Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

The present invention relates to a solid state form, e.g., an amorphous form, N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide, its pharmaceutical compositions and related methods.

BACKGROUND OF THE INVENTION [0002] CFTR is an anionic cAMP / ATP-dependent channel that is expressed in a variety of cell types, including absorption and secretory epithelial cells, where it regulates the anion flux through membranes as well as the activity of other ion channels and proteins. In epithelial cells, the normal functioning of CFTR is critical to maintaining the transport of electrolytes in the body, including the tissues of the airways and the gastrointestinal tract. The CFTR consists of about 1480 amino acids that code for a protein, consisting of repeating tandem transmembrane domains, each containing six transmembrane helixes, and a nucleotide binding domain. The two transmembrane domains are connected by a large polar regulatory domain (R) with multiple phosphorylation sites that regulate channel activity and cell flow.

[0003] A gene coding for CFTR has been identified and sequenced (see Gregory RJ et al (1990) Nature 347: 382-386; Rich, DP et al (1990) Nature 347: 358-362), (Riordan, JR et al. (1989) Science 245: 1066/73). A defect in this gene results in CFTR mutations that result in cystic fibrosis ("CF"), the most common lethal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 children in the United States. As part of the general population of the United States, up to 10 million people carry one copy of a defective gene with no apparent disease effects. In contrast, people with two copies of the CF-related gene suffer from debilitating and fatal CF effects, including chronic lung disease.

[0004] In patients with cystic fibrosis, CFTR mutations of endogenously expressed epithelial pathways lead to a reduction in the apical secretion of anions causing an imbalance in the transport of ions and fluids. As a result, the decrease in anion transport contributes to an increased accumulation of mucus in the lungs and associated bacterial infections that ultimately cause death in patients with cystic fibrosis. In addition to respiratory diseases, patients with CF usually suffer from gastrointestinal problems and pancreatic insufficiency, which, if left untreated, causes death. In addition, most men with cystic fibrosis are infertile and fertility is lower among women with cystic fibrosis. In contrast to the severe symptoms of two copies of a CF-related gene,

[0005] Analysis of the CFTR CFTR gene sequence revealed a number of disease-causing mutations (Cutting, GR et al (1990) Nature 346: 366-369; Dean, M. et al (1990) Cell 61: 863: 870; and Kerem , BS, et al (1989) Science 245: 1073/80, Kerem BS et al (1990) Proc. Natl Acad. Sci USA, 87: 8447-8451). So far,&gt; 1000 pathogenic mutations in the CF gene have been identified (<a href="http://www.genet.sickkids.on.ca/cftr/)._Najbardziej_rozpowszechnion%c4%85_mutacj%c4%85_jest_delecjafenyloalaniny_w_pozycji_508_sekwencji_aminokwasowej_CFTR,_i_jest_powszechnie_przytaczanajako_%ce%94F508-CFTR._Ta_mutacja_wyst%c4%99puje_w_oko%c5%82o_70%25_przypadk%c3%b3w_mukowiscydozy_i_wi%c4%85%c5%bce_si%c4%99z_ci%c4%99%c5%bck%c4%85_postaci%c4%85_choroby">http://www.genet.sickkids.on.ca/cftr/). The most common mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as ΔF508-CFTR. This mutation occurs in about 70% of cases of cystic fibrosis and is associated with a severe form of the disease</a>.

[0006] Deletion of residue 508 in the ΔF508-CFTR prevents the correct assembly of the resulting protein. This results in the inability of the mutant protein to leave the ER, and flow into the plasma membrane. As a result, the number of channels in the membrane is much smaller than that observed in cells expressing wild type CFTR. In addition to the disturbed flow, the mutation results in faulty gate gating. All in all, reducing the number of channels in the membrane and defective gating leads to a reduction in the transport of anions through the epithelium leading to defective transport of ions and fluids. (Quinton, PM (1990), FASEB J. 4: 27092727). However, studies have shown that the lower ΔF508-CFTR in the membrane is functional, although less than wild-type CFTR. (Dalemans et al (1991), Nature Lond. 354: 526-528; Denning et al., Supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to the ΔF508CFTR, other CFTR mutations that cause diseases that cause abnormal flow, channel synthesis and / or gating to alter anion secretion and modify the progression and / or severity of the disease can be regulated by attenuating or amplifying.

[0007] Although CFTR transports different molecules in addition to anions, it is obvious that this role (anion transport) is one of the elements of an important mechanism of ion and water transport across the epithelium. The other elements include the epithelial Na channel⁺, ENaC, co-transporter Na⁺/ 2Cl^-/ K⁺, pump Na⁺-K⁺-ATPases and channels K⁺ basolateral membranes, which are responsible for the uptake of chlorides into the cell.

[0008] These elements cooperate with each other to obtain a directional transport across the epithelium by their selective expression and localization in the cell. Chloride absorption occurs through the coordinated activity of ENaC and CFTR present on the apical membrane and the Na pump⁺-K⁺-ATPases and Cl- channels are expressed on the lateral-basal cell surface. Secondary active transport of chloride from the inside leads to intracellular accumulation of chloride, which can then passively leave the cells through the C1 channels^-, giving vector transport. Ordering the co-transporter Na⁺/ 2Cl^-/ K⁺, pumps Na⁺-K⁺-ATPases and channels K⁺basolateral membrane on the basolateral surface and CFTR on the internal side, coordinates chloride secretion through CFTR on the inside. Because water is probably never actively transported itself, its flow through the epithelium depends on the small trans-epidermal osmotic gradients generated by the mass flow of sodium and chloride.

[0009] In addition to cystic fibrosis, modulation of CFTR activity may be beneficial for other diseases that are not directly caused by a CFTR mutation, such as secretory diseases and other CFTR mediated albumer diseases. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease and Sjogren's syndrome. COPD is characterized by airflow limitation that is progressive and not fully reversible. The limitation of air flow is caused by excessive secretion of mucus, emphysema and bronchiolitis. Activators of the mutant or wild-type CFTR have the potential to treat mucus hypersecretion and impaired mucociliary clearance that are common in COPD. In particular, increasing the release of anions through CFTR may facilitate the transport of fluid to the surface fluid of the airways to hydrate the mucus and optimize the visceral fluidity of the periluminal fluid. This would lead to increased mucociliary clearance and reduced symptoms associated with COPD. The dry eye syndrome is characterized by a decrease in the production of tears and abnormal lipid profile, protein profile and mucin of the tear film. There are many causes of the dry eye, some of which include age, Lasik eye surgery, arthritis, drugs, chemical / thermal burns, allergies and diseases such as cystic fibrosis and Sjogren's syndrome. Increasing anion secretion through CFTR would increase fluid transport from corneal endothelial cells and secretory glands that surround the eye, increasing corneal hydration. This would help alleviate the symptoms associated with dry eye disease. Sjogren's syndrome is an autoimmune disease in which the immune system attacks the glands that cause moisture throughout the body, including the eye, mouth, skin, respiratory system, liver tissue, vagina and intestines. Symptoms include dry eye, lips and vagina, as well as lung disease. This disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis / dermatomyositis. Abnormal protein flow is considered to be the cause of the disease for which treatment options are limited. CFTR activity modulators can hydrate different organs affected by the disease and help relieve the associated symptoms. in which the immune system attacks the glands that produce moisture throughout the body, including the eye, mouth, skin, respiratory system, liver tissues, vagina and intestines. Symptoms include dry eye, lips and vagina, as well as lung disease. This disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis / dermatomyositis. Abnormal protein flow is considered to be the cause of the disease for which treatment options are limited. CFTR activity modulators can hydrate different organs affected by the disease and help relieve the associated symptoms. in which the immune system attacks the glands that produce moisture throughout the body, including the eye, mouth, skin, respiratory system, liver tissues, vagina and intestines. Symptoms include dry eye, lips and vagina, as well as lung disease. This disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis / dermatomyositis. Abnormal protein flow is considered to be the cause of the disease for which treatment options are limited. CFTR activity modulators can hydrate different organs affected by the disease and help relieve the associated symptoms. and lung diseases. This disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis / dermatomyositis. Abnormal protein flow is considered to be the cause of the disease for which treatment options are limited. CFTR activity modulators can hydrate different organs affected by the disease and help relieve the associated symptoms. and lung diseases. This disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and polymyositis / dermatomyositis. Abnormal protein flow is considered to be the cause of the disease for which treatment options are limited. CFTR activity modulators can hydrate different organs affected by the disease and help relieve the associated symptoms.

[0010] As discussed above, it is believed that the deletion of residue 508 in the ΔF508-CFTR prevents the correct assembly of the resulting protein, resulting in the inability of this mutant protein to leave the ER and flow into the plasma membrane. As a result, an insufficient amount of mature protein is present on the cell membrane and transport of chlorides in epithelial tissues is significantly reduced. Indeed, this cellular phenomenon of the ER ERC transporters' ER ERDs being incorrectly processed has proven to be a substrate not only for CF disease, but for many other isolated and inherited diseases. The two ways ER machinery can work improperly is either by losing feedback with the export of ER proteins leading to degradation, or by accumulating in the ER these defective / improperly folded proteins [Aridor M, et al., Nature Med., 5 (7), pp. 745-751 (1999); Shastry, BS et al., Neurochem. International, 43, pp. 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp. 211-222 (2002); Morello, JP et al., TIPS 21, pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198 (1999)]. Diseases associated with first-class ER abnormalities include cystic fibrosis (due to poor ΔF508-CFTR assembly as discussed above), hereditary emphysema (in connection with a1-antitrypsin, non-Piz variants), hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, hereditary type 1 angioedema, deficiencies in lipid metabolism, such as familial hypercholesterolemia, type 1 blood chilomicrons, abetalipoproteinemia, lysosomal storage diseases such as pseudo-hurler I-cell disease / polydystrophy, mucopolysaccharidosis (due to the action of lysosomal enzymes), Sandhof / TaySachs (due to β-hexosaminidase), Krigler-Najjara type II (due to UDPglucuronyl sialyltransferase), polyendocrinopathy / hyperinsulinaemia, diabetes (due to insulin receptor) dwarfism Larona type (due to growth hormone receptor), myeloperoxidase deficiency, primary hypoparathyroidism (due to preproparathormone), melanoma (due to tyrosinase). Diseases associated with the latter class of ER abnormalities include type 1 AMS glycosylation disorder, hereditary emphysema (due to alpha-1-antitrypsin (Piz variant), congenital hyperthyroidism, congenital bone fragility (due to procollagen type I, II, IV) , hereditary deficiency of fibrinogen Sandhof / TaySachs (due to β-hexosaminidase), Krigler-Najjara type II (due to UDPglucuronylyl sialyltransferase), polyendocrinopathy / hyperinsulinaemia, diabetes (due to insulin receptor) Laron type dwarfism (due to growth hormone receptor), deficiency of myeloperoxidase, primary hypoparathyroidism (due to preproparathormone), melanoma (due to tyrosinase). Diseases associated with the latter class of ER abnormalities include type 1 AMS glycosylation disorder, hereditary emphysema (due to alpha-1-antitrypsin (Piz variant), congenital hyperthyroidism, congenital bone fragility (due to procollagen type I, II, IV) , hereditary deficiency of fibrinogen Sandhof / TaySachs (due to β-hexosaminidase), Krigler-Najjara type II (due to UDPglucuronylyl sialyltransferase), polyendocrinopathy / hyperinsulinaemia, diabetes (due to insulin receptor) Laron type dwarfism (due to growth hormone receptor), deficiency of myeloperoxidase, primary hypoparathyroidism (due to preproparathormone), melanoma (due to tyrosinase). Diseases associated with the latter class of ER abnormalities include type 1 AMS glycosylation disorder, hereditary emphysema (due to alpha-1-antitrypsin (Piz variant), congenital hyperthyroidism, congenital bone fragility (due to procollagen type I, II, IV) , hereditary deficiency of fibrinogen poliendokrynopatia / hyperinsulinaemia, diabetes (due to insulin receptor) Laron type dwarfism (due to growth hormone receptor), myeloperoxidase deficiency, primary hypoparathyroidism (due to preproparathormone), melanoma (due to tyrosinase). Diseases associated with the latter class of ER abnormalities include type 1 AMS glycosylation disorder, hereditary emphysema (due to alpha-1-antitrypsin (Piz variant), congenital hyperthyroidism, congenital bone fragility (due to procollagen type I, II, IV) , hereditary deficiency of fibrinogen poliendokrynopatia / hyperinsulinaemia, diabetes (due to insulin receptor) Laron type dwarfism (due to growth hormone receptor), myeloperoxidase deficiency, primary hypoparathyroidism (due to preproparathormone), melanoma (due to tyrosinase). Diseases associated with the latter class of ER abnormalities include type 1 AMS glycosylation disorder, hereditary emphysema (due to alpha-1-antitrypsin (Piz variant), congenital hyperthyroidism, congenital bone fragility (due to procollagen type I, II, IV) , hereditary deficiency of fibrinogen(due to fibrinogen), ACT deficiency (due to a1-antichymotrypsin), diabetes insipidus (DI), pituitary DI (due to vasopressin / V2 receptor), renal DI (due to aquaporins II), Charcot-Marie Tooth syndrome (due to peripheral vascular myeloid), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease (due to pAPP and presenilins), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's disease, Cerebellar ataxia type I, Kennedy's disease, atrophy reddish and pallidoncinoe and myotonic dystrophy, as well as spongiform encephalopathies such as the hereditary disease of Creutzfeldt Jakob (due to the abnormality of the prion protein processing),Fabry disease (due to lysosomal α-galactosidase A) and Straussler-Scheinker syndrome (due to the improper treatment of PrP).

[0011] In addition to the CFTR enhancer activity, the reduction of anion secretion by CFTR modulators may be beneficial in the treatment of secretory diarrhea in which epithelial water transport is dramatically increased as a result of the secretory activation of chloride transport. The mechanism includes elevation of cAMP and CFTR stimulation.

[0012] Although there are many causes for diarrhea, the main consequences of diarrheal diseases resulting from excessive chloride transport are common to all and include dehydration, acidosis, growth disorders and death.

[0013] Acute and chronic diarrheas are a serious medical problem in many regions of the world. Diarrhea is also an important factor in malnutrition and the leading cause of death (5,000,000 deaths / year) in children under the age of five.

[0014] Secretory diarrheas are also a dangerous condition in patients with acquired acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). 16 million people traveling to developing countries from industrialized countries develop diarrhea every year, with varying degrees and cases of diarrhea, depending on the country and region of travel.

[0015] Diarrhea in farm animals and domestic favorites such as cows, pigs and horses, sheep, goats, cats, dogs, also known as diarrhea, is the main cause of death in these animals. Diarrhea may result from any major transition, such as discontinuation or physical movement, as well as in response to various bacterial or viral infections and usually occurs within the first few hours of the animal's life.

