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Abstract

The solubility and dissolution rate of a drug play a pivotal role in determining its therapeutic efficacy, particularly for Biopharmaceutics Classification System (BCS) Class II drugs like Pioglitazone, which exhibit low aqueous solubility and high permeability. The present study aims to enhance the dissolution behavior and oral bioavailability of Pioglitazone using liquisolid systems. Liquisolid technology offers a promising approach to improve the solubility of poorly water-soluble drugs by converting liquid medications or drug solutions into free-flowing and compressible powder mixtures. In this investigation, Pioglitazone was formulated into liquisolid compacts using non-volatile solvents, carriers, and coating materials. A systematic optimization process was employed to achieve formulations with enhanced dissolution rates while ensuring acceptable flow properties and compactibility. The prepared formulations were characterized for physicochemical properties, including flow behavior, dissolution profile, and in vitro drug release. Results suggest that the liquisolid compacts significantly improved the dissolution rate of Pioglitazone compared to conventional tablets, thus promising better oral bioavailability.

Keywords

Solubility, Dissolution rate, Liquisolid, Bioavailability, Pioglitazone

Introduction

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

Angle of repose (?)

Type of flow

< 25>

Excellent

25 - 30

Good

30 – 40

Passable

> 40

Very poor


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

% Compressibility Index

Properties

5-12

Free Flowing

12-19

Good

19-21

Fair

23-31

Poor

33-38

Very poor

> 40

Extremely poor


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

Hausner's ratio

Property

0.1 - 1.25

Free flowing

1.25 - 1.6

Cohesive powder


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)

F. Code

Drug

conc.

R

Lf

Drug (mg)

Q

q

Unit dose

FM

FP1

10%

5

0.825

15

80.72

16.15

172.63

0.535

FP2

10

0.492

15

135.24

13.51

228.45

0.535

FP3

15

0.383

15

174.52

11.63

268.16

0.535

FP4

20

0.329

15

203.89

10.18

297.73

0.535

FP5

15%

5

0.825

15

60.51

12.12

129.78

0.378

FP6

10

0.501

15

101.43

10.43

171.35

0.378

FP7

15

0.383

15

130.88

8.59

201.34

0.378

FP8

20

0.326

15

152.94

7.64

223.35

0.378

FP9

20%

5

0.827

15

30.26

6.05

65.41

0.142

FP10

10

0.495

15

50.71

5.13

85.94

0.142

FP11

15

0.387

15

65.48

4.38

100.55

0.142

FP12

20

0.331

15

76.46

3.83

111.69

0.142

Conventional DC

 

20

-

15

205.12

10.21

241.03

-


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 – Ct = K0t ; Ct = 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

Sr. o.

Properties

Description

1

Appearance / Nature

White to off-white crystalline powder

2

Colour

White

3

Odour

Faint, characteristic smell


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

Solvents/Buffers

Solubility (mg/mL)

Solubility

Water

158.69±5.69

Freely soluble

Ethanol

12.34±0.24

 

Sparingly

soluble

Methanol

10.64±0.69

Chloroform

8.96±0.13

dichloromethane

1.06±0.002

Phosphate buffer pH 1.2

45.62±1.87

Phosphate buffer pH 6.8

10.39±0.95

Practically insoluble


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.jpg
       

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.png
       

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


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

No.

Concentration (ppm)

Absorbance

1

2

0.149

2

4

0.305

3

6

0.459

4

8

0.635

5

10

0.792


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

Sr. No.

Functional group

Observed peaks (cm-1)

1

N-H Stretching (Amine group)

3415.93

2

N-H Stretching (Amine group)

3363.96

3

C=O Stretching (Carbonyl group)

1639.49

4

C=O Stretching (Carbonyl group)

1608.63

5

C-N Stretching (Amino group)

1294.24

6

C-H Bending (Aromatic)

