DESC:Field of the Invention

The present invention relates to improved process for the preparation of 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride of Formula-(I) and its solid state forms thereof.

Background of the Invention

The 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride salt of Formula-I also known as Pitolisant hydrochloride is an antagonist/inverse agonist of the histamine-3 (H3) receptor and it is approved for the treatment of excessive daytime sleepiness (EDS) in adult patients with narcolepsy. Pitolisant hydrochloride is a white or almost white crystalline powder and it is soluble in water, ethanol, and methylene chloride and practically insoluble in cyclohexane.

US patent number 7,910,605 described a process for the preparation of Pitolisant and its pharmaceutically acceptable salts such as hydrochloride, hydrobromide, hydrogen maleate and hydrogen oxalate.

Eur. J. Pharm. Sci. 13 (2001) 249-259 described three steps process for the preparation of Pitolisant hydrochloride starting with piperidine and 3-chloropropanol, to give the intermediate 3-(piperidin-l-yl)propan-l-ol, which is reacted with 3-(4-chlorophenyl)propyl methanesulphonate in presence of sodium hydride and 15-crown-5 to give Pitolisant base which is finally reacted with gaseous hydrochloric acid to obtain Pitolisant HC1 as shown in scheme-1


US patent number 8,207,197 describes a crystalline Pitolisant monohydrochloride having moisture content 2.7 to 6.5% and its preparation thereof. This patent described other salts such as oxalate and maleate and their solubility. This patent revealed that hydrochloride salt of Pitolisant is better solubility and stability over oxalate and maleate salts.

Indian patent number 253991 described a process for the preparation of Pitolisant of formula-I as shown in scheme-2.


The PCT publication WO2021023634 A1 disclosed a process for the preparation of Pitolisant hydrochloride by the reaction of 4-azaspiro[3.5]nonan-4-ium bromide with 3-(4-chlorophenyl)propan-1-ol.
The EP patent number 3239138 A1 described a process for the preparation of Pitolisant hydrogen fumarate and a process for its preparation.

The reported prior arts are using hazardous and pyrophoric reagent such as sodium hydride and crown ethers. They have their own handling issue because of its pyrophoric nature and hence these processes are not suitable in commercial scale.

Hence there is a need for a commercially suitable and non-hazardous process for the preparation of Pitolisant hydrochloride. The present inventors also discovered new solid state forms of Pitolisant hydrochloride of formula-I.

Objectives of the Invention

The main objective of the present invention is to provide a simple process for the preparation of Pitolisant and its pharmaceutically acceptable salts thereof.

Another objective of the present invention is to provide new solid state forms of Pitolisant and its pharmaceutically acceptable salts.

Summary of the Invention
Accordingly the present invention relates to provide an improved process for the preparation of Pitolisant of formula-I comprising:
a) reacting 3-(piperidin-l-yl)propan-l-ol with 3-(4-chlorophenyl)propyl methanesulphonate in presence of base to obtain Pitolisant;
b) treating Pitolisant pharmaceutically acceptable salt; and
c) isolating Pitolisant pharmaceutically acceptable salt.

The present invention also relates to provide a solid state forms for Pitolisant hydrochloride of formula-I.

The present invention also relates to provide a process for the preparation of solid state forms of Pitolisant hydrochloride of formula-I without isolation of Pitolisant hydrochloride of formula-I.

Detailed Description of Drawing
FIG-1 shows an X-ray powder diffraction pattern of Pitolisant Hydrochloride and beta-cyclodextrin solid dispersion.
FIG-2 shows an X-ray powder diffraction pattern of Pitolisant Hydrochloride and povidone solid dispersion.
FIG-3 shows an X-ray powder diffraction pattern of Pitolisant Hydrochloride and povidone solid dispersion.
FIG-4 shows an X-ray powder diffraction pattern of Pitolisant Hydrochloride sesquihydrate and beta-cyclodextrin solid dispersion.
FIG-5 shows an X-ray powder diffraction pattern of Pitolisant Hydrochloride sesquihydrate.

Detailed Description of the Invention
One embodiment of the present invention, wherein the base used in step a) is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium tertiary-butoxide, lithium hydroxide, lithium carbonate, lithium bicarbonate, triethylamine, t-butylamine, trimethylamine and N, N diisopropylamine or combination thereof.

In another embodiment of the present invention, wherein the step a) is carried out in presence of which is selected from N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone, 1-methyl-2-piperidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, acetone and combination thereof.

In another embodiment of the present invention, wherein step a) reaction is carried out at a temperature about 0 °C to reflux temperature of solvent.

In another embodiment of the present invention, wherein the solid state form according to the present invention is selected from solid dispersion, co-crystal, premix, polymorphic forms and hydrates thereof.

In another embodiment of the present invention relates to provide a solid dispersion of Pitolisant hydrochloride comprising Pitolisant hydrochloride and pharmaceutically acceptable excipients.

In another embodiment of the present invention at least one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to mannitol, lactose, fructose, sorbitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. A thorough discussion of pharmaceutically acceptable excipients is presented in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing Company) and Remington: The Science and Practice of Pharmacy (21st ed., Lippincott Williams & Wilkins), which are hereby incorporated by reference.

