A method for preparing microgranules and the microgranules produced thereby

Abstract

The present invention relates to the field of formulations. Particularly, the present invention relates to a method for preparing microgranules. It also relates to microgranules which are suitable for controlled release of active agent. This invention proposes significant advantages, requiring minimal energy for droplet formation and the conversion of liquid droplets into solid granules. Additionally, it enables precise control over the release kinetics of active agents by adjusting the loading of different species within the droplets.

Description

[0001] "A METHOD FOR PREPARING MICROGRANULES AND THE MICROGRANULES PRODUCED THEREBY" FIELD OF THE INVENTION

[0002] The present invention relates to the field of formulations. Particularly, the present invention relates to a method for preparing microgranules. It also relates to microgranules which are suitable for controlled release of active agent.

[0003] BACKGROUND OF THE INVENTION

[0004] Microgranules are small, discrete particles that have gained significant importance across multiple industries, including pharmaceuticals, agriculture, food processing, and cosmetics (Gupta et al. Biomaterials 2000). These particles serve as carriers for active agents such as drugs, nutrients, perfumes, and other functional materials. The encapsulation of active agents within microgranules provides numerous benefits, including controlled release, protection from environmental degradation, and improved stability. As a result, microgranules play a crucial role in enhancing the effectiveness and shelf-life of various formulations.

[0005] Among the most commonly used methods for producing microgranules is spray drying (Biswas et al. Powder Technol 2021). This technique involves atomizing a liquid feed into small droplets, followed by exposure to hot air or electric heating to remove the solvent, thereby forming solid microgranules. Spray drying is widely utilized due to its efficiency and scalability, particularly for encapsulating active agents that are not highly temperature sensitive. However, a main limitation of spray drying is its dependence on elevated temperatures, which can lead to the degradation of heat-sensitive compounds such as certain pharmaceuticals.Another established method for microgranule production is fluidized bed granulation (Zhai et al. Mol Pharm 2014). This process fluidizes a bed of solid particles using a gas stream and binds the particles together with a binder to form microgranules. It is particularly useful in the pharmaceutical industry for achieving controlled release properties. Despite its effectiveness, fluidized bed granulation has drawbacks, including high installation and operational costs. Additionally, like spray drying, it is not suitable for processing thermo-sensitive ingredients, limiting its applicability.

[0006] Super-particle aggregates have also been explored as an alternative approach, wherein particle-laden droplets undergo solvent removal through conventional or microwave heating (Kim et al. J Am Chem Soc 2006). While this technique provides benefits for specific applications, it still presents challenges in handling heatsensitive particles.

[0007] In addition to physical techniques, wet chemistry approaches such as interfacial polymerization and layer-by-layer assembly have been utilized for microencapsulation (Mu et al. ACS Appl Mater Interfaces 2020 and Liang et al. ACS Sustain Chem Eng 2017). These methods rely on forming thin polymeric layers around particles or droplets to encapsulate active agents effectively. However, these techniques often require harsh reaction conditions, multiple chemical steps, or complex processing, making them less attractive for large-scale or cost-sensitive applications.Given the limitations of existing methods, there is a demanding need for a novel microgranule synthesis technique that is simple, scalable, and capable of operating at room temperature.

[0008] The present invention addresses the deficiencies in prior art by proposing an innovative method for synthesizing microgranules at room temperature. Unlike conventional techniques, this method eliminates the need for several chemicals like Chloroform, dichloromethane, ethyl acetate solvents and harsh reaction conditions like operational temperature ranging from 80-120°C, ensuring that sensitive active agents remain stable throughout the encapsulation process.

[0009] OBJECTIVES OF THE INVENTION

[0010] The main objective of the present invention is to provide a method for preparing microgranules.

[0011] Another objective of the present invention is to provide a cost-effective and energy-efficient method for preparing microgranules.

[0012] Another objective of the present invention is to provide a method for preparing microgranules that exhibit controlled drug release.

[0013] Another objective of the present invention is to provide a method for preparing microgranules under mild processing conditions, avoiding high temperature since typically above 100°C, biopolymers and essential nutrients like "Vitamins" degrades or high-energy input, without requiring several chemicals and harsh reaction conditions like chloroform, dichloromethane, acetone chemicals and elevated operational temperature.

