INTRODUCTION:

The original “polymer drug delivery system” eases “controlled-release, extended” medications. There are several issues behind oral consumption of pioglitazone, making it a common reason for its restriction. In this day and age, novel techniques related to polymer platform serve as an emerging approach for therapy. The original mechanism of “platform delivery systems” improves solubility of medications which are poorly soluble, such as “BCS Class II” and retains the concentration of medications at given doses and prevents recurrent doses^1-3. Diabetes leads to various range of metabolic disorders, which have been a major health issue across the world.

The “World Health Organization” has documented diabetes as an epidemic affecting the whole world. There is a dramatic rise of prevalence of diabetes over the past decade and it thrives in poor countries. Diabetes mellitus is prevalent in India cases are rising alarmingly.^4-5

A “thiazolidinedione” named “Pioglitazone (PGZ)” is used adjunctively with workout and diet to control glycemic levels in T2DM or “Type 2 diabetes mellitus” cases. This medication plays a vital role to improve sensitivity of insulin and tissue and control the process of gluconeogenesis, i.e., glucose buildup in the liver. It also enhanced insulin resistance in T2D instead of raising the levels of secretion of insulin by pancreatic beta cells. Pioglitazone works as an agonist at “peroxisome proliferator-activated receptor gamma (PPARy)” in specified tissues like liver, skeletal muscle, and adipose tissue. Stimulating PPARy receptor improves transcription of “insulin-responsive genes” covered in managing lipid and glucose buildup, utilization, and transport^6-7. PGZ is a non-polar medication and cannot break down water’s lattice structure properly. So, there is a low aqueous solubility. It is a “BCS class II” medicine which has lack of bioavailability and solubility.

Fig. 1: Basic structure of Pioglitazone

The dissolution and solubility rate are the major causes of lack of bioavailability of class II drugs and other hydrophobic drugs with poor water solubility in the “biopharmaceutics classification system”. Reducing crystallinity, particle size, and improving surface area can improvise the dissolution rate of those medications. A lot of studies have been conducted to improve the rate of dissolution of medications by reducing the size of the particle⁸. “Solid dispersion (SD)” has been used significantly to improve the dissolution rate, oral absorption, and solubility of drugs with poor water solubility. Solid dispersion is a collection of solid products having minimum 2 components – hydrophobic drug and hydrophobic matrix (which can be either amorphous or crystalline).

Solid dispersion was initially brought to deal with low bioavailability of lipophilic drugs by forming the blend of a eutectic medicine with “water-soluble carriers”. Synthesized by “combinational screening programs”, around 40% of “new chemical entities (NCE)” have excellent pharmacological activities and have lack of solubility. It is a major challenge to develop formulation. The technique of solid dispersion has been useful to boost oral bioavailability and dissolution of several drugs with poor solubility. Solid dispersion consists of dispersion of multiple active ingredients in a matrix or inert carrier in a solid state made by “melting solvent, solvent, or melting (fusion)” approach. Being a potentially effective approach, growth of solid dispersions can improve the bioavailability of drugs with poor water solubility. It helped in dealing with the issue in earlier methods like solubilization, salt formation, and reducing particle size⁹.

MATERIALS AND METHODS:

Pune-based “Lupin Research Park” introduced “Pioglitazone” and “Neusiline” as gift samples. An Indian company, Loba Chemical is an Indian company which sold “CH (93% deacetylation)”. Analytical grade of reagents and distilled water were used for the study. Ingredients/substances were used without purification. The approach of “Microwave irradiation-induced fusion” was used to prepare solid dispersions. With neusiline and Chitosan, Pioglitazone was weighed as per several weighed ratios.

Saturation solubility of Pioglitazone:

The “phosphate buffer pH 7.4” and double distilled water were prepared to experiment the solubility of saturation of “Pio 0.1N HCl buffer (pH 1.2)”. Additional amount of Pio was poured in three conical flasks having “double distilled water, 0.1 N HCL (10ml), and phosphate buffer of pH 7.4” shaken for 48 hours in a mechanized shaker made by Bio Technics, India at the speed of 100rpm. R8C Remi, India centrifuged the sample for 20minutes at the speed of 4000rpm. The “Whatman filter paper (no. 41)” was used to filter all the samples and estimated the medicine in the filtrate at 267 nm by “UV spectrophotometer”¹⁰.

