Description:FIELD OF THE INVENTION
The present invention relates to solid forms of sodium phenytoin of Formula I and preparation thereof

Formula I
BACKGROUND OF THE INVENTION:
Phenytoin sodium of Formula I is chemically known as 5,5-diphenyl-2,4-imidazolidinedione. Phenytoin sodium is the sodium salt form of phenytoin, a hydantoin derivate and non-sedative antiepileptic agent with anticonvulsant activity. Phenytoin sodium promotes sodium efflux from neurons located in the motor cortex, thereby stabilizing the neuron and inhibiting synaptic transmission. This leads to a reduction in posttetanic potentiation at synapses, an inhibition of repetitive firing of action potentials and ultimately inhibits the spread of seizure activity.

Formula I
It also is known as diphenylhydantoin. It is used extensively to treat convulsive disorders such as epilepsy.
Although there are few literatures known for crystallization of Phenytoin Sodium of Formula I, however there is always a need to develop a new crystalline form and a process that can produce the said crystalline form of the product which has good stability, good process ability and other favourable properties with respect to Formulation.
Based on aforesaid, the present invention is focussed towards the development of new crystalline forms of phenytoin sodium of Formula I by employing simple, low cost and less time-consuming processes.
OBJECT OF THE INVENTION
The principle objective of the present invention is to provide novel solid forms of phenytoin sodium.
Another objective of the invention is to provide a process for the preparation of novel solid form of phenytoin sodium.
Another objective of the present invention is to provide novel crystalline forms of phenytoin sodium designated as MK-1, MK-2, and MK-3 and preparation method thereof.
Another objective of the present invention is to provide amorphous form of compound of Formula I and preparation method thereof.
SUMMARY OF THE INVENTION
In the main aspect, the present invention relates to a novel solid forms of phenytoin sodium (Formula I).
Another aspect of the present invention is to provide crystalline forms of phenytoin sodium of Formula I and preparation method thereof.
In another aspect, the solid forms of phenytoin sodium comprise crystalline form and hydrate and solvate thereof, amorphous, solid dispersion or premix.
In another aspect, the present invention provides a process for preparation of novel crystalline forms of phenytoin sodium.
In another aspect, the present invention provides crystalline forms MK-1, MK-2, and MK-3 and amorphous form of phenytoin sodium of Formula 1, characterized by their X-ray (powder) diffraction (XRD), Differential Scanning calorimetry (DSC) and Thermogravimetric analysis (TGA).
In another aspect, the present invention provides a crystalline form MK-1 of phenytoin sodium, characterized by its XRD pattern having one or more peaks (2? values) at about 5.80, 6.22, 6.57, 7.09, 10.58, 11.44, 12.10, 12.34, 13.03, 15.72, 16.19, 17.13, 17.64, 18.08, 18.90, 19.47, 21.14, 22.67, 23.01, 24.38, 24.87, 25.56, 26.19, 26.50, 27.12, 28.01, 29.15, 29.99, 31.04, 31.94, 32.88, 34.13, 35.12, 36.46, and 38.36 ± 0.2°?
In another aspect, the present invention provides a process for preparation of crystalline form MK-1 of phenytoin sodium.
In another aspect, the present invention provides a crystalline form MK-2 of phenytoin sodium, characterized by its XRD pattern having one or more peaks (2? values) at about 6.22, 11.15, 12.17, 13.29, 15.13, 15.72, 16.33, 17.17, 17.46, 18.48, 19.41, 20.57, 21.59, 22.33, 23.12, 23.80, 24.66, 26.03, 26.68, 27.51, 28.07, 28.90, 29.63, 30.74, 31.66, 33.61, 34.71, 35.34, 36.34, 37.21 and 38.98 ± 0.2°?
In another aspect, the present invention provides a process for preparation of crystalline form MK-2 of phenytoin sodium.
In one aspect, the present invention provides a crystalline form MK-3 of phenytoin sodium, characterized by its XRD pattern having one or more peaks (2? values) at about 5.34, 10.55, 11.21, 12.54, 15.06, 15.64, 16.13, 16.60, 17.20, 17.43, 18.40, 19.01, 19.46, 19.69, 20.09, 21.08, 21.46, 22.39, 22.81, 23.20, 23.51, 24.25, 25.13, 26.39, 26.99, 27.54, 27.97, 28.70, 29.10, 29.64, 30.32, 30.77, 31.35, 31.77, 32.27, 32.03, 33.37, 34.06, 34.59, 35.02, 35.85, 37.11, 38.35, 38.85 ± 0.2
In another aspect, the present invention provides a process for preparation of crystalline form MK-3 of Phenytoin sodium.