1176.58


       
            Figure 3 FTIR Spectroscopy of Drug.png
       

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.png
       

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±0.09

FP6

28.96±0.43

0.421±0.02

0.521±0.031

23.54±0.34

1.325±0.01

FP7

30.42±0.16

0.435±0.04

0.536±0.026

24.61±0.25

1.322±0.03

FP8

31.62±0.25

0.461±0.06

0.571±0.024

21.59±0.61

1.269±0.02

FP9

29.86±0.31

0.435±0.01

0.549±0.013

24.75±0.13

1.259±0.01

FP10

31.42±0.42

0.449±0.01

0.557±0.012

21.35±0.11

1.248±0.04

FP11

33.28±0.34

0.426±0.13

0.531±0.112

24.12±0.27

1.302±0.15

FP12

31.49±0.15

0.427±0.25

0.536±0.013

20.64±0.21

1.294±0.24

DC

29.84±0.26

0.468±0.13

0.571±0.012

18.96±0.62

1.265±0.13


Post Compression Evaluation

Physical appearance, In-vitro dissolution tests, disintegration time, weight variation, hardness, friability and drug content were among the post-compression parameters that were assessed for the manufactured tablet batches. All tablet batches' post-compression parameters were verified to be within acceptable bounds during the process.

Physical Appearance

The physical appearance of all tablet batches showed that the tablets were white in colour.


Table 10 Physical Appearance

No.

 

Formulation code

Physical appearance

1

FP1-FP12 Batch tablet

White tablet


Table 11: Post Compression Evaluation

Code

Weight variation

(mg)

Hardness (kg/cm?2;)

Thickness (mm)

Friability (%)

Drug content (%)

Disintegration

time (Sec)

FP1

98.63 ± 2.16

3.32 ± 0.18

2.34 ± 0.14

0.34 ± 0.23

99.68 ± 1.76

45.36 ± 12.19

FP2

101.42 ± 2.16

3.26 ± 0.18

2.61 ± 0.14

0.39 ± 0.23

97.58 ± 1.76

52.37 ± 12.19

FP3

95.86 ± 2.16

3.59 ± 0.18

2.53 ± 0.14

0.58 ± 0.23

100.24 ± 1.76

59.86 ± 12.19

FP4

96.83 ± 2.16

3.46 ± 0.18

2.27 ± 0.14

0.67 ± 0.23

96.86 ± 1.76

63.54 ± 12.19

FP5

99.74 ± 2.16

3.28 ± 0.18

2.16 ± 0.14

0.37 ± 0.23

97.58 ± 1.76

68.49 ± 12.19

FP6

100.52 ± 2.16

3.51 ± 0.18

2.35 ± 0.14

0.58 ± 0.23

94.26 ± 1.76

67.52 ± 12.19

FP7

102.46 ± 2.16

3.66 ± 0.18

2.49 ± 0.14

1.02 ± 0.23

95.68 ± 1.76

73.46 ± 12.19

FP8

98.75 ± 2.16

3.84 ± 0.18

2.58 ± 0.14

0.95 ± 0.23

97.82 ± 1.76

79.02 ± 12.19

FP9

96.43 ± 2.16

3.56 ± 0.18

2.37 ± 0.14

0.67 ± 0.23

96.31 ± 1.76

78.31 ± 12.19

FP10

97.40 ± 2.16

3.30 ± 0.18

2.33 ± 0.14

0.35 ± 0.23

98.60 ± 1.90

47.30 ± 8.67

FP11

100.15 ± 2.16

3.30 ± 0.18

2.58 ± 0.14

0.38 ± 0.23

99.20 ± 1.90

51.00 ± 8.67

FP12

94.80 ± 2.16

3.60 ± 0.18

2.50 ± 0.14

0.55 ± 0.23

94.90 ± 1.90

59.10 ± 8.67


In-Vitro Dissolution Studies

The study investigates the dissolution profiles of various tablet formulations prepared using superdisintegrants to enhance drug release. The fastest release rate, 98.67% within six minutes, was observed in TB1 formulations containing 10 mg of croscarmellose sodium, highlighting the effectiveness of the superdisintegrant approach for sublingual tablet preparation. FP1, prepared via direct compression with 3 mg of crospovidone, exhibited a drug release profile ranging from 22.34% to 98.67% in pH 6.8 buffer during the initial six minutes. Similarly, FP2, with 15 mg of crospovidone, achieved 98.26% drug release by the eighth minute, showcasing the impact of disintegrant concentration on dissolution rates. All formulations were analyzed for drug release in pH 6.8 phosphate buffer for up to 10 minutes. Statistical analysis using one-way ANOVA confirmed significant improvement in drug release for liquisolid formulations (VF11) compared to marketed tablets and plain drugs at lower pH (p < 0> 0.05). This suggests enhanced dissolution at lower pH due to the presence of non-volatile solvents, facilitating the drug’s availability at its absorption site in the upper gastrointestinal tract. The liquisolid formulation VF11 demonstrated complete drug release compared to only 30% release from tablets without propylene glycol (PG) at 120 minutes, underscoring the role of non-volatile solvents in improving dissolution. These findings validate the use of superdisintegrants and liquisolid systems as effective strategies for enhancing the dissolution and bioavailability of poorly water-soluble drugs like Pioglitazone.


