Solid complexes comprising urea and semifluorinated alkanes

Abstract

The present invention provides processes for the purification of semifluorinated alkanes of the Formula (SFA) comprising formation of solid complexes comprising the semifluorinated alkane and urea, processes for the preparation of the solid complexes and the semifluorinated alkanes derived therefrom. Also provided are pharmaceutical compositions comprising the semifluorinated alkanes and uses thereof in the treatment of dry eye disease. F3C(CF2)x(CH2)yCH3 (SFA)

Description

SOLID COMPLEXES COMPRISING UREA AND SEMIFLUORINATED ALKANESTECHNICAL FIELD

[0001] The present invention relates to semifluorinated alkanes, processes for the purification thereof and products produced therefrom. Also provided are pharmaceutical compositions comprising semifluorinated alkanes and uses thereof in the treatment of dry eye disease.BACKGROUND

[0002] Certain semifluorinated alkanes are reported to be useful in the treatment of diseases or conditions affecting ophthalmic tissues. Perfluorohexyloctane (1), is the active pharmaceutical ingredient in branded pharmaceutical MIEBO™, a prescription medication indicated for the treatment of the signs and symptoms of dry eye disease (DED).

[0003] Various synthetic processes for the preparation of semifluorinated alkanes are reported. For example, US 10,717,691 B2, discloses the process for preparation of perfluorohexyloctane (1) depicted in Scheme 1. Perfluorohexyl iodide (B) is reacted with 1 -octene in the presence of radical initiator azobisisobutyronitrile (AIBN) to afford iodinated intermediate (A), which undergoes reductive dehalogenation with sodium borohydride in the presence of a Urushibara metal catalyst (U-cat.) to afford perfluorohexyloctane (1).Scheme 1 (Prior Art)

[0004] Other processes for the preparation of semifluorinated alkanes, including perfluorohexyloctane (1), are reported in, for example, ON 102659507 A, ON 106631681 A, JP 2019-108319 A, Postigo et al. J. Org. Chem. 2010, 75, 6141-6148, US 2019 / 9971376 A1 , ON 115703693 A, Kishikawa et al. J. Org. Chem. 2017, 82, 5469-5474 and WO 2018 / 228975 A1.

[0005] According to the product label, pharmaceutical brand product “MIEBO™ (perfluorohexyloctane ophthalmic solution) is a sterile, clear and colorless liquid containing 100% perfluorohexyloctane, for topical ophthalmic use”. Clearly, the purity of an ophthalmic solution administered in undiluted form directly to the tissue of the eye is of great importance.

[0006] WO 2018 / 228975 A1 reports formation of impurities during synthesis of perfluorohexyloctane (1) according to prior art methods, notably a branched isomer shown below as Formula IMP-BR, as well as an olefinic by-product.(IMP-BR)

[0007] Known methods for the purification of liquid semifluorinated alkanes such as perfluorohexyloctane (1) include distillation and / or chromatography, which are resource-intensive and technically challenging and afford modest results.

[0008] Owing to the need for semifluorinated alkanes such as perfluorohexyloctane (1) having high purity for use in pharmaceuticalapplications, there remains a need for improved processes for the provision of semifluorinated alkanes such as perfluorohexyloctane (1 ), that are amenable to scale-up and use on a commercial scale.SUMMARY OF THE INVENTION

[0009] In the present invention, there is provided a solid complex comprising urea and a semifluorinated alkane of the Formula (SFA):F3C(CF2)x(CH2)yCH3 (SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9.

[0010] Surprisingly, it was discovered by the present inventors that a semifluorinated alkane of the Formula (SFA), most embodiments of which exist as liquids at ambient conditions, can be incorporated with urea into a solid complex. Conveniently, the solid complex is isolatable by simple methods such as filtration and provides a convenient purification opportunity that is amenable to industrial application. An embodiment of the solid complex comprising perfluorohexyloctane and urea exhibits a novel powder x-ray diffractogram (PXRD). The solid complex is also easily dissociated to afford the corresponding semifluorinated alkane in high purity. In particular, the levels of persistent impurities such as a branched impuriy can be reduced by applying the processes of the present invention.

[0011] Accordingly, in a first aspect of the present invention, there is provided a solid complex comprising urea and a semifluorinated alkane of Formula (SFA) F3C(CF2)x(CH2)yCH3, wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9. In a preferred embodiment of the first aspect, the mole ratio of urea to the semifluorinated alkane in the complex ranges from about 1 ,5n to about 2.5n, wherein n is the total number of carbon atoms in the semifluorinated alkane, more preferably the mole ratio of urea to the semifluorinated alkane in the complex is about 2n. In a further preferredembodiment of the first aspect, x is 4 or 5 and y is 6 or 7, more preferably, x is 5 and y is 7.

