FIELD OF THE DISCLOSURE

The present disclosure is related to forms of ibrutinib, i.e., Form H pyridine solvate of ibrutinib Form H, Form I pyridine solvate of ibrutinib and an amorphous form of ibrutinib. The present disclosure also relates to a pharmaceutical composition comprising the forms, their method of use for treating a disease in a patient, and process for the preparation of the forms. BACKGROUND OF THE DISCLOSURE

Ibrutinib, having the chemical designation l-[(3R)-3-[4-Amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yljpiperidin- 1 -yl]prop-2-en- 1 -one, is an orally bioavailable inhibitor of Bruton's tyrosine kinase (BTK) with potential antineoplastic activity. Ibrutinib has the following structure:

Ibrutinib is commercially marketed under the name EVIBRUVICA® and is indicated for the treatment of patients with mantel cell lymphoma who have received at least one prior therapy. IMBRUVICA® is also indicated for the treatment of patients with chronic lymphocytic leukemia and Waldenstrom's macroglobulinemia.

Forms of ibrutinib are described in United States Patents 9296753 (Forms A-F), 9545407 (dispersion), 9751889 (Form A solvate), 9828383 (Forms A-F), 9884869 (amorphous form, and Forms III-IX), 99725455 (Forms A-F) and 10035802 (Forms G, J, and K), United States Patent Applications 20140336203 (Forms A-F), 20170079981 (dispersion), 20170305919 (Forms A-F), 20180028537 (dispersion), 20180051026 (Forms Dl-Dla, D2-D2a, and D3-D13), US20180251463 (amorphous form, and Forms III-IX), 20180065958 (amorphous form), 20180072737 (co-crystal), and 20180072739 (co-crystal), and, PCT publications WO2016/088074 (amorphous form),

WO2016/207172 (amorphous), WO2017/029586 (Forms S1-S4, and amorphous form), WO2017/085628 (amorphous form), WO2017/137446 (amorphous form),

WO2017/174044 (Form C), and WO2018/000250 (Form III), European Patent

EP3243824 Forms α, β, γ, δ, ε and ζ) and Chinese Publication Nos. CN103121999, and CN 103923084 (II- VIII).

The occurrence of different crystalline forms of ibrutinib and salts thereof gives rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors. Polymorphic forms of the compound are important in that the forms having desirable characteristics, such as ease of handling, ease of processing, ease of formulating, storage stability, ease of purification, improved dissolution or bioavailability, or form that facilitates conversion to another desirable polymorphic form. Thus, new polymorphic forms of ibrutinib are useful for providing the compound having desirable characteristics. For at least these reasons, there is a need for additional polymorphic forms of ibrutinib.

Amorphous compounds are considered solid state forms of polymorphs, which are chemically identical to other polymorphs but have different physical properties such as crystal lattice energies, melting points, intrinsic solubilities, rates of dissolution, densities, mechanical properties, chemical and physical stability, hygroscopicity, and morphology. The differences in intrinsic solubilities also may lead to differences in the rate of absorption, thus impacting bioavailability. Amorphous ibrutinib is moisture stable. It is therefore a good alternative to crystalline ibrutinib as amorphous material has a higher solubility, which is connected with better bioavailability, than corresponding crystalline forms. For at least these reasons, there is also a need for processes to prepare amorphous ibrutinib. SUMMARY OF THE DISCLOSURE

The present invention is directed to novel crystalline forms of ibrutinib, designated herein as Form H pyridine solvate of ibrutinib and Form I pyridine solvate of ibrutinib. The present invention is further directed to processes for the preparation of Form H pyridine solvate of ibrutinib or Form I pyridine solvate of ibrutinib. The present invention also is directed to pharmaceutical compositions comprising Form H pyridine solvate of ibrutinib or Form I pyridine solvate of ibrutinib, and a method for treating disease in a patient using Form H pyridine solvate of ibrutinib or Form I pyridine solvate of ibrutinib.

The present invention is also directed to processes for the preparation of amorphous forms of ibrutinib. The present invention also is directed to pharmaceutical compositions comprising crystalline and amorphous ibrutinib, and a method for treating disease using amorphous ibrutinib. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a representative X-ray Powder Diffraction ("XRPD") pattern of Form H pyridine solvate of ibrutinib, expressed in terms of °2Θ.

FIG. 2 provides a representative Differential Scanning Calorimetry ("DSC") and Thermal Gravimetric Analysis ("TGA") plot of Form H pyridine solvate of ibrutinib.

FIG. 3 provides a representative XRPD pattern of amorphous ibrutinib prepared using tetraglyme, expressed in terms of °2Θ.

