DESC:
CROSS REFERENCE TO RELATED APPLICATION
This patent application claims the benefit of priority to Indian Provisional Patent Application No. 201941016250, filed on April 24, 2019, which is incorporated herein by reference in their entirety.

FIELD OF THE INVENTION
The present invention relates to consistently reproducible processes for the production of highly pure and stable crystalline Form II of Otilonium bromide.

BACKGROUND OF THE INVENTION
U.S. Patent No. 3,536,723 (hereinafter referred to as the US‘723 patent) discloses p-(2-alkyloxy-benzoyl)-aminobenzoates of N-alkylamino-alkyl, the quarternary ammonium salts thereof and their preparation. These compounds have antispastic-spasmolytic activities and coronary-dilatory properties. Among them, Otilonium bromide, chemically named as N,N-Diethyl-N-methyl-2-[[4-[[2-(octyloxy)benzoyl]amino]benzoyl]oxy]ethanaminium bromide, is a selective anti-spastic-spasmolytic agent used to relieve spasmodic pain of the gut, especially in irritable bowel syndrome. Otilonium bromide is represented by the following structural formula I:

Otilonium bromide was approved by Central Drugs Standard Control Organization (CDSCO) for use in the treatment of irritable bowel syndrome, painful spastic condition of distal enteric tract and is sold under the brand name Colirid. Colirid is available in the market as 40 mg tablets.
Various processes for the preparation of Otilonium bromide are apparently described in U.S. Patent No. US 3,536,723; Chinese Patent Application Publication Nos. CN 103030572 A and CN 105037193 A, and Journal of Medicinal Chemistry (1973), 16(9), 1063-1065.
U.S. Patent No. 3,536,723 describes several general synthetic routes for the preparation of Otilonium bromide. One of the synthetic routes described in US’723 patent is depicted in scheme 1:

The second synthetic route described in US’723 patent is depicted in scheme 2:

Otilonium bromide is known to exhibit polymorphism and two crystalline forms (Form I and Form II) were reported in the literature. The US’723 patent discloses the melting point (166-168°C) of the resulting Otilonium bromide, which is later designated as crystalline Form II in the Scientific Article “Journal of Pharmaceutical Sciences (2016), pages 1-8”. Journal of Pharmaceutical Sciences discloses another crystalline form of Otilonium bromide, which is designated as Form I. The Journal of Pharmaceutical Sciences characterizes the crystalline forms (Form I and Form II) by powder X-ray diffraction (XRPD), Infra Red spectrum (IR) and Differential Scanning Calorimetry (DSC). The DSC endotherm of Otilonium bromide crystalline Form II (at about 441 K) reported in the Journal of Pharmaceutical Sciences is identical with that of the melting point (166-168°C) reported in US’723 patent.
The X-ray crystallographic data of crystalline form of Otilonium bromide disclosed in the US’723 patent was later reported in the Acta Crystallographica, Section C, Crytstal Structure Communications (1986), C42(4), pages 474-8.
However, the processes described in the aforementioned prior art have failed to consistently produce the pure crystalline Form II of Otilonium bromide.
A need still remains for simple, cost effective, consistently reproducible and environmentally friendly processes for preparing highly pure crystalline Form II of Otilonium bromide which is essentially free of other crystalline forms.

