EP4069674A1

EP4069674A1 - Crystalline form i of bucillamine

Info

Publication number: EP4069674A1
Application number: EP21749519.1A
Authority: EP
Inventors: Desi Reddy SRINIVAS REDDY; Peketi SUBBA REDDY; Chaganti PITCHI REDDY
Original assignee: Optimus Drugs Pvt Ltd
Current assignee: Optimus Drugs Pvt Ltd
Priority date: 2021-01-12
Filing date: 2021-07-14
Publication date: 2022-10-12
Also published as: EP4069674A4; WO2022153101A1

Abstract

The present disclosure provides a crystalline form I of the compound of formula (I), methods for making/ producing the crystalline form I of the compound of formula (I), pharmaceutical compositions comprising such crystalline forms of the compound of formula (I) and therapeutic methods for the use of crystalline form I of the compound of formula (I) in the treatment of COVID-19/ corona virus infections, Rheumatoid Arthritis (RA) and various other disorders.

Description

Title: CRYSTALLINE FORM I OF BUCILLAMINE

Technical Field

The present disclosure relates to crystalline form I of Bucillamine, process for the preparation thereof, pharmaceutical compositions thereof, and methods of treating various disorders/ diseases therewith.

Background

Bucillamine (BA) (hereinafter referred to as “Compound of formula (I)”) is a cysteine derivative originally developed as a disease-modifying anti-rheumatic drug (DMARD) for treatment of rheumatoid arthritis (RA). Bucillamine is chemically known as N-(2-mercaptoisobutyryl)-L- cysteine of formula (I) has the following structure.

Bucillamine - the term per se is an International Non-proprietary Name (INN) given by World Health Organization and the WHO publication reference number is Vol: 40, No. 6, 1986 and List 26.

BA is known to be an analogue of d-pencillamine and was originally introduced in the year 1980 for the treatment of RA. Historically, d-pencillamine was reported to be associated with various side effects and accordingly the western world abandoned the same and replaced it with DMARDs. One such DMARD is BA which reportedly had fewer side effects when compared with d- pencillamine alone and has been widely used as a first-line DMARD for treatment of RA. The most popular brand of BA is Rimatil® (50 mg or 100 mg tablets, manufacturer: Ayumi Pharmaceutical Corporation, Japan) for treatment of RA. It was considered to be a DMARD with immunogenic effects.

In addition, BA is chemically a thiol compound, refer above table 1, and differs from d- pencillamine by the presence of two free sulfhydryl groups and has two S-H bonds in its chemical structure. It acts by suppressing the production of IL-6 and IL-8 from synovial cells. In an in vitro study of its effect on T-cell proliferation, cytokine production, and migration of T- cells, BUC significantly inhibited T-cell proliferation, reduced the expression of CD44 on T- cells, and inhibited the production of IL-2, interferon-γ (IFN-y), TNF-α, and IL-6, thus indicating that it is an inhibitor of type 1 T helper-type cytokine production, pro-inflammatory cytokine production, and trans-endothelial migration of T-cells.

BA was originally developed by Japan, and has been heavily marketed in Japan and Korea for the treatment of gout or RA. As regards patents on BA, JP54-63017 and US4305958 are the two patents, which are incorporated herein by reference, that disclose the process (synthesis) involved in its preparation.

Recently, the repurposing potential of BA was explored by some pharmaceutical companies to determine its potential for treatment of the global pandemic COVID-19. It was found that, Revive Therapeutics, a speciality life sciences company has received USFDA approval to proceed with Phase - III clinical trial studies in patients with mild to moderate COVID- 19; bearing clinical trials identifier number as NCT04504734 (https ://clinicaltrials . gov/) .

Treatment or prevention of the aforementioned diseases/ disorders may be accomplished by administering a therapeutically effective amount of BA to a human or animal subject in need of such treatment or prevention. The treatment with BA may be accomplished by its use as a single compound, as a pharmaceutical composition ingredient, or in combination with other therapeutic agents. BA may be administered by oral administration, continuous intravenous infusion, bolus intravenous administration or any other suitable route such that it preferably achieves the desired effects in the treatment of RA or anti-oxidant/ anti-inflammatory or in treatment of COVID- 19.

Crystalline forms of BA have not been known to exist previously. As such, there exists a need for crystalline forms which may exhibit desirable and beneficial chemical and physical properties. There also exists a need for reliable and reproducible methods for the manufacture, purification, and formulation of BA to permit its feasible commercialization. Accordingly, the present disclosure is directed to these, as well as various other important aspects.