FIG. 4 provides a representative DSC plot of amorphous ibrutinib prepared using tetraglyme.

FIG. 5 provides a representative ¹ H-NMR plot of amorphous ibrutinib prepared using tetraglyme.

FIG. 6 provides a representative XRPD pattern of amorphous ibrutinib prepared using PEG-200, expressed in terms of °2Θ.

FIG. 7 provides a representative DSC plot of amorphous ibrutinib prepared using PEG-200.

FIG. 8 provides a representative ¹ H-NMR plot of amorphous ibrutinib prepared using PEG-200. FIG. 9 provides a representative XRPD pattern of amorphous ibrutinib prepared using pyridine, expressed in terms of °2Θ.

FIG. 10 provides a representative DSC plot of amorphous ibrutinib prepared using pyridine.

FIG. 11 provides a representative TGA plot of amorphous ibrutinib prepared using pyridine.

FIG. 12 provides a representative 1H- MR plot of amorphous ibrutinib prepared using pyridine.

FIG. 13 provides a representative X-ray Powder Diffraction ("XRPD") pattern of Form I of ibrutinib, expressed in terms of °2Θ.

FIG. 14 represents the asymmetric unit of Form I pyridine solvate of ibrutinib. FIG. 15 shows the inter and intra molecular hydrogen bonding between ibrutinib and pyridine in Form I pyridine solvate of ibrutinib. DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure is directed to novel crystalline forms of ibrutinib, designated herein as Form H pyridine solvate of ibrutinib and Form I pyridine solvate of ibrutinib, pharmaceutical compositions comprising the forms, process for their preparation, and their use for treating a patient with a physiological condition in need of treatment, as herein described in detail.

The present disclosure is also directed processes for the preparation of an amorphous form of ibrutinib, pharmaceutical compositions comprising the form, and its use for treating a patient with a physiological condition in need of treatment, as herein described in detail.

As used herein and unless otherwise specified, the terms "about" and

"approximately," when used in connection with a numeric value or a range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, e.g., that describing a DSC or TGA thermal event, including, e.g., melting, dehydration, desolvation or glass transition events, a mass change, such as, e.g., a mass change as a function of temperature or humidity, a solvent or water content, in terms of, e.g., mass or a percentage, or a peak position, such as, e.g., in analysis by IR or Raman spectroscopy or XRPD, indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form.

As used herein and unless otherwise specified, the term "pharmaceutical composition" is intended to encompass the a pharmaceutically effective amount of the amorphous ibrutinib and pharmaceutically acceptable excipient. As used herein, the term "pharmaceutical compositions" includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

As used herein and unless otherwise specified, the term "crystalline" and related terms used herein, when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, mean that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005), The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).

As used herein and unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable organic or inorganic carrier substance. Excipients may be natural or synthetic substances formulated alongside the active ingredient of a medication, included for the purpose of bulking-up formulations that contain potent active ingredients (thus often referred to as "bulking agents," "fillers," or "diluents"), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility. Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation over the expected shelf life.

As used herein and unless otherwise specified, the term "patient" refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. Further, a patient may not have exhibited any symptoms of the disorder, disease or condition to be treated and/prevented, but has been deemed by a physician, clinician or other medical professional to be at risk for developing said disorder, disease or condition.

As used herein and unless otherwise specified, the terms "polymorph,"

"polymorphic form" or related term herein, refer to a crystal form of a molecule, or salt thereof that can exist in two or more forms, as a result different arrangements or conformations of the molecule or salt thereof ions in the crystal lattice of the polymorph.

As used herein and unless otherwise specified, the terms "treat," "treating" and "treatment" refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more therapeutic agents to a patient with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agents, after the onset of symptoms of the particular disease. Ibrutinib is indicated for the treatment of patients with mantel cell lymphoma who have received at least one prior therapy. Ibrutinib is also indicated for the treatment of patients with chronic lymphocytic leukemia and

Waldenstrom's macroglobulinemia. IMBRUVICA® is available as 140 mg capsules. The recommended dose of IMBRUVICA® for mantle cell lymphoma is 560 mg (four 140 mg capsules), orally, once daily. The recommended dose in patients with chronic

lymphocytic leukemia and Waldenstrom's macroglobulinemia is 420 mg (three 140 mg capsules), orally, once daily.

Embodiments

One embodiment of the invention is directed to a process for preparing an amorphous form of ibrutinib, comprising producing amorphous ibrutinib from a solvent - anti- solvent system.

