FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"STABILIZED FLUCONAZOLE POLYMORPH III FORMULATION"
2. APPLICANT:
(a) NAME: FDC Limited
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, Maharashtra, India,
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention

Filed of invention:
The present invention relates to stabilized formulation of Fluconazole polymorph III and method of stabilizing the formulation containing Fluconazole polymorph III.
Background and prior art:
Fluconazole is a triazole antifungal antibiotic used to prevent and treat a variety of fungal and yeast infections. Fluconazole is used to treat infections caused by fungus, which can invade any part of the body including the mouth, throat, esophagus, lungs, bladder, genital area, and the blood. Fluconazole is also used to prevent fungal infection in people with weak immune systems caused by cancer treatment, bone marrow transplant, or diseases such as AIDS.
Fluconazole is designated chemically as 2,4-difluoro-α,αl-bis(lH-l,2,4-triazol-l-ylmethyl) benzyl alcohol. The molecular structure of Fluconazole is represented as:

Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
Polymorphs of a pharmaceutical solid may have different physical and solid state chemical properties. The most stable polymorphic form of a drug substance is often used because it has the lowest potential for conversion from one polymorphic form to another.

Fluconazole, the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration and as a powder for oral suspension. Fluconazole exists in different polymorphic forms like 1, II, III and hydrate.
US patent 4404216 discloses 2-(2,4-Difluorophenyl)-l,3-bis(lH-l,2,4-triazol-l-yl)propan-2-ol (fluconazole) and its pharmaceutically acceptable acid addition salts. This particular bis-triazole derivative and its salts are useful for treating fungal infections in animals, including humans. Patent further discloses methods for preparing these compounds and pharmaceutical composition using pharmaceutical acceptable carrier.
GB patent 2270521 discloses crystalline monohydrate form of fluconazole, which is useful for pharmaceutical formulation as an antifungal agent and is less bitter than the non-hydrated compound. Crystalline monohydrate form of fluconazole was synthesized from anhydrous fluconazole.
The Journal of pharmaceutical sciences 1995 Dec; 84(12): 143 8-41 discloses the characterization of polymorphic forms of fluconazole using Fourier transform Raman spectroscopy. The article describes the crystal forms I and II of fluconazole along with X-ray powder diffraction and Raman spectra of different crystal modifications.

Subsequently crystal modifications I and II was prepared from said fluconazole monohydrate.
US patent 7094904 discloses process for the synthesis of monohydrate and crystal modifications I and II of fluconazole. The process discloses hydrolyzing silyl ether of following formula to form fluconazole monohydrate.

Acta Poloniae Pharmaceutica - Drug Research, Vol. 66, No. 2 pp. 115-122, 2009 explains the effect of pressure on the commercial fluconazole-II sample and the sample aged at room temperature (30°C) for- 36 months. The results indicated that fluconazole-II, on application of pressure transformed to fluconazole-I. Article also discussed about the intrinsic dissolution rates of polymorphic fonm-I and -II and the influence of crystal habit on the drug dissolution process.
Journal of pharmaceutical sciences 2004, vol. 93, 601-611 discusses preparation and crystal characterization of a polymorph, a monohydrate, and an ethyl acetate solvate of the antifungal fluconazole. A solid-state characterization of three crystalline modifications of fluconazole is reported. Recrystallization of fluconazole from propan-2-ol yielded a polymorph Form III, whereas the solvents water and ethyl acetate yielded the solvated products fluconazole monohydrate and fluconazole (ethyl acetate)o.25, respectively.
The book "Basic Pharmacology: Understanding Drug Actions and Reactions" 2006, chapter 5 reveals that the polymorph III of fluconazole has the best dissolution profile and the best bioavailability when compared with fluconazole polymorphs I and II.
From the above prior art it is evident that fluconazole exists in crystal forms of I, II, III, and hydrate form and out of these polymorphs fluconazole polymorph III has best bioavailability. Hence fluconazole polymorph III is most preferred among these polymorphs.
It was found that fluconazole polymorph III API is susceptible to absorb moisture and if it is exposed to high humidity it gets converted to hydrated form. Even if fluconazole polymorph III API is stabilized by controlling storage conditions during the formulation, when subjected to high humidity conditions or if formulation is prepared using aqueous process polymorph III is getting converted to hydrated form. Since fluconazole polymorph III has more bioavailability and keeping polymorph III intact to give maximum therapeutic benefit of the antifungal activity, it is necessary to stabilize polymorph III even during formulation process and its storage.