       
            Figure 5 % In-Vitro Drug Release Study.png
       

Figure 5: % In-Vitro Drug Release Study


6.2.4 Drug Release Kinetic Models

The in-vitro drug release kinetics of Pioglitazone HCl microspheres were studied for formulations FP1 to FP12, and the data were analyzed using various kinetic models, including zero-order, first-order, Higuchi, and Korsmeyer-Peppas. The results indicated that the drug release mechanism predominantly follows zero-order kinetics, as demonstrated by high regression values (R?2; values close to 1), particularly for the optimized formulation FP3, which showed R?2; values of 0.9865 for zero-order, 0.9008 for first-order, 0.8658 for Higuchi, and 0.9953 for Korsmeyer-Peppas. The zero-order kinetics suggest that the drug is released at a constant rate, which is characteristic of controlled-release systems, ensuring a steady concentration of the drug over time. Although the first-order, Higuchi, and Korsmeyer-Peppas models also showed some degree of linearity, they were less fitting compared to the zero-order model, highlighting that diffusion plays a significant role in the release mechanism. The Korsmeyer-Peppas model further indicated that the release process involves both diffusion and other mechanisms such as polymer swelling or erosion. Overall, the findings suggest that the Pioglitazone HCl microspheres, particularly FP3, are suitable for controlled drug delivery, offering a reliable and predictable release profile, which could improve patient compliance and therapeutic outcomes.


       
            6.1.png
       


       
            6.2.png
       


       
            6.3.png
       


       
            6.4.png
       

Figure 6: Different Drug Release Kinetic Models


Stability Study

In compliance with ICH guidelines, stability tests of F8 tablets examined the effects of aging on the physio-chemical properties and dissolve rate of the tablets. Friability, disintegration time, hardness, average tablet weight, appearance, dissolution rates, and drug content were measured at one-month intervals. The evaluation criteria for the original and retained tablets did not differ substantially, according to the results. When kept at 40 ± 2°C and 75 ± 5% relative humidity, the F8 tablets did not change.

The stability study was conducted on FP9 to evaluate the physical, chemical, and therapeutic properties of the tablet formulation over a 3-month period under accelerated conditions (40°C, 75% RH), following ICH guidelines. Throughout the study, the tablets maintained their white appearance and showed no visible changes. The hardness remained constant at 5.62 kg/cm?2;, and the average weight stayed at 121 mg, indicating no significant variations in physical characteristics. The drug content slightly decreased from 98.70% at 0 months to 98.25% at 3 months, demonstrating minimal loss of potency. These results suggest that the formulation is stable and maintains its quality under the tested conditions, supporting its suitability for the recommended storage conditions.

CONCLUSIONS

In conclusion, the development of liquisolid tablets for pioglitazone hydrochloride successfully enhanced its solubility and dissolution rate, addressing the challenge of poor water solubility typically associated with this drug. The use of Tween 80 as a liquid medium played a crucial role in improving the dissolution profile, with a 1:1 ratio of drug to Tween 80 showing the most favorable results. The formulations exhibited excellent flow properties, and the post-compression parameters met the required standards. Among the twelve formulations, F12 demonstrated the highest drug release (98.74%) within 60 minutes, making it the most effective. The liquisolid tablets not only provided a significantly better dissolution rate compared to pure pioglitazone hydrochloride and directly compressed tablets but also showed stability during storage. This study highlights the potential of liquisolid technology as a promising approach to improve the oral bioavailability of poorly soluble drugs, offering a viable solution for enhancing the therapeutic effectiveness of pioglitazone hydrochloride and similar compounds.