[0012] In a second aspect of the present invention, there is provided a process for the preparation of a solid complex comprising urea and a semifluorinated alkane of Formula (SFA), wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, the process comprising a) treating, in the presence of a suitable solvent (S1), the semifluorinated of Formula (SFA) with at least 1 ,5n mole equivalents of urea, wherein n is the total number of carbon atoms in the semifluorinated alkane, and obtaining a solution; b) crystallizing a solid complex comprising urea and the semifluorinated alkane from the solution; and c) isolating the solid complex. In a preferred embodiment of the second aspect, the amount of urea in mole equivalents with respect to the semifluorinated alkane used ranges from 1.5n to about 3n. In a further preferred embodiment of the second aspect, obtaining a solution comprises maintaining the semifluorinated alkane and urea in the suitable solvent (S1) at a temperature ranging from about 40 °C to about 60 °C to afford a solution. In another preferred embodiment of the second aspect, the suitable solvent (S1) is a mixture of methanol and 2-propanol. In a further preferred embodiment of the second aspect, crystallizing comprises cooling the solution to a temperature ranging from about 0 °C to about 15 °C. In another preferred embodiment of the second aspect, the solid complex is isolated by filtration.

[0013] In a third aspect of the present invention, there is provided a process for the purification of a semifluorinated alkane of Formula (SFA) F3C(CF2)x(CH2)yCH3, wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, the process comprising a) treating, in the presence of a suitable solvent (S1 ), a crude semifluorinated alkane of Formula (SFA) with at least 1 ,5n mole equivalents of urea, wherein n is the total number of carbon atoms in the semifluorinated alkane, and obtaining a solution; b) crystallizing a solid complex comprising urea and the semifluorinated alkane from the solution; c) isolating the solid complex; d) dissociating the solid complex in suitable conditions to liberate the semifluorinated alkane; and e) isolating the liberated semifluorinated alkane in purified form. In a further preferred embodiment ofthe third aspect, obtaining a solution comprises maintaining the semifluorinated alkane and urea in the suitable solvent (S1 ) at a temperature ranging from about 40 °C to about 60 °C to afford a solution. In another preferred embodiment of the third aspect, the suitable solvent (S1 ) is a mixture of methanol and 2- propanol. In a further preferred embodiment of the third aspect, crystallizing comprises cooling the solution to a temperature ranging from about 0 °C to about 15 °C. In another preferred embodiment of the third aspect, the solid complex is isolated by filtration. In a further preferred embodiment of the third aspect, the dissociating comprises maintaining an aqueous solution of the complex until dissolution occurs. In another preferred embodiment of the third aspect, the semifluorinated alkane is isolated by extraction of the aqueous solution with an organic solvent and evaporation of the solvent.

[0014] In a fourth aspect of the present invention, there is provided a crystalline form comprising urea and perfluorohexyloctane characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 10.2°, 20.4°, and 27.4°. In a preferred embodiment of the fourth aspect, the crystalline form further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 7.3°, 13.3°, 16.2°, 19.4°, 21.1 °, and 21 .4°. In a further preferred embodiment, the crystalline form further comprises peaks, expressed in degrees 20 (± 0.2°), at 7.3°, 13.3°, 16.2°, 19.4°, 21.1 °, and 21.4°. In another preferred embodiment of the fourth aspect, the crystalline form provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 1.

[0015] In a fifth aspect of the present invention, there is provided a semifluorinated alkane of Formula (SFA): F3C(CF2)x(CH2)yCH3, wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, produced by a process comprising the steps of a) dissociating a solid complex comprising the semifluorinated alkane and urea to liberate the semifluorinated alkane; and b) isolating the liberated semifluorinated alkane. In a further preferred embodiment of the fifth aspect, x is 4 or 5 and y is 6 or 7, preferably still x is 5 and y is 7. In a further preferred embodiment of the fifth aspect, the mole ratio of urea to the semifluorinated alkane in the complex ranges from about 1 ,5n toabout 2.5n, wherein n is the total number of carbon atoms in the semifluorinated alkane. In a further preferred embodiment of the fifth aspect, the dissociating comprises maintaining an aqueous solution of the complex until dissolution occurs. In another preferred embodiment of the fifth aspect, the semifluorinated alkane is isolated by extraction of the aqueous solution with an organic solvent and evaporation of the solvent.