Phase solubility study:

For Pioglitazone, solubility study was conducted as per “Higuchi and Connors” method. Ample amount of it was added to distilled water (10ml) having several amounts of CH with/without NS taken in several test tubes. A solubility tube having tertiary and binary suspension was kept on mechanical shaker (manufactured by “Bio Technics, India”) for 48hours and stirred at room temperature at 100rpm. The centrifugal force of 3000rpm was applied to the samples for 10minutes. The “Whatman filter paper (no. 41)” was used to filter and collect the supernatant. The filtered samples were assayed and diluted with UV analysis for pioglitazone against a blank, prepared in same amount of CH with NS or without NS. Tests were done in triplicate. The diagram of phase solubility was made by plotting of “dissolved pioglitazone concentration” over the respective amount of Chitosan^11-13.

Determination of stoichiometric constant:

The stoichiometric constant was calculated using various PIO and CH molar concentration ratios. Drugs with CH suspension were prepared by mixing. The increasing the molar concentration of PIo and reducing the molar concentration of CH. Then this binary mixture was filtered with Whatman filter paper no. 41 and analysed UV spectroscopically at 267nm.

Preparation of solid dispersion using a polymer as platform technique:

Selection of factors:

Individual variables are assumed to move response in a quadratic and linear way, while considering a potential impact of interaction of individual variables. The formulation design of PIO solid dispersion was done by using Design Expert 12 Trial program software. Solid dispersion was formulated and optimized using 3² level full-factorial design with Design Expert version 12. CH and NS percentages were selected as two independent variables, X₁ and X_2, with three levels from preliminary data of the stoichiometric study and phase solubility study. The software gives 9 experimental batches for evaluating dependable responses Y1, saturation solubility, and Y2, percentage drug release. These factors were studied to obtain an optimized batch of maximum response¹⁴.

Table 1: Different formulation batches (p1-p9)

Batches	A: CH (%)	B: NS (%)
P1	5	5
P2	10	5
P3	15	5
P4	5	7.5
P5	10	7.5
P6	15	7.5
P7	5	10
P8	10	10
P9	15	10

Microwave-assisted dry grinding technology:

Solid Dispersion using a polymer platform was prepared using a microwave-assisted dry grinding technique. The selected amount of ingredients was weighed and ground in a mortar pestle for about 20minutes. Then the mixture is transferred to a microwave oven (Panasonic microwave oven, 230V- 50 Hz- 1250W) and adjusted at 600 W power for 3+3 minutes. Only one beaker was positioned within the microwave at a time. The samples were microwaved for a specific time period. Then, the beaker was kept for being solidified at a room temperature. Solid dispersions were stored and gathered for 24hours in the “desiccators” and pulverized the product with a pestle and mortar.

Microwave assisted ball milling technology:

With various ratios of “Polymer CH, Pioglitazone, and Neusiline”, solid dispersions were made with “microwave-assisted ball milling method”. Optimized amounts of ingredient were grounded without solvent with 100rpm in a ball mill for 48 hours. Then, it was moved for two intervals for being treated in the microwave with 600W for 3 minutes of each interval. In the desiccators, solid dispersions were gathered for 24 hours. Mortar and pestle were used to pulverize the product. At the end, the “Y₁ and Y₂” variables were used to optimize the prepared batches and they are stored in airtight desiccator. These batches were tested for “crystallinity, molecular interaction, solubility, and dissolution rate.”

Saturation solubility Studies:

Solubility studies were conducted for Pio as per the approach recommended by Higuchi & Connors. Pioglitazone’s solid dispersion was prepared and added to distilled water (10ml) in several test tubes. A solubility tube with “solid dispersion of Pioglitazone with Neusiline and CH” was stored on mechanical shaker (made by Bio Technics India) for 48hours with 100rpm of stirring speed at room temperature. The centrifugal of sample was done for 10minutes with 3000rpm. The researchers filtered and gathered the supernatant with “Whatman filter paper (No. 41)”. The filtered samples were assayed and diluted by UV analysis for “pioglitazone content” at 267nm over a blank^11-13.

