1. INTRODUCTION:

Overcoming the limited solubility and slow dissolution rate of poorly hydrophilic drugs persists as a crucial hurdle in pharmaceutical development.¹ concerns about water insolubility hindering oral drug absorption plague an estimated 75% of drugs currently in development.² The majority of these problematic water-insoluble drugs fall under Biopharmaceutical classification system (BCS) class II. For drugs plagued by poor solubility, increasing their surface area to accelerate dissolution presents a viable solution.³Numerous formulation strategies have emerged to tackle the solubility and dissolution challenges of these pharmaceuticals. A particularly effective approach for poorly hydrophilic drugs involves developing micro or nanofibrous amorphous solid dispersions (ASDs) using suitable hydrophilic carriers.⁴ Formulating ASDs offers a promising method for enhancing the solubility and dissolution rate of hydrophobic drugs.⁵ The effectiveness of ASDs stems from their ability to reduce the particle size, exposing a larger surface area for faster dissolution and utilize hydrophilic carriers thereby facilitating interaction with water. Importantly the drug is converted into an amorphous form that increases solubility by disrupting crystal lattices. Despite the immense potential of ASDs, their widespread adoption remains limited due to challenges in Preserving structural stability means of Preventing undesirable physical transformations, cost effective production in balancing scalability with economic feasibility, and Up-scaling manufacturing process that Efficiently translates lab-scale processes to commercial production.⁶

The convergence of ASDs with nanotechnology has reignited interest, particularly in the development of nano/microfiber ASDs using techniques like electrospinning.⁷Compared to conventional methods, nano/microfiber ASDs demonstrate superior drug dissolution enhancement, leading to their growing adoption in drug delivery applications.⁸Electrospinning technique Point out the potential of nanofiber's high porosity and extensive surface area in overcoming the solubility challenges of various drugs.⁷

Although advancements like multi-nozzle, nozzle-free, and high-speed electrospinning offer scaling-up potential, wider commercial adoption remains hindered by the complexity, low yield, slow production rates, and high cost associated with the technique.⁷Also the research carried out for ASD material produced through fast evaporation, lyophilization, and spray-drying techniques, employing griseofulvin as a representative compound.⁹ But less attention was paid to the centrifugal melt spinning Centrifugal spinning, also known as rotary jet spinning, is a modern take on a technique invented in 1924 for producing artificial silk fibers. This method has gained traction for its ability to produce micro and nanofibers from polymeric materials at high rates. Unlike electrospinning, centrifugal spinning doesn't require high voltage, making it safer for industrial applications. The process involves a rotating chamber filled with polymer solution or melt. Centrifugal force pushes the material through nozzles, and as the jet travels towards a collector, it stretches and dries to form nano-sized fibers. This technique offers a promising alternative for high-volume production of polymeric micro and nanofibers. This research explores a Revolutionary Fiber preparation technique Centrifugal melt spinning (CMS) for enhancing the solubility of the poorly soluble drug Griseofulvin (GSF). CMS boasts outstanding productivity, exceeding traditional electrospinning by roughly 500 times for Silica nanofibers with multilevel organization.¹ Importantly, the method readily accommodates sugars and different polymers, including melts and a wide range of crystalline materials.^10-12