[0014] Another objective of the present invention is to provide a scalable method for producing microgranules suitable for industrial applications.Another objective of the present invention is to provide microgranules that exhibit controlled drug release.

[0015] Another objective of the present invention is to provide microgranules with tunable release kinetics.

[0016] SUMMARY OF THE INVENTION

[0017] This summary is intended to introduce, in simplified form, a selection of concepts that are further described in the detailed description. This summary is merely presented as a brief overview of the subject matter described and claimed herein and does not aid in determining the scope of the claimed subject matter.

[0018] The present invention seamlessly integrates two distinct techniques, namely micro-emulsion and crosslinking under ambient condition, to achieve a desired microgranule formulation. The micro-emulsion technique enables us to create droplets in which core liquid hold active agents, while the crosslinking process involves the formation of a solid boundary that separates the two liquids. The microgranules exhibit a narrow size distribution and enable the controlled release of a drug. Here, the drug is hydrophilic.

[0019] Further, the present invention provides a microgranule comprising an active agent selected from the group consisting of metformin hydrochloride, dopamine hydrochloride, fosphenytoin, acetaminophen, diclofenac sodium, diltiazem hydrochloride, papaverine hydrochloride, or vitamins, wherein the active agent is dissolved in an aqueous dispersion of particles, polymers, and cross-linkers, and homogenized with the oil phase.The present invention further provides a method for in-vitro drug release analysis via microgranule as defined herein.

[0020] The method for preparing microgranules of the present invention proposes several key advantages over conventional microgranule production methods. One of the primary benefits is its ability to require minimal energy for both droplet formation and the subsequent conversion of liquid droplets into solid granules. This significantly reduces operational costs and makes the process more energyefficient compared to traditional techniques such as spray drying and fluidized bed granulation, which rely on high-temperature processing.

[0021] Additionally, the invention provides enhanced control over the release kinetics of active agents. By adjusting the loading of different species within the droplets, the release profile can be fine-tuned to meet specific application needs. This flexibility allows for tailored formulations that optimize the effectiveness of active agents, making the process highly useful for applications in pharmaceuticals, agriculture, personal care and other industries requiring controlled release systems.

[0022] BRIEF DESCRIPTION OF DRAWINGS:

[0023] The present invention is accompanied by the following drawings, wherein:

[0024] • Figure 1: It illustrates the structure and morphology of microgranules. al) Optical microscopy image of microgranules with particles. Inset plot depicts the corresponding size distribution ; a2) and a3) SEM images of the microgranules with particles at low and high magnifications respectively; bl) Optical microscopy image of microgranules with out particles. Inset plot depicts the corresponding size distribution; b2) and b3) SEM imagesof the microgranules without particles at low and high magnifications respectively.

[0025] • Figure 2: It illustrates A)FT-IR spectra of a)Metformin hydrochloride, b)drug-loaded microgranules with particles and c) drug-loaded microgranules without particles.

[0026] B)XRD spectra of a)Metformin hydrochloride, b)drug-loaded microgranules with particles and c) drug-loaded microgranules without particles.

[0027] • Figure 3: It illustrates in vitro release profile of a) pure metformin from dialysis bag; the drug loaded microgranules prepared b) with particles and c) without particles.

[0028] DETAILED DESCRIPTION OF THE INVENTION

[0029] At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is only an exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the descri ption is to be understood as an exemplary embodiment and teaching of invention and not intended to be taken restrictively.

[0030] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the present invention.

[0031] Where a ranging from values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictatesotherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the process. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the process, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the process.

[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any microgranules and preparation method similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred microgranules and preparation method are described. For the purposes of the present invention, the following terms are defined below.

[0033] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0034] As used herein, the term "comprises" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.The term "Controlled release" used herein refers to the systematic and predictable release of an active agent from a formulation over a defined period, ensuring sustained and prolonged therapeutic or functional effects.

[0035] The term "colloidal particles" used herein refers to microscopic particles with sizes typically ranging from few nanometres to several hundred nanometres, suspended in a continuous fluid phase.

[0036] The term "vortex" used herein refers to a tool typically use for mixing or dispersing substances via mechanical agitation.

