Solubility Enhancement of Pioglitazone HCL by Spray Drying Technique and Formulation of Oral Dispersible Tablets

Novel drug delivery systems (NDDS) play a vital role in enhancing therapeutic efficacy, minimizing adverse effects, and improving patient compliance by overcoming the limitations of conventional dosage forms such as poor solubility, low bioavailability, and short half-life.¹

Among these, orally disintegrating tablets (ODTs) have gained prominence due to their ability to disintegrate rapidly in the oral cavity without the need of water, making them particularly suitable for geriatric and dysphagic patients. In addition, ODTs facilitate pre-gastric absorption, which helps reduce hepatic first-pass metabolism and enhance bioavailability.²

Pioglitazone hydrochloride, a thiazolidinedione derivative, is an oral hypoglycaemic agent used in the management of type 2 diabetes mellitus. It acts as a selective agonist of the peroxisome proliferator-activated receptor gamma (PPAR-γ), thereby improving insulin sensitivity in peripheral tissues. However, Pioglitazone HCl belongs to Biopharmaceutics Classification System (BCS) Class II, characterized by low aqueous solubility and high permeability, which limits its dissolution rate and bioavailability.³

Among various techniques, spray drying is advantageous for producing uniform, stable, and rapidly dissolving particles. The present study aims to enhance the solubility of Pioglitazone HCl by preparing spray dried Pioglitazone HCl using spray drying technique and subsequently developing orally disintegrating tablets to achieve rapid drug release and improved patient compliance.⁴

Objectives of the Study:

• To enhance the solubility and dissolution rate of Pioglitazone Hydrochloride using spray-drying technique.
• To perform pre-formulation studies including physicochemical characterization, drug–excipient compatibility, and solubility analysis.
• To prepare spray-dried Pioglitazone Hydrochloride.
• To evaluate the physicochemical properties of the spray-dried formulations.
• To determine the λ-max and prepare a calibration curve for quantitative analysis.
• To formulate oral dispersible tablets using the plain drug and spray-dried drug with suitable super-disintegrants.
• To evaluate the tablets for quality control parameters and in-vitro drug release.
• To compare the dissolution profile of the optimized formulation with a marketed product.

Poor aqueous solubility is a major limitation for many orally administered drugs, particularly BCS class II compounds, leading to reduced dissolution and low oral bioavailability. Ramesh et al. and Kumar and Singh reported that improving solubility is essential for achieving effective drug absorption and therapeutic response. Cal and Sollohub demonstrated that spray drying is a versatile and scalable technique capable of producing pharmaceutical particles with improved dissolution characteristics and stability. Pokharkar et al. showed that spray-dried formulations of pioglitazone hydrochloride significantly enhanced solubility, dissolution rate, and in-vivo antidiabetic activity. Further, Thakker et al. developed taste-masked orally disintegrating tablets of pioglitazone that exhibited rapid disintegration, acceptable mechanical strength, and improved patient acceptability. However, limited studies have focused on developing fast-disintegrating tablets of pioglitazone using spray-drying-based approaches to simultaneously enhance solubility and patient compliance.

Orally disintegrating drug delivery system: 

Food and Drug Administration (FDA) defines ODTs as “a solid dosage form containing medicinal substances which disintegrate rapidly, usually within a matter of seconds, when placed upon the tongue”.⁵

Advantages of Orally Disintegrating Drug Delivery System (ODDDS):

• Enhances patient compliance, particularly for those who have difficulty swallowing.
• Provides a faster onset of action and can improve drug bioavailability.
• Ideal for elderly, paediatric, and psychiatric patients who face challenges with conventional tablets or capsules.
• Convenient for use during travel or situations where water is not easily accessible.
• Can be packed using standard blister packs without the need for specialized packaging.
• Offers a pleasant taste and smooth mouthfeel, improving patient acceptance.
• Can be produced using conventional tablet manufacturing equipment.
• Economical to develop and manufacture.
• Exhibits good chemical stability, comparable to traditional solid dosage forms.⁶

Disadvantages of Orally Disintegrating Drug Delivery System (ODDDS):

• Highly moisture-sensitive and must be stored in a dry environment.
• Tablets are often fragile and may require careful handling to prevent damage.
• Special packaging may be necessary to ensure product stability and protection from humidity.⁶

MECHANISM OF ODTS:

Tablet should be broken down into the smaller particles and then subsequently result a solution or suspension of the drug. 