Another embodiment of the invention is wherein the production of the amorphous ibrutinib comprises the steps of:

a. dissolving ibrutinib in a solvent to form a ibrutinib solution; and

b. adding the ibrutinib solution to an anti-solvent to yield amorphous ibrutinib. A further embodiment is wherein the production of the amorphous ibrutinib further comprises recovering the amorphous ibrutinib.

A further embodiment is wherein the recovering of the amorphous ibrutinib further comprises drying the amorphous ibrutinib, optionally under vacuum.

Another embodiment of the invention is wherein the drying occurs under heated conditions.

Another embodiment of the invention is wherein the drying occurs at about at least 35 °C.

Another embodiment of the invention is wherein in the production of the amorphous ibrutinib the solvent is selected from the group consisting of tetraglymes, polyethylene glycols, oligomeric ethylene glycols, oligomeric ethylene glycol monomethyl ethers, polyethylene glycol monomethyl ethers and pyridines.

Another embodiment of the invention is wherein in the production of the amorphous ibrutinib the polyethylene glycol is selected from the group comprising PEG- 200, PEG-400 and PEG-600, or a combination thereof.

Another embodiment of the invention is wherein in the production of the amorphous ibrutinib the anti-solvent is a protic anti-solvent comprising water.

Another embodiment of the invention is an amorphous form of ibrutinib, characterized by a T _g of about 55 °C.

Another embodiment of the invention is an amorphous form of ibrutinib, prepared by the steps of:

a. dissolving ibrutinib in a solvent to form a ibrutinib solution; and

b. adding the ibrutinib solution to an anti-solvent to yield amorphous ibrutinib. Another embodiment of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of an amorphous form of ibrutinib, prepared by the steps of:

a. dissolving ibrutinib in a solvent to form a ibrutinib solution; and

b. adding the ibrutinib solution to an anti-solvent to yield amorphous ibrutinib, and

pharmaceutically acceptable excipient. Another embodiment of the invention is a method of treating disease in a patient comprising administering a pharmaceutical formulation comprising a pharmaceutically effective amount of an amorphous form of ibrutinib, prepared by the steps of:

a. dissolving ibrutinib in a solvent to form a ibrutinib solution; and

b. adding the ibrutinib solution to an anti-solvent to yield amorphous ibrutinib, and

pharmaceutically acceptable excipient,

to a patient in need thereof.

Another embodiment of the invention is wherein the disease is chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's

macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, or chronic graft versus host disease.

Another embodiment of the invention is crystalline Form H pyridine solvate of ibrutinib.

Another embodiment of the invention is crystalline Form I pyridine solvate of ibrutinib.

Another embodiment of the invention is a pharmaceutical composition comprising a pharmaceutically effective amount of crystalline ibrutinib Form H pyridine solvate of ibrutinib or Form I pyridine solvate of ibrutinib and pharmaceutically acceptable excipient.

Another embodiment of the invention is a method of treating disease in a patient comprising administering a pharmaceutical formulation comprising a pharmaceutically effective amount of Form H pyridine solvate of ibrutinib or Form I pyridine solvate of ibrutinib and pharmaceutically acceptable excipient to a patient in need thereof.

Another embodiment of the invention is wherein the disease is chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstrom's

macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, or chronic graft versus host disease.

Another embodiment of the invention is directed to a process for preparing Form H pyridine solvate of ibrutinib, comprising exposing ibrutinib to pyridine to yield Form H pyridine solvate of ibrutinib. Another embodiment of the invention is directed to a process for preparing Form I pyridine solvate of ibrutinib, comprising exposing ibrutinib to pyridine and water to yield Form I pyridine solvate of ibrutinib. Experimental

Techniques for characterizing crystal and amorphous forms include, but are not limited to differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray powder diffractometry (XRPD), proton nuclear magnetic resonance ( ¹ H- MR) and Optical Microscopy.

DSC data are collected using a TA Instruments Q10 DSC. Approximately, samples (2-8 mg) are placed in unsealed but covered hermetic alodined aluminum sample pans and scanned from about 30 to about 300 °C at a rate of about 10 °C/min under a nitrogen purge of about 50 mL/min.

Modulated DSC data are collected using a TA Instruments Q2000 equipped with an auto-sampler and RSC40. Samples are equilibrated at 5 °C in Tzero hermetically sealed aluminum pans with a ramp rate of 1.5 °C/min to 200 °C under a nitrogen purge of about 50 mL/min, modulated ±0.50 °C every 60 seconds in T4P (or T4) mode.

TGA data are collected using a TA Instruments TGA Q500. Approximately, samples (5-10 mg) are placed in an open, pre-tared aluminum sample pan and scanned from about 25 to about 300 °C at a rate of about 10 °C/min using a nitrogen purge at about 60 mL/min.