[0016] The most common bacterium that causes diarrhea is enterotoxogenic E. coli (ETEC) that has the K99 antigen. The most common causes of viral diarrhea include rotavirus and coronavirus. Other infectious agents include Cryptosporidium, Giardia lamblia and Salmonella, among others.

[0017] Symptoms of rotavirus infection include excretion of watery faeces, dehydration and weakness. Coronavirus causes more serious disease in newborn animals and has a higher mortality rate than rotavirus infection. Often, however, a young animal can be infected by more than one virus or a combination of viral and bacterial microbes at once. It increases the severity of the disease.

[0018] Accordingly, there is a need for stable polymorphic forms of CFTR activity modulators, such as compound 1, that can be used to modulate the activity of CFTR in the mammalian cell membrane.

[0019] There is a need for methods of treating CFTR mediated diseases by means of such modulators of CFTR activity.

SUMMARY OF THE INVENTION [0020] The present invention relates to solid forms of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide ("compound 1" as used herein; ), which has the following structure:

<img file="PL1993360T3_D0001.tif" />

[0021] Solid forms of Compound 1 and their pharmaceutically acceptable compositions are useful in treating or reducing the severity of various diseases mediated by CFTR. Compound 1 is known as N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide and N- (5-hydroxy-2,4) -di-tert-butylphenyl) -4-oxo-1Hchinolino-3-carboxamide.

[0022] In one aspect, the invention includes solid amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide. In some embodiments, the solid amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4 dihydro-4-oxoquinoline-3-carboxamide comprises less than about 15% of the crystalline N- [2]. , 4 bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide.

[0023] In one aspect, the invention includes an amorphous preparation of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide essentially free of crystalline N- [ 2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4oksochinolino-3-carboxamide.

[0024] In some embodiments, the formulation further comprises a surfactant, polymer, or inert pharmaceutically acceptable substance. [0025] In some embodiments, the formulation comprises a solid dispersion.

[0026] In some embodiments, the formulation includes solid particles.

[0027] In some embodiments, the formulation comprises less than about 15% of crystalline N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide.

[0028] In some embodiments, the amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide has a particle size distribution.

D10, less than 5 μτι. In some embodiments, the amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide has a particle size distribution of D50, less than 17μτ. In some embodiments, the amorphous N [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide has a particle size distribution of D90, less than 100μτ.

[0029] In one aspect, the invention includes a solid dispersion containing amorphous N [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide.

[0030] In some embodiments, the solid dispersion comprises less than about 40% of crystalline N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide. In some embodiments, the solid dispersion is substantially free of crystalline N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide.

[0031] In some embodiments, the solid dispersion additionally comprises a surfactant, polymer, or inert pharmaceutically acceptable substance. For example, a solid dispersion contains a polymer and the polymer is one or more than one water-soluble polymer or a partially water-soluble polymer.

[0032] In some embodiments, N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] 1,4-dihydro-4-oxoquinoline-3-carboxamide has improved physical and chemical stability relative to Amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide in the absence of a polymer.

[0033] In some embodiments, the solid dispersion has a higher glass transition temperature than the glass transition temperature of pure amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-glass. carboxamide.

[0034] In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC). In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the polymer is a vinyl pyrrolidone / vinyl acetate (PVP / VA) copolymer. In some embodiments, the polymer is present in an amount of 10% by weight to 80% by weight, for example, the polymer is present in an amount of less than about 70% by weight, the polymer is present in an amount of about 50% by weight, or the polymer is present in an amount of about 49.5% by weight.

[0035] In some embodiments, N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] 1,4-dihydro-4-oxoquinoline-3-carboxamide is present in an amount of from 10% by weight to 80 % by weight, for example, N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is present in an amount of less than about 70% by weight or N- [2,4 -bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is present in an amount of about 50% by weight.

[0036] In some embodiments, the solid dispersion comprises a surfactant, for example sodium lauryl sulfate. In some embodiments, the surfactant is present in an amount of from 0.1 to 5%, for example, the surfactant is present in an amount of 0.5%.

[0037] In some embodiments, at least about 80% by weight of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is in the amorphous form . In some embodiments, substantially all N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is in amorphous form.

[0038] In some embodiments, a solid dispersion is obtained by spray drying.

[0039] In one aspect, the invention includes a pharmaceutical composition comprising amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide. In some embodiments, the amorphous N- [2,4-bis (1,1-dimethylethyl) 5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is substantially free of crystalline N- [2.4 bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide.

[0040] In one aspect, the invention includes a pharmaceutical composition comprising amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide as a solid dispersion and one or a higher number of surfactants, a polymer, an inert pharmaceutically acceptable substance or a pharmaceutically acceptable carrier.

[0041] In some embodiments, the solid dispersion comprises a polymer and wherein the polymer is one or more than one water-soluble polymer or a partially water-soluble polymer.

[0042] In some embodiments, the solid dispersion has a higher glass transition temperature than the glass transition temperature of pure amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3 carboxamide.

[0043] In some embodiments, the polymer is HPMC. In some embodiments, the polymer is HPMCAS. In some embodiments, the polymer is PVP / VA.

[0044] In one aspect, the invention includes a pharmaceutical composition comprising: an amorphous solid dispersion of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide, wherein said N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide comprises 30-75% by weight of the pharmaceutical composition, one or more polymers selected from the group including HPMC and HPMCAS, wherein said polymer comprises 30-75% by weight of the pharmaceutical composition and a surfactant, wherein said surfactant comprises 0.25-1% by weight of the pharmaceutical composition.

[0045] In some embodiments, the polymer is HPMCAS. In some embodiments, the polymer is HPMC.

[0046] In some embodiments, the surfactant is sodium lauryl sulphate.

[0047] In some embodiments, said N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide comprises about 50% by weight of the pharmaceutical composition, listed the polymer is HPMCAS and contains about 49.5% by weight of the pharmaceutical composition, and said surfactant is sodium lauryl sulfate and contains about 0.5% by weight of the pharmaceutical composition. [0048] In one aspect, the invention includes a pharmaceutical composition comprising; [0049] An aqueous suspension comprising amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide particles and a pharmaceutically acceptable carrier.

[0050] In some embodiments, the pharmaceutically acceptable carrier is a polymer in a solution selected from the group consisting of HPMC and HPMCAS. In some embodiments, the pharmaceutically acceptable carrier is a polymer in a PVP / VA solution.

[0051] In some embodiments, the amorphous compound is in the form of a solid dispersion. [0052] In some embodiments, the pharmaceutical composition further comprises a surfactant, either as a solution or as a component of a solid dispersion, for example, SLS. In some embodiments, the polymer is either in solution or as a component of solid dispersion particles or both. In some embodiments, the aqueous suspension contains from 0.1% to 20% by weight of surfactant. In some embodiments, the aqueous suspension contains from 0.1% to 2.0% by weight of a polymer, e.g., about 1% by weight of the polymer.

[0053] In one aspect, the invention includes a process for the preparation of an amorphous form of N [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide comprising spray drying N - [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide to give the amorphous form N- [2,4-bis (1,1-dimethylethyl) -5 hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide.

[0054] In some embodiments, the method comprises combining N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide and a suitable solvent to form a mixture and then spray-drying the mixture to obtain an amorphous form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide.

[0055] In some embodiments, the mixture is a solution of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide and a suitable solvent. In some embodiments, a suitable solvent includes acetone or MEK. In some embodiments, a suitable solvent includes a mixture of solvents, e.g. a mixture of acetone and water or a mixture of MEK and water. In some embodiments, the water in the solvent mixture is present in an amount of about 10% by weight.

[0056] In some embodiments, the method comprises a) forming a mixture comprising N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide, a polymer and solvent; and b) spray-drying the mixture to form a solid dispersion containing N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide.

[0057] In some embodiments, the mixture comprises a solution of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide, polymer and solvent. In some embodiments, the polymer is selected from HPMC and HPMCAS. In some embodiments, the polymer is PVP / VA. In some embodiments, the polymer is present in an amount of 30% to 70% by weight in a solid dispersion. In some embodiments, the mixture further comprises a surfactant, e.g., SLS.

[0058] In some embodiments, the solvent comprises acetone, for example, a mixture of acetone and water. In some embodiments, the solvent contains from 0% to 20% water and 70% to 100% acetone.

[0059] In one aspect, the invention includes a solid dispersion prepared according to the method described herein.

[0060] In one aspect, the invention comprises amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide for use in the treatment of a disease in which mediates CFTR in a mammal. In some embodiments, the amorphous solid dispersion of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is used for treatment. In some embodiments, an additional therapeutic agent is used for the treatment.

[0061] In one aspect, the invention includes a pharmaceutical package or kit comprising amorphous N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide and a pharmaceutically acceptable compound. carrier.

[0062] The crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is characterized by one or more peaks occurring from about 4.8 to about 5.2 degrees, e.g., about 5.0 degrees, and from about 15.4 to about 15.8 degrees, e.g., about 15.6 degrees in an X-ray powder diffraction pattern obtained using Cu K radiation alpha. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of about 7, 6 to about 8.0, e.g., 7.8. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1, The 4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak from about 8.3 to about 8.7, e.g., about 8.5. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a next peak of about 9.0. up to about 9.4, e.g., about 9.2. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of about 9, 7 to about 10.1, e.g. about 9.9. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1, The 4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak from about 11.7 to about 12.1, e.g., about 11.9. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a further peak of about 12.4 to about 12.8, e.g., about 12.6. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a further peak of about 13.7. to about 14.1, e.g. about 13.9. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1, The 4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak occurring from about 14.7 to about 15.1, e.g., about 14.9. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a next peak of from about 16.3 to about 16.7, e.g. about 16.5. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a next peak of about 17, 9 to about 18.3, e.g., about 18.1. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of about 18, 3 to about 18.7, for example, about 18.5. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of from about 20.5 to about 20.9, e.g., about 20.7. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of about 21.8. up to about 22.2, e.g., about 22.0. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a further peak from about 23.1 to about 23.7, for example, about 23.5. In some embodiments, the crystalline form of N- [2,4-bis (1, 1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of from about 25.1 to about 25.5, e.g., about 25.3. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of about 27.8 to about 28.2, e.g., about 28.0. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a next peak of from about 29.2 to about 29.6, e.g., about 29.4. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] 1, The 4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of from about 30.7 to about 31.1, e.g., about 30.9. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is characterized by an X-ray powder diffraction pattern obtained using Cu K alpha radiation, substantially similar to

FIGURES 4.

[0063] A pharmaceutical composition comprising the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide has the characteristics of form A, for example as described above , and a pharmaceutically acceptable adjuvant or carrier.

[0064] A process for the preparation of a crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide in form A, e.g. as characterized above, includes a step of heating N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide to about 250 ° C and cooling to room temperature.

[0065] N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide in form A, as exemplified above, can be used to treat the disease that is mediated by CFTR in a mammal. In some embodiments, N [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is part of a pharmaceutical composition. In some embodiments, an additional therapeutic agent is used for the treatment.

[0066] The pharmaceutical package or kit contains crystalline N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide in form A, for example as characterized above , and a pharmaceutically acceptable carrier.

[0067] The crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is characterized by one or more peaks occurring from about 6.2 up to about 6.6, for example, about 6.4, from about 7.5 to about 7.9, e.g., about 7.7, from about 12.5 to about 12.9, e.g., about 12, 7 and from about 17.9 to about 18.3, e.g., about 18.1 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.

[0068] In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) 5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a next peak from about 8.2 to about 8.6, e.g., about 8.4. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a next peak of from about 10.8 to about 11.2, e.g., about 11.0. In some embodiments, the crystalline form

N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of from about 14.6 to about 15.0, for example, about 14.8. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of from about 15.9 to about 16.3, e.g., about 16.1. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of from about 16.9 to about 17.3, e.g., about 17.1. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] 1, The 4-dihydro-4-oxoquinolin-3-carboxamide is further characterized by a further peak from about 18.4 to about 18.8, e.g., about 18.6. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a further peak from about 19.2 to about 19.6, for example, about 19.4. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of about 20, 9 to about 21.3, e.g., about 21.1. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of from about 22.4 to around 22.8, for example, about 22.6. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a next peak of about 23.2 to about 23.6, e.g., about 23.4. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of about 23.7. up to about 24.1, e.g., about 23.9. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a further peak of about 24.7 to about 25.1, e.g., about 24.9. In some embodiments, the crystalline form of N- [2,4-bis (1, 1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of about 25.3 to about 25.7, e.g., about 25.5. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a next peak of from about 26.5 to about 26.9, for example, about 26.7. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a next peak of from about 27.3 to about 27.7, e.g., about 27.5. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] 1, The 4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a further peak of from about 29.4 to about 29.8, e.g., about 29.6. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide is further characterized by a further peak of from about 33.3 to about 33.7, for example, about 33.5. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide is further characterized by a next peak of about 36, 6 to about 37.0, e.g., about 36.8. In some embodiments, the crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,

[0069] The crystalline form N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide, has a monoclinic crystal system, space group P21 and the following unit dimensions elementary:

a = 11.8011 (7) A α = 90 ° b = 5.9819 (3) A β = 105.110 (4) ° c = 14.7974 (8) A γ = 90 °.

[0070] The pharmaceutical composition contains the crystalline form N- [2,4-bis (1,1-dimethylethyl) 5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide according to embodiment B, for example, as characterized above, and a pharmaceutically acceptable adjuvant or carrier.

[0071] A process for preparing a crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide according to embodiment B, for example, as characterized above, includes the steps of alternately heating and cooling the slurry of compound 1 and acetonitrile. In some embodiments, the method comprises heating said suspension at about 50 ° C for about 12 hours. In some embodiments, said cooling step comprises placing said suspension at room temperature for about 12 hours, followed by cooling at about 0 ° C overnight.

[0072] The crystalline form of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide or a pharmaceutical composition containing the crystalline form N- [2,4- Bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide according to embodiment B, as for example, characterized above, can be used in the treatment of a CFTR mediated disease in a patient .

pure or as a solid dispersion component. In some embodiments, the disease is cystic fibrosis.

[0074] The methods described herein can be used to prepare the compositions of the present invention. The amounts and features of the components used in the methods will be described herein.

[0075] As used herein, the term "amorphous" refers to a solid material that does not have a distant order in the position of its molecules. Amorphous solid forms are usually supercooled liquids, in which the molecules are arranged in a random manner, so that the ordering is not well defined, e.g., packing of molecules and lack of far-reaching order. Amorphous solid forms are generally isotropic, i.e. they exhibit similar properties in all directions and do not have a specific melting point. For example, an amorphous material is a solid material without an acute characteristic crystalline peak (s) in its X-ray powder diffraction pattern (XRPD) (i.e., it is not crystalline as determined by XRPD). Instead of one or several wide peaks (for example, halo) visible in the XRPD pattern. Wide peaks are characteristic of an amorphous solid. See, US 2004/0006237 for the comparison of XRPD of amorphous material and crystalline material.