In another aspect, the present invention provides amorphous form of phenytoin sodium compound of Formula I.
In another aspect, the present invention provides a process for preparation of amorphous form of phenytoin sodium compound of Formula I.
BRIEF DESCRIPTION OF THE DRAWINGS:
Fig. 1, which represents the X-ray (powder) diffraction (XRD) pattern of the crystalline form MK-1 of phenytoin sodium (Anhydrate) of the present invention.
Fig. 2, which represents the X-ray (powder) diffraction pattern of the crystalline form MK-2 of phenytoin sodium (Monohydrate) of the present invention.
Fig. 3, which represents the X-ray (powder) diffraction pattern of the Crystalline form MK-3 of phenytoin sodium (Dihydrate) of the present invention.
Fig. 4, which represents the Thermogravimetric analysis (TGA) of the Crystalline form MK-3 of phenytoin sodium (Dihydrate) of the present invention.
Fig. 5, which represents the X-ray (powder) diffraction (XRD) pattern of the amorphous form of phenytoin sodium of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Crystalline is termed as the period pattering or transitioning of molecules and atoms in the solid. In the “Crystalline Form” there is an arrangement of atoms or molecules, which give rise to the three-dimensional format within the single unit repeating which is also termed as the unit cell.
Amorphous form are, by definition, non-crystalline materials which possess no long-range order. Their structure can be thought of as being similar to that of a frozen liquid with the thermal fluctuations present in a liquid frozen out, leaving only “static” structural disorder.
The term “substantially free” used in the context of the present invention means compound of Formula I having impurity less than about 0.2% by area percentage of HPLC. In particular, less than about 0.15% by area percentage of HPLC. More particular, not in detectable amount by area percentage of HPLC.
The terms “amorphous” or “stable amorphous” form of compound of Formula I are interchangeable and “amorphous” compound of Formula I indicate that the compound of Formula I is present in substantially amorphous state "Substantially pure amorphous” denotes that at least 90%, preferably at least 95% of the compound of Formula I is amorphous in nature.
In context of the present invention, the term “reaction mixture” or “reaction mass” are interchangeable and used for the present invention are comprising, but not limited to clear solution, partially dissolved solution, suspension, slurry, turbid solution, mixture, biphasic solution or any other phase as known in the literature.
The present invention is focussed towards the development of amorphous and crystalline forms of Phenytoin sodium by employing simple, low cost and less time consuming process wherein the crystalline forms so obtained possesses good stability, good processability and other favourable properties.
ANALYTICAL INSTRUMENT METHODS:
General Differential Scanning Calorimetry (DSC) Instrument Details:
Differential scanning calorimetry (DSC) is performed using instrument Perkin Elmer, Model: DSC 8000. Sample was placed into the respective sample position in DSC and blank pan at the reference position and scan was run in the scanning temperature range of 30oC to 400oC (10oC per minute) using given instrumental parameter and data was collected. Thermogram was recorded by integrating the endothermic peak.
General Powder X-ray Diffraction (PXRD) Instrument Details:
X-ray Powder Diffraction (VH/VT-XRPD) patterns were recorded on an X-Ray powder diffractometer Bruker D8 Advance diffractometer (Bruker AXS GmbH, Germany) system with Cu Ka1 radiation (?= 1.5406Å) using LYNXEYE-2 detector. Prior to analysis, sufficient quantity of powder sample was grinded gently in a mortar with pestle. Finally, grinded simple was filled in to the groove of the sample holder uniformly and the XRPD patterns were recorded within the 2? range of 3 to 40.
The diffractometer was equipped with a hot-humidity chamber (proUmid MHG-32 Modular humidity generator ProUmid GmbH & Co. KG) and Variable temperature controller with an Anton Paar CCU100 (Anton Paar, Austria) attached to a water bath Julabo HE-4 CORIO CD.
General Thermogravimetric Analysis (TGA) Instrument Details:
Thermogravimetric analysis was performed on Perkin Elmer Pyris 1 TGA and platinum sample pan was loaded onto the hang down wire and waited till the balance become stable and TGA curve was recorded in the temperature range of 20oC to 400oC (100 oC/minute) with air flow 50mL/minute.