[0016] In a sixth aspect of the present invention, there is provided a liquid pharmaceutical composition for administration to ophthalmic tissue comprising the semifluorinated alkane of Formula (SFA) of the fifth aspect, and one or more pharmaceutically acceptable excipients. In a preferred embodiment of the sixth aspect, the composition consists of the semifluorinated alkane. Further preferred in the sixth aspect, is that in the composition, x is 5 and y is 7 and the semifluorinated alkane is perfluorohexyloctane.

[0017] In a seventh aspect of the present invention, there is provided a method of treating keratoconjunctivitis sicca (dry eye disease) in a patient in need of such treatment, comprising topically administering to the affected tissue, a therapeutically effective amount of the liquid pharmaceutical composition of the sixth aspect. In a preferred embodiment of the seventh aspect, the pharmaceutical composition consists of perfluorohexyloctane.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Embodiments of the present invention are described, by way of example only, with reference to the attached Figures.

[0019] Figure 1 is a representative PXRD diffractogram of the solid complex comprising urea and perfluorohexyloctane as prepared in Example 2.

[0020] Figure 2 is a representative PXRD diffractogram of the urea used as starting material in Example 2.DETAILED DESCRIPTION

[0021] The present invention provides solid complexes comprising urea and a semifluorinated alkane of Formula (SFA). These complexes offer anopportunity to purify a semifluorinated alkane, which are predominantly liquids at ambient conditions, by incorporation into a solid phase that is easily isolated by industrially compatible processes such as filtration. Furthermore, the semifluorinated alkanes are easily recovered by dissociation, often in purified form and suitable for use in pharmaceutical compositions.

[0022] As used herein, “ambient conditions” generally refers to a temperature of 20-25 °C and 1 bar.

[0023] As used herein, the term “about” means “close to”, and that variation from the exact value that follows the term is within amounts that a person of skill in the art would understand to be reasonable. For example, when the term “about” is used with respect to temperature, a variation of ± 5 °C is generally acceptable when carrying out the processes of the present invention. When used with respect to mole equivalents, a variation of ± 0.1 moles is generally acceptable.

[0024] As used herein, the term “volumes” refers to the parts of liquids by volume (mL) with respect to the weight of solute (g). For example, when an experiment is conducted using 1 g of starting material and 100 mL of solvent, it is said that 100 volumes of solvent is used.

[0025] As used herein, the term “weight percentage” (wt%) refers to the ratio of the weight of a subject component to the weight of the subject mixture, using the same weight unit, expressed as a percentage.

[0026] Unless otherwise stated, any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of “1 to 10” is intended to include any and all sub-ranges between and including the recited minimum value of 1 and the recited maximum value of 10, that is, all subranges beginning with a minimum value equal to or greater than 1 and ending with a maximum value equal to or less than 10, and all subranges in between, e.g., 1 to 6.3, or 5.5 to 10, or 2.7 to 6.1.

[0027] As used herein, the phrase “therapeutically effective amount” means that amount of semifluorinated alkane of Formula (SFA) that will elicit abiological or medical response of a tissue, system, or patient that is being sought by the administrator (such as a researcher, doctor, or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing, or halting of progression of the condition or disease, including but not limited to a condition or disease of an eye or ophthalmic tissue, such as an inflammatory condition of the ophthalmic tissue or keratoconjunctivitis sicca (dry eye disease). In some examples, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. For convenience, the total daily dosage may be divided and administered in portions during the day as required. In some examples, the dosage can range from about 10 mg / day to about 100 mg / day. Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[0028] As used herein, chromatographic purity, expressed in area%, is determined by area normalisation of a gas chromatography (GC) profile obtained using a method as disclosed herein. The purity of a sample is determined based on the ratio of the peak area of the analyte, such as a semifluorinated alkane of Formula (SFA) or an impurity of Formula SFA-BR, to the total peak area of all components in the sample.

[0029] Depending on the manner of preparation of the form and the methodology and instrument used for PXRD analysis, the intensity of a given peak observed in a PXRD diffractogram may vary when compared to the same peak in the representative PXRD diffractogram provided in Figure 1. Thus, differences in relative peak intensities between peaks in a PXRD diffractogram of a sample may be observed when compared to the relative peak intensities of the peaks in the representative PXRD diffractogram of Figure 1. Any such differences may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, the preparation of the sample for analysis, and the methodology applied for the analysis. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0030] In addition to the differences in relative peak intensities that may be observed in comparison to the representative PXRD diffractogram provided in Figure 1 , it is understood that individual peak positions may vary between ±0.2° 20 from the values observed in the representative PXRD diffractogram provided in Figure 1 or listed in Table 1. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0031] Further, depending on the instrument used for X-ray analysis and its calibration, uniform offsets in the peak position of each peak in a PXRD diffractogram of greater that 0.2° 20 may be observed when compared to the representative PXRD diffractogram provided in Figure 1. Thus, PXRD diffractograms of the form of the present invention may, in some circumstances, display the same relative peak positions as observed in the representative PXRD diffractogram provided in Figure 1 , with the exception that each peak is offset in the same direction, and by approximately the same amount, such that the overall PXRD diffractogram is substantially the same in appearance as the PXRD diffractogram of Figure 1 , with the exception of the uniform offset in peak positions. The observation of any such uniform peak shift in a PXRD diffractogram does not depart from the invention disclosed herein given that the relative peak positions of the individual peaks within the PXRD diffractogram remain consistent with the relative peak positions observed in the PXRD diffractogram of Figure 1 .