REFERENCE

  1. Kim C, Park J. Solubility enhancement for oral drug delivery: can chemical structure modification be avoided. Am.J.Drug Deliv 2004;2:113-30.
  2. 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.
  3. 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.
  4. Patil Dhanashree Sanjay, Magar Deepak, Saudagar Ravindra Bhanudas. Liquisolid technology: technique for formulation with enhanced bioavailability. WJPPS 2013; 3(2):368-87.
  5. 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.
  6. Y. Javadzadeh, M.R. Siahi, S. Asnaashari, A. Nokhodchi. Liquisolid technique as a tool for enhancement of poorly water-soluble drugs and evaluation of their physicochemical properties. Acta Pharm 2007;57:99-109.
  7. Y. Javadzadeh, L. Musaalrezaei, A. Nokhodchi. Liquisolid technique as a new approach to sustain propranolol hydrochloride release from tablet matrices. Int. J. Pharm 2008;362:102-8.
  8. A. Nokhodchi, Y. Javadzadeh, M.R. Siahi-Shadbad, M. Barzegar-Jalali. The effect of type and concentration of vehicles on the dissolution rate of a poorly soluble drug (indomethacin) from liquisolid compacts. J. Pharm. Pharm. Sci 2005;8:18-25.
  9. S. Spireas, S. Sadu. Enhancement of prednisolone dissolution properties using liquisolid compacts. Int. J. Pharm 1998;166:177-188.
  10. S. Spireas, S. Sadu, R. Grover. In vitro release evaluation of hydrocortisone liquisolid tablets. J. Pharm. Sci 1998;87:867-72.
  11. S. Spireas, S.M. Bolton. Liquisolid systems and methods of preparing same, US Patent. 1999;5968(550):1-30.
  12. Y. Javadzadeh, M.R. Siahi, S. Asnaashari, A. Nokhodchi. An investigation of physicochemical properties of piroxicam liquisolid compacts. Pharm. Develop. Tech 2007;12:337-43.
  13. S.A. El-Gizawy. Effect of formulation additives on the dissolution of meloxicam from liquisolid tablets. Egypt. J. Biomed. Sci 2007;25:143-58.
  14. S.A. Tayel, I.I. Soliman, D. Louis. Improvement of dissolution properties ofcarbamazepine through application of the liquisolid tablet technique. Eur. J.Pharm. Biopharm 2008;69:342-47.
  15. Ahmed Abd-El Bary, Dina Louis, Sinar Sayed. Liquisolid tablet formulation as a tool to improve the dissolution of olmesartan medoxomil. Inventi Rapid: NDDS 2014;3:1-8.
  16. Gamal M El Maghraby, Mohamed A Osman, Houyda E Abd-Elrahman, Alaa E. Elsisi. Self emulsifying liquisolid tablets for enhanced oral bioavailability of repaglinide: In vitro and in vivo evaluation. Journal of Applied Pharmaceutical Science 2014;4(9):12-21.
  17. Naveen Chella, Nataraj Narra, Tadikonda Rama Rao. Preparation and characterization of liquisolid compacts for improved dissolution of telmisartan. Journal of Drug Delivery 2014;1-10.
  18. Mohd Zahed Mohiuddin, Shankaraiah Puligilla, Saritha Chukka, Venkatratnam Devadasu, Jyothi Penta. Formulation and evaluation of glyburide liquisolid compacts. International Journal of Pharma Research & Review 2014; 3(2):36-46.
  19. Shobhit Srivastava, Dipti Srivastava, Nimisha, Vedant Prajapat. Liquisolid technique for enhancement of dissolution properties of lornoxicam. Indo Global Journal of Pharmaceutical Sciences 2014; 4(2): 81-90.
  20. Shailesh T. Prajapati, Hitesh H. Bulchandani, Dashrath M. Patel, Suresh K. Dumaniya, Chhaganbhai N. Patel. Formulation and evaluation of liquisolid compacts for olmesartan medoxomil. Journal of Drug Delivery 2013;1-9.