The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative Forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular Forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention.
In the main embodiment, the present invention provides novel solid forms of phenytoin sodium of Formula I.
In another embodiment, the present invention provides a process for the preparation of novel solid forms of phenytoin sodium of.Formula I.
In another embodiment, the present invention is to provide crystalline forms of phenytoin sodium of Formula I.
In another embodiment, the present invention provides process for preparation of novel crystalline forms of phenytoin sodium of Formula I.
In another embodiment, the present invention provides novel crystalline forms of phenytoin sodium are designated as form MK-1, MK-2, MK-3 and their preparation method.
In another embodiment, the one or more solvent used for preparation of the crystalline form or amorphous form of phenytoin sodium of Formula I is selected from the group comprising of ketones such as methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, acetone and the like; alcohol such as ethanol, methanol, n-propanol, 2-propanol (isopropanol), n-butanol, isobutanol, tert-butanol and the like; esters such as ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate and the like; ethers such as dimethyl ether, diethylether, ethyl methyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl tetrahydrofuran and like; hydrocarbon such as n-heptane, cyclohexane, n-hexane, benzene, toluene, o,m,p-xylene; nitriles such as acetonitrile, propanenitrile; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroForm, tetrachloromethane, chlorobenzene, and like; amides such as dimethyl acetamide (DMA), dimethyl formamide (DMF) and like; nitromethane; and water or mixture thereof, preferably the one or more solvent selected from methanol, ethanol, 2-propanol, hexane, heptane, acetonitrile, nitromethane, xylene, acetone, water or mixture thereof.
Accordingly, in another embodiment, the present invention provides a crystalline form MK-1 of phenytoin sodium, characterized by its XRD pattern having one or more peaks (2? values) at about 5.80, 6.22, 6.57, 7.09, 10.58, 11.44, 12.10, 12.34, 13.03, 15.72, 16.19, 17.13, 17.64, 18.08, 18.90, 19.47, 21.14, 22.67, 23.01, 24.38, 24.87, 25.56, 26.19, 26.50, 27.12, 28.01, 29.15, 29.99, 31.04, 31.94, 32.88, 34.13, 35.12, 36.46, and 38.36 ± 0.2°?
In other embodiment, the present invention provides a crystalline form MK-1 of phenytoin sodium, characterized by its XRD pattern as depicted in Fig-1.
In other embodiment, the present invention provides a crystalline form MK-1 of phenytoin sodium, characterized by its DSC having endothermic peaks at 370°C
In other embodiment, the present invention provides a crystalline form MK-1 of phenytoin sodium, characterized by its TGA corresponding to a weight loss of about 0.34 % w/w .
In another embodiment the present invention provides a process for the preparation of form MK-1 of phenytoin sodium of Formula I, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) isolating the crystalline form MK-1 of phenytoin sodium of Formula I.
In another embodiment the present invention provides a process for the preparation of form MK-1 of phenytoin sodium of Formula I, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) heating the reaction mixture at about 30-50°C for about 15-25hrs;
c) cooling the reaction mixture to get wet mass;
d) drying the wet mass at 30-40°C and 10-20% RH for 6-8hrs to get crystalline form MK-1 of Formula I.
In another embodiment solvent used in step a) is selected from methanol , 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethylether, dimethylether, diisopropylether, diphenylether, MTBE, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethyl acetamide (DMA), dimethylformamide (DMF), water or mixture thereof.
Accordingly, in another embodiment, the present invention provides a crystalline form MK-2 of Phenytoin sodium, characterized by its XRD pattern having one or more peaks (2? values) at about 6.22, 11.15, 12.17, 13.29, 15.13, 15.72, 16.33, 17.17, 17.46, 18.48, 19.41, 20.57, 21.59, 22.33, 23.12, 23.80, 24.66, 26.03, 26.68, 27.51, 28.07, 28.90, 29.63, 30.74, 31.66, 33.61, 34.71, 35.34, 36.34, 37.21 and 38.98 ± 0.2°?
In other embodiment, the present invention provides a crystalline form MK-2 of phenytoin sodium, characterized by its XRD pattern as depicted in Fig-2.