The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Pitolisant hydrochloride salt with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant invention.

In another aspect of the present invention provides an improved process for the preparation of Pitolisant hydrochloride solid dispersion comprising:
a. providing Pitolisant first salt;
b. neutralising Pitolisant first salt to obtain Pitolisant free base;
c. treating Pitolisant free base with hydrochloride to obtain Pitolisant hydrochloride solution;
d. adding pharmaceutically acceptable excipients;
e. optionally stirring the reaction mass;
f. removing the solvent; and
g. isolating solid dispersion of Pitolisant hydrochloride

In another aspect of the present invention the above said reaction is carried out without isolating Pitolisant hydrochloride salt from the reaction mass.
In another aspect of the present invention provides the first salt of Pitolisant is selected from oxalic acid, fumaric acid and succinic acid, etc.

In another aspect of the present invention wherein the hydrochloride used in the reaction is hydrochloride gas or it is dissolved in solvent which is selected from methanolic HCl, isopropanolic HCl, ethylacetate HCl and the like.

In another aspect of the present invention wherein the base in step b) is inorganic and organic bases are selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, trimethylamine, diisopropylamine and combinations thereof.

In another aspect of the present invention provides a process for the preparation of solid dispersion of Pitolisant hydrochloride comprising removal of solvent carried out by evaporation or spray drying.

In another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride, comprising the steps of:
a) providing solution of Pitolisant hydrochloride salt with atleast one pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof,
b) removing the solvent from step a); and
c) isolating amorphous solid dispersion of Pitolisant hydrochloride

In another embodiment, Pitolisant hydrochloride salt may be combined with atleast one pharmaceutically acceptable excipient, at room temperature or under heating or mechanical stress to obtain molten mixture of components. In embodiments, the molten mixture may be optionally cooled to obtain solid dispersion of Pitolisant hydrochloride salt with atleast one pharmaceutically acceptable excipient. In one embodiment of the present invention Pitolisant hydrochloride salt may be combined with atleast one pharmaceutically acceptable excipient in suitable equipment such as hot melt extruder, twin screw extruder or the like.

In another embodiment, Pitolisant hydrochloride salt may be combined with pharmaceutically acceptable excipient in presence of a suitable solvent selected from the list of solvents disclosed in the application herein.

In another embodiment, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group of excipients of the previous aspect.

In other embodiments, combining Pitolisant hydrochloride salt may be carried out by dissolving Pitolisant hydrochloride salt and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvents.

In another embodiment, a solution of Pitolisant hydrochloride salt and the excipient may be prepared at any suitable temperature, at about 0 °C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In another embodiment, a solution of Pitolisant hydrochloride salt and the excipient may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove coloured components, etc., before filtration.

In another embodiment, the solid dispersion of present invention prepared without isolating Pitolisant hydrochloride salt from the reaction mass and pharmaceutically acceptable excipient was added to the solution of Pitolisant hydrochloride which is obtained directly from the reaction followed by removal of solvent from the reaction mass.

In another embodiment, the solvent from the solution of Pitolisant hydrochloride salt and the excipient may be removed as per the methods described in this application. The solid obtained can be dried as per the methods disclosed in this application.

In embodiments, the isolation of the solid dispersion of Pitolisant hydrochloride salt with excipient is performed as per the methods described in this application.

In embodiments, the solid dispersions of Pitolisant hydrochloride salt of the present application are stable under thermal, humid and stress conditions.

In another aspect of the present invention, the process for the preparation of Pitolisant hydrochloride solid dispersion comprising
a) providing solution of Pitolisant hydrochloride in a suitable solvent;
b) adding pharmaceutically acceptable excipient to the solution;
c) evaporating the solvent; and
d) isolating Pitolisant hydrochloride solid dispersion

In another aspect of the present invention, the suitable solvent in step a) is selected from solvent which is suitable to dissolve both Pitolisant hydrochloride and pharmaceutically acceptable excipient.

In another aspect of the present invention, the pharmaceutically acceptable excipient is added to the reaction mass as such or it is dissolved in solvent than added to the reaction mass.

In another aspect of the present invention, the evaporation of solvent is carried out by distillation, freeze drying, tray drying or spray drying.

In another aspect of the present invention, process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride comprising
a) providing solution of Pitolisant hydrochloride;
b) adding pharmaceutically acceptable excipient to the solution;
c) spray drying the above solution; and
d) isolating amorphous solid dispersion of Pitolisant hydrochloride

In another aspect of the present invention, the amorphous solid dispersion of Pitolisant hydrochloride comprising Pitolisant hydrochloride and the preferred pharmaceutically acceptable excipients selected from beta-cyclodextrin, povidone K-30, povidone K-60, Povidone K-90, co-povidone, PEG-4000, PEG-6000, hydroxypropylmethyl cellulose and combination thereof.