The information disclosed in this background of the disclosure section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art. Summary

Accordingly, the present disclosure is in relation to a crystalline form I, of a compound of formula (I)

; and is also disclosed is a composition comprising the compound of formula (I), wherein at least about 50 % of the compound of formula (I) in the composition is present in the crystalline form I, and is also disclosed is a pharmaceutical composition comprising (a) the crystalline form I, of the compound of formula (I) and a pharmaceutically acceptable excipient; and is also disclosed is a method for preparation of the crystalline form I, of the compound of formula (I) comprising dissolving crude BA in an organic solvent followed by heating to obtain a clear solution; stirring and cooling the clear solution followed by filtering to isolate the solids; and washing the solids using organic solvent followed by drying to obtain crystalline form I, of the compound of formula (I).

It is to be understood that the aspects and embodiments of the disclosure described above may be used in any combination with each other. Several of the aspects and embodiments may be combined together to form a further embodiment of the disclosure. The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description.

Brief Description of the Accompanying Drawings

The features of the present disclosure will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings. Understanding that these drawings/ figures depict only several of the embodiments in accordance with the disclosure and are therefore not to be construed limiting of its scope. The disclosure will be described with additional specificity and detail through use of the accompanying drawings. Figure 1: shows the x-ray powder diffraction pattern recorded for crystalline form I, of the compound of formula (I) (Example 1) and was recorded on a Bruker™ D8 diffractometer using CuKa radiation (λ=1.54060 A).

Figure 2: shows the differential scanning calorimetry (DSC) trace for crystalline form I, of the compound of formula (I) (Example 1) and was recorded on a Perkin Elmer Diamond DSC instrument with aluminium pan (Perkin Elmer, type BO14-3018); heating rate 50° to 200° at 10° C/min.

The figure depicts embodiments of the disclosure for purposes of scientific support or illustration only. One skilled in the art will readily recognize from the following description that alternative embodiments of the structures and methods illustrated herein may be employed without departing from the principles of the disclosure described herein to arrive at the scientific support as detailed in the following detailed description of the present disclosure.

Detailed Description

Before explaining any one embodiment of the present disclosure by way of drawings, experimentation, results, and pertinent procedures, it is to be understood that the disclosure is not limited in its application to the details as explained in below embodiments set forth in the following description or illustrated in the drawings, experimentation and/or results. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments are meant to be exemplary— not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting in anyway.

Definitions:

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The present disclosure provides, at least in part, crystalline form I of Compound of formula (I) as a novel material, in particular in pharmaceutically acceptable form.

The term ‘active ingredient ’ shall mean the crystalline form I, of compound of formula (I) or BA.

The term ‘Form I’ refers to the crystalline form of the compound of formula (I) or BA.

The term “pharmaceutically acceptable ” , as used herein, refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem complications commensurate with a reasonable benefit/risk ratio. In certain preferred embodiments, Compound of formula (I) is in substantially pure form.

The term “substantially pure ”, as used herein, means a compound having a purity > 95 and 99 weight %, and also including equal to about 100 weight % of Compound of formula (I), based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystalline form of Compound of formula (I) may be deemed substantially pure in that it has a purity greater than 95 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining < 5 weight % of material comprises other form(s) of Compound of formula (I) and/or reaction impurities and/or processing impurities.

As used herein the term “polymorph” refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, and/or ions forming the crystal.

In the present disclosure, the crystalline form refers to crystalline form I, of the compound of formula (I) or BA.

As used herein “solvate ” refers to a crystalline form of a molecule, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline structure. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or non-stoichiometric amount of the solvent molecules.

As used herein “amorphous ” refers to a solid form of a molecule, and/or ions that is not crystalline. An amorphous solid does not display an X-ray diffraction pattern with sharp maxima. Compound of formula (I) may be prepared using the methods taught under US4305958 or JP54- 63017. The synthetic route disclosed under the US patent number US4305958 is shown below as scheme I.

Alternately, the compound of formula (I) can also be prepared by a synthetic process disclosed in JP 54-63017, shown below as scheme II.

Bucillamine

The above schematic (scheme I and II) synthetic process of BA helps obtain only low yield and purity (70 %). Therefore, there is a need for pure/ crystalline forms of BA.

The crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of anti-solvents (counter solvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.

For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility. Suitable solvents for preparing crystals include polar and non-polar solvents.

In one method to prepare crystals, Compound of formula (I) is suspended and/or stirred in a suitable solvent to obtain slurry, which may be heated to promote dissolution to obtain a clear solution. The term “slurry”, as used herein, means a saturated solution of Compound of formula (I) and a solvent at a given temperature. Suitable solvents in this regard include, for example, polar aprotic solvents, and polar protic solvents, and non-polar solvents, and mixtures of two or more of these.

