Formulation and Evaluation of Liquisolid Tablets of Lumefantrine for Enhanced Solubility and Bioavailability

Oral administration remains the most popular route for drug delivery because of its convenience, safety, cost-effectiveness, and high patient compliance. Despite these advantages, many newly discovered drugs, particularly those belonging to Biopharmaceutical Classification System (BCS) Class II and IV, exhibit poor aqueous solubility, which leads to low and variable bioavailability¹. This poses a major challenge for formulation scientists striving to achieve consistent therapeutic effects. Improving the solubility and dissolution rates of poorly water-soluble drugs has become a crucial goal in modern pharmaceutical development². Several strategies have been developed to address solubility limitations, including particle size reduction (micronization and nanonization), solid dispersions, salt formation, complexation with cyclodextrins, self-emulsifying drug delivery systems (SEDDS), lipid-based formulations, and co-crystallization. Among these, the liquisolid compact technique has emerged as a promising and practical approach for enhancing the dissolution and bioavailability of water-insoluble drugs³. Liquisolid systems involve the transformation of liquid medications or drug solutions/suspensions into dry, free-flowing, and compressible powders suitable for tableting or encapsulation. This is achieved by incorporating the liquid drug into porous carrier materials and adsorbing excess liquid using fine coating materials, resulting in powders that look dry yet retain the drug in a solubilized or molecularly dispersed state. The core principle of liquisolid systems is based on the ability of carrier materials to retain liquid medication while maintaining acceptable flowability and compressibility⁴. The liquid load factor (Lf) is a crucial parameter and is defined as:

Lf = W/Q

Improved drug release from liquisolid systems is attributed to several factors: enhanced surface area available for dissolution, improved wettability due to hydrophilic liquid vehicles, and maintenance of the drug in a solubilized state without crystallization during compaction. Moreover, the dispersion of the drug at the molecular level in the carrier matrix contributes to rapid disintegration and dissolution, ultimately improving bioavailability⁵. The choice of non-volatile solvents is critical. Commonly used solvents include polyethylene glycol (PEG 200 and 400), propylene glycol, glycerin, polysorbate 80, and novel vehicles like Labrasol® and Capryol 90®. The solvent must provide high solubility for the drug and support the formation of a stable, compressible system. Carrier materials, such as microcrystalline cellulose (Avicel PH 102), lactose, mannitol, Neusilin®, and Sylysia®, play a vital role by absorbing the liquid medication and maintaining flow properties. Coating materials, like colloidal silicon dioxide (Aerosil®), silica gel (Syloid®), and magnesium aluminometasilicates, are used to cover the wet carrier particles, enhancing flowability and preventing sticking⁶. Liquisolid systems offer several advantages: they enable simple and scalable manufacturing without specialized equipment, are applicable to various poorly soluble and lipophilic drugs, improve dissolution and bioavailability, and represent a cost-effective alternative to complex technologies like solid lipid nanoparticles and self-emulsifying systems. However, they also have limitations, such as difficulty in handling high-dose drugs due to the large quantity of carrier and coating materials required, and potential compatibility issues between drug and excipients⁷. the liquisolid compact technique stands as a novel and effective approach for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. By transforming liquid medications into dry, free-flowing, and compressible powders using suitable carriers and coating materials, this technology overcomes solubility challenges and supports the development of robust oral solid dosage forms. The application of this technique can lead to better therapeutic outcomes, improved patient compliance, and potentially reduced dosing frequency, highlighting its significance in modern pharmaceutical formulation development⁸.

MATERIALS

Lumefantrine is used in the treatment of uncomplicated malaria caused by Plasmodium falciparum. The selected model drug was procured from a reliable pharmaceutical supplier. Excipients such as microcrystalline cellulose (Avicel PH102), colloidal silicon dioxide (Aerosil 200), polyethylene glycol 400 (PEG 400), and other required solvents and chemicals were obtained from certified suppliers and used as received. This Excipients used were of LR grade and sourced from Fine Chem Industries, Mumbai.

METHODS

Spectrometric and Compatibility Studies

a) UV spectroscopy was used to determine λmax and prepare the calibration curve.

b) FTIR analysis was performed to check drug-excipient compatibility.

c) DSC analysis was carried out to assess thermal behaviour and interactions.

Calculation of Liquid Load Factor (Lf)

Based on the solubility data and flowable liquid retention potential (Φ-value) of the carrier (Avicel PH102) and coating material (Aerosil 200), the liquid load factor (Lf) was calculated using the equation: where W is the weight of liquid medication and Q is the weight of carrier.

Preparation of Liquisolid Compacts

The drug was dissolved in the selected non-volatile solvent to prepare the liquid medication. The calculated amounts of carrier and coating materials were added gradually under continuous mixing to convert the liquid medication into a dry, free-flowing, and compressible powder. The powder blend was evaluated for flow properties (angle of repose, Carr’s index, Hausner’s ratio). The optimized liquisolid powder blend was compressed into tablets using a single punch tablet compression machine¹³.

Evaluation of Liquisolid Tablets

The prepared tablets were evaluated for various physicochemical parameters, including weight variation, hardness, thickness, friability, disintegration time, and drug content uniformity. In vitro dissolution studies were performed using USP type II paddle apparatus at 37 ± 0.5 °C in appropriate dissolution media. Samples were withdrawn at predetermined intervals and analysed spectrophotometrically to determine drug release profiles^9,10.

In Vitro Dissolution Study

Dissolution testing was performed using a USP Type II (paddle) apparatus at 50 rpm and 37?±?0.5?°C in 900?mL of suitable medium (e.g., 0.1 N HCl or phosphate buffer pH 6.8). Samples were collected at specific intervals, filtered, and analyzed spectrophotometrically to determine drug release. Fresh medium was added to maintain volume. The cumulative percentage release was calculated and compared with conventional tablets^11,12.

