DESC:FIELD OF THE INVENTION
The present invention relates to novel crystalline forms of lomitapide mesylate and process for preparation thereof.

BACKGROUND OF THE INVENTION
Lomitapide mesylate is a microsomal triglyceride transfer protein inhibitor marketed as JUXTAPID® or LOJUXTA® in US and Europe respectively. It is represented by the following formula

It is indicated as an adjunct to low fat diet to reduce low density lipoprotein cholesterol, total cholesterol, apolipoprotein B and nonhigh density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks.
Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, differential scanning calorimetry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. The present invention provides new crystalline forms Form I, Form II and Form III of lomitapide mesylate and process of preparation thereof.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides crystalline Form I of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.9, 7.9, 11.2, 15.6, 19.6 and 22.1 ± 0.2 degrees 2 theta.
In one aspect, the present invention provides Crystalline Form I of lomitapide mesylate, characterized by DSC thermogram having an endothermic peak at about 153±2oC and at about 205 ±2oC.
In one aspect, the present invention provides crystalline Form I of lomitapide mesylate, characterized by TGA thermogram, showing a weight loss of about 1.48 weight% determined over the temperature range of 30oC to 350oC and heating rate 10oC/min.
In one aspect, the present invention provides process for the preparation of crystalline Form I of lomitapide mesylate, comprising:
(a) dissolving lomitapide in a solvent to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form I of lomitapide mesylate, from the solution in step (b) by inducing crystallization by
(i) seeding the solution of step (b) with seed crystal of crystalline form I of lomitapide mesylate; or (ii) rapidily stirring solution of step (b) ; or
(iii) stirring solution of step (b) for a period of more than about 2 hours.
In another aspect, the present invention provides crystalline Form II of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.1, 11.4, 12.2, 14.3, 17.0 and 22.5 ± 0.2 degrees 2 theta.
In another aspect, the present invention provides crystalline Form II of lomitapide mesylate, characterized by DSC thermogram having an endothermic peak at about 205 ±2oC.
In another aspect, the present invention provides crystalline Form II of lomitapide mesylate, characterized by TGA thermogram, showing a weight loss of about 0.42 weight% determined over the temperature range of 30oC to 350oC and heating rate 10oC/min.
In another aspect, the present invention provides a process for the preparation of crystalline Form II of lomitapide mesylate, comprising:
(a) dissolving lomitapide in a nitrile solvent to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form II of lomitapide mesylate, from the solution in step (b) by inducing crystallization by
(i) seeding the solution of step (b) with seed crystal of crystalline form II of lomitapide mesylate; or (ii) rapidly stirring solution of step (b).
In another aspect, the present invention provides crystalline Form III of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.2, 8.8, 14.1, 18.0, 21.1 and 25.0 ± 0.2 degrees 2 theta.
In another aspect, the present invention provides crystalline Form III of lomitapide mesylate, characterized by DSC thermogram having an endothermic peak at about 132 ±2oC.
In another aspect, the present invention provides crystalline Form III of lomitapide mesylate, characterized by TGA thermogram, showing a weight loss of about 1.76 weight% determined over the temperature range of 30oC to 350oC and heating rate 10oC/min.
In another aspect, the present invention provides a process for the preparation of crystalline Form III of lomitapide mesylate, comprising:
(a) dissolving lomitapide in a solvent selected from ethyl acetate or dimethyl formamide to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form III of lomitapide mesylate by addition of methyltertbutyl ether.
In another aspect, present invention provides a pharmaceutical composition comprising crystalline Form I of lomitapide mesylate together with one or more pharmaceutically acceptable carriers.
In another aspect, present invention provides a pharmaceutical composition comprising crystalline Form II of lomitapide mesylate together with one or more pharmaceutically acceptable carriers.
In another aspect, present invention provides a pharmaceutical composition comprising crystalline Form III of lomitapide mesylate together with one or more pharmaceutically acceptable carriers.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a XRPD of crystalline Form I of lomitapide mesylate.
Figure 2 is a DSC thermogram of crystalline Form I of lomitapide mesylate.
Figure 3 is a TGA of crystalline Form I of lomitapide mesylate.
Figure 4 is a XRPD of crystalline Form II of lomitapide mesylate.
Figure 5 is a DSC thermogram of crystalline Form II of lomitapide mesylate.
Figure 6 is a TGA of crystalline Form II of lomitapide mesylate.
Figure 7 is a XRPD of crystalline Form III of lomitapide mesylate.
Figure 8 is a DSC thermogram of crystalline Form III of lomitapide mesylate.
Figure 9 is a TGA of crystalline Form III of lomitapide mesylate.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel crystalline forms of lomitapide mesylate.
In one embodiment, the present invention provides crystalline Form I of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.9, 7.9, 11.2, 15.6, 19.6 and 22.1 ± 0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline Form I of lomitapide mesylate characterized by X-ray powder diffraction (XRPD) pattern which is substantially in accordance with Figure 1.
In one embodiment, the present invention provides crystalline Form I of lomitapide mesylate, characterized by differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 153±2oC and at about 205 ±2oC.
In one embodiment, the present invention provides crystalline Form I of lomitapide mesylate characterized by differential scanning calorimetry (DSC) endotherm curve, which is substantially in accordance with Figure 2.