Fourier transformation-infrared spectroscopy (FTIR):

The “Fourier transform-infrared (FTIR) spectroscopy” was used to characterize the physicochemical. Samples were analyzed and prepared for this purpose as “KBr pellets” with “FTIR spectrometer”. The “FTIR (BRUKER – ECO – ATR – ALPHA, Germany)” is the spectroscopy technique to observe bond vibrational frequencies and functional group of pure drugs named “Chitosan, Pioglitazone, and Neusiline”. FTIR analysis was conducted for physical drug mixture and formulated solid dispersion with excipients. The samples were analysed on the pan from spectral range of “600 to 4000 cm^-1” with 24 scans.

Differential scanning calorimetry (DSC):

A DSC analyzer was used to measure “differential scanning calorimetry”. The researchers heated all of the solid dispersion samples optimized from 40°C to 260°C. The “DSC analyzer (TA Instruments, SDT Q600 USA)” was used to perform thermal analysis of physical mixture, pure “Drug PIO, CH, NS” and designed solid dispersion. A 5mg of sample was heated at 200⁰C/ min of heating rate under the nitrogen atmosphere over the range of 40 to 260 degrees Celsius in the range of temperature.

Percentage drug content studies

In the volumetric flask of 25ml, solid dispersions of 20 mg of Pio were placed. The 10ml of methanol was blended well with mechanical stirrer at speed of 100 rpm for 48hours. The “Whatman filter paper (no. 41)” was used for filtration after equilibrium. The solution was diluted well with “methanol and assayed spectrophotometrically for the amount of drug at 267 nm. Here is the formula for doing the same –

Actual drug content in meghanol

% drug content = --------------------------------------- × 100

Theoretical equivalent drug taken

X-ray powder diffractometry (XRPD):

The diffraction patterns of X-ray were evaluated for Neusiline physical mixtures, Pioglitazone, and solid dispersions”. An “X-ray diffractometer (BRUKER – D2 PHA-SER, Germany)” was used to record the XRPD patterns with “tube anode Cu over the interval 10–90/2h”. The operational data were lower in “Generator tension (voltage) of 30 kV, Generator current 10mA”.

In vitro dissolution study:

The dissolution apparatus of paddle-type “USP Type II) (LABINDIA Dissolution test apparatus, DS 8000)” was performed for in-vitro dissolution. A fixed amount of “pure Pioglitazone powder having 20mg” similar to PIO were used with each batch of formulation for dissolution. Researchers used “Simulated Gastric Fluid (SGF) 0.1 N HC1” for dissolution where they took 900 ml in each vessel for dissolution at “37±0.5°C” of temperature and 50rpm of paddle speed. A sample of 5ml and dissolution test was conducted for 60 minutes at specified intervals of “5, 10, 15, 20, 30, 45 and 60 min”. Then, the samples of dissolution were analyzed by “UV-VIS spectrophotometer” spectrophotometrically at 267 nm.

Stability study:

It was carried out in a stability chamber (REMI SC 16S) operated at temperature of 40⁰C and 75% RH. The study was conducted for 3 months, and samples were withdrawn after 0 days, 15 days, 1 month, 2 months and 3 months. Samples were evaluated for drug content using UV spectroscopy with methanol as a solvent system at 267nm and for the study of the interaction between PIO and polymers using IR spectroscopy.

RESULT AND DISCUSSION:

Solubility studies in different pH conditions:

Because of non-polar matures, “Antidiabetic drug Pioglitazone (PIO)” has solubility which is very low in aqueous medium. Pio is insoluble as per BP in water due to poor solubility (categorized as “BCS class II drug”). The PIO’s saturation solubility was tested in water and various pH solutions. There is very low solubility in PIO in all given mediums like water (Table 2). However, the solubility profile was known to rely on pH, i.e., a decline in solubility with a rise in pH level. With this observation, it is found that there is a low solubility in PIO in alkaline medium as compared to acidic medium. The researchers found least solubility in “0.1N HCl (pH 1.2)¹⁵”.

Table 2: Solubility studies of PIO in different solvents

Sr. No.	pH	Concentration (µg/ml)
1	0.1N HCl ( pH 1.2)	0.094
2	DD water	0.20
3	Phosphate buffer (pH 7.4)	0.66

The calibration of medicine was conducted in “0.1 N HCI solution” and distilled water from 0 to 50µg/ml and the concentration of 0-40µg/ml, respectively. The equation of straight line for “0.1 N HCl solution” and water was “y = 0.019x + 0.022” and “y = 0.006x + 0.025”, respectively.