Stability Studies

Stability studies were conducted on optimized formulations according to ICH guidelines. Tablets were stored at 25 °C/75% RH for 6 months and analysed periodically for physical appearance, hardness, drug content, and in vitro dissolution.

Method of Preparation for Liquisolid Tablets

Note: above formulation table all ingredient weight in mg, but Sesame oil is in ml

Table no. 4.2: Ratio and Liquid Load Factor for Formulation Table

A The drug was first dissolved in a selected non-volatile solvent (e.g., PEG 400) to prepare the liquid medication. This liquid was then gradually mixed with the calculated amount of carrier material (MCC) under continuous stirring. After complete adsorption, the coating material (Aerosil 200) was added to improve flow properties and convert the mixture into a dry, free-flowing powder. The final blend was evaluated for flow characteristics and then compressed into tablets using a single-punch tablet press^14,15.

Calculation for the W:

W= Drug + Non-volatile solvent

W = 20 + 0.32

W= 20.32

Liquid Load Factor (LF):

LF=WQ

Where,

W= Weight of liquid blend

Q= Weight of carrier material

LF=20.3210

LF= 2.032

Non-Volatile solvent for the API

Solvent Volume=API (mg)Solubility (mg/ml)

solvent Volume = 0.32 ml

Coating Material (q):

q=QR

Where,

Q= Weight of carrier material

R= Ratio of Carrier material

q=1010

q = 1

Carrier (Q):

Q=WLF

Where,

W= Weight of liquid blend

LF= Liquid Load Factor

Q=20.322.032

Q= 10

Ratio of the Tablet =

R value = carrier: coating

R=Qq

Where,

R= Ratio of Carrier

Q= Weight of carrier material

q = Weight of coating material

R=101

R= 10

RESULT

Determination of λ max of Lumefantrine

The determination of λ max of the Lumefantrine was performed in 0.1N HCL using by UV- Visible Spectrophotometer.

Fig 8.2 λ max of Lumefantrine in 0.1N HCL

The calibration curve was obeyed Beer Lambert’s law in the concentration range of 0-50 µg/ml (R2 = 0.999).

Table no.2: Concentration and absorbance

Fig. 1: Calibration Curve

Fourier transforms infrared (FTIR) spectroscopy

Fig.7.4: FTIR of Lumefantrine + Mg. Stearate

Fourier Transform Infrared (FTIR) spectroscopy was performed to assess any potential interactions between Lumefantrine and the excipients used in the liquisolid formulations. The characteristic peaks of pure Lumefantrine were compared with those of the physical mixtures containing various excipients. The FTIR spectrum of pure Lumefantrine (Fig. 7.1) showed characteristic peaks corresponding to its functional groups, including prominent absorption bands around 3340 cm?¹ (N-H stretching), 2920 cm?¹ (C-H stretching), 1640 cm?¹ (C=N stretching), and peaks in the fingerprint region confirming the integrity of the drug structure. FTIR analysis is a critical tool for evaluating drug-excipient compatibility in solid dosage forms. In this study, FTIR spectra confirmed that Lumefantrine maintained its characteristic peaks in all physical mixtures, indicating the absence of chemical interactions that could potentially affect drug stability or efficacy. This compatibility supports the safe incorporation of these excipients in liquisolid tablet formulations, ensuring that the drug remains stable during processing and storage. Thus, the FTIR results strongly support the feasibility of using these excipients for developing liquisolid compacts of Lumefantrine aimed at improving solubility and bioavailability.

Differential scanning colorimetry (DSC)

Fig.: DSC graph of Lumefantrine

DSC is a valuable technique for evaluating the physical state of the drug and for detecting potential interactions between the drug and excipients. In this study, the pure Lumefantrine exhibited a sharp melting endotherm, confirming its crystalline nature. However, in the liquisolid formulations, the decrease or broadening of this peak indicates a possible reduction in crystallinity. The absence of any new or unexpected peaks in the DSC thermograms of the formulations also confirms the absence of strong chemical interactions between Lumefantrine and the excipients. the DSC results complement the FTIR findings and further confirm that the liquisolid technique leads to a reduction in crystallinity of Lumefantrine, which is likely a key factor in enhancing its solubility and improving bioavailability.

Evaluation of Tablet

Drug content (assay): All batches showed uniform drug content within acceptable limits (90–99%), indicating good content uniformity. The highest assay value was observed in F6 (98.54%), suggesting efficient mixing and minimal loss during processing.

Disintegration time: Disintegration time is a critical factor affecting drug release and bioavailability. All formulations disintegrated within a reasonable time frame. F3 exhibited the fastest disintegration (7.6 min), likely due to its optimized formulation and higher super disintegrant content

In-vitro dissolution study

Table no. 7.9 In-Vitro Dissolution Study

Fig. 7.8 % Drug Release

1. Full model for R1 (% drug release) Final

Equation in terms of coded factors

Drug Release= Final Equation in Terms of Coded Factors:

CDR = +89.92 -2.67 * A +0.43 * B -3.39 * A * B

Fig.8.11 Contour plot for R1

Fig 8.12 Effect of independent variables 3D surface plot

Table Analysis of variance for response R1 (% Drug release)

Final Equation in Terms of Actual Factors:

CDR = +66.11000 +3.75250 * SSG +5.30500 * Crospovidone -0.84812 * SSG * Crospovidone

1. Full model for R1 (Friability) Final

Final Equation in Terms of Coded Factors:

Friability = +0.38 +0.065 * A +0.035 * B +0.12 * A * B

Fig.8.11 Contour plot for R2

Fig 8.12 Effect of independent variables 3D surface plot