The present invention relates to a cocrystal of gefitinib with
improved bioavailability. More particularly, it relates to a cocrystal of gefitinib with a coformer, urea wherein the cocrystal shows better equilibrium solubility and intrinsic dissolution rate of all multicomponent forms showing improvement in solubility and thus enhanced bioavailability compared to pure drug.
BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in
understanding the present invention. It is not an admission that any of the
information provided herein is prior art or relevant to the presently claimed
invention, or that any publication specifically or implicitly referenced is prior art.
[0003] The transmembrane glycoprotein epidermal growth factor
receptors (EGFR) is involved in the regulation of cellular differentiation and proliferation. The EGFR is overexpressed in several solid tumours such as lung, colorectal and brain tumour types. Due to involvement of EGFR in tumour cell proliferation, invasion, angiogenesis and metastasis, EGFR inhibitors has become as promising anticancer drugs.
[0004] Gefitinib is a low-molecular weight compound having significant
inhibition of tumour cell proliferation and angiogenesis as well as the induction of apoptosis by virtue of their ability to inhibit EGFR. Gefitinib is a water insoluble dibasic compound with pKa values of 5.28 and 7.17, which shows a pH-dependent solubility in gastrointestinal fluids. Gefitinib has an extremely low aqueous solubility and its oral absorption is limited by its dissolution. Therefore, there is need of increasing the bioavailability of the drug gefitinib by improving solubility and dissolution.
[0005] Co-crystallization is a viable supramolecular synthetic method to
bring multiple molecular components into a crystal lattice, and crystal engineer the molecular solid to get improved physicochemical properties when the solubility of active pharmaceutical ingredient (API) is compromised.

[0006] A pharmaceutical cocrystal is defined as a multicomponent
molecular complex comprising a solid API and a coformer usually which is safe for human consumption that interact through noncovalent interactions in a defined stoichiometric ratio without compromising the structural integrity but improving the solubility.
[0007] WO2015170345 Al relates to pharmaceutical cocrystals of
gefitinib with cocrystal former selected from aliphatic dicarboxylic acid and
aromatic di and tricarboxylic acids which exhibit better solubility, dissolution rate
hence enhanced bioavailability as compared to the pure drug.
[0008] CN112142679 relates to a gefitinib and vanillic acid co-crystal
methanol solvate for use in preparation of a medicament for treating lung cancer.
[0009] However, inventions heretofore known suffer from disadvantages
including that the therapeutic efficacy of gefitinib is limited due to its poor solubility under physiological pH conditions, resulting in poor and variable bioavailability of gefitinib. Also, none of the cited prior arts showed the use of a coformer which is neither acidic or alkaline which is neutral in nature selected from the compounds including urea. The urea is neither acidic or alkaline, highly soluble in water, and is practically non-toxic.
[0010] Accordingly, there is a need for an approach that resolves the
problems of the state of the art by providing improved solid forms of gefitinib having better solubility, dissolution rate and hence enhanced bioavailability as compared to parent drug. Therefore, there is need to provide a cocrystal of gefitinib with urea as coformer which exhibit better solubility, dissolution rate and hence enhanced bioavailability as compared to parent drug. [0011] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
OBJECTS OF THE INVENTION
[0012] Some of the objects of the present disclosure, which at least one
embodiment herein satisfies are as listed herein below.

[0013] The main object of the present invention is to provide a cocrystal
of gefitinib with urea as coformer which shows improved equilibrium solubility
and intrinsic dissolution rate of all multicomponent forms showing improvement
in solubility and thus enhanced bioavailability compared to pure drug.
[0014] Another object of the present invention is to provide a
pharmaceutical composition comprising of gefitinib cocrystal with coformer urea
and pharmaceutically acceptable excipients.
[0015] Another object of the present invention is to provide a process for
preparation of gefitinib cocrystal with coformer urea.
[0016] Yet another object of the present invention is to determine a crystal
structure of a pharmaceutical cocrystal of gefitinib.
[0017] Still another object of the present invention is to provide a
cocrystal which is evaluated for an equilibrium solubility, intrinsic dissolution
rate, pharmacodynamic and pharmacokinetic parameters.
SUMMARY OF THE INVENTION
[0018] The present invention relates to a cocrystal of gefitinib having
enhanced bioavailability compared to pure drug.
[0019] An aspect of the present disclosure pertains to a cocrystal of
gefitinib with a coformer, urea which shows improved equilibrium solubility and
intrinsic dissolution rate of all multicomponent forms showing improvement in
solubility and thus enhanced bioavailability compared to pure drug gefitinib.
[0020] An aspect of the present disclosure relates to a co-crystal
comprising of gefitinib having a chemical structure,

and a coformer, urea.

