INTRODUCTION:

The Oral drug delivery system is the most common method of drug delivery that has been used over the decades¹. Oral Sustained Release dosage form is a dosage form which releases a specific number of doses of a drug over a predefined period of time either systemically or to a specific target site or organ¹. This drug delivery system has a greater control on the plasma drug levels, fewer side effects, fewer dose intervals, increased efficacy and constant delivery of the drugs². Drug properties are quite critical in the design of a sustained release dosage form whereby physicochemical and biological properties of the drug are the most crucial. They are Aqueous solubility and pKa, partition coefficient, Drug stability, protein binding, molecular size and diffusivity, absorption, distribution, metabolism, biological half-life and Dose Size^3-7.

Based on size, structure and material composition, the particulate drug delivery systems are classified into various types. Some of the most important are the nanoparticles, microparticles, liposomes, and polymeric particles, each having its own benefits in targeted drug delivery. Nanoparticles refer to particles with a diameter of 1 to 100nm, which are commonly used in targeted delivery of drugs because of their size and capacity to enter tissues.

Treatment of fungal colon infections with Itraconazole (ITZ), a broad-spectrum triazole antifungal, is given orally at high doses (200-400mg/day). Nonetheless, this is a high dose regimen which is potentially associated with several complications, such as pseudo-hyperaldosteronism, gastrointestinal complications, liver complications, and the tendency of this regimen to induce congestive heart failure. As such, a sustained release therapy method that has a particulate character and ability to minimize the dosage of ITZ would most likely lead to a reduction of these side effects⁸.

Itraconazole is a mildly basic (pKa = 3.7) but highly hydrophobic triazole derivative (octanol/water partition coefficient at pH = 8.1, logP = 5.66) (9). This was because it was aqueously insoluble and this led to large inter and intra-individual variation of its oral bioavailability¹⁰.

Thus, in this study the efforts have been made to prepare a particulate system using rate modulating macromolecules and surfactants that are suitable as well as entrap itraconazole and also to examine various formulations and processing behaviors such as determination of the size of the particle, zeta potential determination etc. It would be anticipated that such a dispersed system would enhance the bioavailability, stability as well as usefulness against broad spectrum mycoses. Delivery in colloidal system is also likely to reduce significantly the toxicity profile of the potent drug presumably because of the decreasing effect dose and the increasing distribution profile.

The formulations are designed with consideration of their reproducibility to describe the impact of different formulations and processing parameters on the quality of lipid nanoparticles and performance¹¹.

MATERIALS AND METHODS:

Procurement of drugs, excipients and other reagents:

The itraconazole was obtained in USV Private Limited Govandi, Mumbai, India. All the other reagents and excipients were purchased through authorised dealers and the used materials were of analytical grade. All the instruments employed in the current research were well calibrated and standardised.

Preformulation studies:

Obtained sample of Itraconazole was tested in the form of organoleptic properties including appearance, colour, taste, etc. Melting point of Itraconazole was done using open capillary method¹². Loss on drying was determined by holding 0.5g of Itraconazole in oven at 105⁰C/2h. Comparison with specification in Certificate of Analysis (COA), drug sample provider was carried out.

The compatibility of itraconazole solubility with 0.1N HCl solution, Ethyl oleate, Tween 80, Tween 20, Propylene Glycol, Ethanol, and purified water was determined by the shake flask method. Finding out whether polymers and pharmaceuticals are compatible was done by FTIR¹³.

Formulation of Itraconazole-based particulate delivery system:

The nanoparticles were prepared in the current work in the case of particulate delivery system. It was developed by employing the emulsification/ solvent evaporation process. Various amounts of itraconazole and chitosan were dissolved in Dichloromethane (DCM) (refer table 1). The probe Sonicator (Athena Technology) at 50 percent amplitude of 10 minutes decreased the size of the globules in the emulsion followed by the 10 mL 2 percent Polyvinyl alcohol (PVA). To isolate the dry NP, the NPs dispersion was centrifuged at 15,000 RCF with 30 minutes using (REMI equipment) following the night evaporation of DCM. The pellet was dispersed in de-ionized water and freeze-dried using a (Vir Tis bencbtop K) freeze drier¹⁴.

Table 1: Composition of different batches of Itraconazole loaded NPs

Formulation Code	Itraconazole (mg)	Chitosan (mg) (X1)	DCM (ml) (X2)	PVA (2%) (ml)
F1	25	50	2	10
F2	25	50	4	10
F3	25	50	6	10
F4	25	75	2	10
F5	25	75	4	10
F6	25	75	6	10
F7	25	100	2	10
F8	25	100	4	10

Characterization of Formulated Nanoparticles Batches:

Nanoparticles were assessed by their naked look, entrapment efficiency by measuring the spectrophotometrically at272nm, yield of production. The average size of nanoparticles and size distribution were determined at room temperature by using Malvern Zetasizer.

Based on the results, an optimum batch was used with minimum particle size with maximum entrapment efficiency¹⁵.

Characterization of Optimized Batches of Itraconazole Loaded Nanoparticles:

The Itraconazole loaded nanoparticles were assessed on parameters of Micrometrics such as Bulk density, Tapped density, Hausners ratio, Carrs Index and angle of repose.