SUMMARY OF THE INVENTION
Provided herein are simple, cost effective and consistently reproducible processes for the preparation of highly pure crystalline Form II of Otilonium bromide essentially free of other crystalline forms.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form II of Otilonium bromide made by the process disclosed herein, and one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form II of Otilonium bromide made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In another aspect, the highly pure crystalline Form II of Otilonium bromide essentially free of other crystalline forms, made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 1 micron to about 110 microns, and most specifically about 4 microns to about 90 microns.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
The term “crystalline Form II of Otilonium bromide”, otherwise called “Otilonium bromide crystalline Form II”, as used herein is intended to mean the crystalline Form II of Otilonium bromide as originally disclosed in the “Journal of Pharmaceutical Sciences 2016, 1-8”, which is further characterized by an X-ray crystallographic data reported in the scientific journal “Acta Crystallographica, Section C, Crytstal Structure Communications (1986), C42(4), pages 474-8”.
In one embodiment, the crystalline Form II of Otilonium bromide essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 7.10, 9.42, 18.82 and 23.21 ± 0.2 degrees substantially in accordance with Figure 1; an infrared (FT-IR) spectrum having main bands at about 3342, 2932, 1712, 1679, 1595 and 1541 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 168.62°C and a sharp endotherm peak at about 170.1°C substantially in accordance with Figure 3.
In one embodiment, the crystalline Form II of Otilonium bromide obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having additional 2-theta angle positions at about 10.80, 11.53, 14.12, 14.70, 15.03, 19.54, 21.22, 21.61, 23.53, 23.83, 24.12, 24.67 and 25.42 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 1486, 1453, 1410, 1322, 1273, 1221, 1174, 1111, 860 and 758 cm-1 substantially in accordance with Figure 2.
In one embodiment, the crystalline Form II of Otilonium bromide obtained by the processes disclosed herein is essentially free from other solid state forms of Otilonium bromide detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The term “crystalline Form II of Otilonium bromide essentially free of other crystalline forms” means that no other polymorphic forms of Otilonium bromide can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Otilonium bromide” is intended to mean the polymorphic forms of Otilonium bromide other than crystalline Form II.
The process disclosed herein above advantageously produces the crystalline Form II of Otilonium bromide with high chemical and polymorphic purity.
The highly pure crystalline Form II of Otilonium bromide obtained by the process disclosed herein has a chemical purity of greater than about 99.3%, specifically greater than about 99.5%, and most specifically greater than about 99.9% as measured by HPLC.
Unless otherwise specified, the term “crude or impure form of Otilonium bromide” refers to any form of Otilonium bromide having purity less than or equal to about 99.3% as measured by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form II of Otilonium bromide.
Figure 2 is a characteristic infra-red (FT-IR) spectrum of crystalline Form II of Otilonium bromide.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form II of Otilonium bromide.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form II of Otilonium bromide essentially free of other crystalline forms, comprising:
a) providing a solution of Otilonium bromide in a solvent selected from the group consisting of a ketone, an alcohol, an ester, and mixtures thereof;
b) optionally, subjecting the solution obtained in step-(a) to carbon treatment at reflux temperature to obtain a filtrate;
c) cooling the solution obtained in step-(a) or step-(b) at a temperature of below about 35°C to cause crystallization; and
d) collecting the highly pure crystalline Form II of Otilonium bromide essentially free of other crystalline forms formed in step-(c).
Specifically, the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. The most preferred solvent used in step-(a) is acetone.
The present inventors have found that the solvent employed is critical in order to consistently produce the highly pure crystalline Form II of Otilonium bromide essentially free of other crystalline forms.
It has been surprisingly and unexpectedly found that the crystalline Form II of Otilonium bromide is obtained with high purity and high yield when acetone is employed as solvent for recrystallization.
Usually, the amount of solvent employed in step-(a) is about 11 volumes to about 30 volumes, specifically about 15 volumes to about 25 volumes, and most specifically about 18 volumes to about 20 volumes, with respect to the quantity of Otilonium bromide used.
Step-(a) of providing a solution of Otilonium bromide includes dissolving Otilonium bromide (crude or pure) in the solvent at reflux temperature, or obtaining an existing solution from a previous processing step.
In one embodiment, the Otilonium bromide is dissolved in the solvent at the reflux temperature of the solvent used. After complete dissolution of Otilonium bromide, the resulting solution is stirred at the reflux temperature for at least 10 minutes, and specifically for about 20 minutes to about 30 minutes.
The carbon treatment in step-(b) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at the reflux temperature for at least 5 minutes, specifically for about 10 minutes to about 30 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Otilonium bromide by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In one embodiment, the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about 10°C to about 40°C for at least 20 minutes, and more specifically at a temperature of about 15°C to about 35°C for about 20 minutes to about 5 hours, and most specifically at a temperature of about 20°C to about 30°C for about 30 minutes to about 3 hours.
The collection of the precipitated solid in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
According to another aspect, there is provided a process for the preparation of crystalline Form II of Otilonium bromide, comprising:
a) providing a suspension of Otilonium bromide (crude or pure) in a suitable solvent at a temperature of about 25°C to the reflux temperature of the solvent used, wherein the solvent is selected from the group consisting of a ketone, an alcohol, an ester, and mixtures thereof;
b) stirring the suspension formed in step-(a) at a temperature of about 20°C to the reflux temperature of the solvent;
c) optionally cooling the suspension obtained in step-(b) to below about 35°C; and
d) recovering the highly pure crystalline Form II of Otilonium bromide formed in step-(b) or step-(c).
Usually, the amount of solvent employed in step-(a) is about 2 volumes to about 10 volumes, specifically about 3 volumes to about 8 volumes, and most specifically about 5 volumes, with respect to the quantity of Otilonium bromide used.
In one embodiment, the suspension in step-(b) is stirred at a temperature of about 25°C to the reflux temperature of the solvent used for at least 10 minutes, specifically stirred at a temperature of about 35°C to the reflux temperature of the solvent used for about 30 minutes to 10 hours, and most specifically at the reflux temperature of the solvent used for about 1 hour to about 5 hours.
In another embodiment, the suspension in step-(c) is cooled while stirring at a temperature of about 0°C to about 35°C for at least 10 minutes, and more specifically at a temperature of about 10°C to about 30°C for about 15 minutes to about 2 hours.
The recovering in step-(d) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
As used herein, the term “room temperature” or “RT” refer to a temperature of about 20°C to about 35°C. For example, “RT” can refer to a temperature of about 25°C to about 30°C.
The highly pure crystalline Form II of Otilonium bromide obtained by the process described herein is found to be more stable.
In one embodiment, the crystalline Form II of Otilonium bromide essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 7.10, 9.42, 18.82 and 23.21 ± 0.2 degrees substantially in accordance with Figure 1; an infrared (FT-IR) spectrum having main bands at about 3342, 2932, 1712, 1679, 1595 and 1541 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 168.62°C and a sharp endotherm peak at about 170.1°C substantially in accordance with Figure 3.
In one embodiment, the crystalline Form II of Otilonium bromide obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having additional 2-theta angle positions at about 10.80, 11.53, 14.12, 14.70, 15.03, 19.54, 21.22, 21.61, 23.53, 23.83, 24.12, 24.67 and 25.42 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 1486, 1453, 1410, 1322, 1273, 1221, 1174, 1111, 860 and 758 cm-1 substantially in accordance with Figure 2.
The highly pure crystalline Form II of Otilonium bromide obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 40°C to about 85°C and most preferably at about 50°C to about 80°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 25 hours, and more preferably about 5 hours to 20 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
Unless otherwise specified, the Otilonium bromide as used herein as starting material can be obtained by the processes known in the prior art, for example, as per the processes described in the U.S. Patent No. 3,536,723.
The stable and highly pure crystalline Form II of Otilonium bromide obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline Form II of Otilonium bromide obtained by the processes disclosed herein exhibits properties making it suitable for formulating Otilonium bromide.
Further encompassed herein is the use of the highly pure crystalline Form II of Otilonium bromide obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline Form II of Otilonium bromide obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.
In one embodiment, the highly pure crystalline Form II of Otilonium bromide obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 1 microns to about 110 microns, and most specifically about 4 microns to about 90 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form II of Otilonium bromide obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form II of Otilonium bromide obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form II of Otilonium bromide obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form II of Otilonium bromide obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, parenteral, or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, suspensions, powders, and the like.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650 cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 210°C.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = Inertsil ODS-3V, (250 × 4.6) mm, 5 µm; Detector wavelength = 294 nm; Flow Rate = 1.8 ml/minute; Injection volume = 10 µL; Oven temperature = 40°C; Run time = 85 minutes; Diluent = A mixture of Acetone : Water (50:50 v/v); Elution = Gradient; and Sample Concentration: 1.0 mg/ml.
Mobile Phase-A: A mixture of buffer and Acetonitrile 90:10 (v/v)
Mobile Phase-B: A mixture of Acetonitrile and water 90:10 (v/v)
The following example is given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of pure crystalline Form II of Otilonium bromide
A mixture of crude Otilonium bromide (10 g, Purity by HPLC: 99.2%) and Acetone (200 ml) were taken in a reaction flask at 25-30°C and the resulting mass was heated to reflux temperature to form a clear solution, and then stirred for 20 to 30 minutes at reflux temperature. The resulting solution was cooled to 25-30°C, followed by stirring for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with acetone (20 ml) and then dried the material to produce 8.0 g of pure crystalline Form II of Otilonium bromide (Purity by HPLC: 99.9%).