[0021] Another aspect of the present disclosure pertains to a cocrystal of
gefitinib with a coformer, urea having a stoichiometric ratio of the urea to
gefitinib is 1:1.
[0022] Another aspect of the present disclosure pertains to a cocrystal of
gefitinib with a coformer, urea characterized by endothermic peak at 193.77,
133.84, 111 .TC for gefitinib, urea and cocrystal of gefitinib respectively.
[0023] Another aspect of the present disclosure pertains to a cocrystal of
gefitinib with a coformer, urea characterized by PXRD pattern having peaks at
2.theta. angles of 22.19, 24.01, 24.31, 29.26.
[0024] Another aspect of the present disclosure pertains to a
pharmaceutical composition comprising of cocrystal of gefitinib with a coformer,
urea and one or more pharmaceutically acceptable carriers.
[0025] Another aspect of the present disclosure pertains to a process for
preparation of a cocrystal of gefitinib with a coformer, urea, wherein the process
comprises the step of:
(a) grinding the gefitinib and urea with the addition of organic solvent as co-crystallizing solvent at constant intervals to obtain a moist product;
(b) drying the moist product to obtain the cocrystal of gefitinib and urea. [0026] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures.
BRIEF DESCRIPTION OF THE FIGURES
[0027] Figure 1 depicts the PXRD of gefitinib, urea and GEF-Urea cocrystal.
[0028] Figure 2 depicts the DSC chromatogram.
[0029] Figure 3 depicts the FT-IR spectrum.
[0030] Figure 4 depicts the simulated powder XRD pattern of GEF-Urea.
[0031] Figure 5 shows the solubility profile of GEF and GEF-Urea.
[0032] Figure 6 depicts the dissolution profile of GEF and GEF-Urea.
[0033] Figure 7 shows plasma concentration profile of Gefitinib and GEF-
Urea.

DETAILED DESCRIPTION OF THE INVENTION
[0034] The following is a detailed description of embodiments of the
disclosure depicted in the accompanying drawings. The embodiments are in such
detail as to clearly communicate the disclosure. However, the amount of detail
offered is not intended to limit the anticipated variations of embodiments; on the
contrary, the intention is to cover all modifications, equivalents, and alternatives
falling within the scope of the present disclosure as defined by the appended
claims.
[0035] Unless the context requires otherwise, throughout the specification
which follow, the word "comprise" and variations thereof, such as, "comprises"
and "comprising" are to be construed in an open, inclusive sense that is as
"including, but not limited to."
[0036] Reference throughout this specification to "one embodiment" or "an
embodiment" means that a particular feature, structure or characteristic described
in connection with the embodiment is included in at least one embodiment. Thus,
the appearances of the phrases "in one embodiment" or "in an embodiment" in
various places throughout this specification are not necessarily all referring to the
same embodiment. Furthermore, the particular features, structures, or
characteristics may be combined in any suitable manner in one or more
embodiments.
[0037] As used in this specification and the appended claims, the singular
forms "a," "an," and "the" include plural referents unless the content clearly
dictates otherwise. It should also be noted that the term "or" is generally
employed in its sense including "and/or" unless the content clearly dictates
otherwise.
[0038] In the following description, numerous specific details are set forth in
order to provide a thorough understanding of embodiments of the present
invention. It will be apparent to one skilled in the art that embodiments of the
present invention may be practiced without some of these specific details.
[0039] Embodiments of the present disclosure relates to a cocrystal of
gefitinib with coformer urea which shows improved equilibrium solubility and

intrinsic dissolution rate of all multicomponent forms showing improvement in
solubility and thus enhanced bioavailability compared to pure drug.
[0040] Gefitinib is an anticancer drug having a chemical structure as given
below.