[0032] In one embodiment of the present invention, there is provided a solid complex comprising urea and a semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3(SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9.

[0033] In the semifluorinated alkanes of the present invention, x is an integer ranging from 2 to 6 and y is an integer ranging from 4 to 9. Preferred examplesinclude perfluorobutyloctane (x is 3, y is 7), perfluorohexyloctane (x is 5, y is 7), perfluorohexylheptane (x is 5, y is 6), perfluorohexylnonane (x is 5, y is 8), perfluorohexyldecane (x is 5, y is 9). Preferably, the semifluorinated alkane is a liquid or semi-solid, most preferably a liquid, at ambient conditions of temperature and pressure. Most preferably, the semifluorinated alkane is perfluorohexyloctane (1 ).

[0034] The solid complex of the present invention comprises urea and a semifluorinated alkane of Formula (SFA). The urea in the complex is often present in a molar excess relative to the semifluorinated alkane. For example, the mole ratio of urea to the semifluorinated alkane in the complex may range from about 1.5n to about 2.5n, wherein n is the total number of carbon atoms in the semifluorinated alkane. Preferably, the mole ratio is about 2n. For example, in a solid complex comprising 2n urea and perfluorohexyloctane (1), the mole ratio of urea to the perfluorohexyloctane in the complex is about 28 to 1.

[0035] In a second embodiment of the present invention, there is provided a crystalline form of a solid complex comprising urea and perfluorohexyloctane, termed Form APO-I. In a certain embodiment, the molar ratio of urea to perfluorohexyloctane in Form APO-I is about 21 :1 to about 28:1.

[0036] Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 20 (± 0.2°), at 10.2°, 20.4°, and 27.4°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of 7.3°, 13.3°, 16.2°, 19.4°, 21.1 °, and 21.4°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 20 (± 0.2°), at 7.3°, 13.3°, 16.2°, 19.4°, 21.1 °, and 21.4°.

[0037] An illustrative PXRD diffractogram of Form APO-I, as prepared in Example 2, is shown in Figure 1. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 1 , and their relative intensities, is provided in Table 1. Although illustrative of the PXRD diffractogram that is provided for the Form APO-I of the present invention, the relative intensities ofthe peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0038] In a third embodiment of the present invention, there is provided a process for the preparation of the solid complex comprising urea and a semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3(SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, the process comprising: a) treating, in the presence of a suitable solvent (S1), the semifluorinated alkane with at least 1 ,5n mole equivalents of urea, wherein n is the total number of carbon atoms in the semifluorinated alkane, and obtaining a solution; b) crystallizing a solid complex comprising urea and the semifluorinated alkane from the solution; andc) isolating the solid complex;

[0039] The semifluorinated alkane is treated with urea in the presence of a suitable solvent (S1). Preferably, the suitable solvent is capable of solubilizing both the semifluorinated alkane and the urea while maintaining some degree of miscibility in the system, particularly at an elevated temperature. Preferably, the suitable solvent (S1) is a short-chain alcohol selected from the group consisting of methanol, 1 -propanol, 2-propanol, 1 -butanol, and mixtures thereof. Most preferably, the suitable solvent (S1) is a mixture of methanol and 2-propanol enriched in methanol.

[0040] The semifluorinated alkane is treated with at least about 1.5n mole equivalents of urea, wherein n is the total number of carbon atoms in the semifluorinated alkane. Preferably, sufficient urea is used to produce a supersaturated solution in the suitable solvent at ambient conditions; often the amount used ranges from about 1 ,5n to about 3n.

[0041] A solution of the semifluorinated alkane and the urea is obtained by heating to a suitable temperature, for example, to a temperature ranging from about 40 °C to about the boiling point of the suitable solvent, if necessary. Preferably, the temperature ranges from about 40 °C to about 60 °C.

[0042] The solid complex comprising urea and the semifluorinated alkane is crystallized from the solution by applying suitable crystallization techniques such as cooling, concentration and / or seeding. Preferably, the solution is cooled to a temperature ranging from about -5 °C to about 15 °C, more preferably from about 0 °C to about 10 °C.