The mechanisms are-

• • High swelling ability of disintegration. 
  • Capillary action^.
• Water enters into the tablet matrix to cause rapid disintegration and instantaneous dissolution of the tablet.  
• Incorporation of an appropriate disintegrating agent or highly water-soluble excipients in the tablet formulation facilitates rapid disintegration.⁷

Figure No 1: ODT

ENHANCEMENT OF SOLUBILITY:

Solubility refers to the process in which a solid dissolves in a liquid to form a uniform solution. It plays a vital role in achieving the required drug concentration in the bloodstream to produce the intended therapeutic effect. Many drugs show poor water solubility, which limits their bioavailability. To overcome this, several solubility enhancement strategies are used, such as particle size reduction, solid dispersion, complex formation, use of surfactants, and co-solvent systems. Improving solubility leads to quicker dissolution, enhanced absorption, and better overall drug performance.⁸

Definition of solubility as per I.P:                      

TABLE NO 1: DEFINITION OF SOLUBILITY AS PER I.P⁹

BCS Class II drugs present significant challenges during pharmaceutical product development due to their poor aqueous solubility and limited dissolution rate. To achieve optimal therapeutic effectiveness, it becomes essential to enhance both solubility and dissolution, particularly in solid dosage forms like tablets and capsules. Over the years, various conventional techniques along with advanced emerging technologies have been explored and implemented to improve the formulation and performance of these drugs.⁹

Techniques for Solubility Enhancement:

• Particle Size Reduction: Nanonization, micronization. 
• Co-solvency.
• Hydrotropy.  
• pH Adjustment.  
• Sono-crystallization.
• Supercritical Fluid Process (SCF). 
• Solid Dispersion. 
• Inclusion Complexation. 
• Self-Emulsifying or Self-Micro Emulsifying Systems.  
• Liqui-solid Methods.     
• Solvent Method.  
• Fusion-Solvent Method. 
• Spray Drying.  
• Lyophilization. 
• Hot-melt Extrusion.  
• Micellar solubilisation.¹⁰

Figure No 2: Techniques for Solubility Enhancement.

SPRAY DRYING TECHNIQUE:

Spray drying is a process in which a liquid feed is converted into a dry powder by dispersing it into a stream of hot air. In pharmaceutical applications, the primary objective of this technique is to produce dried particles with specific and desirable characteristics. The process involves various components such as atomizers, drying chambers, air-droplet interaction systems, product collection units, and auxiliary equipment. Each of these elements, along with the operational parameters, significantly influences the final properties of the dried material.

In this method, active pharmaceutical ingredient is either dissolved or suspended in an appropriate solvent. The solvent is then removed by exposing the mixture to heated air, causing rapid evaporation due to the large surface area of the atomized droplets. This quick solvent removal results in the formation of powders with improved characteristics.¹¹

Figure No 3: Spray drying technique.

Figure No 4: Spray dryer model-SPD-D-111.

MATERIALS AND METHODS:

TABLE NO 2: LIST OF MATERIALS

TABLE NO 3: LIST OF EQUIPMENTS

Pre-formulation studies:

Pre-formulation studies are preliminary investigations conducted to assess the physicochemical and biopharmaceutical characteristics of a drug before developing a formulation. In the case of oral dispersible tablets (ODTs), these studies help to evaluate parameters such as solubility, stability, flow properties, and compatibility with excipients, which influence disintegration and drug release. The data obtained assist in selecting suitable excipients, optimizing processing conditions, and ensuring formulation stability, efficacy, and patient acceptability. Accordingly, pre-formulation studies were performed on Pioglitazone HCl to support ODT development.

