Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the invention pertains to novel crystalline forms of the drug tadalafii, as well as methods for their preparation and use. One or more of these forms can be used as a solid dosage form in pharmaceutical compositions in a variety of drug delivery systems.
• Tadalafii is known as (6R-trans)-6-(l,3-benz ⁇ dioxo!-5-y!- 2,3,6,7,12,12a-hexabydro-2- methyi- ⁇ yrazino[l',2':l,6] ⁇ yrido[3/]-b]indoie-l/]-dione, has the formula C 22 H 19 N 3 O 4 representing a molecular weight of 389.41 g/mol and is depicted by the following chemical structure:
• Tadalafii was originally developed by ICOS in 1994 and marketed via collaboration with EiI Lilly that subsequently took over ICOS in 2007.
• Tadalafii is a white solid particulate material that is practically insoluble in water. It is sparingly soluble in tetrahydrofuran and chloroform but is soluble in dioxane.
• Tadalafii has an apparent partition coefficient (log P) app - 1.7 in n- octanol/buffer pH 7.4.
• Tadalafii currently used for the treatment of erectile dysfunction ⁇ ED ⁇ under the Cialis * brand name, is a cGMP (cyclic gaunosine monophosphate ⁇ specific phosphodiesterase 5 (PDE5) inhibitor which enhances the effect of nitric oxide at the nerve ending and endothelial cells in the corpus cavernosum by inhibiting phosphodiesterase type 5 in the corpus cavernosum of the penis. This results in vasodilation, increased inflow of blood into the corporus cavernosum, and ensuing penile erection upon sexual stimulation. Tadaiafil is also being investigated currently as a treatment for pulmonary hypertension.
• PDE5 cyclic gaunosine monophosphate ⁇ specific phosphodiesterase 5
• tadaiafil is manufactured as a tablet for daily use (2.5 and 5 rng) with doses ranging from 5-20 mg as needed. See Cialis ® Prescribing Information, February 2010. Tadaiafil, the method of preparing tadaiafil, its therapeutic uses, and pharmaceutical compositions containing it are described in U.S. Patents 5,859,006; 6,140,329; 6,821,975; 6,943,166; and 7,182,958 which are incorporated herein by reference in their entirety.
• they may be amorphous, may have different crystaiiine forms (polymorphs), and/or may exist in different solvated or hydrat ⁇ d states with no change in the chemical composition of the original API.
• the discovery of new crystalline forms of a pharmaceutically useful compound may provide an opportunity to improve the physico-chemical characteristics and subsequently the clinical performance of such a compound. Additionally it expands the array of resources available for designing, for example, a pharmaceutical dosage form of an API with a targeted/sustained release profile or improved shelf life due to higher physical stability, improved particle size or size distribution, or powder flowabiiity and handling for easier downstream processing or even for changing its route of delivery.
• polymorphs can have different aqueous solubilities from one another, where typically the more thermodynamically stable the polymorph the less soluble it becomes.
• polymorphs of an API can also differ in physico-chemical properties such as solid phase stability, higher shelf-life, bioavailability, particle morphology, vapor pressure, density, color, melting point and compressibility.
• it is sometimes difficult to produce the desired polymorph consistently or there is little improvement in their aqueous solubility or characterizing of all polymorphic forms can be challenging.
• if only one polymorph is discovered then there is less opportunity to manipulate and improve physico-chemical properties of the API.
• the invention is directed towards generating novel compositions and crystalline forms of tadalafii that could improve aqueous solubility, rate of dissolution and/or shorten Tmax.
• One aspect of the present invention includes novel crystalline molecular complexes of tadalafil, such as cocrystais, and mixtures containing such materials, in addition, the invention further includes methods for the preparation of such complexes and compositions of crystalline molecular complexes of tadaiafil suitable as an APi (active pharmaceutical ingredient) in a pharmaceutical dosage form.
• Specific molecular complexes pertaining to the disclosure include, but are not limited to, complexes of tadaiafii with oxalic acid, 4-hydroxybenzoic acid, malonic acid, 3- phenylpropanoic acid, methyiparaben and propylparaben.
• FiG. 1 shows a PXRD diffractogram of a crystalline tadalafii and oxalic acid molecular complex (1:1).
• FiG. 2 shows an FTiR spectrum of a crystalline tadalafil and oxalic acid molecular complex (1:1).
• FiG. 3 shows a PXRD diffractogram of a crystalline tadalafii and 4-hydroxyb ⁇ nzoic acid molecular complex (1:2).
• FiG. 4 shows an FTiR spectrum of a crystalline tadalafil and 4-hydroxybenzoic acid molecular complex (1:2).
