A process for processing micronized active pharmaceutical ingredients

Abstract

A novel process for processing micronized active pharmaceutical ingredients (API) to improve the crystallinity of the micronized API. The process involves the treatment of micronized API with water to improve the crystallinity of the API without impacting the particle size of the API. The process of the invention involves the treatment of micronized API such as Fluticasone Furoate with water or treatment with water vapor exposure process to reduce the amorphous content in the micronized API without altering the nature of particle size, crystallinity, and the morphology of API.

Description

[0001] A PROCESS FOR PROCESSING MICRONIZED ACTIVE

[0002] PHARMACEUTICAL INGREDIENTS

[0003] Field of the Invention:

[0004] The present invention relates to a process for processing micronized API to improve the crystallinity of API. The process involves the treatment of micronized API such as Fluticasone Furoate with water to obtain an API with a reduced amorphous content. The present invention relates to a water vapor exposure process to reduce the amorphous content of the API. The invention provides a process for reducing the amorphous content formed during the micronization of Fluticasone Furoate, without altering the nature of particle size, crystallinity, and morphology.

[0005] Background of the Invention:

[0006] Corticosteroids have potent anti-inflammatory properties, especially Glucocorticoids which are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. They are used to treat rheumatological diseases like rheumatoid arthritis, lupus, etc. Corticosteroids comprise a large class of medications, including but not limited to Triamcinolone, Beclomethasone, Methylprednisolone, Prednisolone, Prednisone, Betamethasone, Ciclesonide, Mometasone, Fluticasone, Budesonide, Cortisone, and Hydrocortisone. Corticosteroids work by limiting the activity of the immune system. Many drugs such as Fluticasone Propionate and Fluticasone Furoate are marketed in various dosage forms including inhalers.

[0007] The particle size reduction of the API is a critical step to develop APIs, specifically for the products those are meant to deliver the drugs through inhalation routes such as lungs and nasal since optimum particle size enhances the disposition of such drugs to lungs and nasal. Currently, dry-powder inhalers (DPIs) containing Fluticasone Furoate and Vilanterol Tridentate are commercially available. Fluticasone Furoate chemically known as S -fluoromethyl 6a,9a-difluoro-16a-methyl- 3-oxo-l ip hydroxy-17a-[(2-furoyl)oxy]-l,4-diene-17P-carbothioate is represented by the compound of Formula (I).

[0008] Several documents disclose different processes for processing and size reduction of Fluticasone Furoate.

[0009] The patent application US 20210161804, discloses a composition of Fluticasone Furoate and Vilanterol Tridentate in which Fluticasone Furoate is micronized to the desired particle size to prepare the medicament.

[0010] The patent US 9956144 discloses a process for particle processing and size reduction of active pharmaceutical ingredients. The patent discloses a process comprising wet milling, specifically by cavitation at elevated pressure, and is preferably followed by spray drying to control the particle size.

[0011] The US patent application US20070178051 describes a process comprising spray drying of a previously processed formulation containing surface stabilizer for better blending of the mixture of the active ingredients, excipient, and isolation of stable nanoparticles. The prior art process faces several disadvantages. The prior art process as per US 9956144 needs a critical control and maintenance of the high-pressure conditions throughout.

[0012] The process of a micronization of the API involves techniques such as air jet milling, wet milling, and ball milling. However, while achieving the desired particle size of the API, it has been observed that the crystalline nature of the API changes.

[0013] Ball milling and air jet milling cause loss of bonded water and produce anhydrous and amorphous forms. Used for air jet milling to achieve the desired particle size in the API, also leads to the formation of the amorphous content in the API in high quantities.

[0014] The inventors of the present invention also observed an increase in the amorphous content in the Fluticasone Furoate API when kept for a longer duration after micronization.

[0015] None of the prior art documents disclose a method to reduce the amorphous content formed during and post micronization of Fluticasone Furoate.

[0016] The inventors of the present invention developed a novel process for processing a micronized Fluticasone Furoate to reduce the amorphous content without altering the particle size, crystallinity, and morphology of it.

[0017] The inventors of the present invention have designed a novel process for the treatment of micronized Fluticasone Furoate which eliminates the need for high-pressure cavitating equipment while giving an efficient process in which amorphous content is reduced along with the reduction in production cycle time. The present process of the invention improves the crystallinity of the micronized Fluticasone Furoate by reducing the amorphous content without impacting the particle size, crystallinity, and morphology.

[0018] Summary of the invention:

[0019] The present invention relates to a process for processing micronized active pharmaceutical ingredients. The present invention relates to a process of treating the micronized Fluticasone Furoate with water under heating and stirring, followed by cooling, filtering, and then drying under a vacuum to obtain the product as a dry powder. The present invention also reduces the amorphous content by water vapor exposure process. The present invention describes a process of processing micronized Fluticasone Furoate in which amorphous content is reduced without altering the particle size, crystallinity, and morphology.

