Development Of LiquiSolid Systems For Pioglitazone: A Strategy To Overcome Solubility Challenges

The solubility and dissolution rate of a drug are critical factors influencing its therapeutic efficacy, especially for orally administered formulations. For Biopharmaceutics Classification System (BCS) Class II drugs, such as Pioglitazone, the dissolution process is the rate-limiting step in drug absorption, which can lead to poor bioavailability and suboptimal therapeutic outcomes. Pioglitazone, a widely prescribed thiazolidinedione, is used in the treatment of type 2 diabetes mellitus due to its efficacy in enhancing insulin sensitivity [1]. However, its low aqueous solubility presents a significant challenge for formulation scientists aiming to maximize its clinical potential. To address the solubility and dissolution limitations of Pioglitazone, innovative drug delivery approaches are required. Among various strategies, liquisolid systems have emerged as a promising technique to enhance the solubility and dissolution rate of poorly water-soluble drugs. Liquisolid technology involves the conversion of liquid drug formulations or solutions into free-flowing, compressible powder mixtures using a carrier material and a coating agent [2]. This approach improves the wettability and surface area of the drug particles, resulting in enhanced dissolution profiles. The liquisolid technique is a simple, cost-effective, and scalable method suitable for industrial applications. By incorporating a non-volatile solvent as the liquid vehicle, liquisolid systems improve the molecular dispersion of the drug, further contributing to enhanced dissolution and bioavailability [3,4]. Despite these advantages, the successful development of liquisolid formulations requires careful optimization of various formulation parameters, such as the carrier-to-coating ratio, drug load, and choice of non-volatile solvents. The present study aims to formulate and optimize liquisolid oral compacts of Pioglitazone to improve its dissolution rate and bioavailability. The investigation focuses on evaluating the impact of different liquid vehicles, carriers, and coating materials on the physicochemical properties, flow behavior, and dissolution performance of the liquisolid compacts. Additionally, the study aims to establish a correlation between formulation variables and the enhanced dissolution behavior of Pioglitazone, providing a basis for future application of this technique to other poorly soluble drugs. This research contributes to the growing body of knowledge on liquisolid technology and its potential in addressing the challenges associated with poorly soluble drugs, ultimately aiming to improve patient outcomes in antidiabetic therapy [5,6].

MATERIALS AND METHODS

Materials

The materials used in the study included Pioglitazone, procured from Hetero Pharma Limited, Mumbai, India and various excipients and solvents obtained from reputable suppliers.

Methods

Preparation of Standard Calibration Curve

a) Determination of ?max

Pioglitazone hydrochloride (10 mg) was accurately weighed and transferred into a 10 ml volumetric flask. It was dissolved in methanol, filtered, and the filtrate was diluted to the mark with phosphate buffer (pH 7.4), yielding a solution containing 1000 µg/ml of Pioglitazone. From this solution, 1 ml was further diluted to 10 ml with the same buffer to prepare a stock solution containing 100 µg/ml of Pioglitazone. The stock solution was scanned in the wavelength range of 200–400 nm using a UV-Visible Spectrophotometer (UV-1700 Shimadzu Corporation, Japan) to determine the absorption maximum (?max) [7,8].

b) Preparation of Calibration Curve

Using the 100 µg/ml stock solution, a series of standard solutions with concentrations ranging from 5 to 25 µg/ml were prepared by appropriate dilution with distilled water. The absorbance of each solution was measured at the ?max (234 nm) using the UV-Visible Spectrophotometer. A calibration curve was then plotted with concentration (µg/ml) on the X-axis and absorbance on the Y-axis, providing a standard reference for quantitative analysis of Pioglitazone [8,9].

Determination of Melting Point

Melting point provides valuable insights into the properties and purity of a drug and it was determined using the capillary method. A small quantity of the drug was placed in a capillary tube sealed at one end. The tube was then placed in a melting point apparatus, and the temperature at which the drug transitioned from solid to liquid was recorded. The experiment was performed in triplicate, and the average of the three readings was calculated to ensure accuracy and reliability [10].

Solubility Studies

Solubility studies are crucial for selecting the most suitable non-volatile solvents for drug formulation. In this procedure, an excess amount of Pioglitazone hydrochloride was added to various non-volatile solvents, including propylene glycol, Tween 80, polyethylene glycol 400, and distilled water. The mixtures were subjected to continuous shaking on a rotary shaker at 25°C for 48 hours to ensure complete saturation. After this period, the solutions were filtered to remove any undissolved drug, and the filtrates were diluted appropriately. The solubility of Pioglitazone hydrochloride in each solvent was determined by measuring the absorbance of the diluted solutions using a UV Spectrophotometer. Three determinations were performed for each solvent to calculate the average solubility value, ensuring the reliability of the results [11].