In other embodiment, the present invention provides a crystalline form MK-2 of phenytoin sodium, characterized by its DSC having endothermic peaks at 92.39°C and 371.87°C.
In other embodiment, the present invention provides a crystalline form MK-2 of phenytoin sodium, characterized by its TGA corresponding to a weight loss of about 5.95% w/w.
In another embodiment the present invention provides a process for the preparation of form MK-2 of phenytoin sodium, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) stirring the reaction mass at ambient temperature; and
c) isolating the crystalline form MK-2 of the compound of Formula I.
In another embodiment the present invention provides a process for the preparation of form MK-2 of phenytoin sodium, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) heating the reaction mixture at about 30-50 ° C for about 15-25 hrs;
c) cooling the reaction mixture to get wet mass;
d) drying the wet mass at 30-40°C and 35-40% RH for 4-6 hrs to get crystalline form MK-2 of Formula I.
In another embodiment, solvent used in step a) is selected from methanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroForm, acetonitrile, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethylether, dimethylether, diisopropylether, diphenylether, MTBE, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene,m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethyl acetamide (DMA), dimethylFormamide (DMF), or mixture thereof .
Accordingly, in another embodiment, the present invention provides a crystalline form MK-3 of phenytoin sodium, characterized by its XRD pattern having one or more peaks (2? values) at about 5.34, 10.55, 11.21, 12.54, 15.06, 15.64, 16.13, 16.60, 17.20, 17.43, 18.40, 19.01, 19.46, 19.69, 20.09, 21.08, 21.46, 22.39, 22.81, 23.20, 23.51, 24.25, 25.13, 26.39, 26.99, 27.54, 27.97, 28.70, 29.10, 29.64, 30.32, 30.77, 31.35, 31.77, 32.27, 32.03, 33.37, 34.06, 34.59, 35.02, 35.85, 37.11, 38.35, 38.85 ± 0.2
In other embodiment, the present invention provides a crystalline form MK-3 of phenytoin sodium, characterized by its XRD pattern as depicted in Fig-3.
In other embodiment, the present invention provides a crystalline form MK-3 of phenytoin sodium, characterized by its DSC having endothermic peaks at 81°C, 91.23°C and 370.75°C.
In other embodiment, the present invention provides a crystalline form MK-3 of phenytoin sodium, characterized by its TGA corresponding to a weight loss of about 11.43% w/w as depicted in Fig-4.
In another embodiment the present invention provides a process for the preparation of form MK-3 of phenytoin sodium, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) heating the reaction mixture at about 30-50 °C for about 15-25 hrs;
c) cooling the reaction mixture to get wet mass;
d) drying the wet mass to get crystalline form MK-3 of Formula I.
In another embodiment the present invention provides a process for the preparation of dihydrate form MK-3 of phenytoin sodium, comprising,
a) adding compound of Formula I in a mixture of water and inorganic acid;
b) adding suitable solvent to mixture of step a);
c) treating mixture of step b) with suitable base to maintain the pH above 9;
d) stering the reaction mixture of step c) at suitable tempreture for a period of more than 24 hour ; and
e) cooling the suspension obtained in step d) to get the dihydrate form MK-3 of phenytoin sodium.
The inorganic acid used in step (a) is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, preferably the acid used is hydrochloric acid.
In another embodiment, solvent used in step a) is selected from methanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroForm, acetonitrile, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethylether, dimethylether, diisopropylether, diphenylether, MTBE, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene,m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethyl acetamide (DMA), dimethylFormamide (DMF), or mixture thereof .
In another embodiment suitable base is selected from but not limited to inorganic or oraganic base. Inorganic base is selected from but not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert. butoxide, potassium acetate, sodium acetate, cesium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, sodium methoxide, potassium methoxide, and the like. Organic base may be selected from but not limited to pyridine, dimethyl amine, triethyl amine, ?,?-diisopropylethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, ?,?-dimethyl piperazine, N-methyl piperidine most preferably sodium hydroxide
In another embodiment suitable tempreture at which the stering is done is 25-30oC.
In another ebodient colling temperature for the precipitation of dihydrate form MK-3 at step e) is 0-5oC.