[0043] Isolation of the solid complex may be accomplished by any suitable means including decantation, centrifugation, or filtration, preferably filtration. Following filtration, the solid complex is preferably washed with a small amount of a suitable antisolvent, such as an ether like methyl t-buty I ether.

[0044] Preferably, the solid complex is handled expediently and / or in cold temperatures prior to being subjected to further processing to preserve its composition.

[0045] In a fourth embodiment of the present invention, there is provided a process for the purification of a semifluorinated alkane, the process comprising: a) treating, in the presence of a suitable solvent (S1), a crude semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3 (SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, with at least about 1.5n mole equivalents of urea, wherein n is the total number of carbon atoms in the semifluorinated alkane, and obtaining a solution; b) crystallizing a solid complex comprising urea and the semifluorinated alkane from the solution; c) isolating the solid complex; d) dissociating the solid complex in suitable conditions to liberate the semifluorinated alkane; and e) isolating the liberated semifluorinated alkane in purified form.

[0046] In this embodiment, the crude semifluorinated alkane is obtained from any known synthetic process or as described in the examples herein. Preferably, the purity of the crude semifluorinated alkane is at least about 90 area% chromatographic purity as measured by the gas chromatographic method described herein or any suitable chromatographic method. For example, the chromatographic purity of the crude semifluorinated alkane preferably ranges from about 90 area% to about 99 area%. When the crude semifluorinated alkane is prepared by addition of a perfluoroalkyl iodide to an alkene, followed by reduction, the crude semifluorinated alkane often comprises from about 1 area% to about 2 area% of a related methyl-branched impurity of Formula SFA-BR:F3C(CF2)x(CH)CH3(CH2)y-2CH3 (SFA-BR)

[0047] In this embodiment, the steps a), b) and c) may be conducted in accordance with the process described herein for the preparation of the solid complex comprising urea and a semifluorinated alkane.

[0048] The solid complex is dissociated into urea and the semifluorinated alkane under suitable conditions. The conditions preferably comprise treating the complex with an aqueous solution and heating, if necessary, to achieve dissolution. Preferably, the aqueous solution is a mixture of water and a suitable solvent (S2). The suitable solvent (S2) is preferably largely immiscible with water and may be selected from the group consisting of ethers, esters and hydrocarbons including, for example, methyl t-butyl ether, methyltetrahydrofuran, ethyl acetate, and heptanes. Preferably, the suitable solvent(52) is methyl t-butyl ether.

[0049] If necessary, the solid complex is dissociated by heating the aqueous solution to an elevated temperature, for example, to a temperature ranging from about 40 °C to about the boiling point of the suitable solvent, if necessary. Preferably, the temperature ranges from about 50 °C to about 70 °C.

[0050] The liberated semifluorinated alkane is isolated by any suitable means. Preferably, the liberated semifluorinated alkane is isolated by extraction of the aqueous solution with a suitable solvent (S3) and evaporation of the solvent. The suitable solvent (S3) is preferably largely immiscible with water and may be selected from the group consisting of ethers, esters and hydrocarbons including, for example, methyl t-butyl ether, methyltetrahydrofuran, ethyl acetate, and heptanes. Preferably, the suitable solvent(53) is methyl t-butyl ether.

[0051] The liberated semifluorinated alkane is obtained in purified form in comparison to the crude semifluorinated alkane, as measured by a gas chromatography (GC) method described herein, or any other suitable method. For example, the chromatographic purity of the purified semifluorinated alkane as measured is increased by at least about 1 area% as compared to the crude material. In an embodiment, the chromatographic purity of the crude semifluorinated alkane ranges from about 94 area% to about 97 area% and thechromatographic purity of the corresponding purified semifluorinated alkane ranges from about 98.5 area% to about 99.9 area %.

[0052] In a fifth embodiment, the present invention provides a semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3 (SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, produced by a process comprising the steps of: a) dissociating a solid complex comprising the semifluorinated alkane and urea to liberate the semifluorinated alkane; and b) isolating the liberated semifluorinated alkane.

[0053] In this embodiment, the steps a) and b) may be conducted in accordance with steps d) and e) of the process described herein for the purification of a crude semifluorinated alkane of Formula (SFA).

[0054] In a sixth embodiment, the present invention provides a liquid pharmaceutical composition for administration to ophthalmic tissue comprising the semifluorinated alkane of Formula (SFA): F3C(CF2)x(CH2)yCH3 wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, produced by a process comprising the steps of a) dissociating a solid complex comprising the semifluorinated alkane and urea to liberate the semifluorinated alkane; and b) isolating the liberated semifluorinated alkane, and one or more pharmaceutically acceptable excipients. Preferably, the semifluorinated alkane is perfluorohexyloctane (1 ).