GSF a poorly water-soluble, orally administered class II antifungal drug disrupts fungal cell division by interfering with microtubule function. This makes it a valuable therapeutic option for managing various superficial fungal infections, particularly tinea capitis, onychomycosis, and tinea corporis, where topical treatments may prove ineffective.^13-15 GSF holds United States Food and Drug Administration (US FDA) approval for tinea capitis treatment and remains the established first-line therapy due to its proven efficacy and favourable safety profile in children.^14-16 The bitter taste of GSF might contribute to its extended treatment duration for fungal infections, as frequent dosing may be less tolerable due to palatability issues in children. Centrifugal melt spinning was chosen as a viable technique. Sucrose and lactose were chosen as carriers in this centrifugal melt-spinning process due to their well-established ability to enhance the solubility of poorly soluble drugs like griseofulvin. By dispersing the drug throughout the microfibers, these sugars increase their surface area for better contact with water, leading to faster dissolution. Additionally, the hydroxyl groups in sucrose and lactose can form hydrogen bonds with water molecules, further aiding this process. Importantly, both carriers are biocompatible and cost effective, making them attractive choices for improving griseofulvin's bioavailability. They also have a sweet taste that will help mask the unpleasant taste of griseofulvin. . This study introduces a novel application of centrifugal melt spinning for creating micro-fibrous solid dispersions. The research focuses on griseofulvin, a drug with low solubility. By using carriers like sucrose and lactose, the researchers aim to improve the drug's solubility, dissolution rate, and ultimately, its bioavailability.^17-22

2.MATERIALS AND METHODS:

2.1. Materials:

GSF was gifted by Nulife Pharmaceuticals (Pune, India) Sucrose was kindly provided by M. B. Sugars and Pharmaceuticals(Malegaon, India) Lactose was purchased from LobaChemie(Mumbai, India). The study exclusively employed analytical-grade materials for all procedures.

2.2. preparation of microfibres by centrifugal melt spinning:

Sucrose and lactose microfibers loaded with 10%(w/w) GSF were fabricated using our custom-designed cotton candy-inspired apparatus which was calibrated for RPM and temperature using a contact tachometer and digital thermometer respecticely²⁰ To create the physical mixtures (PMs), sucrose (90% w/w) and GSF (10% w/w) were blended for 5 minutes in a mortar, followed by a similar procedure for lactose (90% w/w) and GSF (10% w/w).²10 grams of each original material were precisely Measured and fed into the preheated Spinning wheel at the desired temperature of about 200°C. Spinning was performed at 5000 rpm under room temperature conditions (27 ± 5.0 °C). Characterization of the resulting fibers was completed within 24 hours of preparation.^1,2

3. EVALUATION:

3.1. Percentage Yield and drug loading capacity:

The percent yield of drug-encapsulated microfibers was Established by Employing Equation:

Weight of prepared soild dispersion

Yield (%W/W) = ---------------------------------- X 100

Weight of drug + carrier

Drug Loading capacity was calculatedby Applying Equation:

Amount of drug measured

DLC(%W/W) = ---------------------------------- X 100

Therotical amount of drug based on drug loading

Drug loading capacity for both GSF-loaded sucrose and lactose fibers was quantified by dissolving 10mg of fibers in 10mL of phosphate buffer (pH 6.8) in which both drug and carrier are soluble, The UV absorbance was taken at 291nm. The amount of drug was estimated using the calibration curve.²

Fig. 1. Diagram of a centrifugal spinning system for producing drug-encapsulated microfibers, illustrating key steps.

3.2. Microscopic examination of GSF-Encapsulated Sucrose and lactose Fibers:

A scientific research microscope (motic-B1 advanced series 223) was used to analyse freshly prepared sucrose and lactose fiber loaded with (GSF). Image analysis software (Moticsoft) was employed to measure the diameter of the fine fiber at 5x magnification.¹

3.3. Scanning Electron Microscopy (SEM):

Freshly prepared GSF-loaded sucrose and lactose microfibers underwent SEM analysis (FEI Nova NANOSEM 450) to reveal their morphologic characteristics^.1

3.4. Saturation Solubility of GSF, GSF-Encapsulated Sucrose and lactose Microfibers:

The influence of microfibers on the solubility of GSF was investigated. 10mL of phosphate buffer (pH 6.8) was added to Erlenmeyer flasks, followed by an excess of pure GSF and GSF-loaded sucrose and lactose microfibers. The flasks were incubated at 37°C for 72 hours on a shaking platform(Remi CIS-18 Plus). Following filtration, the GSF concentration in each sample was quantified using UV spectroscopy at 291 nm.Saturation solubilities were then calculated and compared for pure GSF and the microfibre-loaded form of both carriers.^2,9