In another embodiment the present invention provides a process for the preparation of dihydrate form MK-3 of phenytoin sodium, comprising,
a) adding compound of Formula I in a mixture of water and hydrochloric acid ;
b) adding organic solvent to mixture of step a);
c) treating the mixture of step b) with suitable base to maintain the pH in the range of 9.5 to 9.9;
d) stering the reaction mixture of step c) at suitable tempreture for a period of more than 24-29 hour ; and
e) cooling the suspension obtained in step d) to get the dihydrate form MK-3 of phenytoin sodium.
In another embodiment the present invention provides a process for the preparation of form MK-3 of of phenytoin sodium, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) stirring the reaction mass at ambient temperature for about 10-15 hrs; and
c) isolating the crystalline form MK-3 of phenytoin sodium.
In another embodiment, the present invention provides amorphous form of phenytoin sodium.
In other embodiment, the present invention provides an amorphous form of phenytoin sodium, characterized by its XRD pattern as depicted in Fig-5.
In another embodiment, the present invention provides stable amorphous form of phenytoin sodium and their preparation method.
In another embodiment, the present invention provides a process for preparation of amorphous form of phenytoin sodium.
In another embodiment, the present invention provides a process for the preparation of an amorphous form of phenytoin sodium, comprising the steps of:
a) providing a solution of compound of phenytoin sodium I in one or more solvent;
b) lyophilizing the solution as obtained in step a); and
c) isolating the amorphous form of phenytoin sodium
In another embodiment, the present invention provides a process for the preparation of an amorphous form of phenytoin sodium, comprising the steps of:
a) milling/grinding compound of Formula I under suitable milling conditions; and
b) isolating the amorphous form of compound of phenytoin sodium.
In another embodiment, the present invention provides a process for the preparation of an amorphous form of phenytoin sodium, comprising the steps of:
a) providing a solution of compound of Formula I in one or more suitable solvent; and
b) isolating the amorphous form of phenytoin sodium.
In another embodiment of the present invention, the crystallization of the compound of Formula (I) is done by different crystallization method like cooling crystallization, evaporative crystallization, fractional crystallization and precipitation.
In another embodiment, an amorphous solid is often prepared by cooling its molten state apidly.
In another embodiment, amorphous solids can also be produced by additives that interfere with the ability of the primary constituent to crystallize.
In another embodiment, the present invention provides a stable amorphous form includes amorphous form of compound of Formula I that after exposure to 40°C /75% RH for a period of six months or 25°C /60% RH, for a period of at least 12 months contains less than about 0.5% (wt/wt) total impurities and doesn't change to any other solid Forms.
In another embodiment, the compound of Formula I used as input (starting material) for the preparation of any of the solid form is either a crude mass, reaction mixture, an amorphous form, one or more crystalline form or mixture thereof in any proportion.
In another embodiment, the present invention provides the chemical purity of any of the crystalline form of the compound of Formula I as measured by high pressure liquid chromatography is greater than about 90%, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9%.
In another embodiment, the present invention provides any of the crystalline form of the compound of phenytoin sodium is about 99.9% pure as measured by high pressure liquid chromatography.
In another embodiment, the present invention provides, any of the crystalline form of of phenytoin sodium has less than about 2.0%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, or about 0.009% of any one impurity introduced, obtained or produced as a result of the chemical synthesis or degradation, as measured by high pressure liquid chromatography.
In another embodiment, the present invention provides the any of the crystalline form of phenytoin sodium comprises at least about 90% or more pure crystalline form, about 95% or more pure crystalline form, about 98% or more pure crystalline form, about 99% or more pure crystalline form or about 99.9% or more pure crystalline form.
In another embodiment, the crystalline form of the compound of phenytoin sodium of the present invention substantially pure.
In another embodiment, the crystalline form of the compound of phenytoin sodium of the present invention comprises mixture of one or more other crystalline form or amorphous form is not more than about 20%, about 10%, about 5.0%, about 2%, about 1.0%, about 0.5%, about 0.1% or not detectable based on the total volume or weight of the crystalline form.
In another embodiment, the crystalline form of the compound of phenytoin sodium of the present invention comprises one or more other crystalline form less than about 15%, preferably about 10% or less, more preferably about 5.0% or less, most preferably about 2% or less based on the total volume or weight of the crystalline form.
In another embodiment, the crystalline form of the compound of phenytoin sodium of the present invention comprises one or more other crystalline forms less than about 5%, preferably 1.0% or less, more preferably about 0.5% or less, most preferably not detectable based on the total volume or weight of the crystalline form.