The present invention provides an improved stabilized formulation of fluconazole polymorph III by using non aqueous formulation process having advantage over the conventional processes which would otherwise convert fluconazole polymorph III to hydrated form.
The formulation of the present invention includes tablets, capsules, granules, powders and pellets.
Object of the invention:
Accordingly, main objective of the present invention is to provide oral dosage forms of fluconazole polymorph III and at least one pharmaceutically acceptable excipient.
Another objective of the invention is to provide the stable pharmaceutical composition wherein the stabilization is done using non-aqueous granulation process.
Yet another objective of the present invention is to provide said formulations having maximum therapeutic benefit of antifungal activity by retaining polymorphic form of fluconazole polymorph III during its storage.
Other objective of the present invention is to provide a process for preparing the said oral dosage formulations comprising fluconazole polymorph III.
Summary of the invention:
The invention discloses a stabilized pharmaceutical composition comprising fluconazole polymorph III and a process for preparing the same. In particular, it relates to a composition wherein the fluconazole polymorph III retains its polymorphic form and is therefore having maximum therapeutic benefit of antifungal activity. The process employed is non-aqueous in order to avoid transformation of polymorph III into hydrated form.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated
Accordingly, the present invention provides oral dosage forms comprising fluconazole polymorph III and at least one pharmaceutically acceptable excipient. The formulations of the current invention comprising fluconazole polymorph III was stabilized using non¬aqueous process so as to retain the polymorphic form during the storage and thus improved bioavailability..
The present invention provides stabilized oral pharmaceutical composition comprising
A) Fluconazole polymorph III
B) diluent (s)
C) disintegrant
D) binder and
E) other pharmaceutically acceptable excipients.
Wherein, the composition is prepared using non-aqueous granulating process. For the purpose of present invention, the non-aqueous solvents for granulation may be selected from conventionally used solvents like methylene chloride, isopropyl alcohol, ethanol etc.
According to the compositions, the amount of fluconazole polymorph III is present in the range of 30 to 80% by weight of total formulation.
The oral pharmaceutical compositions according to the invention encompass the dosage forms including tablets, capsules, granules, powders and pellets.
Suitable diluent(s) used in the pharmaceutical composition of the present invention is selected from the group consisting of cellulose derivatives such as microcrystalline cellulose, powdered cellulose, starch, calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, kaolin, magnesium oxide, magnesium carbonate, lactose, glucose, fructose, mannitol, dextrates, maltitol, sorbitol and xylitol.

Binder(s) used in the pharmaceutical composition of the present invention is selected from the group consisting of cellulose derivatives such as Hydroxypropyl methylcellulose, Hydroxypropyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, ethyl cellulose, gums such as guar gum, gum acacia, xanthan gum and tragacanth gum, Povidone, aery late polymers, gelatin, starch, and prege latinized starch.
Disintegrant is optionally selected from group consisting of but not limited to croscarmellose sodium, crospovidone, starch, prege latinized starch and sodium starch glycolate.
Lubricant is optionally selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, stearic acid, talc, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, and colloidal silicon dioxide.
The compositions of the present invention further comprise at least one excipient such as glidant, sweetener, surfactant, flavor and colorant.
The pharmaceutical composition of the invention is in solid oral dosage form containing fluconazole polymorph III in conventional pharmaceutical dosages. According to the present invention an oral solid formulation of fluconazole is prepared by granulation method using top spray granulation or by high/low shear granulation process.
Description of drawings:
X-ray powder diffraction was performed to illustrate the crystal behaviour of fluconazole polymorph III and hydrated form in API and formulations. Description of X-ray powder diffraction patterns are as shown in Table 1

Figure 1 Fluconazole Polymorph III API
Figure 2 Fluconazole Polymorph III API after exposure to high
humidity/temperature conditions of 75% at 40°C for 6 months in double

polybag in HDPE container.
• XRD shows formation of monohydrate when exposed to high humidity
Figure 3 Fluconazole Polymorph III API after exposure in open condition to high
humidity of 84%RH at 25 °C for 10 days.
• XRD shows formation of monohydrate even at low temperature but
when exposed to high humidity
Figure 4 Fluconazole Tablets using Polymorph III API prepared by simple mixing of
excipient and compression (Example 1) , after exposure in open condition
to high humidity of 75%RH at 40°C for 10 days.
• XRD shows fluconazole polymorph III API in tablets by direct
compression gets converted to monohydrate.
Figure 5 Fluconazole Tablets using Polymorph III API prepared by Example No. 2
after exposure in open condition to high humidity of 75%RH at 40°C for 10
days.
• XRD of tablets prepared by present invention when compared with figure
4, indicates conversion to monohydrate is prevented by use of invented
process.
Figure 6 Fluconazole Tablets using Polymorph III API prepared by Example No. 3
before exposure to high humidity/temperature conditions.
• XRD of tablets prepared by present invention before exposure to high
humidity
Figure 7 Fluconazole Tablets using Polymorph III API prepared by Example No. 3,
in aluminum strip pack after exposure to high humidity of 75%RH at 40°C
for 3 months.
• XRD of tablets prepared by present invention after exposure to high
humidity for 3 months in marketed pack wherein polymorph III retains
its polymorphic form