[0037] Each embodiment is provided by way of explanation of the invention and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the methods described herein without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present invention includes such modifications and variations and their equivalents. Other objects, features and aspects of the present invention are disclosed in or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not to be construed as limiting the broader aspects of the present invention.

[0038] The present invention provides a method for preparing microgranules, comprising the following steps of:a) mixing water and silica to obtain particle dispersion;

[0039] b) adding polymer to the dispersion of step (a) to form polymer coated particle suspension followed by adding a crosslinker;

[0040] c) adding an active agent to the suspension of step (b); followed by pouring the suspension into an oil phase to form a mixture; d) emulsifying the mixture of step (c) to obtain an emulsion;

[0041] e) allowing the emulsion obtained in step (d) to remain at room temperature, enabling crosslinking to occur and forming a solid residue; f) drying the solid residue of step (e) at 40°C to 70° to obtain the microgranules;

[0042] In an embodiment, the microgranules are solid.

[0043] In some embodiments, the active agent is selected from metformin hydrochloride, dopamine hydrochloride, acetaminophen, diclofenac sodium, diltiazem hydrochloride, papaverine hydrochloride, fosphenytoin, or vitamins.

[0044] In another embodiment, the active agent is in an amount ranging from 0.1 to 0.5 wt% . In a specific embodiment the amount of active agent is 0.15 wt% .

[0045] In some embodiments, the polymer is selected from branched polyethyleneimine (PEI), chitosan, poly-L-lysine (PLL), or polyguanidines. In a specific embodiment the polymer is branched polyethyleneimine.

[0046] In another embodiment, the polymer is in an amount ranging from 0.5 wt% to 1 wt% . In some embodiments, the polymer is in an amount of 0.5 wt%, 0.6 wt%, 0.7wt%, 0.8 wt%, or 0.9 wt%. In a specific embodiment, the amount of polymer is 0.9wt%.

[0047] In some embodiments, the crosslinker is selected from 1,4-Butanediol diglycidyl ether (BDE), glutaraldehyde (GLU), Ethylene glycol diglycidyl ether (EGDGE), Polyethylene glycol diglycidylether (PEGDGE), or 1,6-Hexanediol diglycidylether (HDGE). In a specific embodiment, the crosslinker is 1,4-Butanediol diglycidyl ether (BDE).

[0048] In another embodiment, the crosslinker is in an amount ranging from 0.3wt% to 0.8 wt%.

[0049] In some embodiments, the crosslinker is in an amount of 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, or 0.7 wt%, or 0.8wt%. In a specific embodiment, the amount of crosslinker is 0.75 wt% .

[0050] In some embodiments, the silica particles are present in an amount ranging from lwt% to 5 wt% . In some embodiments, the silica particles are present in an amount of lwt%, 2wt%, 3wt%, 4wt%, or 5 wt%. In a specific embodiment, the amount of silica is 4.3 wt%.

[0051] In some embodiments, the oil phase comprises n-decane and surfactant. In some embodiments, the surfactant is non-ionic surfactant sorbitan monooleate (SPAN) 80. In some embodiments, the amount of n-decane is in a range of 65wt% to 80wt% and the amount of surfactant is in a range of lwt% to 2wt%. In a specific embodiment, the amount of surfactant is 1.2 wt% .

[0052] In some embodiments, the amount of n-decane is in 65wt%, 70wt%, 75wt%, or 80 wt% . in a specific embodiment, the amount of decane is 79wt% .In another embodiment, in step (c), the mixture is oil-water mixture.

[0053] In some embodiments, the solution is emulsified by applying a high energy homogenizer at 4000 rpm to 6000 rpm for the time of 1 to 6 minutes. In some embodiments, the homogenizer speed is at 4000 rpm, 4500 rpm, 5000 rpm, 5500 rpm, or 6000 rpm. In a specific embodiment, the homogenizer speed is at 5000 rpm. In some embodiments, the homogenizing step is performed for 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, or 6 minutes. In a specific embodiment, the homogenizing step is performed for 3 minutes.

[0054] In some embodiments, in step (e) of the method, the solid residue formed is allowed to sediment to the bottom of the container.

[0055] In some embodiments, the room temperature ranges from 20°C to 40°C.

