(12) United States Patent (10) Patent No.: US 9.278,970 B2 Herrera Ruiz Et Al

US00927897OB2

(12) United States Patent (10) Patent No.: US 9.278,970 B2 Herrera Ruiz et al. (45) Date of Patent: Mar. 8, 2016

(54) CO-CRYSTALS OF TADALAFIL ANDA USPC ...... 544/343 HYDROXY-SUBSTITUTED BENZOIC ACID See application file for complete search history. COFORMER AS PHOSPHODESTERASE TYPES INHIBITORS (56) References Cited (71) Applicant: Laboratorios Senosiain S.A. de C.V., FOREIGN PATENT DOCUMENTS Mexico City (MX) CA 2878.360 * 1, 2014 (72) Inventors: Dea Herrera Ruiz, Cuernavaca (MX): WO WO 2010O99323 A1 9, 2010 Karina Mondragón Vásquez, OTHER PUBLICATIONS Cuernavaca (MX); Hugo Morales Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205.* Rojas, Cuernavaca (MX); Herbert Vippagunta, et al. Advanced Drug Delivery Reviews, 48, 2001, 18.* Höpfl. Cuernavaca (MX); Juan Pablo Chawla, et al. Current Research & Information on Pharmaceutical Senosiain Peláez, Mexico City (MX) Sciences (CRIPS), 5(1), 2004, 9-12.* D.R. Weyna et al., “Crystal Engineering of Multiple-Component Organic Solids: Pharmaceutical Cocrystals of Tadalfil with Persistent (73) Assignee: Laboratorios Senosiain S.A. de C.V., Hydrogen Bonding Motifs.” Cryst Eng Comm. Apr. 2012, pp. 2377 Mexico City (MX) 2380, vol. 14. International Search Report of Dec. 12, 2013, in English, for corre (*) Notice: Subject to any disclaimer, the term of this sponding International Application No. PCT/IB2013/055530. patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. * cited by examiner (21) Appl. No.: 14/412,272 Primary Examiner — Douglas MWillis (74) Attorney, Agent, or Firm — Stephen S. Hodgson (22) PCT Filed: Jul. 6, 2013 (57) ABSTRACT (86). PCT No.: PCT/B2013/0555.30 The present invention relates to co-crystals of tadalafil with hydroxyl-substituted benzoic acid coformers having the fol S371 (c)(1), lowing structure. (2) Date: Dec. 31, 2014

(87) PCT Pub. No.: WO2014/006604 OH HO OH PCT Pub. Date: Jan. 9, 2014 O O (65) Prior Publication Data HO HO US 2015/O1521 O7 A1 Jun. 4, 2015 OH HO (30) Foreign Application Priority Data O O OH Jul. 6, 2012 (MX) ...... MXF af2O12/OO7915 HO HO (51) Int. Cl. OH OH CO7D 24I/38 (2006.01) CO7D 47L/4 (2006.01) Said co-crystals can be used to produce a pharmaceutical (52) U.S. Cl. composition containing the same as the useful active ingre CPC ...... C07D 471/14 (2013.01) dient. Said co-crystals can exhibit a constant storage stability. (58) Field of Classification Search CPC ...... CO7D 241A38 9 Claims, 10 Drawing Sheets U.S. Patent Mar. 8, 2016 Sheet 1 of 10 US 9.278,970 B2

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Figure 20 US 9,278,970 B2 1. 2 CO-CRYSTALS OF TADALAFL ANDA The tadalafil molecule, as well as other phosphodiesterase HYDROXY-SUBSTITUTED BENZOIC ACID type 5 inhibitors, is structurally comprised by heterocycles, COFORMER AS PHOSPHODESTERASE aromatic groups and carbonyl groups. Tadalafil has an indole TYPES INHIBITORS group, a pyrazine group and a benzodioxole attached to C as shown in Scheme I. FIELD OF THE INVENTION

The present invention refers to new solid forms of phos Scheme I. Tadalafi structure phodiesterase type 5 inhibitors, in particular to complex coc CH rystals, and to the Solvates, hydrates and polymorphs thereof, 10 and their use in the manufacture of a pharmaceutical compo O N sition useful in the treatment of erectile dysfunction.