3.5. Powder X-ray Diffraction analysis (PXRD):

The crystallinity of pure GSF,GSF-loaded sucrose,and lactose microfibers was investigated using X-ray scattering measurements. Wide-angle X-ray diffraction on a (Rigaku Ultima IV diffractometer) scanned samples across a 2θ range of 10-80° to distinguish between crystalline and amorphous states.^1,9

3.6. Differential Scanning Calorimetry (DSC) Analysis:

Differential scanning calorimetry (DSC) was employed to investigate the thermal melting behaviour of GSF, GSF-loaded sucrose microfibers, and GSF-loaded lactose microfibers prepared using the centrifugal melt spinning technique. Thermal analysis of pure GSF and GSF-Encapsulated sucrose and lactose microfibers (3-5 mg each) was performed using Mettler Toledo Instruments (50mLmin^-1 N₂ flow, 10°Cmin^-1 heating).^1,2,9

3.7. Fourier transform infrared (FTIR) Spectroscopy:

To investigate the impact of high-temperature centrifugal melt spinning on potential drug-carrier interactions, the chemical structure and physical state of microfibers (GSF, GSF-loaded sucrose, and GSF-loaded lactose) were analyzed with the help of Attenuated total reflectance infrared spectrophotometer.(ATR-FTIR Shimadzu).^1,3,9

3.8. In-vitro Dissolution Studies:

GSF release originating from freshly prepared GSF encapsulated microfibers (sucrose and lactose), pure GSF, and non-fibrillated physical mixtures were compared in vitro using a USP II paddle dissolution apparatus. The dissolution medium was phosphate buffer (pH 6.8) at 37°C±0.2°C and carried out at 50rpm. Microfibers (100mg drug equivalent) were dispersed, and the dissolution medium was maintained at a constant volume by replacing 5mL aliquots at Consistent intervals of (3, 5, 10, 20, 30, 40, 50, and 60 minutes) with fresh medium of phosphate buffer (pH 6.8) The released GSF from fiber was quantified using UV-VIS spectrophotometer at 291nm, allowing for comparison of release profiles between the different formulations.^1,3,9

4. RESULTS:

4.1. Percentage Yield and drug loading efficiency:

GSF loaded sucrose microfibers yielded a significantly higher percentage (88.88±1.07%) compared to GSF loaded lactose microfibers (83.35±1.15%). Similarly, GSF-Loaded sucrose microfibers exhibited a higher drug loading efficiency (95.86±0.68%) than GSF loaded lactose microfibers (84.25±0.6%).

4.2. Microscopic examination of GSF Encapsulated Sucrose and lactose Fibers:

The diameter of GSF-encapsulated sucrose fibers ranged from 7.74 to 18.44 microns (µm), with an average diameter of 12.34±3.70µm (as shown in Figure 2a). GSF-encapsulated lactose fibers had a wider diameter range, spanning from 20.51 to 40.99µm. Their average diameter was 28.75±7.24µm (as illustrated in Figure 2b).

4.3 Scanning Electron Microscopy(SEM):

GSF-encapsulated sucrose and lactose microfibers revealed a consistent configuration, smooth covering, and irregular orientation, suggesting that the molecular dispersion of the drug is consistent within both sucrose and lactose microfibers

Fig. 2. a) GSF-loaded sucrose microfibres under moticmicroscope

Fig. 2. b) GSF-loaded lactose microfibres under motic microscope.

Fig. 3 a) SEM image of GSF-encapsulated sucrose microfibers.

Fig. 3 b) SEM image of GSF-encapsulated lactose microfibres.

