Konkan Gyanpeeth Rahul Dharkar College of Pharmacy and Research Institute, Karjat
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.
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
Figure 1: UV-Vis spectra of 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
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
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.
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
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.
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
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