FIELD OF THE INVENTION
Present invention relates to an amorphous solid dispersion of lasmiditan and its salts, comprising lasmiditan and its salts along with pharmaceutical acceptable excipients, and process of preparation thereof.

Present invention further provides premix of lasmiditan and its salts, comprising lasmiditan and its salts along with pharmaceutical acceptable polymers and/or excipients.

BACKGROUND OF THE INVENTION
Lasmiditan is chemically represented as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-yl carbonyl)-pyridin-2-yl]-benzamide having structure as represented below:
.

Lasmiditan, is a 5-HT1F agonist and is structurally different than triptans constituting a class of drugs, “ditans”.

US 7,423,050 B2 (US’050) discloses the preparation of lasmiditan and salts thereof, specifically hydrochloride & hemi succinate as mentioned in the scheme below:
.

US’050 discloses a method for the preparation of hydrochloride salt and hemi succinate salt of lasmiditan using acetone as crystallization solvent.

US 8,697,876 B2 (US’876) discloses a method for preparation of lasmiditan and salts thereof as mentioned in the scheme 2 below:
Scheme 2:

.

US’876 further discloses an anhydrous solid crystalline form (Form A) of lasmiditan hemi succinate wherein said Form A is obtained by crystallization with ethanol. US’876 describes two additional XRPD patterns designated Form B and Form C of lasmiditan hemi succinate as well as amorphous form of lasmiditan free base and hemi succinate salt.

PCT application, WO2018106657 A1 (WO’657) discloses the pseudo-polymorphs of lasmiditan hemi succinate selected from Form D, Form E, and Form F and mixtures thereof, either alone or in combination with Form A. Form D is also referred to as Hydrate 1 or the di-hydrate. Form E is also referred to as the dehydrated hydrate of Form D, and it may exist as a partially or fully dehydrated hydrate of Form D. Form F is also referred to as the tri-hydrate. The structure of Form F was determined based on weight-loss from a crystallization study.

PCT application, WO 2018010345 A1 (WO’345) discloses certain polymorphic forms of lasmiditan free base & hydrochloride salt. WO’345 discloses lasmiditan free base crystalline form selected from Form 1, Form 2 & Form 3. It further discloses crystalline form of hydrochloride salt of lasmiditan selected from Form A, Form B, Form C, Form E & Form G.

As it is apparent from above disclosure, there are several polymorphs of lasmiditan known from the prior published applications. However, there is always a need for the development of a stable polymorph or solid dispersions or premix of lasmiditan having high purity and stability and that can be easily formulated.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an amorphous solid dispersion of lasmiditan and salt thereof.

Another object of the present invention is to provide stable premix of lasmiditan and salt thereof, with atleast one pharmaceutical acceptable polymer and/or excipient.

SUMMARY OF THE INVENTION
In main aspect, the present invention provides a solid dispersion of lasmiditan or salt thereof, comprising of lasmiditan or its salt along with pharmaceutical acceptable excipients.

In another aspect, the present invention provides a process for the preparation of a solid dispersion of lasmiditan or salt thereof, comprising the steps of:
a) providing a solution of lasmiditan or salt thereof in a suitable solvent (s);
b) adding atleast one pharmaceutically acceptable excipient to the solution obtained in step (a); and
c) isolating the solid dispersion of lasmiditan or a salt thereof.

In another aspect, the present invention provides a solid dispersion of lasmiditan free base.

In another aspect, the present invention provides a process for the preparation of a solid dispersion of lasmiditan free base, comprising the steps of:
a) providing a solution of lasmiditan free base in a suitable solvent(s);
b) providing a solution of atleast one pharmaceutically acceptable excipient in a suitable solvent;
c) combining the solution of lasmiditan free base obtained in step a) with the solution obtained in step (b); and
d) isolating to get the solid dispersion of lasmiditan free base.

In another aspect, the present invention provides a solid dispersion of lasmiditan hydrochloride salt.

In another aspect, the present invention provides a process for the preparation of a solid dispersion of lasmiditan hydrochloride salt, comprising the steps of:
a) providing a solution of lasmiditan hydrochloride salt in a suitable solvent(s);
b) providing a solution of atleast one pharmaceutically acceptable excipient in a suitable solvent;
c) combining the solution of lasmiditan hydrochloride salt obtained in step a) with the solution obtained in step (b); and
d) isolating to get the solid dispersion of lasmiditan hydrochloride salt.