In another embodiment, the amorphous form of phenytoin sodium of the present invention is substantially free from any other impurity.
In another embodiment, the amorphous form of the compound of phenytoin sodium comprises not more than about 10%, about 7%, about 5%, about 3%, about 1% or 0.5% of one or more crystalline Form.
In another embodiment, the present invention provides a stable amorphous form of phenytoin sodium of Formula I.
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 crystalline form MK-1 of phenytoin sodium of Formula 1.
Compound of Formula I (2.74 g) and dichloromethane (25 mL) was charged in a round bottom flask (50mL) and was added 2 mL water at 40-45 °C. Reaction mixture was refluxed at 40°C for 20 hours and reaction was cooled at room temperature to obtain the wet material. Wet material was dried in air tray dryer (ATD) at room temperature to get loss on drying (LOD) 11 to 14% w/w. Further dried at 40°C and 10% RH for 6-8hrs to obtain crystals of form MK-1 of Formula I (yield: 90%, 2.6 g), LOD less than 1% w/w.
Example 2: Preparation of crystalline form MK-2 of phenytoin sodium of Formula 1.
Compound of Formula I (2.74 g) and dimethylformamide (25 mL) was charged in a round bottom flask (50mL) and added 2 mL water at 40-45 °C. reaction mixture was refluxed at 40oC for 20 hours and cooled slowly to room temperature and the obtained wet material was unloaded and dried in air tray dryer (ATD) at room temperature to get LOD 11 to 14% w/w. Further dried at 40°C and 40% RH for 4-6hrs to get crystalline form MK-2 (yield: 90%, 2.8g), LOD 6 to 7% w/w, purity 99.9% by HPLC.
Example 3: Preparation of crystalline form MK-2 of phenytoin sodium of Formula 1.
Compound of Formula I (3.1. g) and dichloromethane (25 mL) was charged in a round bottom flask (50mL) and added 2 mL water at 40-45 °C. reaction mixture was refluxed at 40oC for 20 hours and cooled slowly to room temperature and the obtained wet material was unloaded and dried in Air tray dryer (ATD) and was further dried at 40°C and 40% RH for 4-6hrs to get crystalline form MK-2 (yield: 90%, 2.8g) , LOD 6 to 7% w/w, purity 99.9% by HPLC.
Example 4 : Preparation of crystalline form MK-3 of phenytoin sodium of Formula 1.
Compound of Formula I (2.74 g) and Methyl isobutyl ketone (30 mL) was charged in a round bottom flask (50mL) was added 2 mL water at 40-45 °C. Refluxed the reaction mixture at 40oC for 20hrs. Reaction mixture was slowly cooled the at room temperature to obtain wet material.Wet material was dried in Air tray dryer (ATD) to get crystalline form MK-3 of compound of Formula I. (yield: 91%, 2.9 g), LOD 11 to 14% w/w purity, 99.9% by HPLC.
Example 5 : Preparation of crystalline form MK-3 of phenytoin sodium of Formula 1.
Compound of Formula I (3.2 g) and dichloromethane (30 mL) was charged in a round bottom flask (50mL) was added 3.5 ml water at 40-45 °C. Refluxed the reaction mixture at 40oC for 20hrs. Reaction mixture was slowly cooled the at room temperature to obtain wet material.Wet material was dried in Air tray dryer (ATD) to get crystalline form MK-3 of compound of Formula I. (yield: 91%, 2.9 g), LOD 11 to14% w/w, purity 99.9% by HPLC.
Example 6 : Preparation of amorphous form of phenytoin sodium of Formula 1.
Compound of Formula I (1.0gm) was dissolved in acetone (50 mL) at about 25°C and stirred at about 60oC to get the reaction mixture for 4-6hrs. Lyophilized the solution so obtained to get title compound (yield: 95 %, 0.95gm), purity 99.9% by HPLC.
Example 7: Preparation of amorphous form of phenytoin sodium of Formula 1.
Compound of Formula I (10 gm) was dissolved in water (150 mL), stirred for 15 minutes at room temperature. The solution was filtered on hyflo bed, followed by washing with water and distilled off the water under vacuum at about 55 to 60°C to obtain a solid mass. Dried the solid mass at about 90 to 100oC for 5hrs to obtain an amorphous Form (yield 90%, 9.0gm), purity 99.9% by HPLC.