Organoleptic studies:

The colour and odour of Pioglitazone HCl were observed and recorded using descriptive terms.

Melting point:

The melting point was determined by the capillary method. A small quantity of the powdered drug was sealed in a capillary tube, heated gradually, and the temperature range at which it began and completed melting was noted.

Solubility:

Solubility was tested in distilled water, phosphate buffer (pH 6.8), 0.1 N HCl, methanol, and ethanol. The mixtures were shaken at 25 ± 0.5 °C for 24 hours, filtered, and analysed at 268 nm using a UV spectrophotometer. The solubility (mg/mL) was expressed as per Indian Pharmacopoeia standards.

UV Spectroscopic Study and Standard Calibration Curve:

• Preparation of 0.1 N HCl: 8.84 mL of 35% HCl (11.3 N) was diluted to 1000 mL with distilled water using the formula N?V? = N?V?.
• Determination of λ-max: The UV spectrum of Pioglitazone HCl in 0.1 N HCl was scanned between 200–400 nm, showing a distinct absorption peak at its λ-max.
• Preparation of Stock Solutions: 100 mg of the drug was dissolved in 0.1 N HCl and diluted to 100 mL to obtain Stock A (1000 µg/mL). From this, 10 mL was further diluted to 100 mL to prepare Stock B (100 µg/mL).
• Standard Calibration Curve: From Stock B, aliquots of 0.5–4 mL were diluted to 10 mL to yield 5–40 µg/mL solutions. Absorbance was measured at λ-max, and a calibration curve was plotted with concentration on the X-axis and absorbance on the Y-axis to determine slope and R² value.

Drug-excipient compatibility studies:

FTIR spectra of the pure drug, excipients, and formulations were recorded using the KBr pellet method within the 4000–400 cm?¹ range. Characteristic peaks were compared to identify functional groups and confirm that no significant chemical interactions occurred between the drug and excipients.12,13.

Formulation of Oral Dispersible Tablets of Pioglitazone HCl¹⁴

TABLE NO 4: COMPOSITION OF PIOGLITAZONE HCL ORAL DISPERSIBLE TABLETS.

Preparation of Pioglitazone HCl Orally Disintegrating Tablets (ODTs)

Preparation of ODTs Pioglitazone HCl (F1):

ODTs containing 15 mg of Pioglitazone HCl were prepared by the direct compression method. The drug and diluents were accurately weighed, passed through a #40 mesh, and mixed uniformly in a mortar. Talc and magnesium stearate (previously sieved through #80 mesh) were added to the blend and mixed thoroughly. The final powder mixture was evaluated for pre-compression parameters such as angle of repose, bulk density, tapped density, and compressibility index, and then compressed into 180 mg tablets using a rotary tablet press.¹⁴

Preparation of ODTs Spray dried Pioglitazone HCl (F2):

Spray drying technique: 

Spray drying technique was employed to enhance solubility. Pioglitazone HCl (0.6 g) was dissolved in ethanol under continuous stirring to obtain a clear solution. The solution was spray dried under the following optimized conditions: inlet temperature 60± 2 °C, outlet temperature 28± 2 °C, feed rate 5 mL/min, atomizing pressure 2.0 bar, and aspirator 90%. The dried powder was further oven-dried at 60 °C for 24 hours. The average particle size of the spray-dried drug was determined prior to formulation. ODTs of the spray-dried drug (F2) were then prepared using the same direct compression procedure as F1.¹⁴

                                                 Pioglitazone HCl                Spray dried Pioglitazone HCl

Figure No 5: Granules of Pioglitazone half

                                    Pioglitazone HCl Tablets (F1)        Spray dried Pioglitazone HCl Tablets (F2)

Figure No 6: ODTs of Pioglitazone HCl (F1 and F2 Formulations)