[0041] In an embodiment, the present invention provides a cocrystal with enhanced solubility and dissolution, said pharmaceutical cocrystals comprising gefitinib and a coformer, urea in stoichiometric ratio of 1:1.
[0042] In an embodiment, the present invention provides a cocrystal of gefitinib with urea wherein cocrystal forms of gefitinib are selected on the basis of coformer structural property relationship through the understanding of complementary functionality based on synthon approach.
[0043] In accordance with an embodiment of the disclosure, the present invention provides a cocrystal of gefitinib which are characterized using various thermo-analytical techniques using various thermo-analytical techniques including differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and Powder X-ray diffraction (PXRD) is provided which corroborated the formation of the pharmaceutical cocrystals of gefitinib.
[0044] In accordance with another embodiment of the disclosure, the present invention provides a cocrystal of gefitinib which is characterized by endothermic peak at 193.77, 133.84, 111.TC for gefitinib, urea and the pharmaceutical cocrystals of gefitinib respectively. The endothermic peak obtained is in between the melting peaks of the drug and the counter molecule urea which suggests the formation of a new phase which is the cocrystal further confirmed by using other analytical techniques.

[0045] In accordance with some other embodiment of the disclosure, a cocrystal of gefitinib is characterized by peaks at 22.19, 24.01, 24.31, 29.26 in the powder X-ray diffraction (PXRD) pattern. While PXRD pattern of GEF reveals diffraction peak at 20 = 7.08, 15.82, 17.66, 18.64, 19.32, 20.65, 23.9, 24.78, 26.35. The PXRD graph of urea showed characteristic peaks at 29 = 13.07, 25.93 & 39.79. The prominent peaks of GEF at 20 = 11.22, 12.29, 14.19, 17.66, 18.64, 23.9 disappeared in GEF-urea cocrystal.
[0046] The appearance of new peaks in the PXRD pattern of the pharmaceutical cocrystal of gefitinib in comparison to individual components showed that new crystalline entity has been formed. The crystal structure is determined by using Material Studio software (Accelrys) from PXRD data. The pharmaceutical cocrystal showed triclinic symmetry with space group PI. The pharmaceutical cocrystal forms a heterosynthon involving morpholine oxygen and quinazolinone nitrogen of gefitinib.
[0047] In accordance with some other embodiment of the disclosure, a cocrystal of gefitinib is characterized by Fourier transform infrared spectroscopy (FT-IR) analysis of cocrystal that showed shift in amine stretching (to 3446 cm"1) and bending (to 1620 cm"1) vibrations as compared to pure drugs (-N-H stretch at 3396 cm"1 and -N-H bend at 1622 cm"1) indicating -N-H is participating in cocrystal formation while -C=0 showed no shift in peak position. [0048] In accordance with some other embodiment of the disclosure, the present invention provides a cocrystal of gefitinib which shows an improved equilibrium solubility and intrinsic dissolution rate of all multicomponent forms which shows improvement in solubility compared with pure drug gefitinib. The pharmacokinetic parameters showed that there is 7.8 times increase in bioavailability of the pharmaceutical cocrystal of gefitinib than the pure drug gefitinib.
[0049] In accordance with some other embodiment of the disclosure, the present invention provides a pharmaceutical cocrystal of gefitinib is prepared by various co-crystallization techniques like solvent drop grinding method.

[0050] In accordance with some other embodiment of the disclosure, a process for preparation of cocrystal of gefitinib with enhanced solubility and dissolution, said process comprising the steps of:
(a) grinding the gefitinib and urea with the addition of organic solvent as co-crystallizing solvent at constant intervals to obtain a moist product; and
(b) drying the moist product to obtain the cocrystal of gefitinib and urea. [0051] In accordance with some other embodiment of the disclosure, the process for preparation of pharmaceutical cocrystal with enhanced solubility and dissolution wherein the solvent is selected from but not limited to ethanol, methanol, Dimethyl formamide (DMF), Dimethyl sulphoxide (DMSO).
[0052] In accordance with some other embodiment of the disclosure, a process for preparation of cocrystal of gefitinib with enhanced solubility and dissolution, said process comprising the steps of:
(a) grinding the gefitinib and urea with the addition of ethanol as co-crystallizing solvent at constant intervals to obtain a moist product; and
(b) drying the moist product to obtain the cocrystal of gefitinib and urea. [0053] In accordance with some other embodiment of the disclosure, the invention further discloses a pharmaceutical composition comprising therapeutically effective amount of a cocrystal of gefitinib and a coformer, urea with one or more pharmaceutically acceptable carriers.
[0054] In another embodiment of the present invention, the one or more
pharmaceutically acceptable carriers is selected from binders, diluents, lubricants,
disintegrants, emulsifiers, glidants, surface-active agents, thickeners, suspending
agents, flavoring agents, colorants and combinations thereof.
[0055] In accordance with some other embodiment of the disclosure, the
invention further discloses use of the "composition of the invention" in preparing
the medicament intended to treat cancer.
[0056] The invention is further ascribed below by reference of the following,
non-limiting examples:
[0057] Example 1: Preparation of pharmaceutical cocrystals of gefitinib