4.4. Powder X-ray Diffraction (PXRD):

Major X-ray diffraction peaks of griseofulvin, particularly at2θ of 10.76,13.22,16.52,22.56 and 23.83. The API Griseofulvin shown peak at 2θ= 10.76˚c at the intensity of 3850, 2θ= 13.22˚c at the intensity of 3683, 2θ= 16.52˚c at the intensity of 7258.33, 2θ= 22.56˚c at the intensity of 5641.67, 2θ = 23.86˚c at the intensity of 3450, all this indicates crystalline nature of griseofulvin.

Fig. 4. XRD overlay of GSF, Sucrose, Lactose, GSF-Loaded Sucrose and GSF-Loaded Lactose Microfibres.

4.5. Saturation Solubility of GSF, GSF-loaded Sucrose And lactose Microfibers:

GSF solubility was significantly enhanced when incorporated into sucrose and lactose microfibers compared to pure GSF. Sucrose microfibers demonstrated the highest solubility increase (3.21-fold), out performing lactose microfibers (2.38)

Fig. 5.The relative solubility of griseofulvin in a pH 6.8 phosphate buffer.

4.6. Differential Scanning Calorimetric (DSC) Analysis:

Overlaid thermograms of the active GSF, Sucrose, and lactose the drug-loaded sucrose, and lactose fibres. The thermogram of Griseofulvin displays a distinct, sharp endothermic peak at 220.33°C, signifying the melting of its crystalline phase. Sucrose exhibits a single sharp endothermic peak at 184°C. while lactose demonstrates two sharp endothermic peaks at 146°C and 213°C. consistent with established literature values. In contrast, the DSC thermogram of the prepared microfibersreveals only a broad endothermic peak. Notably, the endothermic melting peak associated with the active substance disappears entirely from the microfibers' thermogram, indicating the transition of griseofulvin from a crystalline to an amorphous state during the fibre formation process.

Fig. 6. DSC overlay of GSF, Sucrose, Lactose, GSF-Loaded Sucrose and GSF-Loaded Lactose fibres.

4.7. ATR-FTIR Spectroscopy:

The analysis of GSF using infrared spectroscopy revealed its key functional groups . Prominent peaks were observed at wavenumbers 1658.78 cm⁻¹ (indicative of C=O stretching), 1427.32 cm⁻¹ (attributed to C-H stretching), and 1344.30 cm⁻¹ (corresponding to 0-H bending).³⁰ In contrast, the IR spectrum of sucrose displayed a more complex pattern with numerous peaks corresponding to O-H and C-O stretching vibrations.²⁸Alsolactose spectrum exhibits identifiable bands in 3600-3100 cm⁻¹ (OH stretch) and 1200-900 cm⁻¹ (C-O-C and C-OH stretch modes) regions. Examining the ATR-FTIR spectra of GSF loaded sucrose and lactose fibers (Figure 7&8) unveiled a significant reduction in the number and intensity of characteristic GSF peaks compared to the pure drug spectrum. Furthermore, the peaks in both the fibers spectrum appeared broader, suggesting the transformation of GSF into an amorphous state within the fibers.

Fig. 7. FT-IR overlay of GSF, Sucrose, GSF Loaded Sucrose fibers.

Fig. 8. FT-IR overlay of GSF, Lactose, GSF Loaded Lactosefibers.

4.8 In-vitro Dissolution Studies:

The comparative release profiles of pure GSF, GSF-loaded sucrose, and GSF loaded lactose microfibres (figure 8). Notably, pure GSF displayed the lowest dissolution rate, releasing only 48.17±0.73% within 5 minutes. While physical mixtures with sucrose and lactose exhibited dissolution of 60.17±0.90% and 58.95±049% respectively. In contrast, both the drug loaded sucrose and drug loaded lactose microfibers demonstrated significantly faster release rates, reaching 94.98±0.61% and 91.47±0.52% respectively, with in the same time frame.

Fig. 9. Dissolution profile ofGSF, GSF + Sucrose physical mixture (PM), GSF + Lactose (PM), GSF-Loaded Sucrose and GSF-Loaded Lactose Microfibres.