In another aspect of the present invention, the amorphous solid dispersion of Pitolisant hydrochloride comprising Pitolisant hydrochloride and beta-cyclodextrin present in the ratio from about 1:0.5 to 1:10 preferable in the ratio of about 1:1 to 1:5 more preferably in the ratio of about 1:1 to 1:3.

In another aspect of the present invention, the amorphous solid dispersion of Pitolisant hydrochloride comprising Pitolisant hydrochloride and povidone present in the ratio from about 1:0.1 to 1:5 more preferably in the ratio of about 1:0.2 to 1: 1 more preferably in the ratio of about 1:0.3.

In another aspect of the present invention, the amorphous solid dispersion of Pitolisant hydrochloride comprising Pitolisant hydrochloride and co-povidone present in the ratio from 1:0.5 to 1:10 preferably in the ratio of about 1:1 to 1:5 more preferably in the ratio of about 1:2 to 1:3.

In another aspect of the present invention relates to Pitolisant hydrochloride sesquihydrate and beta-cyclodextrin solid dispersion is characterised by PXRD peaks at about 5.3, 7.2, 9.9, 11.9 and 25.9 ± 2° two-theta. In another aspect of the present invention relates to Pitolisant hydrochloride sesquihydrate and beta-cyclodextrin solid dispersion is characterised by PXRD additional peaks at about 5.9 and 17.4 ± 0.2° two-theta.

In another aspect of the present invention relates to provide co-crystals of Pitolisant hydrochloride comprising Pitolisant hydrochloride and pharmaceutically acceptable co-former.

In an embodiment, the coformer is a "pharmaceutically acceptable coformer". The term "pharmaceutically acceptable coformer" refers to a coformer suitable for use as a pharmaceutical agent in the preparation of compositions with medical use. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.

In another embodiment of the present invention provides, wherein co-crystal is selected from succinic acid, benzoic acid, ketoglutaric acid, maleic acid, malonic acid, adipic acid, oxalic acid, piperazine, succinimide, benzenesulfonamide, proline, L-proline, D-proline, (+) camphoric acid, L-pyroglutamic acid, L-aspartic acid, L-carnitine, citric acid, 4-hydroxybenzoic acid, L-glutamic acid, nicotinamide, nicotinic acid, orotic acid monohydrate, urea, tetraethylpyrazine, tetraethylpyrazine, acetyl salicylic acid, 4-amonobenzoic acid, cinnamic acid, salicylic acid, ferulic acid, methylgallate, thiourea, saccharin, methylparaben, propyl gallate, vanillin and the other embodiment of the present invention the Co-Crystal was prepared by grinding of by solid-solid mixtures or solvent crystallisations.

One embodiment of the present invention provides an amorphous form of Pitolisant hydrochloride. In an embodiment, the amorphous form of Pitolisant hydrochloride is prepared by evaporation of solvent from the reaction solution; freeze drying, ball milling and spray drying.

Another embodiment of the present invention, the amorphous form of Pitolisant hydrochloride is prepared by without isolating solid Pitolisant hydrochloride and the solution obtained from the reaction medium is directly spray dried or freeze dried.

In one more embodiment of the present invention provides Pitolisant hydrochloride hydrate expressed by general formula (II)

wherein X is 1.5, 2, 2.5,3, or 5

In another aspect of the present invention provides a process for the preparation of Pitolisant hydrochloride sesquihydrate comprising:
a. providing Pitolisant first salt;
b. neutralising Pitolisant first salt to obtain Pitolisant free base;
c. treating Pitolisant free base with hydrochloride to obtain Pitolisant hydrochloride solution;
d. optionally adding water to the reaction mass;
e. optionally stirring the reaction mass to get the clear solution;
f. removing the solvent; and
g. isolating Pitolisant hydrochloride.

In one more embodiment of the present invention provides a method for the preparation of hydrate forms of Pitolisant hydrochloride by dissolving Pitolisant hydrochloride of formula (I) in water or mixture of water and organic solvent, optionally treating with carbon, filtering and precipitating the solid by adding solvent in which Pitolisant hydrochloride is not soluble.

In one more embodiment of the present invention provides a method for the preparation of hydrate form comprising
a) providing a solution on Pitolisant hydrochloride in water
b) spray drying the solution to obtain solid

In one more embodiment of the invention provides a solution of Pitolisant hydrochloride is prepared by dissolving Pitolisant hydrochloride in a solvent and the selected solvent capable to dissolve Pitolisant hydrochloride completely which is selected from group consisting of water, methanol, ethanol, isopropanol, butanol, dichloromethane, dimethylformamide and dimethylsulfoxide.

Still one more embodiment of the present invention, the Pitolisant hydrochloride of formula (I) and its solid state forms obtained from the present invention are useful for treatment of excessive daytime sleepiness in adults, treatment of excessive daytime sleepiness in adult patients with narcolepsy or treatment of cataplexy in adult patients with narcolepsy

The starting material for the preparation of Pitolisant hydrochloride of formula (I) in the present invention is prepared by conventional methods.