Suitable polar aprotic solvents include, for example, dichloromethane (CH₂Cl₂ or DCM), tetrahydrofuran (THF), acetone, methyl ethyl ketone (MEK), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), 1,3- dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N- methylacetamide, N-methylformamide, acetonitrile (ACN or MeCN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate, methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IpOAc), butyl acetate (BuOAc), t-butyl acetate, hexachloroacetone, dioxane, sulfolane, N,N-dimethylpropionamide, nitromethane, nitrobenzene and hexamethylphosphoramide.

Suitable polar protic solvents include, for example, alcohols and glycols, such as H2O, methanol, ethanol, 1-propanol, 2-propanol, isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), i- butyl alcohol, t-butyl alcohol, 2 -nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3 -pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol and methyl t-butyl ether (MTBE). Preferred solvents include, for example, EtOAc, IpOAc and cyclohexane. Other solvents suitable for the preparation of slurries of Compound of formula (I), in addition to those exemplified above, would be apparent to one skilled in the art, based on the present disclosure.

Seed crystals may be added to any crystallization mixture to promote crystallization. As will be clear to the skilled artisan, seeding is used as a means of controlling growth of a particular crystalline form or as a means of controlling the particle size distribution of the crystalline product. In general, seeds of small size are needed to effectively control the growth of crystals in the batch. Seeds of small size may be generated by sieving, milling, or micronizing of larger crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity of the desired crystal form or form conversions (i.e., change to amorphous or to another polymorph).

A cooled mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge or in a hot air oven to afford the desired crystalline form. The isolated solids may be characterized by a suitable spectroscopic or analytical technique, such as PXRD, DSC or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 90 weight % isolated yield, but preferably greater than 95 weight % based on the weight of Compound of formula (I) originally employed in the crystallization procedure. The product/ the new crystalline form obtained may be co-milled or passed through a mesh screen of suitable size to remove the lumps, if any, in the product, if necessary.

Crystalline forms may be prepared directly from the reaction medium of the final process step for preparing Compound of formula (I). This may be achieved, for example, by employing in the final process step a solvent or mixture of solvents from which Compound of formula (I) may be crystallized. Alternatively, crystalline forms may be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include any of those solvents described herein, including protic polar solvents such as alcohols, and aprotic polar solvents.

By way of general guidance, the reaction mixture may be filtered to remove any undesired impurities, inorganic salts, and the like, followed by washing with reaction or crystallization solvent. The resulting solution may be concentrated to remove excess solvent or gaseous constituents. If distillation is employed, the ultimate amount of distillate collected may vary, depending on process factors including, for example, vessel size, stirring capability, and the like, by way of general guidance, the reaction solution may be distilled to about 1/10 the original volume before solvent replacement is carried out. The reaction may be sampled and assayed to determine the extent of the reaction and the wt % product in accordance with standard process techniques. If desired, additional reaction solvent may be added or removed to optimize reaction concentration.

It may be preferable to add solvents directly to the reaction vessel without distilling the reaction mixture. Preferred solvents for this purpose are those which may ultimately participate in the crystalline lattice as discussed above in connection with solvent exchange. The reaction mixture may be stirred following solvent addition and simultaneously warmed. By way of illustration, the reaction mixture may be stirred for about 1-2 hours while warming to about 70° C to 75° C. The reaction is preferably filtered hot and washed with either the reaction solvent, the solvent added or a combination thereof. Seed crystals may be added to any crystallization solution to initiate crystallization.

The various forms described herein may be distinguishable from one another through the use of various analytical techniques known to one of ordinary skill in the art. Such techniques include, but are not limited to, PXRD, DSC and other instrumental methods of analysis.

One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X-ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art. The crystalline forms of Compound of formula (I) described herein may be formulated into pharmaceutical compositions and/or employed in therapeutic and/or prophylactic methods. These methods include, but are not limited to, the administration of the crystalline compound of formula (I), alone or in combination with one or more other pharmaceutically active agents, including agents that may be useful in the treatment of the disorders mentioned herein.

The term “Therapeutically effective amount” is intended to include an amount of the crystalline forms of Compound of formula (I) that is effective when administered alone or in combination to act against COVID-19 or in RA or other disease areas. If Compound of formula (I) is used in combination with another medication, the combination of compounds described herein may result in a synergistic combination. Synergy, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antithrombotic effect, or some other beneficial effect of the combination compared with the individual components.

The crystalline forms of Compound of formula (I) and pharmaceutical compositions thereof may be useful in COVID-19 or in RA or other disease areas. The method of administration preferably comprise administering to a patient a pharmaceutically effective amount of the novel crystals of the present invention, preferably in combination with one or more pharmaceutically acceptable carriers and/or excipients. The relative proportions of active ingredient and carrier and/or excipient may be determined, for example, by the solubility and chemical nature of the materials, chosen route of administration and standard pharmaceutical practice.