Quantitative analysis of amount of itraconazole released correspondingly at respective time was performed in-vitro dissolution study with the help of UV-visible spectrophotometer (Shimadzu UV2450, Japan) at 262 nm using the USP XXIII Dissolution apparatus I (basket type) at 50rpm with 225mL of optimised formulation in 0.1 N HCl at 37 +- 0.5^oC.

Itraconazole nanoparticles were tested in terms of chemical and physical stability under different storage temperatures namely room temperature (RT), 4.0+-2degC /15+-5% RH, 30+-2degC/65+-5% RH and 40+-2degC/75+-5% RH according to ICH guidelines (ICH Q1A(R2)).

RESULTS AND DISCUSSION:

Preformulation Study:

Itraconazole was shown to be a white, crystalline powder with no smell by visual inspection.

Itraconazole's bulk melting point was determined to be between 167°C±0.78 and 167°C±0.38, which is quite near to the reference value of 166.4°C.

The LOD of the obtained itraconazole sample was 0.11 percent, which was less than the 0.5% required by the COA.

The results of the sample's organoleptic characteristics, melting point, and LOD were found to fall within the range specified in the COA. As a result, the Itraconazole sample was determined to be pure.

Solubility study:

Drug development is hampered by itraconazole's weak water solubility. Table 2 lists the solubility of itraconazole in the various solvents that were used. Kumar et al.'s experiment produced similar outcomes¹⁶.

Table 2: Solubility of itraconazole in different solvents

Solvents	Concentration (mg/ml) ±STD
Tween 80	9.87±0.04
Tween 20	4.82±0.030
Propylene Glycol	18.77±0.11
Ethyl oleate	19.888±0.293
Water	2.388±0.18
0.1 N HCl	11.59±0.21

The partition coefficient was calculated using a combination of lipophilic and hydrophilic solvents. The partition coefficient of itraconazole was determined for the current activity using a combination of n-octanol and water. Itraconazole's value of 5.34±0.727, which is near to the value of 5.66 units reported in the literature, suggests that it is a lipophile¹⁷.

Compatibility Study:

The FTIR Spectrometer was used to do the initial compatibility. It can be deduced that all of the chosen excipients were compatible with the drug because the provided spectra (figures 1, 2, and 3) show no additional peak in the spectrums from the drug and excipient combo.

Figure 1: FTIR spectrum of pure Itraconazole

Figure 2: FTIR Spectra of Itraconazole and Chitosan

Figure 3: FTIR spectra of Itraconazole and PVA

Evaluation of Itraconazole Nanoparticle formulations:

All of the developed Itraconazole formulations had a transparent, homogenous, and clear look.

% Entrapment Efficiency:

A percentage was used to represent the entrapment efficiency. The percentage entrapment efficiency (% EE) of the nanoparticles is shown in Table 3. The range of the percentage drug content for all formulations loaded with Itraconazole was 43.70±1.2% to 83.90± 1.1%. Formulation F-7 was found to have the highest percentage of EE, with a value of 83.9±1.1%. F6 and F5 came next with 76.80±1.2% EE and 75.70±0.8% EE, respectively.

Table 3: Entrapment efficiency (%) of various formulations

Batches	Entrapment efficiency (%) (mean ± SD, No.=6)
F1	70.40 ± 1.3
F2	62.40 ± 1.2
F3	67.30 ± 0.8
F4	58.30 ± 1.1
F5	75.70 ± 0.8
F6	76.80 ± 1.2
F7	83.90 ± 1.1
F8	43.70 ± 1.2

Particle size

Table 4 below compiles the particle size distribution as observed for various formulations. It was discovered that the particle size ranged from 234.8±0.72 to 498.8±1.2nm.

Table 4: Particle size of different formulation batches

Batches	Particle Size (nm) (mean ± SD, No.=6)
F1	498.8 ± 1.2
F2	369.4 ± 1.2
F3	397.3 ± 0.8
F4	458.3 ± 1.1
F5	351.9 ± 1.1
F6	334.5 ± 1.3
F7	234.8±0.72
F8	475.66 ± 0.8

To summarize up, Batch F-7 exhibits the best particle size of all the itraconazole NP formulations, measuring 234.8±0.72nm.

Zeta potential:

Table 5 below shows the results of three assessments of NP's zeta potential. It was discovered to be between 10.32±1.3 and 31.2±1. mv.

Table 5: Zeta potential (mv) of different formulation batches

Batches	Zeta potential (mv) (mean ± SD, No.= 6)
F1	10.32 ± 1.3
F2	16.32 ± 1.2
F3	15.66 ± 0.8
F4	18.8 ± 1.2
F5	21.33 ± 0.8
F6	27.3 ± 1.1
F7	31.2 ± 1.1
F8	13.7 ± 1.2

According to the aforesaid result, batch F-7 exhibits the best zeta potential (31.2±1.1 mv) among the different itraconazole NP formulations for formulation stability. Other formulations with zeta potentials greater than 20 mv were F6 and F5.