[0056] In another embodiment, in step (f), the solid residue is dried at 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or 70°C for 20 minutes to 50 minutes. In another embodiment, the solid residue is dried for 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, or 50 minutes. In another embodiment, the solid residue is dried at 60°C for 30 minutes.

[0057] In some embodiments, microgranules are prepared for controlled release of the active agent.

[0058] In some embodiments, the microgranules have an average particle size ranging from 5 pm to 70 pm.The method for preparing microgranules of the present invention presents the seamless integration of two distinct techniques, namely micro-emulsion and crosslinking, under ambient conditions. The micro-emulsion technique facilitates the formation of droplets in which the core liquid holds active agents, while the crosslinking process involves the formation of a solid boundary that separates the two liquids. The resulting microgranules exhibit a narrow size distribution and enable the controlled release of a hydrophilic drug.

[0059] In another embodiment, the present invention provides the method for preparing microgranules, comprising the following steps of:

[0060] a) mixing of branched polyethyleneimine (PEI) and dispersed silica particle in water to form a coated particle suspension;

[0061] b) adding 1,4-Butanediol diglycidyl ether (BDE) to the suspension of step (a);

[0062] c) adding metformin hydrochloride to the suspension of step (b), followed by pouring the suspension to an oil phase to form an oil water mixture;

[0063] d) emulsifying the mixture of step (c) to obtain an emulsion; e) allowing the emulsion obtained in step (d) to remain at room temperature, enabling crosslinking to occur and forming a solid residue; and

[0064] f) drying the solid residue of step (e) at 60°C to obtain microgranules.

[0065] The present invention provides a microgranule comprising an active agent selected from the group consisting of metformin hydrochloride, dopamine hydrochloride, fosphenytoin, acetaminophen, diclofenac sodium, diltiazemhydrochloride, papaverine hydrochloride, fosphenytoin, vitamins etc. wherein the active agent is dissolved in an aqueous dispersion of polymers, and cross-linkers, and homogenized with the oil phase.

[0066] In another embodiment, in the microgranule, the active agent is in an amount ranging from 0.1wt% to 0.5wt% . In a specific embodiment the amount of active agent is 0.15 wt% .

[0067] In some embodiments, in the microgranule, the polymer is selected from branched polyethyleneimine (PEI), chitosan, poly-L-lysine (PLL), polyguanidines. In a specific embodiment, the polymer is selected from branched polyethyleneimine.

[0068] In some embodiments, in the microgranule, the polymer is in an amount ranging from 0.5wt% to lwt% . In another embodiment, the polymer is in an amount of 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, or 0.9 wt% . In a specific embodiment, the amount of polymer is 0.9wt% .

[0069] In some embodiments, in the microgranule, the crosslinker is selected from 1,4-Butanediol diglycidyl ether (BDE), glutaraldehyde (GLU), Ethylene glycol diglycidyl ether (EGDGE), Polyethylene glycol diglycidylether ( PEGDGE), or 1,6-Hexanediol diglycidylether (HDGE) In a specific embodiment, the crosslinker is 1,4-Butanediol diglycidyl ether (BDE).

[0070] In some embodiments, in the microgranule, the crosslinker is in an amount ranging from 0.3wt% to 0.8wt%. In some embodiments, the crosslinker is in anamount of 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, or 0.7 wt%, or 0.8wt%. In a specific embodiment, the amount of crosslinker is 0.75 wt%.

[0071] In some embodiments, in the microgranule, the particles are silica particles. The silica particles are present in an amount ranging from lwt% to 5 wt%. In some embodiments, the silica particles are present in an amount of lwt%, 2wt%, 3wt%, 4wt%, or 5 wt%. In a specific embodiment, the amount of silica is 4.3wt%.

[0072] In some embodiments, in the microgranule, the oil phase comprises n-decane and non-ionic surfactant sorbitan monooleate (SPAN) 80.

[0073] In some embodiments, in the microgranule, the oil phase is in amount of 70 wt% to 85wt%. In another embodiment, the amount of oil phase is 70 wt%, 75wt%, 80 wt%, or 85wt%.