[0055] Suitable pharmaceutically acceptable excipients are liquids and / or are soluble and miscible in the semifluorinated alkane and may include one or more of lipids, oils, lubricants, lipophilic vitamins, viscosity agents, antioxidants, surfactants, acids, bases, electrolytes, buffers, solutes, antioxidants, stabilizers, and if required, preservatives. Preferably, the pharmaceuticalcomposition consists of the semifluorinated alkane prepared according to a process described herein. Most preferably, the semifluorinated alkane is perfluorohexyloctane (1) prepared by a process described herein. Preferably, the pharmaceutical composition is a sterile, clear, and colorless ophthalmic solution containing 100% perfluorohexyloctane that is therapeutically equivalent to MEIBO™ drug products.

[0056] In a seventh embodiment, the present invention provides a method for the treatment of the signs and symptoms of keratoconjunctivitis sicca, (dry eye disease), comprising topically administering to the affected tissue, a therapeutically effective amount of a liquid pharmaceutical composition described herein. Preferably, the method comprises instilling liquid drops of a pharmaceutical composition described herein into the affected eye one or more times daily; more preferably, the method comprises instilling one drop of a liquid composition into the affected eye four times daily.

[0057] In an eighth embodiment, the present invention provides a semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3 (SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, particularly perfluorohexyloctane (1), having high purity that may be expressed as a chromatographic purity as measured by the area percent (area%) of the respective peaks attributed to the semifluorinated alkane or its impurities by a gas chromatography (GC) method described herein, or any other suitable method. Preferably, the chromatographic purity of the semifluorinated alkane of Formula (SFA), particularly perfluorohexyloctane (1), is at least about 99.0 area%, at least about 99.5 area%, at least about 99.6 area%, at least about 99.7 area%, at least about 99.8% and at least about 99.9 area%. One impurity that has been identified in processes for the preparation of semifluorinated alkanes of Formula (SFA) is a branched compound shown below as SFA-BR:F3C(CF2)x(CH)CH3(CH2)y-2CH3 (SFA-BR) wherein x and y are as defined for Formula (SFA). Table 2 below depicts examples of semifluorinated alkanes of Formula (SFA) of the present invention and the corresponding branched impurity thereof.

[0058] Preferably, a semifluorinated alkane of Formula (SFA) is provided having no more than about 0.2 area% of a branched impurity of Formula (SFA- BR) as determined by a gas chromatography (GC) method described herein, or any other suitable method. Preferably, a semifluorinated alkane of Formula (SFA) is provided having no more than about 0.1 area% of a branched impurity of Formula (SFA-BR). More preferably, a semifluorinated alkane of Formula (SFA) is provided having no more than about 0.05 area% of a branched impurity of Formula (SFA-BR). Most preferably, the semifluorinated alkane of Formula(SFA) is perfluorohexyloctane (1) having no more than 0.2 area%, no more than 0.1 area% and no more than 0.05 area% branched impurity (IMP-BR).EXAMPLES

[0059] The following examples are illustrative of some of the embodiments of the invention described herein. It will be apparent to the person skilled in the art that various alterations to the described processes in respect of the reactants, reagents, solvents, and conditions may be made when using the processes of the present invention without departing from the scope or intent thereof. All materials and reagents, including the alkenes and the perfluoroalkyl iodides were commercially available. The semifluorinated alkanes of Formula (SFA) can be prepared by known methods, where applicable, or by the procedure provided in the examples that follow.Analysis method for determining the chromatographic purity

[0060] The method shown in Table 3 was used to determine the chromatographic purity of samples of the semifluorinated alkane of Formula (SFA) as provided in the examples that follow.Example 1 : General Procedure for the Preparation of the SemifluorinatedAlkanes of Formula (SFA)CF3(CF2)XI + CH2CH(CH2)y.2CH3(BZ°)2» F3C(CF2)x(CH2)CHI(CH2)y.2CH3(3) (4) (2)wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9

[0061] A suspension of the perfluoroalkyl iodide (3) (1.2 mole equivalent) and benzoyl peroxide (BzO)2 (0.015 mole equivalent) was heated to 85-90 °C, whereupon the alkene (4) was dropwise added over 1 hour (1 mole equivalent). Following addition, the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo using a bath temperature maintained at 40- 60 °C to remove residual perfluoroalkyl iodide (3) and alkene (4). The residue was purified by means of flash chromatography using 60-200 pm silica gel and heptanes eluent to afford the intermediate iodide (2).