[0076] As used herein, the phrase "substantially amorphous compound 1" is used interchangeably with the phrase "substantially amorphous compound 1 substantially free of crystalline compound 1." In some embodiments, substantially amorphous compound 1 contains less than about 30% crystalline 1, for example, less than about 30% of crystalline compound 1, e.g., less than about 25% of crystalline compound 1, less than about 20% of crystalline compound 1, less than about 15% of crystalline compound 1, less than about 10% % of crystalline Compound 1, less than about 2% of crystalline Compound 1. In certain preferred embodiments, Compound 1 contains less than about 15% of crystalline Compound 1.Some embodiments include a preparation of substantially amorphous Compound 1, e.g. having the degree of crystalline Compound 1 as described above.

[0077] As used herein, the term "crystalline solid particles" refers to compounds or compositions in which the structural units are ordered in solid geometric patterns or meshes, such that the crystalline solids have a rigid far-off arrangement. The structural units that make up the crystal structure can be atoms, molecules or ions. The crystalline solids have specific melting points.

[0078] As used herein, the term "dispersion" refers to a dispersion system in which one substance, the disperse phase, is distributed in separate units, in a second substance (continuous phase or carrier). The size of the dispersed phase can vary considerably (e.g., colloidal particles with a nanometric dimension up to several microns). In general, disperse phases may be solids, liquids or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solid. In pharmaceutical applications, a solid dispersion may contain a crystalline drug (disperse phase) in the form of an amorphous polymer (continuous phase), or alternatively, an amorphous drug (disperse phase) in the form of an amorphous polymer (in the continuous phase). In some solutions, the amorphous solid dispersion contains a disperse phase polymer, and the drug is a continuous phase. In some embodiments, the dispersion contains an amorphous compound or substantially amorphous compound 1.

[0079] The term "amorphous solid dispersion" refers generally to a solid dispersion of two or more components, usually a drug and a polymer, but which may contain other ingredients such as surfactants and other pharmaceutical excipients in which compound 1 is amorphous or essentially amorphous (e.g. substantially free of crystalline compound 1), and the physical stability and / or dissolution and / or solubility of the amorphous drug is enhanced by other ingredients.

[0080] A solid dispersion as provided herein, is an especially preferred embodiment of the present invention. Solid dispersions usually contain the compound dispersed in a suitable carrier, such as a solid carrier. In one embodiment, the support of the invention comprises a polymer, preferably a water-soluble polymer or a partially water-soluble polymer. It should be understood that one or more water-soluble polymer may be used in the form of a solid dispersion according to the present invention.

[0081] An example of a solid dispersion is a co-precipitate or a co-melt of N- [2,4bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide from at least one polymer. "Co-precipitate" is a product after dissolving the drug and polymer in a solvent or solvent mixture, and then removing the solvent or solvent mixture. Sometimes the polymer may be suspended in a solvent or a mixture of solvents. The solvent or solvent mixture includes organic solvents and supercritical fluids. "Co-melt material" is a product after heating the drug and the polymer to melt, optionally in the presence of a solvent or a mixture of solvents, and then mixing, removing at least part of the solvent, if applicable, and cooling to room temperature at the selected rate. In some cases, solid dispersions are prepared by adding a drug solution and a solid polymer, followed by mixing and removal of the solvent. To remove the solvent, vacuum drying, spray drying, tray drying, freeze drying and other drying procedures may be used. The use of any of these methods, using the appropriate process parameters of the present invention, will provide N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide in the state of amorphous in the final product of a solid dispersion. To remove the solvent, vacuum drying, spray drying, tray drying, freeze drying and other drying procedures may be used. The use of any of these methods, using the appropriate process parameters of the present invention, will provide N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide in the state of amorphous in the final product of a solid dispersion. To remove the solvent, vacuum drying, spray drying, tray drying, freeze drying and other drying procedures may be used. The use of any of these methods, using the appropriate process parameters of the present invention, will provide N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxoquinoline-3-carboxamide in the state of amorphous in the final product of a solid dispersion.

BRIEF DESCRIPTION OF THE DRAWINGS [0082]

FIGURE 1 is a powder diffraction pattern in the X-rays of compound 1. FIGURE 2 is an NMR spectrum ¹H of compound 1,

FIGURE 3 is a DSC graph of Compound 1.

FIGURE 4 is a powder diffraction pattern in X-ray form A. FIGURE 5 is a DSC graph of the form A.

FIGURE 6 is a TGA graph of form A.

FIGURE 7 is a powder diffraction pattern in X-ray form B. FIGURE 8 is a DSC graph of the form B.

FIGURE 9 is a TGA graph of form B.

FIGURE 10 is an image of conformation of Form B, based on single crystal X-ray analysis.

FIGURE 11 is a powder diffraction pattern in X-rays of an amorphous form.

FIGURE 12 is a TGA graph of the amorphous form.

FIGURE 13 is a DSC graph of the amorphous form.

[099] DETAILED DESCRIPTION OF THE INVENTION

Solid forms of compound 1

Form A [0083] Form A of Compound 1 is characterized by one or more peaks occurring from about 4.8 to about 5.2, for example, about 5.0, for example, 4.99, and from about 15.4 to about 15.8, e.g., about 15.6 for example, 15.58 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation (2θ). Other peaks (2θ), which may be characteristic of Form A, include the following: from about 7.6 to about 8.0, for example, about 7.8, for example, 7.75; from about 8.3 to about 8.7, for example, about 8.5, for example, 8.46; from about 9.0 to about 9.4, e.g., about 9.2, for example, 9.21; from about 9.7 to about 10.1, e.g., about 9.9, e.g., 9.92; from about 11.7 to about 12.1, e.g., about 11.9, e.g., 11.93; from about 12.4 to about 12.8, e.g., about 12.6, for example, 12.64; from about 13.7 to about 14.1, e.g., about 13.9, e.g., 13.88; from about 14.7 to about 15.1, e.g., about 14.9, e.g., 14.91; from about 16.3 to about 16.7, e.g., about 16.5, e.g., 16.46; from about 17.9 to about 18.3, e.g., about 18.1, e.g., 18.09; from about 18.3 to about 18.7, e.g., about 18.5, for example, 18.52; from about 21.5 to about 21.9, for example, about 21.7, for example, 20.65; from about 21.8 to about 22.2, e.g., about 22.0, e.g., 21.95; from about 23.1 to about 23.7, e.g., about 23.5, e.g., 23.49; from about 25.1 to about 25.5, e.g., about 25.3, for example, 25.26; from about 27.8 to about 28.2, e.g., about 28.0, for example, 28.02; from about 29.2 to about 29.6, e.g., about 29.4, for example, 29.35; and about from about 30, 7 to about 31.1, for example, 30.9, for example, 30.85. For example, Form A can be characterized by an X-ray powder diffraction pattern obtained using Cu K alpha radiation, substantially similar to FIGURE 4.

[0084] Pharmaceutical compositions comprising Form A and a pharmaceutically acceptable adjuvant or carrier, such as a polymer or surfactant, are also described. Form A may be formulated in a pharmaceutical composition, in some cases, with another therapeutic agent, for example another therapeutic agent for the treatment of cystic fibrosis or its symptoms.

[0085] Methods for obtaining Form A are provided in the examples herein.

[0086] Form A or a pharmaceutical composition comprising Form A can be used in the treatment of a disease mediated by CFTR, such as cystic fibrosis.

Form B [0087] The solid crystal form B of compound 1 is characterized by one or more peaks present from about 6.0 to about 6.4 for example, about 6.2, for example, 6.17, from about 7.4 to about 7.8, e.g., about 7.6, e.g., 7.61, from about 12.1 to about 12.5, e.g., about 12.3, e.g., 12.33, and from about 17.8 up to about 18.2 for example, about 18.0, for example, 17.96 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation (2θ). Other peaks (2θ), which may be characteristic of form B, include the following: from about 8.2 to about 8.6 for example, about 8.4, for example, 8.40; from about 10.8 to about 11.2, e.g., about 11.0, e.g., 11.02; from about 14.6 to about 15.0, e.g., about 14.8, for example, 14.83; from about 15.9 to about 16, 3 for example, about 16.1, e.g., 16.14; from about 16.9 to about 17.3, e.g., 17.1, for example, 17.11; from about 18.4 to about 18.8, e.g., about 18.6, for example, 18.55; from about 19.2 to about 19.6, e.g., about 19.4, for example, 19.43; from about 20.9 to about 21.3, e.g., about 21.1, e.g., 21.05; from about 22.4 to about 22.8, e.g., about 22.6, e.g., 22.56; from about 23.2 to about 23.6, e.g., about 23.4, for example, 23.37; from about 23.7 to about 24.1, e.g., about 23.9, e.g., 23.94; from about 24.7 to about 25.1, e.g., about 24.9, for example, 24.86; from about 25.3 to about 25.7 for example, about 25.5, for example, 25.50; from about 26.5 to about 26.9, for example, about 26.7, for example, 26.72; from about 27.3 to about 27.7 for example, about 27.5, for example, 27.51; from about 29.4 to about 29.8, for example, about 29.6, e.g., 29.60; from about 33.3 to about 33.7, e.g., about 33.5, e.g., 33.48; and from about 36.6 to about 37.0, e.g., about 36.8, for example, 36.78. Form B may be further characterized, for example, by an X-ray powder diffraction pattern obtained using Cu K alpha radiation, substantially similar to

FIGURES 7.

[0088] Applicants have determined the crystal structure dimensions of Form B by analyzing data for a single crystal. Form B is a monoclinic crystal system having a space group P21, and the following dimensions of the unitary unit: a = 11,8011 (7) A, α = 90 °; b = 5.9819 (3) A, β = 105.110 (4) ° 1; c = 14.7974 (8) A, γ = 90 °. Additional details regarding the structure and packing of form B are given in the examples.

[0089] Pharmaceutical compositions comprising Form B and a pharmaceutically acceptable adjuvant or carrier, such as a polymer or surfactant, are also described. Form B may be formulated in a pharmaceutical composition, in some cases, with another therapeutic agent, for example another therapeutic agent for the treatment of cystic fibrosis or its symptoms.

[0090] Methods for obtaining Form B are provided in the examples herein. [0091] Form B or a pharmaceutical composition comprising Form B can be used in the treatment of a disease mediated by CFTR, such as cystic fibrosis.

Amorphous Compound 1 [0092] Compound 1 may be present as an amorphous solid, e.g. essentially amorphous compound 1 as a substantially pure preparation, or amorphous compound 1 as a component, as a dispersion such as a solid amorphous dispersion.

[0093] In some embodiments, the amorphous form of Compound 1 is substantially free of crystalline Compound 1 (e.g., Form A, Form B or any crystalline form of Compound 1), for example compound 1 contains less than about 30% of crystalline Compound 1, for example, less than about 25% of crystalline compound 1, less than about 20% of crystalline compound 1, less than about 15% of crystalline compound 1, less than about 10% of crystalline compound 1, less than about 5% of crystalline compound 1, less than about about 2% crystalline. Compound 1, preferably less than about 15% of the crystalline compound 1. Compound 1 may be characterized by an X-ray powder diffraction pattern obtained using Cu K alpha radiation substantially similar to FIGURE 11. For example, the substantially amorphous form of compound 1 can be characterized as having XRPD without an acute characteristic crystalline peak (s) in an X-ray powder diffraction pattern (XPRD) (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halo) appear in the XRPD pattern. Polymers [0094] Solid dispersions, including the amorphous compound 1 and the polymer (or solid support) are also included herein. For example, the compound of formula I is in the amorphous form as a solid component of the amorphous dispersion. Solid amorphous dispersion, generally compound 1 and polymer. Exemplary polymers include cellulosic polymers such as HPMC or HPMCAS and pyrrolidones containing polymers such as PVP / VA. In some embodiments,

[0095] In one embodiment, the polymer may be dissolved in an aqueous medium. The solubility of polymers may be pH-independent or pH-dependent. The latter include one or more intestinal polymers. The term "intestinal polymer" refers to a polymer that is preferably soluble in a less acidic environment in the intestine compared to a more acidic environment in the stomach, for example, a polymer that is insoluble in acidic medium in water, but soluble at pH above 5 6. The appropriate polymer should be chemically and biologically inert. In order to improve the physical stability of solid dispersions, the glass transition temperature (Tg) of the polymer should be as high as possible. E.g, preferred polymers have a glass transition temperature at least equal to or above the glass transition temperature of the drug (e.g., compound 1). Other preferred polymers have a glass transition temperature that ranges from about 10 to about 15 ° C of the drug (e.g., compound 1). Examples of suitable glass transition temperatures for polymers include at least about 90 ° C, at least about 95 ° C, at least about 100 ° C, at least about 105 ° C, at least about 110 ° C, at least about 115 ° C, at least about about 120 ° C, at least about 125 ° C, at least about 130 ° C, at least about 135 ° C, at least about 140 ° C, at least about 145 ° C, at least about 150 ° C, at least about 155 ° C, at least about 160 ° C, at least about 165 ° C, at least about 170 ° C, or at least about 175 ° C (measured under dry conditions). Not wanting to be bound by theory, it is considered

[0096] In addition, the hygroscopicity of the polymers should be low, for example, less than about 10%. For comparative purposes in this application, the hygroscopicity of the polymer or composition is characterized at a relative humidity of about 60%. In some preferred embodiments, the polymer has less than about 10% water absorption, e.g. less than about

9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% water absorption. Hygroscopicity may also affect the physical stability of solid dispersions. In general, the moisture adsorbed in the polymers can significantly reduce the Tg of the polymers and the resulting solid dispersion, which results in a further reduction in the physical stability of the solid dispersions as described above.

[0097] In one embodiment, the polymer is one or more water-soluble polymer (s) or partially water-soluble polymer (s). Water-soluble or partially water-soluble polymers include, but are not limited to, cellulose derivatives (e.g. hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as, for example, polymethacrylate (Eudragit E); cyclodextrins (e.g., β-cyclodextrin) and their copolymers and derivatives thereof, including for example PVP-VA (vinyl acetate), polyvinylpyrrolidone.

[0098] In some preferred embodiments, the polymer is hydroxypropyl methylcellulose (HPMC) such as HPMC E50, HPMCE15 or HPMC60SH50). [0099] As discussed herein, the polymer may be a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methylcellulose phthalates (HPMCP), cellulose acetate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or a salt thereof ( e.g. sodium salt, such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetatephthalate (HPCAP), hydroxypropyl methylcellulose phthalate, cellulose acetate (HPMCAP) and methylcellulose acetate phthalate (MCAP) and polymethacrylates (e.g., Eudragit® S). In some preferred solutions,

[0100] In yet another embodiment, the polymer is a polyvinyl pyrrolidone copolymer, for example, a vinyl pyrrolidone / vinyl acetate copolymer, (PVP / VA).