Solvent drop grinding method was exploited to prepare cocrystals of gefitinib. Gefitinib and urea were taken in the ratio of 1:1 and grounded for around 1 hour with drop wise addition of ethanol as cocrystallising solvent. The prepared cocrystal is allowed to dry and stored under controlled conditions in a desiccator. [0058] Example 2: Characterization of cocrystal of gefitinib The cocrystals of gefitinib with urea is characterized by using various analytical tools such as differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and Powder X-ray diffraction (PXRD) techniques. The characterization data for cocrystals is given below.
2.1 Powder X-ray Diffraction (PXRD)
The PXRD pattern of gefitinib reveals diffraction peak at 20 = 7.08, 15.82, 17.66, 18.64, 19.32, 20.65, 23.9, 24.78, 26.35. The PXRD graph of urea showed characteristic peaks at 29 = 13.07, 25.93 & 39.79. In case of gefitinib-urea cocrystal new peaks appeared at 22.19, 24.01, 24.31, 29.26, while prominent peaks of GEF at 20 = 11.22, 12.29, 14.19, 17.66, 18.64, 23.9 disappeared. The distinct pattern of cocrystal as compared to the parent compound confirms the existence of cocrystal. Figure 1 depicts the PXRD of gefitinib, urea and gefitinib-urea cocrystal.
2.2 Differential scanning calorimetry (DSC)
Melting point of gefitinib and urea is 193.77 °C and 133.84°C respectively. The pharmaceutical cocrystals of gefitinib showed a single melting endothermic peak at 177.7 °C. Figure 2 depicts the DSC chromatogram.
2.3 Fourier transform infrared spectroscopy (FT-IR)
The IR spectra of gefitinib and cocrystal of gefitinib are collected using IR spectrometer (Perking Elmer, England). The spectrum of gefitinib shows the -N-H stretch at 3396 cm"1 and a doublet for N-H in urea at 3418 & 3254 cm"1. The -N-H peak shifted to 3446 cm"1 in the cocrystal, this suggests that the -NH is involved in H-bond formation in cocrystal. The bending structures of -NH also showed minor changes from 1622 cm"1 to 1620 cm"1 suggesting involvement in cocrystal formation. The -C=0 stretch was observed at 1685cm"1. The position of this remains unchanged in the cocrystal indicating that this functional group is not

involved in the cocrystal formation. Besides this, the -C-F stretch also showed no change in its position indicating chloroflouro benzyl moiety is not involved in H bonding of cocrystal. Figure 3 depicts the FT-IR spectrum. [0059] Example 3: Crystal structure determination
Material Studio® software by BIOVIA system was exploited to predict crystal structure of cocrystal of GEF using their PXRD patterns. Steps involved in the structure determination are as follow- Indexing, Pawley refinement, Structure solution and Retvield refinement. In indexing, peak positioning in the experimental PXRD pattern was utilized to obtain appropriate crystal lattice using X-cell module. Suitable cell was generated from the unit cell having the highest figure of merits. Further optimisation of this generated unit cell was done in next step i.e. pawley refinement. Additionally production of an appropriate cell was carried out by searching for the space group. The structure of gefitinib and coformer were sketched and optimised geometrically in DMOL3 module. Then these structures after optimisation were imported into the created unit cell and the Powder solve module, using ten simulated annealing cycles each having 2100000 iterations, was exploited to determine the atomic alignment in the asymmetric unit along with its full-profile comparison method. The similarity between the calculated and experimental diffraction pattern can be revealed by the final Rwp obtained by retvield refinement. The final step involved Forcite Geometical Optimization of the generated structure solution and the structure was exported as cif file. The powder XRD pattern of GEF-UREA was indexed using the program X-CELL giving a unit cell with triclinic symmetry (a=9.85, b=7.99, c=8.13, a=80.76, P=l 14.99, y=99.31) with space group PI. The asymmetric unit consists of one molecule each of GEF and Urea. GEF-UREA cocrystal was found to form heterosynthon involving the morpholine oxygen and quinazoline nitrogen of GEF. These interactions are similar to the synthon projected during the design of cocrystals. Figure 4 depicts the simulated powder XRD pattern of GEF-UREA. [0060] Example 4: Equilibrium solubility and intrinsic dissolution rate (IDR) of cocrystal of gefitinib