[0074] In some embodiments, in the microgranule, the dissolved active agent in an aqueous dispersion of particles, polymers, and cross-linkers is homogenized at a speed of 4000 rpm to 6000 rpm for the time of 1 to 6 minutes. In some embodiments, the homogenizer speed is at 4000 rpm, 4500 rpm, 5000 rpm, 5500 rpm, or 6000 rpm. In a specific embodiment, the homogenizer speed is at 5000 rpm. In some embodiments, the homogenizing step is performed for 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, or 6 minutes. In a specific embodiment, the homogenizing step is performed for 3 minutes.

[0075] In another embodiment, microgranules are prepared for controlled release of the active agent.In some embodiments, the microgranules have a diameter ranging from 15 to 60 gm. In some embodiments, the microgranules have a diameter of 15 gm, 20 gm, 25 gm, 30 gm, 35 gm, 40 gm, 45 gm, 50 gm, 55 gm, or 60 gm. In a specific embodiment, the microgranules have a diameter of 15 gm and 30 gm.

[0076] In an embodiment, the present invention provides a method for in-vitro drug release analysis, comprising the steps of:

[0077] a) dispersing the microgranules as claimed in claim 16 in phosphate buffer saline (PBS) buffer solution at pH 7 to obtain a formulation;

[0078] b) placing the formulation of step (a) in PBS dissolution medium under controlled laboratory conditions;

[0079] c) stirring the medium of step (b) at a speed of 50 rpm to 90 rpm, while maintaining a temperature of 35 ± 0.5 °C;

[0080] d) monitoring the release profile of the drug over a time period; and e) analyzing the drug release kinetics,

[0081] wherein the method is conducted entirely in an in-vitro environment without direct application to a living organism.

[0082] In some embodiments, in step (a), the PBS is in amount ranging from 2mL to 8mL. In some embodiments, the PBS is in amount ranging from 2mL, 3mL, 4mL, 5mL, 6mL, 7mL, or 8mL. In a specific embodiment, the PBS is in amount ranging from 5mL.

[0083] In some embodiments, in step (b), the PBS is in amount ranging from 200mL to 300mL. In some embodiments, the PBS is in amount ranging from 210mL, 220mL,230mL, 240mL, 250mL, 260mL, 270 mL, 280mL, 290mL, or 300mL. In a specific embodiment, the PBS is in amount ranging from 250mL.

[0084] In some embodiments, in step (c), the speed is at 80 rpm.

[0085] In some embodiments, in step (d), the release profile of the drug is monitored for 3 days.

[0086] In some embodiments, in step (d), the release profile is monitored via UV-Vis spectroscopy.

[0087] The in vitro drug release profile reveals that microgranules containing particles exhibit a rapid release, with approximately 40% of the drug being released within the first 15 minutes. This is followed by a cumulative release of nearly 80% within three hours, after which a sustained, steady release is observed. The particles in the microgranules facilitate the escape of drug molecules into the matrix fluid.

[0088] The present invention involves encapsulating metformin hydrochloride as a model drug within a microgranule carrier, followed by studying its release profile under simulated biological conditions resembling the pH of human intestines. The microgranule carrier designed in this invention exhibits versatility, as it is capable of encapsulating and releasing a wide range of substances such as drugs, nutrients, pest control agents, and effervescent, provided they can be solubilized in water even under different pH conditions.

[0089] Abbreviations:

[0090] BDE: 1,4-Butanediol diglycidyl etherPEI: Polyethyleneimine

[0091] SPAN: Sorbitan monooleate

[0092] PBS: Phosphate buffer saline

[0093] GLU: Glutaraldehyde

[0094] EGDGE: Ethylene glycol diglycidyl ether

[0095] PEGDGE: Polyethylene glycol diglycidylether

[0096] HDGE: 1,6-Hexanediol diglycidylether

[0097] SEM: Scanning electron microscopy

[0098] UV-vis: Ultraviolet-visible spectroscopy

[0099] °C: Degree Celsius

[0100] min: minutes

[0101] RT: Room temperature: 20°C to 40°C

[0102] EXAMPLES:

[0103] The following examples are given by way of illustration of the working of the invention in actual practice and therefore should not be construed to limit the scope of present invention.