[0062] The iodide (2) (1 mole equivalent), sodium acetate (2 mole equivalent) and type 5R394 Pd / C (5% in water) catalyst (5 wt% with respect to iodide (2)) in 2-propanol (10 volumes) was stirred and heated to 65-70 °C (67°C) overnight in a sealed vessel pressurized to 50 psi with hydrogen gas.The solution was then cooled to room temperature, vacuum filtered through a pad of diatomaceous earth, and rinsed with methyl t-butyl ether (7 volumes). The filtrate was concentrated in vacuo to afford a solid residue. The residuewas dissolved in methyl t-butyl ether (10 volumes) and water (15 volumes) and the phases were separated. The aqueous phase was extracted with methyl t- butyl ether (7.5 volumes) and the combined organic phases were concentrated in vacuo to afford the corresponding semifluorinated alkane of Formula (SFA). Volumes are with respect to the weight of the the iodide (2).

[0063] This general procedure can be used to prepare the crude semifluorinated alkanes of Formula (SFA) of the present invention. Crude perfluorohexylheptane (x is 5, y is 6), perfluorohexyloctane (x is 5, y is 7), perfluorohexylnonane (x is 5, y is 8) and perfluorohexyldecane (x is 5, y is 9) were prepared according to this procedure.Example 2: General Process for the Preparation of a Urea and Semifluorinated Alkane (SFA) Solid Complex

[0064] Urea (4 wt equivalents) was added to a solution of the semifluorinated alkane of Formula (SFA) in methanol (13 volumes) and 2- propanol (2.6 volumes). This biphasic suspension was stirred and heated to 60 °C over 30 minutes, maintained for 30 minutes, cooled to 0 °C over 1 hour, and maintained for 1 hour. The resulting cold suspension was collected by filtration and washed with methyl t-butyl ether (2 volumes) to afford the corresponding solid complex comprising the semifluorinated alkane of Formula (SFA). Volumes and weight (wt) equivalents are with respect to the weight of the semifluorinated alkane. Solid complexes comprising urea and the following semifluorinated alkanes were prepared by this procedure: perfluorobutyloctane (x is 3, y is 7), perfluorohexylheptane (x is 5, y is 6), perfluorohexyloctane (x is 5, y is 7) perfluorohexylnonane (x is 5, y is 8), and perfluorohexyldecane (x is 5, y is 9). The solid complex comprising urea and perfluorohexyloctane was characterized by PXRD as shown in Figure 1. The PXRD of the solid complex in Figure 1 differs from the PXRD of the starting material urea shown in Figure 2.Example 3: General Process for the Dissociation of the Urea and Semifluorinated Alkane (SFA) Solid Complex

[0065] The solid complex comprising urea and the semifluorinated alkane of Formula (SFA) from Example 2 was suspended in methyl t-butyl ether (4 volumes) and water (8 volumes) and the mixture was stirred and heated to a bath temperature of 55-60 °C to dissolve all solids. While hot, the phases were separated, the aqueous phase extracted with methyl t-butyl ether (4 volumes), the combined organic phases were washed with water (4 volumes) and concentrated in vacuo to afford the corresponding liberated semifluorinated alkane of Formula (SFA) in purified form. Volumes are with respect to the weight of the semifluorinated alkane used in Example 2. Table 4 provides the yield and gas chromatographic composition of the semifluorinated alkanes following solid complex formation and dissociation according to the procedures of Examples 2 and 3.Rt refers to retention time of the subject peak

Claims

What is claimed is:

1. A solid complex comprising urea and a semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3 (SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9.

2. The complex of claim 1 , wherein the mole ratio of urea to the semifluorinated alkane in the complex ranges from about 1.5n to about 2.5n, wherein n is the total number of carbon atoms in the semifluorinated alkane.

3. The complex of claim 1 or 2, wherein x is 4 or 5 and y is 6 or 7.4 The complex of claim 3, wherein x is 5 and y is 7.

5. The complex of any one of claims 2 to 4, wherein the mole ratio of urea to the semifluorinated alkane in the complex is about 2n.

6. A process for the preparation of a solid complex comprising urea and a semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3(SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, the process comprising: a) treating, in the presence of a suitable solvent (S1), the semifluorinated of Formula (SFA) with at least about 1.5n mole equivalents of urea, wherein n is the total number of carbon atoms in the semifluorinated alkane, and obtaining a solution; b) crystallizing a solid complex comprising urea and the semifluorinated alkane from the solution; andc) isolating the solid complex;7. The process of claim 6, wherein the amount of urea in mole equivalents with respect to the semifluorinated alkane used ranges from about 1 ,5n to about 3n.