Sr. No. DRY MIXING: mg/tablct
1 Fluconazole polymorph III 150.0
2 Dibasic Calcium Phosphate Anhydrous 109.0
3 Sodium starch glycol ate 21.0
4 Ponceau 4 R lake 2.0
5 PVP K 30 (Kollidon 30) 9.0
6 Sodium lauryl sulfate 1.5
7 Colloidal silicon dioxide 1.5
8 Talc 3.0
9 Magnesium Stearate 3.0
Total 300.0
1. Sifting dibasic calcium phosphate, fluconazole polymorph III, sodium starch Glycolate through sieve no. 30 (ASTM, 600 microns).
2. Sifting Ponceau 4R through sieve no. 100 (ASTM, 150 microns) and mixing in a suitable mixer with step 1.
3. Sifting Povidone, Sodium lauryl sulfate, colloidal silicon dioxide, talc through sieve no. 30 (ASTM, 600 microns), and blending with step 2 in a suitable blend&r.
4. Sifting Magnesium Stearate through sieve no. 40 (ASTM, 425 microns) and blend with step 3 in a suitable blender.
5. Compressing the tablets using suitable tooling.

Example 2

Sr.
No. DRY MIXING: mg/tablet
1 Fluconazole polymorph HI 150.0
2 Dibasic Calcium Phosphate 106.5
3 Croscarmeliose Sodium 15.0
4 Ponceau 4 R lake 3.0
BINDING:
5 PVP K 30 (Kollidon 30) USNF 9.0
6 Isopropyl alcohol q.s
LUBRICATON:
7 Croscarmeliose Sodium (Ac-di-sol) USNF 12.0
8 Colloidal silicon dioxide 1.5
9 Magnesium Stearate 3.0
Total 300.0
Procedure:
1. Sifting dibasic calcium phosphate, fluconazole polymorph III arid croscarmeliose through sieve no. 30 (ASTM, 600 microns).
2. Sifting Ponceau 4R through sieve no. 100 (ASTM, 150 microns) and mix in a suitable mixer with step 1.
3. Dissolving Povidone in isopropyl alcohol, and granulating dry mix in step 2
4. Drying the wet mass till LOD of the granules is below 3%
5. Passing the granules of step 4 through sieve no. 30 (ASTM, 600 microns)
6. Sifting croscarmeliose sodium and colloidal silicon dioxide through sieve no. 30 (ASTM, 600 microns) and mix with step 5.
7. Sifting Magnesium Stearate through sieve no. 40 (ASTM, 425 microns) and blend with step 6 in a suitable blender.
8. Compressing the tablets using suitable tooling.

Example 3

I GRANULATION I mg/tablet
1 Fluconazole polymorph III 100.0
2 Ponceau 4R lake 0.20
3 Ethyl cellulose 20 cps 3.00
4 Methylene Chloride q.s.
II GRANULATION II
5 Microcrystalline cellulose 153.8
6 Ponceau 4R lake 1.00
7 Purified Water q.s.
III LUBRICATON:
8 Aspartame 8.00
9 Trusil Strawberry flavor ASV 8.00
10 Sodium Starch Glycol ate 20.0
11 Talc 3.0
12 Magnesium Stearate 3.0
Total 300.0

Procedure:
1. Sifting Ponceau 4R through sieve no. 100 (ASTM, 150 microns) and sifting fluconazole polymorph III through sieve no. 30 (ASTM, 600 microns)..
2. Mixing ingredients of step 1 in a suitable mixer.
3. Dissolving ethyl cellulose in Methylene Chloride, and granulating dry mix in step 2.
4. Sifting Microcrystalline cellulose through sieve no. 30 (ASTM, 600 microns)
5. Sifting Ponceau 4R through sieve no. 100 (ASTM, 150 microns) and mixing with step 4 in a suitable mixer.
6. Granulating dry mix in step 5 by water
7. Drying the wet mass in step 3 till LOD of the granules step is below 3%
8. Drying the wet mass in step 6 till LOD of the granules step is below 3%

9. Passing the granules of step 3 and step 6 through sieve no. 30 (ASTM, 600 microns) and mixing these granules in a suitable blender.
10. Sifting Aspartame, Trusil Strawberry flavor ASV, Sodium Starch Glycolate and Talc through sieve no. 30 (ASTM, 600 microns) and mixing with step 9.
11. Sifting Magnesium Stearate through sieve no. 40 (ASTM, 425 microns) and blend with step 10 in a suitable blender.
12. Compressing the tablets using suitable tooling.