[0104] Preparation method

[0105] In this method, firstly, 180 mg silica was dispersed in 570 mg water. To this particle dispersion, an aqueous solution of branched polyethyleneimine (PEI) is added and mixed thoroughly. To this particle-polymer dispersion, 1,4-Butanediol diglycidyl ether (BDE) which acts as cross-linker is added and vortex mixed. To this mixture, an active agent (drug) is mixed. The aqueous dispersion is then added to the oil phase comprising n-decane and non-ionic surfactant, sorbitan monooleate (SPAN) 80, and emulsified using a high energy homogenizer at -5000 rpm for 3 minutes.

[0106] Y1The emulsion is maintained at room temperature (RT) so that the polymer-particle complexes as well as the excess polymer in the drop are cross-linked by BDE. Following crosslinking, the solid residue formed is allowed to sediment to the bottom of the container; collected and vacuum dried.

[0107] Table: The microgranules of the present invention include the following amount weight percentage of the components:

[0108]

[0109] As a control, microgranules were prepared without the addition of colloidal particles. The aqueous solution of polymer and crosslinker (at the same polymer to cross-crosslinker ratio) is homogenized (5000 rpm for 3 minutes) with the n-decane under identical experimental conditions. The solid residue was collected and vacuum dried. The obtained microgranules having an average size of 25 pm.

[0110] Microgranules without silica:

[0111] In this example, microgranules are prepared without incorporating silica particles according to the method described above. These microgranules are provided as a control to compare the release profile of the microgranules with silica particles. As silica particles are absent, the weight percentage of each component is as follows:Table:

[0112]

[0113] Drug loading studies

[0114] Here, the Metformin hydrochloride, a hydrophilic drug, is chosen for drug loading studies. 5 mg drug molecule is dissolved in an aqueous dispersion of particles, polymers, and cross-linkers, and homogenized (5000 rpm for 3 minutes) with the oil phase containing SPAN 80. The solid residue is separated by sedimentation, further used for the drug release studies. Control microgranules, without colloidal particles, are prepared using identical protocol for the comparison of drug release kinetics.

[0115] Experimental Results

[0116] Structure and morphology analysis:

[0117] Optical microscopy (OM) reveals the spherical nature of the microgranules (dispersed in n-decane) after the cross-linking process, see Figure 1 (al). The average diameter of the microgranule is measured to be 25 pm. Although the diameter of the microgranules ranged from 15 to 60 pm, majority of microgranules are found to have a diameter between 15 and 30 pm (see Figure 1 (al), inset). The microgranules retain their shape upon drying, as shown by the scanning electronmicroscopy (SEM) in Figure 1 (a2), however, a significant size reduction in the size is observed. The SEM image at higher magnification in Figure 1 (a3) captures the morphology more clearly. The microgranules have a rough surface texture with particles projecting outwards and are held together due to cross-linked polymer.

[0118] The microgranules without particles dispersed in n-decane also retain spherical shape, as shown in the OM images in Figure 1 (bl). However, as seen in the inset, spherical granules have a wider size distribution. Unlike the particle-filled microgranules, most of these capsules appeared collapsed when dried which is evident from the low and high magnification SEM image in Figure 1 (b2) and (b3).

[0119] Characterization of drug loading in microgranules:

[0120] Figure 2A shows the FT-IR spectra of the drug molecules and metformin hydrochloride loaded microgranules, both with and without particles. Metformin displays several peaks in the IR region, including a N-H stretching vibration peak at 3147 cm-1, a C-N stretching vibration peak at 1627 cm-1, and a C-N stretching vibration peak at 1058 cm-1(Figure 2A a) (Di. et al. J Mater Chem B 2024 and Xu. Et al. Biomacromolecules 2021). However, in the drug loaded microgranules, the characteristic peaks of the drug molecule become merged and shifted due to dilution and interaction with the matrix.

[0121] In Figure 2B, the X-ray diffraction (XRD) spectra for the drug, and drug-loaded microgranules with and without particles, are presented. The XRD spectra indicates that the drug is crystalline, with prominent peaks at 17, 24, 35, and 39° for Metformin (Figure 2B a) (Bouriche et al., J Drug Deliv Sci Technol 2019 and Sharma et al., Acta Pharmaceutica 2013). However, after encapsulation, characteristic peaksfor the drug molecules (Figure 2B b-c), suggest that Metformin in the microgranules exist in an amorphous form. This implies that the drug interacts with the matrix, resulting in a change in state from crystalline to amorphous.