BACKGROUND OF THE INVENTION N O 15 The present invention relates to new solid forms (NSF) of 6 phosphodiesterase type 5 inhibitors, particularly to complex crystals, which have a constant quality and which may have NH X improved physicochemical properties Such as the physical n 'o,OO and chemical stability and a modified dissolution rate. For the present invention, the new solid phases (NSP), are also called cocrystals and are obtained by means oftechnical In the commercial pharmaceutical preparations, tadalafil is experimentation. The cocrystals are chemical entities with in neutral form and consists of the D+ isomer (6R,12R), physicochemical properties differing from those of the salts which is almost insoluble in water. The absolute bioavailabil or polymorphs of the base active ingredient, including their 25 ity of tadalafil after its oral delivery has not been yet deter salts and/or their polymorphs, due to the nature of the inter mined. In therapeutic concentrations, 94% of the plasmatic molecular interactions between the active molecule and a tadalafil is bonded to proteins, it has a half life of 17.5 hours, second solid constituent called coformer. and is eliminated by the hepatic metabolism, predominantly A cocrystal is a crystal formed by two or more non-iden as metabolites, mainly in faeces (approximately 61% of the tical molecules, in which the starting components are solidat 30 dose) and to a lesser extent in urine (approximately 36% of room conditions when they are in their pure form, and the dose). Tadalafil inhibits phosphodiesterase type 5 (PDE5) wherein the two or more cocrystal components form aggre and enhances the erectile function by increasing the amount gates that are characterized by being linked by intermolecular of the cyclic guanosine monophosphate (cGMP). The coMP interactions—such as the Van der Waals forces, t-stacking, determines the relaxation of smooth muscle and increases the hydrogen bonding or electrostatic interactions—but without 35 blood flow in the corpora cavernosa. Its delivery is by oral forming covalent bonds. By using crystal engineering tech route in daily doses of 5, 10 or 20 mg. niques, a new compound with modified physicochemical Side effects oftadalafil are usually mild or moderate, tran properties differing from the polymorphs, salts, hydrates and/ sient, and improve without medical treatment. The most fre or the existing Solvates, can be obtained. The adjustable quent side effects are: headache, dyspepsia, backache, myal screening parameters are higher, thus in the case of pharma 40 gia, nasal stuffiness, flushing, dizziness and limb pain. ceutical ingredients, the physical and chemical properties of The drugs that inhibit CYP3A4 such as ketoconazole, the active ingredient with clinical relevance may be opti ritonavir, erythromycin and itriconazole increase the expo mized. sure to tadalafil, as tadalafil is the CYP3A4 substrate, and are The pharmaceutical cocrystals are cocrystals containing at mainly metabolized by this route. On the other hand, the least one therapeutic molecule and a pharmaceutically 45 drugs that induce CYP3A4 such as rifampicine, carbam acceptable coformer. In these crystals, their components— azepine, phenytoin and phenobarbital may decrease tadalafil the active ingredient and the coformer—coexist in a well exposure. Simultaneous delivery of an antacid such as alumi defined stoichiometric ratio. The cocrystals in solid form tend num hydroxide/magnesium hydroxide slows the tadalafil to be more stable than the existing solvates or hydrates. absorption rate. A Substantial alcohol consumption (more The present invention describes cocrystals which will be 50 than 5 units) in combination with tadalafil may increase the called “complex cocrystals”, obtained from a phosphodi risk of orthostatic signs and symptoms, including increased esterase type 5 inhibitor—tadalafil and a neutral coformer, heart rate, decreased blood pressure on standing, dizziness where both are solids at room temperature. The obtained and headaches. When tadalafil is administered jointly with cocrystals have a constant quality and may have improved alpha-blocking agents such as tamsulosine, doxazosine or physicochemical properties, such as a higher solubility and 55 other anti-hypertensive agents such as amlodipine, meto dissolution rate, enhanced flow properties and enhanced sta prolol, bendrofluazide, enalapril or angiotensin II blockers, bility. they may mutually enhance, in greater or lesser extent, its