Specification
"NOVEL POLYMORPHS OF DOLUTEGRAVTR AND SALTS THEREOF" PRIORITY:
This application claims the benefit under Indian Provisional Application No. 4334/CHE/2015 filed on Aug 19, 2015, the content of which is incorporated by reference herein.
FIELD OF THE INVENTION:
The present invention relates to novel polymorphs of dolutegravir and salts thereof, process for their preparation and pharmaceutica] composition comprising the same.
BACKGROUND OF THE INVENTION:
Dolutegravir is chemically known as (4R,12aS)-9-{[(2,4-difluorophenyl)methyl] carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[r,2":4,5]pyrazino [2,1-£>][!,3]oxazin-7-olate and represented by the following structural formula;
Dolutegravir (DTG, GSK1349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-] infection. Sodium sah of dolutegravir was recently approved by FDA and marketed under the brand narrte of TIVICAY by ViiV Healthcare and manufactured by GlaxoSmithKline. TIV1CAY is administered orally as a tablet of 50 mg strength.
Tivicay is a human immunodeficiency virus type 1 (HIV-1) integrase Strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Dolutegravir and process for its preparation were first described in U.S. Patent No. 8129385. However this patent does not discloses any characteristic details of dolutegravir or its salts such as sodium.
WO2010068253 publication discloses anhydrous and monohydrate crystalline form of dolutegravir sodium characterized by PXRD and 1R spectrum. Anhydrous dolutegravir sodium obtained by treating die Solution of dolutegravir in ethanol with aqueous sodium
hydroxide at 80°C; whereas the monohydrate form was obtained by dissolving the anhydrous dolutegravir sodium in THF-water followed by txeatment with aqueous sodium hydroxide. This publication further discloses the crystalline form of dolutegravir free acid along with its PXRD.
WO 2013038407 publication discloses amorphous form of dolutegravir sodium, process for its preparation and pharmaceutical composition comprising the same.
IP.com Journal, ID No: IPCOM000238311D discloses the crystalline form of dolutegravir sodium characterized by PXRD, which is obtained by treating dolutegravir in tetrahydrofuran with aqueous sodium hydroxide at reflux temperature.
WO2015092752 publication discloses crystalline Form-Ml of dolutegravir sodium and process for its preparation.
WO2015118460 publication discloses crystalline Form-M2, Form-M3 and Form-M4 of dolutegravir sodium and process for their preparation.
WO2015138933 publication discloses crystalline Form-11, Form-III, Form-IV, Form-V, Form-VI, Form-VII, Form-VIlI, Form-IX, Form-X and Form-Xl of dolutegravir sodium, process for their preparation, pharmaceutical composition comprising them and uses thereof.
WO2015139591 publication discloses Polymorphie Form-A, Form-B, Form-C, Form-D and Form-E of dolutegravir sodium and pharmaceutical composition comprising them.
■ W02GI6016279 publication discloses crystalline Form-HxA, Form-HylB and Form- • SETOH;H20 of dolutegravir sodium, process for their preparation and pharmaceutical composition comprising them.
WO2016102078 publication discloses crystalline form of dolutegravir sodium 1,2-propylene glycol solvate, process for its preparation and pharmaceutical composition comprising the same.
Our co-pending IN application number 3105/CHE/2015 discloses crystalline form of dolutegravir sodium designated as Form-Ll, Form-L2, Form-L3, Form-L4, Form-L5, Form-L6, Forn>L7 and Form-L8, amorphous form of dolutegravir, solid dispersion of dolutegravir sodium with one or more pharmaceutically acceptable excipient and crystalline benzyltrimethyl ammonium salt of dolutegravir.
Polymorphism is the oecurrence of different crystalline forms of a single Compound and it is a property of some Compounds and complexes. Thus, polymorphs are distinet 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 Polymorphie 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. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable . solubility profiles. It is desirable to investigate all solid State forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolutäon and flow properties of each polymorphic form.
Dolutegravir is one of the important drugs available in the market for the treatment of human immunodeficiency virus (HIV)-I infection. Hence it"s important to discover new Polymorphie forms of dolutegravir and its salt, which may provide a new opportunity to improve the Performance characteristics of a pharmaceutical produet. Hence the main objeet of the present invention is to provide novel polymorphic forms of dolutegravir and salts thereof, especially sodium.
SUMMARY OF THE INVENTION:
The present invention provides novel polymorphic forms of dolutegravir and salts thereof, especially sodium, process for their preparation and pharmaceutical compositions comprising one or more of the novel polymorphic forms of dolutegravir and its salts. The polymorphic forms of dolutegravir sodium of the present invention have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability"to dehydration, and stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.
In one embodiment, the present invention provides novel polymorphic forms of dolutegravir sodium; which are designated herein as dolutegravir sodium Form-L9, dolutegravir sodium Form-LlO, dolutegravir sodium Form-Lll and dolutegravir sodium Form-L12.
In another embodiment the present invention provides a process for the preparation of novel polymorphic forms of dolutegravir sodium Form-L9, Form-LlO, Form-LIL and Form-Ll2 and other crystalline forms of dolutegravir sodium.