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of this invention

Example 1: Process for the preparation of Pitolisant Hydrochloride
To a 100 g of N, N-dimethylacetamide, 12 g of potassium tertiary butoxide was added under stirring. To the reaction mass 3-(piperidin-l-yl)propan-l-ol was added under stirring and the reaction mass was heated to 50 -60 °C and stirred for 60 minutes. The reaction mass was cooled to room temperature and stirred for 15 minutes. To the reaction mass a solution of 3-(4-chlorophenyl) propyl methanesulphonate dissolved in dimethylacetamide was added and stirred for 12-14 hours. The reaction mass was cooled to 0-5 °C, sodium chloride solution was added, stirred and the reaction mass temperature was raised to room temperature. To the reaction mass toluene was added and layer was separated. To the aqueous layer toluene was added, stirred and layers were separated. To the combined organic layer dilute hydrochloride was added, stirred and layers were separated. The aqueous layer was extracted with dichloromethane, layers were separated, and the organic layer was treated with carbon, stirred filtered and bed was washed with methylene dichloride. To the filtrate sodium sulphate was added, stirred, filtered and the filtrate was distilled under vacuum. To the residue, isopropanolic hydrochloride, followed by ethyl acetate was added and solvent was distilled. To the residue, ethyl acetate was added, heated to 50-70 °C the reaction mass to get clear solution. The reaction mass was cooled to 10-25 °C, stirred and filtered. The wet cake was suck dried and dried under vacuum. The obtained solid 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride was recrystallized from ethyl acetate, filtered and dried.

Example 2: Process for the preparation of Pitolisant Hydrochloride
To a methanol and sodium hydroxide solution 3-(piperidin-l-yl)propan-l-ol was added under stirring, the reaction mass was heated to 50 -60 °C and stirred for 60 minutes. The reaction mass was distilled under vacuum to the residue a solution of 3-(4-chlorophenyl) propyl methanesulphonate dissolved in tetrahydrofuran was added and stirred for 12-14 hours. The reaction mass was cooled to 0-5 °C, sodium chloride solution was added, stirred and the reaction mass temperature was raised to room temperature. To the reaction mass toluene was added and layer was separated. To the aqueous layer toluene was added, stirred and layers were separated. To the combined organic layer dilute hydrochloride was added, stirred and layers were separated. The aqueous layer was extracted with dichloromethane, layers were separated, and the organic layer was treated with carbon, stirred filtered and the bed was washed with methylene dichloride. To the filtrate sodium sulphate was added, stirred, filtered and the filtrate was distilled under vacuum. To the residue, isopropanolic hydrochloride, followed by ethyl acetate was added and solvent was distilled. To the residue, ethyl acetate was added, heated to 50-70 °C the reaction mass to get clear solution. The reaction mass was cooled to 10-25 °C, stirred and filtered. The wet cake was suck dried and dried under vacuum. The obtained solid 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride was recrystallized from ethyl acetate, filtered and dried.

Example 3: Process for the preparation of Pitolisant Hydrochloride and povidone solid dispersion
a) 20 g of Pitolisant hydrochloride was dissolved in 200 mL isopropanol, to this solution 6g of povidone was added, stirred to get clear solution. The solution was filtered and the filtrate was spray dried to obtain amorphous solid dispersion shown in Fig-2
Spray type : Closed loop
Spray rate : 5 mL/min
Chamber temperature : 75-80 °C
b) 1 g of Pitolisant hydrochloride was dissolved in 5 mL isopropanol, to this solution 0.3g of povidone was added, stirred to get clear solution. The solution was distilled under vacuum at 50-60 °C.

Example 3: Process for the preparation of Pitolisant Hydrochloride and co-povidone solid dispersion
a) 1g of Pitolisant hydrochloride was dissolved in 50 mL isopropanol, to this solution 5g of co-povidone was added, stirred to get clear solution. The solution was filtered and the filtrate was distilled to obtain amorphous solid dispersion.

b) 5g of Pitolisant hydrochloride was dissolved in 500 mL of isopropanol, to this solution 25g of co-povidone was added, stirred to get clear solution. The solution was spray dried to obtain amorphous solid dispersion.

Example 4: Process for the preparation of Pitolisant Hydrochloride and beta-cyclodextrin solid dispersion
a) 75g of beta-cyclodextrin was added to 1250 mL water and the mixture was heated to 85 °C to get clear solution, to this solution 25g of Pitolisant hydrochloride was added, stirred to get clear solution. The solution was filtered and the filtrate was spray dried to obtain amorphous solid dispersion.
Spray type : Open loop
Spray rate : 5 mL/min
Chamber temperature : 95-100 °C

Example 5: Process for the preparation of Pitolisant Hydrochloride and PEG 6000 solid dispersion
3g of PEG-6000 was dissolved in 10 mL water to get clear solution, to this solution 1g of Pitolisant hydrochloride was added, stirred to get clear solution. The solution was distilled under vacuum at 70-80 °C.

3g of PEG-6000 and 20 mL of isopropanol was heated to 50 °C to get clear solution, to this solution 1g of Pitolisant hydrochloride was added, stirred to get clear solution. The solution was distilled under vacuum at 70-80 °C.