5. DISCUSSIONS:

Sucrose proved a more effective carrier than lactose for GSF in microfibers. It yielded higher drug loading and produced smaller, more uniform fibers. GSF transitioned from a crystalline to an amorphous state during the encapsulation process, improving solubility. Sucrose based microfibers significantly enhanced GSF solubility compared to lactose. Additionally, these microfibers demonstrated superior drug release compared to pure GSF or physical mixtures, likely due to increased surface area and the amorphous state of the drug.

6. CONCLUSION:

Centrifugal melt spinning successfully produced microfibrous solid dispersions of griseofulvin in sucrose and lactose. Sucrose-based microfibers exhibited superior drug loading, release, and solubility compared to lactose. The amorphous state of Griseofulvin within the fibers significantly enhanced drug dissolution. These findings suggest potential for improved bioavailability and therapeutic efficacy, warranting further investigation into optimal processing conditions and drug loading capacities.

7. ACKNOWLEDGMENTS:

The authors express their sincere gratitude to Nulife Pharmaceuticals and M.B. Sugars for providing the necessary materials. They also extend their appreciation to Marathwada Mitra Mandal’s College of Pharmacy for its invaluable support.

8. REFERENCES:

1. Priya R, Satish S. Centrifugal Melt Spun Microfibrous Solid Dispersion of Diclofenac Sodium with Enhanced Solubility. International Journal of Pharmaceutical Quality Assurance [Internet]. 2023; Mar 25; 14(1): 165–70. Available from: https://doi.org/10.25258/ijpqa.14.1.28

2. Marano S, Barker SA, Raimi-Abraham BT, Missaghi S, Rajabi-Siahboomi A, Craig DQM. Development of micro-fibrous solid dispersions of poorly water-soluble drugs in sucrose using temperature-controlled centrifugal spinning. European Journal of Pharmaceutics and Biopharmaceutics [Internet]. 2016; Jun 1; 103: 84–94. Available from: https://doi.org/10.1016/j.ejpb.2016.03.021

3. Marano S, Ghimire M, Missaghi S, Rajabi-Siahboomi A, Craig DQM, Barker SA. Development of Robust Tablet Formulations with Enhanced Drug Dissolution Profiles from Centrifugally-Spun Micro-Fibrous Solid Dispersions of Itraconazole, a BCS Class II Drug. Pharmaceutics [Internet]. 2023; Mar 1; 15(3): 802. Available from: https://doi.org/10.3390/pharmaceutics15030802

4. Mahore JG, Deshkar SS, Kumare PP. Solid dispersion technique for solubility improvement of ketoconazole for vaginal delivery. Research Journal of Pharmacy and Technology [Internet]. 2019; Jan 1; 12(4): 1649. Available from: https://doi.org/10.5958/0974-360x.2019.00276.2.

5. Eswaraiah MC, Jaya S. Enhancement of dissolution rate of telmisartan by solid dispersion technique. Research Journal of Pharmacy and Technology [Internet]. 2020; Jan 1; 13(5): 2217. Available from: https://doi.org/10.5958/0974-360x.2020.00398.4.

6. Sonawane TD, Mujoriya RZ. Role of hydrophilic carrier in solubility enhancement. International Journal of Pharmaceutical Dosage Forms and Technology [Internet]. 2016; Jan 1; 8(3): 173. Available from: https://doi.org/10.5958/0975-4377.2016.00023.9.

7. Adpekar PD, Rama A, Rani U, Naha A. Electrospunnanofibres and their biomedical applications. Research Journal of Pharmacy and Technology [Internet]. 2020; Nov 13; 13(11): 5569–75. Available from: https://doi.org/10.5958/0974-360x.2020.00972.5.

