) -279 (12) 7022 (6) 2704 (4 24 (2) C (7) -951 (13) 6043 (6) 2361 (4 24 (2) C (8) - 5253 (12) 7582 (6) 1812 (4 22 (2) C (9) -2903 (13) 10008 (6) 2114 (4 25 (2), C (10) -5520 (14) 10418 (7) 2588 (4 27 (2) C (ll) -7555 (15) 10885 (7) 2743 (5 39 (3) C (12) 4739 (15) 7096 (8) 3710 (6 44 (3) C (13) - 149 (13) 5019 (7) 2410 (5 27 (2) C (14) 656 (14) 4851 (7) 3085 (5 29 (2) C (15) 3338 (15) 4299 (7) 3846 (5 36 (2) C (16) 4190 (14) 3229 (8) 3772 (5 36 (2) C (17) 4981 (14) 3376 (7) 2664 (5) 32 (2) C (18) 4121 (14) 4434 (7) 2745 (5 31 (2) C (19) 7652 (14) 2726 (7) 3400 (5) 33 (2) C (20) 8481 (14) 2595 (7) 4058 (5) 32 (2 ) C (21) 8767 (16) 3406 (8) 4583 (5) 39 (2) C (2) 2) 9755 (17) 3241 (10) 5166 (6) 54 (3) C (23) 10388 (18) 2291 (11) 5258 (6) 59 (4) C (24) 10121 (18) 1497 (10) 4760 (6) 54 (3) C (25) 9200 (16) 1651 (8) 4168 (6) 42 (3) Na (l) -27 (5) 4278 (2) 751 (2) 32 (1) Na (2) 584 (5) 824 (2) 799 (2) 27 (1) O (I) -582 (9) 2420 (4) 342 (3) 30 (2) 0 (2W) 702 (10) 5950 ( 5) 649 (4) 41 (2) 0 (3) 3223 (10) 3816 (5) 1156 (3) 33 (2) 0 (4) -3536 (9) 4645 (4) 623 (3) 27 (1 ) 0 (5W) -2364 (9) 19 (4) 135 (3) 26 (1) 0 (6) 929 (9) -739 (4) 1222 (3) 30 (2) 0 (7W) 3859 (9 ) 1718 (4) 1081 (3) 29 (1) 0 (8) -868 (11) 1918 (5) 1629 (4) 40 (2) 0 (101) -3944 9520 4308 48 C (101) -4921 10189 4691 79 C (102 > -5079 9811 5309 79 Table 5. Characterization of the Single Crystal of Form 03-E.S-1 Temperature 293 (2) K Wavelength 1.54178 A Crystal system, monoclinic space group, C2 / c Unit cell dimensions a = 35.594 (12) A a = 90 ° b = 6.2790 (4) A ß = 97.080 (3 ) ° c = 30.6961 (19) AY = 90 ° Volume 6808.1 (7) A3 Z, calculated density 8, 1,420 Mg / mJ Absorption Coefficient 1,349 mm-1 F (000) 3064 Glass size 0.62 x 0.02 x 0.01 mm Interval? for data collection 2.50 to 60.58 ° limiting indices -39 < = h < 37, -6 < = k = 6, -34 < = 1 < = 32 Reflections collected / unique 16059/4932 [R (int) = 0.0844] Integrity up to? = 39.60 96.0% Adsorption correction SADABS Max. and min. 1,000 and 0.796 Minimum square refinement method in the complete matrix F2 Data / constraints / parameters 4932/0/472 Ideal virtue in F2 0.955 final R index [I > 2s (I)] Rl = 0.0619, wR2 = 0.1236 R indices (All data) Rl = 0.1245, wR2 = 0.1426 Difference Greater than peak and orifice 0.299 and -0.245 e.A "3 Table 6. Atomic coordinates (x 10) and equivalent isotropic displacement parameters (A2 x 103) for the Form 03-E.5-1. U (eq) is defined < : as a border of the trace of the tensor Uij orthogonally X yz U (eq) P (l) 2596 (1) 6394 (2) 2987 (1) 40 (1) 0 (1) 2976 (1) 7325 (4 ) 2829 (1) 44 (1) 0 (2) 2545 (1) 7326 (4) 3424 (1) 49 (1) 0 (3) 2295 (1) 6805 (4) 2618 (1) 49 (1) 0 (4) 2670 (1) 3962 (4) 3055 (1) 49 (1) 0 (5) 4192 (1) 1209 (5) 4004 (1) 54 (1) 0 (6) 3534 (1) 5503 (5 ) 4738 (1) 65 (1) 0 (7) 4409 (1) 5226 (5) 4729 (1) 61 (1) O (S) 3768 (1) -3613 (6) 5844 (1) 96 (1) 2? (L) 3483 (1) 6854 (5) 3404 (1) 38 (1): s (2) 3986 (1) 2708 (6) 2844 (1) 52 (1): s (3) 3667 (1 ) 5526 (6) 2482 (1) 43 (1) (4) 3842 (1) 7331 (7) 2362 (1) 59 (1) NI (5) 3364 (1) 6428 (7) 1848 (1) 56 ( 1): s (6) 4143 (1) 2180 (6) 4952 (1) 45 (1): M (7) 4070 (1) -758 (6) 5621 (1) 46 (1) C (l) 3483 (1) 6826 (6) 3842 (1) 38 (1) C (2) 3703 (1) 5168 (7) 3281 (1) 36 (1) 0 (3) 3787 (1) 4441 (8) 2880 (1 ) 41 (1) 0 (4) 4121 (1) 1637 (7) 3212 (2) 51 (1) 0 (5) 4061 (1) 2252 (7) 3627 (2) 41 (1) 0 (6) 3847 (1) 4108 (7) 3670 (1) 36 (1) C (7) 3705 (1) 5188 (7) 4030 (1) 37 (1) 0 (8) 3262 (1) 8359 (7) 3107 (1 ) 46 (1) C (9) 3383 (1) 5037 (8) 2172 (2) 52 (1) 0 (10) 364 5 (1) 7796 (8) 1981 (2) 58 (1) 0 (11) 3740 (2) 9697 (9) 1724 (2) 115 (2) 0 (12) 4433 (1) -573 (7) 3969 (2) 63 (2) 0 (13) 3761 (1) 4840 (7) 4507 (2) 43 (1) 0 (14) 4140 (1) 4025 (8) 4732 (1) 45 (1) 0 (15 ) 4480 (1) 1450 (7) 5226 (1) 49 (1) 0 (16) 4374 (1) 812 (7) 5670 (1) 49 (1) 0 (17) 3733 (1) -2 (7) 5348 (2) 59 (1) 0 (18) 3834 (1) 626 (7) 4904 (2) 55 (1) 0 (19) 4062 (2) -2603 (9) 5839 (2) 53 (1) C (20) 4418 (1) -3458 (7) 6084 (2) 44 (1) 0 (21) 4741 (1) -3755 (7) 5886 (2) 51 (1) 0 (22) 5054 (2) - 4692 (8) 6112 (2) 65 (2) 0 (23) 5052 (2) -5317 (8) 6535 (2) 76 (2) 0 (24) 4730 (2) -5082 (8) 6736 (2) 83 (2) 0 (25) 4410 (2) -4182 (8) 6508 (2) 66 (2) W (l? L) 2345 (1) 1293 (6) 3682 (1) 44 (1) 0 (100 ) 2381 (1) 1642 (7) 4167 (1) 40 (1) C (101) 2762 (1) 720 (7) 4368 (2) 55 (1) 0 (101) 3063 (1) 1335 (6) 4132 (1) 65 (1) 0 (102) 2353 (1) 4024 (7) 4246 (1) 57 (1) 0 (102) 2678 (1) 5114 (5) 4152 (1) 67 (1) 0 (103 ) 2058 (2) 516 (8) 4341 (2) 73 (2) O (IOA) 1756 (3) 1422 (14) 4227 (3) 75 (3) O (10B) 2000 (3) -1430 (20) 4230 (4) 92 (4) O (10C) 2038 (3) 504 (16) 4742 (4) 59 (3) 0 (201) 4628 (2) 8300 ( 11) 2632 (2) 79 (2) 0 (201) 4808 (10) 10130 (30) 2382 (19) 125 (11) C (202) 5201 (10) 10250 (30) 2474 (18) 125 (11) Table 7. Simple Crystal Characterization of Form 03-SA-2 Temperature 293 (2) K Wavelength 0.71073 A Crystal system, group of monoclinic space, C2 / c Unit cell dimensions a = 43.985 (2) A OI = 90 ° b = 6.3142 (3) A ß = 125.742 (4 ) ° c = 30.2438 (17) AY = 90 ° Volume 6817.6 (6) A3 Z, calculated density 8, 1.399 Mg / m3 Absorption Coefficient 0.152 mm "1 F (000) 3019 Glass size 0.30 x 0.02 x 0.01 mm Interval? for data collection 2.80 to 24.94 ° limiting indexes -52 < = h < 51, -7 < = k = 7, -35 < = 1 < = 35 Reflections collected / unique 18438/5934 [R (int) = 0.1655] Integrity up to? = 39.60 99.2% Adsorption correction None Minimum square refinement method in the complete matrix F2 Data / constraints / parameters 5934/0/472 Ideal virtue in F2 1.006 final R index [I > 2s (I)] Rl = 0.0718, wR2 = 0.1474 R indices (All data) Rl = 0.1697, wR2 = 0.1917 Extinction Coefficient 0.0010 (2) Greater Difference of peak and hole 0. 