In one embodiment, the present invention provides crystalline Form I of lomitapide mesylate, characterized by TGA thermogram, showing a weight loss of about 1.48 weight% determined over the temperature range of 30oC to 350oC and heating rate 10oC/min.
In one embodiment, the present invention provides crystalline Form I of lomitapide mesylate, characterized by TGA thermogram, which is substantially in accordance with Figure 3.
In one embodiment of the present invention the lomitapide is prepared by any method known in the art.
In one embodiment, the present invention provides process for the preparation of crystalline Form I of lomitapide mesylate, comprising:
(a) dissolving lomitapide in a solvent to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form I of lomitapide mesylate, from the solution in step (b) by inducing crystallization by
(i) seeding the solution of step (b) with seed crystal of crystalline form I of lomitapide mesylate; or (ii) rapidly stirring solution of step (b) ; or
(iii) stirring solution of step (b) for a period of more than about 2 hours.
Solvent used in (a) includes, but is not limited to esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, tert-butyl acetate and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and the like; aliphatic hydrocarbons such as hexane, heptane, cyclohexane and the like; aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as methylene chloride, ethylene chloride and the like; water; or mixtures thereof.
In one embodiment, the methane sulfonic acid in (b) is added slowly.
In one embodiment, crystallization induced in c (i) is by adding seed crystal of crystalline form I of lomitapide mesylate to solution of step (b).
In one embodiment, crystallization induced in c (ii) is by rapidly stirring the solution of step (b) at about more than 50 revolutions per minute (RPM), more preferably about 70 RPM.
In one embodiment, crystallization induced in c (iii) is by stirring solution of step (b) for a period of more than about 2 hours, preferably more than about 3 hours at room temperature.
In one embodiment, the crystalline form I of lomitapide mesylate obtained in (c) may, be filtered and dried.
In one embodiment, the crystalline form I of lomitapide mesylate is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, removal of solvent may be carried out by solvent distillation, concentration, spray drying and the like.
In one embodiment, distillation may be carried out until the solvent is completely distilled off.
In one embodiment, drying may be performed under vacuum at a temperature of about 80-110°C, preferably at a temperature of about 85-95°C.
In one embodiment, the present invention provides process for the preparation of crystalline Form I of lomitapide mesylate, comprising:
(a) dissolving lomitapide in ethyl acetate to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form I of lomitapide mesylate, from the solution in step (b) by inducing crystallization by
(i) seeding the solution of step (b) with seed crystal of crystalline form I of lomitapide mesylate; or (ii) rapidly stirring solution of step (b); or
(iii) stirring solution of step (b) for a period of more than about 2 hours
In one embodiment, seed crystal of crystalline Form I of lomitapide mesylate is obtained by inducing crystallization by stirring lomitapide mesylate in ethyl acetate at high speed.
In one embodiment, seed crystal of crystalline Form I of lomitapide mesylate is obtained by inducing crystallization by stirring lomitapide mesylate in 1-3 volumes of ethyl acetate at high speed for a period of at least 3 hours.
In one embodiment, seed crystal of crystalline Form I of lomitapide mesylate is obtained by inducing crystallization by stirring lomitapide mesylate in 1-3 volumes of ethyl acetate for more than 100 revolutions per minutes (RPM, DEEPALI Stirrer) for a period of at least 3 hours.
In one embodiment, seed crystal of crystalline Form I of lomitapide mesylate is obtained by inducing crystallization by stirring lomitapide mesylate in 1-3 volumes of ethyl acetate for more than 200 revolutions per minutes (RPM) for a period of at least 3 hours.
In one embodiment, seed crystal of crystalline Form I of lomitapide mesylate is obtained by inducing crystallization by stirring lomitapide mesylate in 3 volumes of ethyl acetate at 400 revolutions per minutes (RPM, DEEPALI Stirrer) for a period of about 6 hours.
The crystalline form I of lomitapide mesylate obtained in step (c) may be filtered, isolated and dried by method as discussed supra.
In one embodiment, the present invention provides crystalline Form II of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.1, 11.4, 12.2, 14.3, 17.0 and 22.5 ± 0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline Form II of lomitapide mesylate characterized by X-ray powder diffraction (XRPD) pattern which is substantially in accordance with Figure 4.
In one embodiment, the present invention provides crystalline Form II of lomitapide mesylate, characterized by differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 205 ±2oC.
In one embodiment, the present invention provides crystalline Form II of lomitapide mesylate characterized by differential scanning calorimetry (DSC) endotherm curve, which is substantially in accordance with Figure 5.
In one embodiment, the present invention provides crystalline Form II of lomitapide mesylate, characterized by TGA thermogram, showing a weight loss of about 0.42 weight% determined over the temperature range of 30oC to 350oC and heating rate 10oC/min.
In one embodiment, the present invention provides crystalline Form II of lomitapide mesylate, characterized by TGA thermogram, which is substantially in accordance with Figure 6.
In one embodiment, the present invention provides process for the preparation of crystalline Form II of lomitapide mesylate, comprising
(a) dissolving lomitapide in a nitrile solvent to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form II of lomitapide mesylate, from the solution in step (b) by inducing crystallization by