The phosphodiesterase type 5 inhibitors are a group of hypotensive effect. drugs used in the treatment of erectile dysfunction and for the Document US20090131667A1, describes the obtention treatment of pulmonary arterial hypertension. Structurally, 60 and the process for manufacturing an amorphous form of they consist of heterocycles with nitrogen atoms, aromatic tadalafil by assisted evaporation, with distillation of a tadala groups and carbonyl groups. The phosphodiesterease type 5 fil Solution in an organic solvent. It also describes the obten inhibitors used in the clinical practice are: tadalafil, sidenafil tion and the process for manufacturing the pure crystalline and Vardenafil. In the present invention, a method for obtain form B of tadalafil by precipitation of a tadalafil solution in a ing cocrystals and other Solid forms based on one of these 65 ketone solvent; and describes the preparation of a mixture of phosphodiesterase type 5 inhibitors, e.g., tadalafil, is devel tadalafil form A and form B by precipitation of a tadalafil oped. Solution in an ester solvent. US 9,278,970 B2 3 4 Document US2006/01 11571A1 (MX/a/2007/003719), SUMMARY OF THE INVENTION describes the obtention and the process for making crystalline forms (polymorphs) I, II, III, IV, V, VI, VII and VIII of tad The present invention in the preferred embodiment pro alafil by crystallization and/or precipitation in organic Sol vides several unpublished tadalafil compounds identified as vents; it describes the method of preparing the crystalline complex cocrystals, formed by tadalafil form I and a neutral tadalafil form I by crystallizing tadalafil Solutions in organic coformer. These new solid forms may have improved physi Solvents such as 2-methoxyethanol, ethanol, acetonitrile, cochemical and biopharmaceutical properties, which render 1-propanol, isopropanol, ethyl acetate, toluene, dimethyl Sul them advantageous for the preparation of pharmaceutical foxide, n-butanol, methanol, chloroform, tetrahydrofuran, compositions, such as enhanced bioavailability, enhanced acetone and/or methyl ethyl ketone, and by precipitation 10 solubility and hence fewer side effects. when combining these solutions with solvents such as petro In the preferred embodiment, the present invention com leum ether, cyclohexane, toluene, Xylene, benzene and prises a process for preparing new Solid forms of tadalafil. methyl-tert-butyl-ether, until obtaining a precipitate which which may have enhanced features such as higher solubility, was isolated. It describes the method for obtaining the crys dissolution rate, better drug processing properties and/or bet talline form I starting from crystalline forms II, III and IV 15 ter pharmacokinetic properties, which would allow for dose under certain humidity and temperature conditions; it reduction and consequently for the reduction of side effects. describes the method for obtaining the crystalline form II The present invention is specific for the obtention of NSF from the crystallization of a tadalafil solution in acetone or of phosphodiesterease type 5 inhibitors, such as tadalafil, by methyl ethyl ketone or by precipitation adding a solvent Such the Solid phase transformation method (slurry), by the crys as petroleum ether, cyclohexane or methyl tert-butyl ether, to tallization reaction method, and the chemical mechanical the methylethyl ketone solution; it describes the method for grinding method, with the use of minimum solvents and obtaining the crystalline form III oftadalafil, starting from the under environmental conditions that do not take it to the crystalline form II by heating at 65° C.; it describes the freezing point. This process of obtention lowers operation method for preparing the crystalline form IV, by crystallizing cost of the equipments for producing cocrystals, and has a a tadalafil solution in methylene chloride or by precipitation 25 minimal environmental impact as practically no organic Sol from this solution with the addition of petroleum ether; it vents, or Small quantities thereof, are used. describes the method for obtaining of the crystalline form V from an acetic acid solution; it describes the obtention of the RATIONALE OF THE INVENTION crystalline form VI using form IV by slurry in methanol and drying at 65° C.; it describes the obtention of tadalafil form 30 The rational use of drugs aims to obtain the greatest pos VII using forms II, IV and V by slurry in toluene and drying sible benefit for the people using them and