256 and -0. 291 e. A "3 Table 8. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (A2 x 103) for Form 03-5A-2 U (eq) is defined as a third part of the orthogonalized Uij tensor trace, X and z U (eq) ) P (l) 2400 (1) -1012 (2) 2B97 (1) 45 (1) 0 (1) 2024 (1) -1939 (5) 2360 (1) 49 (1) 0 (2) 2448 (1 ) -1930 (5) 3390 (1) 54 (1) 0 (3) 2702 (1) -1428 (5) 2826 (1) 53 (1) 0 (4) 2324 (1) 1394 (5) 2883 (1 ) 53 (1) 0 (5) 826 (1) 4216 (6) 2334 (2) 61 (1) 0 (6) 1425 (1) -139 (7) 3709 (2) 78 (1) (7) 567 (1) 349 (7) 2788 (2) 80 (1) 0 (8) 1221 (1) 8772 (9) 4661 (2) 108 (2) Nd) 1519 (1) -1468 (6) 2434 (2) 46 (1) N < 2) 1038 (1) 2675 (7) 1370 (2) 55 (1) M (3) 1357 (1) -156 (7) 1330 (2) 49 (1) N (4) 1192 (1) -2003 ( 8) 1064 (2) 64 (1) N (5) 1659 (1) -1090 (8) 996 (2) 61 (1) 6) 842 (1) 3250 (7) 3322 (2) 56 (1) W (7) 909 (1) 6073 (7) 4090 (2) 55 (1) C < 1) 1507 (1 -1409 (8) 2876 (2) 48 (1) C (2) 1306 (1) 222 (8) 2098 (2) 45 (1) C (3) 1232 (1 939 (8) 1609 (2) 46 (1) C (4) 910 (2 3798 (9) 1614 (2) 58 (1) C (5) 956 (1 3162 (8) 2084 (2) 48 (1) C < 6) 1160 (1 1313 (8) 2339 (2) 43 (1) C (7) 1286 (1 216 (8) 2836 (2) 45 (1) C (8) 1740 (2 -2980 (8) 2365 (2) 49 (1) C (9) 1633 (2 333 (9) 1288 (2) 54 (1) C (10) 1385 (2 -2495 (10) 869 (2) 64 (2) C { 11) 1306 (3 -4438 (12) 534 (4) 113 (3) C (12) 582 (2 6006 (9) 2048 (2) 67 (2) C (13) 1213 (2) 567 (8) 3248 (2) 56 (2) C (14) 843 (2 1470 (9) 3088 (2) 55 (1) C (15) 505 (2 4004 (9) 3261 (2) 58 (1) C (16) 599 (2) 4552 (8) 3812 (2) 56 (1) C (17) 1247 (2 5284 (10) 4157 (2) 66 (2) C (18) 1160 (2) 4730 (9) 3614 (3) 66 (2 ) C (19) 923 (2) 7838 (10) 4344 (2) 62 (2) C (20) 575 (2) 8704 (9) 4248 (2) 61 (2) C (21) 269 (2) 9248 (10) 3739 (3) 69 (2) C (22) -38 (2) 10196 (11) 3670 (3) 89 (2) C (23) -38 (3) 10616 (17) 4102 (5) 138 (4) C (24) 271 (4) 10150 (20) 4619 (4) 186 (6) C (25) 580 (3) 9187 (16) 4693 (3) 12 (3) C (100) 2600 (1 ) 3753 (7) 4292 (2) 45 (1) N (101) 2642 (1) 4084 (6) 3838 (2) 45 (1) C (101) 2226 (2) 4698 (9) 4112 (2) 57 (2) 0 (101) 1928 (1) 4131 (8) 3578 (2) 66 (1) C (102) 2612 (2) 1344 ( 9) 4382 (2) 60 (2) O (102) 2286 (1) 338 (6) 3960 (2) 70 (1) C (103) 2924 (2) 4818 (10) 4795 (3) 75 (2) 0 (103) 3003 (3) 6699 (15) 4729 (4) 79 (2) O (1A3) 3240 (4) 3680 (20) 5004 (5) 69 (4) O (1B3) 2913 (8) 5010 ( 40) 5196 (12) 93 (7) O (IW) 0 -1790 (80) 2500 151 (17) 0 (201) 49 (9 > 5520 (50) 705 (14) 129 (10) C (201) -372 (1 6) 4640 (90) -100 (20) 150 (20) C (202) -23 (1 6) 5270 (70) 270 (20) 111 (14) C (203) 229 (1 7) 5170 (90) 220 (30) 140 (20) The present invention is further described in the following examples. All the examples are current examples. These examples are not constructed as limiting the scope of the appended claims.