XRPD patterns are obtained using a Bruker D8 Advance equipped with a Cu Ka radiation source (λ=1.54 A), a 9-position sample holder and a LYNXEYE super speed detector. Samples are placed on zero-background, silicon plate holders for analysis. One skilled in the art would recognize that the °2Θ values and the relative intensity values are generated by performing a peak search on the measured data and the <i-spacing values are calculated by the instrument from the °2Θ values using Bragg' s equation. One skilled in the art would further recognize that the relative intensity for the measured peaks may vary as a result of sample preparation, orientation and instrument used, for example.

1H-NMR data are collected using a Bruker Avance 300 MHz MR equipped with

TopSpin software. Samples were prepared by dissolving the compound in deuterated methanol with 0.05% (v/v) tetramethylsilane (TMS). Spectra are collected at ambient temperature. The number of scans was at least 16 for ¾-NMR.

Form H pyridine solvate of ibrutinib is a unique crystalline phase. Form H pyridine solvate of ibrutinib is an off-white solid material.

The present disclosure provides processes for preparing Form H pyridine solvate of ibrutinib. The process comprises exposing ibrutinib to a processing solvent. The starting material in these processes may be produced by any suitable method, including synthesis known in the art. The processing solvent may include ICH Q3 processing solvents, either alone or in combination, including water. The processing solvent is pyridine.

Form I pyridine solvate of ibrutinib is a unique crystalline phase. Form I is an off- white solid material.

The present disclosure provides processes for preparing Form I pyridine solvate of ibrutinib. The process comprises exposing ibrutinib to a processing solvent and water. The starting material in these processes may be produced by any suitable method, including synthesis known in the art. The processing solvent may include ICH Q3 processing solvents, either alone or in combination. The processing solvent is pyridine and water.

Amorphous ibrutinib is a white solid identified as amorphous by XRPD and has a glass transition (T _g ) of approximately 55 °C. The amorphous ibrutinib described herein has a similar solubility to crystalline ibrutinib.

The present disclosure provides processes for preparing amorphous ibrutinib. The process comprises the steps of dissolving ibrutinib in a solvent to form a solution, adding the solution to an anti-solvent and drying the resulting product to yield amorphous ibrutinib. The starting material in these processes may be produced by any suitable method, including synthesis known in the art. The solvent may be selected from the group comprising tetraglymes, polyethylene glycols, oligomeric ethylene glycols, oligomeric ethylene glycol monomethyl ethers, polyethylene glycol monomethyl ethers and pyridines. Tetraglymes have the general formula Me(OCH2CH2)nOMe and may include diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether

(triglyme) and dimethyoxyethane (glyme). Suitable polyethylene glycols have the general formula H(OCH2CH2)nOH and have a molecular weight of 1000 or less. The

polyethylene glycol may be selected from the group comprising PEG-200, PEG-400, and PEG-600, or a combination thereof. Oligomeric ethylene glycols have the general formula H(OCH2CH2)nOH and may include ethylene glycol, diethylene glycol and triethylene glycol. Oligomeric ethylene glycol monomethyl ethers and PEG monomethyl ethers have the general formula H(OCH2CH2)nOMe and may include methoxyethanol (ethylene glycol monomethyl ether, methyl cellusolve), diethylene glycol monomethyl ether, triethylene glycol monomethyl ether. Pyridines may include pyridine,

methypyridines (picolines), dimethylpyridines (lutidines) and ethylpyridines.

The present disclosure also encompasses pharmaceutical compositions comprising Form H pyridine solvate of ibrutinib, Form I pyridine solvate of ibrutinib or amorphous ibrutinib. Pharmaceutical compositions containing forms ibrutinib may be prepared according to International Publication Nos. WO2009/147238 and

WO2011/003853.

The present disclosure provides for a method of treating disease by administering to a patient, in need thereof, pharmaceutical compositions comprising Form H pyridine solvate of ibrutinib, Form I pyridine solvate of ibrutinib or amorphous ibrutinib. Ibrutinib is indicated for the treatment of patients with mantel cell lymphoma who have received at least one prior therapy. Ibrutinib is also indicated for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), CLL/SLL with 17p deletion, Waldenstrom's macroglobulinemia (WM), marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20- based therapy, and chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

The dosage of the pharmaceutical compositions may be varied over a wide range.