[0122] In-vitro drug release study:

[0123] The in-vitro drug release study was conducted for the following samples: (i) control i.e., metformin hydrochloride is dissolved in PBS buffer at pH 7, and (ii) metformin hydrochloride loaded microgranules with and without silica particles is dispersed in PBS buffer at pH 7. To investigate release kinetics, a known amount sample (~ few mg) is transferred into a dialysis bag containing 5 mL PBS solution. The dialysis bag is then immersed in 250 mL of PBS dissolution medium, which is stirred at a speed of 80 rpm using magnetic beads. The entire system is maintained at a temperature of 35 ± 0.5 °C throughout the experiments. Prior spectroscopy analysis is performed in the UV-Vis range to identify the features of the spectra corresponding to the presence of metformin hydrochloride in the dissolution media. This data is used to construct absorbance vs. drug concentrations i.e., a calibration curve, for further analysis. At specified time intervals, about 2 mL sample was withdrawn and subsequently replaced with an equal volume of the fresh PBS solution to maintain the identical sink condition. The samples that are withdrawn are subjected to analysis using UV-Vis spectroscopy at 233 nm to determine the amount ranging from metformin hydrochloride released from the microgranules.

[0124] Comparative study:

[0125] A comparison of the release kinetics from the microgranules with and without particles along with control are shown in Figure 3, wherein cumulative drugrelease is plotted against time. The data represented is the average of triplicate experiments and the small error bars indicating excellent reproducibility. The release profile demonstrates that microgranules containing particles exhibit a rapid release, with approximately 40% released in the first 15 minutes and close to 80% released within three hours. Thereafter, the drug is released steadily. Conversely, microgranules without silica particles released only 2% of the drug over the experimental period. Pure metformin, however, is completely released (100%) within 15 minutes. This indicates that the incorporation of particles in microgranules is an effective strategy for the rapid release of the drug. However, if the microgranules are made predominantly of the cross-linked polymer (PEI), the drug molecules are strongly trapped within the polymer network and hence cannot be released, even though the drug is highly water-soluble. Thus, the particles in the microgranule facilitate the escape of drug molecules into the matrix fluid. Thus, the microgranules prepared through this route are viable option for encapsulation of temperature sensitive actives and their fast release.

[0126] Advantages:

[0127] The advantages of the present invention are as follows:

[0128] • The present invention's method requires minimal energy for both droplet formation and conversion into solid granules.

[0129] • It reduces operational costs compared to high-temperature processes like spray drying and fluidized bed granulation.

[0130] • It enables precise tuning of active agent release kinetics.

[0131] • It allows customization based on specific application needs.

[0132] • It is suitable for pharmaceuticals, agriculture, food processing, and other controlled-release industries.• It reduces degradation of heat-sensitive active agents in microgranules. • It enhances shelf life and effectiveness of encapsulated materials.

[0133] • It eliminates the need for complex and high-cost equipment.

[0134] • It simplifies manufacturing while maintaining efficiency and scalability.

[0135] The foregoing description of the various embodiments is provided to enable any person skilled in art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein, and instead the claims should be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

We Claim:

1. A method for preparing microgranules, comprising the following steps of:a) mixing water and silica to obtain particle dispersion;b) adding polymer to the dispersion of step (a) to form polymer coated particle suspension followed by adding a crosslinker;c) adding an active agent to the suspension of step (b); followed by pouring the suspension into an oil phase to form a mixture;d) emulsifying the mixture of step (c) to obtain an emulsion; e) allowing the emulsion obtained in step (d) to remain at room temperature, enabling crosslinking to occur and forming a solid residue; andf) drying the solid residue of step (e) at 40°C to 70° to obtain the microgranules;wherein the active agent is hydrophilic in nature.

2. The method as claimed in claim 1, wherein the active agent is selected from metformin hydrochloride, dopamine hydrochloride, fosphenytoin, acetaminophen, diclofenac sodium, diltiazem hydrochloride, papaverine hydrochloride, or vitamins.

3. The method as claimed in claim 1, wherein the active agent is in an amount ranging from 0.1 wt% to 0.5 wt%.

4. The method as claimed in claim 1, wherein the polymer is selected from branched polyethyleneimine (PEI), chitosan, poly-L-lysine (PLL), or poly guanidines.