[0101] In embodiments where compound 1 forms a solid dispersion with a polymer, e.g. with a HPMC polymer or HPMCAS PVP / VA, the amount of polymer relative to the total weight of the solid dispersion is from about 0.1% to 99% by weight. Unless otherwise stated, the percentage of the drug, polymer of other excipients as described in the dispersion is given in percent by weight. The amount of polymer is at least about 20%, preferably at least about 30%, e.g. at least about 35%, at least about 40%, at least about 45%, or about 50% (e.g., 49.5%). The amount is typically about 99% or less, and more preferably about 80% or less, e.g. about 75% or less, about 70% or less, about 65% or less, about 60% or less, or about 55% or less. In one embodiment, the polymer is present in an amount up to about 50% of the total weight of the dispersion (and even more specifically, from about 40% to 50%, such as about 49%, about 49.5% or about 50%). HPMC and HPMCAS are available in various classes from ShinEtsu eg HPMCAS is available in many varieties, including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, AS-HG. Each of these classes differs by the percentage of acetate and succinate. [0102] In certain preferred embodiments, the compound of Formula 1 and the polymer are present in approximately equal amounts, e.g. each of the polymer and drug consist of about half of the weight percentage of the dispersion. For example, the polymer is present in about 49.5% and the drug is present in about 50%. HPMCAS is available in many varieties, including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, AS-HG. Each of these classes differs by the percentage of acetate and succinate. [0102] In certain preferred embodiments, the compound of Formula 1 and the polymer are present in approximately equal amounts, e.g. each of the polymer and drug consist of about half of the weight percentage of the dispersion. For example, the polymer is present in about 49.5% and the drug is present in about 50%. HPMCAS is available in many varieties, including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, AS-HG. Each of these classes differs by the percentage of acetate and succinate. [0102] In certain preferred embodiments, the compound of Formula 1 and the polymer are present in approximately equal amounts, e.g. each of the polymer and drug consist of about half of the weight percentage of the dispersion. For example, the polymer is present in about 49.5% and the drug is present in about 50%.

[0103] In certain preferred embodiments, the dispersion additionally contains other minor ingredients, such as a surfactant (e.g., SLS). In certain preferred embodiments, the surfactant is present in an amount of less than about 10% dispersion, e.g. less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5% , less than about 4%, less than about 3%, less than about 2%, about 1%, or about 0.5%.

[0104] In an embodiment comprising a polymer, the polymer should be present in an amount effective to stabilize the solid dispersion. Stabilization involves inhibiting or preventing the crystallization of compound 1. This stabilization will inhibit the conversion of compound 1 from an amorphous state to a crystalline form. For example, the polymer prevents conversion of at least a portion (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%; 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more) of compound 1 from an amorphous form to a crystalline form. The stabilization can be measured, e.g. by measuring the glass transition temperature of the solid dispersion, measuring the relaxation rate of the amorphous material, or by measuring the solubility or bioavailability of compound 1.

[0105] Suitable polymers for use in combination with Compound 1, for example to form a solid dispersion, such as an amorphous solid dispersion, should have one or more of the following properties:

[0106] The glass transition temperature of the polymer should have a temperature of not less than about 1015 ° C lower than the glass transition temperature of compound 1. Preferably, the glass transition temperature of the polymer is higher than the glass transition temperature of compound 1, and generally at least 50 ° C higher than the storage temperature of the medicinal product. For example, at least about 100 ° C, at least about 105 ° C, at least about 105 ° C, at least about 110 ° C, at least about 120 ° C, at least about 130 ° C, at least about 140 ° C, at least about 150 ° C, at least about 160 ° C, at least about 160 ° C or more.

[0107] The polymer should be relatively non-hygroscopic. For example, the polymer should, when stored under standard conditions, absorb less than about 10% water, e.g. less than about 9%, less than about 8%, less than about 7%, less than about 6% or less about 5%, less than about 4% or less than about 3% water. Preferably, the polymer, when stored under standard conditions, is substantially free of absorbed water.

[0108] The polymer should have similar or better solubility in solvents suitable for spray drying methods relative to Compound 1. In preferred embodiments, the polymer dissolves in one or more of the same solvents or solvent systems as compound 1. It is preferred that the polymer was soluble in at least one solvent containing no hydroxyl groups, such as methylene chloride, acetone or a combination thereof.

[0109] The polymer, when combined with compound 1, e.g. in solid dispersion or in a liquid suspension, should increase the solubility of compound 1 in aqueous and physiologically related media both relative to the solubility of compound 1 in the absence of polymer and in relation to solubility. compound 1 in combination with the reference polymer. For example, the polymer may increase the solubility of the amorphous compound 1 by reducing the amount of amorphous compound 1 that is converted to crystalline compound 1, or from a solid amorphous dispersion or liquid slurry.

[0110] The polymer should reduce the rate of relaxation of the amorphous substance.

[0111] The polymer should increase the physical and / or chemical stability of compound 1.

[0112] The polymer should improve the productivity of compound 1.

[0113] The polymer should improve one or more of the processing, storage or storage properties of Compound 1.

[0114] The polymer should not adversely interact with other pharmaceutical ingredients, for example excipients.

[0115] The suitability of the candidate polymer (or other component) can be tested using spray drying methods (or other methods) described herein to form an amorphous composition. The candidate composition may be compared in terms of stability, resistance to crystal formation or other properties, and compared to a reference preparation, e.g., pure amorphous compound 1 or crystalline compound 1. For example, the candidate composition may be tested to determine whether it inhibits time for solvent-mediated crystallization, or a percentage of the conversions at a given time under controlled conditions of at least 50%, 75%, 100% or 110% as well as the reference preparation, or the candidate composition may be tested to determine,

Surfactants [0116] A solid dispersion or other composition may contain a surfactant. A mixture of surfactant or surfactants will generally decrease the interfacial tension between the solid dispersion and the aqueous medium. A suitable surfactant or mixture of surfactants may also increase the water solubility and bioavailability of Compound 1 from the solid dispersion. Surfactants for use in connection with the present invention include, but are not limited to, sorbitan fatty acid esters (e.g. Spans®), polyoxyethylene fatty acid esters and sorbitan (e.g., Tweens®), sodium lauryl sulfate (SLS), dodecylbenzenesulfonate sodium (SDB) sodium dioctylsulfosuccinate (Dokuzan), A specific example of surfactants that may be used in conjunction with the present invention include, but are not limited to, Span 65, Span 25, Tween 20, Capryol 90, Pluronic F108, sodium lauryl sulfate (SLS), vitamin E TPGS, pluronics and copolymers. SLS is generally preferred.

[0117] The amount of surfactant (e.g. SLS) based on the total weight of the solid dispersion may be 0.1-15%. Preferably, it is from 0.5% to 10%, more preferably from 0.5 to 5%, e.g. about 1%, about 2%, about 3%, about 4% or about 5%.

[0118] In certain embodiments, the amount of surfactant based on the total weight of the solid dispersion is at least 0.1, preferably about 0.5%. In these embodiments, the surfactant will be present in an amount of no more than about 15%, and preferably no more than about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6 %, about 5%, about 4%, about 3%, about 2% or about 1%. Preferred is a form in which the surfactant is present in an amount of about 0.5% by weight. [0119] Candidate surfactants (and other ingredients) may be tested for their suitability for use in the present invention in a manner similar to that described for test polymers.

Methods of Making Solid Forms of Compound 1 [0120] A solid form of Compound 1 may vary depending on the method used to prepare Compound 1. For example, a compound of Formula 1 may be prepared using the method of providing crystalline compound 1, such as Form A or Form B, or compound 1 can be prepared using the amorphous compound 1-providing method, e.g. in the form of a pure formulation or where compound 1 is an ingredient in a dispersion, such as a solid amorphous dispersion (e.g., a dispersion of compound 1 and a polymer such as a cellulose polymer, e.g. HPMC or HPMCAS or a pyrrolidone polymer such as PVP / VA).

Form A [0121] Form A of Compound 1 can be produced, for example, by heating Compound 1 to its melting point or above, e.g. up to about 250 ° C, and then cooling the compound, thereby providing Compound 1 having Form A in the state of constant. Form A may be characterized by one or more characteristic peaks as determinedusing XRPD. For example, compound 1 as Form A can be identified by the presence of one or more 2θ peaks, including one or more of the following peaks with a value of or about: about 5.0 for example 4.99; about 7.8, e.g., 7.75; about 8.5, e.g., 8.46; about 9.2, e.g., 9.21; about 9.9, e.g., 9.92; about 11.9, e.g., 11.93; about 12.6, e.g., 12.64; about 13.9, e.g., 13.88; about 14.9, e.g., 14.91; about 15.6, for example, 15.58; about 16.5, e.g., 16.46; about 18.1, e.g., 18.09; about 18.5, for example, 18.52; about 21.7, e.g., 20.65; about 22.0, e.g., 21.95; about 23.5, e.g., 23.49; about 25.3, e.g., 25.26; about 28.0, e.g., 28.02; about 29.4, for example, 29.35; and about 30.9, e.g., 30.85.

Form B [0122] Form B of compound 1 can be produced, for example, by suspending compound 1 in a solvent for heating and cooling cycles.

[0123] In certain preferred embodiments, the solvent is a solvent in which compound 1 has limited solubility at room temperature, for example, acetone.

[0124] The suspension is subjected to many heating / cooling cycles, where the suspension is usually heated to a temperature above room temperature but below the boiling point of the solvent, e.g. about 40 ° C to about 60 ° C, e.g. about 50 ° C. The suspension is usually subjected to 2 heating / cooling cycles, for example, 2, 3, 4, 5 or 6, preferably 5 cycles. The period of time for each cycle is at least about 8 hours (e.g., 4 hours heating, then 4 hours at room temperature, 6 hours heating, then 6 hours at room temperature, 8 hours heating, and then 8 hours at room temperature, preferably 12 hours). heating hours and then 12 hours at room temperature).

[0125] In an alternative embodiment, the crude compound 1 is refoiled in acetonitrile (for example, in 27 volumes of acetonitrile) in 24 hours. The mixture is then cooled, e.g., to room temperature, e.g., about 20 ° C. Form B is then isolated, for example, by filtration in a white to off-white color. The resulting wet cake is washed with acetonitrile (e.g., 5 volumes) and dried under vacuum at 50 ° C until constant weight.

[0126] Form B may be characterized by one or more characteristic peaks as determined using XRPD. For example, compound 1 in the B form may be identified by the presence of one or more 2θ peaks, including one or more of the following peaks of about or about: about 6.2, for example, 6.17;

about 7.6, e.g., 7.61; about 8.4, e.g., 8.40; about 11.0, e.g., 11.02; about

12.3, for example, 12.33; about 14.8, e.g., 14.83; about 16.1, e.g., 16.14; about 17.1, e.g., 17.11; about 18.0, e.g., 17.96; about 18.6, e.g., 18.55; about

19.4, for example, 19.43; about 21.1, e.g., 21.05; about 22.6, e.g., 22.56; about

23.4, for example, 23.37; about 23.9, for example, 23.94; about 24.9, e.g., 24.86; about

25.5, e.g., 25.50; about 26.7, e.g., 26.72; about 27.5, for example, 27.51; about

29.6, for example, 29.60; about 33.5, e.g., 33.48; and about 36.8, for example, 36.78.

Amorphous Compound 1 [0127] Amorphous Compound 1 can be made using a variety of techniques including, for example, spray-drying a solution of Compound 1 to provide an amorphous Compound 1, e.g., in pure solid form or as a solid dispersion component, said method using spray-drying means calling this transformation. For example, amorphous compound 1 can be prepared by converting a compound of Compound 1, e.g. a crystalline form of a compound of Formula 1, such as Form A or Form B to a substantially amorphous form of Compound 1 by dissolving the compound in solution and spray drying this compound solution. 1, thereby transforming the form of compound 1, such as crystalline compound, 1 into an amorphous compound 1.

[0128] Any method for obtaining amorphous forms of compound 1, including pure amorphous compound 1 and amorphous solid dispersions of compound 1, may be used, including, for example, those described in US 2003/0186952 (see documents cited in point 1092) and the US 2003/0185891). In general, methods that can be used include those that involve rapid removal of the solvent from the mixture or cooling of the molten sample. Such methods include, but are not limited to, rotary evaporation, freeze drying (i.e., lyophilization), vacuum drying, melt freezing and melt extrusion. However, a preferred embodiment includes amorphous compound 1, such as a pure preparation or solid dispersion obtained by spray drying. Therefore, in some embodiments,

[0129] The formulations described herein, for example, a pharmaceutical composition, can be prepared by spray-drying a mixture containing compound 1, a suitable polymer, and a suitable solvent. Spray drying is a method that involves spraying a liquid mixture containing, e.g., a solid and a solvent, and removing the solvent. Spraying can be performed, for example, by means of a nozzle or on a rotating disk.

[0130] Spray drying is a process that converts a liquid substrate to a dry particulate form. Optionally, secondary drying, such as fluidized bed drying or vacuum drying, may be used to reduce the residual solvent to pharmaceutically acceptable levels. Typically, spray-drying involves contacting a highly dispersed liquid suspension or solution and a sufficient amount of hot air to generate evaporation and dry the liquid droplets. The formulation to be spray dried can be any solution, suspension, coarse suspension, colloidal dispersion or paste that can be sprayed using the selected spray drying equipment. In the standard procedure, the preparation is sprayed in a stream of warm filtered air, which the solvent evaporates and transports the dried product to a collector (e.g., a cyclone). The used air is then free of solvent or, alternatively, the used air is sent to the condenser in order to intercept and possibly recycle the solvent. Commercial types of devices can be used to carry out spray drying. Commercial spray dryers, for example, are manufactured by Buchi Ltd. and Niro (e.g., a spray dryer line PSD manufactured by Niro) (see US 2004/0105820, US 2003/0144257). Commercial types of devices can be used to carry out spray drying. Commercial spray dryers, for example, are manufactured by Buchi Ltd. and Niro (e.g., a spray dryer line PSD manufactured by Niro) (see US 2004/0105820, US 2003/0144257). Commercial types of devices can be used to carry out spray drying. Commercial spray dryers, for example, are manufactured by Buchi Ltd. and Niro (e.g., a spray dryer line PSD manufactured by Niro) (see US 2004/0105820, US 2003/0144257).

[0131] Spray drying typically utilizes charges of solid material from about 3% to about 30% by weight (i.e., drugs and excipients), e.g. about 4% to about 20% by weight, preferably at least about 10%. In general, the upper limit of the charge solids content is regulated by means of a viscosity (e.g., pumpability) of the resulting solution and the solubility of the components in solution. In general, the solution viscosity can determine the particle size in the resulting powder product.