to minimize eco at 65° C.; it describes the method for preparing the crystalline nomic costs, so it is important to have drugs which generate form VIII from the crystalline form IV in a range of 50-70° C. the same therapeutic effect with lower doses and conse The present invention, unlike the crystals cited in docu quently to reduce side effects, achieving a greater adherence ments US20090131667A1 and US200601 11571 A1, com 35 to the treatment. prises “complex’ cocrystals which are obtained from a phos Sildenafil. Vardenafil and tadalafil, which are selective phodiesterase type 5 inhibitor Such as tadalafil, using its cGMP inhibitors, specifically of phosphodiesterase type 5 polymorph I. The cocrystals of the present invention are (PDE5), have serious solubility problems in aqueous media, obtained with coformers such as 3-hydroxybenzoic acid, so there is a need for complex cocrystals which increase 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,5-di 40 solubility and consequently their activity, and which allow for hydroxybenzoic acid,3,4,5-trihydroxybenzoic acid, D-malic the reduction of the patient dose. acid and L-tartaric acid. These coformers have one or more There are some prior art documents which disclose the hydroxyl and carboxyl groups, forming an aggregate by obtention of tadalafil cocrystals, but the cocrystals and sol hydrogen bonding and Van der Waals interactions with tad vates disclosed herein are not described in the prior art. Dur alafilor other active ingredients that have structural similari 45 ing the cocrystals obtention process, one could envisage a ties, such as sildenafil and Vardenafil. great amount of combinations with the possible coformers. The application WO20120099323 describes the formation However, not every combination produces a cocrystal or a of tadalafil cocrystals with oxalic acid, salicylic acid, 4-hy stable solid form. droxybenzoic acid, malonic acid, 3-phenylpropanoic acid, Although there is good understanding of the physicochem methylparaben and propylparaben. Document Weyna et al., 50 istry of the cocrystal components, their elucidation a priori is "Crystal engineering of multiple-component organic Solids: almost impossible, as the interactions which determine the Pharmaceutical cocrystals oftadalafil with persistent hydro structure are relatively weak and the number of degrees of gen bonding motifs, CrystEngComm, 2012. 14, 2377 freedom for the optimization problem is immeasurable. For describes the synthesis of tadalafil cocrystals with methylpa these reasons, the new Solid forms disclosed herein are not raben, propylparaben, cinnamic acid and 4-hydroxybenzoic 55 obvious to a person skilled in the art. Further, the cocrystals acid. and Solvates of the present invention have shown physico Although it is true that documents WO20120099323 and chemical stability, allowing their use in pharmaceutical com the Weyna et al. article describe the existence of tadalafil positions. cocrystals, and even when during the process of obtaining cocrystals one may envisage a great amount of combinations 60 BRIEF DESCRIPTION OF THE DRAWINGS with the possible coformers, not all the combinations produce a cocrystal or a stable solid form, as shown in the specification FIGS. 1-20 illustrate the results of the characterization of of the present application. the tadalafil NSF obtained in the present invention. The present invention comprises new solid phases of tad FIG. 1. X-ray powder diffraction pattern of tadalafil coc alafil which may show enhanced physicochemical properties, 65 rystal with 3-hydroxybenzoic acid. Such as a enhanced solubility, dissolution rate, bioavailability, FIG. 2. FT-infrared spectrum of the tadalafil cocrystal with stability and/or flow properties. 3-hydroxybenzoic acid. US 9,278,970 B2 5 6 FIG. 3. X-ray powder diffraction pattern of tadalafil coc The synthesis strategies used for the obtention of the NSF rystal with 2,3-dihydroxybenzoic acid. of tadalafil were the crystallization reaction, the slurry FIG. 4. FT-infrared spectrum of the tadalafil cocrystal with method and the chemical mechanical grinding method. 