Phase solubility Studies of Pioglitazone:

The comparative phase solubility studies of PIO with polymer CH and Neusiline in distilled water are shown in fig 2. Saturation solubility of PIO was carried out in distilled water using a rotatory shaker at 100rpm speed and finally calculated the concentration using UV spectroscopy at 267nm. It was found to be 5.6 µg/ml, and it belongs to a practically insoluble class. This was increased to 16.3µg/ml hydrophilic polymer, which might be due to increased hydrophilic interaction, and to 82.7µg/ml with neusiline US2, surfactant, which might reduce the surface tension of distilled water. But ternary phase of PIO with CH and NS showed saturation solubility of 76.7µg/ml.

Fig. 2: Saturation Solubility studies

Comparison of solubility profile of pure drug PIO, binary Complex of PIO with polymer CH and ternary complex of PIO- CH-NS.

Equilibrium solubility studies of PIO in the presence of CH and surfactant neusiline in concentration range of 0-0.5 mM are shown. Selection of optimized concentration of neusiline, equilibrium solubility studies of PIO were performed in concentration range of (0.0-0.5 mM) with CH polymer. Solubility of PIO increased linearly with increase in concentration of surfactant neusiline. Hence, CH with Neusiline at optimum concentration was selected for preparation of solid dispersion^16-17.

Fig-3: Phase Solubility Studies

Stoichiometric constant determination:

It was calculated by plotting a graph of molar ratio of drug to CH (r) versus ∆A*r. Thus, PIO to CH ratio was confirmed from the stoichiometric constant graph and was found to be 1: 0.4 from the highest peak of plot.

Table 3: Stoichiometric constant

Drug (mM)	CH (mM)	Total	Abs	R	∆A	∆A*r
1.1	0	1.1	0.063	1.00	0.000	0.000
1.05	0.05	1.1	0.528	0.95	0.465	0.444
1	0.1	1.1	0.525	0.91	0.462	0.420
0.95	0.15	1.1	0.527	0.86	0.464	0.401
0.9	0.2	1.1	0.329	0.82	0.266	0.218

Fig 4: Stoichiometric constant determination

Fourier transformation-infrared spectroscopy (FTIR):

The range of band vibrations rely on the stiffness of bond and masses of atoms, along with the factor which affects the stiffness that also affects the vibrating frequency¹⁸. Hence, the spectroscopy of IR can be useful to describe complicated formation^19-20. There was a peak of “3009.00 cm⁻¹” in PGZ spectrum for “N-H stretching”, while there were peaks of “2918.55 cm⁻¹, 2837.84 and 2742.66 cm⁻¹” for “aliphatic C-H structure” stretching. There was a steep absorption peak at “1738.49cm⁻¹” which may be related to “carbonyl C=O stretching” for vibration. There was “C=N group” and “peak at 654 cm⁻¹” at “1505.57 cm⁻¹” attributed to “C-S group”.

The researchers conducted the FTIR test to determine the functional groups of chitosan. They observed the peak in IR range of chitosan (Figure 5B). in the region “3358.90 –3296.67 cm⁻¹”, a strong bond was corresponding to “N-H and O-H stretching” along with “intramolecular hydro bonds”. Hydrophilic CH peaks at 1023.71, 2875.66 and 2258.66 cm^-1for ethereal C-O, CH SP₃, and C-N bond. All these peaks were present in physical mixture of Pio and CH with negligible shifts in Fig 5D. It indicates absence of any interaction with physical mixture and physical compatibility. Neusiline US2 Fig 5C, as a synthetic magnesium alumino metasilicate, do not show any sharp peak with IR spectroscopy fig 5F and does not interfere with peaks of Pio in physical mixture.¹⁸ Thus, like CH, NS not only shows absence interference with Pio physically but also shifts slightly in fig 5G. All those peaks were also present in formulation by different grinding/ milling methods as shown:

Fig 5: A: PIO, B: CH, C: NS, D: PIO-CH, E: PIO Formulation (PIO-CH-NS), F: PIO Drug Ball Milled and G: Ball milled formulation

The physical blend of CH and Pio reflects on the summary of ranges of CH and the drug. Hence, the existence of all such peaks of Pio in the blend shows that the drug stays intact and there is a lack of interaction between excipients and drug. Though all peaks of pioglitazone were supposed to be smoothened in complexes showing strong interaction of CH and pioglitazone, the peak of “32962.67 cm^–1” in OH group of CH was moved to reduced frequency because of intramolecular hydro bond with “pioglitazone in microwave assisted dry grinding technique”. A binary physical blend of CH and Pio reflects on a slight rise in peak values for acidic group and decline for amine group, but there is no new peak for the binary systems of “pioglitazone-CH”, showing no formation of chemical bond in the complexes. There is a presence of complex with various spectroscopic bands confirmed by the changes in typical bands of pure drug.