Compatibility Study

Using a Shimadzu IR Affinity-IS, the FTIR spectra of Pioglitazone and physical mixtures was captured. The drug sample was scanned between 400 and 4000 cm^-1, while in an FTIR sample holder. The spectrum was confirmed by comparing with the IR spectra of Pioglitazone [12].

Pre-Compression Evaluation of Powder [13-15]

Angle of repose

The fixed funnel method was used to calculate the angle of repose. A vertically adjustable funnel was used to pour the mixture until the desired maximum cone height (h) was reached. The following formula was used to determine the angle of repose and measure the heap's radius (r):

Angle of repose ?=tan^-1(h/r)

The radius of the base pile is denoted by r, the height of the pile by h, and the angle of repose by ?.

Table 1: Angle of repose

Bulk density

The precisely weighed powder was poured into a graduated cylinder to measure bulk density. The powder's weight (M) and bulk volume (Vb) were calculated. The following formula was used to get the bulk density:

Bulk density (BD) =  Weight of powder(M) / Bulk volume (Vb)

Tapped density

The 100 ml measuring cylinder was filled with the sample powder. A after that a fixed number of taps (100) where applied to the cylinder. Record the final volume and by the following equation the tapped density was calculated.

Tapped Density (TD) = Weight of powder(M) / Tapped volume (Vt)

Carr’s index

One of the most crucial metrics for describing the characteristics of powders and granules is Carr's index. From the following equation it can be calculated and category of Carr’s Index is shown in the table 2.

Carr’s Index (I) = [Tapped density(TD) - Bulk density (BD) ] X 100/Tapped density (TD) 

Table 2: Carr’s Index

Hausner's ratio

The Hausner's ratio is an index of ease of flow of powder. The    Hausner's ratio less than 1.25 indicates good flow. It is calculated by the formula:

Hausner’s ratio = Tapped Density / Bulk Density 

Table 3: Hausner's ratio

Method for Preparation of Liquisolid Systems

Pioglitazone hydrochloride liquisolid systems were prepared to enhance drug dissolution and bioavailability. The drug (30 mg/tablet) was dispersed in a non-volatile liquid vehicle (e.g., Tween 80) at a 1:1 drug-to-vehicle ratio using a mortar and pestle to form a homogenous liquid medication. The required amounts of Avicel PH102 (carrier) and Aerosil 200 (coating material) were calculated using their flowable liquid retention potentials (?Ca and ?Co) and the liquid load factor (Lf). The carrier was gradually added to the liquid medication with continuous mixing to adsorb the liquid, followed by the incorporation of the coating material to form a dry, free-flowing powder. The mixture was then blended with 5% w/w crospovidone (superdisintegrant) and 0.75% w/w magnesium stearate (lubricant) for uniform distribution. The final blend was compressed into tablets using a multi-punch tablet machine (Fluid Pack, Ahmedabad) with 10 mm flat punches, applying appropriate compression forces. Formulations were prepared with varying drug concentrations (15%, 20%, and 40% w/w) and carrier-to-coating ratios (R-values of 5, 10, 15, and 20). Conventional Pioglitazone tablets were also prepared via direct compression for comparative analysis [16].

Table 4: Formulation Batch (FP1 – FP12)

Table 4 shows the amount of carrier (Q), coating material (q), drug concentration (W/W), and liquid load factor (Lf) and coating material at four different powder ratios (R) used to prepare different liquisolid formulations FP1-FP12.

Evaluation of Prepared Liquisolid Systems [17-19]

Weight variation

Twenty pills of each formulation were weighed in total, and the average was computed. Accurate weight measurements of each tablet were also made, and the weight variation was computed.

Hardness

It gauges the amount of force needed to shatter the tablet during testing. For uncoated tablets, a hardness of roughly 0.1-3 kg/cm2 is adequate, and the force is expressed in kilograms. A Monsanto hardness tester was used to measure the hardness of ten tablets from each formulation.

Thickness

A digital vernier scale was used to measure the tablet's thickness. mm was used to express thickness.

Friability test

Variability in Digital Programmable Friability A device was used to determine how friable the tablets were. Twenty pills of each formulation were weighed and put in a machine that revolved for four minutes at 25 rpm. The tablets were weighed once more after being dedusted. Weight loss as a percentage was determined.

F = (W int -W fin) /W int ×100

Where, W int = Initial Weight of tablets before friability;

W fin = Final Weight of tablets after friability.