2,3-dihydroxybenzoic acid. The present invention worked, among others, with the fol FIG. 5. Crystalline structure of the tadalafil cocrystal with 5 lowing coformers: aliphatic carboxylic acids, aromatic car 3-dihydroxybenzoic acid. boxylic acids, aromatic hydroxycarboxylic acids, aliphatic FIG. 6. X-ray powder diffraction pattern of the tadalafil hydroxycarboxylic acids, aromatic heterocyclic amides, cocrystal with 2,5-dihydroxybenzoic acid. amino acid derivatives, polyphenols, alcohols such as Xylitol FIG. 7. FT-infrared spectrum of the tadalafil cocrystal with and aromatic aminocarboxylic acids Such as 3-aminobenzoic 2,5-dihydroxybenzoic acid. 10 acid. A new solid form (NSF) which was stable with 3-hy FIG. 8. X-ray powder diffraction pattern of the tadalafil droxybenzoic acid was found in the different assays of the cocrystal with 3,4,5-trihydroxybenzoic acid. present invention. The obtained NSF corresponds to a com FIG. 9. FT-infrared spectrum of the tadalafil cocrystal with pound wherein the neutral coformer has a hydroxyl group and 3,4,5-trihydroxybenzoic acid. 15 a carboxylic acid, and further contains a phenyl group as part FIG. 10. X-ray powder diffraction pattern of the tadalafil of its structure. cocrystal with D-malic acid. In addition, and in order to delimit the structural diversity FIG. 11. FT-infrared spectrum of the tadalafil cocrystal of the coformers that generate cocrystals, other reactions with D-malic acid. were carried out, now with aliphatic and aromatic carboxylic FIG. 12. Crystalline structure of the tadalafil cocrystal with acids, such as Oxalic, Succinic, adipic, maleic, benzoic, D-malic acid. phthalic and acetylsalicylic acids. No NSF were obtained as a FIG. 13. X-ray powder diffraction pattern of the tadalafil result of working with aliphatic and aromatic dicarboxilic cocrystal with L-tartaric acid. acids. FIG. 14. FT-infrared spectrum of the tadalafil cocrystal Furthermore, reactions with aromatic monocarboxylic with L-tartaric acid. 25 acids with a hydroxyl group, such as 2-hydroxybenzoic acid, FIG. 15. X-ray powder diffraction pattern of the NSF 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, mandelic formed with tadalafil and 4-hydroxybenzoic acid. acid and 1-hydroxy-2-naphtoic acid were performed. In this FIG. 16. DSC-TGA calorimetric analysis of the NSF case, NSF were obtained with 3-hydroxybenzoic acid and formed with tadalafil and 4-hydroxybenzoic acid. 4-hydroxybenzoic acid. FIG. 17. FT-infrared spectrum of the NSF formed with 30 Other reactions were performed with aromatic monocar tadalafil and 4-hydroxybenzoic acid. boxylic acids, with two and three hydroxyl groups corre FIG. 18. 'H NMR spectrum of the NSF formed with tad sponding to Vanillic acid, 2,3-dihydroxybenzoic acid, 2,4- alafil and 3,4,5-trihydroxybenzoic acid. dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6- FIG. 19. "H NMR spectrum of the NSF formed with tad 35 dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3.5- alafil and L-tartaric acid. dihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid, FIG. 20. "H NMR spectrum of the NSF formed with tad also known as gallic acid. In this case, NSF were obtained alafil and 4-hydroxybenzoic acid. with 2,3-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid. However, no NSF were DESCRIPTION OF THE INVENTION 40 obtained with 3,4-dihydroxibenzoic acid and 3,5-dihydroxi benozic acid, which again shows that the formation of NSF is One of the challenges faced during the development of the unpredictable. present invention consists in obtaining a stable compound Also, reactions with aliphatic hydroxycarboxylic coform formed with a phosphodiesterase type 5 inhibitor such as ers such as glycolic, D-tartaric, L-tartaric, D.L-tartaric, meso tadalafil, with high purity, with physicochemical properties 45 tartaric, D-Malic, L-Malic, DL-Malic and citric acids were Suitable for preparing a pharmaceutical terms of stability, performed. In this case, NSF were obtained with D-malic acid solubility and/or dissolution rate. Due to the complexity of and L-tartaric acid. the interactions in a solid structure, the final structure and thus In other cases, in order to obtain NSF and to determine the properties of the new solid forms are impossible to predict whether the substitution of the alcohol group with an amine theoretically, therefore a large number of experiments had to 50 influenced the NSF obtention, the reaction of 3-aminoben be carried out in order to find the compounds described Zoic acid—in analogy to the 3-hydroxybenzoic acid was herein. assessed. In this case, no NSF was obtained. The complex cocrystals of the present invention, in the Similarly, and in order to determine the NSF formation preferred embodiment, are formed with tadalafil form I and a with molecules containing another type of hydrogen bonding neutral coformer, both being solids at room temperature. The 