8. Kunam V, Suryadevara V, Garikapati DR, Mandava VBR, Sasidhar R. Solubility and Dissolution Rate Enhancement of Ezetimibe by Solid Dispersion and Pelletization Techniques Using Soluplus as Carrier. International Journal of Applied Pharmaceutics [Internet]. 2019; Apr 11; 57–64. Available from: https://doi.org/10.22159/ijap.2019v11i4.32274.

9. Marano S, Barker SA, Raimi-Abraham BT, Missaghi S, Rajabi-Siahboomi A, Aliev AE, et al. Microfibrous solid dispersions of poorly Water-Soluble drugs produced via centrifugal spinning: unexpected dissolution behavior on recrystallization. Molecular Pharmaceutics [Internet]. 2017; Mar 27; 14(5): 1666–80. Available from: https://doi.org/10.1021/acs.molpharmaceut.6b01126.

10. Patil ML, Gaikwad SS, Kapare HS. A Systematic review on Antimicrobial applications of nanofibres. Research Journal of Pharmacy and Technology [Internet]. 2024; Jan 19; 427–32. Available from: https://doi.org/10.52711/0974-360x.2024.00067.

11. Bagade OM, Mali AR, Survase SS, Chaudhari AK, Doke PE. An updated overview on mucoadhesive buccal drug delivery system. Research Journal of Pharmacy and Technology [Internet]. 2021; Aug 6; 4495–500. Available from: https://doi.org/10.52711/0974-360x.2021.00781.

12. Zhang X, Lu Y. Centrifugal spinning: an alternative approach to fabricate nanofibers at high speed and low cost. Polymer Reviews [Internet]. 2014; Aug 30; 54(4): 677–701. Available from: https://doi.org/10.1080/15583724.2014.935858.

13. Rai S, Kamath BV, Subrahmanyam VM. Strategies for treatment of onychomycosis. Research Journal of Pharmacy and Technology [Internet]. 2018; Jan 1; 11(11): 5135. Available from: https://doi.org/10.5958/0974-360x.2018.00937.x.

14. Elewski BE. Treatment of tinea capitis: beyond griseofulvin. Journal of the American Academy of Dermatology [Internet]. 1999; Jun 1; 40(6): S27–30. Available from: https://doi.org/10.1016/s0190-9622(99)70394-4.

15. Sonam Shukla, Swarnakshi Upadhyay, Rajneesh Kumar Gupta. Formulation and Evaluation of Griseofulvin Solid Dispersion incorporated gel for topical application. Research Journal of Pharmacy and Technology. 2022; 15(10): 4389-4. doi: Solid dispersion, Griseofulvin, Gel, Melting method, Franz diffusion cell, Solubility.

16. Ramesh KVRNS, Ower NY, Sarheed O, Islam Q. Dissolution Enhancement of Indomethacin through Binary and Ternary Solid dispersions and Inclusion Complexes – A Comparative Evaluation. Research Journal of Pharmacy and Technology [Internet]. 2022; Dec 24; 5529–36. Available from: https://doi.org/10.52711/0974-360x.2022.00933.

17. Bennett ML, Fleischer AB, Loveless JW, Feldman SR. Oral griseofulvin remains the treatment of choice for tinea capitis in children. Pediatric Dermatology [Internet]. 2000; Jul 1; 17(4): 304–9. Available from: https://doi.org/10.1046/j.1525-1470.2000.01784.x.

18. Aris P, Wei Y, Mohamadzadeh M, Xia X. Griseofulvin: An updated overview of old and current knowledge. Molecules/Molecules Online/Molecules Annual [Internet]. 2022; Oct 18; 27(20): 7034. Available from: https://doi.org/10.3390/molecules27207034.

19. Sebe I, Kállai-Szabó B, Oldal I, Zsidai L, Zelkó R. Development of laboratory-scale high-speed rotary devices for a potential pharmaceutical microfibre drug delivery platform. International Journal of Pharmaceutics [Internet]. 2020; Oct 1; 588: 119740. Available from: https://doi.org/10.1016/j.ijpharm.2020.119740.