In another aspect, the present invention provides a solid dispersion of lasmiditan hemisuccinate salt.

In another aspect, the present invention provides a process for the preparation of a solid dispersion of lasmiditan hemisuccinate salt, comprising the steps of:
a) providing a solution of lasmiditan hemisuccinate salt in a suitable solvent(s);
b) providing a solution of atleast one pharmaceutically acceptable excipient in a suitable solvent;
c) combining the solution of lasmiditan hemisuccinate salt obtained in step a) with the solution obtained in step (b); and
d) isolating to get the solid dispersion of lasmiditan hemisuccinate salt.

In another aspect, the present application provides a pharmaceutical composition comprising a solid dispersion of lasmiditan or a salt thereof, together with atleast one pharmaceutically acceptable excipient.

In another aspect, the present invention provides a premix of lasmiditan or its salt with atleast one pharmaceutical acceptable polymer and/or excipient.

In another aspect, the present invention provides a process for the preparation of a premix of lasmiditan or its salt, comprising the steps of:
a) adding pharmaceutically acceptable excipient to a reaction mixture comprising lasmiditan or its salt and suitable solvent (s); and
b) isolating precipitates to get the premix of lasmiditan or its salt.

In another aspect, the present invention provides substantially pure amorphous form of lasmiditan free base or salt thereof.

DETAILED DESCRIPTION
Brief Description of The Figures:
Fig. 1 represent X-ray powder diffraction pattern of solid dispersion of Lasmiditan hemisuccinate with PVP K-90
Fig. 2 represent X-ray powder diffraction pattern of solid dispersion of Lasmiditan hemisuccinate with HPC

Definitions:
The term "about" as used in the context of the present invention, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value.

The term “inert solvent” as used in the context of the present invention, is a solvent that does not react with the reactants or reagents under conditions that cause the chemical reaction indicated to take place.

The terms “stable amorphous form of lasmiditan or a salt thereof" and “amorphous lasmiditan or a salt thereof” indicate that the lasmiditan or a salt thereof is present in substantially amorphous state and is substantially free from crystalline form. It may be present in the form of solid dispersion, adsorbate or pharmaceutical composition. "Substantially pure amorphous” denotes that 90%, preferably 95% or 99%, more preferably all of the lasmiditan or a salt thereof is amorphous. In other words, “substantially free from crystalline form” preferably means that the amorphous form does not contain noticeable amounts, of crystalline portions of lasmiditan or a salt thereof e.g. measurable upon X-ray powder diffraction analysis, and preferably the crystalline form is less than about 5% w/w of the amorphous form.

“Solid dispersion” as used herein refers to the dispersion of one or more active ingredients in an inert excipient or polymer or carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state. Solid dispersion consists of two or more components, generally a polymer or carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added polymer in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The resulting solid dispersions may have increased solubility. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve. A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within a polymer or carrier. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the polymer dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles.

In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term "solid dispersion" as used herein, refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers. Further the term "solid dispersion" as used herein also refers to stable solid dispersions comprising amorphous drug substance and one or more polymers or carriers with or without adsorbent/absorbent. By "amorphous drug substance," it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.

Further, the term "stable solid dispersion" as used in the context of the present invention, denotes a state where most of the lasmiditan or a salt thereof, preferably 90%, 95% or all of the lasmiditan or a salt thereof of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.

The term "premix" is used herein to describe combinations of lasmiditan or its salt and at least one pharmaceutically acceptable excipient/polymer, wherein individual particles of the components cannot be distinguished using techniques such as optical microscopy. In embodiments, the drug is considered as being uniformly or non-uniformly distributed over surfaces of excipient particles. In other embodiments, the premixes are considered to be in the nature of molecular dispersions, or solid solutions. Simple mixtures of powdered ingredients will not constitute premixes.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function. The pharmaceutically acceptable excipient may be selected from, but not limited to, the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90 (PVP K-90), polyvinylpyrrolidone vinylacetate, co-povidone, polyvinyl alcohol, 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 phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), 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, carboxymethylethylcellulose and the like; proteins such as gelatin and albumin, 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, xylitol, maltodextrin, dextrates, dextrins, lactitol 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. 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 lasmiditan or a salt thereof 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.