(i) seeding the solution of step (b) with seed crystal of crystalline form II of lomitapide mesylate; or (ii) rapidly stirring solution of step (b).
Nitrile solvent used in (a) includes, but is not limited to acetonitrile, propionitrile, butyronitrile and the like.
In one embodiment, the methane sulfonic acid in (b) is added slowly at room temperature.
In one embodiment, the methane sulfonic acid in (b) is added slowly at about -50C to 100C, preferably at about 00C to 10 0C.
In one embodiment, crystallization induced in c (i) is by adding seed crystal of crystalline form II of lomitapide mesylate to solution of step (b).
In one embodiment, crystallization induced in c (ii) is by rapidly stirring the solution of step (b) at about more than 50 revolutions per minute (RPM), more preferably about 70 RPM.
In one embodiment, the crystalline form II of lomitapide mesylate obtained in (c) may be filtered and dried.
In one embodiment, the crystalline form II of lomitapide mesylate is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, removal of solvent may be carried out by solvent distillation, concentration, spray drying and the like.
In one embodiment, distillation may be carried out until the solvent is completely distilled off.
In one embodiment, drying may be performed under vacuum at a temperature of about 75-110°C, preferably at a temperature of about 85-95°C
In one embodiment, the present invention provides crystalline Form III of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.2, 8.8, 14.1, 18.0, 21.1 and 25.0 ± 0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline Form III of lomitapide mesylate characterized by X-ray powder diffraction (XRPD) pattern which is substantially in accordance with Figure 7.
In one embodiment, the present invention provides crystalline Form III of lomitapide mesylate, characterized by differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 132 ±2oC.
In one embodiment, the present invention provides crystalline Form III of lomitapide mesylate characterized by differential scanning calorimetry (DSC) endotherm curve, which is substantially in accordance with Figure 8.
In one embodiment, the present invention provides crystalline Form III of lomitapide mesylate, characterized by TGA thermogram, showing a weight loss of about 1.76 weight% determined over the temperature range of 30oC to 350oC and heating rate 10oC/min.
In one embodiment, the present invention provides crystalline Form III of lomitapide mesylate, characterized by TGA thermogram, which is substantially in accordance with Figure 9.
In one embodiment, the present invention provides process for the preparation of crystalline Form III of lomitapide mesylate, comprising
(a) dissolving lomitapide in a solvent to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form III of lomitapide mesylate by addition of methyl tertiary butyl ether.
Solvent used in (a) includes, but is not limited to esters, alcohols, ketones, cyclic ethers, nitriles, dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water or mixtures thereof.
In one embodiment, the present invention provides process for the preparation of crystalline Form III of lomitapide mesylate, comprising
(a) dissolving lomitapide in a solvent selected from ethyl acetate or dimethyl formamide to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form III of lomitapide mesylate by addition of methyl tertiary butyl ether.
In step (b) methane sulfonic is acid added to the solution at low temperature at about -50C to 100C, preferably at about 00C to 10 0C.
In step (c) methyl tertiary butyl ether is added and stirred for a period of about more than 3 hours, more preferably for about 4 hours to obtain crystalline Form III of lomitapide mesylate.
In one embodiment, the crystalline form III of lomitapide mesylate obtained in (c) may be filtered and dried.
In one embodiment, the crystalline form III of lomitapide mesylate is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, removal of solvent may be carried out by solvent distillation, concentration, spray drying and the like.
In one embodiment, distillation may be carried out until the solvent is completely distilled off.
In one embodiment, drying may be performed under vacuum at a temperature of about 30-70°C, preferably at a temperature of about 35-40°C
The present invention provides a pharmaceutical composition comprising crystalline form of lomitapide mesylate together with one or more pharmaceutically acceptable carriers.
The present invention provides novel crystalline lomitapide mesylate as characterized and analyzed by following techniques:
A. X-ray powder diffraction profile was obtained using an X-ray Diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X’Celerator [1] ; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV ; tube current 40mAmp. The samples were scanned in the full 2? range of 2-50° with a “time-per-step” 50 seconds.
B. DSC (Mettler Toledo 822e): Temperature range is “30°C to 350°C” and heating rate is 10°C/minute.
C. TGA (Q500 Waters): Temperature range is “30°C to 350°C” and heating rate is 10°C/minute.
Pharmaceutical composition comprising crystalline form of lomitapide mesylate includes, but not limited to, solid oral dosage forms such as pellets, powders, granules, tablets, and capsules; liquid oral dosage forms such as suspensions, syrups, dispersions and emulsions; and injectable preparations such dispersions, solutions, and freeze dried compositions. Preferably, the pharmaceutically acceptable composition is a capsule. Pharmaceutically acceptable carriers known in the art may be used in the preparation of the pharmaceutical compositions of the invention.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
EXAMPLE 1: Preparation of crystalline lomitapide mesylate (Form I)
To a solution of lomitapide (5.0 gm, 0.0072 moles) in ethyl acetate, methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly and the reaction mass was stirred for about 3 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 85-95°C to form desired compound.