% Production yield

The percentage production yields for batches F1 through F8 ranged widely, from 74.46 percent to 92.56 percent. With a manufacturing yield of 92.56 percent, this F-7 batch has a high percentage (table 6). Chitosan concentration and stabilizer duration were found to affect the yield of nanoparticle production.

Table 6: Production yield of Itraconazole Nanoparticle formulations

Formulation Code	% Production Yield
F1	84.41±0.13
F2	77.74±0.03
F3	78.54±0.13
F4	84.78±0.04
F5	86.69±0.02
F6	88.53±0.01
F7	92.56±0.13
F8	74.46±0.47

Selection of Optimized Itraconazole formulation for further study:

F-7 was chosen for additional consideration in light of the findings from the aforementioned study formulation. In order to create a comparative profile, formulations F5 and F6 were also taken. Furthermore, a commercial formulation, Iptran, 100mg capsules, purchased from Pranshul Lifescience Pvt Ltd, was also contrasted with these formulations.

Micrometric Evaluation:

The results of the several micrometric parameters that were examined are given in table 7 and figure 4 under the optimized Itraconazole formulation that was chosen.

Figure 4: Different micrometric parameters of NPs formulations of Itraconazole

In-vitro Dissolution study:

Rapid therapeutic drug levels are made possible by the current investigation's findings, which show that Itraconazole NP formulations release 85.33% of their drug in 7 hours with a regulated release pattern after a burst of release.

Table 8: In-vitro dissolution study of itraconazole NPs formulations

Times (hours)	F-7	F-6	F-5	Iptran
0	0	0	0	0
0.5	46.33	41.32	41.66	45.33
1	54.58	49.77	48.54	52.88
2	57.99	58.77	52.33	59.28
3	62.77	62.33	56.88	63.99
4	72.58	69.56	63.77	70.35
5	79.74	73.65	69.11	78.37
6	82.44	74.03	71.56	84.39
7	85.33	76.89	73.66	88.22

Figure 5: Relative in-vitro dissolution study

Stability Study:

Determining how well the batch F-7 formulation maintained its potency and integrity over a three-month period was the main goal of the itraconazole stability research. Throughout the entire study, it retained its original characteristics and therapeutic efficacy, as shown by the findings in Table 9. The instant release pellets found in the samples had a drug concentration ranging from 98.23 to 100.54%. This data shows that the product is stable for up to six months at room temperature and in accelerated environmental conditions, and it falls well within the pharmacopoeial limits (95%–105% w/w).

Furthermore, the Zeta potential, particle size, and entrapment effectiveness were found to be comparable to the results previously reported from various groups ^16-19.

CONCLUSION:

Based on all of the observations and findings, it can be said that the emulsification/solvent evaporation approach has been successfully used to create NPs of itraconazole. Based on the findings of the preformulation research of itraconazole's organoleptic qualities, melting point, and LOD, it can be said that the medication sample that was obtained met the requirements specified in the certificate of analysis. The drug itraconazole was successfully included with a high entrapment efficiency using the Emulsification and Solvent Evaporation technique. The findings indicate that the nanoparticle formulation is more effective than the commercially available traditional gel in treating skin infections, including ringworm, jock itch, athletes foot, and fungal skin infections. The findings of this comprehensive investigation offer crucial data for upcoming pharmacological and itraconazole-based nanoparticle studies and advancements. To assess the combined impact of itraconazole and its metabolites on blood circulation, more research is required. In addition to significantly lowering dose, these extended-release formulations also lessen the negative effects of traditional dosage forms. Its clinical trials and scale-up for industrial-scale manufacture require more research.

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Received on 15.10.2025 Revised on 07.11.2025

Accepted on 27.11.2025 Published on 30.01.2026

Available online from February 05, 2026

Res. J. Pharma. Dosage Forms and Tech.2026; 18(1):17-22.

DOI: 10.52711/0975-4377.2026.00003

This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License.

Optimized Formulation	Bulk Density (gm/ml)	Tapped Density (gm/ml)	Hausner’s ratio (gm/ml)	Carr’s Index (%)	Angle of Repose (°)
F7	0.50±0.09	0.58±0.01	1.16	12.19±0.05	22.68±0.02
F6	0.55±0.03	0.65±0.03	1.15	13.87±0.04	25.68±0.02
F5	0.58±0.06	0.70±0.03	1.17	16.19±0.06	28.15±0.05
Iptran	0.54±0.04	0.63±0.03	1.2	14.14±0.06	27.50±0.08

Sr. No.	Temp (^oC)/RH (%) Condition	Time period (Days)	Observation F-7	Assay
1	4.0/15	30	No change	102.3 ± 0.1
2	4.0/15	60	No change	102.1 ± 0.1
3	4.0/15	90	No change	101.0 ± 0.1
4	25/65	30	No change	101.2 ± 0.1
5	25/65	60	No change	101.1 ± 0.1
6	25/65	90	No change	100.1 ± 0.1
7	40/75	30	No change	101.0 ± 0.1
8	40/75	60	No change	97.00 ± 0.1
9	40/75	90	No change	0.1