Drug Content

10 tablets were weighed and pulverized. Transfer the tablet powder to a 100 ml volumetric flask after calculating how much it is equal to 10 mg of medication. Water used to make up volume. The drug content was ascertained using a UV-visible spectrophotometer following an appropriate dilution with water and a one-hour sonicator shaking of the volumetric flask. Measure the absorbance and calculate the drug content.

In Vitro Dissolution Study

The USP II dissolving testing device was used for the dissolution test. At 50 rpm and 37 ºC ± 0.5 ºC, 900 ml of phosphate buffer pH 7.4 was used as the dissolving media. Every so often, five milliliters of aliquots were taken out, and the sample volume was swapped out for an equivalent volume of brand-new dissolving medium. The percentage of drug release was determined by spectrophotometrically analyzing the samples at 234 nm.

Disintegration Time

A one-liter beaker of 0.1 N HCl and PBS pH 6.8 was filled with the six-glass tube disintegration apparatus, each holding one tablet. The tablets were positioned so that they remained below the liquid's surface during their upward movement and did not descend more than 2.5 cm from the beaker's bottom, and the time it took for the tablet to begin dissolving was recorded.

Drug Release Kinetics Modelling

To understand the release mechanism of the formulated sustained release matrix tablets, the drug release data obtained from the diffusion studies were fitted to various kinetic models [10].

Zero order model

C₀ – C_t = K₀t ; C_t = C₀ + K₀t

Where, Ct is the amount of drug released at time t,

C0 is the initial concentration of drug at time t = 0,

K0 is the Zero order rate constant.

First order model

log C = log C₀ – K1 t/2.303

Where, C is the percent of drug remaining at time t,

C0 is the initial concentration of the drug at time t = 0,

K1 is the First order rate constant.

Higuchi model

Q = KH t ^1/2

Where, Q is the cumulative amount of drug released in time t,

KH is the Higuchi dissolution constant

Korsmeyer-peppas model

log (Mt/M?) = log KKP + n log t

Where, Mt is the amount of drug released at time t,

M? is the amount of drug released after the time ?,

n is the diffusional exponent or drug release exponent,

KKP is the Korsmeyer-peppas release rate constant.

The best-fit model for our formulation was determined based on the regression coefficient (R2R^2R2) values, providing insights into the predominant release mechanism and guiding further optimization of the tablet design.

Stability study

The tablets were formulated and subjected to accelerated stability testing to assess their robustness under stressed conditions. The manufactured tablets were wrapped in aluminum strips to protect them from environmental factors and placed in a humidity chamber set at 40 ± 2°C and 75±5% relative humidity. The stability tests were conducted over 30 and 60 days. At each time point, the samples were removed and examined for changes in physical appearance, drug release behavior, and other quality attributes [20].

RESULTS AND DISCUSSION

Preformulation Studies

Organoleptic Analysis: Pioglitazone hydrochloride was evaluated for its organoleptic properties like appearance, colour, odour, and nature by visual inspection.

Table 5: Organoleptic Analysis

Melting Point

Melting range or temperature gives an idea regarding identity and purity of provided sample. The melting range or temperature of Pioglitazone was found to be 183^?C indicating that it is pure without any impurities as it lies within the standard range.

Solubility

The solubility studies of Pioglitazone hydrochloride in various solvents revealed that the drug is highly soluble in water (158.69 ± 5.69 mg/ml), sparingly soluble in alcohol (12.34 ± 0.24 mg/ml), and practically insoluble in dichloromethane (1.06 ± 0.002 mg/ml). These findings indicate that water is the most suitable solvent for formulating Pioglitazone, ensuring optimal solubility and bioavailability. Alcohol can be used as a secondary solvent, while dichloromethane is unsuitable due to its poor solubility of the drug. The results provide valuable information for the development of effective dosage forms for Pioglitazone hydrochloride (Table 6).

Table 6: The solubility of Pioglitazone HCl

Ultraviolet Visible (UV-Vis) Spectrophotometry

Spectrometric Scanning and Determination of ? Max of Pioglitazone HCl in 0.1 N HCl

• Spectrometric scanning and the measurement of Pioglitazone HCl ? max in 0.1 N HCl revealed the greatest peak at 234 nm, which is regarded as the hydrochloride's maximum absorbance (?-max). The Pioglitazone HCl calibration curve was therefore chosen to use this wavelength. 0.1 N HCl was the solvent that was employed.

       
           
       
Figure 1: UV-Vis spectra of of Pioglitazone HCl in 0.1 N HCl

• Calibration Curve of Pioglitazone HCl in 0.1 N HCl

Pioglitazone HCl concentrations ranging from 2 ppm to 10 ppm in 0.1 N HCl were chosen for the calibration curve. R2 was found to be 0.9994, suggesting that, within the chosen range, the relationship between drug concentration and absorbance was linear. Figure 2 shows the standard calibration curve, while the table 7 shows the absorbance of various drug doses in 0.1 N HCl. In the formula y = 0.0796x - 0.008, x stands for concentration and y for absorbance.