Optimal dosages and dosage regimens to be administered may be readily determined by those skilled in the art, and will vary with the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient's sex, age, weight, diet, physical activity, time of administration and concomitant diseases, will result in the need to adjust dosages and/or regimens. Ibrutinib, marketed under the name IMBRUVICA®, is available as 140 mg capsules. The recommended dose of ibrutinib in patients with mantle cell lymphoma or MZL is 560 mg (four 140 mg capsules), orally, once daily. The recommended dose of ibrutinib in patients with chronic lymphocytic leukemia and Waldenstrom's macroglobulinemia or CLL/SLL is 420 mg (three 140 mg capsules), orally, once daily. The recommended dose in patients with cGVHD after failure of one or more lines of systemic therapy is 420 mg (three 140 mg capsules), orally, once daily

EXAMPLES

Examples 1-5, which follow herein, provide embodiments of the preparation of solid state forms of ibrutinib.

Example 1

Preparation of Form H pyridine solvate of ibrutinib About 250 mg of ibrutinib is dissolved in about 375 μΙ_, of pyridine under ambient temperature conditions. The solution is stirred at about 5 °C overnight. The isolated, wet product is analyzed by XRPD and identified as Form H pyridine solvate of ibrutinib. The dried product is also analyzed and identified as Form H pyridine solvate of ibrutinib.

Example 2

Preparation of Amorphous Ibrutinib Using Tetraglyme

About 57 mg of ibrutinib is dissolved in about 900 μΙ_, of tetraglyme. The solution is slowly added dropwise into about 15 mL of cold water. The resulting material is allowed to stir for approximately 90 minutes and isolated by filtration. The isolated, wet product is analyzed by XRPD and identified as amorphous ibrutinib. The product is dried under vacuum at about 45 °C. The dried product is analyzed and identified as amorphous ibrutinib. Representative XRPD pattern, modulated DSC plot, and ¹ H- MR plot of amorphous ibrutinib prepared using tetraglyme, are shown respectively in Fig. 3-5. Example 3

Preparation of Amorphous Ibrutinib Using PEG-200 About 54 mg of ibrutinib is dissolved in about 1000 μΐ _^ of PEG-200. The solution is slowly added dropwise into about 15 mL of cold water. The resulting material is allowed to stir for approximately 90 minutes and isolated by filtration. The isolated, wet product is analyzed by XRPD and identified as amorphous ibrutinib. The product is dried overnight under ambient conditions or under vacuum at about 45 °C. The dried product is analyzed and identified as amorphous ibrutinib. Representative XRPD pattern, modulated DSC plot, and ¹ H- MR plot of amorphous ibrutinib prepared using PEG-200, are shown respectively in Fig. 6-8.

Example 4

Preparation of Amorphous Ibrutinib Using Pyridine About 63 mg of ibrutinib is dissolved in about 100 μΐ. of pyridine. The solution is slowly added dropwise into about 15 mL of cold water. The resulting material is allowed to stir for approximately 90 minutes and isolated by filtration. The isolated, wet product is analyzed by XRPD and identified as amorphous ibrutinib. The product is dried under vacuum at about 45 °C. The dried product is analyzed and identified as amorphous ibrutinib. Representative XRPD pattern, modulated DSC plot, TGA plot, and ¹ H- MR plot of amorphous ibrutinib prepared using pyridine, are shown respectively in Fig. 9-12. The DSC thermogram of the amorphous ibrutinib, FIG. 10, shows an average thermal event at about 54.9 °C. The amorphous ibrutinib described herein is characterized by a glass transition (T _g ) of approximately 55 °C.

Example 5

Preparation of Form I of ibrutinib

About 100 mg of ibrutinib is dissolved in 1 mL of pyridine. A few drops (4-5) of water are added to the vial with a transfer pipette. The vial is placed in a hood

undisturbed. After 5 days single crystals of Form I pyridine solvate of ibrutinib are isolated and analyzed by SCXRD. A representative XRPD pattern is shown in Fig. 13 The single crystal parameters for the Form I pyridine solvate of ibrutinib as determined by SCXRD are:

Space Group: Tri clinic, PI

a = 9.8179 (4) A

b = 10.8193 (4) A

c = 14.8833 (6) A

a = 71.238 (2)°, β = 80.055 (2)°, γ = 65.289 (2)°

Volume: 1358.52 A ³

Z=2, Z' =2.

Figure 14 shows the asymmetric unit of Form I pyridine solvate of ibrutinib. Figure 15 shows the inter and intra molecular hydrogen bonding between ibrutinib and pyridine molecules in Form I pyridine solvate of ibrutinib.

The above examples are set forth to aid in the understanding of the disclosure, and are not intended and should not be construed to limit in any way the disclosure set forth in the claims which follow hereafter. Although illustrated and herein described with reference to certain specific embodiments, the present disclosure is nevertheless not intended to be limited to the details shown, but various modifications may be made therein without departing from the spirit of the disclosure.