EXAMPLE 2: Preparation of crystalline lomitapide mesylate (Form I)
To a solution of lomitapide (5.0 gm, 0.0072 moles) in ethyl acetate (75 ml, 15vol), methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly at about 0°C to 10°C, and stirred for about 30 minutes. Seed crystal of crystalline Form I of lomitapide mesylate was added to reaction mass and further stirred for about 3 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 85-95°C to form desired compound.
XRPD peaks of lomitapide mesylate Form I (XRPD pattern as per figure 1)
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
3.95 22.35 32.73 15.60 5.67 54.13 25.37 3.50 15.74
6.85 12.89 12.26 15.95 5.55 26.41 26.25 3.39 12.45
7.26 12.17 14.51 16.59 5.34 14.69 26.71 3.33 8.35
7.89 11.19 18.37 17.39 5.09 62.48 27.26 3.26 7.70
8.67 10.19 8.25 17.69 5.01 17.76 27.79 3.20 5.93
8.99 9.82 5.41 18.49 4.79 4.36 28.42 3.13 6.93
9.70 9.11 16.09 18.84 4.70 6.49 28.79 3.09 7.46
9.96 8.88 17.31 19.18 4.62 8.80 29.99 2.97 1.55
11.20 7.89 25.87 19.58 4.53 50.22 30.95 2.88 8.42
11.66 7.58 3.31 20.28 4.37 31.90 32.18 2.77 3.17
12.38 7.14 10.59 20.79 4.27 35.95 35.06 2.55 2.23
12.96 6.83 5.94 21.55 4.12 44.13 36.18 2.48 1.74
13.77 6.42 31.17 22.14 4.01 100.00 39.86 2.25 2.80
14.10 6.28 19.10 22.75 3.90 33.99 43.72 2.06 2.51
14.54 6.09 32.09 23.42 3.79 15.20 46.87 1.93 2.10
15.32 5.78 27.39 24.37 3.64 17.40 - - -