EXAMPLES Example 1.1 Form 01 -H2-1 of Compound (I) 25 mg of the free acid was dissolved in 1 ml of MeOH. 3 open end capillaries were placed in the vial to help stimulate nucleation and crystallization. Slow evaporation at room temperature provides box-like plates and crystalline solids of much smaller particle size in the capillaries.

Example 1.2 Form 02-SA-1 of Compound (I) 1. 100 mg of Compound (I) free acid (0.171 mmol) was mixed with -0.4 ml of 1N NaOH (0.4 mmol), the final pH was 6.5. 2. IPA (3.5 ml) was added in clear aqueous solution @ 30-35 ° C and cooled slowly to room temperature in ~ lh. 3. The solid crystallized slowly from the solution. . Allow the suspension to stir at room temperature for 2 h and the solid collected by filtration. 5. The filter cake was rinsed with IPS (2x 2.5 ml). 6. The resulting solid was dried @ 55 ° C under vacuum housing to provide 72 mg of the white solid. 7. Under a microscope, it was a semi-crystalline solid. 8. The solid was dissolved with 1.5 ml of EtOH @ 50-55 ° C and cooled slowly to room temperature in ~ 1H. 9. The clear solution was maintained at room temperature for 7 days and the hair-type crystals were observed under a microscope.

Example 1.3 Form 03-E. 5-1 of Compound (I) 50 mg of the mono-TRIS salt was dissolved in 0.2 ml of water at room temperature, then 1.0 ml of EtOH was added and a transfer solution was obtained. 2 capillaries of open ends were placed in the vial to help stimulate nucleation and crystallization and the vial was covered with aluminum foil. 2 weeks later the thin plate type crystals formed in the capillaries.

Example 1.4 Form 03-SA-2 of Compound (I) 50 mg of the mono-TRIS salt was first dissolved in 0.2 ml of water at room temperature, then 1.0 ml of acetone was added. A white precipitation occurs after adding 0.6 ml of additional acetone. The vial was heated to 80 ° C until a clear solution was obtained. The solution was removed from the heat and cooled naturally to room temperature. Thin long needles were observed within 2 hours.

EXAMPLE 1.5 Form 03-DSA-2 of Compound (I) Preparation of the di-tri s of Compound (I) -di-tris 1. Compound compound (I) acid-free 0.50 g, in 2 ml of H20 , pH 1.02. 2. 3M aqueous solution of tris amine was added in the acid-free aqueous solution at pH up to 7.32. 3. The crude dark red solution was filtered through a pad of celite, 3 ml of H20 was used to rinse the celite pad. 4. Acetone (75 ml) was added slowly in the aqueous solution at room temperature for a period of 1 h, seeded at room temperature. 5. After stirring at room temperature for 3 h, the suspension was collected by filtration and rinsed with 150: 1 acetone-water (2x5 ml). 6. The solid was dried at high vacuum for 3 h and was housed in a vacuum. 55 ° for 24 h with nitrogen flow. 7. This provides 0.355 g of the product (51% base in SM, 60% based on SM purity). 8. CLAR showed AP > 99%, the mother liquor has 5-10% of the product.