Example 6: Process for the preparation of Pitolisant Hydrochloride and PEG 4000 solid dispersion
3g of PEG-4000 was added to 30 mL of water, heated to 80 °C to get the clear solution. To this solution 1g of Pitolisant hydrochloride was added, stirred to get clear solution. The solution was distilled under vacuum at 70-80 °C.

Example 7: Process for the preparation of Pitolisant Hydrochloride and Hydroxypropyl methylcellulose (HPMC) solid dispersion
5g of Hydroxypropyl methylcellulose (HPMC) was dissolved in 150 mL of mixture of dichloromethane and isopropanol (3:7) by stirring to get clear solution, to this solution 1g of Pitolisant hydrochloride was added, stirred to get clear solution. The solution was distilled under vacuum at 70-80 °C.

Example-8: Preparation of amorphous premix of Pitolisant Hydrochloride of with polyvinyl pyrrolidine (PVP)
Pitolisant Hydrochloride (5 g) was dissolved in water (100 mL). Aqueous polyvinyl pyrrolidine solution (5 g of PVP dissolved in 3 mL of water) was added to the above obtained solution and distilled off the solvent under reduced pressure and then dried to get the title compound.

Example-9: Preparation of amorphous premix of Pitolisant hydrochloride with hydroxy propyl cellulose (HPC)
Pitolisant hydrochloride (5 g) was dissolved in water (100 ml) and stirred for 30 min. Hydroxy propyl cellulose solution (5 g of HPC was dissolved in 100 ml of methanol) was added to the above solution and distilled off the solvent and then dried to get the title compound.

Example-10: Preparation of amorphous premix of Pitolisant hydrochloride with micro crystalline cellulose (MCC)
Pitolisant hydrochloride (5 g) was dissolved in water (100 mL) and stirred for 30 min. MCC (5 g) was added to the above obtained solution. Distilled off the solvent from the mixture and then dried to get the title compound.

Example-11: Preparation of amorphous premix of Pitolisant hydrochloride with hydroxy propyl methyl cellulose - acetyl succinate (HPMC-AS).
Pitolisant hydrochloride (5 g) was dissolved in water (10 mL) and stirred for 30 min and added to HPMC-AS solution (5 g of HPMC-AS dis solved in 30 mL methanol). Distilled off the solvent from the mixture and then dried to provide the title compound.

Example-12: Preparation of amorphous premix of Pitolisant hydrochloride with Syloid.
Pitolisant hydrochloride (5 g) was dissolved in water (100 ml) and stirred for 30 min. Syloid (5 g) was added to the above solution and distilled off the solvent from the mixture and then dried to provide the title compound.

Example 13: Process for the preparation of Pitolisant hydrochloride sesquihydrate by spray drying
10 g of Pitolisant hydrochloride was dissolved in 100 mL water, the obtained solution was filtered and the filtrate was spray dried to obtain Pitolisant hydrochloride sesquihydrate.
Spray type : Open Loop
Spray rate : 5 mL/min
Chamber temperature : 95-100 °C

Example 14: Process for the preparation of Pitolisant hydrochloride sesquihydrate and beta-cyclodextrin solid dispersion
3g of beta-cyclodextrin was added in 60 mL of water, the reaction mass was heated to 85 °C to get the clear solution, to this solution 1g of Pitolisant hydrochloride was added, stirred to get clear solution. The solution was distilled under vacuum at 70-80 °C.

Example 15: General process for the preparation of Solid dispersion without isolating Pitolisant Hydrochloride
To a 100 g of N, N-dimethylacetamide 12 g of potassium tertiary butoxide was added under stirring. To the reaction mass 3-(piperidin-l-yl)propan-l-ol was added under stirring and the reaction mass was heated to 50-60 °C and stirred for 60 minutes. The reaction mass was cooled to room temperature and stirred for 15 minutes. To the reaction mass a solution of 3-(4-chlorophenyl)propylmethane sulphonate was dissolved in dimethylacetamide was added and stirred for 12-14 hours. The reaction mass was cooled to 0-5 °C, sodium chloride solution was added, stirred and the reaction mass temperature was raised to room temperature. To the reaction mass toluene was added and layer was separated. To the aqueous layer toluene was added, stirred and layers were separated. To the combined organic layer dilute hydrochloric acid was added, stirred and layers were separated. The aqueous layer was extracted with dichloromethane, layers were separated, and the organic layer was treated with carbon, stirred filtered and bed was washed with methylene dichloride. To the filtrate sodium sulphate was added, stirred, filtered and the filtrate was distilled under vacuum. To the residue, isopropanolic hydrochloride was added and distilled under vacuum to the syrup. To the syrup isopropanol was added and distilled to get the syrup. To the syrup isopropanol or water was added and stirred, to the solution corresponding excipients was added and heated (if required) to the get the clear solution. The obtained solution was spray dried or distilled to get the corresponding solid dispersion.