Example 2
Preparation of pure crystalline Form II of Otilonium bromide
A mixture of crude Otilonium bromide (10 g, Purity by HPLC: 80-85%) and Acetone (50 ml) were taken into a reaction flask at 25-30°C and the resulting suspension was stirred for 1 hour at the same temperature. The separated solid was filtered, washed with acetone (20 ml) and then dried the material to produce 6.5 g of pure crystalline Form II of Otilonium bromide (Purity by HPLC: 99.3%).

Example 3
Preparation of pure crystalline Form II of Otilonium bromide
A mixture of crude Otilonium bromide (10 g, Purity by HPLC: 99.2%) and Isopropyl alcohol (50 ml) were taken into a reaction flask at 25-30°C and the resulting mass was heated to reflux temperature, and then stirred for 15 to 20 minutes at reflux temperature. The resulting solution was cooled to 25-30°C, followed by stirring for 30 minutes at the same temperature. The separated solid was filtered, washed the solid with Isopropyl alcohol (10 ml) and then dried the material to produce 5.0 g of pure crystalline Form II of Otilonium bromide (Purity by HPLC: 99.8%).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
,CLAIMS:
1. A process for the preparation of a crystalline Form II of Otilonium bromide essentially free of other crystalline forms, comprising:
a) providing a solution of Otilonium bromide in a solvent selected from the group consisting of a ketone, an alcohol, an ester, and mixtures thereof;
b) optionally, subjecting the solution obtained in step-(a) to carbon treatment at reflux temperature to obtain a filtrate;
c) cooling the solution obtained in step-(a) or step-(b) at a temperature of below about 35°C to cause crystallization; and
d) collecting the highly pure crystalline Form II of Otilonium bromide essentially free of other crystalline forms formed in step-(c).