The term "adsorbate" as used in the context of the present invention, specifies that the lasmiditan or a salt thereof is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.

The term “suitable solvent” as used in the context of the present invention used for the preparation of amorphous form and solid dispersion of lasmiditan or its salt(s) is selected from alcohols, ketones, aliphatic or aromatic hydrocarbons, esters, aliphatic or cyclic ethers, nitriles, halogenated hydrocarbons, water or mixtures thereof.

An “alcohol” as used in the context of the present invention, is an organic compound containing a carbon bound to a hydroxyl group. Alcohol includes, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.

An “aliphatic hydrocarbon” as used in the context of the present invention, is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of aliphatic or aromatic hydrocarbons includes, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.

An “ester” as used in the context of the present invention, is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. Ester includes, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

An “ether” as used in the context of the present invention, is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. Ether includes, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.

A “halogenated hydrocarbon” as used in the context of the present invention, is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbon includes, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A “ketone” as used in the context of the present invention, is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. Ketone includes, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.

A “nitrile” as used in the context of the present invention, is an organic compound containing a cyano -(C=N) bonded to another carbon atom. Nitrile includes, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

In one embodiment, the present invention provides a solid dispersion of lasmiditan or salt thereof, comprising of lasmiditan or its salt along with pharmaceutical acceptable excipients.

In another embodiment, the present invention provides a process for the preparation of a solid dispersion of lasmiditan or salt thereof, comprising the steps of:
a) providing a solution of lasmiditan or salt thereof in a suitable solvent (s);
b) adding atleast one pharmaceutically acceptable excipient to the solution obtained in step (a); and
c) isolating the solid dispersion of lasmiditan or a salt thereof.

In another embodiment, the present invention provides a solid dispersion of lasmiditan free base.

In another embodiment, the present invention provides a process for the preparation of a solid dispersion of lasmiditan free base or salt thereof, comprising the steps of:
a) providing a solution of lasmiditan free base in a suitable solvent(s);
b) providing a solution of atleast one pharmaceutically acceptable excipient in a suitable solvent;
c) combining the solution of lasmiditan free base obtained in step a) with the solution obtained in step (b); and
d) isolating to get the solid dispersion of lasmiditan free base.

In another embodiment, the present invention provides a solid dispersion of lasmiditan hydrochloride salt.

In another embodiment, the present invention provides a process for the preparation of a solid dispersion of lasmiditan hydrochloride salt, comprising the steps of:
a) providing a solution of lasmiditan hydrochloride salt in a suitable solvent(s);
b) providing a solution of atleast one pharmaceutically acceptable excipient in a suitable solvent;
c) combining the solution of lasmiditan hydrochloride salt obtained in step a) with the solution obtained in step (b); and
d) isolating to get the solid dispersion of lasmiditan hydrochloride salt.

In another embodiment, the present invention provides a solid dispersion of lasmiditan hemisuccinate salt.

In another embodiment, the present invention provides a process for the preparation of a solid dispersion of lasmiditan hemisuccinate salt, comprising the steps of:
a) providing a solution of lasmiditan hemisuccinate salt in a suitable solvent(s);
b) providing a solution of atleast one pharmaceutically acceptable excipient in a suitable solvent;
c) combining the solution of lasmiditan hemisuccinate salt obtained in step a) with the solution obtained in step (b); and
d) isolating to get the solid dispersion of lasmiditan hemisuccinate salt.

In another embodiment, the present invention provides a process for the preparation of a solid dispersion of lasmiditan hemisuccinate salt with PVP-K90 or HPC, comprising the steps of:
a) providing a solution of lasmiditan hemisuccinate salt in a suitable solvent (s);
b) providing a solution of PVP K-90 or HPC in a suitable solvent;
c) combining the solution of lasmiditan hemisuccinate salt obtained in step a) with the solution obtained in step (b); and
d) isolating precipitates to get the solid dispersion of lasmiditan hemisuccinate salt.

In another embodiment, the present invention provides a solid dispersion of lasmiditan hemisuccinate salt with PVP-K90 characterized by X-ray powder diffraction pattern as shown in Fig 1.

In another embodiment, the present invention provides a solid dispersion of lasmiditan hemisuccinate salt with HPC characterized by X-ray powder diffraction pattern as shown in Fig 2.