Example 16: Process for the preparation of Solid dispersion without isolating Pitolisant Hydrochloride
a) To a 100 g of N, N-dimethylacetamide 12 g of potassium tertiary butoxide was added under stirring. To the reaction mass 3-(piperidin-l-yl)propan-l-ol was added under stirring and the reaction mass was heated to 50-60 °C and stirred for 60 minutes. The reaction mass cooled to room temperature and stirred for 15 minutes. To the reaction mass a solution of 3-(4-chlorophenyl)propyl methanesulphonate in dimethylacetamide was added and stirred for 12-14 hours. The reaction mass was cooled to 0-5 °C, sodium chloride solution was added, stirred and the reaction mass temperature was raised to room temperature. To the reaction mass toluene was added and layer was separated. To the aqueous layer toluene was added, stirred, layers were separated and the organic layer was distilled completely. To the residue acetone was added stirred, fumaric acid was added and stirred for 2 hours. The obtained solid was filtered, washed with acetone and suck dried.

To the Pitolisant fumaric acid salt, aqueous sodium hydroxide solution was added and stirred. The solution was extracted with toluene and layers were separated. To the combined organic layer dilute hydrochloric acid was added, stirred and layers were separated. The aqueous layer was extracted with dichloromethane, layers were separated, and the organic layer was treated with carbon, stirred, filtered and the bed was washed with methylene dichloride. To the filtrate sodium sulphate was added, stirred, filtered and the filtrate was distilled under vacuum. To the residue, isopropanolic hydrochloride was added stirred for 2 hours and distilled under vacuum to the syrup. To the syrup isopropanol was added and distilled to get the syrup.

This syrupy mass was used for the preparation of solid dispersions, cocrystals and polymorphs and hydrate forms of Pitolisant hydrochloride as disclosed herein.

The above example is repeated using oxalic acid instead of fumaric acid and methanol instead of acetone for the preparation of Pitolisant oxalic acid.

Example 17: Process for the preparation of Solid dispersion without isolating Pitolisant Hydrochloride
To a 100 g of N, N-dimethylacetamide 12 g of potassium tertiary butoxide was added under stirring. To the reaction mass 3-(piperidin-l-yl)propan-l-ol was added under stirring and the reaction mass was heated to 50-60 °C and stirred for 60 minutes. The reaction mass was cooled to room temperature and stirred for 15 minutes. To the reaction mass a solution of 3-(4-chlorophenyl) propyl methanesulphonate dissolved in dimethylacetamide was added and stirred for 12-14 hours. The reaction mass was cooled to 0-5 °C, sodium chloride solution was added, stirred and the reaction mass temperature was raised to room temperature. To the reaction mass toluene was added and layer was separated. To the aqueous layer toluene was added, stirred and layers were separated. To the combined organic layer fumaric acid was added, stirred and layers were separated. The aqueous layer was extracted with dichloromethane, layers were separated, and the organic layer was treated with carbon, stirred, filtered and bed was washed with methylene dichloride. To the filtrate sodium sulphate was added, stirred, filtered and the filtrate was distilled under vacuum. To the residue, isopropanolic hydrochloride and distilled under vacuum to obtain the syrup. To the syrup isopropanol was added and distilled to obtain the syrupy mass.

This syrupy mass obtained from above example was used for the preparation of solid dispersions, cocrystals and polymorphs and hydrate forms of Pitolisant hydrochloride as disclosed herein.

Example 18: Process for the preparation of Pitolisant Hydrochloride and povidone solid dispersion
a) 20 g of Pitolisant hydrochloride syrup was dissolved in 200 mL isopropanol, to this solution 6g of povidone was added, stirred to get clear solution. The solution was filtered and the filtrate was spray dried to obtain amorphous solid dispersion shown in Fig-2
Spray type : Closed loop
Spray rate : 5 mL/min
Chamber temperature : 60-65 °C

b) 1g of Pitolisant hydrochloride syrup was dissolved in 5 mL isopropanol, to this solution 0.3g of povidone was added, stirred to get clear solution. The solution was distilled under vacuum at 50-60 °C.

Example 19: Process for the preparation of Pitolisant Hydrochloride and co-povidone solid dispersion
c) 1g of Pitolisant hydrochloride syrup was dissolved in 50 mL isopropanol, to this solution 5g of co-povidone was added, stirred to get clear solution. The solution was filtered and the filtrate was distilled to obtain amorphous solid dispersion.
d) 5g of Pitolisant hydrochloride syrup was dissolved in 500 mL isopropanol, to this solution 25g of co-povidone was added, stirred to get clear solution. The solution was spray dried to obtain amorphous solid dispersion.

Example 20: Process for the preparation of Pitolisant Hydrochloride and beta-cyclodextrin solid dispersion
b) 75g of beta-cyclodextrin was added to 1250 mL of water and the mixture was heated to 85 °C to get clear solution, to this solution 25g of Pitolisant hydrochloride syrup was added, stirred to get clear solution. The solution was filtered and the filtrate was spray dried to obtain amorphous solid dispersion.
Spray type : Open loop
Spray rate : 5 mL/min
Chamber temperature : 90-95 °C

Example-21: Preparation of Amorphous form of 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride.
To a 10 g of crude 1-{3-[3-(4-chlorophenyl)propoxy]propyl} piperidine obtained according to the US patent number 8,207,197 Example-1, 30 mL of methanol was added heating to 50-60 °C and stirred. To the reaction mass methanolic hydrochloride was added, pH was adjusted to 3-4 and stirred. After completion of the reaction, the reaction solution was distilled and freeze dried.