The crystalline forms of Compound of formula (I) may be administered to a patient in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the crystalline forms of Compound of formula (I) will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. By way of general guidance, in the adult, suitable doses may range from about 0.001 to about 1000 mg/Kg body weight, and all combinations and sub combinations of ranges and specific doses therein. The crystalline forms of Compound of formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

For oral administration in solid form such as a tablet or capsule, the crystalline forms of Compound of formula (I) can be combined with a non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.

Preferably, in addition to the active ingredient, solid dosage forms may contain a number of additional ingredients referred to herein as “excipients These excipients include among others diluents, binders, lubricants, glidants and disintegrants. Coloring agents may also be incorporated. “Diluents ”, as used herein, are agents which impart bulk to the formulation to make a tablet a practical size for compression. Examples of diluents are lactose and cellulose. “Binders ”, as used herein, are agents used to impart cohesive qualities to the powered material to help ensure the tablet will remain intact after compression, as well as improving the free-flowing qualities of the powder. Examples of typical binders are lactose, starch and various sugars. “Lubricants” , as used herein, have several functions including preventing the adhesion of the tablets to the compression equipment and improving the flow of the granulation prior to compression or encapsulation. Lubricants are in most cases hydrophobic materials. Excessive use of lubricants is undesired, however, as it may result in a formulation with reduced disintegration and/or delayed dissolution of the drug substance. “Glidants ”, as used herein, refer to substances which may improve the flow characteristics of the granulation material. Examples of glidants include talc and colloidal silicon dioxide. “Disintegrants” , as used herein, are substances or a mixture of substances added to a formulation to facilitate the breakup or disintegration of the solid dosage form after administration. Materials that may serve as disintegrants include starches, clays, celluloses, algins, gums and cross-linked polymers. A group of disintegrants referred to as “ super-disintegrants” generally are used at a low level in the solid dosage form, typically 1% to 10% by weight relative to the total weight of the dosage unit. Croscarmellose, crospovidone and sodium starch glycolate represent examples of cross-linked cellulose, a cross-linked polymer and a cross-linked starch, respectively. Sodium starch glycolate swells seven to twelve-fold in less than 30 seconds effectively disintegrating the granulations that contain it.

The disintegrant preferably used in the present invention is selected from the group comprising modified starches, croscarmellose sodium, carboxymethylcellulose calcium and crospovidone. A more preferred disintegrant in the present invention is a modified starch such as sodium starch glycolate.

Preferred carriers include capsules or compressed tablets which contain the solid pharmaceutical dosage forms described herein. Preferred capsule or compressed tablet forms generally comprise a therapeutically effective amount of the crystalline forms of Compound of formula (I) and one or more disintegrants in an amount greater than about 10% by weight relative to the total weight of the contents of the capsule or the total weight of the tablet.

Preferred capsule formulations may contain the crystalline forms of Compound of formula (I) in an amount from about 5 to about 1000 mg per capsule. Preferred compressed tablet formulations contain the crystalline forms of Compound (I) in an amount from about 5 mg to about 800 mg per tablet. More preferred formulations contain about 50 to about 200 mg per capsule or compressed tablet. Preferably, the capsule or compressed tablet pharmaceutical dosage form comprises a therapeutically effective amount of, crystalline Form I, of Compound of formula (I); a surfactant; a disintegrant; a binder; a lubricant; and optionally additional pharmaceutically acceptable excipients such as diluents, glidants and the like; wherein the disintegrant is selected from modified starches; croscarmellose sodium, carboxymethylcellulose calcium and crospovidone.

For oral administration in liquid form, the crystalline forms of Compound of formula (I) can be combined with any oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. The liquid composition may contain a sweetening agent which to make the compositions more palatable. The sweetening agent can be selected from a sugar such as sucrose, mannitol, sorbitol, xylitol, lactose, etc. or a sugar substitute such as cyclamate, saccaharin, aspartame, etc. If sugar substitutes are selected as the sweetening agent the amount employed in the compositions of the invention will be substantially less than if sugars are employed. Taking this into account, the amount of sweetening agent may range from about 0.1 to about 50% by weight, and all combinations and sub-combinations of ranges and specific amounts therein. Preferred amounts range from about 0.5 to about 30% by weight. Sterile injectable solutions may be prepared by incorporating the crystalline forms of Compound of formula (I) in the required amounts, in the appropriate solvent, with various of the other ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions may be prepared by incorporating the sterilized active ingredient into a sterile vehicle which contains the dispersion medium and any other required ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation may include vacuum drying and the freeze drying technique which may yield a powder of the active ingredient, plus any additional desired ingredient from the previously sterile-filtered solution thereof.