       
           
       
Figure 2: Calibration Curve of Pioglitazone HCl in 0.1 N HCl

Table 7: Calibration Curve of Pioglitazone HCl in 0.1 N HCl

FTIR Spectroscopy of Drug

The drug identity was confirmed by studying the IR spectra of Pioglitazone HCl. The observed peaks were found to be in the range which confirmed that the drug obtained was not degraded and were suitable for the use of experiment and developing formulations. The characteristic bands of drug are reported in the following table 8.

Table 8: FTIR Spectrum Peaks of Pioglitazone HCl

       
           
       
Figure 3: FTIR Spectroscopy of Drug

Drug – Excipient Compatibility Study by FTIR Spectroscopy

FTIR was used to record the infrared spectra of both pure drug and excipients as well as the mixture of drug and excipients. The spectra were then compared to determine whether the drug and excipients were compatible. The sample included all of the distinctive peaks. Pioglitazone HCl did not interact with any of the excipients, according to the results of the FTIR analysis.

1. Drug + All Excipients

       
           
       
Figure 4: FTIR Spectrum Peaks of Drug + All Excipients

Evaluation of Tablet

Pre-Compression Evaluations

The tablet powder blend was evaluated for its flow properties as shown in table 9:

Table 9: Pre-Compression Evaluations

F. Code	Angle of repose (?)	Bulk density (g/cm3)	Tapped density (g/cm3)	Car’s index (%)	Hausner’s Ratio
FP1	29.36±0.25	0.432±0.002	0.516±0.012	16.27±1.24	1.194±0.01
FP 2	30.42±0.36	0.441±0.005	0.602±0.035	26.74±1.35	1.365±0.03
FP 3	34.29±0.25	0.439±0.012	0.553±0.025	20.61±1.05	1.259±0.15
FP 4	36.84±0.16	0.451±0.009	0.579±0.014	22.10±0.98	1.283±0.08
FP 5	27.95±0.42	0.447±0.014	0.594±0.036	24.74±0.68	1.328±0.0 Reference Kim C, Park J. Solubility enhancement for oral drug delivery: can chemical structure modification be avoided. Am.J.Drug Deliv 2004;2:113-30. D. Sharma, M. Soni, S. Kumar, G. D. Gupta. Solubility enhancement— eminent role in poorly soluble drugs. Research Journal of Pharmacy and Technology 2009;2(2):220–224. A. Kumar, S. K. Sahoo, K. Padhee, P. S. Kochar, A. Sathapathy, N. Pathak. Review on solubility enhancement techniques for hydrophobic drugs. Pharmacie Globale 2011;3(3):1-7. Patil Dhanashree Sanjay, Magar Deepak, Saudagar Ravindra Bhanudas. Liquisolid technology: technique for formulation with enhanced bioavailability. WJPPS 2013; 3(2):368-87. R.H. Fahmy, M.A. Kassem. Enhancement of famotidine dissolution rate through liquisolid tablets formulation: in vitro and in vivo evaluation. Eur. J. Pharm.Biopharm 2008;69:993-1003. Y. Javadzadeh, M.R. Siahi, S. Asnaashari, A. Nokhodchi. 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Priya Chandrashekhar Patil Corresponding author Konkan Gyanpeeth Rahul Dharkar College of Pharmacy and Research Institute, Karjat priyap6c@gmail.com Sudarshan Sunil Mirgal Co-author Konkan Gyanpeeth Rahul Dharkar College of Pharmacy and Research Institute, Karjat Dr. Bharat Tekade Co-author Konkan Gyanpeeth Rahul Dharkar College of Pharmacy and Research Institute, Karjat Priya Chandrashekhar Patil*, Sudarshan Sunil Mirgal, Dr. Bharat Tekade, Development Of LiquiSolid Systems For Pioglitazone: A Strategy To Overcome Solubility Challenges, Int. J. Sci. R. Tech., 2024, 1 (12), 290-299. https://doi.org/10.5281/zenodo.14564713 More related articles Current Advances in Pharmacotherapy for Diabetes M... Shreyash Gugliya, Dr. Chandrashekhar Upasani, Rinkesh Zanjari, Dr... PSO_KAN: A Hybrid Particle Swarm Optimization and ... Umar Kabir Umar, Fatima Shitu, Idris Yau Idris, Rumana Kabir Amin... Craniofacial Shotgun Injuries with Intracranial an... stitou kaoutar, zahir ilias, ... 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