Example-22: Preparation of Pitolisant hydrochloride sesquihydrate
a) To a crude 10 g of Pitolisant obtained according to the US patent number 8,207,197 Example -1, 50 mL of dichloromethane was added under stirring. The reaction mass was heated to reflux temperature and stirred. To the reaction mass aqueous solution of hydrochloride was added, pH was adjusted to 3-4 and stirred. The reaction mass was heated to get the clear solution, treated with carbon and stirred. The reaction mass was filtered at hot condition and 100 mL of water was added to the filtrate and stirred at reflux temperature. The reaction mass was transferred to ice bath and cooled to 5 °C and transferred to refrigerator for 12 hours. The obtained solid is washed with dichloromethane followed by water, dried in air to obtain 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride sesquihydrate with purity of 99.5% and a moisture content 7.7%.

Example-23: Preparation of 1-{3-[3-(4-chlorophenyl)propoxy]propyl} piperidine hydrochloride dihydrate
To a 10g of crude 1-{3-[3-(4-chlorophenyl)propoxy]propyl} piperidine obtained according to the US patent number 8,207,197 Example -1, 50 mL of acetone was added under stirring. The reaction mass was heated to reflux temperature and stirred. To the reaction mass aqueous solution of hydrochloride was added, pH was adjusted to 3-4 and stirred. The reaction mass was heated to get the clear solution, treated with carbon and stirred. The reaction mass filtered at hot condition and 120 mL of water was added to the filtrate and stirred at reflux temperature. The reaction mass was transferred to ice bath and cooled to 5°C, stirred and transferred to refrigerator for 12 hours. The obtained solid was washed with dichloromethane and water, dried naturally to obtain 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride dihydrate with purity of 99.5% and a moisture content 9.8%.

Example-24: Preparation of 1-{3-[3-(4-chlorophenyl)propoxy]propyl} piperidine hydrochloride hemipentahydrate

To a 10 g of crude 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine obtained according to the US patent number 8,207,197 Example -1, 50 mL of acetone was added under stirring. The reaction mass was heated to reflux temperature and stirred. To the reaction mass aqueous solution of hydrochloride was added, pH was adjusted to 3-4 and stirred. The reaction mass was heated to get clear solution, treated with carbon and stirred. The reaction mass was filtered at hot condition, 140 mL of water was added to the filtrate and stirred at reflux temperature. The reaction mass was transferred to ice bath and cooled to 5°C, stirred for 10 hours and transferred to refrigerator for 15 hours. The obtained solid is washed with acetone and water, dried naturally to obtain 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride hemipentahydrate with purity of 99.6% and a moisture content 12.3%.

Example-25: Preparation of 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride trihydrate

To a 10 g of crude 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine obtained according to the US patent number 8,207,197 Example-1, 50 mL of isopropanol was added under stirring. The reaction mass was heated to reflux temperature and stirred. To the reaction mass aqueous solution of hydrochloride was added, pH was adjusted to 3-4 and stirred. The reaction mass was heated to get the clear solution, treated with carbon and stirred. The reaction mass was filtered at hot condition and 160 mL of water was added to the filtrate and stirred at reflux temperature. The reaction mass was transferred to ice bath and cooled to 5°C, stirred for 10 hours and transferred to refrigerator for 20 hours. The obtained solid was washed with isopropanol and water, dried naturally to obtain 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride trihydrate with purity of 99.4% and a moisture content 14.4%.

Example-26: Preparation of 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride pentahydrate
To a 10 g of crude 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine obtained according to the US patent number 8,207,197 Example -1, 50 mL of ethylacetate was added under stirring. The reaction mass was heated to reflux temperature and stirred. To the reaction mass aqueous solution of hydrochloride was added, pH was adjusted to 3-4 and stirred. The reaction mass was heated to get the clear solution, treated with carbon and stirred. The reaction mass filtered at hot condition and 180 mL of water was added to the filtrate and stirred at reflux temperature. The reaction mass was transferred to ice bath and cooled to 5°C, stirred for 10 hours and transferred to refrigerator for 24 hours. The obtained solid is washed with ethylacetate and water, dried naturally to obtain 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride pentahydrate with purity of 99.5% and a moisture content 21.2%.

Example-27: Preparation of 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride trihydrate

To a 10 g of crude 1-{3-[3-(4-chlorophenyl)propoxy]propyl} piperidine obtained according to the US patent number 8,207,197 Example -1, 50 mL of water was added under stirring. The reaction mass was heated to reflux temperature and stirred. To the reaction mass aqueous solution of hydrochloride was added, pH was adjusted to 3-4 and stirred. The reaction mass was heated to get the clear solution, treated with carbon and stirred. The reaction mass was filtered at hot condition and 100 mL of water was added to the filtrate and stirred at reflux temperature. To the reaction mass water cyclohexane was added and stirred for 6 hours to get the precipitate. The organic layer was separated reaction mass cooled rapidly to 3 °C in ice bath and stirred for 10 hours and transferred to refrigerator for 18 hours. The obtained solid was dried naturally to obtain 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride trihydrate with purity of 99.6% and a moisture content 14.4%.