[0020] Description of the Drawings:

[0021] Figure 1 : DSC of Fluticasone Furoate before processing of the micronized Fluticasone Furoate.

[0022] Figure 2: DSC of Fluticasone Furoate after processing with water of the micronized Fluticasone Furoate.

[0023] Figure 3 : DSC of Fluticasone Furoate before processing of the micronized Fluticasone Furoate.

[0024] Figure 4: DSC of Fluticasone Furoate after processing with the micronized Fluticasone Furoate.

[0025] Figure 5: DVS of Fluticasone Furoate before processing of the micronized Fluticasone Furoate.

[0026] Figure 6: DVS of Fluticasone Furoate after water vapor exposure the micronized Fluticasone Furoate. Detailed description of the invention:

[0027] The embodiment of the present invention is directed towards the treatment of micronized API of Glucocorticoids.

[0028] The another embodiment of the present invention is directed toward the treatment of micronized API with water.

[0029] The yet another embodiment of the present is directed to the water vapor exposure process for the treatment of the micronized API.

[0030] Another aspect of the present invention is related to the treatment of micronized API of Glucocorticoids wherein API is Triamcinolone, Beclomethasone, Methylprednisolone, Prednisolone, Prednisone, Betamethasone, Ciclesonide, Mometasone, Fluticasone Furoate, Budesonide, Cortisone, and Hydrocortisone.

[0031] Yet another aspect of the present invention is related to the treatment of micronized API of Glucocorticoids wherein API is Fluticasone Furoate.

[0032] The novel processes of the present embodiments provides the desired micronized Fluticasone Furoate with reduced amorphous content without altering the particle size, crystallinity, and morphology of it.

[0033] Further embodiment of the present invention involves treatment of Fluticasone Furoate by exposing the micronized Fluticasone Furoate in climate chamber.

[0034] Further aspects of the invention involves the use of climate chamber wherein Fluticasone Furoate is exposed in the chamber at the temperature maintained at 20°C to 60°C, preferably 30°C to 50°C. The exposure can be performed for 2 to 8 hours, preferably 4 to 6 hours. The humidity is maintained at 60 to 90 % RH. The solid is then dried to yield the desired Fluticasone Furoate with reduced amorphous content without altering the particle size, crystallinity, and morphology of it.

[0035] The embodiment of the present invention is directed toward the treatment of micronized Fluticasone Furoate with water.

[0036] The novel process of the present embodiments provides micronized Fluticasone Furoate with reduced amorphous content without altering the particle size, crystallinity, and morphology of it.

[0037] One aspect of the present invention describes a novel process for the processing of micronized Fluticasone Furoate. It involves treatment with water such as rinsing, suspending, and leaching while heating and stirring. To obtain the dry powder of Fluticasone Furoate of desired particle and crystallinity, the product is suspended in water, cooled, filtered, and then dried under a vacuum.

[0038] Another aspect of the present invention involves a process for reducing the particle size of Fluticasone Furoate while maintaining its polymorphic form.

[0039] The process of the invention is performed on the Fluticasone Furoate isolation, in the absence of any excipients, other than any suspending solvent needed for the processing. The preferred suspending solvent is water in which the Fluticasone Furoate is insoluble. Yet another aspect of the invention is to provide a processes for the treatment of the micronized Fluticasone Furoate in which the amorphous content is about 5% to 15%. Further, the treatment of micronized Fluticasone Furoate provides Fluticasone Furoate with an amorphous content of less than 2%, preferably less than 1%.

[0040] Further aspects of the invention involves the use of water leaching with heating to treat the micronized Fluticasone Furoate while maintaining its polymorphic form. The process of leaching involves suspending the Fluticasone Furoate in water followed by heating at a particular temperature. The process can be carried out at a temperature of 20°C to 60°C, preferably 30°C to 50°C. The heating can be performed for 2 to 8 hours, preferably 4 to 6 hours. The solid is then cooled followed by filtration and drying to yield the desired Fluticasone Furoate with reduced amorphous content without altering the particle size, crystallinity, and morphology of it.

[0041] Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-10 pm, preferably 2-5 pm. Particles having a size above 20 pm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of the compound and the muscarinic receptor antagonist (and any further therapeutically active ingredient) as produced may be size reduced by conventional means like micronization. The particle size of Fluticasone Furoate achieved by micronization is typically the optimum particle size of 1-5 pm.