A physical mixture of VAL and NS, might be due to a very weak Vander Waal force between metal atom and lone pair of electrons present in nitrogen. In case of ternary physical mixture, slightly increase the peak value for both acidic OH group and amine group which might be due to van der Waal force or hydrogen bonds between them. This change in peak value is comparatively more in case of formulation which reveals formation of hydrogen bond between OH and primary amine group of compounds. But it could not show sharp peak for primary amine in IR spectroscopy. Hence PIO interacted only physically with polymer and surfactant. An absence of any chemically interacted bond or peak showed chemically compatible formulation of microwave treatment with simple grinding and ball milling.

Differential scanning calorimetry (DSC):

Fig 6: A: PIO; B: P0; C: PIO+CH+NS; D: P5 and E: P7

Fig. 6 illustrates the “DSC thermogram” of pure physical blends, ternary complex, CH and Pio. There was endothermic peak of 198.54 degrees in the DSC thermogram of pure Pio, consistent to its melting point with 213.89 mJ of integral enthalpy. There were two peaks of CH physical blend and pioglitazone. At 176.97 degrees, the peak happened because of dehydration of CH and change of drug peak led to 63.15 mJ of integral enthalpy to lower temperature. The interaction of crystal nature and microwave energy has formed the true complex. A ternary physical mixture of Pio: CH:Neusilline DSC thermogram observed at lower temperature with reduced integral enthalpy. Reduction in peak may indicates changing crystallinity and increased stability of drug in physical mixture, but variation is too small to confirm it with physical mixture²¹. But endothermic peaks are significantly shift to lower values than present in drug or physical mixture. It is observed at 186.33⁰C and 192.44⁰C in P5 and P7 batch respectively. The studies indicates that P5 and P7 formulation batch prepared by microwave assisted technique is stable than pure drug or its physical mixture. This reducing effect could be due to weak interaction between drug and polymers which showed in infrared spectroscopy²².

Fig 7: Differential scanning calorimetry endothermic and glass transition peaks with endothermic energy A: PIO; B: P0; C: PIO+CH+NS; D: P5 and E: P7

X-ray powder diffractometry (XRPD):

Fig 7: A: PIO; B: P6; C:PIO FBM; D: PIO BM67

A widely used technique named “Powder X-ray diffraction analysis” was used to determine the level of crystallinity in the specific sample. Crystalline samples showed intense, steep peaks in diffractograms while they achieved wide diffuse peaks for amorphous materials. The peak heights were compared to evaluate crystallinity in the diffraction sequences. One can observe various steep heights ranging from 10-35 degrees in the diffractogram X-ray of pioglitazone, which is showing the presence of drug in crystalline form. It is still possible to detect the “characteristic pioglitazone peaks” in ball milling polymer complexes with lower intensity, which shows that there was a reduction in crystallinity of drug to a great level.

Formulation batch by microwave technique of pioglitazone in the presence of CH and NS, peak intensities were enhanced. This might be due to physical interaction of microwave with hydrophilic polymer and rubbery drug molecules²³. Formulation batch P6 peak was very sharp which indicates crystalline nature with rubbery state of drug. P6 formulation a crystalline nature was maintained and somewhat enhanced the of drug due to increase in peak intensity. From the results of XRD and DSC it was confirmed that effect of microwave radiation on the physical interaction of ternary complex which enhance the stability with increment in crystallinity of drug.

Dissolution study:

The crystallization is performed mainly to boost dissolution of Pioglitazone by elevating its “aqueous solubility” with “neusilin” and “chitosan powder” as surfactant. So, they compared dissolution of “Pio:CH:Neusilin” ternary complex with that of Pio powder medicine with a parameter of dissolved percentage in terms of time.

Percentage cumulative drug release was calculated for all the batches and compared with drug PIO. PIO showed 53.13 % drug release due to its stable crystalline form. As hydrophilic polymer and surfactant interact physically, PIO in formulation shows more drug release. Maximum drug release was obtained for P7 batch.