Example-28: Preparation of 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride pentahydrate
To a 10 g of crude 1-{3-[3-(4-chlorophenyl)propoxy]propyl} piperidine obtained according to the US patent number 8,207,197 Example-1, 50 mL of water was added under stirring. The reaction mass was heated to reflux temperature and stirred. To the reaction mass aqueous solution of hydrochloride was added, pH was adjusted to 3-4 and stirred. The reaction mass was heated to get the clear solution, treated with carbon and stirred. The reaction mass filtered at hot condition and 150 mL of water was added to the filtrate and stirred at reflux temperature. To the reaction mass water cyclohexane was added and stirred for 6 hours to get the precipitate. The organic layer was separated reaction mass cooled rapidly to 3 °C in ice bath and stirred for 10 hours and transferred to refrigerator for 24 hours. The obtained solid was dried naturally to obtain 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride trihydrate with purity of 99.6% and a moisture content 21.2%.

Example-29: Preparation of 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride pentahydrate

To a crude 10 g of 1-{3-[3-(4-chlorophenyl)propoxy]propyl} piperidine obtained from according to the US patent number 8,207,197 Example -1, 50 mL of water was added under stirring. The reaction mass was heated to reflux temperature and stirred. To the reaction mass aqueous solution of hydrochloride was added, pH was adjusted to 3-4 and stirred. The reaction mass was heated to get the clear solution, treated with carbon and stirred. The reaction mass filtered at hot condition and 75 mL of water was added to the filtrate and stirred at reflux temperature. To the reaction mass water cyclohexane was added and stirred for 6 hours to get the precipitate. The organic layer was separated reaction mass cooled rapidly to 3 °C in ice bath and stirred for 10 hours and transferred to refrigerator for 12 hours. The obtained solid was dried naturally to obtain 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride dihydrate with purity of 99.6% and a moisture content 9.8%.

Dated this 24th day of December 2021
for Nuray Chemicals Private Limited

Dr. K. Ravi
Technical Director and Plant Head
,CLAIMS:We Claim:
1) An improved process for the preparation of Pitolisant and its pharmaceutically acceptable salt thereof comprising:
a) reacting 3-(piperidin-l-yl)propan-1-ol

with 3-(4-chlorophenyl)propyl methanesulphonate

in presence of base to obtain Pitolisant;
b) treating Pitolisant pharmaceutically acceptable salt; and
c) isolating Pitolisant pharmaceutically acceptable salt

2) The process according to the claim 1, wherein the base used in step a) is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium tertiary-butoxide, triethylamine, t-butylamine, trimethylamine and N, N diisopropylamine or combination thereof.

3) The process according to the claim 1, wherein the solvent used in reaction of step a) is selected from N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 1-methyl-2-pyrrolidone, 1-methyl-2-piperidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, acetone and combination thereof.

4) Solid dispersion comprising Pitolisant hydrochloride and pharmaceutically acceptable excipients.

5) Amorphous solid dispersion comprising Pitolisant hydrochloride and ß-cyclodextrin as depicted in Figure-1

6) Amorphous solid dispersion comprising Pitolisant hydrochloride and povidone as depicted in Figure-2

7) Amorphous solid dispersion comprising Pitolisant hydrochloride and co-povidone as depicted in Figure-3

8) The process for the preparation of amorphous solid dispersion comprising
a) providing solution of Pitolisant hydrochloride salt with atleast one pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof,
b) removing the solvent from step a).

9) The process for according to the claim 7, wherein the removal of solvent from the reaction is carried out by evaporation or spray drying.

10) An improved process for the preparation of Pitolisant hydrochloride solid dispersion comprising:
h. providing Pitolisant first salt;
i. neutralising Pitolisant first salt to obtain Pitolisant free base;
j. treating Pitolisant free base with hydrochloride to obtain Pitolisant hydrochloride solution;
k. adding pharmaceutically acceptable excipients;
l. optionally stirring the reaction mass;
m. evaporating the solvent; and
n. isolating solid dispersion of Pitolisant hydrochloride
wherein the reaction is carried out without isolation of Pitolisant hydrochloride

11) Hydrate of Pitolisant hydrochloride of formula (II).

wherein X is 1.5, 2, 2.5,3, or 5.

12) Pitolisant hydrochloride sesquihydrate.

13) Pitolisant hydrochloride sesquihydrate and beta-cyclodextrin solid dispersion is characterised by PXRD peaks at about 5.3, 7.2, 9.9, 11.9 and 25.9 ± 2° two-theta as depicted in Figure-5.

Dated this 24th day of December 2021
for Nuray Chemicals Private Limited

Dr. K. Ravi
Technical Director and Plant Head