• FIG. 5 shows a PXRD diffractogram of a crystalline tadaiafii and 3-phenylpropanoic acid molecular complex (1:1).
• FIG. 6 shows an FTiR spectrum of a crystalline tadaiafil and 3- ⁇ henyipropanoic acid molecular complex (1:1).
• FIG, 7 shows a PXRD diffractogram of a crystalline tadalafi! and malonic acid molecular complex (1:1).
• FIG. 8 shows an FTIR spectrum of a crystalline tadaiafil and malonic acid molecular complex (1:1).
• FIG. 9 shows a PXRD diffractogram of a crystalline tadalafii and methylparaben molecular complex (1:1).
• FIG. 10 shows an FTIR spectrum of a crystalline tadaiafil and methylparaben molecular complex (1:1).
• FIG. 11 shows a PXRD diffractogram of a crystalline tadalafii and propylparaben molecular complex (1:1).
• FIG. 12 shows an FTIR spectrum of a crystalline tadaiafil and propylparaben molecular complex (1:1).
• the invention provides new crystalline molecular complexes, such as cocrystais, of tadalafii to improve its physico-chemical characteristics and possible clinical profiles.
• a new crystalline form is particularly advantageous if it can improve the aqueous solubility of tadaiafil.
• the crystal properties conferred upon the new crystal forms are also useful when the bioavailability is improved and its plasma concentration and/or serum concentration is improved which is particularly advantageous for orally delivered formulations.
• novel tadalafii crystalline forms have been synthesized, characterized, and disclosed herein.
• the novel tadaiafil crystalline forms may be formulated in pharmaceutical dosage forms as known in the art for tadaiafil and administered for the same therapeutic uses.
• the techniques and approaches set forth herein can further be used by the person of ordinary skill in the art to prepare obvious variants thereof, said variants considered to be part of the inventive disclosure.
• the invention relates to crystalline molecular complexes of tadalafii with a co-former.
• the co-former may be a short-chain short to medium chain organic acid , such as oxalic acid or maionic acid; a hydroxy-benzoic acid or a hydroxybenzoic acid ester, such as 4-hydroxybenzoic acid, salicylic acid, methylparaben, a propylparaben (e.g. n- propylpraben, isopropylparaben); or a phenyl alkanoic acid, such as 3-phenyipropanoic acid.
• Other possible co-formers are described in U.S.
• the molar ratio of the co-former in the molecular complex may range from 1:3 to 3:1 or preferably 1:2 to 2:1.
• the crystalline molecular complexes may be prepared using known techniques such as dry or solvent grinding, heating, slurrying or solvent evaporation of their solution in single or mixed solvent systems. [029] In one aspect, the invention relates to a 1:1 crystalline molecular complex of tadalafil with methyiparaben. As shown in the examples below a 1:1 crystalline molecular complex of tadalafil and methyiparaben may be prepared by dry grinding or in a solvent slurry.
• this crystalline molecular complex of the invention may also be prepared by other techniques known in the art such as, but not limited to, solvent grinding, heating, or solvent evaporation of their solution in single or mixed solvent systems.
• Another aspect of the invention relates to a 1:1 crystalline molecular complex of tadalafil with propylparaben.
• a 1:1 crystalline molecular complex of tadaiafii and propylparaben may be prepared by dry grinding or in a solvent slurry.
• tadalafil and m ⁇ lhylparaben have been shown to cocrystallize.
• this crystalline molecular complex of the invention may also be prepared by other techniques known in the art such as, but not limited to, solvent grinding, heating, or solvent evaporation of their solution in single or mixed solvent systems.
• Another aspect of the invention relates to a 1:2 crystalline molecular complex of tadalafil with 4-hydroxyb ⁇ nzoic acid.
• a 1:2 crystalline molecular complex of tadalafil and 4-hydroxybenzoic acid may be prepared by dry grinding or in a solvent slurry.
• this crystalline molecular complex of the invention may also be prepared by other techniques known in the art such as, but not limited to, solvent grinding, heating, or solvent evaporation of their solution in single or mixed solvent systems.
• Another aspect of the invention relates to a 1:1 crystalline molecular complex of tadalafil with malonic acid.
• a 1:1 crystalline molecular complex of tadalafil and malonic acid may be prepared by dry grinding or in a solvent slurry.
• this crystalline molecular complex of the invention may also be prepared by other techniques known in the art such as, but not limited to, solvent grinding, heating, or solvent evaporation of their solution in single or mixed solvent systems.
• Another aspect of the invention relates to a 1:1 crystalline molecular complex of tadalafil with oxalic acid.