Fig 8: In vitro Dissolution studies

Drug content:

The selected formulation was subjected to drug content studies. It is observed in the results that there was a lack of significant difference (p>0.05) in dissolution and drug content of the given formula. Percentage drug content study was carried out in methanol solvent in which PIO is highly soluble. Percentage drug content was found to be in the range of 98.01% and 99.65%. It indicates no any loss of drug due to degradation and during formulation.

Stability studies:

The formulation which was chosen was the matter of studies on increased stability according to ICH guidelines followed for six months. They tested the optimized formulations for any changes in overall structure, in-vitro dissolution, and drug content every month. The findings indicated that there was a lack of significant difference (p>0.05) in dissolution and drug content of the given formulation.

Percent drug content of the formulation was present within the range of 98.01% and 99.65%. It indicates extended environmental conditions are ineffective on drug content of batches. This was confirmed by studying interaction and functional group variation from IR spectroscopic investigation. All peaks of drug were present in formulation batch which indicates absence of interaction between drug and polymers. At accelerated environmental condition, peaks of PIO were not altered within formulation over the duration of 90 days. This confirms the stability of formulation, might be due to the presence of CH polymer.

CONCLUSION:

This study has tried to attain faster beginning of “hypoglycemic action” with the help of pioglitazone by improving solubility with “ternary complexion” research. The studies related to phase solubility showed the building of complexes in the ratio of 1:1, which formed the inclusion complex, which is highly stable, with “chitosan (CH)” along with “nuesiline surfactant”. There have been improvement in solubility of drug water with “Pioglitazone–CH-neusiline systems”. Microwave assistested milling technology can be used for size reduction, modification of physicochemical properties and maintaining stability without any chemical effect of excipients. FTIR, DSC and XRPD studies showed that PIO-CH-NS complexes can be prepared by microwave assisted milling technology has formed stable crystalline in ternary complex system. Percentage cumulative drug release with optimized batch P7 was found to be higher value as compared with PIO and Other batches. As hydrophilic polymer and surfactant interact physically, PIO in formulation shows more drug release. 93.97% Maximum drug release was obtained for P7 batch.

ACKNOWLEDGEMENTS:

Authors are thankful to Lupin Research Park, Pune and Loba chemical, India for providing the necessary chemicals and reagents for research purposes.

CONFLICT OF INTEREST:

Authors declare no conflict of interest.

REFERENCES:

1. Muller RH, Keck CM. Challenges and solutions for the delivery of biotech drugs—a review of drug nanocrystal technology and lipid nanoparticles. Journal of Biotechnology. 2004; 113(1–3): 151–170. doi.org: 10.1016/j.jbiotec.2004.06.007.

2. Vyas SP, Khar RK. Basis of targeted drug delivery. In Targeted and controlled Drug Delivery, CBS Publishers and Distributors Reprint, 2008;74: 42–46.

3. Omkar A. Patil, Indrajeet S. Patil, Ganesh B. Vambhurkar, Dheeraj S. Randive, Mangesh A. Bhutkar, Srinivas K. Mohite. UV Spectroscopic Degradation Study of Pioglitazone Hydrochloride. Asian J. Pharm. Ana. 2018; 8(3): 125-128.

4. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025 -Prevalence, numerical estimates and projections. Diabetes Care. 1998; 21: 1414–1431. doi.org:10.2337/diacare.21.9.1414.

5. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004 May 1;27:1047–1053. doi.org:10.2337/diacare.27.5.1047.

6. Zhou SF, Zhou ZW, Yang LP, Cai JP. Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Current Medical Chemistry. 2009; 16(27): 3480-675. doi.org:10.2174/092986709789057635.

7. FDA Approved Drug Products: Actos (pioglitazone) oral tablets.

8. Granero GE, Ramchandran C, Amidon GL. Dissolution and Solubility Behavior of Fenofibrate in Sodium Lauryl Sulfate Solutions. Drug Development and Industrial Pharmacy. 2005; 31(9): 917–922. doi.org:10.1080/03639040500272108.

9. Wadke DA, Serajuddin A, Jacobson H. Preformulation testing. In: Lieberman HA, Lachman L, Schwartz JB, eds. Pharmaceutical Dosage Forms: Tablets. New York. NY: Marcel Dekker; 1989; 1-73.