, Claims:WE CLAIM:
1. A crystalline form of phenytoin sodium of Formula 1, wherein the crystalline form is selected from MK-1, MK-2, and MK-3,
a) Crystalline form MK-1 characterized by X-ray powder diffraction pattern comprising one or more peaks at about 5.80, 6.22, 6.57, 7.09, 10.58, 11.44, 12.10, 12.34, 13.03, 15.72, 16.19, 17.13, 17.64, 18.08, 18.90, 19.47, 21.14, 22.67, 23.01, 24.38, 24.87, 25.56, 26.19, 26.50, 27.12, 28.01, 29.15, 29.99, 31.04, 31.94, 32.88, 34.13, 35.12, 36.46, and 38.36 ± 0.2°? and/or differential scanning calorimetry having endotherm peak at about 370 °C;
b) Crystalline form MK-2 characterized by X-ray powder diffraction pattern comprising one or more peaks at about 6.22, 11.15, 12.17, 13.29, 15.13, 15.72, 16.33, 17.17, 17.46, 18.48, 19.41, 20.57, 21.59, 22.33, 23.12, 23.80, 24.66, 26.03, 26.68, 27.51, 28.07, 28.90, 29.63, 30.74, 31.66, 33.61, 34.71, 35.34, 36.34, 37.21 and 38.98 ± 0.2°? and/or differential scanning calorimetry having endotherm peak at peaks at about 92 °C and 371 °C; and
c) Crystalline form MK-3 characterized by X-ray powder diffraction pattern comprising one or more peaks at about 5.34, 10.55, 11.21, 12.54, 15.06, 15.64, 16.13, 16.60, 17.20, 17.43, 18.40, 19.01, 19.46, 19.69, 20.09, 21.08, 21.46, 22.39, 22.81, 23.20, 23.51, 24.25, 25.13, 26.39, 26.99, 27.54, 27.97, 28.70, 29.10, 29.64, 30.32, 30.77, 31.35, 31.77, 32.27, 32.03, 33.37, 34.06, 34.59, 35.02, 35.85, 37.11, 38.35, 38.85 ± 0.2 and/or differential scanning calorimetry having endotherm peaks at about 81 °C, 91 °C, 115°C and 370 °C.
2. A process for the preparation of form MK-1 of phenytoin sodium of Formula 1, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) heating the reaction mixture at about 30-50 °C for about 15-25 hrs;
c) cooling the reaction mixture to get wet mass;
d) drying the wet mass at 30-40°C and 10-20% RH for 6-8hrs to get crystalline form MK-1 of Formula I.
3. A process for the preparation of form MK-2 of phenytoin sodium of Formula 1, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) heating the reaction mixture at about 30-50 ° C for about 15-25 hrs;
c) cooling the reaction mixture to get wet mass;
d) drying the wet mass at 30-40°C and 35-40% RH for 4-6hrs to get crystalline form MK-2 of Formula I.
4. A process for the preparation of dihydrate form MK-3 of phenytoin sodium of Formula 1, comprising,
a) adding compound of Formula I in one or more suitable solvent;
b) heating the reaction mixture at about 30-50 °C for about 15-25 hrs;
c) cooling the reaction mixture to get wet mass;
d) drying the wet mass to get crystalline form MK-3 of Formula I.
5. The process as claimed in the preceeding claims, wherein said solvent is selected from the group comprising of dichloromethane, dimethylformamide, dimethyl sulfoxide, methyl isobutyl ketone, methyl ethyl ketone, methyl tert-butyl ether, dimethylacetamide, water or mixture thereof.
6. The process as claimed in claim 4, wherein said inorganic acid is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.
7. The process as claimed in claim 4, wherein said base is selected from the group comprising of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert butoxide, potassium hydroxide and sodium hydroxide
8. A process for the preparation of amorphous form of phenytoin sodium of Formula 1, comprising the steps of:
a) providing a solution of compound of Formula I in one or more solvent;
b) lyophilizing the solution as obtained in step a); and
c) isolating the amorphous form of phenytoin sodium of Formula 1.
9. The process as claimed in any of the preceding claims having purity more than 99%.
10. The process as claimed in any of the preceding claims wherin, phenytoin sodium prepared is substantially free from any other impurity.

Dated this, 05th day of Dec, 2023 For Mankind Pharma Ltd

Dr. Anil Kumar
Chief Scientific Officer