EXAMPLE 3: Preparation of crystalline lomitapide mesylate (Form I)
To a solution of lomitapide (5.0 gm, 0.0072 moles) in methylene dichloride, methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly and the reaction mass was stirred for about 3 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 85-95°C to form desired compound.

EXAMPLE 4: Preparation of crystalline lomitapide mesylate (Form I)
To a solution of lomitapide (5.0 gm, 0.0072 moles) in isopropyl alcohol, methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly and the reaction mass was stirred for about 3 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 85-95°C to form desired compound.

EXAMPLE 5: Preparation of crystalline lomitapide mesylate (Form II)
To a solution of lomitapide (5.0 gm,0.0072 moles) in acetonitrile (15 ml, 3 vol), methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly and the reaction mass was stirred for about 3 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 85-95°C to form desired compound.
XRPD peaks of lomitapide mesylate Form II (XRPD pattern as per figure 4)
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
7.10 12.43 100.00 18.36 4.83 4.96 27.83 3.20 2.51
8.45 10.46 13.14 18.93 4.68 16.01 28.69 3.11 14.49
8.75 10.09 36.99 19.21 4.61 6.88 29.64 3.01 3.72
10.20 8.66 4.78 19.98 4.44 38.88 30.28 2.95 4.32
11.42 7.74 53.14 20.51 4.32 72.01 30.95 2.88 5.21
12.19 7.25 51.04 20.85 4.25 27.28 31.56 2.83 1.73
13.40 6.60 90.73 21.29 4.17 39.62 33.11 2.70 1.16
14.26 6.20 46.97 21.83 4.07 11.22 33.58 2.66 1.87
14.55 6.08 11.25 22.54 3.94 83.16 34.57 2.59 2.41
14.83 5.97 23.64 23.48 3.78 13.55 35.60 2.52 3.50
15.73 5.76 3.28 24.19 3.67 18.00 36.20 2.48 3.09
15.94 5.55 22.95 24.65 3.61 9.47 37.29 2.41 2.81
16.43 5.39 14.99 25.33 3.51 5.35 40.20 2.24 2.77
17.03 5.20 98.02 26.14 3.40 5.58 40.98 2.20 2.49
17.43 5.08 31.65 26.45 3.36 8.75 42.93 2.10 1.25
17.70 5.00 12.63 26.96 3.30 6.49 44.55 2.03 1.29

EXAMPLE 6: Preparation of crystalline lomitapide mesylate (Form II)
To a solution of lomitapide (5.0 gm, 0.0072 moles) in acetonitrile (15 ml, 3 vol), methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly at about 0°C to 10°C, and stirred for about 30 minutes. Seed crystal of crystalline Form II of lomitapide mesylate was added to reaction mass and further stirred for about 3 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 85-95°C to form desired compound.

EXAMPLE 7: Preparation of crystalline lomitapide mesylate (Form III)
To a solution of lomitapide (5.0 gm, 0.0072 moles) in N,N-Dimethylformamide (10ml, 2vol), methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly at about 0°C to 10°C, and stirred for about 10 minutes. Methyl tertiary butyl ether was added to the reaction mass and further stirred for about 4 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 35-40°C to form desired compound.

XRPD peaks of lomitapide mesylate Form III (XRPD pattern as per figure 7)
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.25 14.12 2.97 17.33 5.11 11.97 25.58 3.48 17.95
7.06 12.50 9.88 17.68 5.01 47.26 26.42 3.37 10.96
8.78 10.06 5.43 18.05 4.91 16.54 26.90 3.31 2.83
9.75 9.06 0.81 18.51 4.79 4.57 27.66 3.22 5.34
10.17 8.69 3.46 19.11 4.64 13.66 28.35 3.14 4.82
11.48 7.70 7.23 19.52 4.54 2.50 28.94 3.08 3.07
11.80 7.49 3.17 19.86 4.46 15.93 29.61 3.01 2.22
12.53 7.05 17.53 20.41 4.35 23.78 30.85 2.89 1.66
13.34 6.63 20.81 21.13 4.20 56.01 31.48 2.84 1.72
13.70 6.46 26.91 21.59 4.11 30.81 31.81 2.81 1.96
14.14 6.24 100.00 22.05 4.03 10.68 32.51 2.75 5.46
14.41 6.14 3.80 23.17 3.83 6.39 32.90 2.72 2.74
15.97 5.54 11.72 23.64 3.76 13.10 33.30 2.69 2.64
16.37 5.41 3.73 24.01 3.70 2.46 34.61 2.59 1.94
16.79 5.27 3.82 24.37 3.65 5.12 35.07 2.55 1.32
17.13 5.17 34.64 25.04 3.55 21.38 35.84 2.50 1.65