Preparation of Compound (I) -monotris 9. 0.35 g of the di-tris salt in H20 (3 ml) was added 50 mg (1 eq.) TFA until pH was 3.3, the reaction it was seeded and heated to 37 ° C and heated slowly to 40 ° C for 2 h. Acetone (60 ml) was added to the solution and the solution was slowly cooled to room temperature in ~2h and the white solid slowly showed. 10. After stirring at room temperature for 3 h, the white suspension was collected by filtration under N2 and rinsed with acetone (2 x 10 ml). The solid was dried under vacuum to provide 0.241 g (80% of the recovered, 49% of the crude acid) of the product, the HPLC showed > 99% of the AP and the MRI showed 529: tris 1: 10-1.01.

Example 2. Measurement of the X-ray of crustal crystals (PXRD) The simple crystal X-ray diffraction method was used to characterize some of the samples obtained in Examples 1.1-1.5 using at least the procedure described below. The simulated PXRD is also grouped. The results are shown in FIGs. 1, 4, 6, 9 and 12. Table 9 lists the selected PXRD peaks that describe Form 01-H2-1, Form 02-SA-1, Form 03-E.5-1, Form 03- SA-2 and Form 03-DSA-2 of Compound (I).

Table 9. Positions (degrees in 2?) Of the selected PXRD peaks Cryptosis (WFD) A Bruker SMART 2K CCD diffractometer equipped with graphite Cu Ka monochrome radiation (? = 1.54056 Á) was used to collect the diffraction data at room temperature. A complete data set was collected using the Review mode? during interval 2? with a distance crystal to detector of 4.98 cm. An empirical absorption correction uses the SADABS routine associated with the diffractometer (Bruker AXS, 1998, SMART and SAINTPLUS, Control Detection Area and Integration Software, Broker AXS, Madison, Wisconsin, USA). The final unit cell parameters were determined using the complete data set. All the structures were solved by direct methods and refined by the techniques of minimum frames of complete matrix, using the software package SHELXTL (Sheldrick, GM, 1997, SHELXTL, Structura Determination Programs, Version 5.10, Broker AXS, Madison, Wisconsin, USES) . The function minimized in the refinements was? W (I F0 | - | Fc |) 2. R is defined as? L I F0 | -IFJI? IFOI while Rw = [? W (I FQI -I Fc |) 2 /? W | F0 | 2] 1/2, where w is an appropriate weight function based on errors in the intensities observed. Different Fourier maps were examined in all stages of refinement. All non-hydrogen atoms were retined with anisotropic thermal shift parameters. The hydrogen atoms associated with hydrogen bonds were located on the different final Fourier maps while the positions of the other hydrogen atoms were calculated from an idealized geometry with standard link lengths and angles. These were assigned to factors of isotropic temperature and are included in the calculations of the structure factor with fixed parameters.

Simulated PXRD patterns All the stimulated PXRD patterns were calculated from the refined atomic coordinates of the crystal structures at room temperature, using the JPOW software (Materials, Data Inc. 2001. JPOWD, Powder Difraction Simulation and Structure Display. Inc., Livermore, California, USA).

Example 3. Differential Scanning Calorimetry (DSC) The DSC was used to characterize some of the samples obtained in Examples 1.1-1.5 using at least the procedure described below. The simulated PXRD is also grouped. The results are shown in FIGs. 2, 7, 10 and 13.

DSC (Open Tile) Differential Scanning Calorimetry (DSC) experiments were performed on a TA Instruments ™ model Q1000 or 2920. The sample (about 2-6 mg) was weighed on an open aluminum saucer or sealed saucer with pin hole and register exactly up to one hundredth of a milligram, and transferred to the DSC. The instrument was purged with gas from nitrogen at 50 ml / min. The data were collected between room temperature and 300 ° C at 10 ° C / min in the Heat Index.