55 donors, aside from carboxylic and hydroxy groups, amino NSF obtained from the combination of these solids is com acids such as L-glutamine, L-phenylalanine, L-serine, prised by an aggregate in which the drug component and the L-threonine and L-tyrosine were tested. As a result, no NSF neutral coformer molecule interact through hydrogen bond were obtained with these coformers. ing and Van der Waals interactions. The new solid forms Reactions with benzamides such as picolinamide, nicoti herein obtained offer the possibility of generating solids of 60 namide and isonicotinamide and alcohols such as Xylitol were active ingredients with improved physicochemical proper also performed, which neither produced NSF. ties, such as enhanced solubility, stability or flowability. Based on the results obtained fortadalafil, the formation of The present invention started with a selective phosphodi cocrystals with sildenafil and Vardenafil is possible through esterase type 5 inhibitor, e.g., tadalafil. the formation of intermolecular hydrogen bonding and Van Tadalafil was reacted with several possible coformers test 65 der Waals interactions of the active ingredients with the neu ing different solvents such as tetrahydrofuran (THF), metha tral coformers, specifically those containing hydroxycar nol (MeOH), acetone or acetonitrile. boxylic groups. US 9,278,970 B2 7 8 Results of the Obtention of NSF by Different Methods tallization reaction method. The tadalafil NSF with 2,3-dihy In the preferred embodiment, equimolar mixtures of tad droxybenzoic acid was also obtained using THF as reaction alafil and the corresponding coformers were prepared, to medium. which a small amount of solvent was added to form a slurry, The NSF of tadalafil with 2,3-dihydroxybenzoic acid and under constant stirring for 8 hours. With this method, several 2,5-dihydroxybenzoic acid were analyzed using X-ray pow possible combinations between tadalafil, the coformers and der diffraction (XRD) and infrared spectrum (FT-IR). FIG.3 the solvents were made. The product of these reactions was shows X-ray powder diffraction pattern of the tadalafil coc characterized by X-ray powder diffraction assay. This test rystal with 2,3-hydroxybenzoic acid. FIG. 4 shows the infra showed the obtention of NSF either as cocrystals or as sol 10 red spectrum (FT-IR). FIG. 5 shows the asymmetric unit of vates thereof. From the results of these tests it is concluded the crystalline structure of the tadalafil cocrystal with 2,3- that the cocrystals formation is not simple, nor predictable. hydroxybenzoic acid, as obtained with monocrystal X-ray The slurry experiments with aliphatic and aromatic car diffraction. FIGS. 6 and 7 show the X-ray powder diffraction boxylic acids, such as Oxalic acid, Succinic acid, adipic acid, 15 (XRD) pattern and the infrared spectrum FT-IR of the tadala maleic acid, benzoic acid, phthalic acid and acetylsalicylic fil cocrystal with 2.5-hydroxybenzoic acid. acid in methanol or acetonitrile, evidenced through an X-ray 3,4,5-trihydroxybenzoic acid also produced a NSF (FIG. powder diffraction analysis that in all cases the solid obtained 8) in acetonitrile. The IR spectrum (FIG. 9) for this solid with the saturated solution crystallization method corre phase has a band at 2250 cm, which corresponds to the sponds exactly withtadalafil and/or the coformer, i.e., no NSF vibrational band of the cyano group, Suggesting the formation were obtained. Similar results were obtained with the amino of an acetonitrile solvate. The 1H Nuclear Magnetic Reso acids, alcohols such as Xylitol, amides and 3-aminocarboxy nance analysis (FIG. 18) shows that the solvated cocrystal lic acid. with 3,4,5-trihydroxybenzoic acid has a stoichiometry of Crystallization experiments carried out with aromatic 25 2:1:1 drug:coformer:solvent (acetonitrile). hydroxycarboxylic acids rendered different results. For In the crystallization by slurry, grinding and/or saturated example, the NSF synthesis with 3-hydroxybenzoic acid and Solutions of the coformer in acetonitrile using aliphatic 4-hydroxybenzoic acid does proceed with the slurry crystal hydroxycarboxylic acids, NSF with D-Malic acid and L-tar lization, grinding or crystallization reaction methods using 30 taric acid were obtained, but this was not the case with D-tar acetonitrile as solvent. The phase obtained with 3-hydroxy taric acid, DL-tartaric acid, meso-tartaric acid, L-Malic acid benzoic acid was also obtained from methanol. In contrast, and DL-Malic