EXAMPLE 8: Preparation of crystalline lomitapide mesylate (Form III)
To a solution of lomitapide (5.0 gm,0.0072 moles) in ethyl acetate (50ml, 10 vol), methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly at about 0°C to 10°C, and stirred for about 10 minutes. Methyl tertiary butyl ether was added to the reaction mass and further stirred for about 4 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 35-40°C to form desired compound

EXAMPLE 9: Preparation of seed crystal of crystalline Form I of lomitapide mesylate.
To a solution of lomitapide (5.0gm,0.0072 moles) in ethyl acetate (15 ml, 3vol), methane sulfonic acid (0.7gm, 0.0072 moles) was added slowly and the reaction mass was stirred at about 400 RPM (vigorous stirring) for about 6 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 85-95°C to form desired compound.

EXAMPLE 10: Capsule containing 5 mg of Lomitapide
Capsule containing 5 mg of Lomitapide are produced from the following ingredients.
Component 5 mg capsule
Amount ( mg/capsule )
Lomitapide mesylate crystalline Form I 5.70 mg (5.0 mg free base)
Pregelatinized Starch 5.0 mg
Microcrystalline Cellulose 10.0 mg
Lactose monohydrate 73.0 mg
Sodium Starch Glycolate 5.0 mg
Colloidal Silicon Dioxide 1.0 mg
Magnesium Stearate 0.3 mg
Purified water USP q.s.
Total Amount 100 mg

The Lomitapide mesylate and colloidal silicon dioxide are blended in a suitable blender with lactose monohydrate, microcrystalline cellulose, pregelatinized starch and a portion of sodium starch glycolate. The resulting blend is wet granulated with water. The wet granulation is dried in a suitable dryer. The remaining portion of sodium starch glycolate is added to the granulation and mixed therein. Magnesium stearate is added to the granulation and mixed therein.
The resulting blend is filled into capsules.
,CLAIMS:1. Crystalline Form I of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 3.9, 7.9, 11.2, 15.6, 19.6 and 22.1 ± 0.2 degrees 2 theta.
2. Crystalline Form I of lomitapide mesylate as defined in claim 1, characterized by DSC thermogram having endothermic peak at about 153±2oC and at about 205 ±2oC.
3. A process for the preparation of crystalline Form I of lomitapide mesylate, comprising:
(a) dissolving lomitapide in a solvent to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form I of lomitapide mesylate, from the solution in step (b) by inducing crystallization by
(i) seeding the solution of step (b) with seed crystal of crystalline form I of lomitapide mesylate; or (ii) rapidly stirring solution of step (b) ; or
(iii) stirring solution of step (b) for a period of more than 2 hours.
4. The process as defined in claim 3, wherein the solvent is selected from ester solvent, alcoholic solvent, halogenated hydrocarbon solvent or mixtures thereof.
5. The process as defined in claim 4, wherein the ester solvent is selected from methyl acetate, ethyl acetate, propyl acetate, butyl acetate, ter-butyl acetate ; alcoholic solvent is selected from methanol, ethanol, isopropanol ; and halogenated hydrocarbon solvent is selected from methylene dichloride, ethylene dichloride.
6. Crystalline Form II of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.1, 11.4, 12.2, 14.3, 17.0 and 22.5 ± 0.2 degrees 2 theta and by DSC thermogram having endothermic peak at about 205 ±2oC.
7. A process for the preparation of crystalline Form II of lomitapide mesylate, comprising:
(a) dissolving lomitapide in a nitrile solvent to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form II of lomitapide mesylate, from the solution in step (b) by inducing crystallization by
(i) seeding the solution of step (b) with seed crystal of crystalline form II of lomitapide mesylate; or (ii) rapidly stirring solution of step (b).
8. The process as defined in claim 7, wherein the nitrile solvent is selected from acetonitrile, propane nitrile.
9. Crystalline Form III of lomitapide mesylate, characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.2, 8.8, 14.1, 18.0, 21.1 and 25.0 ± 0.2 degrees 2 theta and by DSC thermogram having endothermic peak at about 132 ±2oC.
10. A process for the preparation of crystalline Form III of lomitapide mesylate, comprising:
(a) dissolving lomitapide in a solvent selected from ethyl acetate or dimethylformamide to obtain a solution;
(b) adding methane sulfonic acid to the solution; and
(c) isolating crystalline form III of lomitapide mesylate by addition of methyl tertiary butyl ether.