Particle size analysis:

The particle size of Pioglitazone HCl and spray-dried Pioglitazone HCl were determined by dispersing a small quantity of each sample in distilled water. A drop of each suspension was placed on a glass slide, covered with a coverslip, and examined under a Bio Vis MOTIC microscope equipped with a MOTICAM A5 camera. After calibration using a stage micro meter, images were captured and analysed to measure particle diameter.¹⁵

Determination of derived properties of granules:

The granules were evaluated for bulk characterization parameters, including flow properties, bulk density, tapped density, Carr’s index, and Hausner’s ratio. The angle of repose was determined using the fixed funnel method, where the height and radius of the formed powder cone were measured, and the angle was calculated using θ = tan?¹(h/r). Bulk density was determined by measuring the volume of a known weight of powder in a graduated cylinder without tapping, while tapped density was obtained after repeated tapping until a constant volume was reached. Carr’s index was calculated as (Tapped density- Bulk density)/Tapped density*100 and Hausner’s ratio as Tapped density/Bulk density lower values of both indicate better flow characteristics.

Evaluation of oral dispersible tablets of Pioglitazone HCl:

Pioglitazone HCl orally disintegrating tablets (ODTs) were evaluated for weight variation, friability, thickness, uniformity of dispersion, drug content, disintegration time, and in-vitro dissolution.

For the weight variation test, 20 tablets were weighed individually, and their deviation from the mean weight was compared with IP limits (±7.5% for tablets weighing 80–250 mg). Friability was tested using a friabilator at 25 rpm for 100 revolutions, and acceptable weight loss was not more than 1%.

Thickness of ten randomly selected tablets was measured with a calibrated vernier calliper. Uniformity of dispersion was confirmed by dispersing two tablets in 100 mL water and passing through a 710 µm sieve, ensuring no gritty residue. Drug content was determined by dissolving powdered tablets in 0.1 N HCl, filtering, and measuring absorbance at 268 nm, with acceptable limits of 90–110%. Disintegration was tested using a basket-rack assembly in water at 37 ± 2 °C, and the total disintegration time was recorded. Dissolution studies were conducted using USP II apparatus (paddle method) in 900 mL of 0.1 N HCl at 37 ± 0.5 °C and 50 rpm, withdrawing 5 mL samples at intervals and analysing absorbance at 268 nm. According to IP and USP standards, at least 80% of the drug should be released within 30 minutes.^12,13.

RESULT AND DISCUSSION 

Pre-formulation studies:  

Pre-formulation studies of Pioglitazone HCl active ingredient:                

TABLE NO 5: RESULTS OF PRE-FORMULATION STUDIES OF PIOGLITAZONE HCL

The absorbance values of Pioglitazone HCl at different concentration ranges (0–40 µg/ml) in 0.1N

HCl were measured at 268 nm. The absorbance readings at various concentrations are presented in Table No 6., and the corresponding standard plot is shown in Fig. No.7. 

TABLE NO 6: STANDARD PLOT OF PIOGLITAZONE HCL

*All values are represented as mean of 3 readings (n=3) 

Figure No 7: Standard plot of Pioglitazone HCl

The absorbance of Pioglitazone hydrochloride remained linear and followed Beer–Lambert’s law in the concentration range of 0–40 µg/ml, with a regression coefficient (R²) of 0.996 and a slope of 0.0191. 

Particle Size Analysis:

Particle size analysis was done using Bio Vis MOTIC microscope fitted with a MOTICAM A5 camera. After calibration with a stage micro meter, images were captured and analysed for mean particle diameter. 

Figure No 8:  Particle Sizes of Pioglitazone HCl and Spray dried Pioglitazone HCl

Pioglitazone HCl exhibited a mean-area equivalent diameter of 0.742 µm, indicating comparatively larger particle dimensions. In contrast, the spray-dried Pioglitazone HCl sample showed a mean-area equivalent diameter of 0.305 µm. The significant reduction in particle size after spray drying demonstrates the effectiveness of the process in producing finer particles, which can potentially enhance the dissolution rate.