The grouping is done with the endothermic peaks pointing downwards.

Example 4. Thermogravametric Analysis (TGA) The TGA was used to characterize some of the samples obtained in Examples 1.1-1.5 using at least the procedure described below. The simulated PXRD is also grouped. The results are shown in FIGs. 2, 7, 10 and 13.

TGA (open planar) The thermal gravimetric analysis (TGA) experiments were performed on a TA Instruments ™ model Q500 or 2950. The sample (about 10-30 mg) was placed in a previously tared platinum pan. The weight of the sample was accurately measured and recorded to one thousandth of a milligram by the instrument. The furnace was purged with hydrogen gas at 100 ml / min. The data were collected between room temperature and 300 ° C at 10 ° C / minute in the heating index. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (20)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A crystalline form of Compound (I), its salts or solvates. 2. The crystalline form according to claim 1, characterized in that it comprises Form 01-H2-1. 3. The crystalline form according to claim 2, characterized in that the cell unit parameters are substantially the same as the following: Monoclinic spacer group, P2 (l) / c
2. Dimensions of cell unit a = 17.2174 (18) A a = 90 ° b = 18.1242 (19) A ß = 105.191 (4) ° c = 9.3705 (9) A Y = 90 ° Molecules / Cell Unit 4 wherein the crystalline form is at a temperature of about 20 ° C to about 25 ° C. 4. The crystalline form according to claim 2, characterized in that: atomic coordinates fractionated substantially as listed in Table 2. 5. The crystalline form according to claim 2, characterized in that the powder diffraction pattern of X-rays comprises four or more 2T values (CuKa? = l .5418 Á) selected from the group consisting of 5.3 ± 0.2, 7.2 + 0.2, 9.7 ± 0.2, 10.6 ± 0.2, 10.9 + 0.2, 11.7 + 0.2, 13.2 + 0.2, 13.8 ± 0.2, 14.5 ± 0.2, 15.710.2, 17.0 + 0.2, 17.7 + 0.2, 18.210.2, 19.610.2, and 20.310.2, at a temperature of around 20 ° C to around 25 ° C. 6. The crystalline form according to claim 5, further characterized in that the powder diffraction pattern of X-rays comprises five or more 2T values (CuKa? = 1.5418Á) selected from the group consisting of 5.3 + 0.2, 7.2 ± 0.2. , 9.7 ± 0.2, 10.6 ± 0.2, 10.9 ± 0.2, 11.7 ± 0.2, 13.2 ± 0.2, 13.810.2, 14.5 + 0.2, 15.710.2, 17.010.2, 17.710.2, 18.2 + 0.2, 19.6 + 0.2, and 20.310.2, at a temperature of about 20 ° C to about 25 ° C. The crystalline form according to claim 2, characterized in that the X-ray powder diffraction pattern (PXRD), at a temperature of about 20 ° C to about 25 ° C, is substantially in agreement with the one shown in FIG. 1. The crystalline form according to claim 2, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially in accordance with that shown in FIG. 2. The crystalline form according to claim 2, characterized in that the thermogravimetric analysis diagram (TGA) is substantially in agreement with that shown in FIG. 2. The crystalline form according to claim 2, characterized in that it is in a simple crystal form. 11. The crystalline form according to claim 1, characterized in that it comprises Form 02- SA-1. 12. The crystalline form according to claim 11, characterized in that the cell unit parameters are substantially the same as the following: Cell dimensions: a = 6.4392 (12) Á a = 99.082 (11) ° b = 13.349 (2) Á ß = 95.975 (12) ° c = 21.041 (4) AY = 90.207 (12) °