As would be apparent to a person of ordinary skill in the art, once armed with the teachings of the present disclosure, when dissolved, Compound of formula (I) loses its crystalline structure, and is therefore considered to be a solution of Compound of formula (I). All forms of the present invention, however, may be used for the preparation of liquid formulations in which Compound of formula (I) may be, for example, dissolved or suspended. In addition, the crystalline forms of Compound of formula (I) may be incorporated into solid formulations.

The liquid compositions may also contain other components routinely utilized in formulating pharmaceutical compositions. One example of such components is lecithin. It’s use in compositions of the invention as an emulsifying agent in the range of from 0.05 to 1% by weight, and all combinations and sub-combinations of ranges and specific amounts therein. More preferably, emulsifying agents may be employed in an amount of from about 0.1 to about 0.5% by weight. Other examples of components that may be used are antimicrobial preservatives, such as benzoic acid or parabens; suspending agents, such as colloidal silicon dioxide; antioxidants; topical oral anesthetics; flavoring agents; and colorants. The selection of such optional components and their level of use in the compositions of the invention is within the level of skill in the art and will be even better appreciated from the working examples provided hereinafter.

The crystalline forms of Compound of formula (I) may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidine pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyethylene oxide-polylysine substituted with palmitolyl residues. Furthermore, the crystalline Compound of formula (I) may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

Gelatin capsules of the crystalline forms of Compound of formula (I) may contain the crystalline Compound of formula (I) and the liquid or solid compositions described herein. Gelatin capsules may also contain powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Tablets can be sugar coated or film coated to mask any unpleasant taste and to protect the tablet from the atmosphere or enteric coated for selective disintegration in the gastrointestinal track.

In general, water, suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral solutions are prepared by dissolving the crystalline Compound of formula (I) in the carrier and, if necessary, adding buffering substances. Anti -oxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA may also be employed. Parenteral solutions may also contain preservatives, such as benzalkonium chloride, methyl- or propylparaben and chlorobutanol.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules: A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient (i.e., crystalline form I of BA or compound of formula (I)), 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

Tablets: A large number of tablets can be prepared by the present invention contains various quantities ranging from about 10 mg to about 500 mg of Bucillamine Crystalline form I a pharmaceutically acceptable salt thereof. Thus, for example, the preferred formulation can contain about lOmg to 500 mg of Bucillamine Crystalline form I and it excipients is selected from microcrystalline cellulose, croscarmellose sodium, iron oxide yellow, povidone, copovidone, colloidal silicon dioxide, magnesium stearate, Mannitol, Hydroxy propyl cellulose, starch and lactose, Hypromellose or mixture thereof and optionally a pharmaceutical acceptable excipient.

Suspension: An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable: A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

Nasal Spray: An aqueous solution is prepared such that each 1 mL contains 10 mg of active ingredient, 1.8 mg methylparaben, 0.2 mg propylparaben and 10 mg methylcellulose. The solution is dispensed into 1 mL vials.

Lung Inhaler: A homogeneous mixture of the active ingredient in polysorbate 80 is prepared such that the final concentration of the active ingredient will be 10 mg per container and the final concentration of polysorbate 80 in the container will be 1% by weight. The mixture is dispensed into each can, the valves are crimped onto the can and the required amount of dichlorotetrafluoroethane is added under pressure.

Pharmaceutical kits which may be useful for the treatment of various disorders, and which comprise a therapeutically effective amount of a pharmaceutical composition comprising a novel crystalline form I, of Compound of formula (I) in one or more sterile containers, are also within the ambit of the present invention. The kits may further comprise conventional pharmaceutical kit components which will be readily apparent to those skilled in the art, once armed with the present disclosure. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art.

The present disclosure is in relation to a crystalline form I of a compound of formula (I) In another embodiment of the present disclosure, the crystalline form I, is characterized by having an X-ray powder diffraction pattern as shown in figure 1.

In yet another embodiment of the present disclosure, crystalline form I of the compound of formula (I) is characterized by a powder X-ray diffraction pattern (PXRD) comprising peaks at 10.4+0.2, 13.5+0.2, 14.4+0.2, 16.8+0.2, 17.2+0.2, 17.5+0.2, 21.9+0.2, 22.7+0.2, 28.0+0.2, 29.3+0.2, 30.0+0.2 and 30.45+0.2. The Cu Ka radiation is expressed in degrees 29.

In still another embodiment of the present disclosure, the crystalline form I of the compound of formula (I) is characterized by a X-ray powder diffraction pattern (PXRD) comprising peaks at 10.4+0.2, 13.5 +0.2, 14.4 +0.2, 16.8 +0.2, 17.2 +0.2, 17.5 +0.2, 20.1 +0.2, 20.9 +0.2, 21.9 +0.2, 22.7 +0.2, 23.5 +0.2, 28.0 +0.2, 28.7 +0.2, 29.3 +0.2, 30.0 +0.2, 30.45 +0.2, 32.1 +0.2, 37.8 +0.2 and 38.6 +0.2. The Cu Ka radiation is expressed in degrees 29.