Drug-Excipient Compatibility Study:  

FTIR spectroscopy was used to evaluate drug–excipient compatibility by comparing the characteristic peaks of the pure drug with those of the physical mixture, thereby identifying any possible interactions. 

Figure No 9: FTIR spectra of Pioglitazone HCl

TABLE NO 8: INTERPRETATION OF FTIR SPECTRA OF PIOGLITAZONE HCL

FTIR Spectra of Spray dried Pioglitazone HCl and Excipients

Figure No 10: FTIR spectra of Pioglitazone HCl and excipients

TABLE NO 9: INTERPRETATION OF FTIR SPECTRA OF PIOGLITAZONE HCL AND EXCIPIENTS

Evaluation of Derived properties granules: 

The derived properties of the powder blends of formulations were evaluated.

TABLE NO 10: EVALUATION OF DERIVED PROPERTIES OF GRANULES

Pioglitazone HCl possesses superior derived powder properties.

Formulation and Evaluation Tablets: 

Granules were compressed using 10 station Single sided rotary compression machine, the compressed tables were White to off white Round convex tablets with plain on one side and break line on other side. The compressed tablets were evaluated for following parameter as per the Table No.11

Description of Tablets: White to off white Round convex tablets with plain on one side and break line on other side.

TABLE NO 11: EVALUATION PREPARED TABLETS

Evaluation of Tablets:

Weight variation:

Both F1 and F2 complied with the pharmacopeial limits of ±7.5% for tablets weighing less than 250 mg, indicating uniform die filling and good flow properties of the powder blend. F1 showed slightly better weight consistency compared to F2.

Hardness:

The hardness of both formulations was within the acceptable range for orally disintegrating tablets (1.5–3.0 kg/cm²). F2 displayed lower hardness, suggesting faster disintegration but relatively lower mechanical strength compared to F1.

Thickness:

Tablet thickness values for both formulations were consistent, demonstrating uniform die filling and even compression pressure during tableting.

Friability:

Both F1 and F2 showed friability below 1.0%, meeting pharmacopeial requirements. F1 exhibited marginally better mechanical strength compared to F2.

Uniformity of dispersion:

                            Figure No 11: Uniform dispersion        Figure No 12: Sieving of dispersion

TABLE NO 12: UNIFORMITY OF DISPERSION OF FORMULATIONS

Both F1 and F2 exhibited rapid and uniform dispersion with no gritty particles and passed through sieve #10. This indicates fine particle size, good wettability, acceptable breakup, and mouthfeel suitable for orally disintegrating tablets (ODTs). 

Percentage drug content:

TABLE NO 13: PERCENTAGE DRUG CONTENT

The drug content of F1 and F2 was close to 100% with low standard deviation (F1: 98.3±1.86%; F2: 93.37±3.03%), indicating excellent content uniformity and drug loading efficiency. Both formulations meet pharmacopeial acceptance limits (85–115%).

Disintegration test:

F1 and F2 showed rapid disintegration, making them suitable for fast-dissolving ODTs. F1 disintegrated in 90 seconds, while F2 disintegrated even faster, in 30 seconds, reflecting effective formulation and appropriate disintegrant performance.

TABLE NO 14: DISINTEGRATION TEST OF ODTS

In vitro Dissolution studies:

Both formulations achieved rapid drug release consistent with their disintegration times. F1 released >85% of the drug within 30 minutes, while F2 showed slightly faster and higher release, achieving complete drug release within 30 minutes. This indicates excellent drug-excipient compatibility and efficient formulation for immediate-release tablets.

TABLE NO 15: DISSOLUTION OF ODTS WITH PURE DRUG

Figure No 13: Cumulative drug release

Percentage yield:

TABLE NO 16: PERCENTAGE YIELD AT DIFFERENT STAGES