5. The method as claimed in claim 1, wherein the polymer is in an amount ranging from 0.5wt% to 1 wt% .

6. The method as claimed in claim 1, wherein the crosslinker is selected from 1,4-Butanediol diglycidyl ether (BDE), Ethylene glycol diglycidyl ether (EGDGE), Polyethylene glycol diglycidylether (PEGDGE), or 1,6- Hexanediol diglycidylether (HDGE).

7. The method as claimed in claim 1, wherein the crosslinker is in an amount ranging from 0.3wt% to 0.8 wt% .

8. The method as claimed in claim 1, wherein the silica particles are in an amount ranging from 1 wt% to 5 wt% .

9. The method as claimed in claim 1, wherein the oil phase comprises n- decane and non-ionic surfactant sorbitan monooleate (SPAN) 80.

10. The method as claimed in claim 1, wherein the solution is emulsified by applying a high energy homogenizer at 4000 rpm to 6000 rpm for a time of 1 to 6 minutes.

11. The method as claimed in claim 1, wherein in step (e), the solid residue formed is allowed to sediment to the bottom of the container.

12. The method as claimed in claim 1, wherein the room temperature ranges from 20°C to 40°C.

13. The method as claimed in claim 1, wherein the microgranules are solid and prepared for controlled release of the active agent.

14. The method as claimed in claim 1, wherein the microgranules have a diameter ranging from 15 to 60 pm.

15. The method for preparing microgranules as claimed in claims 1-14, comprising the following steps of:a) mixing of branched polyethyleneimine (PEI) and dispersed silica particle in water to form a coated particle suspension;b) adding 1,4-Butanediol diglycidyl ether (BDE) to the suspension of step (a);c) adding metformin hydrochloride to the suspension of step (b), followed by pouring the suspension to an oil phase to form an oil water mixture;d) emulsifying the mixture of step (c) to obtain an emulsion;e) allowing the emulsion obtained in step (d) to remain at room temperature, enabling crosslinking to occur and forming a solid residue; andf) drying the solid residue of step (e) at 60°C to obtain microgranules.

16. A microgranule comprising an active agent selected from the group consisting of metformin hydrochloride, dopamine hydrochloride, fosphenytoin, acetaminophen, diclofenac sodium, diltiazem hydrochloride, papaverine hydrochloride, or vitamins, wherein the active agent is dissolved in an aqueous dispersion of polymers and cross-linkers and homogenized with the oil phase.

17. The microgranule as claimed in claim 16, wherein the polymer is selected from branched polyethyleneimine (PEI), chitosan, poly-L-lysine (PLL), or polyguanidines, the crosslinker is selected from 1,4-Butanediol diglycidyl ether (BDE), Ethylene glycol diglycidyl ether (EGDGE), Polyethylene glycol diglycidylether (PEGDGE), or 1,6-Hexanediol diglycidylether (HDGE); and the oil phase comprises n-decane and non-ionic surfactant sorbitan monooleate (SPAN) 80.

18. The microgranule as claimed in claim 16, wherein the microgranules comprises 0.1wt% to 0.5wt% of active agent, lwt% to 5wt% of silicaparticles, 0.5wt% to lwt% of polymer, 0.3wt% to 0.8 wt% of crosslinker, and 70wt% to 85wt% oil phase.

19. A method for in-vitro drug release analysis, comprising the steps of:a) dispersing the microgranules as claimed in claim 16 in phosphate buffer saline (PBS) buffer solution at pH 7 to obtain a formulation; b) placing the formulation of step (a) in PBS dissolution medium under controlled laboratory conditions;c) stirring the medium of step (b) at a speed of 50 rpm to 90 rpm, while maintaining a temperature of 35 ± 0.5 °C;d) monitoring the release profile of the drug over a time period; and e) analyzing the drug release kinetics,wherein the method is conducted entirely in an in-vitro environment.

20. The method as claimed in claim 19, wherein in step (a), the PBS is in amount ranging from 2mL to 8mL, in step (b), the PBS is in amount ranging from 200mL to 300mL, in step (c), the speed is at 80 rpm, and in step (d), the drug is released for 3 days.

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