In still another embodiment of the present disclosure, the crystalline form particle size distribution D90 is lower than 250 pm.

In still another embodiment of the present disclosure, the crystalline form I of the compound of formula (I) is characterized by having a differential scanning calorimetry (DSC) curve substantially in accordance with that shown in figure 2.

In still another embodiment of the present disclosure, the Form I is characterized by a differential scanning calorimetry curve (DSC) comprising an exotherm at 143 °C ± 2°C.

The present disclosure is in relation to a composition comprising the compound of formula (I), wherein at least about 50 % of the compound of formula (I) in the composition is present in the crystalline form I, of the compound of formula (I).

The present disclosure is in relation to a pharmaceutical composition comprising the crystalline form I, of the compound of formula (I) and a pharmaceutically acceptable and compatible excipient(s).

The present disclosure in relation to a method for preparation of the crystalline form I, of the compound of formula (I), comprises first and foremost step of dissolving crude BA in an organic solvent followed by heating to obtain a clear solution. Secondly, the clear mixture is subjected to stirring and cooled. The cooled solution is filtered to isolate the solid. Thirdly, the obtained solid was washed using organic solvents described in below embodiments and dried to obtain off white solid particles of crystalline Form I of the compound of formula (I).

In another embodiment of the present disclosure, the organic solvents are selected from a group comprising of ethyl acetate, isopropyl acetate and cyclohexane or combinations thereof.

In yet another embodiment of the present disclosure, the heating was carried out at a temperature ranging from 40°C to 75°C, preferably between 40°C to 45°C when cyclohexane was used as a solvent and most preferably between 70°C to 75°C when ethyl acetate was used as a solvent.

In still another embodiment of the present disclosure, the cooling of clear solution was carried out at a temperature ranging from 0°C to 30°C, preferably between 10°C to 15 °C when cyclohexane was employed as a solvent and most preferably between 0°C to 5°C when ethyl acetate was used as a solvent.

In yet another embodiment of the present disclosure, stirring of the reaction mixture was carried out for a time period ranging from 1 to 2 hours.

The present disclosure is in relation to a method for inhibiting the activity of corona virus in a subject comprising administering an effective amount of the crystalline form I, of the compound of formula (I) to the subject in need thereof.

The present disclosure is in relation to a method for treating rheumatoid arthritis or COVID-19, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline form I, of the compound of formula (I) as exemplified in the aforementioned embodiments.

Additionally, the disclosure is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of the present invention. On the contrary, it is to be clearly understood that various other embodiments, modifications, and equivalents thereof, after reading the description herein in conjunction with the drawings/ figures and appended claims, may suggest themselves to those skilled in the art without departing from the spirit and scope of the presently disclosed and claimed invention.

Example 1: Process for preparing crystalline form I, of the compound of formula (I) or BA

Example la: A predetermined amount (20 g) of crude BA was dissolved in ethyl acetate by heating at a temperature ranging between 70°C to 75°C till a clear solution was obtained. Following this, the temperature of the clear solution was cooled and brought to a temperature ranging from about 25°C to 30°C under continuous stirring for a time period of about 1 to 2 hours. The temperature of the clear solution was still reduced to a temperature ranging from about 0°C to 5°C under continuous stirring. As a result of cooling, the solid obtained was isolated by filtration. The filtered product was washed using cyclohexane and was dried in an oven at a temperature ranging between 50°C to 60°C for a time period ranging from about 3 to 4 hours to obtain crystalline form I, of the compound of formula (I) or BA, which is a off-white solid. In the process, if required, the product was subjected to sieving to remove the lumps, if any. In summary, the above process helped achieve a product having a yield of 20 g and purity of about 99.8 %.

Example lb: Alternately, the crystalline form I, of the compound of formula (I) or BA can be prepared by heat reflux method. The proposed method involves dissolving crude BA (20 g) in isopropyl acetate followed by heat reflux to obtain a clear solution which is kept under continuous stirring for a time period ranging from about 1 to 2 hours to cool to a temperature ranging from about 25°C to 30°C. The resultant solid was isolated by filtration followed by washing with isopropyl acetate and dried in an oven at a temperature ranging between 40°C to 45°C for a time period ranging from about 3 to 4 hours to obtain crystalline form I, of the compound of formula (I) or BA, which is a off-white solid. In the process, if required, the product was subjected to sieving to remove the lumps, if any. In summary, the above process helped achieve a product having a yield of 15 g and purity of about 99.5 %.