In another embodiment, the present application provides a pharmaceutical composition comprising a stable solid dispersion of lasmiditan or a salt thereof together with atleast one pharmaceutically acceptable excipient.

In an embodiment, the salt(s) of lasmiditan includes, but not limited to hydrochloride, hydrobromide, hemisuccinate and the like.

In another embodiment, the present invention provides substantially pure amorphous form of lasmiditan free base or salt thereof, wherein said salt is selected from hydrochloride and hemi succinate salt.

In another embodiment, the present invention provides a process for the preparation of substantially pure amorphous form of lasmiditan free base or salt thereof, comprising the steps of:
a) providing a solution of lasmiditan free base or salt thereof in a suitable solvent (s);
b) removing the solvent from the solution obtained in step a); and
c) isolating the substantially pure amorphous form of lasmiditan free base or salt thereof.

In an embodiment, providing a solution of lasmiditan may be obtained by dissolving lasmiditan free form in a suitable solvent or by taking the reaction mixture containing lasmiditan free form directly.

In another embodiment, lasmiditan or a salt thereof as used for preparing amorphous form or solid dispersion can be prepared by any process known in the prior published references or any conventional method.

In an embodiment, providing a solution lasmiditan may be carried out by dissolving a salt of lasmiditan in a suitable solvent or by taking the reaction mixture containing lasmiditan and an acid directly.

In a preferred embodiment, the acid includes, but not limited to succinic acid, hydrochloric acid, hydrobromic acid, hydrophosphoric acid and so on.

In an embodiment, a solution of lasmiditan or a salt thereof can be prepared at any suitable temperatures, such as 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 an embodiment, a solution of lasmiditan or a salt thereof may be filtered to make it clear, free of unwanted particles.

In another embodiment, lasmiditan or a salt thereof as used for preparing amorphous solid dispersion, is either crystalline or amorphous in nature.

In an 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 an embodiment, removal of solvent from the solution containing solid dispersion of lasmiditan or amorphous form of lasmiditan may be carried out by methods known in the art or any procedure disclosed in the present invention wherein said method is selected from, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In an embodiment, the isolation of an amorphous form of lasmiditan or a salt thereof includes, but not limited to, techniques such as scraping, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. In an embodiment, the amorphous form of lasmiditan or a salt thereof, may be optionally dried after isolation.

In a preferred embodiment, the present application provides a stable amorphous form of lasmiditan or a salt thereof which is found to be highly stable under mechanical stress and under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.

In a preferred embodiment, the present invention provides a solid dispersion of lasmiditan or a salt thereof suitable for powder handling and downstream processes. A solid dispersion of lasmiditan or a salt thereof of the present application was found to be highly stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.

In another embodiment, the present application provides a stable solid dispersion of lasmiditan free base, hydrochloride salt or hemisuccinate salt with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.

In preferred embodiment, solid dispersion of lasmiditan or salt thereof, is prepared by combining lasmiditan or salt thereof with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of lasmiditan or a salt thereof and atleast one pharmaceutically acceptable excipient.
In an embodiment, solid dispersion of lasmiditan or salt thereof, is prepared by combining with the pharmaceutical acceptable excipient by evaporating the suspension or solution of lasmiditan or a salt thereof and atleast one pharmaceutically acceptable excipient wherein said lasmiditan is crystalline, amorphous or mixture thereof in nature.

In one another embodiment, the present invention provides a premix of lasmiditan or its salt with atleast one pharmaceutical acceptable polymer and/or excipient.

In one another embodiment, the present invention provides a process for the preparation of a premix of lasmiditan or its salt, comprising the steps of:
a) adding pharmaceutically acceptable excipient to a reaction mixture comprising lasmiditan or its salt and suitable solvent (s); and
b) isolating precipitates to get the premix of lasmiditan or its salt.

In another embodiment, the present application provides a pharmaceutical composition comprising a premix of lasmiditan or a salt thereof, together with atleast one pharmaceutically acceptable excipient.

In another embodiment, pharmaceutically acceptable excipient may include, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, hydroxypropyl cellulose, polyethylene/polyvinyl pyrrolidinone copolymer, PVP K-90, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.

In preferred embodiment, pharmaceutically acceptable excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose derivatives, preferably microcrystalline cellulose.

Stable amorphous form or stable solid dispersion of lasmiditan or a salt thereof is optionally dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

Moreover the techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.