 

Reference

  1. Kim C, Park J. Solubility enhancement for oral drug delivery: can chemical structure modification be avoided. Am.J.Drug Deliv 2004;2:113-30.
  2. 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.
  3. 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.
  4. Patil Dhanashree Sanjay, Magar Deepak, Saudagar Ravindra Bhanudas. Liquisolid technology: technique for formulation with enhanced bioavailability. WJPPS 2013; 3(2):368-87.
  5. 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.
  6. Y. Javadzadeh, M.R. Siahi, S. Asnaashari, A. Nokhodchi. Liquisolid technique as a tool for enhancement of poorly water-soluble drugs and evaluation of their physicochemical properties. Acta Pharm 2007;57:99-109.
  7. Y. Javadzadeh, L. Musaalrezaei, A. Nokhodchi. Liquisolid technique as a new approach to sustain propranolol hydrochloride release from tablet matrices. Int. J. Pharm 2008;362:102-8.
  8. A. Nokhodchi, Y. Javadzadeh, M.R. Siahi-Shadbad, M. Barzegar-Jalali. The effect of type and concentration of vehicles on the dissolution rate of a poorly soluble drug (indomethacin) from liquisolid compacts. J. Pharm. Pharm. Sci 2005;8:18-25.
  9. S. Spireas, S. Sadu. Enhancement of prednisolone dissolution properties using liquisolid compacts. Int. J. Pharm 1998;166:177-188.
  10. S. Spireas, S. Sadu, R. Grover. In vitro release evaluation of hydrocortisone liquisolid tablets. J. Pharm. Sci 1998;87:867-72.
  11. S. Spireas, S.M. Bolton. Liquisolid systems and methods of preparing same, US Patent. 1999;5968(550):1-30.
  12. Y. Javadzadeh, M.R. Siahi, S. Asnaashari, A. Nokhodchi. An investigation of physicochemical properties of piroxicam liquisolid compacts. Pharm. Develop. Tech 2007;12:337-43.
  13. S.A. El-Gizawy. Effect of formulation additives on the dissolution of meloxicam from liquisolid tablets. Egypt. J. Biomed. Sci 2007;25:143-58.
  14. S.A. Tayel, I.I. Soliman, D. Louis. Improvement of dissolution properties ofcarbamazepine through application of the liquisolid tablet technique. Eur. J.Pharm. Biopharm 2008;69:342-47.
  15. Ahmed Abd-El Bary, Dina Louis, Sinar Sayed. Liquisolid tablet formulation as a tool to improve the dissolution of olmesartan medoxomil. Inventi Rapid: NDDS 2014;3:1-8.
  16. Gamal M El Maghraby, Mohamed A Osman, Houyda E Abd-Elrahman, Alaa E. Elsisi. Self emulsifying liquisolid tablets for enhanced oral bioavailability of repaglinide: In vitro and in vivo evaluation. Journal of Applied Pharmaceutical Science 2014;4(9):12-21.
  17. Naveen Chella, Nataraj Narra, Tadikonda Rama Rao. Preparation and characterization of liquisolid compacts for improved dissolution of telmisartan. Journal of Drug Delivery 2014;1-10.
  18. Mohd Zahed Mohiuddin, Shankaraiah Puligilla, Saritha Chukka, Venkatratnam Devadasu, Jyothi Penta. Formulation and evaluation of glyburide liquisolid compacts. International Journal of Pharma Research & Review 2014; 3(2):36-46.
  19. Shobhit Srivastava, Dipti Srivastava, Nimisha, Vedant Prajapat. Liquisolid technique for enhancement of dissolution properties of lornoxicam. Indo Global Journal of Pharmaceutical Sciences 2014; 4(2): 81-90.
  20. Shailesh T. Prajapati, Hitesh H. Bulchandani, Dashrath M. Patel, Suresh K. Dumaniya, Chhaganbhai N. Patel. Formulation and evaluation of liquisolid compacts for olmesartan medoxomil. Journal of Drug Delivery 2013;1-9.

Photo
Priya Chandrashekhar Patil
Corresponding author

Konkan Gyanpeeth Rahul Dharkar College of Pharmacy and Research Institute, Karjat

Photo
Sudarshan Sunil Mirgal
Co-author

Konkan Gyanpeeth Rahul Dharkar College of Pharmacy and Research Institute, Karjat

Photo
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

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