The equilibrium solubility of the cocrystal is determined by shake flask method using by taking an excess amount of drug (approx. 50mg) and 5 mL of phosphate buffer pH 3.0, in triplicate and shaken for 24 hours at 37°C at 150rpm in a water bath shaker (MSW275, Macroscientific Works, Delhi). The resulting samples were then filtered using membrane filter having 0A5[i pore size and GEF was analysed quantitatively using established method in HPLC. The studies demonstrated almost 3-fold improvement in equilibrium solubility and 6.8-times improvement in DDR of pharmaceutical cocrystals of gefitinib in comparison to pure drug gefitinib. Thus, the equilibrium solubility and intrinsic dissolution rate of all multicomponent forms showed improvement in solubility as compared with pure drug. Figure 5 shows the solubility profile of GEF and GEF-Urea. Figure 6 depicts the dissolution profile of GEF and GEF-Urea.
[0061] Example 6: Pharmacokinetic evaluation of pharmaceutical cocrystals of gefitinib
Pharmacokinetic parameters were calculated by the trapezoidal rule using kinetic software. The pharmacokinetic parameter showed that there is 7.8 times increase in bioavailability of drug in pharmaceutical cocrystal of gefitinib with pharmaceutically acceptable coformer urea than pure drug gefitinib. Figure 7 shows plasma concentration profile of Gefitinib and GEF-Urea. [0062] While the foregoing describes various embodiments of the invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
ADVANTAGES OF THE INVENTION
[0063] The present invention provides a cocrystal of gefitinib and a coformer, urea and thus guarantees the non-toxic nature of prepared cocrystals.

[0064] The present invention provides a cocrystal of gefitinib and a coformer, urea having better equilibrium solubility in comparison to other known forms. [0065] The present invention provides a cocrystal of gefitinib and a coformer, urea having enhanced intrinsic dissolution rate in comparison to other known forms.
[0066] The present invention provides a cocrystal of gefitinib and a coformer, urea having improved pharmacodynamic and pharmacokinetic profile in comparison to other known forms.


We Claim:

1. A co-crystal comprising of gefitinib having a chemical structure,
and a coformer, urea.
2. The co-crystal as claimed in claim 1, wherein a stoichiometric ratio of the urea to gefitinib is 1: 1.
3. The cocrystal as claimed in claim 1, wherein said cocrystal is characterized by melting endothermic peaks at 193.77, 133.84, 111 .TC in differential scanning calorimetry (DSC).
4. The cocrystal as claimed in claim 1, wherein said cocrystal is characterized by PXRD pattern having peaks at 2.theta. angles of 22.19, 24.01, 24.31,29.26.
5. The cocrystal as claimed in claim 1, wherein said cocrystal is having tri clinic symmetry with space group PI and said cocrystal forms heterosynthon involving morpholine oxygen and quinazolinone nitrogen of gefitinib.
6. A pharmaceutical composition comprising of a cocrystal as claimed in claim 1 and a pharmaceutically acceptable excipients.
7. A process for preparation of cocrystal, wherein the process comprising the steps of:

a) grinding the gefitinib and urea with the addition of an organic solvent as co-crystallizing solvent at constant intervals to obtain a moist product; and
b) drying the moist product to obtain the cocrystal of gefitinib and urea.

8. The process for preparation of cocrystals as claimed in claim 7, wherein
the solvent is selected from ethanol, methanol, dimethyl formamide, and dimethyl sulphoxide.