In another embodiment, the present invention provides pharmaceutical composition comprising amorphous form of lasmiditan or a salt thereof and atleast one pharmaceutically acceptable excipient.

In further embodiment, the present application provides a pharmaceutical composition comprising a stable solid dispersion of lasmiditan or a salt thereof, together with atleast one pharmaceutically acceptable excipient.

The present invention further provides a pharmaceutical composition comprising therapeutically effective amount of amorphous form or solid dispersion or premix of lasmiditan or pharmaceutically acceptable salts, thereof, one or more of hydrophilic or water-miscible carrier and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients selected from the group comprising diluents, binders, disintegrants, glidants, lubricants, polymers and/ or combinations thereof.

In embodiment, solution of lasmiditan or a salt thereof may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product.

In another embodiment, the present invention provides stable amorphous form of lasmiditan or a salt thereof, its stable solid dispersion or pharmaceutical composition comprising lasmiditan or a salt thereof, wherein said lasmiditan or a salt thereof is having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.

In another embodiment, stable amorphous form or stable solid dispersion of lasmiditan or a salt thereof, as prepared by the process of the present invention is substantially free of impurities wherein each impurity is less than about 0.3% w/w, preferably is less than about 0.15% w/w and most preferably is less than about 0.1% w/w.

In one more embodiment, the present invention provides a stable crystalline form of lasmiditan and salts thereof, wherein said crystalline form is substantially free from amorphous form.

In one more embodiment, the present invention provides a substantially pure amorphous form of lasmiditan and salts thereof, wherein said amorphous form is substantially free of crystalline form.

In another embodiment, the amorphous solid dispersion/ premix of lasmiditan or salt thereof, obtained by the process of the present invention is characterized by particle size distribution of less than about 300µm, preferably less than about 200µm and most preferably about 100µm.

In another embodiment, the amorphous form of lasmiditan or salt thereof, obtained by the process of the present invention is characterized by particle size distribution of less than about 300µm, preferably less than about 200µm and most preferably about 100µm.

In another embodiment, the present invention provides a method of treating migraine by administering a formulation comprising either an amorphous form of lasmiditan or, a solid dispersion or, a premix of lasmiditan or its salt, together with atleast one pharmaceutically acceptable excipient.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES

Example-1: Preparation of amorphous form of Lasmiditan Free base.
Lasmiditan free base (0.4g) was dissolved in methanol (20 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C. The obtain product was re-dissolved in methanol (20 mL) at 25°C and the solvent was evaporated in rotavapour under reduced pressure at 50°C for 20 minutes to get title compound.

Example-2: Preparation of substantially pure amorphous form of Lasmiditan Free base.
Lasmiditan (1.0g) was dissolved in isopopanol (50 mL) at 25°C and stirred at 60oC to get the reaction mixture for 4-6h. Lyophilized the solution to get title compound.
HPLC Purity: 98%

Example-3: Preparation of substantially pure amorphous form of Lasmiditan hydrochloride.
Lasmiditan hydrochloride (0.4 g) was dissolved in methanol (20 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C. The obtain product was re-dissolved in methanol (20 mL) at 25°C and the solvent was evaporated in rotavapour under reduced pressure at 50°C for 20 minutes to get title compound.
HPLC Purity: 99%

Example-4: Preparation of substantially pure amorphous form of Lasmiditan hemisuccinate.
Lasmiditan hemisuccinate (0.4 g) was dissolved in acetone (25 mL) at 25°C and stirred for 5-6h. The solvent was evaporated in rotavapour under reduced pressure at 50°C. The obtained product was re-dissolved in acetone (25 mL) at 25°C and the solvent was evaporated in rotavapour under reduced pressure at 50°C for 20 minutes to get the title compound.
HPLC Purity: 99.5%

Example-5: Preparation of solid dispersion of Lasmiditan free base with PVP K-90.
A mixture of Lasmiditan free base (0.5 g) and PVP K-90 (0.5 g) was dissolved in ethanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get the title compound.

Example-6: Preparation of solid dispersion of Lasmiditan hydrochloride salt with PVP K-90
A mixture of Lasmiditan hydrochloride salt (0.5 g) and PVP K-90 (1.5 g) was dissolved in methanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get the title compound.