10. Yadav NE, Chhabra GU, Pathak KA. Enhancement of solubility and dissolution rate of a poorly water-soluble drug using single and double hydrophilization approach. International Journal of Pharmacy and Pharmaceutical Sciences. 2012; 4(1): 395-405.

11. Waleczek KJ, Marques HM, Hempel B, Schmidt PC. Phase solubility studies of pure (-)-alpha-bisabolol and camomile essential oil with beta-cyclodextrin. European Journal of Pharmaceutics and Biopharmaceutics. 2003; 55(2): 247-251. doi.org:10.1016/S0939-6411(02)00166-2.

12. Bhosale A, Hardikar S, Jagtap R, Patil, Dhawale S. Formulation of β-cyclodextrin complexed controlled release matrix tablets of glipizide and its in-vitro evaluation. International Journal of PharmTech Research. 2009; 1(3): 773-778.

13. Higuchi T, Connors K. Phase-solubility techniques. Advanced Analytical Chemistry of Instrumentation, 1965; 4: 117-212.

14. Sonal C. Bankhele, Rupali B. Harale, Monica R P Rao, Madhura V. Dhoka. Thermoreversible In-Situ Ophthalmic Gelling System of Levofloxacin Hemihydrate: Formulation and Optimization by Factorial Design. Asian J. Pharm. Res. 2012; 2(3): 100-106.

15. Yarraguntla SR. Formulation and evaluation of lornoxicam nanocrystals with different stabilizers at different concentrations. Asian Journal of Pharmaceutics. 2016; 10(3). doi.org:10.22377/ajp.v10i3.727.

16. Kolašinac N, Kachrimanis K, Homšek I, Grujić B, Đurić Z, Ibrić S. Solubility enhancement of desloratadine by solid dispersion in poloxamers. International journal of pharmaceutics. 2012; 436(1-2): 161-70. doi.org:10.1016/j.ijpharm.2012.06.060.

17. Taylor SL, Baird JA. Evaluation of amorphous solid dispersion properties using the thermal analytical technique. Advanced Drug Delivery Reviews 2012; 64 (5): 396-421. doi.org:10.1016/j.addr.2011.07.009.

18. Rajat Rana, Ajay Kumar, Rohit Bhatia. Impact of Infra Red Spectroscopy in Quantitative Estimation: An Update. Asian J. Pharm. Ana. 2020; 10(4):218-230.

19. Noorussaba, Afaq Ahmad. Synthesis, Infrared spectroscopic and Thermal studies of [0.7(Cu2CdI4):0.3(AgIx:CuI(1-x))] of fast-ion conductor (x = 0.2, 0.4, 0.6 and 0.8 mol. wt. %). Asian J. Research Chem. 2015; 8(2): 131-140.

20. Y. Padmavathi, Akari Anjali, Nayaka Raghavendra Babu, P Ravi Kumar. Development and validation of new FTIR method for quantitative analysis of gliclazide in bulk and pharmaceutical dosage forms. Asian J. Research Chem. 2017; 10(3):377-382.

21. Dinesh Sirohi, Pratibha Singh, K. N. Pandey, Vishal Verma, Vijai Kumar, A. K. Saxena. Thermal and morphological behavior of PEEK/PEI blends with polyphosphazene coated carbon nanotube. Asian J. Research Chem. 2012; 5(5): 650-654.

22. Rajendra Jangde, S. J. Daharwal. Compatibility Study of Gatifloxacin with Various excipients. Research J. Pharm. and Tech. 2011; 4(8): 1216-1218.

23. Aishwarya A Jadhav, Rasika P. Devale. Review on Microwave, The General purpose in Microwave Assisted Synthesis for Green Chemistry. Asian Journal of Research in Chemistry. 2022; 15(2): 182-5.

24. Manohar D. Kengar, Jameer A. Tamboli, Chandrakant S. Magdum. Quality by Design in Pharmaceutics. Res. J. Pharma. Dosage Forms and Tech. 2019; 11(3): 235-238.

25. Seema Saini, Rajeev Garg. Stability Study of fast Disintegrating tablets of Nisoldipine as per ICH Guidelines. Research Journal of Pharmacy and Technology. 2021; 14(11): 5843-4.

Received on 18.04.2023 Modified on 21.07.2023

Research J. Pharm. and Tech 2024; 17(2):867-874.

DOI: 10.52711/0974-360X.2024.00134