3. Spacer group: Triclinic, P-l
4. Molecules / cell unit 2 wherein the crystalline form is at a temperature of about 163K to about 183K. 13. The crystalline form according to claim 11, characterized in that: the atomic coordinates are substantially as listed in Table 4. 14. The crystalline form according to claim 11, characterized in that the diffraction pattern of light powder X comprises four or more 2T values (CuKa? = L .5418 Á) selected from the group consisting of 4,310.2, 6.7 + 0.2, 7.4 + 0.2, 8.5 + 0.2, 10.010.2, 11.8 + 0.2, 12.910.2, 13.510.2, 14.1 + 0.2, 14.8 + 0.2, 15.5 + 0.2, 16.010.2, 16.510.2, 17.1 + 0.2, 18.5 + 0.2, at a temperature of about 163K to about 183K. 15. The crystalline form according to claim 14, further characterized in that the powder diffraction pattern of X-rays comprises five or more 2T values (CuKa? = 1.5418 Á) selected from the group consisting of 4.3 + 0.2, 6.710 .2, 7.410.2, 8.510.2, 10.0 + 0.2, 11.8 + 0.2, 12.9 + 0.2, 13.510.2, 14.110.2, 14.8 + 0.2, 15.5 + 0.2, 16.010.2, 16.5 + 0.2, 17.1 + 0.2 , 18.5 + 0.2, at a temperature of around 163K to around 183K. 16. The crystalline form according to claim 11, characterized in that the pattern of
5. X-ray diffraction (PXRD), at a temperature of about 20 ° C to about 25 ° C, is substantially in accordance with that shown in FIG. 4. 17. The crystalline form according to claim 11, characterized in that it is in a simple crystal form. 18. The crystalline form according to claim 1, characterized in that it comprises Form 03-E.5-1. 19. The crystalline form according to claim 18, characterized in that the cell unit parameters are substantially the same as the following: Cell dimensions: a = 35.594 (2) Á = 90 ° b = 6.2790 (4) Á ß = 97.080 ( 3) ° c = 30.6961 (19) Á Y = 90 ° Monoclinic spacer group, C2 / c Molecules / cell unit 8 where the crystalline form is at a temperature of about 20 ° C to about 25 ° C. 20. The crystalline form according to claim 18, characterized in that: the atomic coordinates are substantially as listed in Table 6. 21. The crystalline form according to claim 18, characterized in that the powder diffraction pattern of X-rays comprises four or more values 2T (CuKa? = 1.5418 Á) selected from the group consisting of 5.0 + 0.2, 5.8 + 0.2, 7.210.2, 8.1 + 0.2, 10.010.2, 11.0 + 0.2, 11.6 + 0.2, 12.010.2, 13.2 + 0.2, 16.110.2, 17.0 + 0.2, 17.5 + 0.2, 19.0 + 0.2, 20.410.2, 21.110. 2, at a temperature of about 20 ° C to about 25 ° C. 22. The crystalline form according to claim 21, further characterized in that the powder diffraction pattern of X-rays comprises five or more 2T values (CuKa? = 1.5418 A) selected from the group consisting of 5.0 + 0.2, 5.8 +0.2, 7.2 + 0.2, 8.1 + 0.2, 10.0 + 0.2, 11.0 + 0.2, 11.6 + 0.2, 12.0 + 0.2, 13.210.2, 16.1 + 0.2, 17.0 + 0.2, 17.5 + 0.2, 19.0 + 0.2, 20.4 ± 0.2 , 21.1 + 0.2, at a temperature of around 20 ° C to around 25 ° C. 23. The crystalline form according to claim 18, characterized in that the X-ray powder diffraction pattern (PXRD) is at a temperature of about 20 ° C to about 25 ° C, substantially according to which it is shown in FIG.
6. 6. The crystalline form according to claim 18, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially in accordance with that shown in FIG.