acid. For the latter, the diffraction pattern of the none of the three methodologies allowed obtaining NSF with obtained solid corresponds to that oftadalafil, demonstrating 2-hydroxybenzoic acid. These assays demonstrate that the the formation of an enantiomerically selective molecular crystallization reactions for the formation of cocrystals are 35 assembly. not predictable. The obtention of tadalafil NFS with D-Malic acid and These new phases obtained were mainly verified with L-tartaric acid was verified with X-ray powder diffraction X-ray powder diffraction (XRD) analysis (FIGS. 1 and 15) (XRD) (FIGS. 10 and 13) and infrared spectrum (FT-IR) and infrared spectrum (FT-IR) (FIGS. 2 and 17). Particularly, 40 (FIGS. 11 and 14). FIG. 12 shows the asymmetric unit of the for the phase obtained with 4-hydroxybenzoic acid, the IR crystalline structure of the tadalafil cocrystal with D-malic spectrum (FIG. 17) shows a band at 2250 cm which corre acid, obtained by monocrystal X-ray diffraction. sponds to the vibrational band of the cyano group, Suggesting The IR spectrum for the NFS with tartaric acid (FIG. 14) the formation of an acetonitrile solvate. To elucidate the sto 45 has aband at 2250 cm, which corresponds to the vibrational ichiometric ratio of the components of the obtained solvated band of the cyano group, Suggesting the formation of an cocrystal, a 1H Nuclear Magnetic Resonance analysis was acetonitrile solvate. To elucidate the stoichiometric ratio of performed (FIG. 20). This study shows that the solvated coc the components of the solvated cocrystal, a 1H Nuclear Mag rystal with 4-hydroxybenzoic acid has a stoichiometry of netic Resonance analysis was performed (FIG. 19). This 1:2:1 drug:coformer:solvent (acetonitrile). Finally, FIG. 16 50 study shows that the solvated cocrystal with L-tartaric acid shows the results of the differential scanning calorimetry has a stoichiometry of 2:1:1 drug:coformer:Solvent (acetoni analysis/thermogravimetric analysis (TGA/DSC) of the NSF trile). formed with tadalafil and 4-hydroxybenzoic acid. New Solid Phases (NSP) Obtained On the other hand, with dihydroxybenzoic acids using 55 In the preferred embodiment of the present invention, tad acetonitrile as the reaction medium, NSF were obtained with 2,3-hydroxybenzoic and 2,5-dihydroxybenzoic acids, but no alafil NSF were obtained as a result of the experimentation. new phases were obtained, for example, with 3,5-dihydroxy Some examples are listed below. benzoic acid, 3,4-dihydroxybenzoic acid and 2,4-dihydroxy Combination of tadalafil with a chemical compound of the benzoic acid. Again, it is demonstrated that the the formation 60 kind of aliphatic hydroxycarboxylic acids, such as D-malic of cocrystals is unpredictable. acid and L-tartaric acid. The NSF synthesis with 2,3-dihydroxybenzoic acid pro Combination of tadalafil with a chemical compound ceeds with the three aforementioned synthesis methodolo belonging to the aromatic hydroxycarboxylic acid deriva gies. However, the slurry and chemical mechanical reactions 65 tives, such as 3-hydroxybenzoic acid, 4-hydroxybenzoic appear to be inefficient with 5-dihydroxybenzoic acid, but the acid, 2,3-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid NSF was indeed obtained with this coformer using the crys and 3,4,5-dihydroxybenzoic acid. US 9,278,970 B2 9 10 What is claimed is: 2. The compound according to claim 1, wherein Y is 3.4. 1. A crystalline compound consisting of tadalafil of for 5-trihydroxybenzoic acid. mula T and a coformer Y: 3. The compound according to claim 2, wherein the com pound is an acetonitrile Solvate. 4. The compound according to claim 3, wherein the TY: acetonitrile molar ratio is 2:1:1. 5. The compound according to claim 1, wherein Y is 3-hy droxybenzoic acid. 10 6. The compound according to claim 1, wherein Y is 2,3- dihydroxybenzoic acid. 7. The compound according to claim 1, wherein Y is 2.5- dihydroxybenzoic acid. 15 8. A method for inhibiting phosphodiesterase type 5 activ ity in a patient, comprising administering to said patient an effective amount of the compound according to claim 1. 9. A method for treating erectile dysfunction and/or pull monary arterial hypertension in a patient, comprising admin or an acetonitrile solvate thereof, whereinY is selected from the group consisting of 3-hydroxy istering to said patient an effective amount of the compound benzoic acid, 2,3-dihydroxybenzoic acid, 2,5-dihydroxyben according to claim 1. Zic acid and 3,4,5-trihydroxybenzoic acid.