Example 1c: Similar to the above, in yet another method, a predetermined amount (20 g) of crude BA was dissolved in cyclohexane by slow heating at a temperature ranging between 40°C to 45°C under continuous stirring (1 to 2 hours) till a clear solution was obtained. Following this, the temperature of the clear solution was cooled and brought to a temperature of about 15°C under continuous stirring for 1 to 2 hours. As a result of cooling, the solid obtained was isolated by filtration. The filtered product was washed using cyclohexane and was dried in an oven at a temperature ranging between 40°C to 45°C for a time period ranging from about 3 to 4 hours to obtain crystalline form I, of the compound of formula (I) or BA, which is a off-white solid. In the process, if required, the product was subjected to sieving to remove the lumps, if any. In summary, the above process helped achieve a product having a yield of 17 g and purity of about 99.8 %.

Example 2: Instrumental methods of analyzing/ characterizing the crystalline form I, of the compound of formula (I) or BA Example 2a: XRPD (X-ray Powder Diffraction) analysis was conducted on Rigaku Miniflex 600 X-ray diffractometer using Ni-filtered Cu - K radiation (Cu Ka, X=l.54060 A). Samples were prepared for analysis by depositing the wet cake or powder sample in the center of an aluminum holder equipped with a zero background plate. The X-ray generator was operated at a voltage of 40 kV and amperage of 15 mA. The sample rotation speed during measurement was 2 seconds/revolution. Scans were performed from 2 to 40° 2-theta range. The step size was 0.008° and total scan time was 1 hour.

The XRPD pattern of the crystalline form I of the compound of formula (I) when wet/ dry is shown in Figure 1. The sharp well-resolved peaks in the XRPD data suggest that the material is crystalline. The positions and intensities of the characteristic peaks observed in the XRPD spectrum are provided in Table 2.

Table 2: Position and intensities of peaks in XRPD

The positions of all peaks observed in the XRPD spectrum are provided in Table 3.

Table 3: All peaks in the XRPD spectrum

Example 2b: DSC (Differential Scanning Calorimetry) data were collected on a TA Instruments Q2000 system equipped with a 50 position auto-sampler. The calibration for energy and temperature was carried out using certified indium. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. Typically 2-10 mg of the sample was placed into an aluminium pan. The pan was covered with a lid, then crimped or hermetically sealed or left unsealed. The sample pan was then heated in the DSC cell at rate of 10°C/min up to a final temperature of 250°C with a dry nitrogen purge rate of 50 mL/min maintained over the sample throughout the measurement. The DSC curve is shown in figure 2 and comprises a single exotherm at 143°C ± 2°C.

Example 3: Repeated Dose 28-Day Oral Toxicity Study of the crystalline form I, of the compound of formula (I) or BA in Swiss Albino Mice

A repeated dose 28-day oral toxicity study of the crystalline form I, of the compound of formula (I) or BA was conducted in Swiss Albino Mice. The entire study was performed in accordance with New Drugs and Clinical Trials Rules, 2019, and the Organization for Economic Co-operation and Development (OECD) for Testing of Chemicals No 407 adopted on October 03, 2008.

First and foremost, three groups of Swiss Albino Mice comprising six male and six female animals per group were treated (orally) with the crystalline form I, of the compound of formula (I) at 60.0 mg/kg body weight as low dose, 120.0 mg/kg body weight as mid dose and 240.0 mg/kg body weight as high dose for a period of 28 days. The mice were observed twice a day for any clinical signs and adverse reactions. Body weights and feed consumption were monitored weekly for any treatment related changes. Biochemical and hematological analysis of blood samples and urine analysis were performed on all animals at the end of the 28-day treatment period. All the surviving mice were sacrificed after CO2 asphyxiation and subjected to gross (internal and external) pathological examination at the end of the treatment period. Organs were collected from the vehicle control and three graded dose treatment groups. Histopathological examinations were performed for the organs collected from high dose of active ingredient treated group and vehicle control group. Absolute organ weights were recorded and relative organ weights were calculated for all the organs (vehicle control group and treatment groups) viz., heart, liver, brain, kidneys, adrenals, testes/ovary, epididymis/uterus, lungs and spleen. Different doses of the active ingredient treated male or female mice did not show any treatment related adverse clinical signs such as morbidity and mortality. No significant difference was observed in mean weekly feed consumption and body weights for the active ingredient treated animals at all doses as compared to the vehicle control group animals. Low dose, mid dose or high dose of active ingredient exposed animals did not show any significant changes in clinical chemistry parameters as compared to vehicle control group animals. In addition, low dose, mid dose or high dose of the active ingredient exposed animals did not show any significant changes in hematological parameters as compared to vehicle control group. Urinalysis parameters did not reveal any active ingredient treatment related findings at any of the three doses in male or female animals. Absolute organ weights and relative organ weights did not show significant difference in any of the three groups of active ingredient treated animals as compared to vehicle control group (male and female). Gross pathological and histopathological examination (high dose and vehicle control groups) did not reveal any test item treatment related abnormalities. In summary, the repeated oral administration of the active ingredient to male and female Swiss Albino Mice for a period of 28 days with 60.0, 120.0 and 240.0 mg/kg, body weight doses did not show any significant differences in the body weight, feed consumption and other parameters (male and female) as compared to vehicle control group. Hence, high dose of the active ingredient (240.0 mg/kg, body weight) was concluded as NOAEL (No Observed Adverse Effect Level) in both male and female mice.