[0132] Techniques and methods used for spray drying can be found in Perry Chemical Engineering Handbook, 6th ed., RH Perry, DW Green &amp; JO Maloney, eds.), McGraw-Hill Book CO. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Eng. Monogr. Series 2 (1954). In general, spray-drying is carried out at an inlet air temperature of from about 60 ° C to about 200 ° C, e.g. from about 95 ° C to about 185 ° C, from about 110 ° C to about 182 ° C, from about 96 ° C to about 108 ° C, e.g. about 175 ° C. Spray drying is generally carried out at a temperature of about 30 ° C to about 80 ° C, e.g. about 31 ° C to about 72 ° C, about 37 ° C to about 41 ° C, e.g. about 60 ° C. . The spray flow rate is typically from about 4 kg / hour to 12 kg / hour, e.g., from about 4.3 kg / hour to about 10.5 kg / hour, e.g. about 6 kg / h or about 10.5 kg / h. The feed rate is typically from about 3 kg / hour to 10 kg / hour, e.g., from about 3.5 kg / hour to about 9.0 kg / hour, e.g. from about 8 kg / hour or about 7.1. kg / h. The spraying rate is generally from about 0.3 to 1.7, e.g. from about 0.5 to 1.5, e.g. up to about 0.8 or about 1.5.

[0133] The removal of the solvent may then require a drying step, such as tray drying, fluidized bed drying (e.g., from about room temperature to about 100 ° C), vacuum drying, microwave drying, tumble drying or double-conical vacuum drying (e.g. , from about room temperature to about 200 ° C).

[0134] In one embodiment, the solid dispersion was dried on a fluid bed.

[0135] In preferred methods, the solvent comprises a volatile solvent, e.g. a solvent with a boiling point below about 100 ° C. In some embodiments, the solvent comprises a mixture of solvents, e.g. a mixture of volatile solvents or a mixture of volatile and non-volatile solvents. In the case where mixtures of solvents are used, the mixture may contain one or more non-volatile solvents, e.g. where the nonvolatile solvent is present in the mixture in an amount of less than about 15%, e.g. less than about 12%, less than about 10% , less than about 8%, less than about 5%, less than about 3% or less than about 2%.

[0136] Preferred solvents are those in which the compound 1 has a solubility of at least about 10 mg / ml (e.g., at least about 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml or more). More preferred solvents include those in which compound 1 has a solubility of at least about 50 mg / ml.

[0137] Exemplary solvents that can be tested include acetone, cyclohexane, dichloromethane, N, N-dimethylacetamide (DMA), N, N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethylsulfoxide (DMSO) , dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether, tetrahydrofuran (THF) and pentane. Examples of co-solvents include acetone / DMSO, acetone / DMF, acetone / water, MEK / water, THF / water, dioxane / water. In two-solvent systems, the solvents can range from about 0.1% to about 99.9%. In some preferred embodiments, the water is a co-solvent with acetone, wherein water is present in an amount of from about 0.1% to about 15%, e.g. about 9% to about 11%, e.g. about 10%. In certain preferred embodiments, the water is a co-solvent of MEK, wherein water is from about 0.1% to about 15%, e.g. about 9% to about 11%, e.g. about 10%. In some embodiments, the solvent solution comprises three solvents. For example, acetone and water may be mixed with a third solvent such as DMA, DMF, DMSO, DMI or HAc. In cases where the amorphous compound 1 is a component of the solid amorphous dispersion, preferred solvents dissolve both compound 1 and polymer. Suitable solvents include those described above, for example, MEK, acetone, water and mixtures thereof. In some embodiments, the solvent solution comprises three solvents. For example, acetone and water may be mixed with a third solvent such as DMA, DMF, DMSO, DMI or HAc. In cases where the amorphous compound 1 is a component of the solid amorphous dispersion, preferred solvents dissolve both compound 1 and polymer. Suitable solvents include those described above, for example, MEK, acetone, water and mixtures thereof. In some embodiments, the solvent solution comprises three solvents. For example, acetone and water may be mixed with a third solvent such as DMA, DMF, DMSO, DMI or HAc. In cases where the amorphous compound 1 is a component of the solid amorphous dispersion, preferred solvents dissolve both compound 1 and polymer. Suitable solvents include those described above, for example, MEK, acetone, water and mixtures thereof.

[0138] Particle size and drying temperature range may be modified to produce the optimal solid dispersion. As will be appreciated by qualified practitioners, a small particle size can lead to better solvent removal. Applicants have discovered, however, that smaller particles can lead to soft particles that under certain circumstances do not provide optimal solid dispersions for further processing, such as tableting. At higher temperatures, crystallization or chemical degradation of compound 1 may occur. At lower temperatures, a sufficient amount of solvent may not be removed. The present methods provide optimum particle size and optimal drying temperature.

08 g / cm to about 0.20 g / ml, e.g. from about 0.10 to about 0.15 g / ml, e.g. from about 0.11 g / ml or from about 0.14 g / ml, for example 10 presses; 0.10 g / cm to 0.25 g / ml, e.g. from about 0.11 to about 0.21 g / ml, e.g. from about 0.15 g / ml, about 0.19 g / ml, or from about 0.21 g / cm to 500 pressures; 0.15 g / cm to about 0.27 g / ml, e.g. from about 0.18 to about 0.24 g / ml, e.g. from about 0.18 g / ml, about 0.19 g / ml, about 0.20 g / ml or about 0.24 g / cm at 1250 pressures; and 0.15 g / cm to about 0.27 g / ml, e.g. from about 0.18 to about 0.24 g / ml, e.g. from about 0.18 g / ml, about 0.21 g / ml. , about 0.23 g / ml, or from about 0.24 g / ml to 2500 pressings. for example, from about 0.11 to about 0.21 g / ml, e.g. from about 0.15 g / ml, about 0.19 g / ml, or from about 0.21 g / cm in 500 pressures; 0.15 g / cm to about 0.27 g / ml, e.g. from about 0.18 to about 0.24 g / ml, e.g. from about 0.18 g / ml, about 0.19 g / ml, about 0.20 g / ml or about 0.24 g / cm at 1250 pressures; and 0.15 g / cm to about 0.27 g / ml, e.g. from about 0.18 to about 0.24 g / ml, e.g. from about 0.18 g / ml, about 0.21 g / ml. , about 0.23 g / ml, or from about 0.24 g / ml to 2500 pressings. for example, from about 0.11 to about 0.21 g / ml, e.g. from about 0.15 g / ml, about 0.19 g / ml, or from about 0.21 g / cm in 500 pressures; 0.15 g / cm to about 0.27 g / ml, e.g. from about 0.18 to about 0.24 g / ml, e.g. from about 0.18 g / ml, about 0.19 g / ml, about 0.20 g / ml or about 0.24 g / cm at 1250 pressures; and 0.15 g / cm to about 0.27 g / ml, e.g. from about 0.18 to about 0.24 g / ml, e.g. from about 0.18 g / ml, about 0.21 g / ml. , about 0.23 g / ml, or from about 0.24 g / ml to 2500 pressings.

[0140] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, the (Z) isomers and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. All tautomeric forms of compound 1 are included herein. For example, a compound of Formula 1 may exist in the form of tautomers, both of which are included in the present description:

<img file="PL1993360T3_D0002.tif" />

[0141] In addition, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of formula (I) wherein one or more hydrogen atoms are replaced by a deuterium or tritium, or one or more of the carbon atoms being replaced by 13C or 14C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological analyzes, or compounds with improved therapeutic profile.

Applications, formulation and administration

Pharmaceutically acceptable compositions [0142] In another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds described herein, and optionally include a pharmaceutically acceptable carrier, adjuvant or carrier. In certain embodiments, these compositions optionally further contain one or more additional therapeutic agents.

[0143] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with human tissues and lower animals without excessive toxicity, irritation, allergic reaction and the like. similar and are commensurate with a reasonable benefit / risk ratio. The term "pharmaceutically acceptable salt" means any non-toxic salt or salt of an ester of a compound of this invention that, when administered to a patient, is capable of providing, directly or indirectly, a compound of the present invention or a inhibitory active metabolite or a residue thereof.

[0144] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from the corresponding inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino group salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, acid tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art, such as ion exchange.⁺(C1-4alkyl) 4. The invention also provides quaternization of any groups containing a basic nitrogen atom in the compounds of the invention. Through such quaternization, soluble or dispersible products in water or in oil can be obtained. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In addition, pharmaceutically acceptable salts contain, if appropriate, non-toxic ammonium, quaternary ammonium and amine formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

[0145] As described above, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant or vehicle which, as used herein, includes any and all solvents, diluents or other liquid carrier, dispersion or suspension aids, agents surface active, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, suitable for the particular desired dosage form. Remington Pharmaceutical Sciences XVI edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used to formulate pharmaceutically acceptable compositions and known techniques for their preparation. While any conventional carrier is not incompatible with the compounds of the invention, i.e. it does not cause adverse biological effects or otherwise does not adversely affect any other component (s) of the pharmaceutically acceptable composition, its use is contemplated as being within the scope of the present invention. Some examples of materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or sorbate. potassium, mixtures of partial glycerides of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene polyoxypropylene block copolymers, wool fat, sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; binders such as magnesium hydroxide and buffering aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and flavoring agents, preservatives and antioxidants may also be present in composition, according to the judgment of the formulator.

Use of Compounds and Pharmaceutically Acceptable Compositions [0146] In yet another aspect, the present invention includes compounds for use in treating a condition, disease or disorder, which is directly mediated by CFTR. In certain embodiments, the present invention provides compounds for use in treating a condition, disease or disorder associated with a deficiency in CFTR activity. In one embodiment, a composition comprising a solid form of the compound 1 described herein (e.g., amorphous compound 1, e.g., in pure form or as an ingredient in a dispersion) may be used.

[0147] The term "CFTR mediated disease" as used herein is a disease selected from cystic fibrosis, hereditary emphysema, hereditary haemochromatosis, coagulation deficiency-fibrinolysis, such as protein C deficiency, hereditary type 1 angioedema, deficiencies. lipid processing, such as familial hypercholesterolemia, the presence of type 1 blood chilomicrons, abetalipoproteinemia, lysosomal storage diseases such as pseudo-Hurler cell disease I / polidystrophy, mukopolisacharydoz, Sandhof / Tay-Sachs, Krigler-Najjar type II, poliendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary parathyroidism, melanoma, type 1 AMS glycosylation disorders, hereditary emphysema, congenital hyperthyroidism,congenital bone fragility, hereditary deficiency of fibrinogen, ACT deficiency, diabetes insipidus DI (DI), renal DI syndrome, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive paralysis supranuclear disease, Pick's disease, several polyglutamine neurological disorders such as Huntington's disease, spinal-cerebellar type I, Kennedy's disease, tooth-red and pallidum fibrillosis and myotonic dystrophy, as well as spongiform encephalopathy, such as hereditary Creutzfeldt Jakob disease, Fabry, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.diabetes insipidus (DI), pituitary DI, renal DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders, such as such as Huntington's disease, spinal-cerebellar ataxia type I, Kennedy's disease, atrophy-red and pallidum ascotic dystrophy and myotonic dystrophy, as well as spongiform encephalopathy such as hereditary Creutzfeldt Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eyes and Sjogren's disease.diabetes insipidus (DI), pituitary DI, renal DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders, such as such as Huntington's disease, spinal-cerebellar ataxia type I, Kennedy's disease, atrophy-red and pallidum ascotic dystrophy and myotonic dystrophy, as well as spongiform encephalopathy such as hereditary Creutzfeldt Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eyes and Sjogren's disease.amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders, such as Huntington's disease, spinal-cerebellar type I, Kennedy's disease, atrophy red and pallidum ascitic dystrophy and myotonic dystrophy, as well as spongiform encephalopathy, such as hereditary disease of Creutzfeldt Jakob, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders, such as Huntington's disease, spinal-cerebellar type I, Kennedy's disease, atrophy red and pallidum ascitic dystrophy and myotonic dystrophy, as well as spongiform encephalopathy, such as hereditary disease of Creutzfeldt Jakob, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.such as hereditary Creutzfeldt Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.such as hereditary Creutzfeldt Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease.

hereditary deficiency of fibrinogen, ACT deficiency, diabetes insipidus DI (DI), renal DI syndrome, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick disease , several polyglutamine neurological disorders such as Huntington's disease, spinal cerebellar ataxia type I, Kennedy's disease, toothed reddish and pallidum mesocystic and myotonic dystrophy, as well as spongiform encephalopathy, such as the hereditary disease of Creutzfeldt Jakob, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease and Sjogren's disease. In one embodiment,

[0149] According to an alternative preferred embodiment, the present invention provides compounds for use in the treatment of cystic fibrosis. In one embodiment, a composition comprising a solid form of the compound 1 described herein (e.g., amorphous Compound 1, e.g., in pure form or as an ingredient in a dispersion) may be used.

According to the invention, an "effective amount" of the solid form of compound 1 described herein (e.g., amorphous compound 1, e.g., in pure form or as an ingredient in a dispersion) or a pharmaceutically acceptable composition thereof is an amount effective to treat or reduce severity of any of the diseases listed above.

A solid form of the compound 1 (e.g., amorphous compound 1, e.g., in pure form or as an ingredient in a dispersion) or a pharmaceutically acceptable composition thereof can be administered using any amount and any route of administration effective to treat or reduce the severity of one or more of the diseases listed above.

[0152] In certain embodiments, a solid form of the compound of the invention described herein (e.g., amorphous compound 1, e.g., in pure form or as an ingredient in a dispersion) or a pharmaceutically acceptable composition thereof is useful in treating or reducing the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory or non-respiratory epithelium. The presence of residual CFTR activity on the epithelial surface can be easily detected using methods known in the art, e.g. standard electrophysiological, biochemical or histochemical techniques. Such methods for the identification of CFTR activity using in vivo or ex vivo electrophysiological techniques, measure the concentration of Cl^- in sweat or saliva or ex vivo biochemical or histochemical techniques to monitor cell surface density. By means of such methods, residual CFTR activity can be easily detected in patients heterozygous or homozygous for a variety of mutations, including patients homozygous or heterozygous for the most common mutation, F508.

[0153] In one embodiment, the solid form of the compound 1 described herein (e.g., the amorphous compound 1, e.g., in pure form or as a component of the dispersion) or a pharmaceutically acceptable composition thereof, is useful for treating or reducing cystic fibrosis severity patients within certain genotypes showing residual CFTR activity, for example, Class III mutations (incorrect regulation or gating) Class IV mutations (altered conductivity) or Class V mutations (reduced synthesis) (Lee R. Choo-Kang Pamela L. Zeitlin Type I , II, III, IV and V, cystic fibrosis Tansmembrane Conductance Regulator Defects and Opportunities of Therapy; Current Opinion in Pulmonary Medicine 6: 521-529, 2000). Other genotypes of patients,

[0154] In one embodiment, the solid form of the compound 1 described herein (e.g., the amorphous compound 1, e.g., in pure form or as a component of the dispersion) or a pharmaceutically acceptable composition thereof, is useful for treating or reducing cystic fibrosis in patients within a certain clinical phenotype, e.g., a moderate mild clinical phenotype usually correlates with the amount of residual CFTR activity in the epithelial membrane epithelium. Such phenotypes include patients showing pancreatic insufficiency or patients with idiopathic pancreatitis and with congenital bilateral absence of the vas deferens or mild pulmonary disease.

