Design Development and Formulation of Nanosuspensions of Poorly Water Soluble BCS Class-II Drugs with Limited Bioavailability

Oral drug delivery remains the most preferred route of administration because of convenience, patient compliance, and cost-effectiveness [1]. However, poor aqueous solubility of many therapeutic agents significantly limits their oral bioavailability and clinical efficacy [2]. According to the Biopharmaceutical Classification System (BCS), Class II drugs possess low aqueous solubility and high permeability, resulting in dissolution-limited absorption [3]. Approximately 40–70% of newly discovered drug molecules exhibit poor water solubility [4]. Various formulation approaches including solid dispersions, cyclodextrin complexes, lipid formulations, and micronization have been explored to enhance solubility [5]. Among these, nanosuspension technology has gained considerable attention due to its ability to increase surface area, dissolution velocity, and saturation solubility [6]. Nanosuspensions are submicron colloidal dispersions of pure drug particles stabilized by surfactants or polymers [7]. Reduction of particle size to nanometer range increases dissolution rate according to the Noyes–Whitney equation and improves bioavailability [8].

2. MATERIALS AND METHODS

2.1 MATERIALS

A poorly water-soluble BCS Class II drug was selected as model drug. Poloxamer 188, polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), sodium lauryl sulfate, and other analytical grade reagents were procured from certified suppliers.

2.2 Preparation of Nanosuspensions

High-Speed Homogenization and Ultrasonication Technique

Nanosuspensions were prepared using combined homogenization and ultrasonication method [9].

Procedure

The drug was dispersed in aqueous stabilizer solution under magnetic stirring. The coarse suspension was homogenized at 15,000 rpm for 30 min using high-speed homogenizer. The resulting suspension was further ultrasonicated for 20 min to reduce particle size and obtain nanosuspension.

2.3 Formulation Design

2.4 Characterization of Nanosuspensions

2.4.1 Particle Size and Polydispersity Index

Particle size and PDI were measured using dynamic light scattering.

2.4.2 Zeta Potential

Zeta potential was determined to evaluate stability of nanosuspensions.

2.4.3 Drug Content

Drug Content (%)=Actual Drug ContentTheoretical Drug Content×100Drug\ Content\ (\%) = \frac{Actual\ Drug\ Content}{Theoretical\ Drug\ Content} \times 100Drug Content (%)=Theoretical Drug ContentActual Drug Content​×100

2.4.4 Saturation Solubility Study

Saturation solubility was determined in distilled water and phosphate buffer pH 6.8.

2.4.5 In Vitro Dissolution Study

Dissolution study was carried out using USP dissolution apparatus II in phosphate buffer pH 6.8 at 37 ± 0.5°C.

2.4.6 Entrapment Efficiency

Entrapment Efficiency (%)=Entrapped DrugTotal Drug×100Entrapment\ Efficiency\ (\%) = \frac{Entrapped\ Drug}{Total\ Drug} \times 100Entrapment Efficiency (%)=Total DrugEntrapped Drug​×100

2.4.7 Fourier Transform Infrared Spectroscopy (FTIR)

FTIR studies were performed to identify drug-excipient interactions.

2.4.8 Differential Scanning Calorimetry (DSC)

DSC analysis was performed to determine thermal behavior of drug and formulation.

2.4.9 Scanning Electron Microscopy (SEM)

SEM analysis was carried out to examine morphology of nanoparticles.

2.5 Stability Studies

Accelerated stability studies were conducted at 40°C ± 2°C and 75% ± 5% RH for three months according to ICH guidelines [10].

2.6 Statistical Analysis

Data were expressed as mean ± standard deviation. Statistical analysis was performed using one-way ANOVA, and p < 0.05 was considered significant.

3. Results

3.1 Particle Size and Polydispersity Index

Formulation F3 showed minimum particle size and narrow particle distribution.

3.2 Zeta Potential

The optimized formulation exhibited good physical stability.

3.3 Drug Content and Entrapment Efficiency

F3 demonstrated maximum drug loading and entrapment efficiency.

3.4 Saturation Solubility Study

The nanosuspension exhibited approximately 9-fold enhancement in saturation solubility.

3.5 In Vitro Dissolution Study

The optimized nanosuspension exhibited significantly enhanced dissolution compared with pure drug.

3.6 FTIR Analysis

FTIR spectra showed no significant chemical interaction between drug and stabilizers, indicating compatibility.

3.7 DSC Analysis

DSC thermograms demonstrated reduction in crystallinity of the drug in nanosuspension formulation.

3.8 SEM Analysis

SEM images revealed uniformly distributed nanosized particles with nearly spherical morphology.

3.9 Stability Studies