• a 1:1 crystalline molecular complex of tadalafii and oxalic acid may be prepared by dry grinding.
• this crystalline molecular complex of the invention may also be prepared by other techniques known in the art such as, but not limited to, solvent grinding, heating, a solvent slurry, or solvent evaporation of their solution in single or mixed solvent systems.
• Another aspect of the invention relates to a 1:1 crystalline molecular complex of tadaiafil with 3- ⁇ henylpropanoic acid.
• a 1:1 crystalline molecular complex of tadalafii and 3-phenyipropanoic acid may be prepared by dry grinding or in a solvent slurry.
• Another aspect of the invention provides a crystalline molecular complex of tadalafii and 3- ⁇ henyipropanoic acid by dissolving both compounds in acetonitrile and allowing the solvent mixtures to evaporate.
• this crystalline molecular complex of the invention may also be prepared by other techniques known in the art such as, but not limited to, solvent grinding, heating, or solvent evaporation of their solution in single or mixed solvent systems.
• Another aspect of the invention provides crystalline molecular complexes of tadalafii as discussed above and, as particular examples, crystalline molecular complexes with 4- hydroxybenzoic acid, malonic acid, oxalic acid, 3- ⁇ henyl ⁇ ro ⁇ anoic acid, methyiparab ⁇ n and propylparaben, suitable for pharmaceutical formulations than can be delivered via different routes to the human body.
• such pharmaceutical formulations may include one or more pharmaceutically acceptable carriers, including, without limitation, binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents and other conventional excipi ⁇ nts and additives.
• the crystalline tadalafii molecular complexes of the invention and pharmaceutical formulations containing them may be used in the same therapies known for tadalafii itself. Pharmaceutical formulations of tadalafii, its therapeutic uses, and methods of treatment are described U.S. Patents 5,859,006; 6,140,329; 6,821,975; 6,943,166; and 7,182,958 as mentioned above. Examples
• Tadaiafil as a starting material used in ail experiments in this disclosure was supplied by
• Example 1 Preparation of tadaiafil and oxalic acid complex (1:1)
• Example 2 Preparation of tadaiafil and 4-hydroxybenzoic acid complex (1:2)
• Example 3 Preparation of tadaiafil and 4-hydroxyb ⁇ nzoic acid complex (1:2) by slurry method
• Example 5 Preparation of tadaiafil and 3- ⁇ henyl ⁇ ro ⁇ anoic acid complex (1:1) by slurry method
• tadaiafil 50 mg was slurried with 288.75 mg of 3- phenylpropanoic acid and 1 mL of acetonitriie. The solids gathered after the slurry were dried and stored in a screw cap vial for subsequent analysis.
• Example 6 Preparation of tadaiafii and malonic acid complex (1:1) [049] 110 mg of tadaiafil was ground with 30 mg of malonic acid and 40 ⁇ L of acetonitrile was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis.
• Example 7 Preparation of tadaiafil and malonic acid complex (1:1) by slurry method [051] 200 mg of tadaiafii was slurried with 212 mg of malonic acid and 1 rnL of acetonitriie. The solids gathered after the slurry were dried and stored in a screw cap vial for subsequent analysis.
• Example 8 Preparation of tadaiafii and methyiparaben complex (1:1) [053] 100 mg of tadaiafii was ground with 39 mg of methyiparaben and 20 ⁇ L of acetonitriie was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis.
• Example 9 Preparation of tadaiafii and methyiparaben complex (1:1) by slurry- method
• Example 10 Preparation of tadaiafii and propylparaben complex (1:1) [057] 100 mg of tadaiafil was ground with 46 mg of propylparaben and 20 ⁇ L of ac ⁇ tonitr ⁇ e was added to the solid mixture. The solids gathered after grinding were stored in screw cap vials for subsequent analysis.
• Example 11 Preparation of tadaiafii and propylparaben complex (1:1) by slurry method
• Analytical techniques used to observe the crystalline forms include Fourier Transform FTIR Spectroscopy (FTIR) and powder X-ray diffraction (PXRD).
• FTIR Fourier Transform FTIR Spectroscopy
• PXRD powder X-ray diffraction
• Example 12 Characterization of tadaiafil and oxalic acid complex (1:1)
• Table 1 below lists representative peaks from the PXRD pattern of FIG. 1. The representative peaks in Table 1 or a subset of those peaks, as well as the peaks shown in
• FiG. 1 or a subset of those peaks, can be used to characterize the fadaiafii and oxalic acid crystalline molecular complex (1:1) of the invention.
• FIG. 2 shows Sin FT IR spectrum of a tadaiafii and oxalic acid complex (I-I).