[0155] The exact amount required will vary from subject to subject depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, the mode of administration, and the like. The compounds of the invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit with a suitable agent for the patient to be treated. It will be understood, however, that the total daily dose of the compounds and compositions of the invention will be determined by the attending physician in the field of sound medical judgment.

activity of the specific compound used; the particular composition used; the age, weight, general health, sex and diet of the patient; time of administration, route of administration and rate of excretion of the particular compound employed; duration of treatment; drugs used in combination or coincidentally with the specific compound employed and similar factors well known in the medical field. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human. [0156] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, in a receiver, vaginal, intraperitoneal, topical (as powders, ointments or drops), bucally, or as an oral or nasal spray or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at doses of about 0.01 mg / kg to about 50 mg / kg, and preferably from about 1 mg / kg to about 25 mg / kg of the patient's body weight per day, one or more times a day to get the desired therapeutic effect.

[0157] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solvents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed oil, peanut oil, corn oil, corn seed oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters with sorbitan and mixtures thereof.

[0158] Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated in accordance with the known art using suitable dispersing or wetting and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, a suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, e.g. as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile, fixed oils are traditionally used as a solvent or suspending medium. For this purpose, any inert fixed oil can be used including synthetic mono- or diglycerides. Also,

[0159] Injectable preparations may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that may be dissolved or dispersed before use in sterile water or another sterile injectable medium.

[0160] To prolong the effect of a compound of the present invention, it is often desirable to slow down the absorption of the compound after subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor solubility in water. The rate of absorption of the compound will then depend on the rate of its dissolution, which in turn may depend on the size of the crystal and the crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is accomplished by dissolving or suspending the compound in an oil vehicle. Depot injectable forms are prepared by forming microcapsule compound matrices in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the release rate of the compound can be adjusted. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0161] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of the invention with appropriate non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at room temperature. body, and therefore melt in the anus or cavity of the vagina and release the active compound.

[0162] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binding agents such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, starch potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retardants, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricating agents, such as talc, stearate calcium, magnesium stearate, solid polyethylene glycols, sodium lauryl sulphate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[0163] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be made with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release only the active ingredient (s), or preferably, in some of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0164] The active compounds may also be in microencapsulated form with one or more of the excipients listed above. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be made with coatings and shells, such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, e.g., tabletting lubricants, and other tableting additives, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may also be of a composition such that they release only the active ingredient (s), or preferably, in some of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0165] Dosage forms for topical or transdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffering agents, if required. Ocular formulations, ear drops and eye drops are also contemplated as being within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which has the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used, to increase the flow of the compound through the skin. The rate may be controlled either by introducing the rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0166] It should also be noted that the solid form of the compound 1 described herein (e.g., the amorphous compound 1, e.g., in pure form or as a component of the dispersion) or a pharmaceutically acceptable composition thereof, can be used in combination therapies, i.e. its pharmaceutically acceptable composition may be administered simultaneously, before or after the use of one or more desired therapeutic or medical procedures. When choosing a particular combination of therapies (therapeutic agents or procedures) for use in combination therapy, the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect will be taken into account. It should also be noted that that the therapies used may have the desired effect on the same disorder (e.g. a compound of the invention may be co-administered with another agent used to treat the same disorder) or may have other effects (e.g., control of any side effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are referred to as "suitable for the disease or condition being treated".

[0167] In one embodiment, the additional agent is selected from the group consisting of a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than the compound of the present invention, or a nutrient.

[0168] The amount of the additional therapeutic agent present in the compositions of the present invention will not be greater than the amount that would normally be administered in a composition containing this therapeutic agent as the sole active substance. Preferably, the amount of additional therapeutic agent of the compositions disclosed herein will range from about 50% to 100% of the amount normally present in a composition comprising this agent as the only therapeutically active agent.

The solid form of the compound 1 described herein (e.g., the amorphous compound 1, e.g., in pure form or as a component of the dispersion) or a pharmaceutically acceptable composition thereof, can also be incorporated into coating compositions for implantable medical devices, such as prostheses. , artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, comprises a coating composition of an implantable device comprising a solid form of the compound of the invention described herein (e.g., amorphous compound 1, e.g., in pure form or as a component of a dispersion) or a pharmaceutically acceptable composition thereof, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising the solid form of compound 1 described herein (e.g., amorphous compound 1, e.g., in pure form or as a dispersion component) or a pharmaceutically acceptable composition thereof, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantation devices are described in U.S. Patents 6,099,562; 5,886,026; and 5,304,121. Coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethyl vinyl acetate, and mixtures thereof. The coatings can optionally be additionally coated with a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol,

[0170] To be more fully understood in the present invention, the following examples are given.

EXAMPLES

Metody &amp; materiały

Differential Scanning Calorimetry (DSC) [0171] Differential Scanning Calorimetry (DSC) data for Form A, Form B and Amorphous Compound 1 were collected by DSC Q100 V9.6 Build 290 (TA Instruments, New Castle, DE). The temperature was calibrated with indium and the heat capacity was calibrated using sapphire. Samples of 3-6 mg were weighed into aluminum bowls, which were closed with a lid with a pin-sized hole. Samples were scanned from 25 ° C to 350 ° C at a heating rate of 10 ° C / min and under a nitrogen gas flow of 50 ml / min. Data were collected using the Advantage Thermal Q Series TM 2.2.0.248 software and analyzed by Universal Analysis 4.1D (TA Instruments, New Castle, DE). The given numbers represent individual analyzes.

Thermogravimetirc analysis (TGA) [0172] Thermogravimetric analysis (TGA) was carried out with TGA Q500 v6.3 Build 189 (TA Instruments, New Castle, DE) used to measure TGA. The temperature was equilibrated through the Curie point using nickel. Samples of 10-20 mg were scanned from 25 ° C to 350 ° C at a heating rate of 10 ° C / min. Blow-in nitrogen gas balancing at 10 ml / min was used, and a 90 ml / min sample was blown. Data were collected using the Advantage Thermal Q Series TM 2.2.0.248 software and analyzed by Universal Analysis 4.1D (TA Instruments, New Castle, DE). The given numbers represent individual analyzes.

XRPD (X-ray powder diffraction) [0173] X-ray diffraction data (XRD) for form A, form B and amorphous compound 1 were collected on a Bruker D8 Discover diffractometer from GADDS with a 2-dimensional Hi-Star detector and a flat graphite monochrome. The sealed tube from Cu with Kn radiation was used at 40 kV, 35mA. Samples were placed on a zero background silicon wafers at 25 ° C. For each trial, two data frames were collected for 120 seconds each at 2 different angles 2θ: 8 ° and 26 °. The frame data has been integrated with the GADDS software and connected to the DIFFRACT software^plus EVA.

[0174] Synthesis of N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide (Compound 1):

<img file="PL1993360T3_D0003.tif" />

2-Phenylaminomethylenemalonic acid diethyl ether A mixture of aniline (25.6 g, 0.275 mol) and diethyl 2- (ethoxymethylene) malonate (62.4 g,

0.288 mol) was heated at 140-150 ° C for 2 hours. The mixture was cooled to room temperature and dried in vacuo to give the 2-phenylaminomethylenemalonic acid diethyl ester in solid form which was used in the next step. Without further purification. NMR¹H (DMSO-d6) δ 11.00 (d, 1H), 8.54 (d, J = 13.6 Hz, 1H), 7.369.39 (m, 2H), 7.13-7.17 (m , 3H), 4.17-4. 33 (m, 4H), 1.18-1.40 (m, 6H).

4-Hydroxyquinoline-3-carboxylic acid ethyl ester A 1-liter three-necked flask combined with a mechanical stirrer was charged with 2-phenylaminomethylenemalonic acid diethyl ester (26.3 g, 0.100 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 mL). g). The mixture was heated to 70 ° C and stirred for 4 hours. The mixture was cooled to room temperature and filtered. The residue was treated with aqueous Na 2 CO 3 solution, filtered, washed with water and dried. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained in the form of a pale brown solid (15.2 g, 70%). The crude product was used in the next step without further purification.

4-Oxo-1,4-dihydroquinoline-3-carboxylic acid [0177] 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in a sodium hydroxide solution (2N, 150 mL) and stirred for 2 hours. at boiling point. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give 4-oxo-1,4-dihydroquinoline-325-carboxylic acid as a pale white solid (10.5 g, 92%). NMR¹H (DMSO-d6) δ.16 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H); ), 7.88 (m, 1H), 7.81 (d, J

8.4 Hz, 1H), 7.60 (m, 1H).

<img file="PL1993360T3_D0004.tif" />

2,4-di-tert-butylphenyl-methyl ester of carbonic acid Methyl chloroformate (58 ml, 750 mmol) was added dropwise to a solution of 2,4-di-tert-butylphenol (103.2 g, 500 mmol), Et3N ( 139 ml, 1000 mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 ml), cooled in an ice bath to 0 ° C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered through silica gel (about 1 L) using 10% ethyl acetate-hexanes (~ 4 L) as eluent. The combined filtrates were concentrated to give 2,4-di-tert-butylphenyl methyl ester of carbonic acid in the form of a yellow oil (132 g, quant.). NMR¹H (400 MHz, DMSO-d6) δ 7.35 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.5, 2.0 Hz, 1H), 7.06 ( d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H).

2,4-di-tert-butyl-5-nitrophenyl-methyl ester of carbonic acid and 2,4-di-tert-butyl-6-nitrophenyl-methyl of carbonic acid To a stirred mixture of 2,4-di-tert-butylphenyl ester -methyl carbonic acid (4.76 g, 180 mmol) in conc. sulfuric acid (2 ml), cooled in an ice bath, a cooled mixture of sulfuric acid (2 ml) and nitric acid (2 ml) was added. The addition was carried out slowly, so that the reaction temperature did not exceed 50 ° C. The reaction was allowed to stir for 2 hours while warming to room temperature. The reaction mixture was then added to ice water and extracted into diethyl ether. The ether layer was dried (MgSO4), concentrated and purified by column chromatography (0 10% ethyl acetate-hexanes) to give the ester mixture 2,

2.4-Di-tert-butyl-5-nitrophenol and 2,4-Di-tert-butyl-6-nitrophenol A mixture of tert-butyl-5-nitrophenyl methyl ester of carbonic acid and

2.4-di-tert-butyl-6-nitrophenyl-methyl carbonic acid (4.2 g, 14.0 mmol) was dissolved in MeOH (65 mL) before addition of KOH (2.0 g, 36 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then acidified (pH 2-3) by adding conc. HCl and partitioned between water and diethyl ether. The ether layer was dried (MgSO4), concentrated and purified by column chromatography (0-5% ethyl acetate hexanes) to give 2,4-di-tert-butyl-5-nitrophenol (1.31 g, 29% over 2 steps) and 2,4-di-tert-butyl-6-nitrophenol. 2,4-Di-tert-butyl-5-nitrophenol: NMR¹H (400 MHz, DMSO-d6) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1, 30 (s, 9H). 2,4-Di-tert-butyl-6-nitrophenol:

NMR ¹H (400 MHz, CDCl 3) δ 11.48 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H),

1.47 (s, 9H), 1.34 (s, 9H).

5-Amino-2,4-di-tert-butylphenol [0181] To the refluxed solution of 2,4-di-tert-butyl-5-nitrophenol (1.86 g,

7.40 mmol) and ammonium formate (1.86 g) in ethanol (75 ml) was added 5 wt% Pd on activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature and filtered through celite. The celite was washed with methanol and the combined filtrates were concentrated to give 5-amino-2,4-di-tert-butylphenol as a gray solid (1.66 g, quant.). NMR¹H (400 MHz, DMSO-d6) δ 8.64 (s, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, NH2), 1.27 (m, 18H); HPLC ret time 2.72 min, 10-99% CH 3 CN, 5 min run; ESI-MS 222.4 m / z [M + H]⁺.

N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-oxo-quinoline-3-carboxamide

<img file="PL1993360T3_D0005.tif" />

[0183] To a suspension of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (35.5 g, 188 mmol) and HBTU (85.7 g, 226 mmol) in DMF (280 mL) was added Et 3 N (63, 0 mL, 451 mmol) at ambient temperature. The mixture was homogenized and allowed to stir for 10 min before adding 5-amino-2,4-di-tert-butylphenol (50.0 g, 226 mmol) in small portions. The mixture was allowed to stir overnight at ambient temperature. The mixture became heterogeneous during the course of the reaction. After the whole acid was consumed (LC-MS analysis, MH + 190, 1.71 min), the solvent was removed under reduced pressure. EtOH was added to the orange solid material to form a slurry. The mixture was stirred on a rotary evaporator (bath temperature 65 ° C) for 15 min without placing the system under reduced pressure. The mixture was filtered and the trapped solid was washed with a mixture of hexanes to give a white solid, which was crystalline EtOH. Et 2 O was added to the material obtained above until the slurry formed. The mixture was stirred on a rotary evaporator (bath temperature 25 ° C) for 15 min without placing the system under reduced pressure. The mixture was filtered and the solid collected. This procedure was carried out five times. The solid obtained after the fifth precipitation was placed under reduced pressure overnight to give 8 N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide as white powdery solid (38 g, 52%). The mixture was stirred on a rotary evaporator (bath temperature 25 ° C) for 15 min without placing the system under reduced pressure. The mixture was filtered and the solid collected. This procedure was carried out five times. The solid obtained after the fifth precipitation was placed under reduced pressure overnight to give 8 N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide as white powdery solid (38 g, 52%). The mixture was stirred on a rotary evaporator (bath temperature 25 ° C) for 15 min without placing the system under reduced pressure. The mixture was filtered and the solid collected. This procedure was carried out five times. The solid obtained after the fifth precipitation was placed under reduced pressure overnight to give 8 N- [2,4-bis (1,1-dimethylethyl) -5-hydroxyphenyl] -1,4-dihydro-4-quinoquinoline-3-carboxamide as white powdery solid (38 g, 52%).

[0184] HPLC ret ret time 3.45 min, 10-99% CH 3 CN, 5 min run; NMR¹H (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 11.83 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 ( dd, J = 8.2, 1.0 Hz, 1H), 7.837,79 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54-7.50 (m , 1 H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H); ESI-MS 393.3 m / z [M + H]⁺.