Example-7: Preparation of solid dispersion of Lasmiditan hemisuccinate with PVP K-90
A mixture of Lasmiditan hemisuccinate (0.5 g) and PVP K-90 (1.0 g) was dissolved in acetone (30 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get title compound.

Example-8: Preparation of solid dispersion of Lasmiditan free base with HPC.
A mixture of Lasmiditan free base (1.0 g) and HPC (1.0 g) was dissolved in methanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get title compound.

Example-9: Preparation of solid dispersion of Lasmiditan hydrochloride salt with HPC
A mixture of Lasmiditan hydrochloride salt (0.5 g) and HPC (1.0 g) was dissolved in methanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get title compound.

Example-10: Preparation of solid dispersion of Lasmiditan hemisuccinate with HPC
A mixture of Lasmiditan hemisuccinate (1.0 g) and HPC (1.0 g) was dissolved in acetone (30 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to get title compound.

Example-11: Ball mill mixed-grinding process
Using a ball mill (SPEX Industries), a mixture of lasmiditan free base (1 g), hydroxypropylmethylcellulose (5 g), low-substituted hydroxypropylcellulose (3 g) and crystalline cellulose (12 g) is mix-ground for 4 hours to provide a solid dispersion.

Example 12: Preparation of solid dispersion of lasmiditan hemisuccinate with HPC using spray drying technique
Lasmiditan succinate (1.0g) was dissolved in methanol and 1.0g of HPC is dissolved in water. Solutions are then mixed by sonication to produce a clear solution, which is then spray dried using spray dryer.

Example 13: Preparation of solid dispersion of lasmiditan hemisuccinate with HPMC
1.0g of Hydroxyl propyl methyl cellulose was dissolved in acetone to form a clear and transparent gel. Then 1.0g of lasmiditan hemisuccinate was dissolved in gel by sonication for few minutes. Organic solvent was evaporated under vacuum. Solid dispersions was then reduced in size by mortar and sieved.

CLAIMS:WE CLAIM
1. A solid dispersion of lasmiditan or salt thereof, comprising of lasmiditan or its salt along with pharmaceutical acceptable excipients.

2. The solid dispersion as claimed in claim 1 wherein said lasmiditan salt is selected from succinate, and hydrochloride salt.

3. A process for the preparation of a solid dispersion of lasmiditan or salt thereof, comprising the steps of:
a) providing a solution of lasmiditan free base or salt thereof in a suitable solvent(s);
b) providing a solution of atleast one pharmaceutically acceptable excipient in a suitable solvent;
c) combining the solution of lasmiditan free base or salt thereof obtained in step a) with the solution obtained in step (b); and
d) isolating to get the solid dispersion of lasmiditan free base or salt thereof.

4. The process as claimed in claim 3, wherein said process comprises the steps of:
a) providing a solution of lasmiditan hemisuccinate salt in a suitable solvent (s);
b) providing a solution of PVP K-90 or HPC in a suitable solvent;
c) combining the solution of lasmiditan hemisuccinate salt obtained in step a) with the solution obtained in step b); and
d) isolating precipitates to get the solid dispersion of lasmiditan hemisuccinate salt.

5. The process as claimed in claims 3 and 4, wherein said solution of lasmiditan may be obtained by dissolving lasmiditan free form in a suitable solvent or by taking the reaction mixture containing lasmiditan free form directly.

6. The process as claimed in claims 3 and 4, wherein said lasmiditan or a salt thereof as used for preparing amorphous solid dispersion, is either crystalline or amorphous in nature.

7. The process as claimed in any of the preceding claim, wherein said solid dispersion of lasmiditan or salt thereof, is stable under mechanical stress and under hygroscopic conditions including higher relative humidity conditions of more than 60% RH.

8. A process for the preparation of a premix of lasmiditan or its salt, comprising the steps of:
a) adding pharmaceutically acceptable excipient to a reaction mixture comprising lasmiditan or its salt and suitable solvent (s); and
b) isolating precipitates to get the premix of lasmiditan or its salt.

9. An amorphous solid dispersion or premix of lasmiditan as obtained by the process claimed in any of the preceding claim, wherein said solid dispersion or premix of lasmiditan is characterized by particle size distribution of less than about 300µm.

10. A pharmaceutical composition comprising therapeutically effective amount of amorphous solid dispersion or premix of lasmiditan as claimed in claim 9, wherein said composition further comprises of one or more pharmaceutically acceptable excipients.