• Table 2 below I isls representative peaks from the FTIR spectrum of FiG. 2.
• the representative peaks in " f able 2 or a subset of those peaks, as well as the peaks shown in FiG. 2 or a subset of those peaks, can be used to characterize the ladaiafil and oxahc acid crystalline molecular complex (1:1) of the invention.
• FIG. 3 or a subset of those peaks can be used to characterize the tadaiafii and 4- hydroxybenzoic acid crystalline molecular complex (1:2) of the invention.
• FiG. 4 shows an FTIR spectrum of a tadaiafil and 4-hydroxybenzo ⁇ c acid complex (1:2).
• Table 2 below lists representative peaks from the FT iR spectrum of FIG. 4. T he representative peaks in Table 2 or a subset of those peaks, as well as the peaks shown in
• FiG. 4 or a subset of those peaks can be used to characterize the tadaiafii and 4- hydroxybenzoic acid crystalline molecular complex (1:2) of the invention.
• Example 14 Characterization of tadaiafii and 3-phenyipropano ⁇ c acid complex (1:1) [070]
• the PXRD diffractogram of a tadalafil and 3-phenyipropanoic acid complex ( 3 :1) is shown in FIG. 5.
• Table 1 below lists representative peaks from the PXRD pattern of FIG. 5.
• FIG. 6 shows an FTIR spectrum of a tadalafil and 3-phenylpropanoic acid complex (1:1).
• Table 2 below lists representative peaks from the FTIR spectrum of FIG. 6. The representative peaks in Table 2 or a subset of those peaks, as well as the peaks shown in
• FIG. 6 or a subset of those peaks can be used to characterize the tadalafil and 3- phenyipropanoic acid crystalline molecular complex (1:1) of the invention.
• Example 15 Characterization of tadalafil and malonic acid complex (1:1)
• Table 1 below lists representative peaks from the PXRD pattern of FIG. 7. The representative peaks in Table 1 or a subset of those peaks, as well as the peaks shown in
• FIG. 7 or a subset of those peaks can be used to characterize the tadalafil and malonic acid crystalline molecular complex (1:1) of the invention.
• FIG. 8 shows an FTIR spectrum of a tadalafil and malonic acid complex (1:1).
• Table 2 below lists representative peaks from the FTIR spectrum of FIG. 8. The representative peaks in Table 2 or a subset of those peaks, as well as the peaks shown in FIG. 8 or a subset of those peaks, can be used to characterize the tadalafii and malonic acid crystalline molecular complex (1:1) of the invention.
• Example 16 Characterization of tadalafil and methylparaben complex (1:1)
• Table 1 lists representative peaks from the PXRD pattern of FiG. 9. The representative peaks in Table 1 or a subset of those peaks, as well as the peaks shown in
• FiG. 9 or a subset of those peaks, can be used to characterize the tadalafil and methylparaben crystalline molecular complex (1:1) of the invention.
• FIG. 10 shows an FTiR spectrum of a tadalafil and methylparaben complex (1:1).
• Table 2 below lists representative peaks from the FTIR spectrum of FiG. 10. The representative peaks in Table 2 or a subset of those peaks, as well as the peaks shown in FIG. 10 or a subset of those peaks, can be used to characterize the tadalafii and methylparaben crystalline molecular complex (1:1) of the invention.
• Example 17 Characterization of tadaiafii and propylparaben complex (1: 3 ⁇
• Table 1 below lists representative peaks from the PXRD pattern of FIG. 11. The representative peaks in Table 1 or a subset of those peaks, as well as the peaks shown in
• FIG. 11 or a subset of those peaks can be used to characterize the tadalafil and propylparaben crystalline molecular complex (1:1) of the invention.
• FIG. 12 shows an FTIR spectrum of a tadalafil and propylparaben complex (1:1).
• Table 2 below lists representative peaks from the FTiR spectrum of FIG. 12. The representative peaks in Table 2 or a subset of those peaks, as well as the peaks shown in FiG. 12 or a subset of those peaks, can be used to characterize the tadalafil and propylparaben crystalline molecular complex (1:1) of the invention.

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• 2010
  • 2010-02-25 JP JP2011552157A patent/JP6074142B2/ja not_active Expired - Fee Related
  • 2010-02-25 US US13/203,297 patent/US8586587B2/en not_active Expired - Fee Related
  • 2010-02-25 EP EP10746835A patent/EP2400848A4/en not_active Withdrawn
  • 2010-02-25 WO PCT/US2010/025421 patent/WO2010099323A1/en not_active Ceased
• 2013
  • 2013-10-07 US US14/047,463 patent/US9040535B2/en not_active Expired - Fee Related
• 2015
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