2. The process as claimed in claim 1, wherein the amount of solvent employed in step-(a) is about 11 volumes to about 30 volumes with respect to the quantity of Otilonium bromide used; wherein the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof; and wherein the solution in step-(a) is prepared by dissolving Otilonium bromide in the solvent at the reflux temperature of the solvent used.

3. The process as claimed in claim 2, wherein the amount of solvent employed in step-(a) is about 18 volumes to about 20 volumes with respect to the quantity of Otilonium bromide used; and wherein the solvent used in step-(a) is acetone.

4. The process claimed in claim 1, wherein the carbon treatment in step-(b) is carried out by stirring the solution with finely powdered carbon at the reflux temperature for at least 5 minutes, followed by filtering the resulting mixture through charcoal bed to obtain a filtrate containing Otilonium bromide; wherein the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about 10°C to about 40°C for at least 20 minutes; and wherein the collection of precipitated solid in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

5. The process as claimed in claim 4, wherein the carbon treatment in step-(b) is carried out by stirring the solution with finely powdered carbon for about 10 minutes to about 30 minutes, followed by filtering the resulting mixture through charcoal bed to obtain a filtrate containing Otilonium bromide; and wherein the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about 15°C to about 35°C for about 20 minutes to about 5 hours.

6. The process as claimed in claim 5, wherein the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about 20°C to about 30°C for about 30 minutes to about 3 hours.

7. A process for the preparation of crystalline Form II of Otilonium bromide, comprising:
a) providing a suspension of Otilonium bromide (crude or pure) in a suitable solvent at a temperature of about 25°C to the reflux temperature of the solvent used, wherein the solvent is selected from the group consisting of a ketone, an alcohol, an ester, and mixtures thereof;
b) stirring the suspension formed in step-(a) at a temperature of about 20°C to the reflux temperature of the solvent;
c) optionally cooling the suspension obtained in step-(b) to below about 35°C; and
d) recovering the highly pure crystalline Form II of Otilonium bromide formed in step-(b) or step-(c).

8. The process as claimed in claim 7, wherein the amount of solvent employed in
step-(a) is about 2 volumes to about 10 volumes with respect to the quantity of Otilonium bromide used; wherein the suspension in step-(b) is stirred at a temperature of about 25°C to the reflux temperature of the solvent used for at least 10 minutes; wherein the suspension in step-(c) is cooled while stirring at a temperature of about 0°C to about 35°C for at least 10 minutes; and wherein the recovery in step-(d) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

9. The process as claimed in claim 8, wherein the amount of solvent employed in
step-(a) is about 3 volumes to about 8 volumes with respect to the quantity of Otilonium bromide used; wherein the suspension step-(b) is stirred at a temperature of about 35°C to the reflux temperature of the solvent used for about 30 minutes to about 10 hours; and wherein the suspension in step-(c) is cooled while stirring at a temperature of about 10°C to about 30°C for about 15 minutes to about 2 hours.

10. The process as claimed in claim 9, wherein the amount of solvent employed in
step-(a) is about 5 volumes with respect to the quantity of Otilonium bromide used; and wherein the suspension in step-(b) is stirred at the reflux temperature of the solvent used for about 1 hour to about 5 hours.

11. The process as claimed claims 1 and 7, wherein the crystalline Form II of Otilonium bromide obtained is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 7.10, 9.42, 10.80, 11.53, 14.12, 14.70, 15.03, 18.82, 19.54, 21.22, 21.61, 23.21, 23.53, 23.83, 24.12, 24.67 and 25.42 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3342, 2932, 1712, 1679, 1595, 1541, 1486, 1453, 1410, 1322, 1273, 1221, 1174, 1111, 860 and 758 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 168.62°C and a sharp endotherm peak at about 170.1°C substantially in accordance with Figure 3.

12. Highly pure crystalline Form II of Otilonium bromide having a chemical purity of greater than about 99.3% as measured by HPLC.

13. The compound as claimed in claim 12, wherein the crystalline Form II of Otilonium bromide has a chemical purity of greater than about 99.5% as measured by HPLC.

14. The compound as claimed in claim 12, wherein the crystalline Form II of Otilonium bromide has a chemical purity of greater than about 99.9% as measured by HPLC.

15. A pharmaceutical composition comprising highly pure crystalline Form II of Otilonium bromide having a chemical purity of greater than about 99.9% as measure by HPLC.

16. The pharmaceutical composition as claimed in claim 15, wherein the crystalline Form II of Otilonium bromide has a D90 particle size of about 1 micron to about 110 microns.