8. The process of claim 6 or 7, wherein obtaining a solution comprises maintaining the semifluorinated alkane and urea in the suitable solvent (S1) at a temperature ranging from about 40 °C and about 60 °C to afford a solution.

9. The process of any one of claims 6 to 8, wherein the suitable solvent (S1 ) is a mixture of methanol and 2-propanol.

10. The process of any one of claims 6 to 9, wherein crystallizing comprises cooling the solution to a temperature ranging from about 0 °C to about 15 °C.11 . The process of any one of claims 6 to 10, wherein the solid complex is isolated by filtration.

12. A process for the purification of a semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3(SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, the process comprising: a) treating, in the presence of a suitable solvent (S1), a crude semifluorinated alkane of Formula (SFA) with at least about 1.5n mole equivalents of urea, wherein n is the total number of carbon atoms in the semifluorinated alkane, and obtaining a solution; b) crystallizing a solid complex comprising urea and the semifluorinated alkane from the solution; c) isolating the solid complex;d) dissociating the solid complex in suitable conditions to liberate the semifluorinated alkane; and e) isolating the liberated semifluorinated alkane in purified form.

13. The process of claim 12, wherein the amount of urea in mole equivalents with respect to the semifluorinated alkane used ranges from about 1 ,5n to about 3n.

14. The process of claim 12 or 13, wherein obtaining a solution comprises maintaining the semifluorinated alkane and urea in the suitable solvent (S1) at a temperature ranging from about 40 °C and about 60 °C to afford a solution.

15. The process of any one of claims 12 to 14, wherein the suitable solvent (S1) is a mixture of methanol and 2-propanol.

16. The process of any one of claims 12 to 15, wherein crystallizing comprises cooling the solution to a temperature ranging from about 0 °C to about 15 °C.

17. The process of any one of claims 12 to 16, wherein the solid complex is isolated by filtration.

18. The process of any one of claims 12 to 17, wherein the dissociating comprises maintaining an aqueous solution of the complex until dissolution occurs.

19. The process of any one of claims 12 to 18, wherein the semifluorinated alkane is isolated by extraction of the aqueous solution with an organic solvent and evaporation of the solvent.

20. A crystalline form comprising urea and perfluorohexyloctane characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 10.2°, 20.4°, and 27.4°.21 . The crystalline form of claim 20, further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 7.3°, 13.3°, 16.2°, 19.4°, 21.1 °, and 21.4°.

22. The crystalline form of claim 20, further comprising peaks, expressed in degrees 20 (± 0.2°), at 7.3°, 13.3°, 16.2°, 19.4°, 21.1 °, and 21.4°.

23. The crystalline form of any one of claims 20 to 22 providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 1 .

24. A semifluorinated alkane of Formula (SFA):F3C(CF2)x(CH2)yCH3(SFA) wherein x is an integer ranging from 2 to 6; and y is an integer ranging from 4 to 9, produced by a process comprising the steps of: a) dissociating a solid complex comprising the semifluorinated alkane and urea to liberate the semifluorinated alkane; and b) isolating the liberated semifluorinated alkane.

25. The semifluorinated alkane of claim 24, wherein x is 4 or 5 and y is 6 or 7.

26. The semifluorinated alkane of claims 24 or 25, wherein x is 5 and y is 7.

27. The semifluorinated alkane of any one of claims 24 to 26, wherein the mole ratio of urea to the semifluorinated alkane in the complex ranges from about 1 ,5n to about 2.5n, wherein n is the total number of carbon atoms in the semifluorinated alkane.

28. The semifluorinated alkane of any one of claims 24 to 27, wherein the dissociating comprises maintaining an aqueous solution of the complex until dissolution occurs.

29. The semifluorinated alkane of any one of claims 24 to 28, wherein the semifluorinated alkane is isolated by extraction of the aqueous solution with an organic solvent and evaporation of the solvent.

30. A liquid pharmaceutical composition for administration to ophthalmic tissue comprising the semifluorinated alkane of Formula (SFA) of any one of claims 24 to 29, and one or more pharmaceutically acceptable excipients.

31. The liquid pharmaceutical composition of claim 30, wherein the composition consists of the semifluorinated alkane.

32. The liquid pharmaceutical composition of claim 30 or 31 , wherein x is 5 and y is 7 and the semifluorinated alkane is perfluorohexyloctane.

33. A method of treating keratoconjunctivitis sicca (dry eye disease) in a patient in need of such treatment, comprising topically administering to the affected tissue, a therapeutically effective amount of the liquid pharmaceutical composition of any one of claims 30 to 32.

34. The method of claim 33, wherein the pharmaceutical composition consists of perfluorohexyloctane.

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