■ In another embodiment, the present invention provides novel solvates of dolutegravir such as morpholine solvate and 1 -amino-2-propanol solvate.
In another embodiment, the present invention provides Polymorphie forms of morpholine and l-amino-2-propanol solvate of dolutegravir as well as process for their preparation.
In another embodiment, the present invention provides a pharmaceutical composition comprising the novel Polymorphie forms of dolutegravir and salts thereof described above and at least orte pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS:
The accompanying drawings, which are incorporated in and constitute a part of this speeification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
Figure 1 is die characteristic powder X-ray diffraction (XRD) pattem of dolutegravir sodium Form-L9.
Figure 2 is the characteristic differential scanning calorimetric (DSC) thermogram of dolutegravir sodium Form-L9.
Figure 3 is die characteristic üiermo gravimetric analysis (TGA) of dolutegravir sodium Form-L9.
Figure 4 is the characteristic powder X-ray diffraction (XRD) pattern of dolutegravir sodium Form-LlO.
Figure 5- is the characteristic differential scanning calorimetric (DSC) thermogram 50C and stiired For 1.5 mins. Methyl tertiary butyl ether (500 ml) was added to the reaction mass at 25-35°C and stirred for an hour. The solid obtained was filtered, washed with methyl tertiary butyl ether and suck dried to get the title Compound. Yield: 12.9 g The XRPD is set forth in Figure 16; The DSC is set forth in Figure 17; The TGA is set forth in Figure 18.
EXAMPLE-9: Preparation of crystalline form of dolutegravir I-amino-2-propanol solvate:
Dolutegravir (3 g) was dissolved in N-methyl-2-pyrollidone (15 ml) at 25-35°C. To this Solution, l-amino-2-propanol (l.l ml) was added and the obtained Suspension was stirred for 10 mins at 25-35°C DM water (30 ml) was added to the reaction mass at 25-35°C and stirred for 1.5 hr. The solid obtained was filtered, washed with water and dried at 50-55°C under vacuum for 4 hrs to get the title Compound. Yield: 2.4 g
EXAMPLE-13: Thermal stability of dolutegravir sodium Form-L9
Dolutegravir sodium Form-L9 was kept in an oven at 60°C and 100°C for 24 hxs. The samples were analyzed by PXRD and DSC and observed that same Polymorphie nature retained after die studies. Table-2 shows Polymorphie nature of the dolutegravir sodium F7orm-L9 at 60°C and 100°C for 24 hrs by PXRD and DSC.
The analytical data provided in Table-2 suggest that the dolutegravir sodium Form-L9 is stable even at elevated temperatures. Overlaid PXRD pattern and DSC thermogram of dolutegravir sodium Form-L9 subjeeted to thermal stress study at 60°C and 100°C for 24 hours is represented as Figure-24a and Figure-24b respectively.
EXAMPLE-14: Hygroscopic study of dolutegravir sodium Form-L9
Dolutegravir sodium Form-L9 was exposed to 85% relative humidity at room temperature for one week and was analyzed by PXRD at different time intervals such as 24 hours, 48 hours, 72 hours and 168 hours. The samples were analyzed by PXRD and DSC and observed that same Polymorphie nature retained after die studies. The overlaid PXRD pattern of dolutegravir sodium Form-L9 subjeeted to hygroscopic study at 85% RH is represented as Figure-25.
EXAMPLE-15: Solubility studies of dolutegravir sodium Form L9:
Aqueous solubility was performed for dolutegravir sodium anhydrous form (prepared aecording to Ex-11 of WO2010/068253) and Form-L9 of the present invention at
different pH buffers and solubility profile was found to be comparable. The results of aqueous solubility profile after 24 hours by UV quantification was shown in the following Table-3:
EXAMPLE-16:
Composition for che preparation of dolutegravir sodium tablets with dolutegravir .sodium Form L9.
Tablets are prepared by using direct compression process and the dissolution of dolutegravir sodium tablets are performed in 0.0IM pH-6.8 Phosphate buffer + 0.25 % Sodium lauryl sulfate, 900 mL, Paddle, 50 rpm and the results are as follows:
EXAMPLE 17: Intrinsic dissolution study of dolutegravir sodium Form L9.
Dissolution experiments were carried out in ELECTROLAB-8 dissolution apparatus equipped with an ETC-112 temperature Controller. An intrinsic dissolution apparatus
(Woods apparatus) was used. Samples were compressed at 2.0 metric tons for 1 min in KBr hydraulic press, giving a sample surface of 0.50 cm". A dissolution medium consisting of 0.0IM pH-6.8 Phosphate buffer + 0.25 % Sodium lauryl Sulfate, 900 mJL, Paddle, 50 rpm, was used for each experiment. The results of dissolution studies were shown in Table-4:
While the invention has been described with reference to above detailed description and the preferred examples, it is not intended to be limited thereto. Therefore the above description should not be constnied as limiting, but merely as exemplifications of preferred embodiments. For example, the functiotis described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.