While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims. Example 4:

Example 5:

Claims

We claim:

1) A crystalline form I, of a compound of formula (I)

2) The crystalline form as claimed in claim 1, wherein said crystalline form I is characterized by having an X-ray powder diffraction pattern substantially in accordance with that shown in figure 1.

3) The crystalline form as claimed in claim 1, wherein said form I is characterized by a X-ray powder diffraction pattern comprising peaks at 10.4+0.2, 13.5+0.2, 14.4+0.2, 16.8+0.2, 17.2+0.2, 17.5+0.2, 21.9+0.2, 22.7+0.2, 28.0+0.2, 29.3+0.2, 30.0+0.2 and 30.45+0.2 (Cu Ka radiation, expressed in degrees 2θ).

4) The crystalline form as claimed in claim 1, wherein said form I is characterized by a X-ray powder diffraction pattern comprising peaks at 10.4+0.2, 13.5 +0.2, 14.4 +0.2, 16.8 +0.2, 17.2 +0.2, 17.5 +0.2, 20.1 +0.2, 20.9 +0.2, 21.9 +0.2, 22.7 +0.2, 23.5 +0.2, 28.0 +0.2, 28.7 +0.2, 29.3 +0.2, 30.0 +0.2, 30.45 +0.2, 32.1 +0.2, 37.8 +0.2 and 38.6 ±0.2 (Cu Ka radiation, expressed in degrees 29).

5) The crystalline form as claimed in claim 1, wherein said crystalline form I particle size distribution D90 is lower than 250 pm.

6) The crystalline form as claimed in claim 1, wherein said crystalline form I is characterized by having a differential scanning calorimetry curve substantially in accordance with that shown in figure 2.

7) The crystalline form as claimed in claim 1, wherein said crystalline form I is characterized by a differential scanning calorimetry curve comprising an exotherm at 143°C + 2°C.

8) A composition comprising the compound of formula (I), wherein at least about 50 % of the compound of formula (I) in the composition is present in the crystalline form I as claimed in claim 1. 9) A pharmaceutical composition comprising (a) the crystalline form I of claim 1 and a pharmaceutically acceptable excipient.

10) A method for preparation of the crystalline form I as claimed in claim 1, comprising steps of: a) dissolving crude bucillamine in an organic solvent followed by heating to obtain a clear solution; b) stirring and cooling the clear solution obtained in step (a) followed by filtering to isolate the solids; and c) washing the solids obtained in step (b) using organic solvent followed by drying to obtain crystalline Form I of the compound of formula (I).

11) The process as claimed in claim 10, wherein said organic solvent is selected from a group comprising of ethyl acetate, isopropyl acetate and cyclohexane or combinations thereof.

12) The process as claimed in claim 10, wherein the heating was carried out at a temperature ranging from 40°C to 75°C, preferably between 40°C to 45°C and most preferably between 70°C to 75°C.

13) The process as claimed in claim 10, wherein the cooling of clear solution was carried out at a temperature ranging from 0°C to 30°C, preferably between 10°C to 15°C and most preferably between 0°C to 5 °C.

14) The process as claimed in claim 10, wherein the stirring was carried out for a time period ranging from 1 to 2 hours.

15) A method for inhibiting the activity of corona virus in a subject, comprising administering an effective amount of the crystalline form I as claimed in claim 1 to the subject.

16) A method for treating rheumatoid arthritis or COVID-19, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline form I as claimed in claim 1.

17) A pharmaceutical composition comprising of Bucillamine Crystalline form I or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient. 18) The pharmaceutical composition as claimed in claim 17, Bucillamine Crystalline form I in a range from about 10 mg to about 500 mg along with and one or more pharmaceutically acceptable excipient.

19) The pharmaceutical composition as claimed in claim 17, wherein preferably excipients are selected from microcrystalline cellulose, croscarmellose sodium, iron oxide yellow, povidone, copovidone, colloidal silicon dioxide, magnesium stearate, Mannitol, Hydroxy propyl cellulose, starch and lactose, Hypromellose or mixture thereof and optionally a pharmaceutical acceptable excipient.