[0042] In the crystalline or polymorphic form of the crystals, the Fluticasone Furoate particles after processing or treatment in accordance with the invention are preferably 95% (by weight) or more, more preferably 99% (by weight) or more, identical with the particles of Fluticasone Furoate prior to processing. If a crystalline starting material is employed, then amorphous material should be not more than 2% (by weight) in the micronized Fluticasone Furoate, ideally not more than 1% (by weight) of the crystalline particles after processing. In other words, after processing, crystalline material makes up at least 98% (by weight), preferably more than 99% of the particles.

[0043] Additionally, by adjusting operating parameters such as heating, stirring at a temperature for a time, cooling, filtering, and vacuum drying, the invention described herein allows the precise control of particle size while maintaining the required crystallinity. This novel process of the treatment of the micronized particle size provides the required crystallinity of the Fluticasone Furoate which can be employed in a variety of formulations where particle size is crucial, such as injectable suspensions, powders, or suspensions for nasal or oral delivery to the respiratory system.

[0044] The Differential Scanning Calorimetry (DSC) patterns were recorded on Universal V4.5A TA Instruments and PerkinElmer.

[0045] The Dynamic Vapor Sorption (DVS) pattern was recorded on Surface measurement systems Ltd UK 1996-2014.

[0046] The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing examples. The invention, which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.

[0047] Examples

[0048] Example -1

[0049] 160 grams of micronized Fluticasone Furoate containing 7.93% w / w amorphous content was charged in the reactor, and 1600 ml of water was added. The slurry mass was heated and stirred at 35°C for 6 hours, the mixture was cooled to 30°C and filtered, followed by drying the wet cake under a vacuum the dried Fluticasone Furoate was tested for particle size and amorphous content. Input material Results:

[0050] Output material Results: The resultant amorphous content in the processed Fluticasone Furoate was 0.9%, which was reduced as compared to that of the 7.93% in the micronized Fluticasone Furoate.

[0051] Example -2

[0052] 20 grams of micronized Fluticasone Furoate containing 14.4 % w / w amorphous content was charged in the reactor, and 200 ml of water was added. The slurry mass was heated and stirred at 45°C for 5 hrs. The mixture was cooled at 30°C and filtered, followed by drying the wet cake under a vacuum the dried Fluticasone Furoate was tested for particle size and amorphous content.

[0053] Input material Results: Output material Results:

[0054] The resultant amorphous content in the processed Fluticasone Furoate was 0.93%, which was reduced as compared to that of the 14.4% in the micronized Fluticasone Furoate.

[0055] Example -3

[0056] 40 grams of micronized Fluticasone Furoate containing 24.6 % w / w amorphous content was charged in the reactor, and 400 ml of water was added. The slurry mass was heated and stirred at 40-45°C for 4-5 hrs. The mixture was cooled at 30°C and filtered, followed by drying the wet cake under a vacuum the dried Fluticasone Furoate was tested for particle size and amorphous content.

[0057] Input material Results:

[0058] Output material Results: The resultant amorphous content in the processed Fluticasone Furoate was below 1.0%, which was reduced as compared to that of the 24.6% in the micronized Fluticasone Furoate.

[0059] Example -4 60 grams of micronized Fluticasone Furoate containing amorphous content 16.34% was kept in climate chamber for conditioning at temperature 40-50°C & humidity 75 % RH. Further the material was dried at 50-55°C for 3-5 hours. yield : 59.0 gm.

[0060] Input material Results:

[0061] Output material Results:

[0062] The resultant amorphous content in the processed Fluticasone Furoate was 0.0%, which was reduced as compared to that of the 16.34% in the micronized Fluticasone Furoate.

Claims

CLAIMS:

1. A process for processing micronized Fluticasone Furoate with reduced amorphous content.

2. The process of claim 1, wherein micronized Fluticasone Furoate is treated with water.

3. The process of claim 2, wherein treatment with water comprises rinsing, suspending, leaching, heating or stirring of micronized Fluticasone Furoate.

4. The process of claim 3, wherein micronized Fluticasone Furoate is treated with water at 20° C to 60° C.

5. The process of claim 4, wherein micronized Fluticasone Furoate is treated with water at 30° C to 50° C.

6. The process of claim 2, wherein micronized Fluticasone Furoate is treated with water for 2-6 hours.

7. The process of claim 1, wherein micronized Fluticasone Furoate is treated with water vapor exposure process.

8. The process of claim 7, wherein the micronized Fluticasone Furoate is kept in the climate chamber.

9. The process of claim 8, wherein the temperature in the climate chamber is about 20-60°C.

10. The process of claim 8, wherein the relative humidity of climate chamber is about 60% to 90%.

11. Micronised Fluticasone Furoate of claim 1, having amorphous content less than 15%.

12. Micronised Fluticasone Furoate of claim 11, having amorphous content less than 5%.

13. Micronised Fluticasone Furoate of claim 12, having amorphous content less than 1%.

Images