[0185] Characteristic data for Compound 1 are shown below: Table 2 [0186] XRPD

<td>md nr</td><td>C-MS +1</td><td>C-RT in</td>

<td></td><td>93.2</td><td>71</td>

the spectrum of compound 1 is shown in FIG. 1.

[0187] NMR data ¹H for compound 1 are shown in FIG. 2.

[0188] The DSC graph of Compound 1 is shown in FIG. 3.

Preparation of Form A [0189] Form A was obtained by heating compound 1 in solid form to 250 ° C and cooling to room temperature. The DSC thermogram for Compound 1 (see FIG 6) shows that the compound melts with a start temperature of 195 ° C, followed by recrystallization at 220 ° C. [0190] The XRPD pattern of form A is shown in FIG. 4.

[0191] DSC data for Form A are shown in FIG. 5.

[0192] The TGA trace for form A is shown in FIG. 6.

Preparation of Form B [0193] Crude compound 1 was a suspension in refluxing acetonitrile (27 volumes) for 24 hours. After 24 hours, the mixture was allowed to cool to 20 ° C. Form B was isolated by filtration in white to off-white form. The wet cake was washed with acetonitrile (5 volumes) and dried under reduced pressure at 50 ° C until constant weight was obtained, thus providing form B.

[0194] The XRPD pattern of form B is shown in FIG. 7.

[0195] The DSC graph of the character B is shown in FIG. 8.

[0196] The TGA trace for form B is shown in FIG. 9.

[0197] Data for a single crystal was obtained for Form B, providing additional details about the crystal structure, including mesh size and packaging.

Crystal production:

[0198] 1 g of compound 1 was added to 10 ml of isopropanol acetate. The suspension was heated and kept at 60 ° C for 3 hours. The suspension was cooled to room temperature and kept stirring overnight. The solid suspension was filtered and washed with isopropanol acetate. The collected solid was dried in vacuo at room temperature. 300 mg of dried solids were dissolved in 5 ml of a 10% aqueous solution of ethyl acetate. The solution was heated to 70 ° C for 10 minutes before it was cooled to room temperature. Over time, the crystals grew in a vial.

Experimental part:

[0199] A single crystal of form B was mounted in a MicroMount loop and centered on a Bruker Apex II diffractometer, equipped with a sealed copper x-ray tube and an Apex II CCD sensor. Initially, 3 sets of 40 frames were collected to determine the initial elementary unit. A full set of data was then taken, consisting of 15 scans and 6084 frames. Data collection was carried out at 100 K. The data was integrated and scaled using the Apex II software from Bruker AXS. Integration and scaling resulted in 7528 reflections, 3071 of which were unique [R (int) = 0.0466)]. The structure was solved by direct methods in the space group P21 using the SHELXTL software. The refinement was performed using the least squares method in the complete matrix on F²also using the SHELXTL software. A total of 375 parameters were used for refining, resulting in a refractive index to the parameter of 8.19. The final refinement yielded a chiral structure with the Flacka parameter of 0.0 (3). The final refinement index is wR2 = 0,1242 and R1 = 0,0663 (wR2 = 0,1137 R1 = 0,0482, for reflections with I&gt; 2 sigma (I)).

[0200] A conformational image of Form B is given in FIGURE 10. Table 1. Crystal data and refinement of the structure for compound 1.

<td>Identification code</td><td>Compound 1</td><td></td>

<td>The empirical formula</td><td>C24 H28 N2 03</td><td></td>

<td>Molecular weight</td><td>392.48</td><td></td>

<td>Temperature</td><td>100 (2) K</td><td></td>

<td>Wavelength</td><td>1,54178 A</td><td></td>

<td>Crystal system</td><td>monoclinic</td><td></td>

<td>Spatial group</td><td>P21</td><td></td>

<td>Dimensions of the elementary unit</td><td>a = 11.8011 (7) A</td><td>α = 90 °.</td>

<td></td><td>b = 5.9819 (3) A</td><td>β = 105.110 (4) °.</td>

<td></td><td>c = 14.7974 (8) A</td><td>γ = 90 °.</td>

<td>Volume</td><td>1008.48 (10) A³</td><td></td>

<td>WITH</td><td>2</td><td></td>

<td>Density (calculated)</td><td>1.293 mg / m³</td><td></td>

<td>Absorption coefficient</td><td>0.681 mm^-1</td><td></td>

<td>F (000)</td><td>420</td><td></td>

<td>The size of the crystal</td><td>0.20 x 0.08 x 0.08 mm³</td><td></td>

<td>Theta range for the data set</td><td>3.09 to 68.67 °.</td><td></td>

<td>Limits of coefficients</td><td colspan="2">-14 &lt;= ​​h &lt;= 14, -7 &lt;= k &lt;= 7, -14 &lt;= ​​1 &lt;= 17</td>

<td>Reflections collected</td><td>7528</td><td></td>

<td>Independent reflections</td><td>3071 [R (int) = 0.0466]</td><td></td>

<td>Completeness to theta = 68.67 °</td><td>94.6%</td><td></td>

<td>Max and min transmission</td><td>0.9475 and 0.8758</td><td></td>

<td>Method of refinement</td><td colspan="2">least squares in the full matrix on F²</td>

<td>Data / og ran iczenie / pa rametry</td><td>3071/1/375</td><td></td>

<td>Adjustment factor to F²</td><td>1,001</td><td></td>

<td>Final indicators R [I&gt; 2sigma (I)]</td><td>R1 = 0.0482, wR2 = 0.1137</td><td></td>

<td>R indicators (all data)</td><td>R1 = 0.0663, wR2 = 0.1242</td><td></td>

<td>Absolute structure parameter</td><td>0.0 (3)</td><td></td>

<td>Extinction coefficient</td><td>0.0008 (6)</td><td></td>

<td>The biggest difference. peak and hole</td><td>0.200 and -0.218 eA^-3</td><td></td>

Table 2. Atomic coordinates (x 10⁴) and equivalent isotropic swing parameters (A²x 10³) for compound 1. U (eq.) is defined as one-third of the trace of the zonogonalized tensor

Uij.

<td></td><td>x</td><td>s</td><td>with</td><td>U (eq)</td>

<td>N (1)</td><td>11624 (2)</td><td>-530 (5)</td><td>8667 (2)</td><td>33 (1)</td>

<td>C (3)</td><td>10407 (3)</td><td>2650 (6)</td><td>8133 (2)</td><td>31 (1)</td>

<td>C (4)</td><td>10335 (3)</td><td>2115 (6)</td><td>7158 (2)</td><td>30 (1)</td>

<td>C (5)</td><td>11006 (3)</td><td>150 (6)</td><td>7013 (2)</td><td>31 (1)</td>

<td></td><td>x</td><td>s</td><td>with</td><td>U (eq)</td>

<td>C (2)</td><td>11034 (3)</td><td>1269 (6)</td><td>8830 (2)</td><td>32 (1)</td>

<td>C (8)</td><td>12233 (3)</td><td>-3643 (7)</td><td>6701 (3)</td><td>38 (1)</td>

<td>C (7)</td><td>11610 (3)</td><td>-2371 (7)</td><td>5947 (3)</td><td>37 (1)</td>

<td>C (6)</td><td>11015 (3)</td><td>-530 (6)</td><td>6093 (2)</td><td>35 (1)</td>

<td>C (9)</td><td>12255 (3)</td><td>-3039 (7)</td><td>7618 (2)</td><td>36 (1)</td>

<td>C (11)</td><td>9786 (3)</td><td>4549 (6)</td><td>8431 (2)</td><td>32 (1)</td>

<td>C (15)</td><td>6468 (3)</td><td>9414 (6)</td><td>7354 (2)</td><td>30 (1)</td>

<td>C (19)</td><td>7049 (3)</td><td>7025 (6)</td><td>6127 (2)</td><td>31 (1)</td>

<td>C (18)</td><td>8461 (3)</td><td>8580 (6)</td><td>8706 (2)</td><td>32 (1)</td>

<td>C (13)</td><td>8275 (3)</td><td>7448 (6)</td><td>7859 (2)</td><td>29 (1)</td>

<td>C (16)</td><td>6578 (3)</td><td>10442 (6)</td><td>8223 (2)</td><td>31 (1)</td>

<td>C (17)</td><td>7639 (3)</td><td>10044 (6)</td><td>8889 (2)</td><td>30 (1)</td>

<td>C (14)</td><td>7271 (3)</td><td>7965 (6)</td><td>7130 (2)</td><td>30 (1)</td>

<td>C (23)</td><td>5586 (3)</td><td>11841 (6)</td><td>8438 (2)</td><td>34 (1)</td>

<td>C (21)</td><td>8075 (3)</td><td>7722 (7)</td><td>5705 (2)</td><td>35 (1)</td>

<td>C (22)</td><td>5943 (3)</td><td>8034 (7)</td><td>5474 (2)</td><td>35 (1)</td>

<td>C (20)</td><td>6879 (3)</td><td>4481 (7)</td><td>6096 (3)</td><td>37 (1)</td>

<td>C (24)</td><td>4478 (3)</td><td>11888 (7)</td><td>7605 (3)</td><td>39 (1)</td>

<td>C (25)</td><td>5981 (3)</td><td>14254 (7)</td><td>8672 (3)</td><td>39 (1)</td>

<td>C (26)</td><td>5207 (3)</td><td>10760 (7)</td><td>9264 (3)</td><td>37 (1)</td>

<td>N (12)</td><td>9082 (2)</td><td>5775 (5)</td><td>7752 (2)</td><td>31 (1)</td>

<td>AT 11)</td><td>9923 (2)</td><td>4910 (4)</td><td>9289 (2)</td><td>37 (1)</td>

<td>AT 4)</td><td>9748 (2)</td><td>3206 (4)</td><td>6485 (2)</td><td>35 (1)</td>

<td>O (17)</td><td>7888 (2)</td><td>11078 (5)</td><td>9758 (2)</td><td>37 (1)</td>

<td>C (10)</td><td>11644 (3)</td><td>-1165 (6)</td><td>7761 (2)</td><td>32 (1)</td>

Table 3. Lengths of bonds [A] and angles [°] for compound 1.

<td>Tie</td><td>Length (° A)</td>

<td>N (1) -C (2)</td><td>1.337 (5)</td>

<td>N (1) -C (10)</td><td>1,400 (5)</td>

<td>C (3) -C (2)</td><td>1,377 (5)</td>

<td>C (3) -C (4)</td><td>1,458 (4)</td>

<td>C (3) -C (11)</td><td>1.481 (5)</td>

<td>C (4) -O (4)</td><td>1.240 (4)</td>

<td>C (4) -C (5)</td><td>1,465 (5)</td>

<td>C (5) -C (10)</td><td>1,406 (5)</td>

<td>C (5) -C (6)</td><td>1,423 (5)</td>

<td>C (8) -C (7)</td><td>1,391 (5)</td>

<td>C (8) -C (9)</td><td>1.398 (5)</td>

<td>C (7) -C (6)</td><td>1,353 (5)</td>

<td>C (9) -C (10)</td><td>1,379 (5)</td>

<td>C (11) -O (11)</td><td>1,255 (4)</td>

<td>C (11) -N (12)</td><td>1.343 (4)</td>

<td>C (15) -C (14)</td><td>1,387 (5)</td>

<td>C (15) -C (16)</td><td>1,399 (5)</td>

<td>C (19) -C (22)</td><td>1.531 (4)</td>

<td>C (19) -C (20)</td><td>1,534 (5)</td>

<td>C (19) -C (14)</td><td>1.544 (4)</td>

<td>C (19) -C (21)</td><td>1,558 (5)</td>

<td>C (18) -C (17)</td><td>1,385 (5)</td>

<td>C (18) -C (13)</td><td>1,390 (5)</td>

<td>C (13) -C (14)</td><td>1.413 (4)</td>

<td>C (13) -N (12)</td><td>1.418 (4)</td>

<td>C (16) -C (17)</td><td>1.397 (4)</td>

<td>C (16) -C (23)</td><td>1,539 (5)</td>

<td>Tie</td><td>Length (° A)</td>

<td>C (17) -O (17)</td><td>1.387 (4)</td>

<td>C (23) -C (25)</td><td>1,528 (5)</td>

<td>C (23) -C (24)</td><td>1,546 (5)</td>

<td>C (23) -C (26)</td><td>1.548 (5)</td>

<td>Tie</td><td>Angle (degrees)</td>

<td>C (2) -N (1) -C (10)</td><td>122.0 (3)</td>

<td>C (2) -C (3) -C (4)</td><td>119.4 (3)</td>

<td>C (2) -C (3) -C (11)</td><td>116.6 (3)</td>

<td>C (4) -C (3) -C (11).</td><td>123.9 (3)</td>

<td>O (4) -C (4) -C (3)</td><td>123.8 (3)</td>

<td>O (4) -C (4) -C (5)</td><td>120.9 (3)</td>

<td>C (3) -C (4) -C (5)</td><td>115.3 (3)</td>

<td>C (10) -C (5) -C (6)</td><td>117.2 (3)</td>

<td>C (10) -C (5) -C (4)</td><td>122.2 (3)</td>

<td>C (6) -C (5) -C (4)</td><td>120.6 (3)</td>

<td>N (1) -C (2) -C (3)</td><td>123.4 (3)</td>

<td>C (7) -C (8) -C (9)</td><td>120.6 (4)</td>

<td>C (6) -C (7) -C (8)</td><td>120.3 (4)</td>

<td>C (7) -C (6) -C (5)</td><td>121.2 (3)</td>

<td>C (10) -C (9) -C (8)</td><td>118.7 (3)</td>

<td>O (11) -C (11) -N (12)</td><td>123.7 (3)</td>

<td>O (11) -C (11) -C (3)</td><td>119.4 (3)</td>

<td>N (12) -C (11) -C (3)</td><td>117.0 (3)</td>

<td>C (14) -C (15) -C (16)</td><td>126.1 (3)</td>

<td>C (22) -C (19) -C (20)</td><td>106.8 (3)</td>

<td>C (22) -C (19) -C (14)</td><td>111.5 (3)</td>

<td>C (20) -C (19) -C (14)</td><td>112.2 (3)</td>

<td>Tie</td><td>Length (° A)</td>

<td>C (22) -C (19) -C (21)</td><td>105.4 (3)</td>

<td>C (20) -C (19) -C (21)</td><td>111.3 (3)</td>

<td>C (14) -C (19) -C (21)</td><td>109.4 (3)</td>

<td>C (17) -C (18) -C (13)</td><td>122.0 (3)</td>

<td>C (18) -C (13) -C (14)</td><td>119.0 (3)</td>

<td>C (18) -C (13) -N (12)</td><td>119.4 (3)</td>

<td>C (14) -C (13) -N (12)</td><td>121.5 (3)</td>

<td>C (17) -C (16) -C (15)</td><td>115.1 (3)</td>

<td>C (17) -C (16) -C (23)</td><td>122.4 (3)</td>

<td>C (15) -C (16) -C (23)</td><td>122.4 (3)</td>

<td>C (18) -C (17) -O (17)</td><td>118.2 (3)</td>

<td>C (18) -C (17) -C (16)</td><td>120.9 (3)</td>

<td>O (17) -C (17) -C (16)</td><td>120.8 (3)</td>

<td>C (15) -C (14) -C (13)</td><td>116.3 (3)</td>

<td>C (15) -C (14) -C (19)</td><td>120.1 (3)</td>

<td>C (13) -C (14) -C (19)</td><td>123.5 (3)</td>

<td>C (25) -C (23) -C (16)</td><td>110.9 (3)</td>

<td>C (25) -C (23) -C (24)</td><td>107.9 (3)</td>

<td>C (16) -C (23) -C (24)</td><td>112.1 (3)</td>

<td>C (25) -C (23) -C (26)</td><td>110.5 (3)</td>

<td>C (16) -C (23) -C (26)</td><td>109.2 (3)</td>

<td>C (24) -C (23) -C (26)</td><td>106.1 (3)</td>

<td>C (11) -N (12) -C (13)</td><td>127.2 (3)</td>

<td>C (9) -C (10) -N (1)</td><td>120.5 (3)</td>

<td>C (9) -C (10) -C (5)</td><td>121.9 (3)</td>

<td>N (1) -C (10) -C (5)</td><td>117.6 (3)</td>

[0201] Symmetry transformations used to generate equivalent atoms:

Table 4. Anisotropic swing parameters (A²x 10³) for compound 1. The exponent of the anisotropic tilt factor takes the form: -2²[h²and*²AT¹¹ + ... + 2 hka * b * U¹²]

<td></td><td>AT¹¹</td><td>U22</td><td>U33</td><td>U23</td><td>AT¹³</td><td>AT¹²</td>

<td>N (1)</td><td>42 (1)</td><td>41 (2)</td><td>14 (2)</td><td>5 (1)</td><td>4 (1)</td><td>3 (1)</td>

<td>C (3)</td><td>34 (2)</td><td>40 (2)</td><td>16 (2)</td><td>-1 (1)</td><td>4 (1)</td><td>-4 (1)</td>

<td>C (4)</td><td>34 (2)</td><td>38 (2)</td><td>17 (2)</td><td>0 (1)</td><td>4 (1)</td><td>-1 (1)</td>

<td>C (5)</td><td>34 (2)</td><td>42 (2)</td><td>17 (2)</td><td>-2 (1)</td><td>6 (1)</td><td>-6 (1)</td>

<td>C (2)</td><td>37 (2)</td><td>42 (2)</td><td>16 (2)</td><td>1 (1)</td><td>5 (1)</td><td>1 (2)</td>

<td>C (8)</td><td>44 (2)</td><td>41 (2)</td><td>30 (2)</td><td>-4 (2)</td><td>10 (1)</td><td>5 (2)</td>

<td>C (7)</td><td>46 (2)</td><td>44 (2)</td><td>22 (2)</td><td>-4 (1)</td><td>9 (1)</td><td>-5 (2)</td>

<td>C (6)</td><td>41 (2)</td><td>40 (2)</td><td>23 (2)</td><td>1 (2)</td><td>9 (1)</td><td>-1 (2)</td>

<td>C (9)</td><td>41 (2)</td><td>40 (2)</td><td>24 (2)</td><td>5 (1)</td><td>4 (1)</td><td>3 (2)</td>

<td>C (11)</td><td>35 (2)</td><td>41 (2)</td><td>18 (2)</td><td>1 (1)</td><td>4 (1)</td><td>-4 (2)</td>

<td>C (15)</td><td>37 (2)</td><td>37 (2)</td><td>15 (2)</td><td>4 (1)</td><td>3 (1)</td><td>1 (1)</td>

<td>C (19)</td><td>38 (2)</td><td>38 (2)</td><td>14 (2)</td><td>2 (1)</td><td>5 (1)</td><td>4 (1)</td>

<td>C (18)</td><td>36 (2)</td><td>42 (2)</td><td>14 (2)</td><td>4 (1)</td><td>0 (1)</td><td>0 (1)</td>

<td>C (13)</td><td>39 (2)</td><td>34 (2)</td><td>16 (2)</td><td>2 (1)</td><td>9 (1)</td><td>-3 (1)</td>

<td>C (16)</td><td>46 (2)</td><td>29 (2)</td><td>19 (2)</td><td>1 (1)</td><td>10 (1)</td><td>-3 (1)</td>

<td>C (17)</td><td>43 (2)</td><td>33 (2)</td><td>14 (2)</td><td>-2 (1)</td><td>7 (1)</td><td>-6 (1)</td>

<td>C (14)</td><td>38 (2)</td><td>38 (2)</td><td>11 (2)</td><td>1 (1)</td><td>3 (1)</td><td>-3 (2)</td>

<td>C (23)</td><td>46 (2)</td><td>40 (2)</td><td>20 (2)</td><td>2 (1)</td><td>13 (1)</td><td>3 (2)</td>

<td>C (21)</td><td>51 (2)</td><td>45 (2)</td><td>8 (2)</td><td>2 (1)</td><td>7 (1)</td><td>0 (2)</td>

<td>C (22)</td><td>44 (2)</td><td>41 (2)</td><td>16 (2)</td><td>-7 (1)</td><td>1 (1)</td><td>2 (2)</td>

<td>C (20)</td><td>40 (2)</td><td>46 (2)</td><td>20 (2)</td><td>-1 (2)</td><td>3 (1)</td><td>1 (2)</td>

<td>C (24)</td><td>44 (2)</td><td>49 (2)</td><td>24 (2)</td><td>-2 (2)</td><td>10 (1)</td><td>5 (2)</td>

<td>C (25)</td><td>52 (2)</td><td>43 (2)</td><td>24 (2)</td><td>3 (1)</td><td>12 (2)</td><td>9 (2)</td>

<td>C (26)</td><td>48 (2)</td><td>40 (2)</td><td>24 (2)</td><td>1 (1)</td><td>14 (1)</td><td>0 (2)</td>

<td>N (12)</td><td>40 (1)</td><td>41 (2)</td><td>12 (2)</td><td>0 (1)</td><td>5 (1)</td><td>0 (1)</td>

<td>AT 11)</td><td>48 (1)</td><td>47 (1)</td><td>13 (1)</td><td>1 (1)</td><td>4 (1)</td><td>5 (1)</td>

<td></td><td>AT¹¹</td><td>AT²²</td><td>AT³³</td><td>AT²³</td><td>AT¹³</td><td>AT¹²</td>

<td>AT 4)</td><td>46 (1)</td><td>46 (2)</td><td>12 (1)</td><td>3 (1)</td><td>4 (1)</td><td>7 (1)</td>

<td>O (17)</td><td>44 (1)</td><td>45 (2)</td><td>18 (1)</td><td>-6 (1)</td><td>4 (1)</td><td>4 (1)</td>

<td>C (10)</td><td>37 (2)</td><td>37 (2)</td><td>21 (2)</td><td>0 (1)</td><td>8 (1)</td><td>-2 (2)</td>

Table 5. Hydrogen coordinates (x 10⁴) and isotropic swing parameters (A²x 10³) for a relationship

1.

<td></td><td>x</td><td>s</td><td>with</td><td>U (eq)</td>

<td>H (7)</td><td>11560 (30)</td><td>-2840 (70)</td><td>5320 (30)</td><td>35 (10)</td>

<td>H (9)</td><td>12670 (30)</td><td>-3980 (70)</td><td>8120 (30)</td><td>38 (10)</td>

<td>H (8)</td><td>12680 (30)</td><td>-4860 (70)</td><td>6660 (30)</td><td>36 (10)</td>

<td>H (6)</td><td>10550 (30)</td><td>350 (80)</td><td>5580 (30)</td><td>51 (13)</td>

<td>H (15)</td><td>5770 (30)</td><td>9730 (70)</td><td>6900 (30)</td><td>30 (9)</td>

<td>H (18)</td><td>9150 (20)</td><td>8310 (50)</td><td>9160 (20)</td><td>12 (7)</td>

<td>H (17)</td><td>8620 (30)</td><td>10600 (60)</td><td>10030 (30)</td><td>25 (9)</td>

<td>H (20A)</td><td>7470 (30)</td><td>3650 (70)</td><td>6460 (30)</td><td>32 (10)</td>

<td>H (20B)</td><td>6130 (30)</td><td>4320 (80)</td><td>6280 (30)</td><td>43 (11)</td>

<td>H (21A)</td><td>8840 (30)</td><td>6840 (70)</td><td>5980 (30)</td><td>40 (11)</td>

<td>H (21B)</td><td>8160 (30)</td><td>9370 (80)</td><td>5790 (30)</td><td>42 (11)</td>

<td>H (22B)</td><td>5990 (30)</td><td>9620 (70)</td><td>5480 (30)</td><td>31 (9)</td>

<td>H (22A)</td><td>5790 (30)</td><td>7200 (80)</td><td>4820 (30)</td><td>48 (12)</td>

<td>H (24A)</td><td>3800 (40)</td><td>12810 (90)</td><td>7750 (30)</td><td>57 (13)</td>

<td>H (24B)</td><td>4210 (30)</td><td>10410 (70)</td><td>7420 (30)</td><td>34 (10)</td>

<td>H (25A)</td><td>5370 (30)</td><td>15130 (60)</td><td>8770 (20)</td><td>24 (9)</td>

<td>H (25B)</td><td>6240 (30)</td><td>15040 (70)</td><td>8150 (30)</td><td>41 (11)</td>

<td>H (25C)</td><td>6690 (30)</td><td>14100 (80)</td><td>9230 (30)</td><td>44 (11)</td>

<td>H (26A)</td><td>4600 (30)</td><td>11790 (60)</td><td>9320 (20)</td><td>17 (8)</td>

<td>H (26B)</td><td>5000 (30)</td><td>9350 (70)</td><td>9090 (30)</td><td>28 (9)</td>

<td>H (1)</td><td>12000 (30)</td><td>-1450 (70)</td><td>9140 (30)</td><td>40 (11)</td>

<td></td><td>x</td><td>s</td><td>with</td><td>U (eq)</td>

<td>H (2)</td><td>11050 (40)</td><td>1550 (80)</td><td>9460 (40)</td><td>56 (13)</td>

<td>H (26C)</td><td>5950 (30)</td><td>10770 (80)</td><td>9820 (30)</td><td>51 (12)</td>

<td>H (24C)</td><td>4720 (40)</td><td>12850 (100)</td><td>7170 (40)</td><td>69 (15)</td>

<td>H (22C)</td><td>5150 (40)</td><td>7470 (70)</td><td>5610 (30)</td><td>42 (11)</td>

<td>H (21C)</td><td>7820 (40)</td><td>7310 (90)</td><td>5040 (40)</td><td>62 (14)</td>

<td>H (20C)</td><td>6780 (30)</td><td>3790 (70)</td><td>5480 (30)</td><td>48 (12)</td>

<td>H (12)</td><td>9030 (40)</td><td>5290 (90)</td><td>7280 (40)</td><td>62 (16)</td>

Preparation of the amorphous form from form B [0202] In this method, a Buchi spray dryer was used, under the following conditions: Inlet set temperature: 130 ° C

Outlet temperature (start of run) 55 ° C Outlet temperature (end of run): 58 ° C. Nitrogen pressure: 120psi

Aspirator: 100%

Pump: 40%

The filter pressure is 11 mbar

Condenser temperature: 10 ° C Operating time 15 min. Efficiency: 86.5%

It is dried at 25 ° C under vacuum for 24 hours.

[0203] 4g of form B was dissolved in 86.4g of acetone and 9.6g of water under the above conditions.

The working time was 15 minutes. The product was dried under reduced pressure at 25 ° C for over 24 hours to produce the amorphous form.

[0204] The XRPD spectrum of the amorphous form is shown in FIG. 11.

[0205] The TGA trace for the amorphous form is shown in FIG. 12.

[0206] The DSC trace for the amorphous form is shown in FIG. 13.

PK and solubility of various solid forms of compound 1 [0207] The bioavailability of crystalline form B, 85% of amorphous compound 1 and solid dispersion of compound 1 and HPMCAS, was evaluated in rat, the results of which are shown in Table 4 below. These forms of the compound were administered in the form of an oral suspension with a carrier containing 0.5% methylcellulose / 0.5% SLS / 99% water. The bioavailability of the various solid forms was evaluated in comparison to the multi-component solution IV of Compound 1. The bioavailability of the crystalline polymorph B was 3-6%, compared with 61-95% for the amorphous material and 109-111% for the solid dispersion. In FaSSIF, the crystalline polymorph B has a measured solubility of

1.0 μg / ml, while 85% of the amorphous material has a solubility of 67.4 μg / ml. The crystalline material showed 67-74% bioavailability when administered as a PEG solution, indicating that the absorption was limited by solubility.

Table 4

<td>The form of the drug</td><td>Carrier</td><td>Dose (Mg / kg)</td><td colspan="2">AUC (Ug * hr / ml)</td><td colspan="2">Tmax (H)</td><td colspan="2">% F</td>

<td>85% Amorphous</td><td>0.5% MC / 0.5% SLS</td><td>50</td><td>135.5</td><td>27.6</td><td>6.0</td><td>0.0</td><td>95.0</td><td>20.0</td>

<td>85% Amorphous</td><td>0.5% MC / 0.5% SLS</td><td>200</td><td>371.9</td><td>46.1</td><td>6.0</td><td>0.0</td><td>61.0</td><td>7.0</td>

<td>Crystalline</td><td>0.5% MC / 0.5% SLS</td><td>50</td><td>8.0</td><td>1.2</td><td>4.0</td><td>0.0</td><td>5.5</td><td>0.8</td>

<td>Crystalline</td><td>0.5% MC / 0.5% SLS</td><td>200</td><td>16.9</td><td>3.0</td><td>4.7</td><td>1.2</td><td>3.1</td><td>0.3</td>

<td>Crystalline</td><td>PEG</td><td>50</td><td>135.1</td><td>43.0</td><td>5.5</td><td>1.0</td><td>74.0</td><td>23.0</td>

<td>Crystalline</td><td>PEG</td><td>200</td><td>431.5</td><td>101.1</td><td>14.5</td><td>11.0</td><td>67.0</td><td>16.0</td>

<td>Constant dispersion</td><td>0.5% MC / 0.5% SLS</td><td>25</td><td>90.1</td><td>8.1</td><td>6.0</td><td>0.0</td><td>111.0</td><td>10.0</td>

<td>Constant dispersion</td><td>0.5% MC / 0.5% SLS</td><td>100</td><td>260.8</td><td>28.4</td><td>6.0</td><td>0.0</td><td>109.0</td><td>12.0</td>

Vertex Pharmaceuticals Incorporated, USA

Proxy:

EP 1 993 360 B1

Z-15762