7. 7. 25. The crystalline form according to claim 18, characterized in that the thermogravimetric analysis diagram (TGA) is substantially in agreement with that shown in FIG. 7. The crystalline form according to claim 18, characterized in that it is in a simple crystal form. 27. The crystalline form according to claim 1, characterized in that it comprises Form 03-SA-2. 2
8. 8. The crystalline form according to claim 27, characterized in that the cell unit parameters are substantially the same as the following: Cell dimensions: a = 43.985 (2) Á a = 90 ° b = 6.3142 (3) A ß = 125,742 (4) ° c = 30.2438 (17) Á? = 90 ° Monoclinic spacer group, C2 / c Molecules / cell unit 8 wherein the crystalline form is at a temperature of about 20 ° C to about 25 ° C. 2
9. 9. The crystalline form in accordance with claim 27, characterized in that: the atomic coordinates are substantially as listed in Table 8. 30. The crystalline form according to claim 27, characterized in that the powder diffraction pattern of X-rays comprises four or more values 2T (CuK). ? = 1.5418 Á) selected from the group consisting of 5.0
10. 10.2, 7.2 + 0.2, 8.210.2, 9.910.2, 10.9 + 0.2,
11. 11.810.2, 14.9 + 0.2, 15.4 + 0.2, 15.9 + 0.2, 16.7 + 0.2 , 17.3 + 0.2, 17.7 + 0.2, 20.1 + 0.2, 20.6 + 0.2, 21.9 + 0.2, at a temperature of around 20 ° C to around 25 ° C. 31. The crystalline form according to claim 30, further characterized in that the powder diffraction pattern of X-rays comprises five or more 2T values (CuKa? = 1.5418 A) selected from the group consisting of 5.010.2, 7.2 + 0.2, 8.210.2, 9.9 + 0.2, 10.9 + 0.2, 11.8 + 0.2, 14.910.2, 15.410.2, 15.9 + 0.2, 16.7 + 0.2, 17.310.2, 17.7 + 0.2, 20.1 + 0.2, 20.6 +0.2, 21.9 + 0.2, at a temperature of around 20 ° C to around 25 ° C. 32. The crystalline form according to claim 27, characterized in that the diffraction pattern of X-ray powder (PXRD), at a temperature of about 20 ° C to about 25 ° C, is substantially in accordance with that it is shown in FIG. 9. 33. to crystalline form in accordance with claim 27, characterized in that the differential scanning calorimetry (DSC) thermogram substantially in accordance with that shown in FIG. 10. The crystalline form according to claim 27, characterized in that the thermogravimetric analysis diagram (TGA) is substantially in agreement with that shown in FIG. 10. The crystalline form according to claim 27, characterized in that it is in a simple crystal form. 36. The crystalline form according to claim 1, characterized in that it comprises Form 03-DSA-2. 37. The crystalline form according to claim 36, characterized in that the diffraction pattern of X-ray powder (PXRD), at a temperature of about 20 ° C to about 25 ° C, is substantially in accordance with that it is shown in FIG.
12. 12. The crystalline form according to claim 36, characterized in that the differential scanning calorimetry (DSC) thermogram is substantially in accordance with that shown in FIG.
13. 13. 39. The crystalline form in accordance with claim 36, characterized in that the thermogravimetric analysis diagram (TGA) is substantially in accordance with that shown in FIG. 13 / 40. The crystalline form according to claim 36, characterized in that the powder diffraction pattern of X-rays comprises four or more values 2T (CuKa? = 1.5418 A) selected from the group consisting of 5.010.2, 7.310. 2. 8.3 + 0.2, 10.1 + 0.2, 11.0 + 0.2,
14. 14.4 + 0.2,
15. 15.010.2, 15.5 + 0.2,
16. 16.0 + 0.2,
17. 17.4 + 0.2,
18. 18.4 + 0.2, 18.9 + 0.2,
19. 19.410.2,
20. 20.2 + 0.2, 20.6+ 0.2, at a temperature of around 20 ° C to around 25 ° C. 41. The crystalline form according to claim 40, further characterized in that the powder diffraction pattern of X-rays comprises five or more 2T values (CuKa? = 1.5418 Á) selected from the group consisting of 5.0 + 0.2, 7.3 +0.2, 8.3 + 0.2, 10.1 + 0.2, 11.010.2, 14.4 + 0.2, 15.0 + 0.2, 15.5 + 0.2, 16.0 + 0.2, 17.4 + 0.2, 18.4 + 0.2, 18.9 + 0.2, 19.4 + 0.2, 20.2 + 0.2 , 20.6 + 0.2, at a temperature of around 20 ° C to around 25 ° C. 42. Use of the crystalline form according to claim 1 for the manufacture of a medicament for treating AIDS or HIV in a mammal. 43. Use according to claim 42, wherein the mammal is a human. 44. a composition, characterized in that it comprises at least 5% by weight of the crystalline form according to claim 1, based on the weight of the composition. 45. The crystalline form according to claim 1, characterized in that the Compound (I), its salts or solvates are substantially pure. 46. The crystalline form according to claim 45, characterized in that the substantially pure weight of Compound (I), its salts or solvates is at least 90% of the total weight.